Miracle-dz/UniFAR-FTUs huggingface dataset:
Interferon Kappa Inhibits Human Papillomavirus 31 Transcription by Inducing Sp100 Proteins

ABSTRACT High-risk human papillomaviruses (hr-HPV) establish persistent infections in keratinocytes, which can lead to cancer of the anogenital tract. Interferons (IFNs) are a family of secreted cytokines that induce IFN-stimulated genes (ISGs), many of which display antiviral activities. Transcriptome studies have indicated that established hr-HPV-positive cell lines display a reduced expression of ISGs, which correlates with decreased levels of interferon kappa (IFN-κ), a type I IFN constitutively expressed in keratinocytes. Prior studies have also suggested that IFN-β has anti-hr-HPV activity but the underlying mechanisms are not well understood. The downregulation of IFN-κ by hr-HPV raises the possibility that IFN-κ has anti-HPV activity. Using doxycycline-inducible IFN-κ expression in CIN612-9E cells, which maintain extrachromosomally replicating HPV31 genomes, we demonstrated that IFN-κ inhibits the growth of these cells and reduces viral transcription and replication. Interestingly, the initiation of viral early transcription was already inhibited at 4 to 6 h after IFN-κ expression. This was also observed with recombinant IFN-β, suggesting a common mechanism of IFNs. Transcriptome sequencing (RNA-seq) analysis identified 1,367 IFN-κ-regulated genes, of which 221 were modulated >2-fold. The majority of those (71%) matched known ISGs, confirming that IFN-κ acts as a bona fide type I IFN in hr-HPV-positive keratinocytes. RNA interference (RNAi) and cotransfection experiments indicated that the inhibition of viral transcription is mainly due to the induction of Sp100 proteins by IFN-κ. Consistent with published data showing that Sp100 acts as a restriction factor for HPV18 infection, our results suggest that hr-HPV target IFN-κ to prevent Sp100 expression and identify Sp100 as an ISG with anti-HPV activity. IMPORTANCE High-risk HPV can establish persistent infections which may progress to anogenital cancers. hr-HPV interfere with the expression of interferon (IFN)-stimulated genes (ISGs), which is due to reduced levels of IFN-κ, an IFN that is constitutively expressed in human keratinocytes. This study reveals that IFN-κ rapidly inhibits HPV transcription and that this is due to the induction of Sp100 proteins. Thus, Sp100 represents an ISG for hr-HPV.
AN ELECTRO-ENCEPHALOGRAPHIC STUDY OF THE ANALEPTIC ACTION OF ββ ETHYL METHYL GLUTARIMIDE

PP ETHYL methyl glutarimide (Megimide) was first synthesized in 1911. Its antibarbiturate activity was first observed by Shaw and others in 1951. It was subsequently investigated by him, in animals (Shaw et al., 1954) and in man (Shulman et al., 1955). Megimide is of particular clinical interest because attempted suicide and accidental overdose with barbiturates are common, and an effective antidote would help to reduce the morbidity and mortality which results. Such an antidote must be free from dangerous side actions, e.g. convulsions, and effective because careful conservative care without the use of drugs has already brought the mortality down to 1.6 per cent (Clemmensen, 1954) in Scandinavian centres devoted to this problem. A further clinical application of an antidote is the reversal of barbiturate anaesthesia in outpatients who have had minor surgical procedures. Finally, following neurosurgery performed during anaesthesia maintained by thiopentone, it is desirable to have a quick return to consciousness as variations in the level of 324 consciousness assist in assessing the postoperative course. Some preliminary electro-encephalographical work was done by the author previously (Shaw et al., 1954) and this work is an extension of it.
Porcine Mx1 Protein Inhibits Classical Swine Fever Virus Replication by Targeting Nonstructural Protein NS5B

ABSTRACT Mx proteins are interferon (IFN)-induced GTPases that have broad antiviral activity against a wide range of RNA and DNA viruses; they belong to the dynamin superfamily of large GTPases. In this study, we confirmed the anti-classical swine fever virus (CSFV) activity of porcine Mx1 in vitro and showed that porcine Mx2 (poMx2), human MxA (huMxA), and mouse Mx1 (mmMx1) also have anti-CSFV activity in vitro. Small interfering RNA (siRNA) experiments revealed that depletion of endogenous poMx1 or poMx2 enhanced CSFV replication, suggesting that porcine Mx proteins are responsible for the antiviral activity of interferon alpha (IFN-α) against CSFV infection. Confocal microscopy, immunoprecipitation, glutathione S-transferase (GST) pulldown, and bimolecular fluorescence complementation (BiFC) demonstrated that poMx1 associated with NS5B, the RNA-dependent RNA polymerase (RdRp) of CSFV. We used mutations in the poMx1 protein to elucidate the mechanism of their anti-CSFV activity and found that mutants that disrupted the association with NS5B lost all anti-CSV activity. Moreover, an RdRp activity assay further revealed that poMx1 undermined the RdRp activities of NS5B. Together, these results indicate that porcine Mx proteins exert their antiviral activity against CSFV by interacting with NS5B. IMPORTANCE Our previous studies have shown that porcine Mx1 (poMx1) inhibits classical swine fever virus (CSFV) replication in vitro and in vivo, but the molecular mechanism of action remains largely unknown. In this study, we dissect the molecular mechanism of porcine Mx1 and Mx2 against CSFV in vitro. Our results show that poMx1 associates with NS5B, the RNA-dependent RNA polymerase of CSFV, resulting in the reduction of CSFV replication. Moreover, the mutants of poMx1 further elucidate the mechanism of their anti-CSFV activities.
Retrovirus-Specific Differences in Matrix and Nucleocapsid Protein-Nucleic Acid Interactions: Implications for Genomic RNA Packaging

ABSTRACT Retroviral RNA encapsidation involves a recognition event between genomic RNA (gRNA) and one or more domains in Gag. In HIV-1, the nucleocapsid (NC) domain is involved in gRNA packaging and displays robust nucleic acid (NA) binding and chaperone functions. In comparison, NC of human T-cell leukemia virus type 1 (HTLV-1), a deltaretrovirus, displays weaker NA binding and chaperone activity. Mutation of conserved charged residues in the deltaretrovirus bovine leukemia virus (BLV) matrix (MA) and NC domains affects virus replication and gRNA packaging efficiency. Based on these observations, we hypothesized that the MA domain may generally contribute to NA binding and genome encapsidation in deltaretroviruses. Here, we examined the interaction between HTLV-2 and HIV-1 MA proteins and various NAs in vitro. HTLV-2 MA displays higher NA binding affinity and better chaperone activity than HIV-1 MA. HTLV-2 MA also binds NAs with higher affinity than HTLV-2 NC and displays more robust chaperone function. Mutation of two basic residues in HTLV-2 MA α-helix II, previously implicated in BLV gRNA packaging, reduces NA binding affinity. HTLV-2 MA binds with high affinity and specificity to RNA derived from the putative packaging signal of HTLV-2 relative to nonspecific NA. Furthermore, an HIV-1 MA triple mutant designed to mimic the basic character of HTLV-2 MA α-helix II dramatically improves binding affinity and chaperone activity of HIV-1 MA in vitro and restores RNA packaging to a ΔNC HIV-1 variant in cell-based assays. Taken together, these results are consistent with a role for deltaretrovirus MA proteins in viral RNA packaging.
Downregulation of Toll-Like Receptor 9 Expression by Beta Human Papillomavirus 38 and Implications for Cell Cycle Control

ABSTRACT Innate immunity is the first line of host defense against infections. Many oncogenic viruses can deregulate several immune-related pathways to guarantee the persistence of the infection. Here, we show that the cutaneous human papillomavirus 38 (HPV38) E6 and E7 oncoproteins suppress the expression of the double-stranded DNA sensor Toll-like receptor 9 (TLR9) in human foreskin keratinocytes (HFK), a key mediator of the antiviral innate immune host response. In particular, HPV38 E7 induces TLR9 mRNA downregulation by promoting accumulation of ΔNp73α, an antagonist of p53 and p73. Inhibition of ΔNp73α expression by antisense oligonucleotide in HPV38 E6/E7 HFK strongly rescues mRNA levels of TLR9, highlighting a key role of ΔNp73α in this event. Chromatin immunoprecipitation experiments showed that ΔNp73α is part of a negative transcriptional regulatory complex with IκB kinase beta (IKKβ) that binds to a NF-κB responsive element within the TLR9 promoter. In addition, the Polycomb protein enhancer of zeste homolog 2 (EZH2), responsible for gene expression silencing, is also recruited into the complex, leading to histone 3 trimethylation at lysine 27 (H3K27me3) in the same region of the TLR9 promoter. Ectopic expression of TLR9 in HPV38 E6/E7 cells resulted in an accumulation of the cell cycle inhibitors p21WAF1 and p27Kip1, decreased CDK2-associated kinase activity, and inhibition of cellular proliferation. In summary, our data show that HPV38, similarly to other viruses with well-known oncogenic activity, can downregulate TLR9 expression. In addition, they highlight a new role for TLR9 in cell cycle regulation. IMPORTANCE The mucosal high-risk HPV types have been clearly associated with human carcinogenesis. Emerging lines of evidence suggest the involvement of certain cutaneous HPV types in development of skin squamous cell carcinoma, although this association is still under debate. Oncogenic viruses have evolved different strategies to hijack the host immune system in order to guarantee the persistence of the infection. Their capability to evade the immune system is as important as their ability to promote cellular transformation. Therefore, understanding the viral mechanisms involved in viral persistence is a valid tool to evaluate their potential role in human carcinogenesis. Here, we show that E6 and E7 oncoproteins from the cutaneous HPV38 downregulate the expression of the double-stranded DNA sensor TLR9 of innate immunity. We also present evidence that the HPV38-mediated downregulation of TLR9 expression, in addition to its potential impact on the innate immune response, is linked to cell cycle deregulation.
Antiviral Therapy during Primary Simian Immunodeficiency Virus Infection Fails To Prevent Acute Loss of CD4+ T Cells in Gut Mucosa but Enhances Their Rapid Restoration through Central Memory T Cells

ABSTRACT Gut-associated lymphoid tissue (GALT) is an early target of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) and a site for severe CD4+ T-cell depletion. Although antiretroviral therapy (ART) is effective in suppressing HIV replication and restoring CD4+ T cells in peripheral blood, restoration in GALT is delayed. The role of restored CD4+ T-cell help in GALT during ART and its impact on antiviral CD8+ T-cell responses have not been investigated. Using the SIV model, we investigated gut CD4+ T-cell restoration in infected macaques, initiating ART during either the primary stage (1 week postinfection), prior to acute CD4+ cell loss (PSI), or during the chronic stage at 10 weeks postinfection (CSI). ART led to viral suppression in GALT and peripheral blood mononuclear cells of PSI and CSI animals at comparable levels. CSI animals had incomplete CD4+ T-cell restoration in GALT. In PSI animals, ART did not prevent acute CD4+ T-cell loss by 2 weeks postinfection in GALT but supported rapid and complete CD4+ T-cell restoration thereafter. This correlated with an accumulation of central memory CD4+ T cells and better suppression of inflammation. Restoration of CD4+ T cells in GALT correlated with qualitative changes in SIV gag-specific CD8+ T-cell responses, with a dominance of interleukin-2-producing responses in PSI animals, while both CSI macaques and untreated SIV-infected controls were dominated by gamma interferon responses. Thus, central memory CD4+ T-cell levels and qualitative antiviral CD8+ T-cell responses, independent of viral suppression, were the immune correlates of gut mucosal immune restoration during ART.
Workplace factors: The key to successful and sustained continuation of a general practice-based smoking cessation programme

Health promotion activity such as smoking cessation is now expected in primary care settings, including general practice. However, successful implementation and continuation of health promotion programmes is often difficult to achieve in any consistent way across a locality. This study aimed to investigate factors associated with implementation and maintenance difficulties for a smoking cessation programme in primary care, despite the provision of well-received training and support for practice nurses and general practitioners. A descriptive evaluation using numerical data and semi-structured interviews was used for general practices in the Wellington region of New Zealand during 2001-2002. The Can Quit Practice smoking cessation programme was developed and made available to all 114 general practices in the Wellington area. Data were collected and interviews conducted about implementation and ongoing programme delivery. One-third (39/114, 34%) of practices accepted and completed training for at least one staff member, usually a practice nurse. Subsequently, only 44% of practices (17/39) went on to achieve full programme implementation. Key factors precluding implementation included inadequate funding for practice nurse and general practitioner time, high patient workloads, lack of practice nurse autonomy and limited practice-wide commitment to smoking cessation. Unfavourable workplace factors can preclude the successful implementation and maintenance of an effective smoking cessation programme for patients, even when health professionals are aware of the benefits of smoking cessation, recognise the worth of offering such programmes, and receive acceptable training and ongoing support at no cost.
Foot and Ankle Fellowship Websites: An Assessment of Accessibility and Quality

Background. The Internet has been reported to be the first informational resource for many fellowship applicants. The objective of this study was to assess the accessibility of orthopaedic foot and ankle fellowship websites and to evaluate the quality of information provided via program websites. Methods. The American Orthopaedic Foot and Ankle Society (AOFAS) and the Fellowship and Residency Electronic Interactive Database (FREIDA) fellowship databases were accessed to generate a comprehensive list of orthopaedic foot and ankle fellowship programs. The databases were reviewed for links to fellowship program websites and compared with program websites accessed from a Google search. Accessible fellowship websites were then analyzed for the quality of recruitment and educational content pertinent to fellowship applicants. Results. Forty-seven orthopaedic foot and ankle fellowship programs were identified. The AOFAS database featured direct links to 7 (15%) fellowship websites with the independent Google search yielding direct links to 29 (62%) websites. No direct website links were provided in the FREIDA database. Thirty-six accessible websites were analyzed for content. Program websites featured a mean 44% (range = 5% to 75%) of the total assessed content. The most commonly presented recruitment and educational content was a program description (94%) and description of fellow operative experience (83%), respectively. Conclusions. There is substantial variability in the accessibility and quality of orthopaedic foot and ankle fellowship websites. Clinical Relevance. Recognition of deficits in accessibility and content quality may assist foot and ankle fellowships in improving program information online. Levels of Evidence: Level IV
Technique Tip: Single-Incision Endoscopic Plantar Fasciotomy

Two-incision endoscopic plantar fasciotomy (EPF) is an accepted surgical technique in the treatment of recalcitrant plantar fasciitis. Single-incision plantar fasciotomy is a relatively new technique in the surgeons’ armamentarium; however, it is not without pitfalls, specifically poor visualization. This article aims to help the foot and ankle surgeon make a smooth transition from 2-incision EPF to single-incision EPF while maintaining optimum visualization. Levels of Evidence: Level V: Expert opinion
Decentralized Thermal-Aware Task Scheduling for Large-Scale Many-Core Systems

Technology scaling has enabled fast increase in the number of cores integrated in many-core systems. However, feature size shrinking also makes large-scale many-core systems vulnerable to thermal failures. Thermal-aware task scheduling is an efficient technique to reduce the run-time temperatures of many-core processors. Most existing thermal-aware task scheduling algorithms leverage centralized scheduling schemes to gather the overall information and generate the task schedule at a center scheduler. Although that scheme can achieve the optimal temperature reduction, however, it faces severe computation bottleneck and communication congestion when the many-core processors evolve to large-scale with hundreds or thousands of cores. In this paper, we propose a decentralized thermal-aware scheduling algorithm to address this problem in large-scale systems. Experiment results on various benchmarks show that our decentralized algorithm achieves significant improvement on scalability (up to 84.3% reduction in monitoring traffic) and similar benefits on temperature reduction (by 5%) when compared with the state-of-the-art thermal-aware scheduling algorithm.
Methicillin-Resistant Staphylococcus aureus as the Most Common Cause of Perineal Abscesses

Methicillin-resistant Staphylococcus aureus (MRSA) is increasingly recognized as an important pathogen in female reproductive health. Vulvar abscesses are also an increasingly common condition seen in the gynecologic field. This investigation demonstrates that MRSA is the most common cause of vulvar abscesses at a large urban women's hospital. No demographic factors were demonstrated to be sufficiently predictive of the presence of MRSA. Given these findings, empiric treatment with antimicrobials providing MRSA coverage seems warranted in cases where antimicrobial therapy is indicated.
Age-Associated Aggravation of Clinical Disease after Primary Metapneumovirus Infection of BALB/c Mice

ABSTRACT Human metapneumovirus (hMPV) is associated with respiratory tract infections among children and adults. Because hMPV induces significant morbidity and mortality in the elderly, a model of hMPV infection in aged BALB/c mice was established. Young (8 weeks old) and aged (18 months old) mice were intranasally inoculated with hMPV. The infected mice showed respiratory dysfunction, as measured by plethysmography, a marked loss in weight (up to 24%), and severe histopathological abnormalities including bronchiolitis obliterans organizing pneumonia. However, clinical severity was far higher in the aged mice, and none of the young infected mice died. Although virus replication in the lung was greater in the older mice, clearance of virus was not delayed compared to young mice. Production of virus-specific antibody as well as neutralizing antibody was lower. Gamma interferon and monocyte chemotactic protein-1 levels in bronchoalveolar lavage fluid were significantly lower in older mice, whereas interleukin-6 and interleukin-4 levels were significantly higher. We observed by flow cytometry a significant increase in the CD4+ T lymphocytes (P < 0.05) of the aged mice and no difference in CD8+ T-cell recruitment to the respiratory tract between the two groups. The present study investigated the effects of aging on the immunopathogenesis of hMPV infection and suggests that CD4+ T lymphocytes, the cytokine response, or a defect in humoral response may be associated with the increased disease severity observed in the aged mice.
Design-Efficient Approximate Multiplication Circuits Through Partial Product Perforation

Approximate computing has received significant attention as a promising strategy to decrease power consumption of inherently error tolerant applications. In this paper, we focus on hardware-level approximation by introducing the partial product perforation technique for designing approximate multiplication circuits. We prove in a mathematically rigorous manner that in partial product perforation, the imposed errors are bounded and predictable, depending only on the input distribution. Through extensive experimental evaluation, we apply the partial product perforation method on different multiplier architectures and expose the optimal architecture-perforation configuration pairs for different error constraints. We show that, compared with the respective exact design, the partial product perforation delivers reductions of up to 50% in power consumption, 45% in area, and 35% in critical delay. In addition, the product perforation method is compared with the state-of-the-art approximation techniques, i.e., truncation, voltage overscaling, and logic approximation, showing that it outperforms them in terms of power dissipation and error.
Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

ABSTRACT Shedding of microparticles (MPs) is a consequence of apoptotic cell death and cellular activation. Low levels of circulating MPs in blood help maintain homeostasis, whereas increased MP generation is linked to many pathological conditions. Herein, we investigated the role of MPs in dengue virus (DENV) infection. Infection of various susceptible cells by DENV led to apoptotic death and MP release. These MPs harbored a viral envelope protein and a nonstructural protein 1 (NS1) on their surfaces. Ex vivo analysis of clinical specimens from patients with infections of different degrees of severity at multiple time points revealed that MPs generated from erythrocytes and platelets are two major MP populations in the circulation of DENV-infected patients. Elevated levels of red blood cell-derived MPs (RMPs) directly correlated with DENV disease severity, whereas a significant decrease in platelet-derived MPs was associated with a bleeding tendency. Removal by mononuclear cells of complement-opsonized NS1–anti-NS1 immune complexes bound to erythrocytes via complement receptor type 1 triggered MP shedding in vitro, a process that could explain the increased levels of RMPs in severe dengue. These findings point to the multiple roles of MPs in dengue pathogenesis. They offer a potential novel biomarker candidate capable of differentiating dengue fever from the more serious dengue hemorrhagic fever. IMPORTANCE Dengue is the most important mosquito-transmitted viral disease in the world. No vaccines or specific treatments are available. Rapid diagnosis and immediate treatment are the keys to achieve a positive outcome. Dengue virus (DENV) infection, like some other medical conditions, changes the level and composition of microparticles (MPs), tiny bag-like structures which are normally present at low levels in the blood of healthy individuals. This study investigated how MPs in culture and patients' blood are changed in response to DENV infection. Infection of cells led to programmed cell death and MP release. In patients' blood, the majority of MPs originated from red blood cells and platelets. Decreased platelet-derived MPs were associated with a bleeding tendency, while increased levels of red blood cell-derived MPs (RMPs) correlated with more severe disease. Importantly, the level of RMPs during the early acute phase could serve as a biomarker to identify patients with potentially severe disease who require immediate care.