Miracle-dz/UniFAR-FTUs huggingface dataset:
Cytokine Imbalance after Measles Virus Infection Has No Correlation with Immune Suppression

ABSTRACT Measles virus infection leads to immune suppression. A potential mechanism is the reduction of interleukin 12 (IL-12) secretion during acute measles, resulting in a TH2 response. Studies in humans have reported conflicting results, detecting either a TH2 or a TH1 response. We have investigated the correlation between a TH2 response and immune suppression in specific-pathogen-free inbred cotton rats which were infected with measles vaccine and wild-type viruses. After infection of bone marrow-derived macrophages with wild-type virus, IL-12 secretion was reduced in contrast to the level for vaccine virus infection. In bronchoalveolar lavage cells, IL-12 secretion was suppressed after infection with both wild-type and vaccine virus on days 2, 4, and 6 and was detectable on days 8 and 10. After stimulation of mediastinal lymph node and spleen cells with UV-inactivated measles virus at various time points after infection, gamma interferon but no IL-4 was found. After stimulation with phorbol myristate acetate-ionomycin, high gamma interferon and low IL-4 levels were detected. To investigate whether the secretion of IL-4 contributes to immune suppression, a recombinant vaccine virus was created which secretes cotton rat IL-4. After infection with this recombinant virus, IL-4 secretion was enhanced. However, neither inhibition of concanavalin A-stimulated spleen cells nor keyhole limpet hemocyanin-specific proliferation of spleen cells was altered after infection with the recombinant virus in comparison to the levels with the parental virus. Our data indicate that measles virus infection leads to a decrease in IL-12 secretion and an increase in IL-4 secretion, but this does not seem to correlate with immune suppression.
MicroRNA miR-27 Inhibits Adenovirus Infection by Suppressing the Expression of SNAP25 and TXN2

ABSTRACT Recent studies have reported that host microRNAs (miRNAs) regulate infections by several types of viruses via various mechanisms and that inhibition of the miRNA processing factors enhances or prevents viral infection. However, it has not been clarified whether these effects of miRNAs extend to adenovirus (Ad) infection. Here we show that miR-27a and -b efficiently inhibit infection with an Ad via the downregulation of SNAP25 and TXN2, which are members of the SNARE proteins and the thioredoxin family, respectively. Approximately 80% reductions in Ad genomic copy number were found in cells transfected with miR-27a/b mimics, whereas there were approximately 2.5- to 5-fold larger copy numbers of the Ad genome following transfection with miR-27a/b inhibitors. Microarray gene expression analysis and in silico analysis demonstrated that SNAP25 and TXN2 are target genes of miR-27a/b. A reporter assay using plasmids containing the 3′ untranslated regions of the SNAP25 and TXN2 genes showed that miR-27a/b directly suppressed SNAP25 and TXN2 expression through posttranscriptional gene silencing. Knockdown of SNAP25 led to a significant inhibition of Ad entry into cells. Knockdown of TXN2 induced cell cycle arrest at G1 phase, leading to a reduction in Ad replication. In addition, overexpression of Ad-encoded small noncoding RNAs (VA-RNAs) restored the miR-27a/b-mediated reduction in infection level with a VA-RNA-lacking Ad mutant due to the VA-RNA-mediated inhibition of miR-27a/b expression. These results indicate that miR-27a and -b suppress SNAP25 and TXN2 expression via posttranscriptional gene silencing, leading to efficient suppression of Ad infection. IMPORTANCE Adenovirus (Ad) is widely used as a platform for replication-incompetent Ad vectors (Adv) and replication-competent oncolytic Ad (OAd) in gene therapy and virotherapy. Regulation of Ad infection is highly important for efficient gene therapies using both Adv and OAd. In this study, we demonstrate that miR-27a and -b, which are widely expressed in host cells, suppress SNAP25 and TXN2 expression through posttranscriptional gene silencing. Suppression of SNAP25 and TXN2 expression leads to inhibition of Ad entry into cells and to cell cycle arrest, respectively, leading to efficient suppression of Ad infection. Our findings provide important clues to the improvement of gene therapies using both Adv and OAd.
Limited Dissemination and Shedding of the UL128 Complex-Intact, UL/b′-Defective Rhesus Cytomegalovirus Strain 180.92

ABSTRACT The UL128 complex of human cytomegalovirus (CMV) is a major determinant of viral entry into epithelial and endothelial cells and a target for vaccine development. The UL/b′ region of rhesus CMV contains several open reading frames, including orthologs of the UL128 complex. We recently showed that the coding content of the rhesus CMV (RhCMV) UL/b′ region predicts acute endothelial tropism and long-term shedding in vivo in the rhesus macaque model of CMV infection. The laboratory-passaged RhCMV 180.92 strain has a truncated UL/b′ region but an intact UL128 complex. To investigate whether the presence of the UL128 complex alone was sufficient to confer endothelial and epithelial tropism in vivo, we investigated tissue dissemination and viral excretion following experimental RhCMV 180.92 inoculation of RhCMV-seronegative rhesus macaques. We show the presence of at least two virus variants in the RhCMV 180.92 infectious virus stock. A rare variant noted for a nontruncated wild-type-virus-like UL/b′ region, rapidly emerged during in vivo replication and showed high-level replication in blood and tissues and excretion in urine and saliva, features similar to those previously reported in naturally occurring wild-type RhCMV infection. In contrast, the predominant truncated version of RhCMV 180.92 showed significantly lower plasma DNAemia and limited tissue dissemination and viral shedding. These data demonstrate that the truncated RhCMV 180.92 variant is attenuated in vivo and suggest that additional UL/b′ genes, besides the UL128 complex, are required for optimal in vivo CMV replication and dissemination. IMPORTANCE An effective vaccine against human CMV infection will need to target genes that are essential for virus propagation and transmission. The human CMV UL128 complex represents one such candidate antigen since it is essential for endothelial and epithelial cell tropism, and is a target for neutralizing antibodies in CMV-infected individuals. In this study, we used the rhesus macaque animal model of CMV infection to investigate the in vivo function of the UL128 complex. Using experimental infection of rhesus macaques with a rhesus CMV virus variant that contained an intact UL128 complex but was missing several other genes, we show that the presence of the UL128 complex alone is not sufficient for widespread tissue dissemination and virus excretion. These data highlight the importance of in vivo studies in evaluating human CMV gene function and suggest that additional UL/b′ genes are required for optimal CMV dissemination and transmission.
Challenges and prospects for pharmacotherapy in functional gastrointestinal disorders

Functional gastrointestinal disorders, such as irritable bowel syndrome and functional dyspepsia, are complex conditions with multiple factors contributing to their pathophysiology. As a consequence they are difficult to treat and have posed significant challenges to the pharmaceutical industry when trying to develop new and effective treatments. This review provides an overview of these difficulties and how the industry is reshaping its drug developmental strategies. It describes some of the more significant and encouraging advances that have occurred, and discusses how future research might embrace the opportunities provided by advances in genetic and in particular, epigenetic research.
Determination of B-Type Natriuretic Peptides: Clinical And Analytical Quality

Determination of B-Type Natriuretic Peptides: Clinical And Analytical Quality B-type natriuretic peptide (BNP), a neurohormone synthesized in the cardiac ventricles, is released as preproBNP and then enzymatically cleaved to the N-terminal-proBNP (NT-proBNP) and BNP upon ventricular myocite stretch. This hormone has a role in the body's defense against hypertension and plasma volume expansion. Measurements of circulating B-type natriuretic peptides have been shown to be of diagnostic value in patients with heart failure. BNP levels correlate with the severity of heart failure, as well as with prognosis. Better control of the preanalytical and analytical sources of variations will undoubtedly lead to improvement in B-type natriuretic peptides measurements. A number of preanalytical and analytical factors including specimen type and stability, assay imprecision, and standardization are reviewed here. Further research is required to better define the performance characteristics necessary for assays bearing the designation natriuretic peptides. These characteristics include developing guidelines for the total analytical error from a careful review of the intraindividual biological variability of the analyte under conditions that will be encountered in clinical practice, then validating these guidelines in the clinical setting, and completing the standardization efforts. OdređIvanje B-Tipa Natriuretskih Peptida: KliničKi I AnalitičKi Kvalitet Neurohormon koji se sintetiše u srčanim komorama, B-tip natriuretskog peptida (BNP), usled rastezanja zidova komora oslobađa se kao preproBNP i enzimski se cepa na N-terminalni-proBNP (NT-proBNP) i BNP. Ovi hormoni štite organizam od povećanja pritiska i povećanja volumena tečnosti. Merenje vrednosti B-tipa natriuretskih peptida je značajno za dijagnostikovanje pacijenata sa srčanom insuficijencijom. Vrednosti cirkulišućeg B-tipa natriuretskih peptida kod ovih bolesnika koreliraju sa težinom bolesti i prognozom bolesti. Bolja kontrola preanalitičkih i analitičkih izvora varijacija sigurno vodi poboljšanju određivanja B-tipa natriuretskih peptida. U ovom radu je opisan veliki broj preanalitičkih i analitičkih faktora, kao što su vrsta uzorka, stabilnost, nepreciznost određivanja i standardizacija, važnih za određivanje B-tipa natriuretskih peptida. Neophodna su dodatna ispitivanja vezana za definisanje karakteristika izvođenja testova za određivanje B-tipa natriuretskih peptida. Ove karakteristike uključuju preporuke vezane za ukupnu analitičku grešku nastalu zbog intraindividualne biološke varijacije B-tipa natriuretskog peptida, koja mora da se uzme u obzir pri donošenju kliničkih odluka. Neophodno je da se izvrši validacija ovih preporuka u specifičnim kliničkim situacijama i završe aktivnosti vezane za standardizaciju određivanja.
The Crystal Structures of Chikungunya and Venezuelan Equine Encephalitis Virus nsP3 Macro Domains Define a Conserved Adenosine Binding Pocket

ABSTRACT Macro domains (also called “X domains”) constitute a protein module family present in all kingdoms of life, including viruses of the Coronaviridae and Togaviridae families. Crystal structures of the macro domain from the Chikungunya virus (an “Old World” alphavirus) and the Venezuelan equine encephalitis virus (a “New World” alphavirus) were determined at resolutions of 1.65 and 2.30 Å, respectively. These domains are active as adenosine di-phosphoribose 1″-phosphate phosphatases. Both the Chikungunya and the Venezuelan equine encephalitis virus macro domains are ADP-ribose binding modules, as revealed by structural and functional analysis. A single aspartic acid conserved through all macro domains is responsible for the specific binding of the adenine base. Sequence-unspecific binding to long, negatively charged polymers such as poly(ADP-ribose), DNA, and RNA is observed and attributed to positively charged patches outside of the active site pocket, as judged by mutagenesis and binding studies. The crystal structure of the Chikungunya virus macro domain with an RNA trimer shows a binding mode utilizing the same adenine-binding pocket as ADP-ribose, but avoiding the ADP-ribose 1″-phosphate phosphatase active site. This leaves the AMP binding site as the sole common feature in all macro domains.
Vaccination with Live Attenuated Simian Immunodeficiency Virus (SIV) Protects from Mucosal, but Not Necessarily Intravenous, Challenge with a Minimally Heterologous SIV

ABSTRACT Few studies have evaluated the impact of the viral challenge route on protection against a heterologous simian immunodeficiency virus (SIV) challenge. We vaccinated seven macaques with a live attenuated SIV that differed from SIVmac239Δnef by 24 amino acids, called m3KOΔnef. All animals were protected from an intrarectal SIVmac239 challenge, whereas only four animals were protected from subsequent intravenous SIVmac239 challenge. These data suggest that immune responses elicited by vaccination with live attenuated SIV in an individual animal can confer protection from intrarectal challenge while remaining insufficient for protection from intravenous challenge. IMPORTANCE Our study is important because we show that vaccinated animals can be protected from a mucosal challenge with a heterologous SIV, but the same animals are not necessarily protected from intravenous challenge with the same virus. This is unique because in most studies, either vaccinated animals are challenged multiple times by the same route or only a single challenge is performed. An individually vaccinated animal is rarely challenged multiple times by different routes, so protection from different challenge routes cannot be measured in the same animal. Our data imply that vaccine-elicited responses in an individual animal may be insufficient for protection from intravenous challenge but may be suitable for protection from a mucosal challenge that better approximates human immunodeficiency virus (HIV) exposure.
Interactions of Human Complement with Virus Particles Containing the Nipah Virus Glycoproteins

ABSTRACT Complement is an innate immune response system that most animal viruses encounter during natural infections. We have tested the role of human complement in the neutralization of virus particles harboring the Nipah virus (NiV) glycoproteins. A luciferase-expressing vesicular stomatitis virus (VSV) pseudotype that contained the NiV fusion (F) and attachment (G) glycoproteins (NiVpp) showed dose- and time-dependent activation of human complement through the alternative pathway. In contrast to our findings with other paramyxoviruses, normal human serum (NHS) alone did not neutralize NiVpp infectivity in vitro, and electron microscopy demonstrated no significant deposition of complement component C3 on particles. This lack of NiVpp neutralization by NHS was not due to a global inhibition of complement pathways, since complement was found to significantly enhance neutralization by antibodies specific for the NiV F and G glycoproteins. Complement components C4 and C1q were necessary but not sufficient by themselves for the enhancement of antibody neutralization. Human complement also enhanced NiVpp neutralization by a soluble version of the NiV receptor EphrinB2, and this depended on components in the classical pathway. The ability of complement to enhance neutralization fell into one of two profiles: (i) anti-F monoclonal antibodies showed enhancement only at high and not low antibody concentrations, and (ii) anti-G monoclonal antibodies and EphrinB2 showed enhancement at both high and very low levels of antibody (e.g., 3.1 ng) or EphrinB2 (e.g., 2.5 ng). Together, these data establish the importance of human complement in the neutralization of particles containing the NiV glycoproteins and will help guide the design of more effective therapeutics that harness the potency of complement pathways.
The LUCK study: Laxative Usage in patients with GP-diagnosed Constipation in the UK, within the general population and in pregnancy. An epidemiological study using the General Practice Research Database (GPRD)

Background: Despite the high prevalence of constipation and its related public health implications, there is relatively little research available on the condition from large epidemiological studies. The aim of this study was to investigate the epidemiology of general practitioner (GP)-diagnosed constipation and the prescribing trends for laxatives in the UK, within the general population and during pregnancy. Methods: A cohort study for the period from 2005 to 2009 was performed using the UK primary care database (General Practice Research Database), which contains information on over 3 million individuals. Results: The prevalence of GP-diagnosed constipation ranged from 12 per 1000 persons in 2005 (0.012 per person year) to 12.8 per 1000 in 2009 (0.013 per person year). The prevalence was almost twice as high in women as in men, and was higher in older patients. In 2005 the most commonly prescribed laxatives were lactulose (37%), senna (26%), macrogol (19%), ispaghula (6%), docusate sodium (5%), bisacodyl (4%) and glycerol suppositories (2%). By 2009, this pattern had changed: macrogol (31%), lactulose (29%), senna (22%), ispaghula (5%), docusate sodium (6%), bisacodyl (3%) and glycerol suppositories (3%). In pregnancy, lactulose accounted for 81% of laxative use in 2005, falling to 64% by 2009. In contrast, macrogol use in pregnancy rose from 13% in 2005 to 32% in 2009. Conclusions: GP-diagnosed constipation is common, accounting for a large number of consultations. Laxative prescribing trends have changed over the 5-year study period, prescriptions for macrogol becoming increasingly common and prescriptions for lactulose and senna less common. Macrogol also appears to have been replacing lactulose for treating constipation in pregnant women.
Conformational Epitope Consisting of the V3 and V4 Loops as a Target for Potent and Broad Neutralization of Simian Immunodeficiency Viruses

ABSTRACT Inducing neutralizing antibodies (NAb) is the key to developing a protective vaccine against human immunodeficiency virus type 1 (HIV-1). To clarify the neutralization mechanism of simian immunodeficiency virus (SIV), we analyzed NAb B404, which showed potent and broad neutralizing activity against various SIV strains. In 4 SIVsmH635FC-infected macaques, B404-like antibodies using the specific VH3 gene with a long complementarity-determining region 3 loop and λ light chain were the major NAbs in terms of the number and neutralizing potency. This biased NAb induction was observed in all 4 SIVsmH635FC-infected macaques but not in 2 macaques infected with a SIV mix, suggesting that induction of B404-like NAbs depended on the inoculated virus. Analysis using Env mutants revealed that the V3 and V4 loops were critical for B404 binding. The reactivity to the B404 epitope on trimeric, but not monomeric, Env was enhanced by CD4 ligation. The B404-resistant variant, which was induced by passages with increasing concentrations of B404, accumulated amino acid substitutions in the C2 region of gp120. Molecular dynamics simulations of the gp120 outer domains indicated that the C2 mutations could effectively alter the structural dynamics of the V3/V4 loops and their neighboring regions. These results suggest that a conformational epitope consisting of the V3 and V4 loops is the target for potent and broad neutralization of SIV. Identifying the new neutralizing epitope, as well as specifying the VH3 gene used for epitope recognition, will help to develop HIV-1 vaccines.
Health resource utilization and multidisciplinary impact of endoscopic ultrasonography in a tertiary referral medical center

Background: Endoscopic ultrasound (EUS) is a resource-intensive endoscopic procedure, but may result in high downstream health resource utilization and multispecialty impact. Our aim was to examine the downstream impact of EUS by specialty and by indication. Methods: A retrospective chart review was performed at an academic medical center for patients for whom EUS represented the first point of contact at the study institution within a 20-month period. Results: A total of 552 EUS procedures were reviewed and 208 represented the first point of contact. The most common principle indication involved the pancreas (n = 117, 56%). Downstream health utilization was calculated for an average of 313 days postprocedure (range: 35–632 days). Following unique referral for endoscopic ultrasound, 52% of the patients in the study were retained within the institution for further management and, of these, 34% had a major intervention in the form of surgery or chemoradiotherapy. Compared with other indications, patients presenting with a pancreatic mass were significantly more likely to remain in the study institution for further management (62% versus 39%, p = 0.005), were more likely to have a downstream surgery (29% versus 14%, p = 0.020) and were more likely to have downstream chemo-radiotherapy (11% versus 3%, p = 0.012). Conclusions: EUS represents a unique portal of entry into tertiary referral medical centers. First point of contact EUS referrals are associated with major downstream health resource utilization and significantly increased utilization for mass lesions of the pancreas.
Four groups of illicit substance users amongst the adult ‘hidden’ non-problematic community

This paper describes and distinguishes between adult drug users’ perceptions of their own drug use. Focusing on ‘non-problematic’ (non-addicted) users over the age of 25 amongst a non-agency attending population, the paper delineates adult drug users as a group, using qualitative data from a three-year investigation. Interviewees were located utilizing a combination of snowball and opportunistic sampling, gaining privileged access to a hidden network of drug users. Open ended qualitative interviews explored personal histories of substance use over time, covering patterns and perceptions of use. Four distinct groups of adult ‘non-problematic’ users are identified, each having different purposes, approaches to and understandings of their own drug use, and thus experiencing the phenomenon in fundamentally different ways. The identified groups are presented and discussed in terms of furthering research understanding of this group of illicit substance users. Implications for future research are discussed.
The Mind Has No Sex? Women in the Origins of Modern Science

Londa Schiebinger's adventure in scholarly sleuthing discovers the hidden, finds the lost, and celebrates the forgotten women in medicine and science in Western Europe and America from the 16th through the 19th centuries. This important, intellectually powerful book is often very funny in relating historical reasons why there are so few women scientists. Seventeenth-century pundits, imitating Aristotle, asserted that women's brains were too cold and too soft to sustain rigorous thought. Some 18th-century theorists thought that female cranial cavities were too small to encompass powerful scientific brains. A common 19th-century belief was that vigorous exercise of a woman's brain shriveled her ovaries. And the great philosopher Hegel thought that women should study botany because the mind of a woman is as placid as a plant. Beyond comedic virtues, this book's true power lies in its revelation of women's scientific achievements and its recasting of the question at hand: why are