Miracle-dz/UniFAR-FTUs huggingface dataset:
Nipah Virus C and W Proteins Contribute to Respiratory Disease in Ferrets

ABSTRACT Nipah virus (NiV) is a highly lethal paramyxovirus that recently emerged as a causative agent of febrile encephalitis and severe respiratory disease in humans. The ferret model has emerged as the preferred small-animal model with which to study NiV disease, but much is still unknown about the viral determinants of NiV pathogenesis, including the contribution of the C protein in ferrets. Additionally, studies have yet to examine the synergistic effects of the various P gene products on pathogenesis in animal models. Using recombinant NiVs (rNiVs), we examine the sole contribution of the NiV C protein and the combined contributions of the C and W proteins in the ferret model of NiV pathogenesis. We show that an rNiV void of C expression resulted in 100% mortality, though with limited respiratory disease, like our previously reported rNiV void of W expression; this finding is in stark contrast to the attenuated phenotype observed in previous hamster studies utilizing rNiVs void of C expression. We also observed that an rNiV void of both C and W expression resulted in limited respiratory disease; however, there was severe neurological disease leading to 60% mortality, and the surviving ferrets demonstrated sequelae similar to those for human survivors of NiV encephalitis. IMPORTANCE Nipah virus (NiV) is a human pathogen capable of causing lethal respiratory and neurological disease. Many human survivors have long-lasting neurological impairment. Using a ferret model, this study demonstrated the roles of the NiV C and W proteins in pathogenesis, where lack of either the C or the W protein independently decreased the severity of clinical respiratory disease but did not decrease lethality. Abolishing both C and W expression, however, dramatically decreased the severity of respiratory disease and the level of destruction of splenic germinal centers. These ferrets still suffered severe neurological disease: 60% succumbed to disease, and the survivors experienced long-term neurological impairment, such as that seen in human survivors. This new ferret NiV C and W knockout model may allow, for the first time, the examination of interventions to prevent or mitigate the neurological damage and sequelae experienced by human survivors.
Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

ABSTRACT HIV establishes reservoirs of infected cells that persist despite effective antiretroviral therapy (ART). In most patients, the virus begins to replicate soon after treatment interruption. However, a low frequency of infected cells at the time of treatment interruption has been associated with delayed viral rebound. Likewise, individuals who control the infection spontaneously, so-called HIV-1 controllers (HICs), carry particularly low levels of infected cells. It is unclear, however, whether and how this small number of infected cells contributes to durable viral control. Here we compared 38 HICs with 12 patients on effective combined antiretroviral therapy (cART) and found that the low frequency of infected cells in the former subjects was associated both with less efficient viral reactivation in resting CD4+ T cells and with less efficient virion production ex vivo. We also found that a potent HIV-specific CD8+ T cell response was present only in those HICs whose CD4+ T cells produced virus ex vivo. Long-term spontaneous control of HIV infection in HICs thus appears to be sustained on the basis of the inefficient reactivation of viruses from a limited number of infected cells and the capacity of HICs to activate a potent HIV-specific CD8+ T cell response to counteract efficient viral reactivation events. IMPORTANCE There is a strong scientific interest in developing strategies to eradicate the HIV-1 reservoir. Very rare HIV-1-infected patients are able to spontaneously control viremia for long periods of time (HIV-1 controllers [HICs]) and are put forward as a model of HIV-1 remission. Here, we show that the low viral reservoirs found in HICs are a critical part of the mechanisms underlying viral control and result in a lower probability of HIV-1 reactivation events, resulting in limited HIV-1 release and spread. We found that those HICs in whom viral reactivation and spread from CD4+ T cells in vitro were the most difficult were those with diminished CD8+ T cell responses. These results suggest that, in some settings, low HIV-1 reservoirs decisively contribute to at least the temporary control of infection without antiretroviral therapy. We believe that this work provides information of relevance in the context of the search for HIV-1 remission.
Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization

Significance Allergic diseases are characterized by inappropriate inflammatory responses to benign environmental antigens (Ags). Primary clinical approaches to allergic disease consist of symptom control or administration of soluble Ag to skew the immune response to alternate phenotypes or induce immune tolerance. However, such approaches carry a significant risk of adverse events and require a long treatment course to achieve efficacy. In this paper, we describe the use of i.v. -administered nanoparticles as carriers of whole-protein Ag to induce tolerance safely and effectively in the absence of nonspecific immunosuppression for the prevention and treatment of a mouse model of allergic asthma. Specific immunotherapy (SIT) is the most widely used treatment for allergic diseases that directly targets the T helper 2 (Th2) bias underlying allergy. However, the most widespread clinical applications of SIT require a long period of dose escalation with soluble antigen (Ag) and carry a significant risk of adverse reactions, particularly in highly sensitized patients who stand to benefit most from a curative treatment. Thus, the development of safer, more efficient methods to induce Ag-specific immune tolerance is critical to advancing allergy treatment. We hypothesized that antigen-associated nanoparticles (Ag-NPs), which we have used to prevent and treat Th1/Th17-mediated autoimmune disease, would also be effective for the induction of tolerance in a murine model of Th2-mediated ovalbumin/alum-induced allergic airway inflammation. We demonstrate here that antigen-conjugated polystyrene (Ag-PS) NPs, although effective for the prophylactic induction of tolerance, induce anaphylaxis in presensitized mice. Antigen-conjugated NPs made of biodegradable poly(lactide-co-glycolide) (Ag-PLG) are similarly effective prophylactically, are well tolerated by sensitized animals, but only partially inhibit Th2 responses when administered therapeutically. PLG NPs containing encapsulated antigen [PLG(Ag)], however, were well tolerated and effectively inhibited Th2 responses and airway inflammation both prophylactically and therapeutically. Thus, we illustrate progression toward PLG(Ag) as a biodegradable Ag carrier platform for the safe and effective inhibition of allergic airway inflammation without the need for nonspecific immunosuppression in animals with established Th2 sensitization.
Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: a population pharmacokinetic/pharmacodynamic study

Abstract Background Low efficacy of miltefosine in the treatment of visceral leishmaniasis was recently observed in Eastern Africa. Objectives To describe the pharmacokinetics and establish a pharmacokinetic/pharmacodynamic relationship for miltefosine in Eastern African patients with visceral leishmaniasis, using a time-to-event approach to model relapse of disease. Methods Miltefosine plasma concentrations from 95 patients (48 monotherapy versus 47 combination therapy) were included in the population pharmacokinetic model using non-linear mixed effects modelling. Subsequently a time-to-event model was developed to model the time of clinical relapse. Various summary pharmacokinetic parameters (various AUCs, Time > EC50, Time > EC90), normalized within each treatment arm to allow simultaneous analysis, were evaluated as relapse hazard-changing covariates. Results A two-compartment population model with first-order absorption fitted the miltefosine pharmacokinetic data adequately. Relative bioavailability was reduced (−74%, relative standard error 4.7%) during the first week of treatment of the monotherapy arm but only the first day of the shorter combination regimen. Time to the relapse of infection could be described using a constant baseline hazard (baseline 1.8 relapses/year, relative standard error 72.7%). Miltefosine Time > EC90 improved the model significantly when added in a maximum effect function on the baseline hazard (half maximal effect with Time > EC90 6.97 days for monotherapy). Conclusions Miltefosine drug exposure was found to be decreased in Eastern African patients with visceral leishmaniasis, due to a (transient) initial lower bioavailability. Relapse hazard was inversely linked to miltefosine exposure. Significantly lower miltefosine exposure was observed in children compared with adults, further urging the need for implementation of dose adaptations for children.
In vitro iCLIP-based modeling uncovers how the splicing factor U2AF2 relies on regulation by cofactors

Alternative splicing generates distinct mRNA isoforms and is crucial for proteome diversity in eukaryotes. The RNA-binding protein (RBP) U2AF2 is central to splicing decisions, as it recognizes 3′ splice sites and recruits the spliceosome. We establish “in vitro iCLIP” experiments, in which recombinant RBPs are incubated with long transcripts, to study how U2AF2 recognizes RNA sequences and how this is modulated by trans-acting RBPs. We measure U2AF2 affinities at hundreds of binding sites and compare in vitro and in vivo binding landscapes by mathematical modeling. We find that trans-acting RBPs extensively regulate U2AF2 binding in vivo, including enhanced recruitment to 3′ splice sites and clearance of introns. Using machine learning, we identify and experimentally validate novel trans-acting RBPs (including FUBP1, CELF6, and PCBP1) that modulate U2AF2 binding and affect splicing outcomes. Our study offers a blueprint for the high-throughput characterization of in vitro mRNP assembly and in vivo splicing regulation.
Predictors of Health-related Quality of Life in Irritable Bowel Syndrome Patients Compared With Healthy Individuals

Background: Irritable bowel syndrome (IBS) reduces health-related quality of life (HRQOL). It is unclear how having IBS modifies the impact of gastrointestinal (GI), psychosocial, and somatic symptom variables on HRQOL compared with healthy controls (HCs). Aims: (1) Determine psychosocial, somatic, and physical status variables most predictive of HRQOL in IBS and HCs and (2) determine if IBS status modifies relationships between predictive factors and HRQOL. Methods: IBS patients and HCs completed validated questionnaires measuring GI symptoms, psychosocial/somatic variables, and physical [physical component score (PCS)] and mental [mental component score (MCS)] HRQOL via the Short-Form-36. Associations between these variables and HRQOL were evaluated with multiple linear regressions. Variables were standardized to determine the strongest predictors of HRQOL. Statistical significance level was 0.01. Results: Mean HRQOL was higher in 417 HCs versus 290 IBS subjects (PCS: 55.6 vs. 48.6, P<0.001; MCS: 53.7 vs. 44.8, P<0.001). The GI symptom measures were negatively associated with PCS in IBS, but only usual severity was associated with MCS (P<0.01). In all subjects, psychosocial and somatic measures were associated with MCS and not PCS excluding GI symptom anxiety, which correlated with both (P<0.01). The strongest predictor of MCS was perceived stress in IBS and depression symptoms in HCs. GI symptom anxiety was the strongest predictor of PCS in both. Greater perceived stress and somatic symptom severity and less mindfulness was linked to larger reductions in HRQOL for IBS compared with HCs (P<0.01). Conclusions: GI symptom severity and anxiety correlate with PCS, whereas psychosocial/somatic measures parallel MCS. However, HRQOL is comparable in IBS and HCs when perceived stress, somatic symptom severity, and mindfulness are at optimal levels. These findings may have important implications in the management of IBS.
A Linear Empirical Model of Self-Regulation on Flourishing, Health, Procrastination, and Achievement, Among University Students

This research aimed to analyze the linear bivariate correlation and structural relations between self-regulation -as a central construct-, with flow, health, procrastination and academic performance, in an academic context. A total of 363 college students took part, 101 men (27.8%) and 262 women (72.2%). Participants had an average age of 22 years and were between the first and fifth year of studies. They were from five different programs and two universities in Bogotá city (Colombia). A validated ad hoc questionnaire of physical and psychological health was applied along with a battery of tests to measure self-regulation, procrastination, and flourishing. To establish an association relationship, Pearson bivariate correlations were performed using SPSS software (v. 22.0), and structural relationship predictive analysis was performed using an SEM on AMOS software (v. 22.0). Regarding this linear association, it was established that (1) self-regulation has a significant positive association on flourishing and overall health, and a negative effect on procrastination. Regarding the structural relation, it confirmed that (2) self-regulation is a direct and positive predictor of flourishing and health; (3) self-regulation predicts procrastination directly and negatively, and academic performance indirectly and positively; and (4) age and gender have a prediction effect on the analyzed variables. Implications, limitations and future research scope are discussed.
Sustainability of rainwater harvesting systems in multistorey residential buildings

Problem statement: The urban water supply systems in Australian large cities, which generally depend on large surface water reservoirs, are highly stressed due to rapid urban growth and severe drought conditions during the current decade . To ensure the long term sustainability of urban water supply, various alternative water sources inc luding rainwater tanks, grey water, wastewater and desalination plants are being examined in Australia . In the previous research, it has been shown that rainwater tank of appropriate size, installed in de tached small dwellings, can meet a significant proportion of household water demand, but there has been limited study on water savings and financial viability of Rain Water Harvesting System (RWHS) for multistorey residential buildings. This study examines the sustainability of RWHS in multistorey residential buildings in Sydney under different scenarios such as varying roof area, number of floo rs in the building, water price and interest rate t o identify favorable condition where RWHS proves to be sustainable. Approach: A hypothetical multistorey building was considered and various sce narios in relation to site area and floor arrangement were established. A water balance model was developed to calculate water savings for various scenarios. Finally, life cycle costing was undertaken to identify most sustainable RWHS scenario for the hypothetical multistorey building. Results: It was found that a higher roof area is more favorable in terms of water savings and financial b enefits. Capital and maintenance costs account for the majority of the expenditure of a RWHS. Plumbing cost forms the largest single component of the capital cost. It is shown that lower interest and i ncreased water price regimes enhance the financial viability of RWHS. Conclusion: It was found that it is possible to achieve "pay b ack" for a RWHS under some favorable scenarios and conditions thus making the RWHS for multistorey buildings in Sydney sustainable.
CFAI‐Plus: Adding cognitive frailty as a new domain to the comprehensive frailty assessment instrument

Cognitive frailty is characterized by the presence of cognitive impairment in exclusion of dementia. In line with other frailty domains, cognitive frailty is associated with negative outcomes. The Comprehensive Frailty Assessment Instrument (CFAI) measures 4 domains of frailty, namely physical, psychological, social, and environmental frailty. The absence of cognitive frailty is a limitation.
CoERG11 A395T mutation confers azole resistance in Candida orthopsilosis clinical isolates

Background Candida orthopsilosis is a human fungal pathogen responsible for a wide spectrum of symptomatic infections. Evidence suggests that C. orthopsilosis is mainly susceptible to azoles, the most extensively used antifungals for treatment of these infections. However, fluconazole-resistant clinical isolates are reported. Objectives This study evaluated the contribution of a single amino acid substitution in the azole target CoErg11 to the development of azole resistance in C. orthopsilosis. Methods C. orthopsilosis clinical isolates (n = 40) were tested for their susceptibility to azoles and their CoERG11 genes were sequenced. We used a SAT1 flipper-driven transformation to integrate a mutated CoERG11 allele in the genetic background of a fluconazole-susceptible isolate. Results Susceptibility testing revealed that 16 of 40 C. orthopsilosis clinical isolates were resistant to fluconazole and to at least one other azole. We identified an A395T mutation in the CoERG11 coding sequence of azole-resistant isolates only that resulted in the non-synonymous amino acid substitution Y132F. The SAT1 flipper cassette strategy led to the creation of C. orthopsilosis mutants that carried the A395T mutation in one or both CoERG11 alleles (heterozygous or homozygous mutant, respectively) in an azole-susceptible genetic background. We tested mutant strains for azole susceptibility and for hot-spot locus heterozygosity. Both the heterozygous and the homozygous mutant strains exhibited an azole-resistant phenotype. Conclusions To the best of our knowledge, these findings provide the first evidence that the CoErg11 Y132F substitution confers multi-azole resistance in C. orthopsilosis.
Study about the computer virus dissemination model based on complex network

In this paper, several basic models of complex networks be studied, and I improve the BA scale-free network model. According to the characteristics of transmission of the virus in real network, I take some experiments, and get the experimental data. According to experimental results, I put forward a specific containment strategy, and do the simulations. Find that this containment strategy plays a very good deterrent in the early spread of the virus.
A Survey on Neural Network-Based Summarization Methods

Automatic text summarization, the automated process of shortening a text while reserving the main ideas of the document(s), is a critical research area in natural language processing. The aim of this literature review is to survey the recent work on neural-based models in automatic text summarization. We examine in detail ten state-of-the-art neural-based summarizers: five abstractive models and five extractive models. In addition, we discuss the related techniques that can be applied to the summarization tasks and present promising paths for future research in neural-based summarization.
Arterial coupling for microvascular free tissue transfer in head and neck reconstruction.

OBJECTIVE To demonstrate the efficacy of arterial coupling. DESIGN We report our experience in head and neck reconstruction with the Unilink Microvascular Anastomotic System (Synovis MCA, Birmingham, Ala). Data were collected in a consecutive series of 49 patients undergoing composite resection of head and neck tumors followed by free tissue transfer. SETTING All patient care took place at Yale-New Haven Hospital, New Haven, Conn, a university-based tertiary care facility. PATIENTS Forty-nine consecutive patients aged 43 to 85 years underwent a total of 50 microvascular free tissue transfers using the Unilink coupling device. There were 18 women and 31 men, and the following 3 types of flaps were performed: radial forearm (n = 36), fibula (n = 12), and rectus abdominus (n = 2). INTERVENTIONS The Unilink coupling device was used in this case series. Each arterial and venous anastomosis was performed with the coupling device. Free tissue transfers were monitored clinically and outcomes were recorded. MAIN OUTCOME MEASURES Flap survival and thrombosis of the arterial anastomoses were determined, as was median length of stay. RESULTS There were no flap failures in the series. Of the 50 coupled arterial anastomoses, the predominant coupler size used was 2.5 mm in diameter. Reconstructions included 36 radial forearm, 12 fibular osteocutaneous, and 2 rectus abdominus myocutaneous free flaps. One intraoperative arterial thrombosis occurred, requiring hand-sewn anastomosis, and another pulled away from the intact coupler in a steroid-dependent patient. There were no complications related to technical performance of the coupling device. The median length of stay was 14 days. CONCLUSION While hand-sewn anastomoses in free tissue transfer remain the preferred technique for many microsurgeons, use of the coupler is a viable alternative to sutured anastomoses.
Highly Polarized Photoluminescence and Photodetection from Single Indium Phosphide Nanowires

We have characterized the fundamental photoluminescence (PL) properties of individual, isolated indium phosphide (InP) nanowires to define their potential for optoelectronics. Polarization-sensitive measurements reveal a striking anisotropy in the PL intensity recorded parallel and perpendicular to the long axis of a nanowire. The order-of-magnitude polarization anisotropy was quantitatively explained in terms of the large dielectric contrast between these free-standing nanowires and surrounding environment, as opposed to quantum confinement effects. This intrinsic anisotropy was used to create polarization-sensitive nanoscale photodetectors that may prove useful in integrated photonic circuits, optical switches and interconnects, near-field imaging, and high-resolution detectors.