Miracle-dz/UniFAR-FTUs huggingface dataset:
West Nile Virus-Induced Activation of Mammalian Target of Rapamycin Complex 1 Supports Viral Growth and Viral Protein Expression

ABSTRACT Since its introduction in New York City, NY, in 1999, West Nile virus (WNV) has spread to all 48 contiguous states of the United States and is now the leading cause of epidemic encephalitis in North America. As a member of the family Flaviviridae, WNV is part of a group of clinically important human pathogens, including dengue virus and Japanese encephalitis virus. The members of this family of positive-sense, single-stranded RNA viruses have limited coding capacity and are therefore obligated to co-opt a significant amount of cellular factors to translate their genomes effectively. Our previous work has shown that WNV growth was independent of macroautophagy activation, but the role of the evolutionarily conserved mammalian target of rapamycin (mTOR) pathway during WNV infection was not well understood. mTOR is a serine/threonine kinase that acts as a central cellular censor of nutrient status and exercises control of vital anabolic and catabolic cellular responses such as protein synthesis and autophagy, respectively. We now show that WNV activates mTOR and cognate downstream activators of cap-dependent protein synthesis at early time points postinfection and that pharmacologic inhibition of mTOR (KU0063794) significantly reduced WNV growth. We used an inducible Raptor and Rictor knockout mouse embryonic fibroblast (MEF) system to further define the role of mTOR complexes 1 and 2 in WNV growth and viral protein synthesis. Following inducible genetic knockout of the major mTOR cofactors raptor (TOR complex 1 [TORC1]) and rictor (TORC2), we now show that TORC1 supports flavivirus protein synthesis via cap-dependent protein synthesis pathways and supports subsequent WNV growth. IMPORTANCE Since its introduction in New York City, NY, in 1999, West Nile virus (WNV) has spread to all 48 contiguous states in the United States and is now the leading cause of epidemic encephalitis in North America. Currently, the mechanism by which flaviviruses such as WNV translate their genomes in host cells is incompletely understood. Elucidation of the host mechanisms required to support WNV genome translation will provide broad understanding for the basic mechanisms required to translate capped viral RNAs. We now show that WNV activates mTOR and cognate downstream activators of cap-dependent protein synthesis at early time points postinfection. Following inducible genetic knockout of the major mTOR complex cofactors raptor (TORC1) and rictor (TORC2), we now show that TORC1 supports WNV growth and protein synthesis. This study demonstrates the requirement for TORC1 function in support of WNV RNA translation and provides insight into the mechanisms underlying flaviviral RNA translation in mammalian cells.
Neuroanatomical and neuropsychological features of euthymic patients with bipolar disorder.

OBJECTIVE Previous studies reported that the severity of cognitive deficits in euthymic patients with bipolar disorder (BD) increases with the duration of illness and postulated that progressive neuronal loss or shrinkage and white matter changes may be at the origin of this phenomenon. To explore this issue, the authors performed a case-control study including detailed neuropsychological and magnetic resonance imaging analyses in 17 euthymic elderly patients with BD and 17 healthy individuals. METHODS Neuropsychological evaluation concerned working memory, episodic memory, processing speed, and executive functions. Volumetric estimates of the amygdala, hippocampus, entorhinal cortex, and anterior cingulate cortex were obtained using both voxel-based and region of interest morphometric methods. Periventricular and deep white matter were assessed semiquantitatively. Differences in cognitive performances and structural data between BD and comparison groups were analyzed using paired t-test or analysis of variance. Wilcoxon test was used in the absence of normal distribution. RESULTS Compared with healthy individuals, patients with BD obtained significantly lower performances in processing speed, working memory, and episodic memory but not in executive functions. Morphometric analyses did not show significant volumetric or white matter differences between the two groups. CONCLUSIONS Our results revealed impairment in verbal memory, working memory, and processing speed in euthymic older adults with BD. These cognitive deficits are comparable both in terms of affected functions and size effects to those previously reported in younger cohorts with BD. Both this observation and the absence of structural brain abnormalities in our cohort do not support a progressively evolving neurotoxic effect in BD.
Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy.

PURPOSE To assess patient and tumor characteristics associated with a complete pathologic response (pCR) in both the breast and axillary lymph node specimens and the outcome of patients found to have a pCR after neoadjuvant chemotherapy for locally advanced breast cancer (LABC). PATIENTS AND METHODS Three hundred seventy-two LABC patients received treatment in two prospective neoadjuvant trials using four cycles of doxorubicin-containing chemotherapy. Patients had a total mastectomy with axillary dissection or segmental mastectomy and axillary dissection followed by four or more cycles of additional chemotherapy. Patients then received irradiation treatment of the chest-wall or breast and regional lymphatics. Median follow-up was 58 months (range, 8 to 99 months). RESULTS The initial nodal status, age, and stage distribution of patients with a pCR were not significantly different from those of patients with less than a pCR (P>.05). Patients with a pCR had initial tumors that were more likely to be estrogen receptor (ER)-negative (P<.01), and anaplastic (P = .01) but of smaller size (P<.01) than those of patients with less than a pCR. Upon multivariate analysis, the effects of ER status and nuclear grade were independent of initial tumor size. Sixteen percent of the patients in this study (n = 60) had a pathologic complete primary tumor response. Twelve percent of patients (n = 43) had no microscopic evidence of invasive cancer in their breast and axillary specimens. A pathologic complete primary tumor response was predictive of a complete axillary lymph node response (P<.01 ). The 5-year overall and disease-free survival rates were significantly higher in the group who had a pCR (89% and 87%, respectively) than in the group who had less than a pCR (64% and 58%, respectively; P<.01). CONCLUSION Neoadjuvant chemotherapy has the capacity to completely clear the breast and axillary lymph nodes of invasive tumor before surgery. Patients with LABC who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival rate. However, a pCR does not entirely eliminate recurrence. Further efforts should focus on elucidating the molecular mechanisms associated with this response.
Plasma Concentrations of Afamin Are Associated With the Prevalence and Development of Metabolic Syndrome

Background—Afamin is a human plasma vitamin E–binding glycoprotein primarily expressed in the liver and secreted into the bloodstream. Because little is known about (patho)-physiological functions of afamin, we decided to identify phenotypes associated with afamin by investigating transgenic mice overexpressing the human afamin gene and performing large-scale human epidemiological studies. Methods and Results—Transgenic mice overexpressing afamin revealed increased body weight and serum concentrations of lipids and glucose. We applied a random-effects meta-analysis using age- and sex-adjusted baseline and follow-up investigations in the population-based Bruneck (n=826), Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR; n=1499), and KOoperative Gesundheitsforschung in der Region Augsburg (KORA) F4 studies (n=3060). Mean afamin concentrations were 62.5±15.3, 66.2±14.3, and 70.6±17.2 mg/L in Bruneck, SAPHIR, and KORA F4, respectively. Per 10 mg/L increment in afamin measured at baseline, the number of metabolic syndrome components increased by 19% (incidence rate ratio=1.19; 95% confidence interval [CI], 1.16–1.21; P=5.62×10−64). With the same afamin increment used at baseline, we observed an 8% gain in metabolic syndrome components between baseline and follow-up (incidence rate ratio=1.08; 95% CI, 1.06–1.10; P=8.87×10−16). Afamin concentrations at baseline were highly significantly related to all individual metabolic syndrome components at baseline and at follow-up. This observation was most pronounced for elevated waist circumference (odds ratio, 1.79; 95% CI, 1.54–2.09; P=4.15×10−14 at baseline and odds ratio, 1.46; 95% CI, 1.31–1.63; P=2.84×10−11 for change during follow-up) and for elevated fasting glucose concentrations (odds ratio, 1.46; 95% CI, 1.40–1.52; P=1.87×10−69 and odds ratio, 1.46; 95% CI, 1.24–1.71; P=5.13×10−6, respectively). Conclusions—This study in transgenic mice and >5000 participants in epidemiological studies shows that afamin is strongly associated with the prevalence and development of metabolic syndrome and all its components.
Surfactant levels after reversible tracheal occlusion and prenatal steroids in experimental diaphragmatic hernia.

BACKGROUND/PURPOSE In normal lungs, fetal tracheal occlusion (TO) induces lung growth but decreases the number of type II cells; this is remedied if TO is released (TR) before delivery. In the current study, the effects of TO with or without TR on pulmonary structure and surfactant were assessed in the ovine model in which lung hypoplasia was induced by creation of a diaphragmatic hernia (CDH). METHODS A left-sided CDH was created in fetal lambs at 80 days gestation; TO was done at 108 days; and TR at 129 days. All ewes were given 1 dose of glucocorticoids at 135 days. At 136 days, the fetus was delivered. Lung weight to body weight ratio, mean terminal bronchiole density, type II cell density, bronchoalveolar lavage fluid (BAL) phosphatidylcholine (PC), BAL surfactant protein A (SP-A) and B (SP-B), and lung tissue SP-A and SP-B were assessed in CDH, CDH with TO, CDH with TO and TR, and controls. RESULTS CDH lungs were hypoplastic and structurally immature, but had increased type II cell density. TO with or without TR caused lung growth with normalization of lung parenchymal architecture and type II cell density. Although the BAL SP-A and BAL SP-B were similar in all 4 groups, the BAL PC was low in CDH with or without TO or TR. Also, lung tissue SP-B levels were low in CDH with or without TO or TR. However, lung tissue SP-A levels were normal in CDH, but low in CDH with TO with or without TR. CONCLUSIONS Despite the finding that lung morphology was improved in CDH with TO with or without TR animals, surfactant content and composition remained abnormal. Although surfactant secreted early by the fetus into alveolar spaces contained normal levels of BAL SP-A and BAL SP-B, the low levels of BAL PC and low lung tissue stores of SP-B indicate that these experimental lambs may experience respiratory insufficiency soon after birth. This implies that prophylactic surfactant at birth might be beneficial for CDH.
Equine Arteritis Virus Subgenomic RNA Transcription: UV Inactivation and Translation Inhibition Studies

Abstract The expression of the genetic information of equine arteritis virus (EAV), an arterivirus, involves the synthesis of six subgenomic (sg) mRNAs. These are 5′ and 3′ coterminal since they are composed of a leader and a body sequence, which are identical to the 5′ and 3′ ends of the genome, respectively. Previously, it has been suggested thatcis-splicing of a genome-length precursor RNA is involved in their synthesis. This was reevaluated in a comparative analysis of the sg RNA synthesis of EAV, the coronavirus mouse hepatitis virus (MHV), and the alphavirus Sindbis virus. UV transcription mapping showed that the majority of the EAV sg RNAs made at later stages of infection is not derived from a genome-length precursor. However, complete independence of sg RNA synthesis from that of genomic RNA was never observed during the course of infection. The possibility that this resulted from UV irradiation-induced effects on the synthesis of the viral replicase was investigated by inhibiting translation using cycloheximide. For EAV, ongoing protein synthesis was found to be more important for the synthesis of sg RNA than for that of genomic RNA. In general, MHV transcription was extremely sensitive to translation inhibition, whereas EAV genomic RNA synthesis became independent ofde novoprotein synthesis late in infection.
Low Power Illinois Scan Architecture for Simultaneous Power and Test Data Volume Reduction

We present low power illinois scan architecture (LPILS) to achieve power dissipation and test data volume reduction, simultaneously. By using the proposed scan architecture, dynamic power dissipation during scan testing in registers and combinational cells can be significantly reduced without modifying the clock tree of the design. The proposed architecture is independent of the ATPG patterns and imposes a very small combinational area penalty due to the logic added between the scan cells and the CUT. Experimental results for two industrial circuits show that we can simultaneously achieve up to 47% reduction in dynamic power dissipation due to switching and 10X test data volume reduction with LPILS over basic scan.
Concentrations in Plasma, Urinary Excretion, and Bactericidal Activity of Linezolid (600 Milligrams) versus Those of Ciprofloxacin (500 Milligrams) in Healthy Volunteers Receiving a Single Oral Dose

ABSTRACT In a randomized crossover study, 12 volunteers (6 males, 6 females) received a single oral dose of 600 mg of linezolid or 500 mg of ciprofloxacin to assess the concentrations in plasma (up to 24 h), urinary excretion (by high-pressure liquid chromatography), and bactericidal titers in urine (UBT) at intervals up to 120 h. The mean maximum concentration of linezolid in plasma was 13.1 mg/liter, and that of ciprofloxacin was 2.46 mg/liter. The median cumulative levels of renal excretion of the administered dose of the parent drug were 44% for linezolid (range, 28 to 47%; mean ± standard deviation, 40% ± 7.8%) and 43% for ciprofloxacin (range, 20 to 56%; mean ± standard deviation, 40% ± 9.3%). The UBTs, i.e., the highest twofold dilution (with antibiotic-free urine used as the diluent) of urine that was still bactericidal, were determined for a reference strain and five gram-positive clinical uropathogens for which the MICs of linezolid and ciprofloxacin were as follows: Staphylococcus aureus ATCC 27278, 2 and 0.25 mg/liter, respectively; Staphylococcus aureus (methicillin susceptible), 1 and 16 mg/liter, respectively; Staphylococcus aureus (methicillin resistant), 2 and 64 mg/liter, respectively; Staphylococcus saprophyticus (methicillin susceptible), 1 and 0.25 mg/liter, respectively; Enterococcus faecalis, 2 and 1 mg/liter, respectively; and Enterococcus faecium, 2 and 1 mg/liter, respectively. The median UBTs of linezolid measured within the first 6 h were 1:96 for each of the two enterococcal strains and between 1:128 and 1:256 for the four staphylococcal strains. The median UBTs of ciprofloxacin were 1:64 for the two enterococcal strains; between 1:384 and 1:512 for the two ciprofloxacin-susceptible strains; and 1 (bactericidal activity of undiluted urine only) and 1:2 for the two resistant staphylococcal strains, respectively. The areas under the UBT-time curve (AUBT) for linezolid and ciprofloxacin showed no statistically significant (P < 0.05) differences except for a better AUBT for linezolid for the two ciprofloxacin-resistant staphylococcal strains. For linezolid there were no statistically significant differences in UBTs or AUBTs for ciprofloxacin-susceptible and -resistant strains. Thus, the bactericidal activities of linezolid and ciprofloxacin against susceptible strains in urine were comparable, whereas linezolid also exhibited the same good bactericidal activity against ciprofloxacin-resistant strains. Therefore, linezolid should be tested for use as empirical treatment for complicated urinary tract infections due to gram-positive uropathogens in an appropriate clinical trial.
Using the Research Domain Criteria Framework to Track Domains of Change in Comorbid PTSD and SUD

Objectives: Comorbidity in diagnosis raises critical challenges for psychological assessment and treatment. The Research Domain Criteria (RDoC) Project, launched by the National Institutes of Mental Health, proposes domains of functioning as a way to conceptualize the overlap between comorbid conditions and inform treatment selection. However, further research is needed to understand common comorbidities (e.g., posttraumatic stress disorder [PTSD] and substance use disorder [SUD]) from an RDoC framework and how existing evidence-based treatments would be expected to promote change in the RDoC domains of functioning. To address these gaps, the current study examined change in 3 RDoC domains (Negative Valence Systems, Arousal/Regulatory Systems, and Cognitive Systems) during concurrent prolonged exposure (PE) and substance use treatment. Method: Participants were 85 individuals with co-occurring PTSD and SUD who received PE in a residential substance use treatment facility. They completed an experimental task to assess physiological reactivity to trauma and alcohol cues at pre- and posttreatment. Results: Results showed decreased severity in all 3 RDoC domains of interest across the study period. Pairwise comparisons between domains revealed that Arousal/Regulatory Systems had the lowest severity at posttreatment. Subsequent hierarchical linear regression analyses showed that posttreatment domain scores were associated with posttreatment cue reactivity for trauma and alcohol cues. Conclusions: The findings provide preliminary evidence of how the RDoC domains of functioning may change with evidence-based treatments and are discussed in terms of the assessment and treatment of mental health problems using the RDoC framework.
Deviation of Chinese Adults’ Diet from the Chinese Food Pagoda 2016 and Its Association with Adiposity

Changing diet in China contributes to a raising prevalence of overweight and obesity. This study aimed to evaluate the dietary status of Chinese adults (20–59 years old) using the China Food Pagoda (CFP) proposed in the Chinese Dietary Guidelines 2016 (CDG), and investigate the association between adiposity and deviation of real diet from CFP using an ordered logistic regression. Results showed that the consumption of fruits, eggs, meat, and poultry increased significantly during 2004–2011, while the consumption of cereal, potatoes, and beans dropped down significantly during the same period (all p < 0.05). Meanwhile, great disparity was detected between real consumption and recommended intake in CFP. In particular, a deficient intake was found for milk and milk products, eggs, and fruit, while over-consumption was observed for cereal, potatoes and beans, meat and poultry, legumes and nuts, oil, and salt. In addition, over-consumption of cereal, legumes and nuts, and salt, as well as under-consumption of vegetables, and meat and poultry, were associated with a higher risk of having high body mass index (BMI), while lower consumption of cereal, potatoes and beans, eggs, and higher consumption of vegetables contributed to low hazard of overweight/obesity (all p < 0.05). The huge disparity between real consumption and the CFP calls for specific health education campaigns.
Cost effectiveness of screening for and eradication of Helicobacter pylori in management of dyspeptic patients under 45 years of age

Abstract Objective: To assess the cost effectiveness of screening for and eradicating Helicobacter pylori in patients under 45 years of age presenting with dyspepsia. Design: A decision analytic model composed of a decision tree to represent the epidemiology of dyspepsia and a Markov process to model the outcomes of treatment. Patients: Patients under the age of 45 years presenting to their general practitioner with (peptic type) dyspepsia. Interventions: Conventional empirical treatment with healing and maintenance doses of cimetidine v eradication treatment solely in patients with confirmed peptic ulcer; and conventional empirical treatment for all dyspeptic patients compared with the use of a serology test to identify patients with H pylori, who then receive endoscopy to investigate the presence of peptic ulcer disease and, when disease is found, are given eradication treatment with a breath test to confirm successful eradication. Main outcome measures: Expected cumulative costs over a period of 10 years. The proportion of time patients spend without a recurrent ulcer. Results: After receiving eradication treatment, patients with confirmed ulcer spend an average of 99% of their time free from recurrent ulcer disease compared with 95% after treatment with cimetidine. Eradication treatment costs less than that with cimetidine. When the initial cost of identifying appropriate patients to receive eradication treatment is added to the analysis, however, these cost savings take almost eight years to accrue. Conclusions: Enthusiasm for introducing testing for and eradication of H pylori for dyspeptic patients in general practice should be tempered by an awareness that cost savings may take many years to realise. Key messages Patients under the age of 45 years presenting with peptic-type dyspepsia without sinister symp- toms are usually managed empirically Only a minority of these patients will have peptic ulcer disease and Helicobacter pylori infection Identification of appropriate patients for H pylori eradication treatment from among dyspeptic patients will entail a considerable investment of resources Consequently, the cost savings associated with a reduction in use of H2 antagonists by patients who receive successful H pylori eradication may take many years to materialise
Fixed Posterior Subluxation in Posterior Cruciate Ligament-Deficient Knees

Among 248 patients seen for posterior cruciate ligament insufficiency, 109 (44%) had fixed posterior subluxation of the tibia, defined as a condition in which posterior sag could not be reduced to a neutral position, as evidenced by posterior tibial displacement of 3 mm or more on anterior stress radiographs at 200 N. The mean fixed posterior displacement was 6.23 mm (range, 3 to 20). The fixed posterior subluxation was divided into three grades: I, 3 to 5 mm (57.8%); II, 6 to 10 mm (33.9%); and III, more than 10 mm (8.3%). Comparison of the 109 study patients with the 139 control patients revealed a history of a failed posterior cruciate ligament operation or of a patellar tendon harvest, male sex, and a long history of posterior cruciate ligament insufficiency as significant risk factors for the development of a fixed posterior subluxation. After patients were treated with a posterior tibial support brace, the fixed posterior subluxation could be reduced to a mean of 2.58 ± 5.22 mm within an average treatment period of 180 days. Fixed posterior subluxation can be detected in patients with posterior cruciate ligament deficiency by anterior and posterior stress radiographs and should be addressed before posterior cruciate ligament reconstruction to prevent early overloading of the graft.