Recursos de Sanidad, Biomedicina y Salud

Noticias Externas del Thursday 08 de March de 2012

The New York Times
Some people may be thinking of second careers, while others hope to forestall the mental declines of age.
PLoS Pathogens

by Lucy J. Hathaway, Silvio D. Brugger, Brigitte Morand, Mathieu Bangert, Jeannine U. Rotzetter, Christoph Hauser, Werner A. Graber, Suzanna Gore, Aras Kadioglu, Kathrin Mühlemann

The polysaccharide capsule of Streptococcus pneumoniae defines over ninety serotypes, which differ in their carriage prevalence and invasiveness for poorly understood reasons. Recently, an inverse correlation between carriage prevalence and oligosaccharide structure of a given capsule has been described. Our previous work suggested a link between serotype and growth in vitro. Here we investigate whether capsule production interferes with growth in vitro and whether this predicts carriage prevalence in vivo. Eighty-one capsule switch mutants were constructed representing nine different serotypes, five of low (4, 7F, 14, 15, 18C) and four of high carriage prevalence (6B, 9V, 19F, 23F). Growth (length of lag phase, maximum optical density) of wildtype strains, nontypeable mutants and capsule switch mutants was studied in nutrient-restricted Lacks medium (MLM) and in rich undefined brain heart infusion broth supplemented with 5% foetal calf serum (BHI+FCS). In MLM growth phenotype depended on, and was transferred with, capsule operon type. Colonization efficiency of mouse nasopharynx also depended on, and was transferred with, capsule operon type. Capsule production interfered with growth, which correlated inversely with serotype-specific carriage prevalence. Serotypes with better growth and higher carriage prevalence produced thicker capsules (by electron microscopy, FITC-dextran exclusion assays and HPLC) than serotypes with delayed growth and low carriage prevalence. However, expression of cpsA, the first capsule gene, (by quantitative RT-PCR) correlated inversely with capsule thickness. Energy spent for capsule production (incorporation of H3-glucose) relative to amount of capsule produced was higher for serotypes with low carriage prevalence. Experiments in BHI+FCS showed overall better bacterial growth and more capsule production than growth in MLM and differences between serotypes were no longer apparent. Production of polysaccharide capsule in S. pneumoniae interferes with growth in nutrient-limiting conditions probably by competition for energy against the central metabolism. Serotype-specific nasopharyngeal carriage prevalence in vivo is predicted by the growth phenotype.

by MarCia T. Ekworomadu, Catherine B. Poor, Cedric P. Owens, Miriam A. Balderas, Marian Fabian, John S. Olson, Frank Murphy, Erol Balkabasi, Erin S. Honsa, Chuan He, Celia W. Goulding, Anthony W. Maresso

To replicate in mammalian hosts, bacterial pathogens must acquire iron. The majority of iron is coordinated to the protoporphyrin ring of heme, which is further bound to hemoglobin. Pathogenic bacteria utilize secreted hemophores to acquire heme from heme sources such as hemoglobin. Bacillus anthracis, the causative agent of anthrax disease, secretes two hemophores, IsdX1 and IsdX2, to acquire heme from host hemoglobin and enhance bacterial replication in iron-starved environments. Both proteins contain NEAr-iron Transporter (NEAT) domains, a conserved protein module that functions in heme acquisition in Gram-positive pathogens. Here, we report the structure of IsdX1, the first of a Gram-positive hemophore, with and without bound heme. Overall, IsdX1 forms an immunoglobin-like fold that contains, similar to other NEAT proteins, a 310-helix near the heme-binding site. Because the mechanistic function of this helix in NEAT proteins is not yet defined, we focused on the contribution of this region to hemophore and NEAT protein activity, both biochemically and biologically in cultured cells. Site-directed mutagenesis of amino acids in and adjacent to the helix identified residues important for heme and hemoglobin association, with some mutations affecting both properties and other mutations affecting only heme stabilization. IsdX1 with mutations that reduced the ability to associate with hemoglobin and bind heme failed to restore the growth of a hemophore-deficient strain of B. anthracis on hemoglobin as the sole iron source. These data indicate that not only is the 310-helix important for NEAT protein biology, but also that the processes of hemoglobin and heme binding can be both separate as well as coupled, the latter function being necessary for maximal heme-scavenging activity. These studies enhance our understanding of NEAT domain and hemophore function and set the stage for structure-based inhibitor design to block NEAT domain interaction with upstream ligands.

by Gleb Pishchany, Eric P. Skaar


by Kouyuki Hirayasu, Jun Ohashi, Koichi Kashiwase, Hathairad Hananantachai, Izumi Naka, Atsuko Ogawa, Minoko Takanashi, Masahiro Satake, Kazunori Nakajima, Peter Parham, Hisashi Arase, Katsushi Tokunaga, Jintana Patarapotikul, Toshio Yabe

Cerebral malaria is a major, life-threatening complication of Plasmodium falciparum malaria, and has very high mortality rate. In murine malaria models, natural killer (NK) cell responses have been shown to play a crucial role in the pathogenesis of cerebral malaria. To investigate the role of NK cells in the developmental process of human cerebral malaria, we conducted a case-control study examining genotypes for killer immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) class I ligands in 477 malaria patients. We found that the combination of KIR2DL3 and its cognate HLA-C1 ligand was significantly associated with the development of cerebral malaria when compared with non-cerebral malaria (odds ratio 3.14, 95% confidence interval 1.52–6.48, P = 0.00079, corrected P = 0.02). In contrast, no other KIR-HLA pairs showed a significant association with cerebral malaria, suggesting that the NK cell repertoire shaped by the KIR2DL3-HLA-C1 interaction shows certain functional responses that facilitate development of cerebral malaria. Furthermore, the frequency of the KIR2DL3-HLA-C1 combination was found to be significantly lower in malaria high-endemic populations. These results suggest that natural selection has reduced the frequency of the KIR2DL3-HLA-C1 combination in malaria high-endemic populations because of the propensity of interaction between KIR2DL3 and C1 to favor development of cerebral malaria. Our findings provide one possible explanation for KIR-HLA co-evolution driven by a microbial pathogen, and its effect on the global distribution of malaria, KIR and HLA.

by Anna Smed-Sörensen, Cécile Chalouni, Bithi Chatterjee, Lillian Cohn, Peter Blattmann, Norihiro Nakamura, Lélia Delamarre, Ira Mellman

Influenza A virus (IAV) infection is normally controlled by adaptive immune responses initiated by dendritic cells (DCs). We investigated the consequences of IAV infection of human primary DCs on their ability to function as antigen-presenting cells. IAV was internalized by both myeloid DCs (mDCs) and plasmacytoid DCs but only mDCs supported viral replication. Although infected mDCs efficiently presented endogenous IAV antigens on MHC class II, this was not the case for presentation on MHC class I. Indeed, cross-presentation by uninfected cells of minute amounts of endocytosed, exogenous IAV was ∼300-fold more efficient than presentation of IAV antigens synthesized by infected cells and resulted in a statistically significant increase in expansion of IAV-specific CD8 T cells. Furthermore, IAV infection also impaired cross-presentation of other exogenous antigens, indicating that IAV infection broadly attenuates presentation on MHC class I molecules. Our results suggest that cross-presentation by uninfected mDCs is a preferred mechanism of antigen-presentation for the activation and expansion of CD8 T cells during IAV infection.

by Annalisa Bianco, Veronica Reghellin, Lorena Donnici, Simone Fenu, Reinaldo Alvarez, Chiara Baruffa, Francesco Peri, Massimiliano Pagani, Sergio Abrignani, Petra Neddermann, Raffaele De Francesco

4-anilino quinazolines have been identified as inhibitors of HCV replication. The target of this class of compounds was proposed to be the viral protein NS5A, although unequivocal proof has never been presented. A 4-anilino quinazoline moiety is often found in kinase inhibitors, leading us to formulate the hypothesis that the anti-HCV activity displayed by these compounds might be due to inhibition of a cellular kinase. Type III phosphatidylinositol 4-kinase α (PI4KIIIα) has recently been identified as a host factor for HCV replication. We therefore evaluated AL-9, a compound prototypical of the 4-anilino quinazoline class, on selected phosphatidylinositol kinases. AL-9 inhibited purified PI4KIIIα and, to a lesser extent, PI4KIIIβ. In Huh7.5 cells, PI4KIIIα is responsible for the phosphatidylinositol-4 phosphate (PI4P) pool present in the plasma membrane. Accordingly, we observed a gradual decrease of PI4P in the plasma membrane upon incubation with AL-9, indicating that this agent inhibits PI4KIIIα also in living cells. Conversely, AL-9 did not affect the level of PI4P in the Golgi membrane, suggesting that the PI4KIIIβ isoform was not significantly inhibited under our experimental conditions. Incubation of cells expressing HCV proteins with AL-9 induced abnormally large clusters of NS5A, a phenomenon previously observed upon silencing PI4KIIIα by RNA interference. In light of our findings, we propose that the antiviral effect of 4-anilino quinazoline compounds is mediated by the inhibition of PI4KIIIα and the consequent depletion of PI4P required for the HCV membranous web. In addition, we noted that HCV has a profound effect on cellular PI4P distribution, causing significant enrichment of PI4P in the HCV-membranous web and a concomitant depletion of PI4P in the plasma membrane. This observation implies that HCV – by recruiting PI4KIIIα in the RNA replication complex – hijacks PI4P metabolism, ultimately resulting in a markedly altered subcellular distribution of the PI4KIIIα product.

by Xiaoyun Liu, Beile Gao, Veronica Novik, Jorge E. Galán

Campylobacter jejuni is the major cause of bacterial food-borne illness in the USA and Europe. An important virulence attribute of this bacterial pathogen is its ability to enter and survive within host cells. Here we show through a quantitative proteomic analysis that upon entry into host cells, C. jejuni undergoes a significant metabolic downshift. Furthermore, our results indicate that intracellular C. jejuni reprograms its respiration, favoring the respiration of fumarate. These results explain the poor ability of C. jejuni obtained from infected cells to grow under standard laboratory conditions and provide the bases for the development of novel anti microbial strategies that would target relevant metabolic pathways.

by Youngkyun Kim, Sanghyun Lee, Sungchul Kim, Donghyun Kim, Jin-Hyun Ahn, Kwangseog Ahn

The human cytomegalovirus (HCMV) clinical strain Toledo and the attenuated strain AD169 exhibit a striking difference in pathogenic potential and cell tropism. The virulent Toledo genome contains a 15-kb segment, which is present in all virulent strains but is absent from the AD169 genome. The pathogenic differences between the 2 strains are thought to be associated with this additional genome segment. Cytokines induced during viral infection play major roles in the regulation of the cellular interactions involving cells of the immune and inflammatory systems and consequently determine the pathogenic outcome of infection. The chemokine RANTES (Regulated on activation, normal T-cell expressed and secreted) attracts immune cells during inflammation and the immune response, indicating a role for RANTES in viral pathogenesis. Here, we show that RANTES was downregulated in human foreskin fibroblast (HFF) cells at a later stage after infection with the Toledo strain but not after infection with the AD169 strain. miR-UL148D, the only miRNA predicted from the UL/b' sequences of the Toledo genome, targeted the 3′-untranslated region of RANTES and induced degradation of RANTES mRNA during infection. While wild-type Toledo inhibited expression of RANTES in HFF cells, Toledo mutant virus in which miR-UL148D is specifically abrogated did not repress RANTES expression. Furthermore, miR-UL148D-mediated downregulation of RANTES was inhibited by treatment with a miR-UL148D-specific inhibitor designed to bind to the miR-UL148D sequence via an antisense mechanism, supporting the potential value of antisense agents as therapeutic tools directed against HCMV. Our findings identify a viral microRNA as a novel negative regulator of the chemokine RANTES and provide clues for understanding the pathogenesis of the clinical strains of HCMV.

by Matthew R. Henn, Christian L. Boutwell, Patrick Charlebois, Niall J. Lennon, Karen A. Power, Alexander R. Macalalad, Aaron M. Berlin, Christine M. Malboeuf, Elizabeth M. Ryan, Sante Gnerre, Michael C. Zody, Rachel L. Erlich, Lisa M. Green, Andrew Berical, Yaoyu Wang, Monica Casali, Hendrik Streeck, Allyson K. Bloom, Tim Dudek, Damien Tully, Ruchi Newman, Karen L. Axten, Adrianne D. Gladden, Laura Battis, Michael Kemper, Qiandong Zeng, Terrance P. Shea, Sharvari Gujja, Carmen Zedlack, Olivier Gasser, Christian Brander, Christoph Hess, Huldrych F. Günthard, Zabrina L. Brumme, Chanson J. Brumme, Suzane Bazner, Jenna Rychert, Jake P. Tinsley, Ken H. Mayer, Eric Rosenberg, Florencia Pereyra, Joshua Z. Levin, Sarah K. Young, Heiko Jessen, Marcus Altfeld, Bruce W. Birren, Bruce D. Walker, Todd M. Allen

Deep sequencing technologies have the potential to transform the study of highly variable viral pathogens by providing a rapid and cost-effective approach to sensitively characterize rapidly evolving viral quasispecies. Here, we report on a high-throughput whole HIV-1 genome deep sequencing platform that combines 454 pyrosequencing with novel assembly and variant detection algorithms. In one subject we combined these genetic data with detailed immunological analyses to comprehensively evaluate viral evolution and immune escape during the acute phase of HIV-1 infection. The majority of early, low frequency mutations represented viral adaptation to host CD8+ T cell responses, evidence of strong immune selection pressure occurring during the early decline from peak viremia. CD8+ T cell responses capable of recognizing these low frequency escape variants coincided with the selection and evolution of more effective secondary HLA-anchor escape mutations. Frequent, and in some cases rapid, reversion of transmitted mutations was also observed across the viral genome. When located within restricted CD8 epitopes these low frequency reverting mutations were sufficient to prime de novo responses to these epitopes, again illustrating the capacity of the immune response to recognize and respond to low frequency variants. More importantly, rapid viral escape from the most immunodominant CD8+ T cell responses coincided with plateauing of the initial viral load decline in this subject, suggestive of a potential link between maintenance of effective, dominant CD8 responses and the degree of early viremia reduction. We conclude that the early control of HIV-1 replication by immunodominant CD8+ T cell responses may be substantially influenced by rapid, low frequency viral adaptations not detected by conventional sequencing approaches, which warrants further investigation. These data support the critical need for vaccine-induced CD8+ T cell responses to target more highly constrained regions of the virus in order to ensure the maintenance of immunodominant CD8 responses and the sustained decline of early viremia.
The New York Times
African-American women may process azithromycin at the same rate in pregnancy that they do otherwise, but that women of other races tend to metabolize the drug more slowly.
An interview with Victor Fuchs, who has spent decades studying the economics of health care.
Because 25 to 30 percent of identical twins have separate placentas and amniotic sacs, they are sometimes misclassified as fraternal twins.
Doctors talk about science, but they also believe deeply in chance.
Partnering with an international nonprofit group, the Nigerian government plans to improve access to pain medications for cancer and AIDS patients.
Researchers recruited 965 people with stable coronary artery disease, tracking their statin use and depressive symptoms over six years.
“How people look is a very important part of their whole approach to the diagnosis of cancer and to the treatment of cancer,” one doctor said.
Veterans with post-traumatic stress disorder are more likely to be prescribed opioid pain killers than other veterans and more likely to use the opioids in risky ways, according to a new study.
Plenty of people forgo happy hour to fit in exercise, but with evening party workouts, gyms are making it so that clients don’t have to choose.
Dr. Robert Truog, a medical ethicist, talks about transparency between patients and doctors, the challenges to this ideal and the future of the patient-doctor relationship.
Dr. Eric R. Kandel, a Nobel Prize-winning neuroscientist who fled Vienna as a child after the Nazi invasion, delves into the mysteries of memory.
National Institutes of Health (NIH)
Notice NOT-OD-12-066 from the NIH Guide for Grants and Contracts
Notice NOT-OD-12-081 from the NIH Guide for Grants and Contracts
Notice NOT-ES-12-010 from the NIH Guide for Grants and Contracts
Notice NOT-ES-12-009 from the NIH Guide for Grants and Contracts
Notice NOT-ES-12-008 from the NIH Guide for Grants and Contracts
The New York Times
As the prognosis grows more bleak, a study finds, family members begin to misinterpret what doctors are trying to tell them.
Prices of drugs used widely by older adults showed an increase of 26 percent from 2005 to 2009, according to a new report issued by AARP.
Firms are racing to cut the cost of sequencing the human genome, which will yield new approaches for treating cancers and other serious diseases, biologists say.
Shark cartilage, hyped as a cancer preventive and joint-health supplement, may contain a neurotoxin that has been linked with Alzheimer's and Lou Gehrig's disease, a new study suggests.
The Wall Street Journal
Scientists are scrutinizing a new approach to preventing the spread of HIV that involves healthy people taking drugs to prevent them from being infected by a partner with the virus.
National Institutes of Health (NIH)
In recognition of World Kidney Day on March 8, the National Institutes of Health is promoting efforts to reduce disparities in organ transplantation. This is particularly important among African-Americans, Hispanics, and American Indians, all of whom are disproportionately affected by kidney failure — yet are less likely to receive organ transplants.
The New York Times
Prepared rice flour wrappers are a convenient vehicle for marinated tofu and crisp vegetables and herbs.
The Wall Street Journal
ATM operators have until March 15 to make the devices accessible to the visually impaired, but many machines are unlikely to be ready.
Eureka Alert!
(Johns Hopkins Medical Institutions) Johns Hopkins scientists have published laboratory data refuting studies that suggest blood vessels that form within brain cancers are largely made up of cancer cells. The theory of cancer-based blood vessels calls into question the use and value of anticancer drugs that target these blood vessels, including bevacizumab (Avastin).
(Oregon State University) Researchers have tapped into the extraordinary power of carbon "nanotubes" to increase the speed of biological sensors, a technology that might one day allow a doctor to routinely perform lab tests in minutes, speeding diagnosis and treatment while reducing costs. The new findings have almost tripled the speed of prototype nano-biosensors, and should find applications not only in medicine but in toxicology, environmental monitoring, new drug development and other fields.
(University of Illinois at Chicago) The hair cells of the inner ear have a previously unknown "root" extension that may allow them to communicate with nerve cells and the brain to regulate sensitivity to sound vibrations and head position, researchers at the University of Illinois at Chicago College of Medicine have discovered.
(International Vaccine Access Center) The scientific journal Clinical Infectious Diseases has released its March Special Supplement focusing entirely on the research design of and pilot data from the Pneumonia Etiology Research for Child Health Project, which seeks to identify the causes of pneumonia among the world's most vulnerable populations.
(Binghamton University) Nanoparticles are everywhere. From cosmetics and clothes, to soda and snacks. But as versatile as they are, nanoparticles also have a downside, say researchers at Binghamton University and Cornell University in a recent paper published in the journal Nature Nanotechnology. These tiny particles, even in low doses, could have a big impact on our long-term health.
(Juvenile Diabetes Research Foundation International) A new JDRF-funded study shows that many of the genes known to play a role in Type 1 diabetes (T1D) are expressed in pancreatic beta cells, suggesting that the cell responsible for producing insulin may be playing a part in its own destruction to lead to T1D. Published in the March issue of PLoS Genetics, researchers in Belgium suggest this interpretation after producing an extensive catalog of more than 15,000 genes expressed in human islets.
(Emory University) Scientists have discovered that blocking PD-1, an immune molecule that inhibits the immune response to viral infections, can have a significant effect on HIV-like illness in non-human primates.
The Wall Street Journal
A year after Florida stepped up its battle against pill mills, the state can point to some notable successes. But the problem hasn't gone away and pharmacists now find themselves on the front line.
A tumor's genetic makeup can vary significantly even within the same sample, a discovery that underscores challenges to the personalized-medicine movement in cancer.
The Food and Drug Administration is considering making a wider range of drugs available over-the-counter instead of by prescription as it tries to expand access to medications.
Un equipo internacional de investigadores ha descubierto una forma más efectiva de obtener imágenes de proteínas, un paso más hacia la filmación de vídeos sobre su funcionamiento a nivel molecular. El equipo, compuesto por científicos de Alemania, Suecia y Estados Unidos, se basó en trabajos anteriores dirigidos por uno de los autores, el profesor Richard Neutze de la Universidad de Gotemburgo, uno de los primeros investigadores del mundo en obtener imágenes de proteínas mediante pulsos de rayos X muy cortos e intensos. Cuanto mayor sea la capacidad de los científicos para dilucidar la estructura de las proteínas y su comportamiento en el interior de las células, más se acercarán a la cura de enfermedades notorias como el cáncer y la malaria. Quality validation date: 2012-03-08
Las interacciones entre los niños y su entorno están limitadas por sus capacidades motoras, lo que dificulta la investigación de los procesos de cognición a estas edades. ¿Cómo es posible distinguir qué reacción sensorial es fruto de la acción motora del niño? Investigadores del Instituto de Estudios Avanzados de Fráncfort del Meno y de la Universidad Goethe de la misma ciudad (Alemania) podrían haber dado con una solución. Su estudio recibió fondos del proyecto IM-CLEVER («Robots versátiles de aprendizaje acumulativo motivados de forma intrínseca»), financiado mediante el área temática «Tecnologías de la información y la comunicación (TIC)» del Séptimo Programa Marco (7PM) de la UE por valor de 5,9 millones de euros. Quality validation date: 2012-03-08
Las mujeres de todo el mundo, sin importar su raza, edad, nacionalidad, profesión o nivel educativo, celebraron el 8 de marzo el 101° Día Internacional de la Mujer. Pese a los avances logrados con el paso de los años, las mujeres siguen luchando contra innumerables cuestiones que afectan a sus vidas de forma cotidiana. Es una carrera contra la desigualdad que no debe pasarse por alto. Quality validation date: 2012-03-08
The Wall Street Journal
Novartis recently made an approach to buy Pfizer's animal-health business. The preliminary offer, valued at as much as $16 billion, was rebuffed as too low.
Prudential Financial joined a growing roster of big insurers to cut back on sales of long-term-care insurance.