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xtruss · 2 years

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How Stanford Failed The Academic Freedom Test! For America’s New Clerisy, Scientific Debate Is A Danger To Be Suppressed

— By Jay Bhattacharya | January 11, 2023 | TabletMag.Com

Stanford ‘created an environment in which slander, threats, and abuse aimed at lockdown critics could flourish’. Justin Sullivan/Getty Images

We live in an age when a high public health bureaucrat can, without irony, announce to the world that if you criticize him, you are not simply criticizing a man. You are criticizing “the science” itself. The irony in this idea of “science” as a set of sacred doctrines and beliefs is that the Age of Enlightenment, which gave us our modern definitions of scientific methodology, was a reaction against a religious clerisy that claimed for itself the sole ability to distinguish truth from untruth. The COVID-19 pandemic has apparently brought us full circle, with a public health clerisy having replaced the religious one as the singular source of unassailable truth.

The analogy goes further, unfortunately. The same priests of public health that have the authority to distinguish heresy from orthodoxy also cast out heretics, just like the medieval Catholic Church did. Top universities, like Stanford, where I have been both student and professor since 1986, are supposed to protect against such orthodoxies, creating a safe space for scientists to think and to test their ideas. Sadly, Stanford has failed in this crucial aspect of its mission, as I can attest from personal experience.

I should note here that my Stanford roots go way back. I earned two degrees in economics there in 1990. In the ’90s, I earned an M.D. and a Ph.D. in economics. I’ve been a fully tenured professor at Stanford’s world-renowned medical school for nearly 15 years, happily teaching and researching many topics, including infectious disease epidemiology and health policy. If you had asked me in March 2020 whether Stanford had an academic freedom problem in medicine or the sciences, I would have scoffed at the idea. Stanford’s motto (in German) is “the winds of freedom blow,” and I would have told you at the time that Stanford lives up to that motto. I was naive then, but not now.

Academic freedom matters most in the edge cases when a faculty member or student is pursuing an idea that others at the university find inconvenient or objectionable. If Stanford cannot protect academic freedom in these cases, it cannot protect academic freedom at all.

To justify this depressing claim, I would like to relate the story of my experience during the pandemic regarding a prominent policy proposal I co-authored called the Great Barrington Declaration (GBD). I could relate many additional incidents that illustrate Stanford’s stunning failure to protect academic freedom, but this one suffices to make my point.

On Oct. 4, 2020, along with two other eminent epidemiologists, Sunetra Gupta of the University of Oxford and Martin Kulldorff of Harvard University, I wrote the GBD. The declaration is a one-page document that proposed a very different way to manage the COVID-19 pandemic than had been used up to that date. The lockdown-focused strategy that much of the world followed mimicked the approach that Chinese authorities adopted in January 2020. The extended lockdowns—by which I mean public policies designed to keep people physically separate from one another to avoid spreading the SARS-CoV-2 virus—were a sharp deviation from Western management of previous respiratory virus pandemics. The old pandemic plans prioritized minimizing disruption to normal social functioning, protecting vulnerable groups, and rapidly developing treatments and vaccines.

The same priests of public health that have the authority to distinguish heresy from orthodoxy also cast out heretics, just like the medieval Catholic Church did.

Even by October 2020, it was clear that the Chinese-inspired lockdowns had done tremendous harm to the physical and psychological well-being of vast populations, especially children, the poor, and the working class. Closed schools consigned a generation of children worldwide to live shorter, less healthy lives. In July 2020, the Centers for Disease Control released an estimate that 1 in 4 young adults in the United States had seriously considered suicide during the previous month. The U.N. estimated that an additional 130 million people would be thrown into dire food insecurity—starvation—by the economic dislocation caused by the lockdowns. The primary beneficiaries of the lockdown—if there were in fact any beneficiaries of these drastic anti-social measures—were among a narrow class of well-off people who could work from home via Zoom without risk of losing their jobs.

It was amply clear by October 2020 that the lockdown policy adopted by many Western governments, with the exception of a few holdouts like Sweden, had failed to stop the spread of COVID. It was in fact too late to adopt a policy goal of eradicating the virus. We did not have the technological means to achieve this goal, then or now. By the fall of 2020, it was abundantly clear that COVID-19 was here to stay and that many future waves would occur.

Governments had imposed lockdowns on the premise that there was nearly unanimous scientific consensus in support of them. Yet an extraordinary policy like a lockdown requires, or should require, an extraordinary scientific justification. Only near unanimity among scientists, backed by solid empirical data, suffices.

Like Gupta and Kulldorf, I knew that such unanimity did not exist. Many scientists worldwide had contacted us to tell us about their qualms with the lockdowns—their destructiveness and the poor evidence of their effectiveness. Many epidemiologists and health policy scholars favored an alternative approach, though many were scared to say so. It seemed clear to the three of us that as the next inevitable wave appeared, there was a risk that the lockdowns might return, and that scientific evidence against such steps would be ignored and smothered, at tremendous social cost.

We wrote the GBD to tell the public that there was no scientific unanimity about the lockdown. Instead, the GBD proposed a focused strategy to protect the elderly and other vulnerable populations. There is more than a thousandfold difference in mortality risk from COVID-19 infection between the old and the young, with healthy children at negligible risk of dying. The humane thing is to devote resources and ingenuity to protect the most vulnerable. The GBD and its accompanying FAQ provided many suggestions about how to do that and invited local public health communities, which know best the varied local living circumstances of the vulnerable, to devise local solutions. At the same time, the GBD advocated lifting lockdowns and opening schools to alleviate harms to children. We put the GBD on the internet, and invited other members of the public to sign it.

The GBD was published on Oct, 4, 2020. Almost immediately, tens of thousands of scientists, epidemiologists, and physicians signed the document, including many from top universities. Simultaneously, people started sending us translations of the GBD—ultimately into 40 languages—and to date, nearly a million people have signed from almost every country on Earth.

The plan received the attention of the American press, at first curious and fair, but soon thereafter hostile and tendentious. I started getting calls from reporters, including outlets like The New York Times and Washington Post, asking me why I wanted to “let the virus rip” through the population, even though that was the very opposite of what we were proposing, and questioning my credentials and motives.

It was at first quite perplexing to be the target of what turned out to be a well-organized, government-sponsored campaign of smears and suppression of scientific argument and evidence. I had taken no money for writing the declaration. Yet press outlets somehow turned Gupta, Kulldorf, and me into tools of a nefarious plot to destroy the world by spreading “disinformation” that would cause mass death. I started receiving death threats and racist hate mail.

About a year later, after historian Phil Magness made a FOIA request, I learned a part of the story of how the U.S. government-sponsored propaganda campaign against the GBD came into being. Four days after we wrote the GBD, Francis Collins, the geneticist and lab scientist who was then the head of the U.S. National Institutes of Health, wrote an email to Anthony Fauci, the immunologist and lab scientist who headed the National Institute of Allergy and Infectious Diseases until the end of 2022. In the email, Collins called Martin, Sunetra, and me “fringe epidemiologists” and called for a devastating public takedown. The attacks on the three of us, aided by the cooperation of supposedly private social media platforms like Twitter, were launched shortly after Collins sent that email.

But this is not an article about the ethics of social media companies whose profits depend to a large extent on the friendliness of government regulators and whose employees may see themselves as partisan political activists. This is a critique of our best universities, which are supposed to be dedicated to the pursuit of knowledge—yet which turn out to be no different than government propagandists and private corporations in their self-seeking, amoral behavior.

Collins and Fauci sit atop tens of billions of dollars that the NIH uses to fund the work of nearly every biomedical scientist of note in the United States. Stanford University receives hundreds of millions of dollars of funding from the NIH, without which researchers would not have the resources to conduct many worthwhile experiments and studies. NIH funding also confers prestige and status within the scientific community. At Stanford, it is very difficult for a biomedical researcher in her department to earn tenure without landing a major NIH grant. The attack by Collins and Fauci sent a clear signal to other scientists that the GBD was a heretical document.

Among Stanford faculty, the reaction to GBD was mixed. Some members, including Nobel Prize winner Michael Levitt, signed on enthusiastically. I received encouragement from many others throughout the university. Junior medical school faculty wrote telling me they secretly supported the GBD but were reticent to sign officially for fear of reprisal from their department heads and Stanford administrators. Others were hostile. One faculty member and former friend wrote that he was defriending me on Facebook, perhaps the mildest form of retaliation I received during the pandemic.

There is a distinction in philosophy between negative and positive rights. A negative right is a constraint placed on the authorities not to take action that would violate that right. For example, the First Amendment prohibits Congress from enacting a law limiting the free exercise of religion or speech. A positive right entails an obligation on authorities to actively promote some desirable state of the world, for instance, the right to protection in the face of dire threats to bodily harm.

The same distinction pertains to academic freedom at a university. Stanford did not fire me or break my tenure for writing the GBD. Therefore, it met the bare minimum standard of negative academic freedom. But Stanford failed to meet the higher standard of positive academic freedom, which would have required it to promote an environment where faculty members engage with each other respectfully despite fierce disagreement.

The most egregious violation of academic freedom was an implicit decision by the university to deplatform me. Though I have given dozens of talks in seminars at Stanford over the past decades, in December 2020, my department chair blocked an attempt to organize a seminar where I would publicly present the ideas of the GBD. Stanford’s former president, John Hennessey, tried to set up a discussion between me and others on COVID policy, but he was unable to, owing to the absence of support from the university.

I never received an invitation from the medical school to present a “Grand Rounds,” a high-profile presentation by a faculty member on a topic of importance to the entire medical school. Instead, Grand Rounds and other seminars and webinars at Stanford univocally promoted positions which it is now obvious were devastatingly wrong, but which no one on campus was allowed to debate or challenge. Around the world in 2020 and early 2021, the GBD was a central topic of discussion—but not officially at Stanford.

More than a year later, in early 2022, I asked the dean of the medical school, Lloyd Minor, why I and other prominent lockdown-skeptic members of the Stanford faculty never received an invitation to present. He told me that the experience of caring for COVID patients in March 2020 had scared some Stanford clinical faculty and that it was still too early for a dispassionate “academic” discussion on COVID policy. Had I been given the opportunity, I would have told my colleagues that the focused protection ideas contained in the GBD could have prevented many of those hospitalizations.

Stanford failed to create a work environment where these discussions could happen. And I was not the only one to suffer—Stanford deplatformed other lockdown-skeptic academics, including John Ioannidis, one of the world’s most highly cited scientists and the most prolific and influential Stanford faculty on peer-reviewed COVID-19 publications; Michael Levitt, a Nobel Prize winner who made fundamental original contributions to modeling; and Scott Atlas, a former chair of neuroradiology at Stanford, widely acknowledged health policy expert and a key adviser to former President Donald Trump on COVID policy.

Faculty at Stanford should rightly worry whether their professional work will lead to deplatforming, excommunication, and political targeting.

The university’s refusal to defend dissenting voices created an environment in which slander, threats, and abuse aimed at lockdown critics could flourish. In August 2020, when President Trump chose Dr. Atlas as a White House adviser on the pandemic, around 100 Stanford faculty members signed an open letter accusing Atlas of “falsehoods and misrepresentations,” without giving any specific examples. Instead, the faculty letter falsely implied that Atlas opposed handwashing. When Martin Kulldorff challenged the signatories to a debate on the topic, none accepted. Instead, the Stanford Faculty Senate voted to censure Atlas formally, though no one voting had his expertise in public health policy.

In August 2021, Melissa Bondy, the chair of epidemiology at Stanford, helped circulate a secret petition around the medical school asking the university president to censor me for accurate testimony that I had given to Florida Gov. Ron DeSantis at a publicly televised policy roundtable. I testified that no randomized trials yet demonstrate the efficacy of masks on children to contain COVID. Though the secret petition did not name me specifically, it quoted me and asked the university to suppress such speech by faculty members. This petition imposed unethical pressure on faculty members—especially junior faculty members worried about tenure votes—to sign on.

When I finally read a copy of the petition, it felt like a gut punch. Was I preaching heresy? To date, no one at any level of the university leadership has expressed their support for me voicing my ideas. My efforts to engender discussion were met with silence. My colleagues John Ioannidis and Michael Levitt both report similar treatment.

The undisguised aim of this petition was to expel dissenting Stanford faculty like me from public academic life, making a mockery of the idea of academic freedom at exactly the time when we needed it the most. Ironically, if Stanford had defended my right to speak, there would have been no need for such a petition, as there would have been no confusion about the fact that my opinions were my own and not that of my colleagues.

The faculty’s excommunication motion yielded dividends in its goal of suppressing speech. An anonymous group on campus organized a campaign to intimidate me in response to a tweet by DeSantis, which included a picture of me from the policy roundtable and an (accurate) quote: “By vaccinating the old, we have protected the vulnerable.” The group glued posters all over campus with a picture of my face, the tweet from DeSantis, and a graph of COVID cases in Florida, which at the time were high. (Florida’s age-adjusted COVID mortality throughout the pandemic is lower than the average American state and on a par with California’s.) The implication was that I was a thought-criminal whose work was somehow responsible for the inevitable spread of a highly infectious respiratory virus.

On a progressive-dominated campus, these posters were clearly an incitement to violence. The group placed them on kiosks all over campus, including near a campus coffee shop that I frequent. For a few days, I feared for my physical safety. I reported this harassment to Stanford, but the university minimized my concerns, referring me to a counselor who advised me to engage with a firm that would help reduce the personal information about me available online. At that point, I decided to return to campus despite the threat—after 36 years, Stanford remains my home. But those posters stayed up for months. While I refused to be intimated, I can certainly understand those who are bullied into silence—which is, after all, the point.

Academic freedom at Stanford is clearly dying. It cannot survive if the administration fails to create an environment where good-faith discussions can occur outside of a framework of ideological rigidity and the false certainties that ideologues—and governments—wish to impose on us. Stanford missed the opportunity to sponsor COVID policy forums and it deplatformed dissenting voices. Several prominent faculty exploited this environment, engaging in actions that directly violated basic academic norms.

A precedent has now been established. Faculty at Stanford should rightly worry whether their professional work will lead to deplatforming, excommunication, and political targeting. In this environment, professors and students alike would be wise to look over their shoulders at all times, in the knowledge that the university no longer has your back. And members of the public should understand that many of those urging them to “trust the science” on complicated matters of public concern are also those working to ensure that “the science” never turns up answers that they don’t like.

— Jay Bhattacharya is a Professor of Health Policy at Stanford University.

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vinayakmahajan · 2 years

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shompinice2 · 3 years

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2) Research background

The Guangdong-Hong Kong-Macao Greater Bay Area includes Hong Kong Special Administrative Region, Macau Special Administrative Region and Guangzhou, Shenzhen, Zhuhai, Foshan, Huizhou, Dongguan, Zhongshan, Jiangmen, Zhaoqing (hereinafter referred to as the nine Pearl River Delta cities) With a total area of 56,000 square kilometers and a total population of approximately 70 million at the end of 2017, it is one of the most open and economically vigorous regions in China, and has an important strategic position in the overall development of the country. The construction of the Guangdong-Hong Kong-Macao Greater Bay Area is not only a new attempt to promote the formation of a new pattern of comprehensive opening up in the new era, but also a new practice to promote the development of "one country, two systems".

Since the reform and opening up, especially after the return of Hong Kong and Macao to the motherland, the cooperation between Guangdong, Hong Kong and Macao has been continuously deepened and actualized. The economic strength and regional competitiveness of the Guangdong-Hong Kong-Macao Greater Bay Area have been significantly enhanced, and the basic conditions for building a world-class bay area and a world-class city cluster have been established. .

3. The economy, positioning and opportunities of the Greater Bay Area

A vibrant world-class city cluster. Relying on the advantages of Hong Kong and Macau as a free and open economy and Guangdong as a pioneer in reform and opening up, continue to deepen reforms and expand opening up, take the lead in the country in building a system and mechanism for high-quality economic development, play a leading role in demonstration, and accelerate institutional innovation and advancement First try to build a modern economic system, better integrate into the global market system, build the world's emerging industries, advanced manufacturing and modern service industry bases, and build a world-class city cluster.

An international scientific and technological innovation center with global influence. Aiming at the frontiers of world technology and industrial development, strengthening the construction of innovation platforms, vigorously developing new technologies, new industries, new business forms, and new models, and accelerating the formation of an economic system with innovation as the main driving force and support; solidly pushing forward comprehensive innovation reform experiments, and giving full play to Guangdong The advantages of Hong Kong and Macao in technological research and development and industrial innovation have broken the bottlenecks and constraints that affect the free flow of innovative elements, further stimulated the vitality of various innovation entities, and built a global technological innovation highland and an important source of emerging industries.

Huge integrated market

The vast territory of the Greater Bay Area, rapid economic growth, and interconnected markets provide huge business opportunities for infrastructure and real estate, financial services, capital markets, mergers and acquisitions and investment financing, technology, taxation, and retail. Strengthen cooperation between local governments in areas such as economic system, immigration and taxation policies, environment and transportation, supervision and coordination mechanisms, promote the smooth flow of materials, funds, talents and information, and optimize the regional operating environment.

Complementary advantages of cities in the region

Cities in the Greater Bay Area have their own advantages and characteristics, and use their respective advantages to create huge and comprehensive business opportunities. Dongguan, Guangzhou and Foshan are important manufacturing bases, Shenzhen has advantages in high-end manufacturing, information technology and technological innovation, and Macau is a global tourism and leisure center. Hong Kong is a world-renowned center for international finance, shipping, trade, asset management and offshore RMB. Its professional services and financial services industries have a large number of diversified talents with international experience.

Local and international business opportunities

Located in the Pearl River Delta, the Bay Area has great development potential and is expected to drive the economic growth of neighboring provinces such as Fujian, Jiangxi, Hunan, Guangxi, Hainan, Guizhou, and Yunnan. The Bay Area supports the implementation of China's "One Belt One Road" initiative. The Belt and Road Initiative covers more than 70 countries and is the backbone of future global infrastructure investment, trade and economic growth. China's state-owned enterprises-many of which have domestic and international headquarters in the Gulf region-will play a very active role in the Belt and Road Initiative.

4) Existing cooperation mechanism and its characteristics

There are four main cooperation mechanisms in the Guangdong-Hong Kong-Macao Greater Bay Area for collaborative innovation:

(1) Method of coordination and cooperation mechanism

Method synergy refers to the value-added effects produced by various innovation entities through the use of diversified synergistic methods. The synergy produced by methods essentially pursues technological synergy, which effectively promotes the spillover, diffusion and application of knowledge, and effectively reduces The innovation cost of enterprises, through the economics of scope and scale of technological innovation, can improve the innovation synergy effect of the entire Greater Bay Area.

(2) Space coordination and cooperation mechanism

Space synergistic effect refers to the added value of innovative elements of innovation within the body between Guangdong, Hong Kong 11 Bay Area cities across the urban space configuration produced. Mainly in three aspects: First, a large Bay Area resource elements or the main innovation between different cities together. The main innovation between different cities large Bay Area through shared synergies arising from the interaction. Second, the internal elements of corporate synergy. Become interactive elements of collaborative links to promote enterprise synergies. Third, the main innovation or resource elements in the Bay Area city together. Synergies between enterprises in different cities in the Bay Area and other large main innovation generated by the collaboration.

(3) Resource element cooperation mechanism

The Guangdong-Hong Kong-Macao Greater Bay Area resource element cooperation mechanism can be carried out from three dimensions: innovation function elements, innovation main elements and innovation environment elements. First, the innovation function element refers to the element linkage mechanism and function operation mechanism between the innovation entities in the Guangdong-Hong Kong-Macao Greater Bay Area. Second, innovation subject elements include macro-level innovation activity actors, which are users and owners of innovation resources; and micro-level innovation subject elements mainly refer to elements that are directly related to technological innovation. Third, innovation and environmental factors. Refers to an innovation environment that promotes and guarantees coordinated operation and stable cooperation between innovative actors.

(4) Cooperation mechanism of innovation entities

The Guangdong-Hong Kong-Macao Greater Bay Area has the basic conditions for building and building a collaborative innovation network. The spatial nodes in the innovation network are the main body of collaborative innovation and also carry the diversified mechanism of collaborative innovation operation. Among them, enterprises are the main body of technological innovation; Universities and research institutes are the main body of knowledge innovation; the government is the main body of system innovation; science and technology intermediary is the link that accelerates the flow of factors and links the main body of innovation.

5) Challenges of industrial coordination facing the Greater Bay Area

The Guangdong-Hong Kong-Macao Greater Bay Area is under the framework of "one country, two systems". There are "gene" differences in culture, law, space, and industry. The free flow of elements has not yet been realized in the Bay Area.

(1) The regional distribution of innovation resources is uneven, and the effect of technology diffusion is not obvious

The innovation capabilities of the Guangdong-Hong Kong-Macao Greater Bay Area are uneven. The uneven distribution of innovation resources has to some extent caused the spatial heterogeneity of innovation capabilities in the Guangdong-Hong Kong-Macao Greater Bay Area. The geographical proximity and unbalanced technological innovation levels and capabilities mean that the technology spillover effect in the Greater Bay Area is relatively weak.

(B) innovation resources input mix similar, serious waste of resources

The low level of connection and collaboration among innovation entities in the Greater Bay Area has caused certain obstacles to the extension of creativity to industries. The unclear division of labor in the cities in the Bay Area has led to serious similarities in the industrial structure of the Guangdong-Hong Kong-Macao Greater Bay Area, and the coexistence of waste of resources and insufficient supply.

(3) The flow of innovation factors is blocked, and the overall innovation efficiency needs to be improved

The flow of innovative R&D talents to enterprises in the Greater Bay Area lacks motivation and institutional guarantees. There are still large geographical differences in the Greater Bay Area, which makes it difficult for the relatively backward cities in the Greater Bay Area to absorb and gather innovative elements and resources.

(4) The innovation and cooperation system and mechanism of the Greater Bay Area need to be improved

Guangdong, Hong Kong and Macao high-level consultation and coordination mechanisms for innovation and cooperation has not been established, innovative cooperation within the Bay Area too few large projects. Cooperation in scientific research institutions and enterprises is relatively weak. Science and technology intermediary service system is still not perfect.

(5) Collaborative innovation network for science and technology services has not yet formed

In the Pearl River Delta, there is still repeated construction and relatively lagging behind, which has a certain impact on the utilization of network service capabilities. Capacity development and technology services in 11 cities in the Bay Area is not balanced, Guangdong, Hong Kong will hinder large Bay Area collaborative innovation process.

lCooperative development of innovative ideas

6) Case content

1. Guangzhou Municipal Government, Guangzhou Automobile Group and Tencent signed a strategic cooperation framework agreement to build a "smart city "

2. Borrowing from the international experience: the early establishment of a synergy agency in the San Francisco Bay Area to solve the problem of industrial synergy

3. ? ?

4.? ?

5. Collaborative and innovative development of the biomedical industry in the Yangtze River Delta

7) Main points

1. Strategic emerging industries become dominant (knowledge-based and innovative jobs are increasing

2. In order to solve the problem of industrial and policy coordination between cities, institutions should be established to undertake the function of inter-city coordination

3. ? ?

4.? ?

5. Under the special background of the new crown epidemic, cooperation in the medical industry should be accelerated, and cross-border medical connections should be deepened

8) Suggestions

1. Respond to the general trend of artificial intelligence and establish an AI industry ecosystem

The technological competitiveness of the Greater Bay Area needs to be caught up

In the early days of the Guangdong-Hong Kong-Macao Greater Bay Area, due to the low level of collaboration and unbalanced level of technological innovation, technological competitiveness was still far from its benchmark San Francisco Bay Area and Tokyo Bay Area. Therefore, we believe that it is necessary for the Greater Bay Area to accelerate the flow and aggregation of technological innovation, and combine its advantages in technological innovation resources to transform it into a member of the global technological innovation center. In addition, by encouraging exchanges and cooperation in technological innovation between Guangdong, Hong Kong and Macao, the capacity of cross-border industry collaboration in the Greater Bay Area will be enhanced.

Give full play to the advantages of each city and jointly build an AI industry ecosystem

On the road to promote regional science and technology investment, artificial intelligence bears the brunt of becoming a symbol of innovation in science and technology investment in the Greater Bay Area. Just in 2017, the Guangzhou Municipal Government and Guangzhou Automobile Group signed a strategic cooperation framework agreement with Tencent respectively, and this is only the first step towards the construction of a smart city in the Greater Bay Area. In addition, the development potential of artificial intelligence in the Greater Bay Area is huge. Major cities such as Shenzhen, Guangzhou, and Hong Kong have the most complete robot industry chain. In addition, there are technology giants like Tencent in Shenzhen that provide long-term technology accumulation for labor. The development of intelligence provides a certain foundation. Therefore, in light of this development trend, we suggest that the Greater Bay Area work with all regions to jointly establish an artificial intelligence industry ecosystem, increase technology-level R&D investment, so as to promote sustainable development and strengthen collaboration among other industries. Among them, Guangzhou has innate resource advantages in the new information industry and intelligent manufacturing industry, coupled with the high proportion of artificial intelligence companies in Shenzhen, and the advantages of Hong Kong's basic scientific research, it can be seen that the Greater Bay Area has the elements of the artificial intelligence industry ecosystem. .

Accelerated integration of AI and service industry

Therefore, the development of artificial intelligence should be combined with the advantages of the major cities to encourage regions to establish long-term cooperation mechanism, only effective in the closely combine elements of innovation and innovation ability of researchers and enterprises. In addition, with Hong Kong and Macao service industry continues to mature, especially in terms of trade, finance, retail, tourism, and high level of digital, artificial intelligence provides a number of scenes landing; Furthermore, in recent years between the heads the company has been committed to the implementation of the transformation of intelligence services, such as artificial intelligence and big data landing in depth in recent years, the financial industry, which all contribute to the integration of intelligent manufacturing and service sectors to strengthen exchanges and cooperation between Guangdong, Hong Kong Science and Technology.

2. Establish the Greater Bay Area Development Coordination Agency under the framework of one country, two systems

①Public policies can provide guarantee and support for the innovation system

The fragmentation of local government is a common governance problem faced by metropolises. The Guangdong-Hong Kong-Macao Greater Bay Area and the San Francisco Bay Area have many similarities in the urban spatial structure. Under the policy advantages of one country, two systems, we believe that more attention should be paid to innovation and development. In the role.

The tax reduction and exemption policies of the San Francisco Bay Area are mainly reflected in the following three aspects: one is to stimulate enterprises to increase their R&D investment, the other is to reduce the tax burden on enterprises and their employees, and the third is to indirectly increase the salary of R&D personnel to attract talents. The San Francisco Bay Area also provides additional tax incentives specifically for technological innovation companies and related employees to help the Bay Area attract high-tech companies and talents.

For the government departments of the Guangdong-Hong Kong-Macao Greater Bay Area, in the R&D stage, it is necessary to start with both capital and legislation, increase R&D investment in key scientific research projects, innovate preferential tax policies, and pass clear intellectual property laws to protect innovative companies’ Benefit.

②Transfer talents and technology from higher education institutions

The perfection of the university's talent training system, the diversification of disciplines, and outstanding research capabilities in the San Francisco Bay Area are important sources of innovation in the San Francisco Bay Area. For the higher education institutions in the Guangdong-Hong Kong-Macao Greater Bay Area, on the one hand, they promote the construction of universities at different levels, including research universities, and actively guide the establishment of entrepreneurial courses to cultivate the entrepreneurial thinking of scientific and technological talents. On the other hand, it is necessary to strengthen cooperation with universities in the region, and jointly promote cooperation in some scientific research projects with high-level universities in other regions.

③Coordinate the development of urban areas

In the early days, the industries in the cities in the San Francisco Bay Area were highly homogenized and vicious competition. The establishment of the Bay Area Committee sponsored by enterprises in 1945 greatly improved the coordination issues between cities in the Bay Area.

At present, the Guangdong-Hong Kong-Macao Greater Bay Area also has similar problems. In July 2019, among the nine cities in the Pearl River Delta, housing prices in eight cities except Zhaoqing were all higher than the national average. Shenzhen, which has the highest housing prices, ranks second in the country, with housing prices in Guangzhou, Zhuhai, Dongguan, Foshan, and Zhongshan all in the top 50 in the country. Due to the high prices and other reasons, Guangdong, Hong Kong Bay Area attraction of talent is bound to weaken. At present, the Guangdong-Hong Kong-Macao Greater Bay Area has established a construction leading group. With reference to the experience of the San Francisco Bay Area, some semi-official and unofficial joint organizations can be established in addition to official institutions to solve specific issues such as environment, transportation, and housing prices, and promote coordinated development among regions.

3. Responding to historical opportunities to promote the integration of Hong Kong and Macao talents into the development wave of the Greater Bay Area

Why choose the Greater Bay Area?

In the more than 20 years since its reunification, Hong Kong has achieved world-renowned development achievements. However, Hong Kong’s local industrial structure is relatively single, asset prices are high, and the market is small. This has led to a decrease in local employment opportunities for Hong Kong youth in recent years. Now many Hong Kong and Macao students have returned from overseas studies. after the township is still looking not to the right positions. The development of the motherland has brought more new opportunities for Hong Kong youths, and the Guangdong-Hong Kong-Macao Greater Bay Area and even the inland provinces have provided a broad stage for Hong Kong youths to pursue their dreams. Facts have proved that by actively integrating into the overall development of the country, Hong Kong youth, especially relying on the Greater Bay Area, seeking a win-win development model with Mainland talents, has become an important development direction for Hong Kong youth in the future.

Moreover, the destiny of Hong Kong has always been closely connected with the motherland. Integrating Hong Kong and Macao into the overall development of the country is the proper meaning of "one country, two systems". The implementation of the Guangdong-Hong Kong-Macao Greater Bay Area is a major plan made by the central government based on the overall situation and long-term, and it is also a major decision to maintain the long-term prosperity and stability of Hong Kong and Macau.

Give full play to the advantages of high-quality locations and policies and systems to promote the integration of young talents from Hong Kong and Macau into the development wave of the Greater Bay Area

How to give full play to the advantages of the Greater Bay Area has already been pointed out in the "Opinions of the Central Committee of the Communist Party of China and the State Council on Supporting Shenzhen in Building a Pilot Demonstration Zone of Socialism with Chinese Characteristics". The core is to continuously improve the level of openness to Hong Kong and Macau. Shenzhen-Hong Kong cooperation in scientific and technological innovation to speed up the construction zone.

The "Fourteenth Five-Year Plan for National Economic and Social Development of the People's Republic of China and the Outline of Long-Term Goals for 2035" released this year also pointed out that the integration of Hong Kong and Macao into the overall development of the country and the complementary and coordinated development mechanism of the Mainland will be improved. Support the participation of Hong Kong and Macao, assist the country's comprehensive opening up and modern economic system construction, and create a functional platform for the joint construction of the "Belt and Road". Deepen the economic and trade, science and innovation cooperation relationship between the Mainland and Hong Kong and Macao, and deepen and expand the interconnection of the financial markets between the Mainland and Hong Kong and Macao. Strengthen exchanges and cooperation between the Mainland, Hong Kong and Macao in various fields, and improve policies and measures to facilitate the development and living of Hong Kong and Macao residents in the Mainland. This series of policy measures are of great significance in order to attract more Hong Kong and Macao youths to study, work and live in the Mainland, promote extensive exchanges, comprehensive exchanges and in-depth integration among Guangdong, Hong Kong and Macao youths, and enhance their centripetal force to the motherland.

Responding to historical opportunities to build dreams in the Greater Bay Area

Young people are the future and hope of the motherland. Without the healthy growth of young people, the country will not have great development. For contemporary Hong Kong youths, the construction of the Guangdong-Hong Kong-Macao Greater Bay Area is a precious historical opportunity. At present, an average of more than 60,000 Hong Kong youth and students participate in exchange and internship programs in the Mainland organized, funded or coordinated by various departments of the Hong Kong Special Administrative Region Government each year. As of September 2020, Qianhai Shenzhen-Hong Kong Youth Dream Workshop has incubated a total of 446 entrepreneurial teams, including 227 Hong Kong, Macau, Taiwan and international teams, with a cumulative financing of more than 1.5 billion yuan. In recent years, the Hong Kong Special Administrative Region Government has also allocated funds to support the “Guangdong-Hong Kong-Macao Greater Bay Area Youth Entrepreneurship Funding Program” and the “Guangdong-Hong Kong-Macao Greater Bay Area Innovation and Entrepreneurship Base Experience Funding Program” to help Hong Kong youths innovate and start businesses in the Greater Bay Area.

Each generation of young people has its own historical mission and opportunities. In the future, the central government and the Hong Kong Special Administrative Region government will continue to optimize and expand various Hong Kong youth internship, entrepreneurship and exchange programs in the Mainland to provide Hong Kong youth with deeper, broader and more diversified opportunities. Young people in Hong Kong must first understand the historical mission entrusted by the times, maintain an open, inclusive and healthy competition mentality, strive to enhance their own strength, make full use of the vast platform of the Greater Bay Area, and truly find a place to use their abilities, forge ahead in the new era, and build a dream in the Greater Bay Area .

4.? ?

5. play synergies big medical and health development of the cause of the Bay Area

①Industrial cluster

Since 1991, the State Council has successively approved the establishment of a total of 5 national-level high-tech industrial development zones, most of which involve the biotechnology industry. In recent years, under the dual promotion of policies and the market, the pharmaceutical industry bases, biological parks, and medicine valleys in the Greater Bay Area have also continued to heat up, forming industrial clusters.

Industrial clusters are conducive to technical exchanges and management, are conducive to obtaining government and policy support, and are also the successful experience of mature medical and health parks in foreign countries. Guangdong, Hong Kong and Macao have their own strengths in medical and health, and each performs its own duties. They should also comply with the "Planning Outline", strengthen scientific research cooperation, promote biotechnology innovation, and promote the construction of medical and health industry clusters.

② Talent transfer

With its strong economic foundation and open environment, the Greater Bay Area has maintained a net influx of population and talents for a long time. There are two main reasons: On the one hand, the Greater Bay Area has many job opportunities and high wages, especially in Hong Kong and Macau. The level is much higher than that of the Mainland, and it has strong global competitiveness. At the same time, according to Zhaolian recruitment statistics, the average salary of Shenzhen, Guangzhou, Dongguan and Foshan is among the top ten cities in the country; on the other hand, all parts of the Greater Bay Area have launched Talent introduction programs to attract outstanding talents at home and abroad, such as Hong Kong’s "Excellent Talent Entrance Program", etc., through various methods to provide outstanding talents in scientific and technological innovation, academic education, culture and art and other fields with preferential settlement.

In addition to absorbing talents, there are many colleges and universities in the Greater Bay Area, cultivating and delivering talents to the Greater Bay Area. Hong Kong and Macao high standard of teaching, the education system with international standards, University of Hong Kong, Chinese University of Hong Kong, such as medical homes colleges and universities not only for the local cultivation of talent, but also to attract the best students Mainland and overseas. Among the nine cities in the Pearl River Delta, Guangzhou has the richest educational resources. It has two "985" universities, Sun Yat-sen University and South China University of Technology, as well as medical colleges such as Southern Medical University, which provide talent motivation for the development of the Greater Bay Area.

③Capital empowerment

The capital market in the Greater Bay Area is relatively developed, with the characteristics of large volume and frequent financial activities. As one of the world’s three major financial centers, Hong Kong can provide the most convenient investment and financing services; Macau can take advantage of the establishment of the Sino-Portuguese fund headquarters in Macau to undertake financial cooperation services between China and Portuguese-speaking countries; Guangzhou is an international trade center and a comprehensive transportation hub , The economy is diversified; Shenzhen relies on the Shenzhen Stock Exchange to have access to the capital market.

In addition, the "Planning Outline" clearly states that it will continue to vigorously develop the financial industry and promote the interconnection of financial markets. In addition to the above-mentioned four cities having their respective focuses in the financial field, cities such as Zhuhai are also supported to develop characteristic financial service industries.

④Speeding up circulation

Convenient transportation network helps population and industry layout, accelerates the flow and reasonable distribution of resources between cities, and is also the basis for the development of urban agglomerations. At present, the Guangzhou-Shenzhen-Hong Kong Passenger Dedicated Line and the Hong Kong-Zhuhai-Macao Bridge in the Greater Bay Area have been successfully put into use, and further transportation construction to cope with the continued population growth is already under planning .

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theetangerine · 4 years

Text

What it’s real like being a Dyslexic

Today's post shall be about Dyslexia from "Dyslexia the Gift". Well I didn't know that I was blessed with such an omnipotent power. Thank you Dyslexia the Gift for Awakening my abilities. Anyways this post is just my rebuttal to this list as an Anthropomorphic Tangerine with severe dyslexia. Here we go: General:

1. Appears bright, highly intelligent, and articulate but unable to read, write, or spell at grade level.

Ahhhhh.......... so I am all those big words that I can't spell or pronounce.

BTW who ever came up with the word Dyslexia is a troll cause you knew damn well I can't spell that.

2. Labelled lazy, dumb, careless, immature, “not trying hard enough,” or “behavior problem.”

Hey I am not lazy just because Suzie spends her the night figuring out Algebra questions and I on the other hand will look at her formula, "Copy and Paste" for myself and even then at the end of the day I stilled will have learned it. Einstein did say there are different types of genius.

3.Isn’t “behind enough” or “bad enough” to be helped in the school setting.

Let's just pretend it didn't take me 3 times to read this inorder to understand it. Anywhose.

The school suggested to my parents to take me to get tested. Although I think it was because they wanted justify their discrimination against me.

4. High in IQ, yet may not test well academically; tests well orally, but not written.

Lies. I failed in both.

5.Feels dumb; has poor self-esteem; hides or covers up weaknesses with ingenious compensatory strategies; easily frustrated and emotional about school reading or testing.

*clear throat* In best Beyonce voice "I'm survivor................"

6.Talented in art, drama, music, sports, mechanics, story-telling, sales, business, designing, building, or engineering.

Ohh.......come on I suppose to be talented in these fields why didn't Dyslexia tell me this.

7.Seems to “Zone out” or daydream often; gets lost easily or loses track of time.

They were in the Zone like in Soul

woahh..... that was a bar.

8.Difficulty sustaining attention; seems “hyper” or “daydreamer.”

As I type this I peer out through the window wondering if clouds really are made of precipitation or that is what the Illuminati wants you to think.

9. Learns best through hands-on experience, demonstrations, experimentation, observation, and visual aids.

Crash Course history is my religion.

Vision, Reading, and Spelling:

10.Complains of dizziness, headaches or stomach aches while reading.

Starts going in the 4th dimension if I pick up a book.

11.Confused by letters, numbers, words, sequences, or verbal explanations.

Algebra is not for dyslexics. You mix letters and numbers together. Mathematicians were not thinking of dyslexics when Algebra was created.

12. Reading or writing shows repetitions, additions, transpositions, omissions, substitutions, and reversals in letters, numbers and/or words.

Yes Yes . Truly feal for all of of my teacher who read my essays.

13.Complains of feeling or seeing non-existent movement while reading, writing, or copying.

I am Percy Jackson so I am a god.

14.Seems to have difficulty with vision, yet eye exams don’t reveal a problem.

I actually had glasses.

15.Extremely keen sighted and observant, or lacks depth perception and peripheral vision.

Yet another sentence I can't understand. Hold up let me go and look up “depth perception” so I can understand this sentence, real quick.........................This is true.

16.Reads and rereads with little comprehension.

Reading number fifteen (15) proves this.

17.Spells phonetically and inconsistently.

Hooked on Phonics told me otherwise.

Hearing and Speech:

18.Has extended hearing; hears things not said or apparent to others; easily distracted by sounds.

Being an only child while being home alone this ability doesn't have any benefits.

19.Difficulty putting thoughts into words; speaks in halting phrases; leaves sentences incomplete; stutters under stress; mispronounces long words, or transposes phrases, words, and syllables when speaking.

I feel called out.

Writing and Motor Skills:

20.Trouble with writing or copying; pencil grip is unusual; handwriting varies or is illegible.

I may have changed my writing style multiple times. Some legible, some not.

21.Clumsy, uncoordinated, poor at ball or team sports; difficulties with fine and/or gross motor skills and tasks; prone to motion-sickness.

But if I am supposed to be talented at sports in the afro-mention point why can't I catch a ball.

Dyslexia being confused since 1877.

22.Can be ambidextrous, and often confuses left/right, over/under.

Yip...A 20 something that doesn't know their left from their right.

Math and Time Management:

23.Has difficulty telling time, managing time, learning sequenced information or tasks, or being on time.

Well if I can't tell time I can't manage my time thus I don't have enough time to do tasks so that is why I am never on time.

24.Computing math shows dependence on finger counting and other tricks; knows answers, but can’t do it on paper.

Only if Math exam were oral I would have accolades in Math.

25.Can count, but has difficulty counting objects and dealing with money.

Y'all I have nightmares about being a cashier.

26.Can do arithmetic, but fails word problems; cannot grasp algebra or higher math.

As I said before Algebra not, for dyslexics.

Memory and Cognition:

27:Excellent long-term memory for experiences, locations, and faces.

I wish could forget about that time I fell down in front the entire school. And yes this is not an exaggeration. The ENTIRE school saw this.

28.Poor memory for sequences, facts and information that has not been experienced.

Subjects dyslexics shouldn't do:

Science: too many big words you can't spell.

History or Literature: reading is detrimental to your health.

Math: A-L-G-E-B-R-A

29.Thinks primarily with images and feeling, not sounds or words (little internal dialogue).

Sad truth I wear my heart on my sleeves. It's fricking annoying cause I want to be mad in peace without anyone knowing Goddamn it .

Behavior, Health, Development, and Personality:

30.Extremely disorderly or compulsively orderly.

I am Death the Kid.

(If you don't get that reference you are uncultured)

31.Can be class clown, trouble-maker, or too quiet.

Like I was disliked in school for being too quiet. You would think that it was students oh no no no Patricia it was teachers.

Sorry Mrs. Emily for not giving you grey hairs, so you have the opportunity to go home to your loving husband to complain about how much you hate your job and kids. While you thinking about your affair with the young nextdoor neighbour, who you would end up marrying only to then leave them for a hot 20 yea.............................Ummmm that got a bit personal there lets continue shall we

32.Had unusually early or late developmental stages (talking, crawling, walking, tying shoes).

It took a while to learn how to tie my laces.

33.Prone to ear infections; sensitive to foods, additives, and chemical products.

So wait not only did Dyslexia inhibit my ability to read, comprehend and to tell my right from my left to function normally in society but it caused my ear infections too. That is it I'm done

Moving to Siberia.

34.Can be an extra deep or light sleeper; bedwetting beyond appropriate age.

I was a very well trained tangerine.

35.Unusually high or low tolerance for pain.

Everytime I stub my pinky toes it feels like an aeroplane wheel rolled over it.

36.Strong sense of justice; emotionally sensitive; strives for perfection.

Facts!

37.Mistakes and symptoms increase dramatically with confusion, time pressure, emotional stress, or poor health.

2 second Rant

Examiners don't think of dyslexic people, even with extra time. The sheer amount of times it takes just to understand the question then to answer with the best possible Grammar is straight cruelty.

You automatically want me to fail and not finish don't you.

You Demon.

Mini sidestory:

While writing this I asked my significant other to spell "Exaggerate", dude looked at me and told me to sound it out. Past me knew he was going to say this and I did sound it out before he asked me to sound it out. I told him that I did and that I don't know what letter comes after "Ex", he was like babe sound it out..................................

Tangerine internal thoughts: (Exsqueeze me) Every time try that a ""H" is coming up in my head. I thought this through ya know.

In conclusion I sound it out to my phone.

To anyone who don't understand Dyslexia fully I do suggest researching.

My commentary is completely subjective but if you relate that is good :)

That's all my Fruits until next time

- TheeTangerine

Proof read by TheeApple<3

https://www.dyslexia.com/about-dyslexia/signs-of-dyslexia/test-for-dyslexia-37-signs/

#funny memes #dyslexic #dyslexia #long reads #long post #relatable #funny content #funny

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script-a-world · 4 years

Note

I'm trying to build a wuxia world that's modern. But I'm having serious trouble with all the outdated ideas and lifestyles as well as modern understanding of science. All the mechanics as well as fighting are basically scientific, but extended and exaggerated to be made like it's magic. Problem is, modern science refutes all that. Especially about the readily known or secret everything is in the modern world. I could explain in more detail or specific ideas, but it's not easy in English.

Mod Note: The asker later sent an ask that they had found someone privately to help with their questions, but as Tex had already put the work into this response, and there may be others interested, we are still posting our reply.

Tex: Wuxia is inherently a genre of historical fantasy, so I understand the struggle with bringing it into a modern setting. Let me paste a short Wikipedia synopsis in to help orient me, with a Chinese version so you have something in a more navigable language.

The word "wǔxiá" is a compound composed of the elements wǔ (武, literally "martial", "military", or "armed") and xiá (俠, literally "chivalrous", "vigilante" or "hero"). A martial artist who follows the code of xia is often referred to as a xiákè (俠客, literally "follower of xia") or yóuxiá (遊俠, literally "wandering xia"). In some translations, the martial artist is referred to as a "swordsman" or "swordswoman" even though he or she may not necessarily wield a sword.

The heroes in wuxia fiction typically do not serve a lord, wield military power, or belong to the aristocratic class. They often originate from the lower social classes of ancient Chinese society. A code of chivalry usually requires wuxia heroes to right and redress wrongs, fight for righteousness, remove oppressors, and bring retribution for past misdeeds. Chinese xia traditions can be compared to martial codes from other cultures such as the Japanese samurai bushidō.

Source: Wikipedia in English

武侠文化是華人界特有的一種流行文化，體現於武俠類作品的盛行，乃至影響到小說、漫畫、影視、電子遊戲和音樂等各種娛樂媒介。武俠文化多以各式俠客為主角，神乎其神的武術技巧為特點，刻畫宣揚俠客精神。

Source: Wikipedia in Chinese

Both versions have a section on common elements and themes found in the wuxia genre. This is good, because it helps us break down the core of the genre, and how we can bring this out of the historical setting.

“Wu” encompasses the traditions of martial arts and its accompanying subculture. There are plenty of martial arts schools in China and other parts of the world, so it would be easy to research how they have adapted to the modern world.

“Xia” is a bit harder. The Chinese version stops at the definition that it is a Confucian value, whereas the English version breaks the definition down into more items. Let me copy down what the English version states in its “Code of xia” section:

The eight common attributes of the xia are listed as benevolence, justice, individualism, loyalty, courage, truthfulness, disregard for wealth, and desire for glory. Apart from individualism, these characteristics are similar to Confucian values such as ren (仁; "benevolence", "kindness"), zhong (忠; "loyalty"), yong (勇; "courage", "bravery") and yi (義; "righteousness").[11] The code of xia also emphasises the importance of repaying benefactors after having received deeds of en (恩; "grace", "favour") from others, as well as seeking chou (仇; "vengeance", "revenge") to bring villains to justice. However, the importance of vengeance is controversial, as a number of wuxia works stress Buddhist ideals, which include forgiveness, compassion and a prohibition on killing.

These attributes, as well as the mentioned Buddhist ones, can also be found in works set in modern times.

One core tenet, Jianghu, is emphasized in the Chinese version that it is an idea rather than a tangible location. Below is the original Chinese as well as the Google Translate version in English:

江湖不是一個實際存在的場所，在武俠文化中，江湖則是俠客們的活動範圍，「江湖」強調了它的變動性及危險性，「綠林」顯示了他的違法及不合理性，「武林」則限制了他屬於「武人」的屬性。

這個世界即使偶與歷史背景做結合，但虛構的成分仍然很濃厚，「這場域，自成一格，既模擬現實世界，又別闢蹊徑，擁有自足而完整的範疇、規律，與現實世界大相逕庭，基本上是由作者、讀者在某種默契下『虛構』而成。」

抽離歷史情境而虛構，從另一個角度而言，卻也等同於束縛的鬆綁，無論是經濟、政治、社會、法律的歷史實情如何，都無須顧慮，只須假借個虛擬的「古代」，作者只須擁有歷史常識（不是知識），即足以盡情馳騁在此一想像的空間，將重心置放在英雄的江湖事業、兒女情長及恩怨讎報之中。

虛擬的「江湖世界」，除了存在「俠客」之外，也出現了大量的外來人物，「如文人社會中的書生、官吏、僚佐；宗教社會中的僧人、尼姑、道士；農村社會中的漁夫、樵子、農人；商人社會中的商賈、仕紳；其他如乞丐、妓女、兒童等。」這些三教九流的人物充實且豐富了新的江湖。經過了歷代小說家的改造，新的江湖走出了歷史，成為了一種虛擬但完整的社會型態。

江湖世界中的人物遵守正邪之分和實力至上的原則，同時也藐視世俗禮法，是自由自在的獨立個體，一般而言分為兩類：一是獨行俠，二是集團人物。前者獨來獨往，不受他人約束，後者統屬在某一具有成文或不成文規範下的「集團」，也就是所謂的「幫派」。

Google Translated English:

Jianghu is not an actual place. In the martial arts culture, Jianghu is the range of activities of the knights. "Jianghu" emphasizes its variability and danger. "Green Forest" shows his illegality and irrationality. "Wulin" "Restricts his attributes as "Martial Man".

Even if this world is combined with historical background, the fictitious component is still very strong. "This domain is self-contained. It not only simulates the real world, but also has no other way. It has a self-contained and complete category, law, and real world. Very different, basically made by authors and readers under some kind of tacit understanding."

From the historical context and fiction, from another point of view, it is also equivalent to loose bondage. No matter what the historical facts of the economy, politics, society, and law, there is no need to worry about, just fake a virtual "ancient", The author only needs to have historical common sense (not knowledge), which is enough to ride the space imagined here, and put the focus on the hero's cause and effect, the love of children and the complaint.

In addition to the existence of " knights ", there are also a large number of foreign characters in the virtual "Jianghu World", "such as scholars, officials, and bureaucrats in a literati society; monks, nuns, and priests in a religious society; and fishermen in a rural society. , Woodcutters, peasants; merchants, gentry in the merchant society; others such as beggars, prostitutes, children, etc." These three-religious figures have enriched and enriched the new rivers and lakes. After the transformation of novelists in the past, new rivers and lakes have gone out of history and become a virtual but complete social form.

The characters in the Jianghu world abide by the principles of righteousness and evil and the supremacy of power, and also despise the secular etiquette. They are free and independent individuals, generally divided into two categories: one is the lone traveler, and the other is the group characters. The former travels alone and is not bound by others, while the latter belongs to a "group" under written or unwritten norms, so-called " gangs ."

This reflects well the core definition of the wuxia genre, as well as highlighting that its historical format is not strictly necessary. A modern setting is quite possible!

There are more themes and concepts covered in the Wikipedia articles, but for now the main definition of the genre has been covered.

The issue of “scientific” versus “magical” is a complex one to tackle, specifically because many of the subgenres in martial arts films (or literature) rely upon a suspension of disbelief in some element or another. Usually this relates to either the plot - lending an element of the ridiculous - or the style of fighting - lending an element of skepticality.

This is usually because the goal of the story matters more. In wuxia and related genres, this is due to a moral compass being instilled in main characters, and functions as one of the main driving forces behind the plot. This is something popular of many action films, ranging from John Wick to Kill Bill to Kingsman. Morality is a popular element in storytelling, though admittedly popularity often rests on how visually appealing it is (something more difficult with text).

Because of this, it ultimately does not matter how realistic the fighting is or is not - so long as the main concepts are covered, then you have a wuxia story. That being said, martial arts often stretches the preconceived notions of what a human body can do; with sufficient training, things like high jumps (x, x) and triple kicks (x, x) are well within the realm of believability.

Ninja Assassin has realistic martial artistry, but it bends believability under the assumption that an audience’s preconceived scope of potential is very narrow. The same goes approximately for The Grandmaster (2013), albeit from a literally historical perspective while being set in the mid 20th century.

Some popular films that you could use as a reference for varying degrees of suspending disbelief are: Kung Fu Hustle (2004), The Night Comes for Us (2018), The Karate Kid (either version), and Fatal Contact (2006).

In terms of moving around the “fantasy” part of wuxia to something similar, The Matrix series accomplishes many wuxia themes, and some rather pointedly, while occupying a futuristic setting.

While I don’t know if this precisely answers your question, particularly in regards to the technical feasibility of martial arts as popularly demonstrated in wuxia, I would be more than happy to expand on my answer if you wish.

#pylons #wuxia #Anonymous

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strangenewneighborhood · 4 years

Note

wait u guys get signatures?? oh i guess thats on me, anyway, whats the meaning of the symbol on our necklace gordo? - 🐟

Hey, yeah, good question.

Examples of the symbolic use of lowercase lambda include:

Lambda indicates the wavelength of any wave, especially in physics, electronics engineering, and mathematics.[5]

In evolutionary algorithms, λ indicates the number of offspring that would be generated from μ current population in each generation. The terms μ and λ are originated from Evolution strategy notation.

Lambda indicates the radioactivity decay constant in nuclear physics and radioactivity. This constant is very simply related (by a multiplicative constant) to the half-life of any radioactive material.

In probability theory, lambda represents the density of occurrences within a time interval, as modeled by the Poisson distribution.

In mathematical logic and computer science, lambda is used to introduce anonymous functions expressed with the concepts of lambda calculus.

Lambda is a unit of volume, synonymous with one microliter (1 μL), that is, one cubic millimetre (1 mm3). This use is currently deprecated.

Lambda indicates an eigenvalue in the mathematics of linear algebra.

In the physics of electric fields, lambda sometimes indicates the linear charge density of a uniform line of electric charge (measured in coulombs per meter).

Lambda denotes a Lagrange multiplier in multi-dimensional calculus.

In solid-state electronics, lambda indicates the channel length modulation parameter of a MOSFET.

In ecology, lambda denotes the long-term intrinsic growth rate of a population. This value is often calculated as the dominant eigenvalue of the age/size class matrix (mathematics).

In formal language theory and in computer science, lambda denotes the empty string.

Lambda is a nonstandard symbol in the International Phonetic Alphabet for the voiced alveolar lateral affricate [dɮ].

Lambda denotes the Lebesgue measure in mathematical set theory.

The Goodman and Kruskal's lambda in statistics indicates the proportional reduction in error when one variable's values are used to predict the values of another variable.

Lambda denotes the oxygen sensor in a vehicle that measures the air-to-fuel ratio in the exhaust gases of an internal-combustion engine.

A Lambda 4S solid-fuel rocket was used to launch Japan's first orbital satellite in 1970.[6]

Lambda denotes the failure rate of devices and systems in reliability theory, and it is measured in failure events per hour. Numerically, this lambda is also the reciprocal of the mean time between failures.

In criminology, lambda denotes an individual's frequency of offenses.

In cartography and navigation, lambda denotes the longitude of a location.

In electrochemistry, lambda also denotes the ionic conductance of a given ion (the composition of the ion is generally shown as a subscript to the lambda character).

In neurobiology, lambda denotes the length constant (or exponential rate of decay) of the electric potential across the cell membrane along a length of a nerve cell's axon.

In the science and technology of heat transfer, lambda denotes the heat of vaporization per mole of material (a.k.a. its "latent heat").[7]

In the technology and science of celestial navigation, lambda denotes the longitude as opposed to the Roman letter "L", which denotes the latitude.

In 1970, a lowercase lambda was chosen by Tom Doerr as the symbol of the New York chapter of the Gay Activists Alliance.[10][11] The lambda symbol became associated with Gay Liberation[12][13] and recognized as an LGBT symbol for some time afterwards, being used as such by the International Gay Rights Congress in Edinburgh,[14] the gay rights organization Lambda Legal, and the Lambda Literary Foundation, among others.

... How many Wikipedia articles do you just have memorized?

A lot!

#anon #asks #;

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eintsein · 4 years

Note

Hello! I wanted to ask about your major in computer science. How is it? What were some of your fave courses? Is there something you specifically want to do after? I'm honestly interested but I struggle with math (calc and physics sucked for me). I'm not sure what to do because I enjoyed it in grade 11 a lot, but I'm worried. I'm thinking of transferring but at the back of my mind, I'm not sure TT Regardless, I hope you have a lovely day :")

Hi, thanks for asking! It’s pretty fun but a lot of work. Cornell’s computer science program is more theoretical than most, but the projects have been really great.

I would say my favorite CS course I’ve taken so far is Intermediate Web Development because it went through the entire process of web development, i.e. all the way from user research to delivering a product (the website). The class also had 4(?) projects that were pretty flexible in terms of what we had to build as long as we incorporated the things we learned. For the final project, we had to develop a website for a real client.

Web development has always been an interest of mine, but I’m not sure if that’s what I want to do. Recently, I’ve gotten interested in data science, especially because I can use both my CS and Economics degrees. It’s hard to say for sure, though, because most of the CS classes I’ve taken are core classes (i.e. more theoretical and building up the skills required for other classes, e.g. object-oriented programming, functional programming) as opposed to application-based classes (e.g. computer vision, machine learning, etc.).

To be honest, the level of math required in CS really depends on what specific field you’re pursuing. Tech-related majors and jobs have a much wider range as well. In any case, I think that if you’re really interested in CS, you should try to pursue it. A lot of the math skills you’ll need will be taught to you in college. You may need to spend more time and effort in understanding it, but that doesn’t mean you can’t do it.

I hope that helped, and feel free to reach out with any questions!

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dunitask · 3 years

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15 Best Ways To Earn Money Both Online and Offline

Once you're able to turn your enthusiasm to generate money, chances can be endless! Just have a rest and think profoundly about individuals living around you. Which services do they really want daily/monthly? In those, which solutions can you provide to them? The epic earning suggestions lie inside your mind! Happy earning! Dunitask is here with the 15 best ways to earn more money both online and offline. Here we go.

Trading electronic stuff & used phones:

If you have a used mobile phone or game station system (PS4/PS5), you can sell it on sites. You can look into a trade program, which pays participants and offers money for your gadget. Direct Selling Method: Usually, you capture photos of your phone, confirm ESN (Electronic Serial Number) is pretty clean and post your listing. Some sites will review and approve postings, where the time is negligible. You will be paid as fast as the item is sold. Selling to Reseller Method: At first, you need to ship your mobile phone to the reseller party. Inspecting is required before payment, usually done via check or online paying procedure depending on the reseller.

Ride-Sharing:

Join ride-sharing companies and gain money by driving passengers around. These companies can pay instantly via debit card or transfer your income to your bank account very quickly. You have to keep few things in mind as – - Loading fuel (gas, octane, diesel, etc.) and maintenance costing. - Owning a functional car, - An agreement with the company for background checking, - Sharing a review of your driving history with the company. - Don’t forget to notify the car insurance company about start driving.

Making deliveries:

Nowadays the delivery trend is overgrowing, and you can be part of this to make some side income. You will be paid for every delivery, and sometimes you may earn tips a bit! If you’re thinking about making deliveries, you’ll have to keep in mind a few things such as – - You will have to sign up for a service. - A smartphone is essential to accept and process deliveries. - You’ll need a means of transport to deliver products. It could be a bike, scooter, or car, depending on the company. To make deliveries, few companies will allow you to use a motorcycle or scooter. - Payment procedure varies by companies like daily, weekly or twice a week.

YouTube videos:

A smartphone is very available today. With some videography skills, you can use your smartphone to make videos for YouTube. You can film from anywhere with high-resolution cameras. Usually, smartphones contain high-resolution cameras. These videos can be about any topic in which sphere you are skilled, like sports, gaming, cooking, Tech related, educational, etc. You can receive donations on Youtube! Did you know? By adding this feature, receiving the donation is an extra way to generate passive income. In live streaming, you will notice the amounts rise significantly. You will have to build a large number audience firstly. So, you can assume that they will give you something. Isn’t it cool? Say, for example, you do a one-hour live stream in which you have a Q&A session (answering questions). Here you can earn a pretty extra cent with this. Besides, you’ll be able to view the live stream again later, where you can place advertisements all over again. If you repeatedly merge regular videos with live streams, you’ll be able to earn money in two ways simultaneously.

E-book writing:

Do you have a passion for writing? If the answer is yes, then you can use your love to earn money from the internet. You can sell your own written book via your website. On the other way, you can sell your own written book on e-reader sites. There remain possibilities that you will get up to seventy percent of the whole profit! You may write about any topic, but you must know a lot about that. By the way, make sure that your e-book is worth reading! Happy writing!

Sell your Photos & Video footages:

If you are good at taking pictures or recording footage, then you can gain money from this passion. There are lots of sites that allow you to upload your photos and footage. These sites have massive user bases. People usually do visit, and if anyone does license your photo, you will be paid! At a point, you'll create your stock portfolio, where you need to spend a lot of time. You may browse through the marketplaces above to find the most popular styles. Finally, you can create your niche and upload frequently. Make a better portfolio, increase chances of success! It's not only about making money; it's a matter of honor also. Using your good-quality video clips and photos, you can build a fanbase for your work.

Customer Support Jobs:

The Internet makes the world connected. With the progress of internet-based businesses, people are becoming more independent. They are earning plenty of money from the internet nowadays. Besides, these jobs can be both online and offline. You can support the customer services from home or being at an office following company policies. Both day & night shift exists for this type jobs. Find which shift and company suits you, make your career fruitful!

Supermarket Jobs:

Whether you're a student searching for the easiest ways to how to earn money offline to start a career, grocery stores provide a spread of employment prospects. Open schedule availableness will increase probabilities for hire, as several grocery stores keep open late at midnight or throughout weekends and holidays. Entry-level grocery positions typically don't need candidates who hold previous work expertise or high school diplomas, although some employers might favor pursuing candidates with formal educations.

Tutor:

Whenever it comes to earning money as a student, tutoring jobs are a way to make income without a long-term commitment. In this case, whether you’re a college student or a teacher, it doesn’t matter much. For tutoring cases, the academic background is needed for the subject you want to tuition. Patience, communication skills, and minimal experiences are required for tutor jobs.

Teacher’s Assistant Jobs:

If you’re studious, disciplined, and brainstorm about the best ways to make passive income, the Teacher’s Assistant job is perfect for you! What does a teacher’s assistant do? A teacher’s assistant informs a lead teacher and insists the lead teacher runs smoothly by taking on everyday classroom tasks in the lead teacher’s way. An assistant teacher’s daily tasks include performing clerical duties like recording attendance, grading exams, and home tasks. The payment system depends on university policies.

Developing online courses:

This is the most trendy way to make money online. Amongst online passive income ideas, conducting online courses is both smarter and honorable. If you're dynamic at something, making an online course for this is more stylish. Out there remains a lot of websites with millions of students looking for new online classes every day. You can conduct a study plan for these guys as well as sell courses. There are plenty of sales channels to sell an online course; use Google to find what suits you best and earn money with that. You can also categorize your programs as free, standard & premium by fixing these packages' reasonable prices. In this way, people will quickly grab courses by their capability. See also: How to deal With Stress For Students - What are the best foods to eat when studying? - Top 20 Interview Questions to Ask a Software Engineer - 11 Best Reasons Why Students Ignore Computer Science

Stock Investment:

Buying stocks is also part of passive income online for a long period. Here the process is - you buy shares and claim a part of the profit after a certain period. If you’re about to buy shares, keep in mind that you are buying shares from reliable companies which are likely to generate fruitful profit! Your earnings depend on the amount of money you have been provided. When you become a master at how stock markets working, your predictions will be more appropriate.

Virtual Assistant:

If you're dynamic at doing the plan and organize stuff, then a virtual assistant might be the appropriate choice for you. A virtual assistant's work responsibilities include general bookkeeping, entering data, managing emails, research, etc. This profession can be an excellent way to earn money online and contact essential people as well. Nowadays, a bunch of small business owners is dropping the idea of taking full-time team members. They prefer virtual assistants for their tasks.

Teaching University/College students:

During university or College break time, students pass their free time by gossiping, chatting, gaming, etc. You can pick that time and teach students in that free time. At first, you need to reach them in your convenient way (online or offline), convince them to learn (the subject you will conduct), and advertise yourself. If you don't want to waste your valuable time, You can get ideas to earn money in university life.

Delivering Accessories for University/College projects:

Those who always think about how to earn money offline, It's the best idea for them. In every educational institute, there happen many projects like DIY projects, microcontroller-based projects, science projects, etc. You can provide equipment for these projects as a circuit board, ultrasonic sensor, ready-made projects, etc. You can collect products from wholesale or retailers and give parts to students with a convenient profit.

Conclusion:

You can always do a brainstorm and find a suitable way to how to earn money offline. Just make sure that your works are worth reading/watching/learning. When you can turn your passion to make money, possibilities can be endless! Just take a break and think deeply about people living around you. Which services do they need daily/monthly? In those, which services can you provide for them? If you think about these through virtual reality, find out which online services you can provide. The epic earning tricks lie within your brain! Just find it out and hit it. Happy earning! Read the full article

#bestwaystomakepassiveincome #easyearn #moneyfrominternet #onlinepassiveincomeideas

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irispublishersagriculture · 3 years

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World Journal of Agriculture and Soil Science (WJASS)

New Trends of the Polysaccharides as a Drug

Authored by Ebtsam M El Kady

Introduction

Polysaccharides (PSs) are a high molecular weight polymer, consisting of at least ten monosaccharides mutually joined by glyosidic linkages. The glycosyl moiety of hemiacetal or hemiketal, together with the OH group of another sugar unit, formed the glyosidic linkages [1]. Unlike protein and nucleic acid, the structure of PSs is far more complicated based on the differences in (i) composition of monosaccharide residues, (ii) glyosidic linkages, (iii) sequence of sugar units, (iv) degrees of polymerization, and (v) branching point. Apart from those, other factors, such as differences of cultivars, origins, and batches, or even extraction methods and fraction procedures are evidenced to have significant influence on the physicochemical and structural properties of PSs. Owing to the rapid development of modern analytical techniques; the identification of PSs structures is becoming more and more feasible and convenient [1]. In recent years, researches have confirmed that PSs from natural products possess wide-ranging beneficial therapeutic effects and health-promoting properties. Specifically, seaweed derived PSs, such as alginate, fucoidan, carrageenan, laminaran, and agar [2], are widely distributed in biomedical and biological applications [3-7], for example, tissue engineering, drug delivery, wound healing, and biosensor due to their biocompatibility and availability.

Fungal PSs, derived from Grifola frondosa, Lentinula edodes, oyster mushroom, as well as Ganoderma, Flammulina, Cordyceps, Coriolus, and Pleurotus, and so forth, are demonstrated to have multiple bioactivities [8-11], including immunomodulating, anticancer, antimicrobial, hypocholesterolemic, and hypoglycemic effects. Bacterial extracellular PSs, loosely associated with bacterium, capsular PSs, tightly bound to bacteria surface, and lipopolysaccharides, always anchored to cell surface by lipid, are nontoxic natural biopolymers and provide extensive applications in areas such as pharmacology, nutraceutical, functional food, cosmeceutical, herbicides, and insecticides [12].

If PSs contains only one kind of monosaccharide molecule, it is known as a homopolysaccharide, or homoglycan, whereas those containing more than one kind of monosaccharide are heteropolysaccharides. The most common constituent of PSs is glucose, but fructose, galactose, galactose, mannose, arabinose, and xylose are also frequent [13,14]. PSs are structurally diverse classes of macromolecules able to offer the highest capacity for carrying biological information due to a high potential for structural variability [15]. Whereas the nucleotides and amino acids in nucleic acids and proteins effectively, interconnect in only one way, the monosaccharide units in PSs can interconnect at several points to form a wide variety of branched or linear structures [16]. This high potential for structural variability in PSs gives the necessary flexibility to the precise regulatory mechanisms of various cell-cell interactions in higher organisms. The PSs of mushrooms occurs mostly as glucans. Some of which are linked by β-(1---3), (1---6) glycosidic bonds and α-(1---3)-glycosidic bonds but many are true heteroglycans. Most often there is a main chain, which is either β-(1---3), β-(1---4) or mixed β-(1---3), β-(1---4) with β-(1---6) side chains. Hetero-β-D-glucans, which are linear polymers of glucose with other D-monosaccharides, can have anticancer activity but α-D-glucans from mushroom usually lack anticancer activity [15]. Heteroglucan side chains contain glucuronic acid, galactose, mannose, arabinose or xylose as a main component or in different combinations

The number of potential PSs structures is almost limitless but in practice many such polymers are unlikely to possess useful physical properties. Even now it is difficult to relate the chemical structure elucidated for any specific PSs to its physical functionality [17]. Currently only a small number of biopolymers are produced commercially on a large scale. However, this limited group of products exhibits an extensive range of physical properties and also provides several models for study by microbiologists, carbohydrate and physical chemists and molecular biologists.

PSs widely exist in the animals, plants, algae and microorganism. Together with proteins and polynucleotides, they are essential biomacromolecules in the life activities and play important roles in cell–cell communication, cell adhesion, and molecular recognition in the immune system [18]. In recent years, some bioactive PSs isolated from natural sources have attracted much attention in the field of biochemistry and pharmacology. They exhibit various biological activities affected by different chemical structures. Suarez et al. [19] reported that the immunostimulatory activity of arabinogalactans extracted from Chlorella pyrenoidosa cells depended on their molecular weights. The higher molecular weight arabinogalactans exhibited immunostimulatory activity, but the lower molecular weight fractions did not. Further researches show that the activities of PSs are not only dependent on their chemical structures, but also are related to their chain conformations [20]. It is known that the anti-tumor activities may be related to the triple helical conformation of the β-D-(1---3)-glucan backbone chain for some PSs, such as lentinan from Lentinus edodes [19,21] and schphylizophyllan from Schizophyllum commune [22,23]. In view of the fact that, Sakurai and Shinkai [24] were the first to find that schizophyllan may form a helical complex with single stranded homopolynucleotides, many works about preparing a complex of schizophyllan and DNA or RNA for a nontoxic gene delivery system have been developed [25-32]. Generally, it is interesting and important to elucidate the relation among chemical structures, chain conformations of PSs and their biological activities. However, PSs are usually composed of various monosaccharides linked with different glucoside bonds. Some PSs has hyperbranched structures. Moreover, PSs often has high molecular weights, and tends to form aggregates in solution that can mask the behavior of individual macromolecules. In consequence, to characterize the chemical structures and chain conformations of PSs is not an easy task.

The chemical structures were analyzed by FTIR, NMR, GC, GC– Mass and HPLC. The chain conformations of PSs in solutions were investigated using static and dynamic light scattering.

PSs already proved to have several important properties [33- 43]. However, the attempts to establish a relationship between the structures of the PS and their bioactivities/actions have been a challenge due to the complexity of this type of polymers. In fact, aside from the homogalactan from Gyrodinium impudicum [44], the β-glucan from Chlorella vulgaris [45] and the PSs from a few species of algae, most of these carbohydrates are highly branched hetero polymers with different substituents in the various carbons of their backbone and side sugar components. Additionally, the monosaccharide composition and distribution within the molecule, and the glyosidic bonds between monosaccharides can be very heterogeneous, which is a real impairment for the study of their structures. Moreover, this heterogeneity also depends on the species, between strains of the same species, and on the time and place of harvest. Nevertheless, there are always some similarities between the PSs from each group of seaweeds: often, fucoidans are extracted from brown algal species, agaroids and carrageenans come from red algae, and ulvans are obtained from green algae. Regarding cyanobacteria and as far as we know, there are not common names for their PSs, to the exception of spirulan from Arthrospira platensis. There are species that, besides producing large amounts of these useful polymers, they secrete them out into the culture medium and these polymers are easily extracted [38]. Both algae are cyanobacteria excellent sources of PSs, most of them being sulfated (S-PSs). They are associated with several biological activities and potential health benefits, making them interesting compounds for the application in pharmaceuticals, therapeutics, and regenerative medicine. Some of the beneficial bioactivities demonstrated by the crude PSs and their derivatives, either in-vitro or in-viv, upon various kinds of cell-lines and animal models, include anticoagulant and/or antithrombotic properties, immunomodulatory ability, anti-tumor and cancer preventive activity. They are also good antidislipidaemic and hypoglycaemic agents, and can be powerful antioxidants, antibiotics and antiinflammatory. The S-PSs from Enteromorpha and Porphyridium have demonstrated strong antitumor and immunomodulating properties [46-48] those from Caulerpa cupressoides and Dyctiota menstrualis are good antinociceptive agents [49,50], and the S-PSs from Cladosiphon okaramanus showed angiogenic, gastro- and cardioprotective bioactivities [33,51,52].

Some Structural Characteristics of Polysaccharides from Algae

The chemical structure of PSs from algae may significantly determine their properties, namely physico-chemical and biochemical, and reflect their physical behavior and biological activities.

Macroalgae

Macroalgae who’s PSs have been studied more often; belong to the group’s brown algae (Phaeophyceae) green algae (Chlorophyta) and red macroalgae (Rhodophyta). Brown algae usually contain fucoidans; the oligosaccharides obtained from the hydrolysis of fucoidans may often contain galactose, glucose, uronic acids, and/or other monosaccharides, linked together and to the main chain by different types of glycosidic bonds. This is the case, for example, for the laminaran from E. bicyclis, or the galactofucan from Sargassum sp., and the fucan from P. tetrastromatica. However, the structure complexity of these fucoidans makes difficult to establish a relationship between the PS-chains/composition and their biological actions, and/or some kind of protocols to design universal pharmaceuticals or other drug-like substances to prevent and/ or cure specific diseases [53]. The monosaccharide composition, the linkage types, the overall structure of fucoidans, and some of their di- and oligosaccharides were well explored by Li et al. [54], Ale et al. [55] and Fedorov et al. [35]. Ale et al. [55] showed the difference between S-PSs from three species of Fucus by focusing on the various substituents at C-2 and C-4 carbons, despite the similarities of their backbones; they also highlighted the possible structures of fucoidans from two species of Sargassum [56,57]. Among them are the schemes for the components of the main chain showing either the (1---3)-, and (1---3)- and (1---4)-linked fucose residues or some di- and trisaccharide repeating units for A. nodosum, C. okamuranus, L. saccharina and some species of Fucus. On the other hand, Fedorov et al. [35] focused on the structures and bioactivities of different S-PSs, such as galactofucan from Laminaria and laminarans from E. bicyclis. Red algae contain large amounts of S-PSs, mostly agaroids and carrageenans, with alternating repeating units of α-(1---3)-galactose and β-D-(1---4)-galactose [58], and/or (3---6)-anhydrogalactose [59]. Substituents can be other monosaccharides (mannose, xylose), sulfate, methoxy and/or pyruvate groups and the pattern of sulfation dividing carrageenans into different families, for example, in C-4 for κ-carrageenan, and in C-2 for λ-carrageenan. In addition, the rotation of galactose in 1,3-linked residues divides agaroids from carrageenans [60]. Apart from agarans [60], found in species of Porphyra, Polysiphonia, Acanthophora, Goiopeltis, Bostrychia or Cryptopleura are also good sources of κ-carrageenan (E. spinosa and K. alvarezii), λ-carrageenan (Chondrus sp, G. skottsbergii and Phillophora) [61], I-carrageenan (E. spinosa) [62], and other heterogalactans with mannose and/ or xylose building up their backbones. Among these, we may find xylogalactans in N. fastigiata and xylomannans in S. polydactyla [63,64].

Regarding green algae, the information on their structures and applications is scarce. Wangs et al. [41] has made an excellent overview on those properties for the S-PSs from several genera of green algae. These S-PSs are very diverse and complex, with various types of glycosidic bonds between monomers, and include galactans (Caulerpa spp.), rhamnans (C. fulvescens and Enteromorpha), arabino- and pyruvylated galactans (Codium spp.), and the most known ulvans from Ulva spp and E. prolifera. Wang et al. [41] also included some repeating aldobiuronic di-units for the backbone of ulvans, containing aldobiouronic acid or glucouronic acid (U. armoricana and U. rigida, respectively), disaccharides sulfated xylose-sulfated-rhamnose, and a trisaccharide unit composed by 1,4-linked glucouronic acid, glucouronic acid and sulfatedrhamnose. The backbone of rhamnans seems to be somewhat simpler, but other types of glycosidic bonds can also appear. Four repeating disaccharide units were indicated for the homo polymer of M. latissimum [65]. Species from Codium are very interesting: their S-PSs may include different percentages of arabinose and galactose, giving place to arabinans (C. adhaerens [66], galactans (C. yezoense) [67], arabinogalactans [41]. Pyruvylated galactans were also identified in C. yezoense [67], C. isthmocladium [68] and C. fragile [69]. Some other species of Codium present other PS-types such as β-D-(1---4)-mannans in C. vermilara [70], or the rare β-D- (1---3)-mannans in C.

An overview on the antiviral activity against several kinds of virus and retrovirus, enveloped or naked was well documented by Carlucci et al. [96] & Wijesekara et al. [2]. These reviews focused on the HIV type 1 and type 2, the human papilloma virus (HPV), the encephalo-myocarditis virus, the hepatitis virus type A and type B and the dengue and yellow fever virus. The inhibition of infection by most of these viruses was explained by the action of S-PSs, which might block the attachment of visions to the host cell surfaces [97,98]. Another way of exerting their activity is by inhibiting the replication of the enveloped virus, such as the HIV, the human cytomegalovirus (HCMV) and the respiratory syncytial virus (RSV) [60,66,99], either by inhibiting the virus adsorption or the entry into the host cells. Some of the S-PSs are effective only if applied simultaneously with the virus or immediately after infection [60]. Another mechanism of action of fucoidans and other S-PSs is through the inhibition of the syncytium formation induced by viruses [2,100]. Some sulfated-xylomannans were reported to present antiviral sulfate-dependent activity, as it was the case of PSs from S. polydactyla and S. latifolium, which inhibited the multiplication of HSV-1 in Vero-cells [1,101]. Additionally, the molecular weight (MW) seems to play an important role in the antiviral properties of the S-PSs, the effect increasing with the molecular weight [60]. However, other structural features can be co-responsible for the reinforcement of the antiviral effectiveness, like sulfation patterns, composition and distribution of sugar residues along the backbone, and the complexity of the polymers [60,64,83,90]. Further, the fucoidans from L. japonica already proved their effectiveness in fighting both RNA and DNA viruses [54], such as poliovirus III, adenovirus III, ECHO6 virus, coxsackie B3 and A16 viruses. Moreover, these S-PSs can protect host cells by inhibiting the cytopathic activity of those viruses [102].

In addition to their virucidal activity against HIV and other viruses associated to sexually transmitted diseases (STD) [103], including HPV, some carrageenans might find application as vaginal lubricant gels and coatings of condoms, with microbicidal activity, for they do not present any significant anticoagulant properties or cytotoxicity [104,105]. Furthermore, some fucoidans, apart from inhibiting attachment of virus particles to host cells, were able to inhibit the attachment of human spermatozoids to the zona pellucida of oocytes [106]; this property could be used for the development of a contraceptive gel with microbicidal characteristics [40]. The PSs from some algae, and which may be released into the culture medium, showed antiviral activity against different kinds of viruses, such as the HIV-1, HSV-1 and HSV-2, VACV and Flu-A, as described by Raposo et al. [72] S-PSs, in particular, proved to increase the antiviral capacity [107]. In fact, the antiviral activity of the PSs may depend on the culture medium, algal strain and cell line used for testing, but also on the methodology, and the degree of sulfation, as is the case of PSs from P. cruentum [108,72]. Despite the slight toxicity that some PSs may present, they could be safely applied in in vivo experiments, decreasing the replication of the virus VACV, for instance [109]. The mechanisms involved in the antiviral activity of S-PSs may be understood analyzing what happens when cells are infected by a virus. Just before infection, viruses have to interact with some glycosaminoglycan receptors (GAG), such as heparin sulphate (HS) [110]. The GAG to which a protein can be covalently bound are part of the target cell surface and can also be found in the intracellular matrix of various connective and muscle tissues. S-PSs may impair the attachment of the virus particles by competing for those GAG-receptors, as they are chemically similar to HS [96,111], most of them having a covalently linked core protein [112,113].

Besides, as it happens with GAG, S-PSs are negatively charged and highly sulfated polymers [96,114,115], whose monosaccharide distribution pattern might influence the specificity of the bound protein, determining several biological functions [110]. For viruses to attach to the host cell surface, the linkage between the basic groups of the glycoproteins of the virus and the anionic components of the PSs (sulfate) at the cell surface must be established [83]. In fact, whichever the algal PSs are, either from algae, by mimicking this GAG, they may induce the formation of a virus-algal PSs complex, thus, impairing the cell infection by blocking the interaction virus-host cell receptor. Hidari et al. [114], for instance, showed that dengue virus (DENV) establishes an exclusive complex with fucoidan, and viral infection is, therefore, inhibited. They suggested that arginine-323 had a high influence on the interaction between the DENV-2 virus and the fucoidan, in an in-vitro experiment with BHK-21 cells. These researchers also found that glucuronic acid seems to be crucial since no antiviral activity was observed when this compound was reduced to glucose. Sulfated polysaccharides from algae, such as alginates, fucoidans and laminaran appear to have antibacterial activity against E. coli and species from Staphylococcus. A fucoidan from L. japonica and sodium alginate were found to inhibit E. coli [116], for example, by adhering to bacteria and killing those microorganisms [103], thus showing bactericidal properties. This type of PS is also a good antibacterial agent against Helicobacter pylori, eradicating their colonies, restoring the stomach mucosa, in clinical trial studies, and regenerating biocenosis in the intestines [117]. Laminaran from Fucus, Laminaria, A. nodosum and U. pinnatifida demonstrated to have an effect on pathogenic bacteria [118] as well, with the advantage of being unable to promote blood coagulation [119]. In contrast, the carrageenans from some seaweeds [120] and the S-PSs from the red algae Porphyridium cruentum, despite the higher concentration used [72], showed a significant inhibitory activity against S. enteritidis. In fact, some PSs from microalgae, such as A. platensis, may present antibacterial properties against some specific bacteria, the activity depending on the solvent used to extract the polymer [38]. By stimulating the production and/or expression of ILs, dectin-1 and toll-like receptors-2 on macrophages and dendritic cells, respectively, (1---3)-β-glucans from C. vulgaris, and laminarans, also induced antifungal and antibacterial responses in rats [121], and some resistance to mammal organisms towards infections by E. coli [122]. Therefore, these types of PSs promise to be good antimicrobial agents.

Anti-Inflammatory and immunomodulatory activities

PSs from algae have long demonstrated to have biological and pharmaceutical properties, such as anti-inflammatory and immunomodulation [81,123,72]. Nevertheless, the antiinflammatory properties may be shown in several ways, depending on the PSs, its source and type/site of inflammation. There is growing evidence that S-PSs are able to interfere with the migration of leukocytes to the sites of inflammation. For example, the heterofucan from D. menstrualis decreases inflammation by directly binding to the cell surface of leukocytes, especially polymorphonuclear cells (PMNs). It completely inhibits the migration of the leukocytes into the peritoneal cavity of mice where the injured tissue was after being submitted to simulated pain and inflammation, without the production of pro-inflammatory cytokines [49]. Every so often, the recruitment of these PMNs shows to be dependent on P- and/or L-selectins, as it was demonstrated for fucoidans of some brown algae [33,124]. Some other studies refer the association of the anti-inflammatory activity with the immunomodulatory ability. This seems to be the case in the work by Kang et al. [125] who simulated an inflammation process in RAW 264.7 cells induced by lipopolysaccharides (LPS). They found that the fucoidan from E. cava inhibited, in a dose-dependent manner, the enzyme nitric oxide synthase induced by LPS (iNOS) and the gene expression for the enzyme cyclooxygenase-2 (COX-2) and, as a consequence, the production of nitric oxide (NO) and prostaglandin E2 (PGL2). Li et al. [65] confirmed the anti-inflammation mechanism in vivo via the immunomodulatory system in-vivo, since the fucoidan from L. japonica reduced the inflammation of rats’ myocardium damaged cells, by inactivating the cytokines HMG B1 and NF-κB, two groups of proteins secreted by the immune cells during inflammatory diseases. These protective and regenerative effects of fucoidans, via the immunomodulatory system, were also verified in the destruction/proteolysis of connective tissue by Senni et al. [126]. These researchers referred to the fact that severe inflammation and the subsequent excessive release of cytokines and matrix proteinases could result in rheumatoid arthritis or chronic wounds and leg ulcers, which could be treated with fucoidans [126].

In addition to the SPs from Ulva rigida, green algae [127], the S-PSs p-KG03 from the marine dinoflagellate G. impudicum, also activates the production of nitric oxide and immunostimulates the production of cytokines in macrophages [128]. The enhancement of the immunomodulatory system by some S-PSs from marine algae is also a way for S-PSs to suppress tumour cells growth and their proliferation, and to be natural neoplastic-cell killers. Studies with arabinogalactan and other fucoidans revealed them to be immunostimulators by activating macrophages and lymphocytes, which suggests their effectiveness in the immuno-prevention of cancer [43,129]. The PSs from U. pinnatifida was also suggested to treat/relieve the symptoms of pulmonary allergic inflammation as it suppresses the activity of Th2 immune responses [130]. On the other hand, fucoidan activated macrophages and splenocytes to produce cytokines and chemokines [131]. PSs from algae, such as Porphyridium, Phaeodactylum, and C. stigmatophora, showed pharmacological properties, such as anti-inflammatory activity and as immunomodulatory agents, as reported by Raposo et al. [72]. Some of these S-PSs, for example, the ones from C. stigmatophora and P. tricornutum, have revealed anti-inflammatory efficacy in vivo and in vitro [132]. The mechanisms underlying the anti-inflammatory and immunomodulatory activities may be understood by making some considerations at the molecular level. On one side, the protein moiety that is covalently bound to most PSs seems to play a critical role in the activation of NF-κB and MAPK pathways involved in the macrophage stimulation [133,113]. This was evidenced in an in vitro experiment performed by Tabarsa et al. [113]. They showed that the PSs from C. fragile was not able to stimulate RAW264.7 cells to produce NO and the protein alone was also unable to induce NO release, but the complex S-PS-protein did inhibit the inflammatory process. On the other side, several other researchers found that proteins were not essential or responsible for the immunostimulatory responses of the cells [134,127]. Additionally, Tabarsa et al. [135] confirmed that the sulfate content and the MW were not crucial for the stimulation of murine macrophage cells. In fact, both desulfated and LMW-PS derivatives of C. fragile produced immunomodulatory responses similar to the ones of the original PSs. In contrast, the S-PSs from U. rigida induced a strong sulfatedependent release of NO [127], thus, the sulfate content showing to be essential for the stimulation of macrophages.

These researchers mentioned the possibility of the sulfate interfering in the interaction PS-cell surface receptors. The interaction of algal S-PSs with the complement system suggests that they might influence the innate immunity to reduce the proinflammatory state [91,81]. In addition, algal polysaccharides have been shown to regulate the innate immune response directly by binding to pattern recognition receptors (PRRs) [136]. For example, λ-carrageenan stimulated mouse T cell cultures in a tolllike receptor-4 (TLR4) [138]. Different effects were observed in other types of S-PSs: Zhou et al. [137] proved that carrageenans from Chondrus with LMW s better stimulated the immune system. The same trend was verified for the S-PSs from the red algae Porphyridium [139], a 6.53 kDa LMW-fragment at 100 μg/mL presenting the strongest immunostimulating activity. It is worth remarking that carrageenans from red seaweeds are recognized for triggering potent inflammatory and carcinogenic effects either in rats or mice cells [111]. However, while some carrageenans stimulate the activity of macrophages, others inhibit macrophage activities [2]. While PSs from various algae do not show anticoagulant and/or antithrombotic activities, attention should be paid to the anticoagulant properties of some PSs, since their use could cause severe bleeding complications.

Anti-proliferative, tumour suppressor, apoptotic and cytotoxicity activities

The current understanding of the anti-cancer and immunomodulating effects of PSs are as follows: (i) prevention of onset of cancer by oral consumption of mushrooms or their preparations; (ii) direct inhibition of growth of various types of cancer cells; (iii) immunostimulating activity against cancers in combination with chemotherapy; (iv) preventive effect on spreading or migration of cancer cells in the body [15]. On the whole, the indirect anti-cancer as well as immunostimulatory effects of lentinan is attributed to the activation of many immune cells. Lentinan can activate them to modulate the release cell signal messengers such as cytokines. The increases in cytokine production in immune cells have been studied in mice and in humans [140,141].

Because of the growing number of individuals suffering from different types of cancer and the secondary effects of synthetic chemicals and other types of treatment used against tumour damages, research was driven towards demand for natural therapeutics with bioactive compounds. In this context, S-PSs from both macro algae and micro algae already proved to have antitumor biological activities. A sulfated-fucoidan from C. okamuranus exhibited anti-proliferative activity in U937 cells by inducing cell apoptosis following a pathway dependent of Caspases-3 and -7 [142]. In another study, conducted by Heneji et al. [143], a similar fucoidan induced apoptosis in two different leukaemia cell lines. These results indicate that fucoidans might be good candidates for alternative therapeutics in treating adult T-cell leukaemia [43]. Sulfated-fucoidans from E. cava also seem to be promising to treat other types of human leukaemia cell-lines [144]. There was some evidence that the fucoidan from L. guryanovae inactivated the epidermal growth factor (tyrosine kinase) receptor (EGFR), which is greatly involved in cell transformation, differentiation and proliferation [145,146]. Therefore, this kind of S-PSs could be used as anti-tumor and anti-metastatic therapeutical/preventing agent, which might act either on tumour cells or by stimulating the immune response [147]. Further, the S-PSs from E. bicyclis and several other algae have demonstrated their potent bioactivity against different kinds of tumours, including lung and skin, both invitro and in-vivo [55,148-150] causing apoptosis in various tumour cell-lines [151,55,152].

The mechanisms involved in this antitumor activity might be associated again with the production of pro-inflammatory interleukins IL-2 and IL-12 and cytokine interferon-gamma (INF-γ) by the immune-stimulated macrophages, together with the increase of the activity of the natural killer cells (NK cells) and the induction of apoptosis [55,21]. NK cells can also upregulate the secretion of IFN-γ, which can activate either the T-cells for the production of IL-2 or the macrophages, which, after being activated, keep on producing IL-12 and activating NK cells [153,154]. The enhancement of the cytotoxicity of these NK cells (lymphocytes and macrophages) can be stimulated by other S-PSs such as fucoidans and carrageenans from other algae [129,137]. PSs can also activate some signaling receptors in the membranes of macrophages, such as Toll-like receptor-4 (TLR-4), cluster of differentiation 14 (CD14), competent receptor-3 (CR-3) and scavenging receptor (SR) [155]; these are also activated by other intracellular pathways, involving several other protein-kinases, that enhance the production of NO, which, in turn, plays an important role in causing tumour apoptosis [155]. These immunomodulation properties of S-fucoidans could be used for the protection of the damaged gastric mucosa as it was already demonstrated by using rat-models [156]. More information on the pathways and mechanisms responsible for the immune-inflammatory activities, including the involvement of the complementary system, may be found [60]. The anti-adhesive properties of some S-PSs, especially fucoidans might also explain their anti-metastatic activity, both in-vitro and in-vivo, in various animal models [157,33], as they can inhibit the adhesion of tumour cells to platelets, thus decreasing the possibilities of proliferation of neoplastic cells. The mechanisms by which fucoidans and other S-PSs exert their anti-adhesive ability were well documented by Li et al. [54]. Some researchers also highlighted the mitogenic properties and the cytotoxicity and tumoricidal activity of some arabinogalactans and fucoidans as well [129,158], either in different cell-lines or various animal models.

The anti-adhesive properties of algal S-PSs may also be relevant as these polymers can block the adhesion of tumour cells to the basal membrane, thus demonstrating to impair implantation of tumour cells and metastatic activity by binding to the extracellular matrix [159]. For example, the S-PSs from Cladosiphon were shown to prevent gastric cancer in-vivo, since it inhibited the adhesion of H. pylori to the stomach mucosa of gerbils [160]. Metastasis appearance could also be reduced in vivo by sulfated-laminaran, a (1---3): (1---6)-β-D-glucan, because this compound inhibited the activity of heparanase, an endo-β-D-glucuronidase involved in the degradation of the main PSs component in the basal membrane and the extracellular matrix. The expression of this enzyme is known to be associated with tumour metastasis [161]. These anti-tumor properties may also be found in some PSs from platensis, which are inhibitors of cell proliferation [78]. Other S-PSs, such as S-PSs p-KG03 from G. impudicum, has also anti-proliferative activity in cancer cell lines and inhibitory activity against tumour growth [128,162,163]. Other PSs from algae, such as C. vulgaris, and S-PS or LMW-derivatives of S-PS from P. cruentum, for example, are described as having similar properties [38]. In some research work, the immunomodulatory activity was associated to the ability of inhibiting carcinogenesis. Jiao et al. [47] found that a sulfated-rhamnan and some derivatives from the green seaweed E. intestinalis suppressed tumour cell growth in-vivo, but they did not show any toxicity against tumour cells in-vitro.

The oral administration of the S-PSs to mice enhanced the spleen and thymus indexes, and also induced the production of TNF-α and NO in macrophages, increased lymphocyte proliferation, and enhanced TNF-α release into serum. The degree of sulfation may play some role in the carcinogenesis process, although the action of the S-PSs may also depend on the type of tumour. In fact, an over S-PSs demonstrated the capacity of inhibiting the growth of L-1210 leukaemia tumour in mice, but, on the other hand, it was unable to inhibit the growth of Sarcoma-180 tumour in mice [149,123]. In addition to the sulfation level, MW may also influence the anticancer activity. For instance, LMW-PS derivatives showed to enhance anti-tumor activity [164]. On the other hand, the increment in the anticancer activity greatly depends on the conditions of the PSs depolymerisation [165]. Kaeffer et al. [82] suggested that the in-vitro anti-tumor activity of LMW-PS sulfated or not, against cancerous colonic epithelial cells might be associated with the inhibition of tumour cells proliferation and/or differentiation.

Lentinan can also increase engulfing ability of certain immune cells to search and destroy migratory cancer cells in the human body [166,167]. Treatment with lentinan can also enhance production of chemical messenger such as nitric oxide to stimulate the immune system [140,168]. In addition, the immune-activating ability of lentinan may be linked with its modulation of hormonal factors, which are known to play a role in cancer growth. The anticancer activity of lentinan is strongly reduced by administration of hormones such as thyroxin orhydrocortisone [169]. Moreover, lentinan can also enhance the immune response to the presence of cancer cells in the body by triggering cancer-specific reactions to fight against them. The mechanism of anti-cancer activity of lentinan is summarized in Figure (1) [170]. Overall, lentinan can suppress the growth and even kill cancer cells directly via multiple pathways involving activation of human immune system by different mechanisms such as stimulation of various immune cells and production of cell signal messengers [171].

Anticoagulant and antithrombotic activities

There are several studies on the anticoagulant properties of PSs isolated from algae, presented in a recent review [72] by different researchers: Cumashi et al. [33], Athukorala et al. [172], Costa et al., [68], Wijesekara et al., [42] and Wang et al. [41]. The main sources of the S-PSs from green algae with anticoagulant properties are Codium and Monostroma [143,144]. Some of the PSs, such as S-rhamnans, showed their action by extending the clotting time via the intrinsic and extrinsic pathways [174]. In fact, Codium spp present strong anticoagulant effects [175,176], but other species from Chlorophyta also contain S-PSs (native, LMW or otherwise modified) with anticoagulant properties. The mechanism of action of the referred PSs is mostly attributed to either a direct inhibition of thrombin or by enhancing the power of antithrombin III [177,178]. Some other PSs from green seaweeds also showed potent anticoagulant properties but their mechanisms of action are associated not only to a direct increase in the clotting time (APTT assays) by inhibiting the contact activation pathway, but also by inhibiting the heparin cofactor II-mediated action of thrombin [179,180] thus showing a potent antithrombotic bioactivity. In addition to their anticoagulant properties demonstrated in-vitro by APTT and TT tests, several S-PSs from algae of different groups present antithrombotic qualities in-vivo [181,50] by increasing the time of clot formation. In fact, Wang et al. [41] published an exhaustive work on this issue by including a summary table with 24 references about both the anticoagulant, and anti-and prothrombotic activities of several S-PS from various green algae.

In two other studies, Costa et al. [68] & Wijesekara et al. [42] also included the S-PS from brown and red algae that present effects on the blood clotting time. Wijesekara et al. [42] referred to the fact that there are few reports on the interference of PSs from algae on the PT (prothrombin) pathway, meaning that most of the marine S-PSs may not affect the extrinsic pathway of coagulation [42]. As a matter of fact, Costa et al. [68] did not detect any inhibition in the extrinsic coagulation pathway (PT test), for the concentrations used; only C. cupressoides increased the clotting time. Also, they found no anticoagulant properties (APTT and PT assays) in the S-PS from S. filipendula (brown algae) and G. caudate (red algae). Additional, in our laboratory we found no anticoagulant properties in the S-PSs from different strains of the red algae P. cruentum, despite the high content in sulfate and molecular weight. As Costa et al. [68] observed this could be due to the absence of sulfate groups in the monosaccharides at the non-reducing ends of the branches, which impaired the interaction between target proteases and coagulation factors. Nishino et al. [87] & Dobashi et al. [182] defended that there might be no effect above an upper limit for the content in sulfate, since the difference in the anticoagulant and antithrombotic activities decreased with the increase of the sulfate content. It seems that some of the chemical and structural features of the S-PSs may have some influence on their anticoagulant and/ or antithrombotic activities. The degree and distribution pattern of sulfate, the nature and distribution of monosaccharides, their glycosidic bonds and also the molecular weight showed to play some role on the coagulation and platelet aggregation processes induced by sulfated-galactans and sulfated-fucoidans [68,183,184]. In fact, at least for some fucoidans, the anticoagulant properties are related to the content in C-2 and C-2, 3 di-sulfates, this last feature being usually common in these PSs [185,186,131]. Several other studies documented the anticoagulant activity and inhibition of platelet aggregation [54,111,43], supplying more information on the mechanisms of different S-PSs for these biological activities. HMW-PS usually presents stronger anticoagulant activity [187] and if PSs has a more linear backbone, a longer polymer is required to accomplish the same anticoagulant effects [88]. On the other hand, both the native PSs and LMW-derivatives of M. latissimum presented strong anticoagulant activities [188]. Nishino and colleagues also observed that HMW fucans (27 and 58 kDa) showed greater anticoagulant activity than the ones with LMW (~10 kDa) [189].

They found that a higher content of fucose and sulfate groups coincided with higher anticoagulant activities of fractions from E. kurome [189]. However, despite its high sulfation level, the galactofucan from U. pinnatifida lacks significant anticoagulation activity [159]. In addition, a sulfated-galactofucan from schröederi did not present any anticoagulant properties in-vitro but demonstrated a strong antithrombotic activity when administered to an animal model during an experimental induced venous thrombosis, this effect disappearing with the desulfation of the polymer [190]. As for other PSs, the anticoagulant properties of the PSs from marine algae may not only depend on the percentage of sulfate residues, but rather on the distribution/position of sulfate groups and, probably, on the configuration of the polymer chains [72]. Spirulan from A. platensis is one of the PSs from microalgae that strongly interfere with the blood coagulation-fibrinolytic system and exhibits antithrombogenic properties [97], then, promising to be an anti-thrombotic agent in clots’ breakdown, although care should be taken regarding hemorrhagic strokes [38].

Figure (4) summarizes the preponderant target sites for the S-PSs from marine organisms on the coagulation system. Blue and red arrows indicate anticoagulant and pro-coagulant effects, respectively. (+) indicates activation and (−) indicates inhibitory effects. Anticoagulant effect: SG and FCS inhibit the intrinsic tenase and prothrombinase complexes [202,203]. It is still unclear if sulfated fucans (SF) have similar effects. These PS also potentiate the inhibitory effect of antithrombin (AT) and/or heparin cofactor II (HCII) on thrombin [199,204]. Their effects on factor Xa are very modest. The serpin-independent action preponderates on the plasma system. Pro-coagulant effect: SG and FCS activate factor XII [205,206]. This effect may result in severe hypotension (due to bradykinin release) and pro-coagulant (pro-thrombotic) action. It is unclear if SF activates factor XII. SF inhibits Tissue Factor Protease Inhibitor (TFPI), a specific inhibitor of the extrinsic tenase complex. So, SF has a pro-coagulant effect [207,208]. Of course, further studies are necessary to investigate whether this distinct mechanism of action may confer favorable effects to the PSs for the prevention and treatment of thromboembolic events. In particular, it is necessary to clarify which one of the two mechanisms (serpindependent or serpin-independent) is more favorable for an antithrombotic therapy.

Antilipidaemic, hypoglycemic and hypotensive activities

S-PSs from algae are potent inhibitors of human pancreatic cholesterol esterase, an enzyme that promotes its absorption at the intestinal level; this inhibitory effect is enhanced by higher molecular weights and degree of sulfation [2]. A sulfated-ulvan from U. pertusa in an in-vivo study using mice models regulated the ratio HDL/LDL-cholesterol and reduced the levels of triglycerides (TG) in serum [209]. On the other hand, in another experiment with rats and mice, using native ulvans from the same species, the animals experienced a hypocholesterolaemic effect but no reduction in the TG profile [210]. An opposite reaction was observed when the PSs was acetylated and over sulfated, as TG levels were normalized. It seems that the ability to sequester bile extracts may be involved [210]. The contents in sulfate and acetylate groups play important roles during the dislipidaemia process [211,212]. Ulvans from Ulva spp also showed antiperoxidative properties, preventing liver tissues from hyperlipidaemia, including that induced by toxic chemicals and protecting the injured tissue from the oxidative stress [213], and improving antioxidant performance of the animal models. In fact, these S-PSs regulated superoxide dismutase (SOD) and catalase, increased vitamins E and C, and reduced glutathione, and had some role in reducing the levels of aspartate and alanine transaminases in the rats’ liver [214,209]. Additionally, the S-PSs from M. nitidum also demonstrated hepatoprotective activity by increasing the expression of liver detoxifying enzymes, and, therefore, showed to be good agents for chemoprevention medicine [215].

The activity of these PSs may be related to their uronic acid and sulfate content, which are able to sequester and bind to bile acids [216], reducing their levels. Other S-PSs from green algae also revealed hypolipidaemic properties, such as that from E. prolifera. These PSs regulated the lipidic profile both in plasma and liver, increasing HDL-cholesterol, in rats [217]. Fucoidans from L. japonica, the native or LMW-derivate, have hypolipidaemic effects, decreasing total and LDL-cholesterol in the serum and TG in rats [218], and they prevented hyperchole-sterolaemia in mice [133]. Another mechanism to reduce blood cholesterol in humans by S-PSs is associated to their high capacity to inhibit pancreatic cholesterol esterase, which is responsible for the absorption of cholesterol and fatty acids at the intestine [2]. It seems that the presence of sulfate at the C-3 position of the sugar residues greatly enhances that inhibition [2]. Porphyran from P. yezoensis has antihyperlipidaemic properties [219,220] by reducing the release of apolipoprotein-B100 (apoB100) and decreasing the synthesis of lipids in human liver cultured cells [221]. By reducing the secretion of apoB100, porphyran has the potential to be used as a therapeutic agent to treat CVD. Additionally, some types of carrageenans have already proved to decrease blood cholesterol in humans [222] and in rats fed on a diet enriched with a mixture of κ/λ- carrageenans from G. radula [223]. Most of the PSs from marine algae are naturally highly sulfated, with high molecular weights, making them not easily absorbable and thus enabling them to be used as anticholesterolaemic agents. Few studies were carried out in this area, namely focusing on Porphyridium, P. cruentum, R. reticulata [224-227], but these suggest a strong potential of S-PSs from unicellular algae to be used as hypolipidaemic and hypoglycaemic agents, and as promising agents for reducing coronary heart disease, due to their hypocholesterolaemic effects [72]. As far as we know, scarce research was performed on the mechanisms underlying the antihyper-lipidaemic activity. However, the sequestration and disruption of the enterophatic circulation of the bile acids may be involved [209,228,229]. Ulvans and their LMW-derivatives, and also the S-PSs from Porphyridium showed to increase the excretion of bile [230,210]. Another explanation for the antihyperlipidaemic activity of S-PSs may be associated to the fact that they can effectively increase the anionic charges on the cell surface, which improve the removal of cholesterol excess from the blood, thus, resulting in a decrease of serum cholesterol [54]. In addition, most PSs have ion exchange capacity, such as those from Porphyridium and Rhodella [231], and they can function as dietary fibres. This could also explain the ability to lower down cholesterol [232]. PSs may act as dietary fibres, immunostimulating the goblet cells in the intestine to increase the release and effects of mucin [233]. Moreover, the administration of PSs may increase the viscosity of the intestinal contents, interfering with the formation of micelles and nutrient absorption, thus, lowering lipid absorption, and reducing gastrointestinal transit time (GTT) [230,57]. Other PSs have the ability to inhibit the enzyme α-glucosidase, thus improving the postprandial hyperglycaemia [234], and another can also reduce the blood pressure by inhibiting the release of plasma angiotensin II [235].

Wound healing and wound dressing

Due to their inherent biocompatibility, low toxicity, and pharmaceutical biomedical activity, various PSs, suchas chitin, chitosan, cellulose, hyaluronan, and alginate, have been widely used to prepare wound healing materials [236,142,237]. Hyaluronan, a major extracellular component with unique hygroscopic, rheological, and viscoelastic properties, has been extensively developed for tissue repair purposes due to its physicochemical properties and specific interactions with cells and extracellular matrix. It is generally accepted that hyaluronan plays multifaceted roles in the mediation of the tissue repair process and is involved in all the stages of wound healing, i.e. inflammation, granulation tissue formation, reepithelialization, and remodeling. Derivatives of hyaluronan, such as cross-linked, esterified or other chemically modified products have also been developed for tissue repair or wound healing purposes [238,239]. Remarkably, wound healing promoting activity of the materials is also important in the designing of materials for tissue engineering. All-natural composite wound dressing films prepared by dispersion and encapsulation of essential oils in sodium alginate matrices have been reported to show remarkable antimicrobial and antifungal properties and may find applications disposable wound dressings [240].

Chitosan/silk fibroin blending membranes crosslinked with dialdehyde alginate have been developed for wound dressing and the membranes were found to promote the cell attachment and proliferation, which suggests a promising candidate for wound healing applications [241]. Blending aqueous dispersions of sodium alginate and povidone iodine (PVPI) complex was prepared as free standing NaAlg films oras Ca2+ cross-linked alginate beads. These products were demonstrated to show antibacterial and antifungal activity and controlled release of PVP Iinto open wounds when the composite films and beads were brought into direct contact with water or with moist media [240]. This proved that they could be suitable for therapeutic applications such as wound dressings. In situ injectable nano-composite hydrogels composed of curcumin, N, O-carboxymethyl chitosan, and oxidized alginate as a novel wound dressing was successfully developed for dermal wound repair application [139]. In-vitro release, in-vivo wound healing, and histological studies all suggested that the developed nanocurcumin/ N, O-carboxymethyl chitosan/ oxidized alginate hydrogel as apromising wound dressing might have a potential application in the wound healing. Silver nanoparticles containing polyvinyl pyrrolidone and alginate hydrogels were synthesized using gamma radiation and showed the ability of preventing fluid accumulation in exudating wound [242]. The incorporation of nanosilver particles provided as trong antimicrobial effect and therefore made such polyvinyl pyrrolidone/alginate hydrogels suitable for use as wound dressing. Except the alginate and its various derivatives, other natural PSs such as cellulose, chitin, chitosan, and hyaluronic acid have also been explored for wound dressingor wound healing applications [243-245].

Antioxidant activity

Oxidation is an essential process for all living organisms for the production of energy necessary for biological processes [246]. In addition, oxygen-centered free radicals are involved in development of a variety of diseases, including cellular aging, mutagenesis, carcinogenesis, coronary heart disease, diabetes and neurodegeneration [247]. Though almost all organisms possess antioxidant defense and repair systems to protect against oxidative damage, these systems are often insufficient to prevent the damage entirely [98]. Recently, much attention was paid to screening natural biomaterials in the case of several clinical situations since use of synthetic antioxidants is restricted due to their carcinogenicity [135]. Among various natural antioxidants, PSs in general has strong antioxidant activities and can be explored as novel potential antioxidants [248,249]. Recently, PSs isolated from fungal, bacterial and plant sources were found to exhibit antioxidant activity and were proposed as useful therapeutic agents [250,251].

essential process for all living organisms for the production of energy necessary for biological processes [246]. In addition, oxygen-centered free radicals are involved in development of a variety of diseases, including cellular aging, mutagenesis, carcinogenesis, coronary heart disease, diabetes and neurodegeneration [247]. Though almost all organisms possess antioxidant defense and repair systems to protect against oxidative damage, these systems are often insufficient to prevent the damage entirely [98]. Recently, much attention was paid to screening natural biomaterials in the case of several clinical situations since use of synthetic antioxidants is restricted due to their carcinogenicity [135]. Among various natural antioxidants, PSs in general has strong antioxidant activities and can be explored as novel potential antioxidants [248,249]. Recently, PSs isolated from fungal, bacterial and plant sources were found to exhibit antioxidant activity and were proposed as useful therapeutic agents [250,251]. The main mechanism by which S-PSs from green algae exert their primary antioxidant action is by scavenging free-radicals (DPPH-radicals) or by inhibiting their appearance [251]. They also demonstrated to have total antioxidant capacity, and a strong ability as reducing agents and as ferrous chelators [251]. However, some S-PSs, such as sulfated-heterogalactan from C. cupressoides do not show a good scavenging power, but they are rather powerful against reactive oxygen species (ROS) [252]. It is interesting to note that fucoidans from brown algae seem to exert a reducing power bigger than the S-PSs from other groups [68]; the PSs from S. filipendula has an effect even stronger than vitamin C. Moreover, the fucoidan from L. japonica has a great potential to be used in medicine in order to prevent free-radical mediated diseases, as it successfully prevented peroxidation of lipids in plasma, liver and spleen in-vivo, despite showing no effects in-vitro

The S-PSs from S. fulvellum has shown a NO scavenging activity higher than some commercial antioxidants [253]. In addition, the S-PSs from the red algae P. haitanensishas demonstrated to decrease antioxidant damages in aging mice [254]. It seems that LMWS- PS may present higher antioxidant activity than the native polymers, as it was verified with the PSs from U. pertusa and E. prolifera [255,256]. It is probably related with the ability of PSs to be incorporated in the cells and to donate protons [42]. As noted by Raposo et al. [72], S-PSs produced and secreted out by marine algae have shown the capacity to prevent the accumulation and the activity of free radicals and reactive chemical species. Hence, S-PSs might act as protecting systems against these oxidative and radical stress agents. The S-PSs from Porphyridium and Rhodella reticulata exhibited antioxidant activity [257,258], although some research revealed no scavenging activity and no ability to inhibit the oxidative damage in cells and tissues for the crude S-PSs with high molecular weight from P. cruentum, while the PS-derived products after microwave treatment showed antioxidant activity [259].

In all cases, the antioxidant activity was dose dependent. PSs from A. platensis also exhibit a very high antioxidant capacity [260]. Due to their strong antioxidant properties, most of the S-PSs from marine algae are promising since they may protect human health from injuries induced by ROS, which can result in cancer, diabetes, some inflammatory and neurodegenerative diseases, and some other aging-related disorders, such as Alzheimer and CVD. The influence of sulfate content on the antioxidant activity depends rather on the origin of the PSs. For example, the PS from U. fasciata and other algae with lower sulfate content demonstrated a strong antioxidative power [261,262,258,259], while the antioxidant activity observed in PSs from E. linza and other seaweeds showed to be sulfate-dependent [263,264]. Furthermore, high sulfated PSs were shown to have an enhanced scavenging power [251,265], this property being also dependent on the sulfate distribution pattern [68]. It seems, in addition, that the protein moiety of PSs may play some role on the antioxidative power. For example, Tannin-Spitz et al. [258] reported a stronger antioxidant activity for the crude PSs of Porphyridium than for the denatured PSs. Zhao et al. [266] found that the antioxidant activity of S-PSs was apparently related, not only to MW and sulfated ester content, but also to glucuronic acid and fructose content. This antioxidant activity seems to be attributable to metal chelating, free radical and hydroxyl radical scavenging activities of the S-PSs.

Toxicity of polysaccharides

The toxicity of polysaccharide is very crucial to the development of any product for the medical treatments. An animal experiment was conducted to evaluate the toxicity of polysaccharide and the results found that no toxicity was exhibited to the liver, kidney, heart, thymus or spleen of the mice which were fed with the polysaccharide conjugate and none of the mice died throughout the period of the experiment. There was no significant difference between the thymus index, spleen index and liver index of the mice from the test and control groups. It might be a candidate of dietary supplements besides the bioactivities as a polysaccharide [267- 293].

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