Miracle-dz/UniFAR-FTUs huggingface dataset:
Association Between Antipsychotics and All-Cause Mortality Among Community-Dwelling Older Adults.

Background Antipsychotics are prescribed to treat various symptoms in older adults, however, their safely in this context has not been fully evaluated. The objective was to evaluate mortality risks associated with off- label use of antipsychotics among older adults with no pre-existing mental illness or dementia relative to those with diagnosis of dementia. Methods Data (2007-2015) were derived from Department of Veterans Affairs registries for 730,226 patients (≥65 years) with no baseline serious mental illness, dementia). We estimated the cumulative incidence of antipsychotics prescription and 10-year cause mortality The extended Cox model models were used to estimate Hazard Ratios (HRs) associated with antipsychotics use, adjusted for time varying covariates, dementia diagnosis, comorbidity index score, and age at time of first exposure to antipsychotics. Results The study included 98% males, 13% African Americans, and 81% Caucasian. Patients with dementia and antipsychotics had the highest risk of mortality (78.0%), followed by (73.0 %) for patients with dementia alone and compared to patients without dementia or antipsychotics exposure who had the lowest mortality risk (42.0%). Exposure to typical antipsychotics was associated with (HR:2.1 Confidence Interval [CI] 2.0-2.2) compared to atypical antipsychotics (HR: 1.5, CI (1.4-1.5), p-value=<. 0001. Conclusion In a large cohort of older adults, antipsychotics were associated with an increased risk of all-cause mortality. While significant increase in mortality was attributable to the diagnosis of dementia, the addition of antipsychotics resulted in added mortality risk among all patients. Antipsychotic medications should be used cautiously in all older adults, not only those with dementia.
Chlamydia pneumoniae enhances Interleukin 8 (IL‐8) production with reduced azithromycin sensitivity under hypoxia

Obligate intracellular bacterium Chlamydia pneumoniae causes respiratory tract infections such as community‐acquired pneumonia. During infection, C. pneumoniae induces inflammatory responses in host cells and the oxygen concentration at the infection sites subsequently decreases. Because hypoxic conditions influence further inflammatory responses and reduced antibacterial effects, this may exacerbate the C. pneumoniae infection. Here, we show inflammatory responses and drug sensitivity in C. pneumoniae‐infected cells under hypoxic conditions. First, we confirmed the enhanced growth of C. pneumoniae under hypoxia, which indicates that the hypoxic condition we used could adequately reproduce past reports. We then demonstrated a significant increase in production of the pro‐inflammatory cytokine Interleukin 8 (IL‐8) in C. pneumoniae‐infected cells under hypoxic conditions. Furthermore, hypoxia decreased the antibacterial effects of azithromycin against C. pneumoniae compared with normoxic conditions. Together, our data suggest that inflammatory responses and drug sensitivity may have been underestimated in C. pneumoniae infection in previous studies. Thus, to accurately understand the Chlamydia infection, it may be necessary to perform in vitro experiments under hypoxic conditions.
Transcriptome Analysis of Diurnal Gene Expression in Chinese Cabbage

Plants have developed timing mechanisms that enable them to maintain synchrony with daily environmental events. These timing mechanisms, i.e., circadian clocks, include transcriptional/translational feedback loops that drive 24 h transcriptional rhythms, which underlie oscillations in protein abundance, thus mediating circadian rhythms of behavior, physiology, and metabolism. Circadian clock genes have been investigated in the diploid model plant Arabidopsis thaliana. Crop plants with polyploid genomes—such as Brassica species—have multiple copies of some clock-related genes. Over the last decade, numerous studies have been aimed at identifying and understanding the function of paralogous genes with conserved sequences, or those that diverged during evolution. Brassica rapa’s triplicate genomes retain sequence-level collinearity with Arabidopsis. In this study, we used RNA sequencing (RNAseq) to profile the diurnal transcriptome of Brassica rapa seedlings. We identified candidate paralogs of circadian clock-related genes and assessed their expression levels. These genes and their related traits that modulate the diurnal rhythm of gene expression contribute to the adaptation of crop cultivars. Our findings will contribute to the mechanistic study of circadian clock regulation inherent in polyploidy genome crops, which differ from those of model plants, and thus will be useful for future breeding studies using clock genes.
Updates in the function and regulation of α1‐adrenoceptors

α1‐Adrenoceptors are seven transmembrane domain GPCRs involved in numerous physiological functions controlled by the endogenous catecholamines, noradrenaline and adrenaline, and targeted by drugs useful in therapeutics. Three separate genes, whose products are named α1A‐, α1B‐, and α1D‐ adrenoceptors, encode these receptors. Although the existence of multiple α1‐adrenoceptors has been acknowledged for almost 25 years, the specific functions regulated by each subtype are still largely unknown. Despite the limited comprehension, the identification of a single class of subtype‐selective ligands for the α1A‐ adrenoceptors, the so‐called α‐blockers for prostate dysfunction, has led to major improvement in therapeutics, demonstrating the need for continued efforts in the field. This review article surveys the tissue distribution of the three α1‐adrenoceptor subtypes in the cardiovascular system, genitourinary system, and CNS, highlighting the functions already identified as mediated by the predominant activation of specific subtypes. In addition, this review covers the recent advances in the understanding of the molecular mechanisms involved in the regulation of each of the α1‐adrenoceptor subtypes by phosphorylation and interaction with proteins involved in their desensitization and internalization.
Incidence of surgical-site infection following open reduction and internal fixation of a distal femur fracture

Abstract Surgical-site infection (SSI) is a common complication in orthopedic surgery; however, SSI after surgically managed distal femur fractures was not well studied. The aim of this study was to investigate the incidence of SSI and identify some modifiable and nonmodifiable risk factors. The patients’ electronic medical records (EMRs) were reviewed to identify those who sustained a distal femur fracture and treated by open reduction and internal fixation (ORIF) between March 2014 and February 2018. SSI was defined based on the Centers for Disease Control criteria and confirmed according to the descriptions in EMR. Univariate and multivariate logistic regression models were used to determine the independent risk factors associated with SSI. Totally, EMRs of 665 patients who underwent ORIF of distal femur fractures were reviewed and 24 SSIs were found, indicating the overall incidence of SSI was 3.6%. The rate of deep SSI was 1.2% and superficial SSI was 2.4%. Staphylococcus aureus was the most common causative pathogen, either alone (7/15, 46.7%) or as a mixed infection (3/15, 20%), followed by mixed bacterial (4/15, 26.7%) and S epidermidis (2/15, 13.3%) and others. Patients with SSI had approximately twice the length of hospital stay as those without SSIs (29.0 vs 16.0 days, P < .001). Open fracture, temporary use of external fixation, obesity, smoking, diabetes mellitus, and preoperative reduced albumin level were identified as independent risk factors associated with SSI, and current smoking and preoperative reduced albumin level were the true modifiable factors. Patients should be encouraged to cease smoking as early as possible and increase the good-quality protein intake to reduce or prevent the occurrence of SSI. An explanation of the nonmodifiable risk factors should be included when patients are counseled about their increased risk of SSI.
Acute Release of Plasminogen Activator Inhibitor-1 in ST-Segment Elevation Myocardial Infarction Predicts Mortality

Background—A few studies have suggested that von Willebrand factor (vWF) or plasminogen activator inhibitor-1 (PAI-1) can be associated with outcomes of acute coronary syndromes. The present study was designed to assess the acute release of these markers in ST-segment elevation myocardial infarction (STEMI) and their relations to death. Methods and Results—In 153 consecutive patients with STEMI, vWF and PAI-1 antigens were measured on admission (H0) and 24 hours later (H24). At 30 days, the death rate was 7.2%. Heart failure (Killip stage ≥3) on admission was present in 13.7% of patients. The acute release of PAI-1 (H24−H0, in ng/mL) and of vWF (H24−H0, in %) was dramatically higher in patients who died than in those who survived (46.9±26.3 versus −0.6±2.8 ng/mL, P =0.0001 and 65.8±20.0% versus 10.0±5.1%, P =0.004 for PAI-1 and vWF, respectively) and in patients developing heart failure compared with those without (24.8±10.1 versus −1.1±3.3 ng/mL, P =0.004 and 47.3±11.0% versus 8.1±5.6%, P =0.005 for PAI-1 and vWF, respectively). The release of PAI-1 correlated weakly with the left ventricular ejection fraction (R =−0.195, P =0.01) and the peak of troponin (R =0.149, P =0.045). Postangioplasty TIMI-3 flow and the acute release of PAI-1 were the only 2 independent predictors of death at 30 days. Conclusions—The acute release of vWF and PAI-1 over the first 24 hours of STEMI is associated with death and heart failure. The acute rise of PAI-1 is also a strong independent predictor of death at 30 days.
A facile forward-genetic screen for Arabidopsis autophagy mutants reveals twenty-one loss-of-function mutations disrupting six ATG genes

ABSTRACT Macroautophagy is a process through which eukaryotic cells degrade large substrates including organelles, protein aggregates, and invading pathogens. Over 40 autophagy-related (ATG) genes have been identified through forward-genetic screens in yeast. Although homology-based analyses have identified conserved ATG genes in plants, only a few atg mutants have emerged from forward-genetic screens in Arabidopsis thaliana. We developed a screen that consistently recovers Arabidopsis atg mutations by exploiting mutants with defective LON2/At5g47040, a protease implicated in peroxisomal quality control. Arabidopsis lon2 mutants exhibit reduced responsiveness to the peroxisomally-metabolized auxin precursor indole-3-butyric acid (IBA), heightened degradation of several peroxisomal matrix proteins, and impaired processing of proteins harboring N-terminal peroxisomal targeting signals; these defects are ameliorated by preventing autophagy. We optimized a lon2 suppressor screen to expedite recovery of additional atg mutants. After screening mutagenized lon2-2 seedlings for restored IBA responsiveness, we evaluated stabilization and processing of peroxisomal proteins, levels of several ATG proteins, and levels of the selective autophagy receptor NBR1/At4g24690, which accumulates when autophagy is impaired. We recovered 21 alleles disrupting 6 ATG genes: ATG2/At3g19190, ATG3/At5g61500, ATG5/At5g17290, ATG7/At5g45900, ATG16/At5g50230, and ATG18a/At3g62770. Twenty alleles were novel, and 3 of the mutated genes lack T-DNA insertional alleles in publicly available repositories. We also demonstrate that an insertional atg11/At4g30790 allele incompletely suppresses lon2 defects. Finally, we show that NBR1 is not necessary for autophagy of lon2 peroxisomes and that NBR1 overexpression is not sufficient to trigger autophagy of seedling peroxisomes, indicating that Arabidopsis can use an NBR1-independent mechanism to target peroxisomes for autophagic degradation. Abbreviations: ATG: autophagy-related; ATI: ATG8-interacting protein; Col-0: Columbia-0; DSK2: dominant suppressor of KAR2; EMS: ethyl methanesulfonate; GFP: green fluorescent protein; IAA: indole-3-acetic acid; IBA: indole-3-butyric acid; ICL: isocitrate lyase; MLS: malate synthase; NBR1: Next to BRCA1 gene 1; PEX: peroxin; PMDH: peroxisomal malate dehydrogenase; PTS: peroxisomal targeting signal; thiolase: 3-ketoacyl-CoA thiolase; UBA: ubiquitin-associated; WT: wild type
Shakti-T: A RISC-V Processor with Light Weight Security Extensions

With increased usage of compute cores for sensitive applications, including e-commerce, there is a need to provide additional hardware support for securing information from memory based attacks. This work presents a unified hardware framework for handling spatial and temporal memory attacks. The paper integrates the proposed hardware framework with a RISC-V based micro-architecture with an enhanced application binary interface that enables software layers to use these features to protect sensitive data. We demonstrate the effectiveness of the proposed scheme through practical case studies in addition to taking the design through a VLSI CAD design flow. The proposed processor reduces the metadata storage overhead up to 4 x in comparison with the existing solutions, while incurring an area overhead of just 1914 LUTs and 2197 flip flops on an FPGA, without affecting the critical path delay of the processor.
Targeting IDH1-Mutated Malignancies with NRF2 Blockade.

Background Neomorphic IDH1 mutations disrupt the redox balance by promoting reactive oxygen species (ROS) production. However, the mechanism by which IDH1-mutant cells maintain ROS homeostasis remains elusive. It is also not known whether reprogrammed ROS homeostasis establishes targetable vulnerability in IDH1-mutated cancers. Methods We investigated ROS homeostasis in wild-type (GSC827, GSC923, GSC627, and GSC711) and IDH1-mutated cells (IDH1R132C- and IDH1R132H-transduced U87, U251; MGG152, and TS603 cells). We analyzed the stability and transcriptional activity of NRF2 in IDH1-mutated cells. The oxidative DNA damage was analyzed using NRF2-targeting small interfering RNA. Moreover, we evaluated the effect of the NRF2 inhibitor brusatol in an IDH1-mutated subcutaneous xenograft nude mouse model (control group, n = 5; brusatol-treated group, n = 6). All statistical tests were two-sided. Results We showed that IDH1-mutated cells develop a dependency on the NRF2 antioxidative pathway. Genetic or pharmacologic blockade of NRF2 not only disrupted ROS homeostasis (mean [SD] ROS levels increased by 317 [42.1]%, P = .001, in IDH1R132C and by 286. 5 [48.7]%, P = .003, in IDH1R132H cells) but also enhanced oxidative DNA damage and decreased proliferation of IDH1-mutated cells. Brusatol selectively suppressed IDH1-mutated cancer progression in vivo (mean [SD] final tumor volume was 761.6 [391.6] mm3 in the control and 246.2 [215] mm3 in the brusatol-treated group, P = .02). Conclusions IDH1 mutation reprograms ROS homeostasis in cancer cells, which leads to dependency on the NRF2 antioxidant pathway for ROS scavenging. NRF2 blockade might be a novel therapeutic approach to treat malignancies with IDH1 mutation.
Benefits of Sequentially Adding Cognitive-Behavioral Therapy or Antidepressant Medication for Adults With Nonremitting Depression.

OBJECTIVE: Adults with major depressive disorder frequently do not achieve remission with an initial treatment. Addition of psychotherapy for patients who do not achieve remission with antidepressant medication alone can target residual symptoms and protect against recurrence, but the utility of adding antidepressant medication after nonremission with cognitive-behavioral therapy (CBT) has received little study. The authors aimed to evaluate the acute and long-term outcomes resulting from both sequences of combination treatments. METHODS: Previously untreated adults with major depression who were randomly assigned to receive escitalopram, duloxetine, or CBT monotherapy and completed 12 weeks of treatment without achieving remission entered an additional 12 weeks of combination treatment. For patients who did not achieve remission with CBT, escitalopram was added (CBT plus medication group) to their treatment, and for those who did not achieve remission with an antidepressant, CBT was added (medication plus CBT group) to their treatment. Patients who responded to the combination treatment entered an 18-month follow-up phase to assess risk of recurrence. RESULTS: A total of 112 patients who did not achieve remission with a monotherapy entered combination treatment (41 who responded to monotherapy but did not achieve remission and 71 who did not respond to monotherapy). Overall, remission rates after subsequent combination therapy were significantly higher among patients who responded to monotherapy but did not achieve remission (61%) than among patients who did not respond to monotherapy (41%). Among patients who responded to monotherapy but did not achieve remission, the remission rate in the CBT plus medication group (89%) was higher than in the medication plus CBT group (53%). However, among patients whose depression did not respond to monotherapy, rates of response and remission were similar between the treatment arms. Higher levels of anxiety, both prior to monotherapy and prior to beginning combination treatment, predicted poorer outcomes for both treatment groups. CONCLUSIONS: The order in which CBT and antidepressant medication were sequentially combined did not appear to affect outcomes. Addition of an antidepressant is an effective approach to treating residual symptoms for patients who do not achieve remission with CBT, as is adding CBT after antidepressant monotherapy. Patients who do not respond to one treatment modality warrant consideration for addition of the alternative modality.
Engineering a murine cell line for the stable propagation of hamster prions

Prions are infectious protein aggregates that cause several fatal neurodegenerative diseases. Prion research has been hindered by a lack of cellular paradigms for studying the replication of prions from different species. Although hamster prions have been widely used to study prion replication in animals and within in vitro amplification systems, they have proved challenging to propagate in cultured cells. Because the murine catecholaminergic cell line CAD5 is susceptible to a diverse range of mouse prion strains, we hypothesized that it might also be capable of propagating nonmouse prions. Here, using CRISPR/Cas9-mediated genome engineering, we demonstrate that CAD5 cells lacking endogenous mouse PrP expression (CAD5-PrP−/− cells) can be chronically infected with hamster prions following stable expression of hamster PrP. When exposed to the 263K, HY, or 139H hamster prion strains, these cells stably propagated high levels of protease-resistant PrP. Hamster prion replication required absence of mouse PrP, and hamster PrP inhibited the propagation of mouse prions. Cellular homogenates from 263K-infected cells exhibited prion seeding activity in the RT-QuIC assay and were infectious to naïve cells expressing hamster PrP. Interestingly, murine N2a neuroblastoma cells ablated for endogenous PrP expression were susceptible to mouse prions, but not hamster prions upon expression of cognate PrP, suggesting that CAD5 cells either possess cellular factors that enhance or lack factors that restrict the diversity of prion strains that can be propagated. We conclude that transfected CAD5-PrP−/− cells may be a useful tool for assessing the biology of prion strains and dissecting the mechanism of prion replication.
Body weight and eGFR during dulaglutide treatment in type 2 diabetes and moderate‐to‐severe chronic kidney disease (AWARD‐7)

In patients with type 2 dibetes and moderate‐to‐severe chronic kidney disease, dulaglutide treatment led to body weight (BW) loss and lesser eGFR decline compared to insulin glargine. As BW may affect muscle mass, creatinine‐based eGFR can be altered independently of kidney function. Cystatin C‐based eGFR is not affected by muscle mass. The objective of this post‐hoc analysis was to determine whether the lesser eGFR decline with dulaglutide was related to BW loss. Baseline characteristics were similar between treatments ([mean ± SD] age, 64.6 ± 8.6 years; women, 48%; BW, 89.1 ± 17.7 kg; eGFR [CKD‐EPI‐cystatin C] 38 ± 14 mL/min/1.73m2). BW decreased with dulaglutide 1.5 and 0.75 mg and increased with insulin glargine ([LSM change (SE)], −2.66 [0.47] kg and −1.71 [0.45] vs 1.57 [0.43] kg; P < 0.001). Changes in eGFR were not significant with dulaglutide 1.5 and 0.75 mg, but eGFR significantly decreased with insulin glargine (eGFR‐CKD‐EPI‐cystatin C [LSM change (95%CI)], −0.7 [−2.5, 1.0] and −0.7 [−2.4, 1.1] vs −3.3 [−5.1, −1.6] mL/min/1.73 m2; P ≤ 0.037 vs glargine). Changes in BW did not correlate with changes in eGFR‐CKD‐EPI‐cystatin C (r = −0.041; n = 471; P = 0.379) or eGFR‐CKD‐EPI‐creatinine (r = −0.074; n = 473; P = 0.106). In conclusion, the lesser decline in eGFR observed with dulaglutide was not influenced by BW loss.
Human Mutation

UCL Institute of Ophthalmology, University College London, London, United Kingdom Department of Genetics, Moorfields Eye Hospital, London, United Kingdom Department of Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, United Kingdom Department of Genetics, UCL Genetics Institute, Evolution and Environment, London, United Kingdom Exploration de la Vision et Neuro‐Ophtalmologie, Centre Hospitalier Universitaire, Lille, France Department of Haematology, University of Cambridge, Cambridge, United Kingdom NIHR BioResource‐Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom Biochemistry and Molecular Biology Department–UF Génopathies, CHU Lille, Univ Lille, Inserm UMR‐S 1172, F‐59000, Lille, France Department of Ophthalmology, The Kennedy Eye Clinic, Rigshospitalet Glostrup, Glostrup, Denmark Department of Ophthalmology, UCSF School of Medicine, San Francisco, CA,
Future Time Perspective and Well-Being in Chinese Older Adults: Moderating Role of Age Stereotypes

Through this cross-sectional study, we aimed to examine the association between future time perspective (FTP) and well-being among older adults, with age stereotypes as a moderator. The participants, 333 Chinese older adults (60–88 years), completed measures related to FTP, age stereotypes, and well-being. The results showed that opportunity and limitation emerged as two subcomponents of FTP, and their effects on well-being depended on older adults’ negative age stereotypes. Specifically, for older adults holding less negative age stereotypes, FTP-opportunity and FTP-limitation had a positive effect on well-being, whereas for older adults holding more negative age stereotypes, FTP-opportunity’s positive effect became stronger and FTP-limitation’s positive effect became weaker and even detrimental. These results indicate that certain qualifiers should be taken into account when considering the relationship between FTP and well-being. These findings contribute to the theoretical understanding of the role of FTP in older adults’ well-being.