quinta-feira, 31 de março de 2011

Apresentação antigênica "indireta"


Cross-dressers turn on T cells

Jonathan W. Yewdell & Brian P. Dolan
AffiliationsCorresponding author
Nature 471, 581–582 (31 March 2011) doi:10.1038/471581a
Published online 30 March 2011
Memory T cells remember viruses from previous infections, providing immunity by facilitating the killing of infected cells. For this, they exploit cross-dressing, the transfer of antigens between antigen-presenting cells. See Letterp.629
As their name suggests, antigen-presenting cells flag up the presence of foreign molecules (antigens) to killer T cells of the immune system, triggering the appropriate immune response. The cells generally acquire antigens in one of two ways: by direct presentation, in which the cell itself is infected with the antigen it presents; and by cross-presentation, in which the presenting cell engulfs components of an infected cell and then processes and presents the associated antigen. A third mechanism — cross-dressing — has also been postulated1, 2, 3, in which an antigen-presenting cell acquires the requisite processed antigen directly from another infected antigen-presenting cell. On page 629 of this issue, Wakim and Bevan4 report the strongest evidence yet for the relevance of cross-dressing, showing in mice that this process is required for an effective antiviral response.

Humans possess some 100 billion versions of killer (cytotoxic) T cells, each of which carries a T-cell receptor on its cell membrane that recognizes a specific set of antigens. Antigenic peptides of 8–10 residues are presented to T cells as complexes with MHC class I molecules of the immune system. Unnecessary T-cell responses can gravely damage the host by triggering autoimmune effects, so safeguards are in place to prevent this. The most important safeguard is that naive T cells — those that have not previously been exposed to an antigen — must initially be activated by dendritic cells, a type of antigen-presenting cell. Dendritic cells are present in immune tissues such as the spleen and lymph nodes, and sample the blood and lymphatic system respectively for antigens. They are derived from the bone marrow and specialize in presenting viral and tumour antigens to T cells.

Once activated, T cells replicate at an astonishing speed (a 4–6-hour division time), leading to a 10,000-fold increase in effector-cell numbers within a few days. The effector cells live for weeks, but a subset called memory cells, which constitute only 1% of the cytotoxic T cells in the body, can live for decades. Having run the gauntlet of the activation safeguards as naive cells, memory cells' safeguards for preventing autoimmunity are relaxed, so they can respond more rapidly to an infection. Wakim and Bevan4 report that memory T cells can be activated through cross-dressing.

If viruses infect dendritic cells, the direct presentation of processed viral proteins can efficiently activate T cells (Fig. 1a). Many viruses, however, infect only one or a few cell types. They could therefore potentially avoid recognition by not infecting dendritic cells. To prevent this — and to be able to present tumour antigens — dendritic cells use cross-presentation, whereby they acquire antigens from extracellular fluids through the process of endocytosis, or from infected cells either by engulfing them or by the diffusion of antigenic peptides through 'gap junctions' formed between the cells (Fig. 1b). Cross-presentation seems to be essential for cytotoxic T-cell responses to many viruses5.

Figure 1: Pathways to antigen presentation.

a, Direct presentation occurs when an antigen-presenting cell such as a dendritic cell is infected, and displays processed antigenic peptides in complex with MHC class I molecules on its surface, thereby activating T cells. b, In cross-presentation, dendritic cells acquire antigens obtained by infected cells through endocytosis and phagocytosis, and — with or without some processing — load them onto class I molecules for presentation to T cells. c, In a third pathway, called cross-dressing, dendritic cells acquire preformed MHC class I molecules in complex with antigens from other cells by the process of trogocytosis or through gap junctions. Wakim and Bevan4 show that cross-dressing is used to activate memory T cells, but not naive T cells, in response to viral infection.

Full size image (103 KB)
Cross-presentation can also occur by a process called trogocytosis — the transfer of cell-membrane patches or individual proteins between cells6, 7 (Fig. 1c). This allows antigen presentation by acceptor dendritic cells to occur immediately, without any processing. Such cross-dressing has been demonstrated in proof-of-principle experiments2, 3, and Wakim and Bevan confirm that dendritic cells in culture transfer MHC class I–antigen peptide complexes by trogocytosis. Nonetheless, convincingly extending such findings to situations more like those encountered in vivo has remained notoriously difficult. Wakim and Bevan elegantly do just that using chimaeric mice that had received transplanted bone marrow.

To generate the chimaeric animals, the authors used γ-irradiation to destroy short-lived bone-marrow-derived cells — including the resident dendritic cells of the spleen and lymph nodes — in normal mice. They then transferred bone-marrow-derived stem cells to these animals from a variety of genetically manipulated mice. In this way, they could distinguish dendritic cells that generate MHC class I–peptide complexes from dendritic cells presenting the class I–peptide complexes to T cells. This revealed that cross-dressed dendritic cells (cells that had acquired the complexes) have a crucial role in activating memory, but not naive, T cells.

How can this selectivity be explained? One possibility is that memory T cells specifically interact with a subset of dendritic cells that are specialized for cross-dressing-based activation. Although Wakim and Bevan show that, in frozen sections of chimaeric spleens, memory and naive cells have a similar anatomical distribution, imaging the tissues of living animals might reveal differences in T-cell localization or behaviour relating to their immunological experience. However, the authors favour another explanation, which indeed seems more likely: that naive T cells, with their high activation threshold, disfavour cross-dressing, which involves the presentation of vanishingly small numbers of MHC class I–antigen complexes.

Whatever the explanation, it will be essential to characterize cross-dressed dendritic cells in more detail, particularly because they belong to a subset of immune cells (CD8−) that are less adept at many types of cross-presentation than their cytotoxic (CD8+) counterparts. What's more, cross-dressing may prove particularly important in cancer immunology, because the killing of infiltrating cross-presenting immune cells by T cells may be crucial for tumour eradication8.

Although these elegant experiments highlight the biological relevance of cross-dressing, it is likely that, under many circumstances, the standard direct-presentation and cross-presentation pathways are more prevalent. Nevertheless, Wakim and Bevan4 raise a noteworthy, yet largely neglected, issue: how the activation of memory and naive T cells differs for immune responses ranging from those to acute (sporadic) pathogens such as influenza virus and rotavirus, to persistent pathogens including HIV and hepatitis B and C viruses, and to tumours, where the rules are likely to differ altogether. More generally, their findings illustrate the astounding ability of the immune system to use minimal packets of information to control pathogens that seek to exploit the slightest chinks in our immune armour.

quarta-feira, 30 de março de 2011

Colaboração entre pesquisadores é importante para aumento da produção científica


O número de colaboradores por trabalho publicado pelo Brasil parece estar diminuindo. Aparentemente essa estratégia é ruim se compararmos que todos os demais países aumentam os numero de publicações quanto mais cooperam com pesquisadores de outros países



Research sans frontières

Academy report finds that international collaboration is on the rise, and should not be seen as an 'easy target' for cuts.
Scientists used to interact with colleagues based abroad mainly at conferences. These days they are increasingly meeting at the lab bench, says a report by the Royal Society, Britain's national academy of science. More than 35% of all articles published in international journals are now the product of such collaboration, an increase of 10% in 15 years, says the study, Knowledge, Networks and Nations: Global Scientific Collaboration in the 21st Century.
Collaboration can boost citation impact, spread costs and broaden research horizons. It has, for example, enabled researchers at the International Rice Research Institute in Los Baños, the Philippines, to tackle scientific questions on a scale once thought impossible, says Robert Zeigler, director-general of the institute, which is part of the developing world's network of agricultural research centres — known as the Consultative Group on International Agricultural Research (CGIAR).
The CGIAR used to be "physically isolated from the advanced research institutes" in developed countries, says Zeigler. Today, the centres have partnerships with world-leading labs in Europe and the United States, working on challenging projects such as re-engineering photosynthesis in rice to be more efficient. "This would have been unheard of a decade ago," says Zeigler.



Click for larger image

The Royal Society's study, published on 28 March, finds that collaboration involving US scientists has grown the most during the past 15 years. The number of papers published with lead authors based in the United States and collaborators abroad has risen from about 50,000 in 1996 to around 95,000 in 2008. But the new total represents just 29% of the US research output. By contrast, almost half of all Germany's research output in 2008 involved international collaborations (see 'A world of collaboration').
The numbers are not rising across the board, however. Although in China collaboration is increasing overall, it is "not keeping pace with the even more dramatic rise in its overall publication productivity", according to the report. As a proportion of China's annual national output, papers based on international collaboration fell from around 18% in 1996 to 15% in 2008. Other nations whose science base is growing rapidly, such as Brazil, show similar trends.
Each collaborating country increases a paper's impact, up to a tipping point of about ten countries, the report says. In some cases, the effect can be dramatic. Compared with papers by authors in Mexico alone, those with authors in both Mexico and Germany had three times the impact. And for authors in Russia, collaboration with researchers in Canada boosted impact by a factor of almost five.
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For the traditional science powers, collaborating with up-and-coming countries such as China and Brazil is not just about increasing research impact, says Jonathan Adams, director of research-performance analysts Evidence, part of Thomson Reuters, in Leeds. "It's about keeping in touch with what they are doing," he says.
The report notes that "the scientific superpowers of the 20th century remain strong". But it warns these governments against viewing multinational research efforts as "easy targets" for spending cuts during tight fiscal times. Doing so, it says, could isolate national science activities, threatening quality and impact. 

segunda-feira, 28 de março de 2011

resultados negativos em pesquisa são publicáveis?



Negative results are published

BOB O'HARA
Jonathan Schooler argues in favour of an open-access database of negative results ( Nature 470, 437; 2011). But publishing such results in scientific journals is advantageous for authors, who can then list them among their papers.


Several journals specifically publish negative results. I'm aware of the Journal of Negative Results in Biomedicine, the Journal of Negative Results — Ecology and Evolutionary Biology and the psychology Journal of Articles in Support of the Null Hypothesis. There is a forum in the Journal of Universal Computer Sciences for negative results, and PLoS ONE also publishes them. Several other such journals have come and gone; all, I think, are open access.

Even so, negative findings are still a low priority for publication, so we need to find ways to make publishing them more attractive.

domingo, 27 de março de 2011

A história dos experimentos que deram pistas sobre a origem da vida

Antesdepois

Por milhões de anos a terra não teve vida. A pergunta sobre como surgiu a vida na terra foi e ainda é a pergunta que mais intriga os cientistas e a humanidade. Há 50 anos e com experimentos simples esse mistério começou a ser desvendado. Veja a reportagem da Folha sobre essa descoberta

Experiência de 50 anos dá pista sobre origem da vida 

Novo estudo resgatou dados de amostras obtidas por bioquímico em 1958

Pesquisa americana analisou resquícios com técnica mais sensível; moléculas orgânicas teriam vindo de vulcões

RICARDO BONALUME NETO
DE SÃO PAULO

Um experimento clássico, com meio século de idade, voltou a trazer pistas sobre a mais antiga das questões: como surgiu a vida?

O bioquímico Stanley Miller (1930-2007) fez sua primeira simulação da atmosfera primitiva da Terra em 1952. Dois frascos redondos conectados faziam o papel do oceano e da atmosfera, com vapor d'água e gases como metano e hidrogênio; faíscas elétricas faziam as vezes de raios.
"A água no frasco se tornou perceptivelmente rosa depois do primeiro dia. No final da semana, a solução estava profundamente vermelha e turva", relatou Miller em artigo na revista "Science" em 15 de maio de 1953. "A cor vermelha é devida a compostos orgânicos."

Ele tinha produzido aminoácidos, os "tijolos" bioquímicos com os quais são construídas as proteínas.
Guardada em uma coleção de material deixado por Miller estava uma amostra de outro experimento do gênero, feito em 1958, mas misteriosamente não relatado por ele. Um grupo de pesquisadores decidiu analisar a amostra usando técnicas modernas de identificação de compostos químicos.
O experimento de 1958 diferia na composição da "atmosfera"; saía o hidrogênio, entrava o gás sulfídrico.
A equipe, liderada por Jeffrey Bada, da Universidade da Califórnia em San Diego, poderia ter replicado o experimento; mas, como escreveram em artigo na revista científica "PNAS", "a oportunidade única de investigar amostras preparadas pelo pioneiro" era irresistível.
O resultado foi surpreendente. Usando técnicas analíticas mil vezes mais precisas que as de Miller, foram achados 23 aminoácidos diferentes, incluindo a primeira síntese dessas substâncias com enxofre em experimentos do gênero.
"O cenário atual é que compostos simples, feitos por processos como nós descrevemos no artigo, acumularam-se em diversas áreas da Terra primitiva. Em seguida, passaram por processos químicos adicionais, produzindo moléculas cada vez mais complexas", diz Bada.
"A partir da crescente complexidade, uma molécula que poderia catalisar sua própria multiplicação apareceu. E isso teria marcado tanto a origem da vida como o início dos processos evolutivos que deram origem ao moderno mundo de DNA e proteínas", explicou ele à Folha.
Os adeptos da "sopa primordial", como Bada, especulam que, depois dessa fase inicial de autorreplicação, a vida tinha como base o "primo" do DNA, o RNA, mais versátil quimicamente.
Hoje, os cientistas acreditam que a atmosfera primitiva não era como Miller a simulou. Mas Bada diz que condições semelhantes poderiam ter existido em escala local, especialmente vinculadas a emissões de gases por vulcões. E os novos resultados obtidos ao analisar o experimento de 1958 dariam apoio a essa hipótese. Relâmpagos, gases e atividade vulcânica interagiriam para produzir os "tijolos" da vida.

sábado, 26 de março de 2011

Os gastos em F35 versus gastos com mosquiteiros para prevenir malária



Leia aqui a critica feita no The Economist contra as políticas que gastam mais em intervenções militares, como está ocorrendo na Líbia, do que na prevenção primária (como mosquiteiros) que são eficientes contra malária.

A distribuição gratuita em massa de mosquiteiros provou ser incrivelmente poderoso. Com base na experiência e os principais conceitos de saúde pública, política global oficial aprovou a distribuição gratuita de MILD anti-malária como a política mundial .

Evidência mostrou há muito que nas África rurais pobres são tão pobres que muitos são incapazes de pagar ainda uma pequena quantidade de salva-vidas intervenções de saúde, mesmo quando os custos são subsidiados. Não surpreendentemente, as tentativas de vender RILDs subsidiada durante os anos 2000-2005 caiu mal, mesmo com preços tão baixos quantoUS $ 2 a US $ 3 por rede .

A Organização Mundial da Saúde aprovou a distribuiçãode massa como o seu padrão básico em 2007. No plano de Ação Global contra malária, a parceria internacional conhecida como Roll Back Malaria definir uma meta de distribuir cerca de 300 milhões RILDs na África através da distribuição de massa durante 2008-2010, a fim de cobrir todos os sites dormindo em regiões de transmissão da malária . como resultado da distribuição em massa, a cobertura com insecticida de longa, duração mosquiteiros saltou de talvez 10 milhões em 2004 e 170.000.000 redes a partir do final de 2008.


Anti-malaria bed nets v F-35s

Mar 25th 2011, 16:41 by M.S.

WHEN you argue for humanitarian military intervention, my colleaguerightly says, you should be able to show how your military intervention serves humanitarian goals. In the case of the decision to intervene in Libya, though, I think this low bar is pretty easy to clear. When you have a column of armoured forces loyal to a ruthless dictator advancing on a city full of weakly-armed rebels (initially non-violent protestors who took up arms in self-defence) upon whom he has openly promised to wreak bloody vengeance, you pretty much have the paradigmatic case for military intervention. We know how that picture ends; in Srebrenica in 1992 it ended with the bodies of 7,000 able-bodied males in unmarked graves, in Hama in 1982 it ended with 20,000 civilian dead in flattened apartment blocks, in Basra in 1991 it ended in mass graves and in the dungeons of Abu Ghraib, and so forth. It's true, as my colleague says, that people are clumsy with counterfactual scenarios, and have a patriotic wish to see their state as a force for good. But I don't think that these are the main reasons why we think things would have been worse if we hadn't intervened in Libya. At least for that initial intervention, I think you'd have to make some heroically naive assumptions to believe that things wouldn't have been worse once Mr Qaddafi retook Benghazi.
My colleague's chief concern, however, is why we seem to be so often faced with calls for military humanitarian interventions, rather than peaceful ones.
If our foreign policy aims to prevent suffering and death with finite resources, it makes sense to ask whether this war makes sense on those grounds. I grasp the tiresome point that the choice on the table was not a choice between taking out Libya's air defences and buying bed nets. The choice was between taking out Libya's air defences or not. But the question nagging some of us is why this was the choice on the table. Why did this come up as a matter requiring urgent attention and immediate decision? Why is it that the choice to express our humanitarian benevolence through the use of missiles and jets gets on the table—to the top of the agenda, even—again and again, but the choice to express it less truculently so rarely does? If our humanitarian values really set the agenda, how likely is it that the prospect of urgent military intervention would come up so often?
Let me answer this in a roundabout way. First of all, I don't share my colleague's sense that it's tiresome to insist that the choice in Libya was not between bombing Muammar Qaddafi's tanks or providing more anti-malarial bed nets in Malawi, but between bombing Muammar Qaddafi's tanks or not bombing them. At the least, I think there is a standoff in tiresomeness between making this point, and making the familiar anti-malarial bed-net argument to which it responds.
In fact, the existence of high returns to investment on anti-malarial health campaigns in the developing world has become something of a catch-all argument against any other form of government intervention in recent years; most notably, it figures prominently in Bjorn Lomborg's arguments against spending on reducing carbon emissions. And yet somehow we don't seem to be increasing the amount we spend to fight malaria, even as we are increasingly regaled with arguments that spending on things besides fighting malaria is foolish and wasteful, because we could save so many more lives by spending more on fighting malaria. Indeed, the 2011 budget submitted by the House slashes the State Department's budget for aid to fight malaria (and AIDS, and tuberculosis) in the developing world by billions of dollars, while leaving the budget for bombing Libya (and everything else the Defence Department does) untouched.
Congress is slashing foreign aid to fight malaria in large part because the one category of government spending that the American public actually wants to slash, by a wide margin, is foreign aid. Meanwhile, the public opposes cuts to the defence budget (though they oppose cuts to education, Medicare and domestic anti-poverty programmes even more). So the fact that the political sphere is debating whether or not to bomb Muammar Qaddafi's tanks, rather than whether or not to raise spending on anti-malarial bed nets in Malawi, isn't really that surprising. But why does the public want to cut foreign aid, rather than defence? One reason is that for the past decade and more, both serious development experts like William Easterly and unserious politicians, mainly on the right, have been strenuously arguing that most foreign aid doesn't work. In fact, in Mr Easterly's case, one of the things he argued didn't work (in his excellent book " The White Man's Burden") was centrally planned efforts to distribute anti-malarial bed nets. He thought this was one of those things that would work better with a market solution: we should subsidise at most $8 of the cost of each $10 bed net, but let the rest of the distribution work itself out via market mechanisms.
Again, it's not surprising that the public doesn't want to spend more on foreign aid for anti-malarial bed nets, when people keep telling them such aid doesn't work. What makes the situation more piquante is that, as Jeffrey Sachs argued in a 2009 article inScientific American, in the specific case of bed nets, the claim appears to be completely wrong. The reason anti-malarial bed nets hadn't been much of a success in Africa before 2005 or so was that donors and executing agencies hadn't spent enough money buying them, and hadn't yet figured out how to distribute them. With subsequent experience,
the case for mass free distribution of bed nets has proved to be stunningly powerful. On the basis of experience and key public health concepts, official global policy has now adopted mass free distribution of anti-malaria LLINs as the global policy... Evidence has long shown that Africa’s rural poor are so destitute that many are unable to pay even a tiny amount for lifesaving health interventions, even when the costs are subsidized. Not surprisingly, attempts to sell them subsidized LLINs during the years 2000 to 2005 fell badly short, even at prices as low as $2 to $3 per net... The World Health Organization adopted mass distribution as its basic standard in 2007. In a Global Malaria Action Plan, the international partnership on malaria control known as Roll Back Malaria set a goal to distribute around 300 million LLINs in Africa through free mass distribution during 2008-2010, in order to cover all sleeping sites in malaria-transmission regions. Already, as the result of mass distribution, the coverage with long-lasting insecticide treated bed nets has jumped from perhaps 10 million in 2004 to 170 million nets as of the end of 2008.
Recently the Poverty Action Lab at the Massachusetts Institute of Technology carried out a detailed experiment in Western Kenya that compared mass distribution with a partial-subsidy approach. The results: even a small charge for bed nets led to a tremendous drop in their adoption. Moreover, there was no greater wastage of the nets received for free than for the nets that were purchased at the discount price. The conclusion of the M.I.T. study was clear: “Free distribution is both more effective and more cost-effective than cost-sharing.”
Mr Easterly and Mr Sachs have a long-running and intense debate on this and other development issues. I usually agree with Mr Easterly more than Mr Sachs, but in the specific case of bed nets he's had to retreat; more recently he's been sensibly pointing out that even if free distribution works better, you have to figure out a reliable way of identifying organisations that will actually do the distribution for free (rather than selling them illicitly, failing to distribute, etc), and there's no obvious scalable way to do that. But this only raises a further problem for the "bomb Libya or fight malaria" paradigm: how can you even ask the question if spending more on anti-malaria campaigns may not have any effect, since it's about the quality of the agencies, not the amount of funding? If there's no fungible way to shift effort from bombing Libya to fighting malaria, how can there even be a trade-off here?
Still, let's stipulate that shifting spending from the government bombardment of Libya to government anti-malaria efforts in the developing world would work. Certainly, few public-health experts would dispute that many health problems can be most efficiently addressed by having the government undertake preventive measures and distribute them for free. But here's the thing: you will hear approximately no voices on the right-hand side of the political aisle making this case in the United States today. The strategic direction of conservative political thought over the past 30 to 50 years has been to minimise the consensus on the extent of public goods: to argue that there are almost no areas of the economy or society in which government has a constructive role to play, except for national defence, and a few other areas such as law enforcement.Certainly not health.
I would suggest that if we're wondering why the American public devotes so much of its political attention to wars, and so little to anti-malarial bed nets, we might want to consider the role played by consistent efforts over the past 30 years to convince the public that government has almost no legitimate or positive role to play in society apart from a few narrow categories, including law enforcement and national defence, and not including health care. People who believe that virtually all social and economic endeavours, apart from defence and law enforcement, are best addressed by leaving them up to market forces and private industry will not naturally see much else for political discussion to focus on apart from military activity and law enforcement. To put it another way: if we don't think peaceful humanitarian interventions (like anti-malaria campaigns in Malawi) work, then, yes, military humanitarian interventions (like bombing Libya) are the best possible use of American resources towards humanitarian ends. If we do think government humanitarian programmes like anti-malaria campaigns in Malawi work, then I would expect to see a rather different attitude towards foreign aid and public health-care spending than I have seen in American politics these last few years.
To put things in one last way: it simply isn't true that we aren't faced with calls for peaceful humanitarian interventions as often as we are faced with calls for military ones. We are faced with calls for peaceful humanitarian interventions all the time. People are asking for more money for USAID. People are asking for more money for UN peacekeepers. People are asking for more money for the United States Institute for Peace. They're asking for more money for the Global Fund to Fight AIDS, Tuberculosis and Malaria. If you want America, collectively, to be doing more of this sort of thing and less of the bombing sort of thing, then what you need to do is to argue that those sorts of activities are central missions of the United States government, because the most powerful political forces in America over the past couple of decades have been arguing that they aren't, and that's why we're not doing more of them.