Miracle-dz/UniFAR-FTUs huggingface dataset:
The Translesion Polymerase Pol η Is Required for Efficient Epstein-Barr Virus Infectivity and Is Regulated by the Viral Deubiquitinating Enzyme BPLF1

ABSTRACT Epstein-Barr virus (EBV) infection and lytic replication are known to induce a cellular DNA damage response. We previously showed that the virally encoded BPLF1 protein interacts with and regulates several members of the translesion synthesis (TLS) pathway, a DNA damage tolerance pathway, and that these cellular factors enhance viral infectivity. BPLF1 is a late lytic cycle gene, but the protein is also packaged in the viral tegument, indicating that BPLF1 may function both early and late during infection. The BPLF1 protein expresses deubiquitinating activity that is strictly conserved across the Herpesviridae; mutation of the active site cysteine results in a loss of enzymatic activity. Infection with an EBV BPLF1 knockout virus results in decreased EBV infectivity. Polymerase eta (Pol η), a specialized DNA repair polymerase, functions in TLS and allows for DNA replication complexes to bypass lesions in DNA. Here we report that BPLF1 interacts with Pol η and that Pol η protein levels are increased in the presence of functional BPLF1. BPLF1 promotes a nuclear relocalization of Pol η molecules which are focus-like in appearance, consistent with the localization observed when Pol η is recruited to sites of DNA damage. Knockdown of Pol η resulted in decreased production of infectious virus, and further, Pol η was found to bind to EBV DNA, suggesting that it may allow for bypass of damaged viral DNA during its replication. The results suggest a mechanism by which EBV recruits cellular repair factors, such as Pol η, to sites of viral DNA damage via BPLF1, thereby allowing for efficient viral DNA replication. IMPORTANCE Epstein-Barr virus is the causative agent of infectious mononucleosis and infects approximately 90% of the world's population. It causes lymphomas in individuals with acquired and innate immune disorders and is strongly associated with Hodgkin's lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphomas, nasopharyngeal carcinoma (NPC), and lymphomas that develop in organ transplant recipients. Cellular DNA damage is a major determinant in the establishment of oncogenic processes and is well studied, but there are few studies of endogenous repair of viral DNA. This work evaluates how EBV's BPLF1 protein and its conserved deubiquitinating activity regulate the cellular DNA repair enzyme polymerase eta and recruit it to potential sites of viral damage and replication, resulting in enhanced production of infectious virus. These findings help to establish how EBV enlists and manipulates cellular DNA repair factors during the viral lytic cycle, contributing to efficient infectious virion production.
Identifying Host Factors Associated with DNA Replicated During Virus Infection*

Viral DNA genomes replicating in cells encounter a myriad of host factors that facilitate or hinder viral replication. Viral proteins expressed early during infection modulate host factors interacting with viral genomes, recruiting proteins to promote viral replication, and limiting access to antiviral repressors. Although some host factors manipulated by viruses have been identified, we have limited knowledge of pathways exploited during infection and how these differ between viruses. To identify cellular processes manipulated during viral replication, we defined proteomes associated with viral genomes during infection with adenovirus, herpes simplex virus and vaccinia virus. We compared enrichment of host factors between virus proteomes and confirmed association with viral genomes and replication compartments. Using adenovirus as an illustrative example, we uncovered host factors deactivated by early viral proteins, and identified a subgroup of nucleolar proteins that aid virus replication. Our data sets provide valuable resources of virus-host interactions that affect proteins on viral genomes.
A Systematic Critical Appraisal of Non-Pharmacological Management of Rheumatoid Arthritis with Appraisal of Guidelines for Research and Evaluation II

Clinical practice guidelines (CPGs) have been developed to summarize evidence about the management of rheumatoid arthritis (RA) and facilitate the uptake of evidence-based knowledge by consumers, health professionals, health administrators and policy makers. The objectives of this review was to assess the quality of CPGS on non-pharmacological management of RA with a standardized and validated instrument - the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool and summarize the key recommendations from these CPGs. Scientific literature databases from 2001 to 2013 were systematically searched and a total of 13 CPGs for RA was identified. Only a minority of AGREE II domains were effectively addressed by the CPGS. Scope and purpose was effectively addressed in 10 out of 13 CPGs, stakeholder involvement in 11 CPGs, rigor of development in 6 CPGs, clarity/presentation in 9 CPGs, editorial independence in 1 CPGs, and applicability in none of the CPGs. The overall quality of the included CPGs according to the 7-point AGREE II scoring system was 4.8±1.04. Patient education/self-management, aerobic, dynamic and stretching exercises were the commonly recommended for the non-pharmacological management of RA by the high-quality CPGs. The general clinical management recommendations tended to be similar among high-quality CPGs. Non-pharmacological management interventions were superficially addressed in more than half of the selected CPGs. CPGs creators should use the AGREE II criteria when developing guidelines. Innovative and effective methods of CPGs implementation to users are needed to ultimately enhance the quality of life of arthritic individuals. In addition, it was difficult to establish between strongly recommended, recommended and weakly recommended, as there is no consensus between the strength of the recommendations between the appraised CPGs.
Molecular Dynamics Study of Diffusion of O2 Penetrates in Uncrosslinked Polydimethysiloxane (PDMS), Crosslinked PDMS, and PDMS-based Nanocomposites

Molecular dynamics simulations are used to study diffusion of O2 molecules in pure polydimethysiloxane (PDMS), crosslinked PDMS, and PDMS-based nanocomposites. The PDMS chains and penetrates are modeled using a hybrid interatomic potential which treats the Si-O atoms along the chain backbone explicitly while coarse-graining the methyl side groups and penetrates. By tracking the diffusion of penetrates in the system and subsequently computing their mean-squared displacement, diffusion coefficients are obtained. In pure PDMS models of varying molecular weight, diffusivity of the O2 penetrates is found to have an inverse relationship with chain length. Simulation models with longer chains have more entanglements which restrict the evolution of free volume in the system necessary for diffusion of the penetrants, thus reducing their diffusivity. In agreement with experiment, the crosslinked models studied in this work maintain a PDMS to crosslink molecule weight ratio of 5:1 or 10:1. In order to satisfy this weight ratio criterion, the crosslinked models in this study are oversaturated (number of crosslink molecule ends exceeds PDMS chain ends). Despite crosslinking, the presence of these unbonded crosslink molecules in the system enhances diffusivity for the crosslinked cases in comparison to the pure PDMS models. In the nanocomposite models, diffusivity of O2 has an inverse relationship with volume fraction. Nanoparticles act as geometric obstacles for diffusion of the atmospheric penetrates, reducing the available porosity for diffusion. In models with the smallest gap between nanoparticles, a “crossover” behavior is observed at the lowest temperatures examined, resulting in diffusivities higher than the crosslinked and pure PDMS models. This is attributed to the preferential diffusion of the penetrants through localized regions of low density within the PDMS matrix. The creation of these low density regions is due to a combination of the limited mobility of the PDMS chains at temperatures near glass transition and the close proximity of nanoparticles at 20% volume fraction. For all models, the role of temperature on diffusion is captured using the WilliamsLandel-Ferry (WLF) equation. The relationship between WLF parameters and molecular weight or nanoparticle volume fraction is studied. This thesis is approved for recommendation to the Graduate Council.
Clinical outcomes in a specialist male genital skin clinic: prospective follow‐up of 600 patients

It is important to assess outcomes for medical interventions in order to focus scarce resources on outcomes with a known positive benefit. An open, observational study was performed to assess the clinical outcomes of 600 male patients with a genital skin problem attending a specialist secondary care dermatology facility. Patients were mainly referred by general practitioners and genitourinary medicine physicians. Outcome was measured at 3 and 6 months, and was determined by clinical examination and assessment of patient symptoms. The mean age of the group was 45.3 years. The commonest diagnoses were lichen sclerosus (30.5%), balanitis (17.3%), eczema (12.8%), lichen planus (7.3%), psoriasis (7.2%) and benign lesions (5.5%). The commonest presenting symptoms were genital rash (43%), genital soreness, pain or burning (17.5%), and penile lesions (15.7%). Lichen sclerosus and all forms of balanitis were more common in uncircumcised patients, whereas lichen planus was more common in circumcised males. Short‐term outcome was excellent, with 11.5% of patients being reassured and discharged on their first visit, and after 6 months 58% of all patients were clear and 12% had improved. Only 4.5% reported no improvement in symptoms. Diagnostic biopsy demonstrated malignant or premalignant lesions in nearly a fifth of those having a procedure. Close working with urological and genitourinary medicine colleagues is important to manage the various aspects of male health.
Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson’s disease

Mitochondrial pyruvate carrier may be a therapeutic target in Parkinson’s disease. A mitochondrial target for slowing Parkinson's disease Currently, there are no disease-modifying treatments to stall progression of Parkinson’s disease (PD). A drug in development to treat diabetes might provide a new way to slow the progression of PD according to new work by Ghosh and colleagues. The drug, MSDC-0160, targets a recently identified carrier of pyruvate (a major substrate for energy production) into the mitochondria. Ghosh et al. now show that this drug, which attenuates the mitochondrial pyruvate carrier, blocks neurodegeneration in several different cellular and animal models of PD. Furthermore, cellular autophagy was restored, and neuroinflammation was reduced in two mouse models of PD. These results support continued investigations into whether the mitochondrial pyruvate carrier will be a useful therapeutic target in PD. Mitochondrial and autophagic dysfunction as well as neuroinflammation are involved in the pathophysiology of Parkinson’s disease (PD). We hypothesized that targeting the mitochondrial pyruvate carrier (MPC), a key controller of cellular metabolism that influences mTOR (mammalian target of rapamycin) activation, might attenuate neurodegeneration of nigral dopaminergic neurons in animal models of PD. To test this, we used MSDC-0160, a compound that specifically targets MPC, to reduce its activity. MSDC-0160 protected against 1-methyl-4-phenylpyridinium (MPP+) insult in murine and cultured human midbrain dopamine neurons and in an α-synuclein–based Caenorhabditis elegans model. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–treated mice, MSDC-0160 improved locomotor behavior, increased survival of nigral dopaminergic neurons, boosted striatal dopamine levels, and reduced neuroinflammation. Long-term targeting of MPC preserved motor function, rescued the nigrostriatal pathway, and reduced neuroinflammation in the slowly progressive Engrailed1 (En1+/−) genetic mouse model of PD. Targeting MPC in multiple models resulted in modulation of mitochondrial function and mTOR signaling, with normalization of autophagy and a reduction in glial cell activation. Our work demonstrates that changes in metabolic signaling resulting from targeting MPC were neuroprotective and anti-inflammatory in several PD models, suggesting that MPC may be a useful therapeutic target in PD.
Psychological stress‐induced colonic barrier dysfunction: Role of immune‐mediated mechanisms

Evidence suggests that patients with irritable bowel syndrome (IBS) exhibit increases in gut permeability and alterations in tight junction (TJ) protein expression. Although psychological stress worsens IBS symptoms, the mechanisms by which stress enhances gut permeability and affects TJ protein expression remain to be determined. Here, we test the hypothesis that chronic intermittent psychological stress activates the release of proinflammatory cytokines to alter TJ proteins and promotes increased gut permeability.
Evaluation of the beat-to-beat detection accuracy of PulseOn wearable optical heart rate monitor

Heart rate variability (HRV) provides significant information about the health status of an individual. Optical heart rate monitoring is a comfortable alternative to ECG based heart rate monitoring. However, most available optical heart rate monitoring devices do not supply beat-to-beat detection accuracy required by proper HRV analysis. We evaluate the beat-to-beat detection accuracy of a recent wrist-worn optical heart rate monitoring device, PulseOn (PO). Ten subjects (8 male and 2 female; 35.9±10.3 years old) participated in the study. HRV was recorded with PO and Firstbeat Bodyguard 2 (BG2) device, which was used as an ECG based reference. HRV was recorded during sleep. As compared to BG2, PO detected on average 99.57% of the heartbeats (0.43% of beats missed) and had 0.72% extra beat detection rate, with 5.94 ms mean absolute error (MAE) in beat-to-beat intervals (RRI) as compared to the ECG based RRI BG2. Mean RMSSD difference between PO and BG2 derived HRV was 3.1 ms. Therefore, PO provides an accurate method for long term HRV monitoring during sleep.
Measuring Evolutionary Isolation for Conservation

Conservation planning needs to account for limited resources when choosing those species on which to focus attention and resources. Currently, funding is biased to small sections of the tree of life, such as raptors and carnivores. One new approach for increasing the diversity of species under consideration considers how many close relatives a species has in its evolutionary tree. At least eleven different ways to measure this characteristic on phylogenies for the purposes of setting species-specific priorities for conservation have been proposed. We find that there is much redundancy within the current set, with three pairs of metrics being essentially identical. Non-redundant metrics represent different trade-offs between the unique evolutionary history represented by a species verses its average distance to all other species. Depending on which metric is used, species priority lists can differ as much as 85% for the top 100 species. We call for some consensus on the theory behind these metrics and suggest that all future developments are compared to the current published set, and offer scripts to aid such comparisons.
Variation in Cilia Protein Genes and Progression of Lung Disease in Cystic Fibrosis

Rationale: Cystic fibrosis, like primary ciliary dyskinesia, is an autosomal recessive disorder characterized by abnormal mucociliary clearance and obstructive lung disease. We hypothesized that genes underlying the development or function of cilia may modify lung disease severity in persons with cystic fibrosis. Objectives: To test this hypothesis, we compared variants in 93 candidate genes in both upper and lower tertiles of lung function in a large cohort of children and adults with cystic fibrosis with those of a population control dataset. Methods: Variants within candidate genes were tested for association using the SKAT‐O test, comparing cystic fibrosis cases defined by poor (n = 127) or preserved (n = 127) lung function with population controls (n = 3,269 or 3,148, respectively). Associated variants were then tested for association with related phenotypes in independent datasets. Results: Variants in DNAH14 and DNAAF3 were associated with poor lung function in cystic fibrosis, whereas variants in DNAH14 and DNAH6 were associated with preserved lung function in cystic fibrosis. Associations between DNAH14 and lung function were replicated in disease‐related phenotypes characterized by obstructive lung disease in adults. Conclusions: Genetic variants within DNAH6, DNAH14, and DNAAF3 are associated with variation in lung function among persons with cystic fibrosis.
Patient-ventilator asynchrony, leaks and sleep in patients with amyotrophic lateral sclerosis

Abstract Sleeping with non-invasive ventilation (NIV) in amyotrophic lateral sclerosis appears to be accompanied by a high patient-ventilator asynchrony (PVA) index. This prospective observational cohort study quantifies PVA and leaks, and searches for effects of these events on sleep after polysomnographic NIV titration. Full-video polysomnography, with incorporation of transcutaneous carbon dioxide and ventilator software, was used to analyse sleep epoch-by-epoch and respiratory events and PVA breath-by-breath in 35 patients (17 non-bulbar). After diagnostic polysomnography, NIV was titrated during three consecutive nights. Sleep, PVA and leaks were evaluated at discharge and after one month. Results showed that non-bulbar patients improved in sleep architecture and oxygen and carbon dioxide levels while bulbar patients only improved oxygen saturation. PVA remained present at discharge (non-bulbar 54 (21–101) and bulbar 31 (9–39)/h sleep) and one month (non-bulbar 31 (9–39) and bulbar 32 (17–55)/h sleep), with ineffective effort as most prominent asynchrony. Leaks also persisted after titration (non-bulbar 16.6 (3.1–44.6) and bulbar 5.1 (0.0–19.5)% of total sleep time (TST)) and one month (non-bulbar 7.7 (1.4–29.3) and bulbar 12.7 (0.0–35.2)% TST). PVA and leaks have none to minor effect on sleep architecture. In conclusion, although PVA and leaks remain present after meticulous NIV titration, these events seem not to interfere with sleep.
Respiratory Morbidity in Children with Repaired Congenital Esophageal Atresia with or without Tracheoesophageal Fistula

Congenital esophageal atresia with or without tracheoesophageal fistula (CEA ± TEF) is a relatively common malformation that occurs in 1 of 2500–4500 live births. Despite the refinement of surgical techniques, a considerable proportion of children experience short- and long-term respiratory complications, which can significantly affect their health through adulthood. This review focuses on the underlying mechanisms and clinical presentation of respiratory morbidity in children with repaired CEA ± TEF. The reasons for the short-term pulmonary impairments are multifactorial and related to the surgical complications, such as anastomotic leaks, stenosis, and recurrence of fistula. Long-term respiratory morbidity is grouped into four categories according to the body section or function mainly involved: upper respiratory tract, lower respiratory tract, gastrointestinal tract, and aspiration and dysphagia. The reasons for the persistence of respiratory morbidity to adulthood are not univocal. The malformation itself, the acquired damage after the surgical repair, various co-morbidities, and the recurrence of lower respiratory tract infections at an early age can contribute to pulmonary impairment. Nevertheless, other conditions, including smoking habits and, in particular, atopy can play a role in the recurrence of infections. In conclusion, our manuscript shows that most children born with CEA ± TEF survive into adulthood, but many comorbidities, mainly esophageal and respiratory issues, may persist. The pulmonary impairment involves many underlying mechanisms, which begin in the first years of life. Therefore, early detection and management of pulmonary morbidity may be important to prevent impairment in pulmonary function and serious long-term complications. To obtain a successful outcome, it is fundamental to ensure a standardized follow-up that must continue until adulthood.
Oviposition Deterrent Activities of Pachyrhizus erosus Seed Extract and Other Natural Products on Plutella xylostella (Lepidoptera: Plutellidae)

Abstract An extract of a rotenone-containing plant yam bean, Pachyrhizus erosus (L.) Urban, seeds was tested against the diamondback moth, Plutella xylostella (L.) in a greenhouse to determine its potential as an oviposition deterrent and compared with coumarin and rutin, known as diamondback moth oviposition deterrent compounds, rotenone, and an extract of Peruvian cube root, at a concentration of 0.5% (w/v). Oviposition deterrent index (ODI) was used to determine effects of extracts or compounds in inhibiting oviposition of diamondback moth. Coumarin showed a stronger deterrent effect than the yam bean seed extract with a higher ODI value. On the contrary, rotenone, rutin, and the cube root extract, containing 6.7% (w/w) of rotenone, showed no significant deterrent effects having low or negative ODI values, suggesting that the deterrent effect of the yam bean seed extract is not due to rotenone content of the yam bean seeds. The extract of yam bean seed and coumarin partially deterred the moth from laying eggs on treated leaves in a concentration-dependent manner. The effective concentration for 50% deterrency of coumarin and the yam bean seed extract were 0.11 and 0.83% (w/v), respectively. However, the yam bean seed extract showed a residual deterrent effect on the moth even at 3 d after the treatment and is probably because of its low volatile nature. A long-term deterrency of the yam bean seed extract is an advantage over coumarins. Both the yam bean seed extract and coumarin deterred diamondback moth from laying eggs in total darkness, indicating their nonvisual deterrent effect. This made the extract an effective deterrence to diamondback moth in light and in darkness. To conclude, this study revealed the potential of the crude extract of the yam bean seed to prevent diamondback moth from ovipositing on its plant host.