Miracle-dz/UniFAR-FTUs huggingface dataset:
SUMO Modification of Hepatitis B Virus Core Mediates Nuclear Entry, Promyelocytic Leukemia Nuclear Body Association, and Efficient Formation of Covalently Closed Circular DNA

HBV cccDNA is formed from the incomplete rcDNA involving several host DDR proteins. The exact process and the site of cccDNA formation are poorly understood. ABSTRACT Persistence of hepatitis B virus (HBV) infection is due to a nuclear covalently closed circular DNA (cccDNA), generated from the virion-borne relaxed circular DNA (rcDNA) genome in a process likely involving numerous cell factors from the host DNA damage response (DDR). The HBV core protein mediates rcDNA transport to the nucleus and likely affects stability and transcriptional activity of cccDNA. Our study aimed at investigating the role of HBV core protein and its posttranslational modification (PTM) with SUMO (small ubiquitin-like modifiers) during the establishment of cccDNA. HBV core protein SUMO PTM was analyzed in His-SUMO-overexpressing cell lines. The impact of HBV core SUMOylation on association with cellular interaction partners and on the HBV life cycle was determined using SUMOylation-deficient mutants of the HBV core protein. Here, we show that the HBV core protein is posttranslationally modified by the addition of SUMO and that this modification impacts nuclear import of rcDNA. By using SUMOylation-deficient HBV core mutants, we show that SUMO modification is a prerequisite for the association with specific promyelocytic leukemia nuclear bodies (PML-NBs) and regulates the conversion of rcDNA to cccDNA. By in vitro SUMOylation of HBV core, we obtained evidence that SUMOylation triggers nucleocapsid disassembly, providing novel insights into the nuclear import process of rcDNA. HBV core protein SUMOylation and subsequent association with PML bodies in the nucleus constitute a key step in the conversion of HBV rcDNA to cccDNA and therefore a promising target for inhibiting formation of the HBV persistence reservoir. IMPORTANCE HBV cccDNA is formed from the incomplete rcDNA involving several host DDR proteins. The exact process and the site of cccDNA formation are poorly understood. Here, we show that HBV core protein SUMO modification is a novel PTM regulating the function of HBV core. A minor specific fraction of the HBV core protein resides with PML-NBs in the nuclear matrix. SUMO modification of HBV core protein mediates its recruitment to specific PML-NBs within the host cell. Within HBV nucleocapsids, SUMOylation of HBV core induces HBV capsid disassembly and is a prerequisite for nuclear entry of HBV core. SUMO HBV core protein association with PML-NBs is crucial for efficient conversion of rcDNA to cccDNA and for the establishment of the viral persistence reservoir. HBV core protein SUMO modification and the subsequent association with PML-NBs might constitute a potential novel target in the development of drugs targeting the cccDNA.
Real Change or Performative Anti-Racism? Clinical Psychology Programs’ Efforts to Recruit and Retain BIPOC Scholars

ABSTRACT Objective This study assessed perceptions of Clinical Psychology doctoral programs’ efforts to recruit and retain faculty and graduate students of color, as well as differences in perceptions based on participants’ position within their program (i.e. graduate student versus faculty) and race. Method Participants (n = 297; 35% people of color; 79% female; mean age: 32) were graduate students and faculty from Clinical Psychology doctoral programs who completed an anonymous online survey about their programs’ efforts to recruit and retain graduate students and faculty of color; sense of belonging and perceptions of racial discrimination within programs; and experiences of cultural taxation and racism within programs. Results Faculty (n = 95) reported significantly greater perceptions of recruitment and retention efforts and fewer perceptions of racial discrimination than did graduate students (n = 202). Asian (n = 31), Black (n = 25), and Latinx (n = 35) participants reported significantly fewer perceptions of recruitment and retention efforts, less sense of belonging, and greater perceptions of racial discrimination than did White participants (n = 192). Cultural taxation was common among participants of color, and approximately half (47%) reported they have considered leaving academia – and approximately one third (31%) have considered leaving their program – due to experiences of racism in their program or field. Conclusions Cultural taxation and racial discrimination were common among scholars of color in this sample. Whether intentional or not, these experiences contribute to racially-toxic environments and negatively impact the racial diversity of the mental health workforce.
Factors Influencing Maintenance of Alignment and Functional Improvement Following Adult Spinal Deformity Surgery

Study Design. This was a retrospective review. Objective. To assess the factors contributing to durability of surgical results following adult spinal deformity (ASD) surgery. Summary of Background. Factors contributing to the long-term sustainability of ASD correction are currently undefined. Materials and Methods. Operative ASD patients with preoperatively (baseline) and 3-year postoperatively radiographic/health-related quality of life data were included. At 1 and 3 years postoperatively, a favorable outcome was defined as meeting at least three of four criteria: (1) no proximal junctional failure or mechanical failure with reoperation, (2) best clinical outcome (BCO) for Scoliosis Research Society (SRS) (≥4.5) or Oswestry Disability Index (ODI) (<15), (3) improving in at least one SRS-Schwab modifier, and (4) not worsening in any SRS-Schwab modifier. A robust surgical result was defined as having a favorable outcome at both 1 and 3 years. Predictors of robust outcomes were identified using multivariable regression analysis with conditional inference tree for continuous variables. Results. We included 157 ASD patients in this analysis. At 1 year postoperatively, 62 patients (39.5%) met the BCO definition for ODI and 33 (21.0%) met the BCO for SRS. At 3 years, 58 patients (36.9%) had BCO for ODI and 29 (18.5%) for SRS. Ninety-five patients (60.5%) were identified as having a favorable outcome at 1 year postoperatively. At 3 years, 85 patients (54.1%) had a favorable outcome. Seventy-eight patients (49.7%) met criteria for a durable surgical result. Multivariable adjusted analysis identified the following independent predictors of surgical durability: surgical invasiveness >65, being fused to S1/pelvis, baseline to 6-week pelvic incidence and lumbar lordosis difference >13.9°, and having a proportional Global Alignment and Proportion score at 6 weeks. Conclusions. Nearly 50% of the ASD cohort demonstrated good surgical durability, with favorable radiographic alignment and functional status maintained up to 3 years. Surgical durability was more likely in patients whose reconstruction was fused to the pelvis and addressed lumbopelvic mismatch with adequate surgical invasiveness to achieve full alignment correction.
Progress in high-power high-speed VCSEL arrays

Flip-chip bonding enables a unique architecture for two-dimensional arrays of VCSELs. Such arrays feature scalable power outputs and the capability to separately address sub-array regions while maintaining fast turn-on and turn-off response times. These substrate-emitting VCSEL arrays can also make use of integrated micro-lenses for beam shaping and directional control. Advances in the performance of these laser arrays will be reviewed and emerging applications are discussed.
Resonant properties of fast leaky surface acoustic waves on lithium niobate

Fast leaky surface acoustic waves in lithium niobate correspond to complex valued singular points of effective permittivity function. Due to the trapping effect under large periodical loading these waves effectively resonate in long IDTs. The admittance characteristics of an infinitely long IDT are analyzed in the complex plane of frequencies. The poles and zeros of the admittance represent the resonant and anti resonant frequencies respectively. The position of poles and zeros as a function of electrode height to wavelength ratio has been calculated. It is shown that in IDTs with thick aluminum electrodes together with the Rayleigh wave resonance a new additional resonance occurs in the low frequency region where there is no energy dissipation into the bulk waves. This new resonant behavior can be associated with an interaction between the Rayleigh wave and a leaky wave with high intrinsic attenuation.
Whipple’s disease-associated infective endocarditis: a systematic review

Abstract Whipple’s disease is an uncommon chronic systemic disease caused by Tropheryma whippelii. The most characteristic findings of late Whipple’s disease include diarrhoea, abdominal pain, weight loss, and arthralgias, however, other clinical findings can occur, including lymphadenopathy, fever, neurologic manifestations, myocarditis and endocarditis. The aim of the present study was to systematically review all cases of Whipple’s disease-associated infective endocarditis (IE) in the literature. A systematic review of PubMed, Scopus, and Cochrane Library (all published studies up to 28 May 2022) for studies providing data on epidemiology, clinical characteristics as well as data on treatment and outcomes of Whipple’s disease-associated IE was performed. A total of 72 studies, containing data for 127 patients, were included. A prosthetic valve was present in 8% of patients. The aortic valve was the most commonly involved intracardiac site followed by the mitral valve. Heart failure, embolic phenomena, and fever were the most common clinical presentations, however, fever occurred in less than 30% of patients. Sepsis was rarely noted. The diagnosis was most commonly performed through pathology through positive PCR or histology in cardiac valves in 88.2% of patients. Trimethoprim with sulfamethoxazole were the most commonly used antimicrobials followed by cephalosporins and tetracyclines. Surgery was performed in 84.3% of patients. Mortality was 9.4%. A multivariate logistic regression analysis model identified presentation with sepsis or development of a paravalvular abscess to be independently associated with increased mortality, while treatment with the combination of trimethoprim with sulfamethoxazole was independently associated with reduced mortality.
Stability and exponential stability of an adaptive control scheme for plants of any relative degree

Relying on a new adaptive pole assignment control scheme for plants with unknown relative degree and uncertain order which can be made minimum phase by means of a relative-degree-one first order parallel compensator, a new adaptation mechanism is proposed in this note in order to tackle with the problem of the attainment of an exponentially stable behavior of the output error. In particular, the connection between exponential stability and persistent excitation is outlined, and a complete stability analysis is performed. >
Role of PFKFB3-driven glycolysis in sepsis

Abstract Sepsis is still the leading cause of death as a result of infection. Metabolic disorder plays a vital role in sepsis progression. Glycolysis intensification is the most characteristic feature of sepsis-related metabolic disorders. The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a critical engine that controls the rate of glycolysis. Recent studies have revealed that sepsis accelerates the rate of PFKFB3-driven glycolysis in different cells, including macrophages, neutrophils, endothelial cells and lung fibroblasts. Furthermore, increased PFKFB3 is closely related to the excessive inflammatory response and high mortality in sepsis. Interestingly, inhibition of PFKFB3 alone or in combination has also shown great potential in the treatment of sepsis. Therefore, an improved understanding of the canonical and noncanonical functions of PFKFB3 may provide a novel combinatorial therapeutic target for sepsis. This review summarizes the role of PFKFB3-driven glycolysis in the regulation of immunocyte activation and nonimmune cell damage in sepsis. In addition, we present recent achievements in the development of PFKFB3 drugs and discuss their potential therapeutic roles in sepsis. KEY MESSAGE Sepsis induces high expression of PFKFB3 in immunocytes and nonimmune cells, thereby enhancing cellular glycolytic flux. PFKFB3-driven glycolysis reprogramming is closely related to an excessive inflammatory response and high mortality in sepsis. Inhibition of PFKFB3 alone or in combination provides a novel combinatorial therapeutic target for sepsis.
Microglia‐specific knock‐out of NF‐κB/IKK2 increases the accumulation of misfolded α‐synuclein through the inhibition of p62/sequestosome‐1‐dependent autophagy in the rotenone model of Parkinson's disease

Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide, with a greater prevalence in men than women. The etiology of PD is largely unknown, although environmental exposures and neuroinflammation are linked to protein misfolding and disease progression. Activated microglia are known to promote neuroinflammation in PD, but how environmental agents interact with specific innate immune signaling pathways in microglia to stimulate conversion to a neurotoxic phenotype is not well understood. To determine how nuclear factor kappa B (NF‐κB) signaling dynamics in microglia modulate neuroinflammation and dopaminergic neurodegeneration, we generated mice deficient in NF‐κB activation in microglia (CX3CR1‐Cre::IKK2fl/fl) and exposed them to 2.5 mg/kg/day of rotenone for 14 days, followed by a 14‐day post‐lesioning incubation period. We postulated that inhibition of NF‐κB signaling in microglia would reduce overall inflammatory injury in lesioned mice. Subsequent analysis indicated decreased expression of the NF‐κB‐regulated autophagy gene, sequestosome 1 (p62), in microglia, which is required for targeting ubiquitinated α‐synuclein (α‐syn) for lysosomal degradation. Knock‐out animals had increased accumulation of misfolded α‐syn within microglia, despite an overall reduction in neurodegeneration. Interestingly, this occurred more prominently in males. These data suggest that microglia play key biological roles in the degradation and clearance of misfolded α‐syn and this process works in concert with the innate immune response associated with neuroinflammation. Importantly, the accumulation of misfolded α‐syn protein aggregates alone did not increase neurodegeneration following exposure to rotenone but required the NF‐κB‐dependent inflammatory response in microglia.
Association of fructose consumption with prevalence of functional gastrointestinal disorders manifestations: results from Hellenic National Nutrition and Health Survey (HNNHS)

Abstract The study aimed to assess the total prevalence of functional gastrointestinal disorders (FGID), and separately, irritable bowel syndrome (IBS) among adults and to determine their potential association with fructose consumption. Data from the Hellenic National Nutrition and Health Survey were included (3798 adults; 58·9 % females). Information regarding FGID symptomatology was assessed using self-reported physician diagnosis questionnaires the reliability of which were screened using the ROME III, in a sample of the population. Fructose intake was estimated from 24 h recalls, and the MedDiet score was used to assess adherence to the Mediterranean diet. The prevalence of FGID symptomatology was 20·2 %, while 8·2 % had IBS (representing 40·2 % of total FGID). The likelihood of FGID was 28 % higher (95 %CI: 1·03–1·6) and of IBS 49 % (95 %CI: 1·08–2·05) in individuals with higher fructose intake than with lower intake (3rd tertile compared with 1st). When area of residence was accounted for, individuals residing in the Greek islands had a significantly lower probability of FGID and IBS compared with those residing in Mainland and the main Metropolitan areas, with Islanders also achieving a higher MedDiet score and lower added sugar intake, comparatively to inhabitants of the main metropolitan areas. FGID and IBS symptomatology was most prominent among individuals with higher fructose consumption, and this was most conspicuous in areas with a lower Mediterranean diet adherence, suggesting that the dietary source of fructose rather than total fructose should be examined in relation to FGID.
INTERPOLATION OF MISSING PRECIPITATION RECORDS

Abstract Since 1948, when the Weather Bureau discontinued the practice of publishing interpolated precipitation data, monthly and annual totals have been omitted from its publications whenever any portion of the record was missing. In view of objections by the users of precipitation data, this policy was reviewed for possible revision. A series of tests involving some 1200 storms was conducted to determine if missing records could be satisfactorily estimated by simple procedures which could be applied in the limited time available. Results of these investigations are presented and two methods of interpolation, namely, the normal-ratio and 3-station-average, me selected for use by the Weather Bureau. Procedures to be followed in applying these methods are outlined. Because of the early deadlines for the issuance of monthly Climatological Data, estimated data, properly identified, will appear in the annual number only, beginning with the 1952 issue. In order to limit the magnitude of the errors of interpola.
Superiority of compensatory reserve measurement compared with the Shock index for early and accurate detection of reduced central blood volume status

This work focuses on providing the physiological basis underlying the limitations of using the shock index as a monitoring tool for the assessment of the clinical status and outcome of patients suffering from hemorrhagic injuries. BACKGROUND Shock index (SI) equals the ratio of heart rate (HR) to systolic blood pressure (SBP) with clinical evidence that it is more sensitive for trauma patient status assessment and prediction of outcome compared with either HR or SBP alone. We used lower body negative pressure (LBNP) as a human model of central hypovolemia and compensatory reserve measurement (CRM) validated for accurate tracking of reduced central blood volume to test the hypotheses that SI: (1) presents a late signal of central blood volume status; (2) displays poor sensitivity and specificity for predicting the onset of hemodynamic decompensation; and (3) cannot identify individuals at greatest risk for the onset of circulatory shock. METHODS We measured HR, SBP, and CRM in 172 human subjects (19–55 years) during progressive LBNP designed to determine tolerance to central hypovolemia as a model of hemorrhage. Subjects were subsequently divided into those with high tolerance (HT) (n = 118) and low tolerance (LT) (n = 54) based on completion of 60 mm Hg LBNP. The time course relationship between SI and CRM was determined and receiver operating characteristic (ROC) area under the curve (AUC) was calculated for sensitivity and specificity of CRM and SI to predict hemodynamic decompensation using clinically defined thresholds of 40% for CRM and 0.9 for SI. RESULTS The time and level of LBNP required to reach a SI = 0.9 (~60 mm Hg LBNP) was significantly greater (p < 0.001) compared with CRM that reached 40% at ~40 mm Hg LBNP. Shock index did not differ between HT and LT subjects at 45 mm Hg LBNP levels. ROC AUC for CRM was 0.95 (95% CI = 0.94–0.97) compared with 0.91 (0.89–0.94) for SI (p = 0.0002). CONCLUSION Despite high sensitivity and specificity, SI delays time to detect reductions in central blood volume with failure to distinguish individuals with varying tolerances to central hypovolemia. LEVEL OF EVIDENCE Diagnostic Test or Criteria; Level III.
Lessons Learned From Limited Overlap of 15 In Vitro COVID-19 Drug Repurposing Screens

Drug repurposing can quickly and cost-effectively identify medical countermeasures against pathogens with pandemic potential and could be used as a down-selection method for selecting US Food and Drug Administration-approved drugs to test in clinical trials. We compared results from 15 high-throughput in vitro screening efforts that tested approved and clinically evaluated drugs for activity against SARS-CoV-2 replication. From the 15 studies, 304 drugs were identified as displaying the highest level of confidence from the individual screens. Of those 304 drugs, 30 were identified in 2 or more screens, while only 3 drugs (apilimod, tetrandrine, and salinomycin) were identified in 4 screens. The lack of concordance in high-confidence hits and variations in protocols makes it challenging to use the collective data as down-selection criteria for identifying repurposing candidates to move into a clinical trial.
Prevention of Venous Thromboembolism in Medical Patients with Thrombocytopenia or with Platelet Dysfunction: The Last 10 Years

Abstract Current guideline recommendations for primary prophylaxis of venous thromboembolism (VTE) are based on randomized clinical trials that usually exclude subjects at a potentially high risk of bleeding complications. For this reason, no specific guideline is available for thromboprophylaxis in hospitalized patients with thrombocytopenia and/or platelet dysfunction. However, except in patients with absolute contraindications to anticoagulant drugs, antithrombotic prophylaxis should always be considered, for example, in hospitalized cancer patients with thrombocytopenia, especially in those with multiple VTE risk factors. Low platelet number, platelet dysfunction, and clotting abnormalities are also very common in patients with liver cirrhosis, but these patients have a high incidence of portal venous thrombosis, implying that cirrhotic coagulopathy does not fully protect against thrombosis. These patients may benefit from antithrombotic prophylaxis during hospitalization. Patients hospitalized for COVID-19 need prophylaxis, but frequently experience thrombocytopenia or coagulopathy. In patients with antiphospholipid antibodies, a high thrombotic risk is usually present, even in the presence of thrombocytopenia. VTE prophylaxis in high-risk conditions is thus suggested in these patients. At variance with severe thrombocytopenia (< 50,000/mm 3 ), mild/moderate thrombocytopenia (≥ 50,000/mm 3 ) should not interfere with VTE prevention decisions. In patients with severe thrombocytopenia, pharmacological prophylaxis should be considered on an individual basis. Aspirin is not as effective as heparins in lowering the risk of VTE. Studies in patients with ischemic stroke demonstrated that thromboprophylaxis with heparins is safe in these patients also during antiplatelet treatment. The use of direct oral anticoagulants in the prophylaxis of VTE in internal medicine patients has been recently evaluated, but no specific recommendation exists for patients with thrombocytopenia. The need for VTE prophylaxis in patients on chronic treatment with antiplatelet agents should be evaluated after assessing the individual risk of bleeding complications. Finally, the selection of patients who require post-discharge pharmacological prophylaxis remains debated. New molecules currently under development (such as the inhibitors of factor XI) may contribute to improve the risk/benefit ratio of VTE primary prevention in this setting of patients.