Miracle-dz/UniFAR-FTUs huggingface dataset:
Herpes Simplex Virus Glycoprotein D Interferes with Binding of Herpesvirus Entry Mediator to Its Ligands through Downregulation and Direct Competition

ABSTRACT To initiate membrane fusion and virus entry, herpes simplex virus (HSV) gD binds to a cellular receptor such as herpesvirus entry mediator (HVEM). HVEM is a tumor necrosis factor (TNF) receptor family member with four natural ligands that either stimulate (LIGHT and LTα) or inhibit (BTLA and CD160) T cell function. We hypothesized that the interaction of gD with HVEM affects the binding of natural ligands, thereby modulating the immune response during infection. Here, we investigated the effect that gD has on the interaction of HVEM with its natural ligands. First, HSV gD on virions or cells downregulates HVEM from the cell surface. Similarly, trans-interaction with BTLA or LIGHT also downregulates HVEM from the cell surface, suggesting that HSV may subvert a natural mechanism for regulating HVEM activity. Second, we showed that wild-type gD had the lowest affinity for HVEM compared with the four natural ligands. Moreover, gD directly competed for binding to HVEM with BTLA but not LTα or LIGHT, indicating the possibility that gD selectively controls HVEM signals. On the other hand, natural ligands influence the use of HVEM by HSV. For instance, soluble BTLA, LTα, and LIGHT inhibited the binding of wild-type gD to HVEM, and soluble BTLA and LTα blocked HSV infection of HVEM-expressing cells. Thus, gD is at the center of the interplay between HVEM and its ligands. It can interfere with HVEM function in two ways, by competing with the natural ligands and by downregulating HVEM from the cell surface.
A survey of patient satisfaction as a means of evaluating quality of care in an open psychiatric ward

Patients' satisfaction with their stay in an open psychiatric ward was studied retrospectively by means of a standardized questionnaire. The questionnaire was mailed during the autumn of 1995 to all patients discharged from the ward in 1990 and 1994. Overall response rate was 66.5%. Patients discharged during 1994 were more satisfied with the hospitalization, but the differences between the two populations were small. A major proportion of patients, including compulsorily admitted subjects, were highly satisfied. Men were more satisfied than women. The only factor that related to symptom relief at the time of the study was the reported benefit from pharmacotherapy. The questionnaire may be used in further research towards a consensus on good quality of inpatient psychiatric care.
Amniotic Fluid

Our aim was to review the use of high-dimensional biology techniques, specifically transcriptomics, proteomics, and metabolomics, in amniotic fluid to elucidate the mechanisms behind preterm birth or assessment of fetal development. We performed a comprehensive MEDLINE literature search on the use of transcriptomic, proteomic, and metabolomic technologies for amniotic fluid analysis. All abstracts were reviewed for pertinence to preterm birth or fetal maturation in human subjects. Nineteen articles qualified for inclusion. Most articles described the discovery of biomarker candidates, but few larger, multicenter replication or validation studies have been done. We conclude that the use of high-dimensional systems biology techniques to analyze amniotic fluid has significant potential to elucidate the mechanisms of preterm birth and fetal maturation. However, further multicenter collaborative efforts are needed to replicate and validate candidate biomarkers before they can become useful tools for clinical practice. Ideally, amniotic fluid biomarkers should be translated to a noninvasive test performed in maternal serum or urine.
The Role of TGF-β in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic oligoanovulation and hyperandrogenism and associated with insulin resistance, type 2 diabetes, and cardiovascular risk. In recent years, genetic studies have linked PCOS to a dinucleotide marker D19S884 in the fibrillin 3 gene. Fibrillins make up the major component of microfibrils in the extracellular matrix (ECM) and interact with molecules in the ECM to regulate transforming growth factor β (TGF-β) signaling. Therefore, variations in fibrillin 3 and subsequent dysregulation of TGF-β may contribute to the pathogenesis of PCOS. Here, we review the evidence from genetic studies supporting the role of TGF-β in PCOS and describe how TGF-β dysregulation may contribute to (1) the fetal origins of PCOS, (2) reproductive abnormalities in PCOS, and (3) cardiovascular and metabolic abnormalities in PCOS.
Effect of Nitric Oxide and Th1/Th2 Cytokine Supplementation Over Ectopic Endometrial Tissue Growth in a Murine Model of Endometriosis

Using a murine model, we evaluated the growth of ectopic endometrial tissue in the presence of T helper 1 (Th1) or Th2 cytokines or a nitric oxide donor (S-nitroso-N-acetyl-penicillamine [SNAP]). Female mice were autografted with endometrial tissue in the peritoneum. Different combinations and concentrations of cytokines or SNAP were injected intraperitoneally for 8 weeks. Implants were recovered, measured, and weighed. Cytokines were determined in plasma. Implants (weight and area) were smaller in mice that received interferon γ plus interleukin 2 (IFN-γ + IL-2) compared to mice treated with IL-2, IL-4 + IL-10 or saline solution, and saline solution compared to different concentrations of SNAP. The IL-2, IFN-γ, and IL-4 concentrations in plasma decreased in accordance with the increase in SNAP concentrations compared to saline solution. The promotion of a Th1 milieu in the peritoneum reduced the weight and area of the implant. Different concentrations of SNAP suppressed Th1 and Th2 cytokines and enabled the growth of the implant in this murine model.
University of Birmingham Identification of a residue in hepatitis C virus E2 glycoprotein that determines scavenger receptor BI and CD81 receptor dependency and sensitivity to neutralizing antibodies

Hepatitis C virus (HCV) infection is dependent on at least three coreceptors: CD81, scavenger receptor BI (SR-BI), and claudin-1. The mechanism of how these molecules coordinate HCV entry is unknown. In this study we demonstrate that a cell culture-adapted JFH-1 mutant, with an amino acid change in E2 at position 451 (G451R), has a reduced dependency on SR-BI. This altered receptor dependency is accompanied by an increased sensitivity to neutralization by soluble CD81 and enhanced binding of recombinant E2 to cell surface-expressed and soluble CD81. Fractionation of HCV by density gradient centrifugation allows the analysis of particle-lipoprotein associations. The cell culture-adapted mutation alters the relationship between particle density and infectivity, with the peak infectivity occurring at higher density than the parental virus. No association was observed between particle density and SR-BI or CD81 coreceptor dependence. JFH-1 G451R is highly sensitive to neutralization by gp-speciﬁc antibodies, suggesting increased epitope exposure at the virion surface. Finally, an association was observed between JFH-1 particle density and sensitivity to neutral- izing antibodies (NAbs), suggesting that lipoprotein association reduces the sensitivity of particles to NAbs. In summary, mutation of E2 at position 451 alters the relationship between particle density and infectivity, disrupts coreceptor dependence, and increases virion sensitivity to receptor mimics and NAbs. Our data suggest that a balanced interplay between HCV particles, lipoprotein components, and viral receptors allows the evasion of host immune responses.
A Genetically Engineered Waterfowl Influenza Virus with a Deletion in the Stalk of the Neuraminidase Has Increased Virulence for Chickens

ABSTRACT A deletion of about 20 amino acids in the stalk of the neuraminidase (NA) is frequently detected upon transmission of influenza A viruses from waterfowl to domestic poultry. Using reverse genetics, a recombinant virus derived from a wild duck influenza virus isolate, A/Mallard/Marquenterre/Z237/83 (MZ), and an NA stalk deletion variant (MZ-delNA) were produced. Compared to the wild type, the MZ-delNA virus showed a moderate growth advantage on avian cultured cells. In 4-week-old chickens inoculated intratracheally with the MZ-delNA virus, viral replication in the lungs, liver, and kidneys was enhanced and interstitial pneumonia lesions were more severe than with the wild-type virus. The MZ-delNA-inoculated chickens showed significantly increased levels of mRNAs encoding interleukin-6 (IL-6), transforming growth factor-β4 (TGF-β4), and CCL5 in the lungs and a higher frequency of apoptotic cells in the liver than did their MZ-inoculated counterparts. Molecular mechanisms possibly underlying the growth advantage of the MZ-delNA virus were explored. The measured enzymatic activities toward a small substrate were similar for the wild-type and deleted NA, but the MZ-delNA virus eluted from chicken erythrocytes at reduced rates. Pseudoviral particles expressing the MZ hemagglutinin in combination with the MZ-NA or MZ-delNA protein were produced from avian cultured cells with similar efficiencies, suggesting that the deletion in the NA stalk does not enhance the release of progeny virions and probably affects an earlier step of the viral cycle. Overall, our data indicate that a shortened NA stalk is a strong determinant of adaptation and virulence of waterfowl influenza viruses in chickens.
An AP-1 Binding Site in the Enhancer/Core Element of the HIV-1 Promoter Controls the Ability of HIV-1 To Establish Latent Infection

ABSTRACT Following integration, HIV-1 in most cases produces active infection events; however, in some rare instances, latent infection events are established. The latter have major clinical implications, as latent infection allows the virus to persist despite antiretroviral therapy. Both the cellular factors and the viral elements that potentially determine whether HIV-1 establishes active or latent infection events remain largely elusive. We detail here the contribution of different long terminal repeat (LTR) sequences for the establishment of latent HIV-1 infection. Using a panel of full-length replication-competent virus constructs that reflect naturally occurring differences of HIV-1 subtype-specific LTRs and targeted LTR mutants, we found the primary ability of HIV-1 to establish latent infection in this system to be controlled by a four-nucleotide (nt) AP-1 element just upstream of the NF-κB element in the viral promoter. Deletion of this AP-1 site mostly deprived HIV-1 of the ability to establish latent HIV-1 infection. Extension of this site to a 7-nt AP-1 sequence massively promoted latency establishment, suggesting that this promoter region represents a latency establishment element (LEE). Given that these minimal changes in a transcription factor binding site affect latency establishment to such large extent, our data support the notion that HIV-1 latency is a transcription factor restriction phenomenon.
Women prisoners: an analysis of the process of hospital transfers

Department of Health guidelines (Bradley, 2009) suggest that transfers of prisoners with mental health problems to hospital using the Mental Health Act should take 14 days from first assessment to transfer. This study examines the extent to which transfers of women prisoners from a large women's prison in England is meeting this target. It considers in detail 100 recommendations for hospitalisation and analyses the process to establish rate of transfer and where applicable reasons for slow transfer. Of the 86 women who completed transfer, the process took 37 days (median) with only 13% of cases being moved within the 14-day recommended period. This study also found that legal routes intended for urgent hospitalisation were no quicker than other methods. The study recommends review of Section 48, the urgent treatment order.
Cognitive Resource Demands of Redirected Walking

Redirected walking allows users to walk through a large-scale immersive virtual environment (IVE) while physically remaining in a reasonably small workspace. Therefore, manipulations are applied to virtual camera motions so that the user's self-motion in the virtual world differs from movements in the real world. Previous work found that the human perceptual system tolerates a certain amount of inconsistency between proprioceptive, vestibular and visual sensation in IVEs, and even compensates for slight discrepancies with recalibrated motor commands. Experiments showed that users are not able to detect an inconsistency if their physical path is bent with a radius of at least 22 meters during virtual straightforward movements. If redirected walking is applied in a smaller workspace, manipulations become noticeable, but users are still able to move through a potentially infinitely large virtual world by walking. For this semi-natural form of locomotion, the question arises if such manipulations impose cognitive demands on the user, which may compete with other tasks in IVEs for finite cognitive resources. In this article we present an experiment in which we analyze the mutual influence between redirected walking and verbal as well as spatial working memory tasks using a dual-tasking method. The results show an influence of redirected walking on verbal as well as spatial working memory tasks, and we also found an effect of cognitive tasks on walking behavior. We discuss the implications and provide guidelines for using redirected walking in virtual reality laboratories.
Crystallographic Definition of the Epitope Promiscuity of the Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 Antibody 2F5: Vaccine Design Implications

ABSTRACT The quest to create a human immunodeficiency virus type 1 (HIV-1) vaccine capable of eliciting broadly neutralizing antibodies against Env has been challenging. Among other problems, one difficulty in creating a potent immunogen resides in the substantial overall sequence variability of the HIV envelope protein. The membrane-proximal region (MPER) of gp41 is a particularly conserved tryptophan-rich region spanning residues 659 to 683, which is recognized by three broadly neutralizing monoclonal antibodies (bnMAbs), 2F5, Z13, and 4E10. In this study, we first describe the variability of residues in the gp41 MPER and report on the invariant nature of 15 out of 25 amino acids comprising this region. Subsequently, we evaluate the ability of the bnMAb 2F5 to recognize 31 varying sequences of the gp41 MPER at a molecular level. In 19 cases, resulting crystal structures show the various MPER peptides bound to the 2F5 Fab′. A variety of amino acid substitutions outside the 664DKW666 core epitope are tolerated. However, changes at the 664DKW666 motif itself are restricted to those residues that preserve the aspartate's negative charge, the hydrophobic alkyl-π stacking arrangement between the β-turn lysine and tryptophan, and the positive charge of the former. We also characterize a possible molecular mechanism of 2F5 escape by sequence variability at position 667, which is often observed in HIV-1 clade C isolates. Based on our results, we propose a somewhat more flexible molecular model of epitope recognition by bnMAb 2F5, which could guide future attempts at designing small-molecule MPER-like vaccines capable of eliciting 2F5-like antibodies.
Developmental Programming

Excess of prenatal testosterone (T) induces reproductive defects including follicular persistence. Comparative studies with T and dihydrotestosterone (DHT) have suggested that follicular persistence is programmed via estrogenic actions of T. This study addresses the androgenic and estrogenic contributions in programming follicular persistence. Because humans are exposed to estrogenic environmental steroids from various sources throughout their life span and postnatal insults may also induce organizational and/or activational changes, we tested whether continuous postnatal exposure to estradiol (E) will amplify effects of prenatal steroids on ovarian function. Pregnant sheep were treated with T, DHT, E, or ED (E and DHT) from days 30 to 90 of gestation. Postnatally, a subset of the vehicle (C), T, and DHT females received an E implant. Transrectal ultrasonography was performed in the first breeding season during a synchronized cycle to monitor ovarian follicular dynamics. As expected, number of ≥8 mm follicles was higher in the T versus C group. Postnatal E reduced the number of 4 to 8 mm follicles in the DHT group. Percentage of females bearing luteinized follicles and the number of luteinized follicles differed among prenatal groups. Postnatal E increased the incidence of subluteal cycles in the prenatal T-treated females. Findings from this study confirm previous findings of divergences in programming effects of prenatal androgens and estrogens. They also indicate that some aspects of follicular dynamics are subject to postnatal modulation as well as support the existence of an extended organizational period or the need for a second insult to uncover the previously programmed event.
Pandemic H1N1 2009 Influenza A Virus Induces Weak Cytokine Responses in Human Macrophages and Dendritic Cells and Is Highly Sensitive to the Antiviral Actions of Interferons

ABSTRACT In less than 3 months after the first cases of swine origin 2009 influenza A (H1N1) virus infections were reported from Mexico, WHO declared a pandemic. The pandemic virus is antigenically distinct from seasonal influenza viruses, and the majority of human population lacks immunity against this virus. We have studied the activation of innate immune responses in pandemic virus-infected human monocyte-derived dendritic cells (DC) and macrophages. Pandemic A/Finland/553/2009 virus, representing a typical North American/European lineage virus, replicated very well in these cells. The pandemic virus, as well as the seasonal A/Brisbane/59/07 (H1N1) and A/New Caledonia/20/99 (H1N1) viruses, induced type I (alpha/beta interferon [IFN-α/β]) and type III (IFN-λ1 to -λ3) IFN, CXCL10, and tumor necrosis factor alpha (TNF-α) gene expression weakly in DCs. Mouse-adapted A/WSN/33 (H1N1) and human A/Udorn/72 (H3N2) viruses, instead, induced efficiently the expression of antiviral and proinflammatory genes. Both IFN-α and IFN-β inhibited the replication of the pandemic (H1N1) virus. The potential of IFN-λ3 to inhibit viral replication was lower than that of type I IFNs. However, the pandemic virus was more sensitive to the antiviral IFN-λ3 than the seasonal A/Brisbane/59/07 (H1N1) virus. The present study demonstrates that the novel pandemic (H1N1) influenza A virus can readily replicate in human primary DCs and macrophages and efficiently avoid the activation of innate antiviral responses. It is, however, highly sensitive to the antiviral actions of IFNs, which may provide us an additional means to treat severe cases of infection especially if significant drug resistance emerges.
Space-time analysis and iterative focusing for synthetic aperture sonar

In this paper, we describe a space-time analysis for synthetic aperture sonar (SAS) employing Green's functions, and show that it's basically an inverse problem. Iterative focusing is proposed based on this viewpoint. In order to mitigate difficulties of slow convergence and computational costs inherent in iterative methods, an acceleration technique is used. Applications to SAS imaging is demonstrated through reconstructions from simulated data, with emphasis on high resolution and image quality.
THE BACTERIOPHAGE: ITS NATURE AND ITS THERAPEUTIC USE

There appeared inThe Journalduring December 1934 a series of articles on bacteriophage therapy by Drs. M. D. Eaton and Stanhope Bayne-Jones. 1 The phases of the subject covered included the experimentally determined facts relating to the bacteriophage phenomenon, the laboratory and clinical evidence for and against the therapeutic usefulness of bacteriophage and the role of so-called antivirus in crude lysates containing bacteriophage. The survey served most effectively as a timely basis for determining the status of commercial phage preparations. In the six years since the report of Eaton and Bayne-Jones was published, much more information about both phage itself and its clinical utility has accumulated; it has been thought advisable therefore to supplement their paper with an analysis of the recent literature, using as a background certain of their summarized material. We propose to consider the following subjects: 1. The nature of bacteriophage and its mode of action
Uterine Infusion With Bone Marrow Mesenchymal Stem Cells Improves Endometrium Thickness in a Rat Model of Thin Endometrium

Bone marrow mesenchymal stem cells (BMSCs) show multidirectional differentiation and possess immunoregulatory properties. Although transplantation of BMSCs has a therapeutic effect on many diseases, it is unclear whether BMSC transplantation can be used as a therapy for a thin endometrium. To explore whether transplantation of BMSCs directly into the uterine cavity can improve endometrium thickness, a thin endometrium rat model was established by infusing ethanol into the uterine cavity. In all, 48 rats with thin endometrium and 24 normal rats were divided into 3 groups: (1) normal group, (2) experimental group transplanted with BMSCs into uterine cavity, and (3) control group transplanted with saline into the uterine cavity. The morphology of the endometrium, the regeneration and receptivity of the endometrium, and the mechanisms involved in BMSC therapy were subsequently analyzed by hematoxylin and eosin staining, Western blot analysis, and reverse transcription-polymerase chain reaction throughout an observation period of 3 estrus cycles. The rats in the experimental group had a significantly thicker endometrial lining and exhibited higher expression of cytokeratin, vimentin, integrin αγβ3, and leukaemia inhibitor factor (LIF) than that of the control group (P < .05). Bromodeoxyuridine -positive cells were detected in the endometrium after BMSC transplantation. Some proinflammatory cytokines, such as tumor necrosis factor α messenger RNA (mRNA) and interleukin (IL)-1βmRNA, were significantly downregulated, and anti-inflammatory cytokines, such as basic fibroblast growth factor (bFGF) mRNA and IL-6mRNA, were significantly upregulated in the experimental group compared to the control group (P < .05). In conclusion, BMSCs improved endometrium thickness, probably via their migration and immunomodulatory properties. Uterine perfusion with BMSCs represents a promising new tool for the currently intractable problem of an inadequate, thin endometrium.