Miracle-dz/UniFAR-FTUs huggingface dataset:
Tetraspanins TSP-12 and TSP-14 function redundantly to regulate the trafficking of the type II BMP receptor in Caenorhabditis elegans

Significance Tetraspanins are a unique family of eukaryotic 4-pass transmembrane proteins. However, their functions in vivo are poorly understood. We find that 2 tetraspanins that share redundant functions are primarily localized to endosomes, which are major sorting centers for membrane proteins and lipids within the cell. We show that these 2 tetraspanins regulate the recycling of the type II receptor of the bone morphogenetic protein (BMP) signaling pathway. In their absence, the BMP type II receptor is mistargeted to lysosomes, leading to reduced cell-surface levels available to receive extracellular signals. Our work highlights the importance of tetraspanin-mediated intracellular trafficking in regulating BMP signaling in vivo, and suggests a similar mode of action for the mammalian counterparts of these 2 tetraspanins. Tetraspanins are a unique family of 4-pass transmembrane proteins that play important roles in a variety of cell biological processes. We have previously shown that 2 paralogous tetraspanins in Caenorhabditis elegans, TSP-12 and TSP-14, function redundantly to promote bone morphogenetic protein (BMP) signaling. The underlying molecular mechanisms, however, are not fully understood. In this study, we examined the expression and subcellular localization patterns of endogenously tagged TSP-12 and TSP-14 proteins. We found that TSP-12 and TSP-14 share overlapping expression patterns in multiple cell types, and that both proteins are localized on the cell surface and in various types of endosomes, including early, late, and recycling endosomes. Animals lacking both TSP-12 and TSP-14 exhibit reduced cell-surface levels of the BMP type II receptor DAF-4/BMPRII, along with impaired endosome morphology and mislocalization of DAF-4/BMPRII to late endosomes and lysosomes. These findings indicate that TSP-12 and TSP-14 are required for the recycling of DAF-4/BMPRII. Together with previous findings that the type I receptor SMA-6 is recycled via the retromer complex, our work demonstrates the involvement of distinct recycling pathways for the type I and type II BMP receptors and highlights the importance of tetraspanin-mediated intracellular trafficking in the regulation of BMP signaling in vivo. As TSP-12 and TSP-14 are conserved in mammals, our findings suggest that the mammalian TSP-12 and TSP-14 homologs may also function in regulating transmembrane protein recycling and BMP signaling.
Prostaglandin E2 and its receptor EP2 trigger signaling that contributes to YAP‐mediated cell competition

Cell competition is a biological process by which unfit cells are eliminated from “cell society. ” We previously showed that cultured mammalian epithelial Madin‐Darby canine kidney (MDCK) cells expressing constitutively active YAP were eliminated by apical extrusion when surrounded by “normal” MDCK cells. However, the molecular mechanism underlying the elimination of active YAP‐expressing cells was unknown. Here, we used high‐throughput chemical compound screening to identify cyclooxygenase‐2 (COX‐2) as a key molecule triggering cell competition. Our work shows that COX‐2‐mediated PGE2 secretion engages its receptor EP2 on abnormal and nearby normal cells. This engagement of EP2 triggers downstream signaling via an adenylyl cyclase‐cyclic AMP‐PKA pathway that, in the presence of active YAP, induces E‐cadherin internalization leading to apical extrusion. Thus, COX‐2‐induced PGE2 appears a warning signal to both abnormal and surrounding normal cells to drive cell competition.
Rapid reversal of a potentially constraining genetic covariance between leaf and flower traits in Silene latifolia

Abstract Genetic covariance between two traits generates correlated responses to selection, and may either enhance or constrain adaptation. Silene latifolia exhibits potentially constraining genetic covariance between specific leaf area (SLA) and flower number in males. Flower number is likely to increase via fecundity selection but the correlated increase in SLA increases mortality, and SLA is under selection to decrease in dry habitats. We selected on trait combinations in two selection lines for four generations to test whether genetic covariance could be reduced without significantly altering trait means. In one selection line, the genetic covariance changed sign and eigenstructure changed significantly, while in the other selection line eigenstructure remained similar to the control line. Changes in genetic variance–covariance structure are therefore possible without the introduction of new alleles, and the responses we observed suggest that founder effects and changes in frequency of alleles of major effect may be acting to produce the changes.
Bleeding and recurrent VTE with apixaban vs warfarin as outpatient treatment: time-course and subgroup analyses.

In the phase 3 trial Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy, apixaban was noninferior to enoxaparin, overlapped and followed by warfarin, in the treatment of venous thromboembolism (VTE) with significantly less bleeding; in a real-world evaluation, risks for bleeding and recurrent VTE were lower with apixaban vs warfarin plus parenteral anticoagulant (PAC) bridge therapy. The present study extends this research by comparing outcomes over time and within selected subgroups. A retrospective observational cohort design and 4 US private health care claims databases were used. Study population included patients who initiated outpatient treatment with apixaban or warfarin (plus PAC bridge therapy) for VTE. Major bleeding, clinically relevant nonmajor (CRNM) bleeding, and recurrent VTE were compared during the 180-day follow-up period, at selected follow-up time points (days 21, 90, 180), and within subgroups (pulmonary embolism [PE] with or without deep vein thrombosis [DVT], DVT only, provoked VTE, unprovoked VTE) using multivariable shared frailty models. Study population consisted of 20 561 apixaban patients and 35 080 warfarin patients; baseline characteristics were comparable. Overall, at selected follow-up time points, and within the aforementioned subgroups, adjusted risks were lower among apixaban vs warfarin patients: major bleeding, by 27% to 39%, CRNM bleeding, by 17% to 28%, and recurrent VTE, by 25% to 39% (all P ≤ .01). In this real-world study of VTE patients, risks of bleeding and recurrent VTE were lower among apixaban (vs warfarin) patients during the 180-day follow-up period, at selected follow-up time points, and within subgroups defined by index VTE episode.
Indirect frontocingulate structural connectivity predicts clinical response to accelerated rTMS in major depressive disorder

Background Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for major depressive disorder (MDD), but its clinical efficacy remains rather modest. One reason for this could be that the propagation of rTMS effects via structural connections from the stimulated area to deeper brain structures (such as the cingulate cortices) is suboptimal. Methods We investigated whether structural connectivity — derived from diffusion MRI data — could serve as a biomarker to predict treatment response. We hypothesized that stronger structural connections between the patient-specific stimulation position in the left dorsolateral prefrontal cortex (dlPFC) and the cingulate cortices would predict better clinical outcomes. We applied accelerated intermittent theta burst stimulation (aiTBS) to the left dlPFC in 40 patients with MDD. We correlated baseline structural connectivity, quantified using various metrics (fractional anisotropy, mean diffusivity, tract density, tract volume and number of tracts), with changes in depression severity scores after aiTBS. Results Exploratory results (p < 0.05) showed that structural connectivity between the patient-specific stimulation site and the caudal and posterior parts of the cingulate cortex had predictive potential for clinical response to aiTBS. Limitations We used the diffusion tensor to perform tractography. A main limitation was that multiple fibre directions within voxels could not be resolved, which might have led to missing connections in some patients. Conclusion Stronger structural frontocingular connections may be of essence to optimally benefit from left dlPFC rTMS treatment in MDD. Even though the results are promising, further investigation with larger numbers of patients, more advanced tractography algorithms and classic daily rTMS treatment paradigms is warranted. Clinical trial registration http://clinicaltrials.gov/show/NCT01832805
The association between dual-task walking and counting responses and cognitive function and disability after severe head injury: A preliminary study

ABSTRACT Adverse outcomes after severe head injury (SHI) can be difficult to detect in primary care and other settings where there is not specialist expertise for interpretation. Walking and counting dual-task (DT) measures are strongly associated with cognitive impairment and dementia and this preliminary study investigates whether performance on DT walking and counting tasks are associated with cognitive function and disability in 125 participants who sustained a SHI on average 26 years before. Single Task (ST) walking (speed over 6 metres) and ST counting (Serial 3s) and DT performance of concurrent walking and Serial 3s were compared with neuropsychological, wellbeing and disability tests for strength of association. The strongest correlations were between ST Correct Cognitive Responses (CCRs) and MMSE (rho = 0.435), DT CCRs and Short-term Memory Binding Tests (STMBT) binding accuracy (rho = 0,409) and DT CCRs and STROOP (rho = 0.420), but associations were less strong with disability. Developing this test, as a cost-efficient screening tool for triage to onward referral for neuropsychological assessment, holds promise, but requires further research.
Coronary Artery Disease and Type 2 Diabetes: A Proteomic Study

OBJECTIVE Coronary artery disease (CAD) is a major challenge in patients with type 2 diabetes (T2D). Coronary computed tomography angiography (CCTA) provides a detailed anatomic map of the coronary circulation. Proteomics are increasingly used to improve diagnostic and therapeutic algorithms. We hypothesized that the protein panel is differentially associated with T2D and CAD. RESEARCH DESIGN AND METHODS In CAPIRE (Coronary Atherosclerosis in Outlier Subjects: Protective and Novel Individual Risk Factors Evaluation—a cohort of 528 individuals with no previous cardiovascular event undergoing CCTA), participants were grouped into CAD− (clean coronaries) and CAD+ (diffuse lumen narrowing or plaques). Plasma proteins were screened by aptamer analysis. Two-way partial least squares was used to simultaneously rank proteins by diabetes status and CAD. RESULTS Though CAD+ was more prevalent among participants with T2D (HbA1c 6.7 ± 1.1%) than those without diabetes (56 vs. 30%, P < 0.0001), CCTA-based atherosclerosis burden did not differ. Of the 20 top-ranking proteins, 15 were associated with both T2D and CAD, and 3 (osteomodulin, cartilage intermediate-layer protein 15, and HTRA1) were selectively associated with T2D only and 2 (epidermal growth factor receptor and contactin-1) with CAD only. Elevated renin and GDF15, and lower adiponectin, were independently associated with both T2D and CAD. In multivariate analysis adjusting for the Framingham risk panel, patients with T2D were “protected” from CAD if female (P = 0.007), younger (P = 0.021), and with lower renin levels (P = 0.02). CONCLUSIONS We concluded that 1) CAD severity and quality do not differ between participants with T2D and without diabetes; 2) renin, GDF15, and adiponectin are shared markers by T2D and CAD; 3) several proteins are specifically associated with T2D or CAD; and 4) in T2D, lower renin levels may protect against CAD.
Nanomagnetic logic based runtime Reconfigurable area efficient and high speed adder design methodology

In this study, we present a runtime reconfigurable nanomagnetic (RRN) adder design offering significant area efficiency and high speed operations. Subsequently, it is implemented using a micromagnetic simulation tool, by exploiting the reversal magnetization and energy minimization nature of the nanomagnets. We compute the carry and sum of the 1-bit full adder using only two majority gates comprising a total of 7 nanomagnets and single design layout. Consequently, the on-chip clocking schematic for the proposed RRN adder implementation for both horizontal and vertical layouts are introduced. The quantitative analysis of the required resources for higher bit adder architecture using the proposed design is performed and compared with state-of-the art. The proposed design methodology leads to ∼86%, ∼83% and ∼93% reduction in the number of nanomagnets, majority gates and clock cycles respectively resulting in an area efficient and high speed RRN adder architecture.
The multifarious roles of heterogeneous ribonucleoprotein A1 in viral infections

Viruses are obligate parasites known to interact with a wide variety of host proteins at different stages of infection. Current antiviral treatments target viral proteins and may be compromised due to the emergence of drug resistant viral strains. Targeting viral‐host interactions is now gaining recognition as an alternative approach against viral infections. Recent research has revealed that heterogeneous ribonucleoprotein A1, an RNA‐binding protein, plays an essential functional and regulatory role in the life cycle of many viruses. In this review, we summarize the interactions between heterogeneous ribonucleoprotein A1 (hnRNPA1) and multiple viral proteins during the life cycle of RNA and DNA viruses. hnRNPA1 protein levels are modulated differently, in different viruses, which further dictates its stability, function, and intracellular localization. Multiple reports have emphasized that in Sindbis virus, enteroviruses, porcine endemic diarrhea virus, and rhinovirus infection, hnRNPA1 enhances viral replication and survival. However, in others like hepatitis C virus and human T‐cell lymphotropic virus, it exerts a protective response. The involvement of hnRNPA1 in viral infections highlights its importance as a central regulator of host and viral gene expression. Understanding the nature of these interactions will increase our understanding of specific viral infections and pathogenesis and eventually aid in the development of novel and robust antiviral intervention strategies.
Ketoconazole - p-aminobenzoic acid cocrystal: revival of an old drug by crystal engineering.

The 1:1 cocrystal of the antifungal agent Ketoconazole with p-aminobenzoic acid was successfully crystallized and systematically characterized from a physical and pharmacological point of view. Crystal structure determination confirmed the cocrystal identity, giving full insight in its crystal packing and degree of disorder. Powder dissolution measurement revealed a 10 fold aqueous solubility increase that induce a 6.7 fold oral bioavailability improvement compared to Ketoconazole. In vitro cell assays showed good toxicity profile of the cocrystal with lower oxidative stress and inflammation, and enhanced antifungal activity against several Candida species. The in vivo study of the cocrystal indicated similar pharmacokinetic profile and liver toxicity with increased transaminases, as reported for Ketoconazole. Notably, besides minor signs of inflammation, no morphological changes in liver parenchyma or signs of fibrosis and necrosis were detected. The enhanced solubility and oral bioavailability of the cocrystal over Ketoconazole, together with the improved antifungal activity and good in vitro/in vivo toxicity indicate its potential use as an alternative antifungal agent to the parent drug. Our results bring evidence of cocrystallization as a succesful approach for bioavailability improvement of poorly soluble drugs.
Affective state determination in a mouse model of colitis-associated colorectal cancer

Behavioural indicators of affective state, including burrowing, clinical scores and the Mouse Grimace Score have not yet been validated in mouse models of chronic gastrointestinal disease. Additionally, a comparison of these methods has not been characterised. This study aimed to determine which behavioural assessment was the optimal indicator of disease, evidenced by correlation with clinically-assessed measures, in an azoxymethane (AOM)/dextran sulphate sodium (DSS) mouse model of colitis-associated colorectal cancer. C57BL/6 mice were allocated to four groups (n = 10/group); 1) saline control, 2) saline+buprenorphine, 3) AOM+DSS+water, 4) AOM+DSS+buprenorphine. Mice were gavaged thrice weekly with water or buprenorphine (0.5mg/kg; 80μL) for 9 weeks. Disease activity index (DAI) was measured daily; burrowing and grimace analyses occurred on days -1, 5, 19, 26, 40, 47 and 61. Colonoscopies were performed on days 20, 41 and 62. All animals were euthanized on day 63. Burrowing activity and retrospective grimace analyses were unaffected (P>0.05), whilst DAI was significantly increased (P<0.05) in mice with colitis-associated colorectal cancer compared to normal controls. In addition, DAI was positively correlated with colonoscopically-assessed severity and tumour number (P<0.05). We conclude that traditional measures of DAI or clinical scoring provide the most reliable assessment of wellbeing in mice with colitis-associated colorectal cancer.
Predictive Value of the Get With The Guidelines Heart Failure Risk Score in Unselected Cardiac Intensive Care Unit Patients

Background The cardiac intensive care unit (CICU) population is no longer composed of only patients with acute coronary syndromes, and includes those with acute heart failure and multiple comorbidities. We hypothesized that the GWTG‐HF (Get With The Guidelines–Heart Failure) risk score that predicts inpatient mortality in hospitalized patients with heart failure would predict mortality in CICU patients. Methods and Results We retrospectively analyzed CICU patients at a tertiary care hospital from 2007 to 2015. The GWTG‐HF risk score was calculated at CICU admission. As a secondary analysis, the EFFECT (Enhanced Feedback for Effective Cardiac Treatment), OPTIMIZE‐HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure), and ADHERE (Acute Decompensated Heart Failure National Registry) risk scores were calculated. Kaplan–Meier survival analysis and the area under the receiver operating characteristic curve value were determined for inpatient and 1‐year mortality. The GWTG‐HF risk score was calculated in 9532 (95%) patients, with a median value of 40 (interquartile range, 35–47). Inpatient mortality occurred in 824 (8.6%) patients, and 2075 (21.8%) patients died by 1 year. Patients who died in hospital had a significantly higher mean GWTG‐HF score (47.7 versus 40.2; P<0.001). Inpatient and 1‐year mortality increased in each GWTG‐HF risk score quartile (P<0.0001). Discrimination of the GWTG‐HF, EFFECT, OPTIMIZE‐HF, and ADHERE risk scores was assessed using area under the receiver operating characteristic curve values for hospital mortality, and were similar for all risk scores (0.72–0.74; P>0.05). The Hosmer–Lemeshow statistic suggested poor calibration for hospital mortality by the GWTG‐HF risk score (P<0.001). Conclusions The GWTG‐HF risk score and other heart failure prediction tools demonstrate good discrimination for inpatient and 1‐year mortality in a heterogeneous cohort of CICU patients. Our study emphasizes that prognostic variables overlap in cardiac patients, regardless of the admission diagnosis.
Cross‐lateralisation in children with attention‐deficit/hyperactivity disorder and motor skill performance

Cross‐lateralisation and increased motor difficulties have been reported in children with attention‐deficit/hyperactivity disorder (ADHD). Nevertheless, the question of how crossed (i.e. mixed preference) or uncrossed (i.e. same side preference) lateralisation impacts motor performance in children with ADHD has yet to be examined. In this study, previously validated observational measures of hand and foot preference were used to identify right‐handed children with ADHD who display cross‐ (n = 29) and uncross‐lateralisation (n = 31). An uncross‐lateralised typically developing (TD) group (n = 32) was also identified, and included as a control. Motor performance was assessed with seven valid and reliable fine and gross motor tasks performed with both preferred and non‐preferred limbs. Group, task and sex‐related effects were examined. Findings revealed that male (but not female) cross‐lateralised children with ADHD performed significantly worse, respectively, in two of the fine motor tasks (spiral tracing [p < .01], and dot filling [p < .05]). Results suggest that cross‐lateralised hand and foot preference may affect complex motor skills in male children with ADHD. Furthermore, characteristics of ADHD may manifest differently in male and female children. Findings highlight the importance of considering both hand and foot preference when targeting motor interventions for children with ADHD.
Polymerase IV Plays a Crucial Role in Pollen Development in Capsella[OPEN]

Unlike in Arabidopsis, loss of function of Polymerase IV in the Brassicaceae species Capsella rubella causes microspore arrest, revealing an important role for Polymerase IV in pollen development. In Arabidopsis (Arabidopsis thaliana), DNA-dependent RNA polymerase IV (Pol IV) is required for the formation of transposable element (TE)-derived small RNA transcripts. These transcripts are processed by DICER-LIKE3 into 24-nucleotide small interfering RNAs (siRNAs) that guide RNA-directed DNA methylation. In the pollen grain, Pol IV is also required for the accumulation of 21/22-nucleotide epigenetically activated siRNAs, which likely silence TEs via post-transcriptional mechanisms. Despite this proposed role of Pol IV, its loss of function in Arabidopsis does not cause a discernible pollen defect. Here, we show that the knockout of NRPD1, encoding the largest subunit of Pol IV, in the Brassicaceae species Capsella (Capsella rubella), caused postmeiotic arrest of pollen development at the microspore stage. As in Arabidopsis, all TE-derived siRNAs were depleted in Capsella nrpd1 microspores. In the wild-type background, the same TEs produced 21/22-nucleotide and 24-nucleotide siRNAs; these processes required Pol IV activity. Arrest of Capsella nrpd1 microspores was accompanied by the deregulation of genes targeted by Pol IV-dependent siRNAs. TEs were much closer to genes in Capsella compared with Arabidopsis, perhaps explaining the essential role of Pol IV in pollen development in Capsella. Our discovery that Pol IV is functionally required in Capsella microspores emphasizes the relevance of investigating different plant models.