Functional deficits induced by cortical microinfarcts

published_or_final_versio

Theoretical analysis of the mechanisms of a gender differentiation in the propensity for orthostatic intolerance after spaceflight

<p>Abstract</p> <p>Background</p> <p>A tendency to develop reentry orthostasis after a prolonged exposure to microgravity is a common problem among astronauts. The problem is 5 times more prevalent in female astronauts as compared to their male counterparts. The mechanisms responsible for this gender differentiation are poorly understood despite many detailed and complex investigations directed toward an analysis of the physiologic control systems involved.</p> <p>Methods</p> <p>In this study, a series of computer simulation studies using a mathematical model of cardiovascular functioning were performed to examine the proposed hypothesis that this phenomenon could be explained by basic physical forces acting through the simple common anatomic differences between men and women. In the computer simulations, the circulatory components and hydrostatic gradients of the model were allowed to adapt to the physical constraints of microgravity. After a simulated period of one month, the model was returned to the conditions of earth's gravity and the standard postflight tilt test protocol was performed while the model output depicting the typical vital signs was monitored.</p> <p>Conclusions</p> <p>The analysis demonstrated that a 15% lowering of the longitudinal center of gravity in the anatomic structure of the model was all that was necessary to prevent the physiologic compensatory mechanisms from overcoming the propensity for reentry orthostasis leading to syncope.</p

Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies

Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine. In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin. The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT. Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated haemoglobin degradation. Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes.This work was funded in part by the National Institutes of Health (R01 AI50234, AI124678 and AI109023) and a Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Diseases award to D.A.F. This research also received funding from the Portuguese Fundacao para a Ciencia e Tecnologia (FCT), cofunded by Programa Operacional Regional do Norte (ON.2-O Novo Norte); from the Quadro de Referencia Estrategico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and from the Projeto Estrategico - LA 26 - 2013-2014 (PEst-C/SAU/LA0026/2013). M.I.V. is the recipient of a postdoctoral fellowship from FCT/Ministerio da Ciencia e Ensino Superior, Portugal-MCES (SFRH/BPD/76614/2011). A.M.L. was supported by an Australian National Health and Medical Research Council (NHMRC) Overseas Biomedical Fellowship (585519). R.E.M. was supported by an NHMRC RD Wright Biomedical Fellowship (1053082). A.C.U. was supported by an Irving scholarship from Columbia University. We thank Dr Andrea Ecker for her help with plasmid design and Pedro Ferreira for his expert help with Fig. 6.info:eu-repo/semantics/publishedVersio

International evidence-based medicine survey of the veterinary profession: information sources used by veterinarians

Veterinarians are encouraged to use evidence to inform their practice, but it is unknown what resources (e.g. journals, electronic sources) are accessed by them globally. Understanding the key places veterinarians seek information can inform where new clinically relevant evidence should most effectively be placed. An international survey was conducted to gain understanding of how veterinary information is accessed by veterinarians worldwide. There were 2137 useable responses to the questionnaire from veterinarians in 78 countries. The majority of respondents (n = 1835/2137, 85.9%) undertook clinical work and worked in a high income country (n = 1576/1762, 89.4%). Respondents heard about the survey via national veterinary organisations or regulatory bodies (31.5%), online veterinary forums and websites (22.7%), regional, discipline-based or international veterinary organisations (22.7%) or by direct invitation from the researchers or via friends, colleagues or social media (7.6%). Clinicians and non-clinicians reportedly used journals most commonly (65.8%, n = 1207/1835; 75.6%, n = 216/286) followed by electronic resources (58.7%, n = 1077/1835; 55.9%, n = 160/286), respectively. Respondents listed a total of 518 journals and 567 electronic sources that they read. Differences in veterinarian preference for resources in developed, and developing countries, were found. The nominated journals most read were the Journal of the American Veterinary Medical Association (12.7% of nominations) for clinicians and the Veterinary Record (5.7%) for non-clinicians. The most accessed electronic resource reported was the Veterinary Information Network (25.6%) for clinicians and PubMed (7.4%) for non-clinicians. In conclusion, a wide array of journals and electronic resources appear to be accessed by veterinarians worldwide. Veterinary organisations appear to play an important role in global communication and outreach to veterinarians and consideration should be given to how these channels could be best utilised for effective dissemination of key research findings

Study of CP violation in Dalitz-plot analyses of B0 --> K+K-KS, B+ --> K+K-K+, and B+ --> KSKSK+

We perform amplitude analyses of the decays $B^0 \to K^+K^-K^0_S$, $B^+ \rightarrow K^+K^-K^+$, and $B^+ \to K^0_S K^0_S K^+$, and measure CP-violating parameters and partial branching fractions. The results are based on a data sample of approximately $470\times 10^6$ $B\bar{B}$ decays, collected with the BABAR detector at the PEP-II asymmetric-energy $B$ factory at the SLAC National Accelerator Laboratory. For $B^+ \to K^+K^-K^+$, we find a direct CP asymmetry in $B^+ \to \phi(1020)K^+$ of $A_{CP}= (12.8\pm 4.4 \pm 1.3)$, which differs from zero by $2.8 \sigma$. For $B^0 \to K^+K^-K^0_S$, we measure the CP-violating phase $\beta_{\rm eff} (\phi(1020)K^0_S) = (21\pm 6 \pm 2)^\circ$. For $B^+ \to K^0_S K^0_S K^+$, we measure an overall direct CP asymmetry of $A_{CP} = (4 ^{+4}_{-5} \pm 2)$. We also perform an angular-moment analysis of the three channels, and determine that the $f_X(1500)$ state can be described well by the sum of the resonances $f_0(1500)$, $f_2^{\prime}(1525)$, and $f_0(1710)$.Comment: 35 pages, 68 postscript figures. v3 - minor modifications to agree with published versio

Search for rare quark-annihilation decays, B --> Ds(*) Phi

We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context of the Standard Model, these decays are expected to be highly suppressed since they proceed through annihilation of the b and u-bar quarks in the B- meson. Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected with the BABAR detector at SLAC. We find no evidence for these decays, and we set Bayesian 90% confidence level upper limits on the branching fractions BF(B- --> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid Communications

The clinical and functional significance of c-Met in breast cancer: a review

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.CMH-Y is funded by a Cancer Research UK Clinical Research Fellowship. JLJ is funded by the Breast Cancer Campaign Tissue Bank

The Concise Guide to PHARMACOLOGY 2015/16:Ligand-gated ion channels

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13349/full. Ligand-gated ion channels are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates

The Concise Guide to PHARMACOLOGY 2015/16:Nuclear hormone receptors

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13352/full. Nuclear hormone receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates

The Concise Guide to PHARMACOLOGY 2015/16:Enzymes

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13354/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates