Miracle-dz/UniFAR-FTUs huggingface dataset:
Functional Analysis of the Short Isoform of Orf Virus Protein OV20.0

ABSTRACT Orf virus (ORFV) OV20.0L is an ortholog of vaccinia virus (VACV) gene E3L. The function of VACV E3 protein as a virulence factor is well studied, but OV20.0 has received less attention. Here we show that like VACV E3L, OV20.0L encodes two proteins, a full-length protein and a shorter form (sh20). The shorter sh20 is an N-terminally truncated OV20.0 isoform generated when a downstream AUG codon is used for initiating translation. These isoforms differed in cellular localization, with full-length OV20.0 and sh20 found throughout the cell and predominantly in the cytoplasm, respectively. Nonetheless, both OV20.0 isoforms were able to bind double-stranded RNA (dsRNA)-activated protein kinase (PKR) and dsRNA. Moreover, both isoforms strongly inhibited PKR activation as shown by decreased phosphorylation of the translation initiation factor eIF2α subunit and protection of Sindbis virus infection against the activity of interferon (IFN). In spite of this apparent conservation of function in vitro, a recombinant ORFV that was able to express only the sh20 isoform was attenuated in a mouse model. IMPORTANCE The OV20.0 protein of orf virus (ORFV) has two isoforms and contributes to virulence, but the roles of the two forms are not known. This study shows that the shorter isoform (sh20) arises due to use of a downstream initiation codon and is amino-terminally truncated. The sh20 form also differs in expression kinetics and cellular localization from full-length OV20.0. Similar to the full-length isoform, sh20 is able to bind dsRNA and PKR, inactivate PKR, and thus act as an antagonist of the interferon response in vitro. In vivo, however, wild-type OV20.0 could not be replaced with sh20 alone without a loss of virulence, suggesting that the functions of the isoforms are not simply redundant.
Adaptive LS- and MMSE-Based Beamformer Design for Multiuser MIMO Interference Channels

In the presence of perfect channel state information (CSI), the achievable degrees of freedom (DoF) in wireless interference networks can be linearly scaled up with the number of users. Achievability is based on the idea of interference alignment (IA). However, in the presence of imperfect CSI, the sum rate becomes degraded, and full DoF may no longer be achievable. In this paper, we propose novel least squares (LS)- and minimum mean square error (MMSE)-based IA schemes that adaptively design beamformers by relying on the availability of imperfect CSI and knowledge of the channel estimation error variance in advance. Interestingly and unlike the other robust algorithms, the proposed adaptive schemes do not impose extra computational complexity compared to their nonadaptive counterparts. It is shown that the LS-based IA is able to outperform interference leakage minimization algorithms under both perfect and imperfect CSI. Furthermore, we compare the performance of the proposed MMSE-based IA with maximum signal-to-interference-plus-noise ratio (Max-SINR) algorithm. We show that while under perfect CSI, the MMSE-based IA achieves the same performance as that of Max-SINR, the former outperforms the latter under CSI mismatch. Meanwhile, it is shown that the proposed MMSE-based IA needs less CSI to be available and has less computational complexity compared to Max-SINR.
Diuretic drugs benefit patients with hypertension more with night-time dosing

Objectives: Night-time chronotherapy in antihypertensive drugs has been shown to produce better blood pressure control and protect from cardiovascular morbidity and mortality. To date, this has been proven for several drug classes excluding thiazides diuretics. Given the peculiar response of blood pressure to thiazides in black people we sought to determine whether nighttime chronotherapy with thiazides produces better control as already shown with other drug classes. Methods: A subanalysis of a larger chronotherapy study with antihypertensive drugs in Nigerian Africans was done. The subpopulation of those whose disease was controlled after 12 weeks of diuretic monotherapy was analysed. Those who received drugs in the morning and at night were compared along control lines and some cardiac indices. Results: Both groups were similar on all scores at baseline. After 12 weeks of monotherapy patients who received drugs at night had significantly lower systolic and diastolic blood pressure though control was achieved with both morning and night-time dosing. Also the left ventricular posterior and septal walls regressed better as well as left ventricular mass in the night-time group. Conclusion: Though equally effective in reducing blood pressure and cardiac indices related to hypertension, patients taking their drugs at night recorded better values. This makes diuretics equally amenable to night-time chronotherapy as other drug classes. This effect should be explored to reduce the morbidity and mortality consequences of hypertension.
Deciphering the Role of the Gag-Pol Ribosomal Frameshift Signal in HIV-1 RNA Genome Packaging

ABSTRACT A key step of retroviral replication is packaging of the viral RNA genome during virus assembly. Specific packaging is mediated by interactions between the viral protein Gag and elements in the viral RNA genome. In HIV-1, similar to most retroviruses, the packaging signal is located within the 5′ untranslated region and extends into the gag-coding region. A recent study reported that a region including the Gag-Pol ribosomal frameshift signal plays an important role in HIV-1 RNA packaging; deletions or mutations that affect the RNA structure of this signal lead to drastic decreases (10- to 50-fold) in viral RNA packaging and virus titer. We examined here the role of the ribosomal frameshift signal in HIV-1 RNA packaging by studying the RNA packaging and virus titer in the context of proviruses. Three mutants with altered ribosomal frameshift signal, either through direct deletion of the signal, mutation of the 6U slippery sequence, or alterations of the secondary structure were examined. We found that RNAs from all three mutants were packaged efficiently, and they generate titers similar to that of a virus containing the wild-type ribosomal frameshift signal. We conclude that although the ribosomal frameshift signal plays an important role in regulating the replication cycle, this RNA element is not directly involved in regulating RNA encapsidation. IMPORTANCE To generate infectious viruses, HIV-1 must package viral RNA genome during virus assembly. The specific HIV-1 genome packaging is mediated by interactions between the structural protein Gag and elements near the 5′ end of the viral RNA known as packaging signal. In this study, we examined whether the Gag-Pol ribosomal frameshift signal is important for HIV-1 RNA packaging as recently reported. Our results demonstrated that when Gag/Gag-Pol is supplied in trans, none of the tested ribosomal frameshift signal mutants has defects in RNA packaging or virus titer. These studies provide important information on how HIV-1 regulates its genome packaging and generate infectious viruses necessary for transmission to new hosts.
Preparing for safety issues following drug approval: pre-approval risk management considerations

Risk management plans and risk minimization plans as well as postapproval commitment studies are based on risks identified pre-approval that need to be further characterized or minimized in the postmarketing environment. Although the implementation of these activities are conducted in the postapproval arena, the design of the plans and studies as well as the development of effective postapproval tools and mitigation strategies should be carried out pre-approval. The pre-approval period also provides the opportunity to fully understand the treatment population that is included in the clinical trial program and to determine how the target population for the drug after approval may differ from the clinical trial patient population. When regulators or sponsors have expressed concerns about safety issues identified during clinical development, the result may be a postapproval commitment in the form of a registry or an observational safety study or, in the US, a Risk Evaluation and Mitigation Strategy (REMS) as a condition of approval. Specific examples are given for risk mitigation activities that can be conducted pre-approval.
Preliminary investigation of the pharmacology of the human internal anal sphincter

The smooth muscle from the human internal anal sphincter has been investigated pharmacologically in vitro. The upper and lower parts of the sphincter responded to catecholamines in a similar manner. Noradrenaline caused contraction which could be antagonized by phenoxybenzamine. After phenoxybenzamine, noradrenaline caused relaxation which could be blocked by pronethalol. Isoprenaline caused relaxation which could be specifically prevented by pronethalol. Adrenaline was variable in its effect: low concentrations caused relaxation and high concentrations caused contraction. It is suggested that the anal smooth muscle contains α-adrenergic receptors subserving contraction and β-receptors subserving relaxation. The lower part of the sphincter was generally insensitive to acetylcholine and nicotine whereas the upper part of the sphincter contracted with acetylcholine and regularly relaxed with nicotine. The nicotine response was antagonized by hexamethonium, procaine, and pronethalol. It is suggested that nicotine stimulated some part of the nervous mechanism in the upper part of the sphincter and that a catecholamine was the mediator of the inhibitory response.
EFFECTS OF CHRONIC EXCESS SALT INGESTION

By selective inbreeding, two strains of rats were developed previously that differed markedly in their susceptibility to the development of experimental hypertension from excess salt ingestion (1, 2). The present report indicates that with animals derived from the same strains, similar differences in response were obtained in rats subjected to either combined desoxycorticosterone-NaCl (DOCA-salt) treatment or unilateral renal artery compression without extra dietary salt. Thus differences in genetic substrate appear to influence the development of experimental hypertension produced by these three techniques and possibly this may hold true for all "varieties" of experimental hypertension. If true, it might allow the development of a unifying hypothesis that could be relevant not only to experimental hypertension but perhaps to human hypertension as well. The DOCA-salt regimen was more toxic to the animals than unilateral renal artery compression. Tentatively, this was ascribed to either, or both, the younger age or the higher NaCl intake of the animals in the former.
Enhanced Control of Pathogenic Simian Immunodeficiency Virus SIVmac239 Replication in Macaques Immunized with an Interleukin-12 Plasmid and a DNA Prime-Viral Vector Boost Vaccine Regimen

ABSTRACT DNA priming has previously been shown to elicit augmented immune responses when administered by electroporation (EP) or codelivered with a plasmid encoding interleukin-12 (pIL-12). We hypothesized that the efficacy of a DNA prime and recombinant adenovirus 5 boost vaccination regimen (DNA/rAd5) would be improved when incorporating these vaccination strategies into the DNA priming phase, as determined by pathogenic simian immunodeficiency virus SIVmac239 challenge outcome. The whole SIVmac239 proteome was delivered in 5 separate DNA plasmids (pDNA-SIV) by EP with or without pIL-12, followed by boosting 4 months later with corresponding rAd5-SIV vaccine vectors. Remarkably, after repeated low-dose SIVmac239 mucosal challenge, we demonstrate 2.6 and 4.4 log reductions of the median SIV peak and set point viral loads in rhesus macaques (RMs) that received pDNA-SIV by EP with pIL-12 compared to the median peak and set point viral loads in mock-immunized controls (P < 0.01). In 5 out of 6 infected RMs, strong suppression of viremia was observed, with intermittent “blips” in virus replication. In 2 RMs, we could not detect the presence of SIV RNA in tissue and lymph nodes, even after 13 viral challenges. RMs immunized without pIL-12 demonstrated a typical maximum of 1.5 log reduction in virus load. There was no significant difference in the overall magnitude of SIV-specific antibodies or CD8 T-cell responses between groups; however, pDNA delivery by EP with pIL-12 induced a greater magnitude of SIV-specific CD4 T cells that produced multiple cytokines. This vaccine strategy is relevant for existing vaccine candidates entering clinical evaluation, and this model may provide insights into control of retrovirus replication.
The Members of an Epstein-Barr Virus MicroRNA Cluster Cooperate To Transform B Lymphocytes

ABSTRACT Epstein-Barr virus (EBV) transforms B lymphocytes through the expression of the latent viral proteins EBNA and latent membrane protein (LMP). Recently, it has become apparent that microRNAs (miRNAs) also contribute to EBV's oncogenic properties; recombinant EBVs that lack the BHRF1 miRNA cluster display a reduced ability to transform B lymphocytes in vitro. Furthermore, infected cells evince a marked upregulation of the EBNA genes. Using recombinant viruses that lack only one member of the cluster, we now show that all three BHRF1 miRNAs contribute to B-cell transformation. Recombinants that lacked miR-BHRF1-2 or miR-BHRF1-3 displayed enhanced EBNA expression initiated at the Cp and Wp promoters. Interestingly, we find that the deletion of miR-BHRF1-2 reduced the expression level of miR-BHRF1-3 and possibly that of miR-BHRF1-1, demonstrating that the expression of one miRNA can potentiate the expression of other miRNAs located in the same cluster. Therefore, the phenotypic traits of the miR-BHRF1-2 null mutant could result partly from reduced miR-BHRF1-1 and miR-BHRF1-3 expression levels. Nevertheless, using an miR-BHRF1-1 and miR-BHRF1-3 double mutant, we could directly assess and confirm the contribution of miR-BHRF1-2 to B-cell transformation. Furthermore, we found that the potentiating effect of miR-BHRF1-2 on miR-BHRF1-3 synthesis can be reproduced with simple expression plasmids, provided that both miRNAs are processed from the same transcript. Therefore, this enhancing effect does not result from an idiosyncrasy of the EBV genome but rather reflects a general property of these miRNAs. This study highlights the advantages of arranging the BHRF1 miRNAs in clusters: it allows the synchronous and synergistic expression of genetic elements that cooperate to transform their target cells.
Comparison of the Actions of Chloramphenicol (Chloromycetin) and Penicillin G Against Relapsing Fever in Mice

Spirochetes are included in the spectrum of pathogenic agents susceptible in vitro to the action of chloramphenicol (Chloromycetin). 1 In view of the limited number of therapeutic agents available for the treatment of relapsing fever, the discovery of antispirochetal action of a new drug is of interest. This is particularly true when the new agent is suitable for oral as well as parenteral administration in human therapeutics.2-7 The present investigation, demonstrating a therapeutic action of chloramphenicol against experimental
Methadone, QTc interval prolongation and torsade de pointes: Case reports offer the best understanding of this problem

We reviewed the literature and found 31 adult cases and 1 newborn case of methadone-associated QTc interval prolongation and/or torsade de pointes (TdP). Parametric statistics may not be useful in studying this issue because methadone-associated TdP is a very rare event and, hence, “an extreme outlier” consistent with scalable randomness. We may have to rely upon narrative medicine in the form of case reports with all its limitations and hazards to provide our best understanding. We report risk factors for methadone-associated QTc interval prolongation and TdP based on review of published case reports. We believe both drug manufacturers and the FDA would better serve our patients and inform clinicians if they more readily reported drug-induced outliers such as methadone-associated TdP using a case report format.
Identification of a Pyridopyrimidinone Inhibitor of Orthopoxviruses from a Diversity-Oriented Synthesis Library

ABSTRACT Orthopoxviruses include the prototypical vaccinia virus, the emerging infectious agent monkeypox virus, and the potential biothreat variola virus (the causative agent of smallpox). There is currently no FDA-approved drug for humans infected with orthopoxviruses. We screened a diversity-oriented synthesis library for new scaffolds with activity against vaccinia virus. This screen identified a nonnucleoside analog that blocked postreplicative intermediate and late gene expression. Viral genome replication was unaffected, and inhibition could be elicited late in infection and persisted upon drug removal. Sequencing of drug-resistant viruses revealed mutations predicted to be on the periphery of the highly conserved viral RNA polymerase large subunit. Consistent with this, the compound had broad-spectrum activity against orthopoxviruses in vitro. These findings indicate that novel chemical synthesis approaches are a potential source for new infectious disease therapeutics and identify a potentially promising candidate for development to treat orthopoxvirus-infected individuals.
Continuing clozapine with granulocyte colony-stimulating factor in patients with neutropenia

Background: The current guidelines dictate that clozapine should be stopped following the emergence of neutropenia. Various alternative approaches have been tried in the past, among them one rarely used alternative being to continue treatment with clozapine with coprescription of granulocyte colony-stimulating factor (G-CSF). Aim and method: In this case series we aim to describe the treatment and progress of a number of patients in a secure psychiatric hospital in the UK. These patients were restarted on clozapine in combination with G-CSF, in spite of previous neutropenia associated with clozapine treatment. Discussion and conclusion: We hope that this case series will raise the profile of a potentially effective alternative to discontinuing clozapine after neutropenia.
On the Value of Collaboration in Location Estimation

Recently, extensive simulation-based research has shown a benefit to collaboration in wireless location estimation. However, an open question is “Is collaboration always inherently beneficial for location estimation? ” In this paper, we answer this question affirmatively under very general conditions and prove that the Cramér-Rao lower bound (CRLB) is strictly decreasing when nodes attempting to determine their locations collaborate, with very mild restrictions. More specifically, for a network of arbitrary size, we establish the value of collaboration in node positioning problems by proving that the inclusion of an additional collaborator strictly reduces the CRLB of the original network nodes' position estimates. Previous work has shown a related result, but only for 1-D and 2-D positioning using pairwise observations. We generalize previous work in several ways: 1) by presenting results that apply to any dimensionality; 2) by generalizing to any observation types, including allowing for mixed observation types and models; and 3) by including nuisance parameter estimation. Several mild conditions arise during the derivation of the proof, which must be satisfied to claim a strictly decreasing lower bound, and these are discussed. Additionally, the results of our analysis allow us to draw further insights into the value of collaboration for the individual nodes in the original network and for the newly introduced collaborator. The theoretical results are supported by numerical results, considering the special case of time-of-arrival (TOA)-based positioning in both line-of-sight and non-line-of-sight conditions. Finally, we draw some qualitative insights into the factors that affect the value of collaboration.
Adolescents' view on smoking, quitting and health education

Purpose – The aim of this paper is to explore the beliefs of 15‐17 year‐old Dutch adolescents about starting or quitting smoking and to explore their preferences regarding education concerning this topic.Design/methodology/approach – The paper shows that a total of 12 group interviews were held with 101 students in the highest classes in secondary school (lower and higher secondary school and first class of intermediate vocational education). Findings – The findings in this paper indicate that most adolescents started smoking to be cool and because they were curious about the taste of a cigarette. Smokers felt that smoking is sociable and relaxing, while non‐smokers emphasized the negative consequences of smoking. Smokers expected to quit smoking when the price of cigarettes further increased, or when they fell ill as a result of smoking. They did not expect to receive social support from their friends and parents during a quit attempt. The hardest times during their quit attempts would be in the presence .
Drug models of schizophrenia

Schizophrenia is a complex mental health disorder with positive, negative and cognitive symptom domains. Approximately one third of patients are resistant to currently available medication. New therapeutic targets and a better understanding of the basic biological processes that drive pathogenesis are needed in order to develop therapies that will improve quality of life for these patients. Several drugs that act on neurotransmitter systems in the brain have been suggested to model aspects of schizophrenia in animals and in man. In this paper, we selectively review findings from dopaminergic, glutamatergic, serotonergic, cannabinoid, GABA, cholinergic and kappa opioid pharmacological drug models to evaluate their similarity to schizophrenia. Understanding the interactions between these different neurotransmitter systems and their relationship with symptoms will be an important step towards building a coherent hypothesis for the pathogenesis of schizophrenia.
Full-Duplex Massive MIMO AF Relaying With Semiblind Gain Control

This paper proposes an amplify-and-forward-based massive multiple-input-multiple-output full-duplex relaying (AF-MM-FDR) protocol, where multiple source-destination pairs communicate simultaneously with a common full-duplex relay. A zero-forcing (ZF)-based relay transceiver design with semiblind gain control is presented, considering the problem of relay oscillation. The asymptotic expression of end-to-end signal-to-interference-plus-noise power (SINR) is derived under the general power scaling scheme. The scaling behaviors of echo interference (EI) and effective channel estimation error are determined. Scaling results show that the deployment of very large antenna arrays at the relay has the potential to eliminate the effect of EI due to the full-duplex operation, if the power scaling scheme is selected properly. Moreover, based on the asymptotic analysis, a low-complexity power control scheme is proposed to optimize the spectral efficiency of AF-MM-FDR. Simulation results show that the proposed power control scheme improves the spectral-energy efficiency tradeoff of AF-MM-FDR significantly.