Miracle-dz/UniFAR-FTUs huggingface dataset:
The influence of computer-based cognitive flexibility training on subjective cognitive well-being after stroke: A multi-center randomized controlled trial

Background Stroke can result in cognitive complaints that can have a large impact on quality of life long after its occurrence. A number of computer-based training programs have been developed with the aim to improve cognitive functioning. Most studies investigating their efficacy used only objective outcome measures, whereas a reduction of subjective cognitive complaints may be equally important for improving quality of life. A few studies used subjective outcome measures but were inconclusive, partly due to methodological shortcomings such as lack of proper active and passive control groups. Objective The aim of the current study was to investigate whether computer-based cognitive flexibility training can improve subjective cognitive functioning and quality of life after stroke. Methods We performed a randomized controlled double blind trial (RCT). Adults (30–80 years old) who had a stroke 3 months to 5 years ago, were randomly assigned to either an intervention group (n = 38), an active control group (i.e., mock training; n = 35), or a waiting list control group (n = 24). The intervention and mock training consisted of 58 half-hour sessions within 12 weeks. The primary subjective outcome measures were cognitive functioning (Cognitive Failure Questionnaire), executive functioning (Dysexecutive Functioning Questionnaire), quality of life (Short Form Health Survey), instrumental activities of daily living (IADL; Lawton & Brody IADL scale), and participation in society (Utrecht Scale for Evaluation of Rehabilitation-Participation). Secondary subjective outcome measures were recovery after stroke, depressive symptoms (Hospital Anxiety Depression Scale—depression subscale), fatigue (Checklist Individual Strength—Fatigue subscale), and subjective cognitive improvement (exit list). Finally, a proxy of the participant rated the training effects in subjective cognitive functioning, subjective executive functioning, and IADL. Results and conclusions All groups improved on the two measures of subjective cognitive functioning and subjective executive functioning, but not on the other measures. These cognitive and executive improvements remained stable 4 weeks after training completion. However, the intervention group did not improve more than the two control groups. This suggests that improvement was due to training-unspecific effects. The proxies did not report any improvements. We, therefore, conclude that the computer-based cognitive flexibility training did not improve subjective cognitive functioning or quality of life after stroke.
Approaches to hepatitis C treatment and cure using NS5A inhibitors

Recent progress in the understanding of hepatitis C virus (HCV) biology and the availability of in vitro models to study its replication have facilitated the development of direct-acting antiviral agents (DAAs) that target specific steps in the viral replication cycle. Currently, there are three major classes of DAA in clinical development: NS3/4A protease inhibitors, NS5B polymerase inhibitors, and NS5A directed inhibitors. Several compounds thought to bind directly with NS5A are now in various clinical trial phases, including the most advanced, daclatasvir (BMS-790052), ledipasvir (GS-5885), and ABT-267. While many NS5A-targeted compounds demonstrate picomolar potency, the exact mechanism(s) of their action is still unclear. In the clinic, NS5A HCV inhibitors show promise as important components in DAA regimens and have multifunctionality. In addition to inhibiting viral replication, they may synergize with other DAAs, possibly by modulating different viral proteins, to help suppress the emergence of resistant viruses. Structure-based models have identified target interaction domains and spatial interactions that explain drug resistance for mutations at specific positions (eg, residues 93 and 31) within NS5A and potential binding partners. This review provides, insights into the unique complexity of NS5A as a central platform for multiple viral/host protein interactions, and possible mechanism(s) for the NS5A inhibitors currently undergoing clinical trials that target this nonstructural viral protein.
Alpha-Bulges in G Protein-Coupled Receptors

Agonist binding is related to a series of motions in G protein-coupled receptors (GPCRs) that result in the separation of transmembrane helices III and VI at their cytosolic ends and subsequent G protein binding. A large number of smaller motions also seem to be associated with activation. Most helices in GPCRs are highly irregular and often contain kinks, with extensive literature already available about the role of prolines in kink formation and the precise function of these kinks. GPCR transmembrane helices also contain many α-bulges. In this article we aim to draw attention to the role of these α-bulges in ligand and G-protein binding, as well as their role in several aspects of the mobility associated with GPCR activation. This mobility includes regularization and translation of helix III in the extracellular direction, a rotation of the entire helix VI, an inward movement of the helices near the extracellular side, and a concerted motion of the cytosolic ends of the helices that makes their orientation appear more circular and that opens up space for the G protein to bind. In several cases, α-bulges either appear or disappear as part of the activation process.
Skeletal muscle IL‐6 and regulation of liver metabolism during high‐fat diet and exercise training

Interleukin (IL)‐6 is released from skeletal muscle (SkM) during exercise and has been shown to affect hepatic metabolism. It is, however, unknown whether SkM IL‐6 is involved in the regulation of exercise training‐induced counteraction of changes in carbohydrate and lipid metabolism in the liver in response to high‐fat diet (HFD) feeding. Male SkM‐specific IL‐6 KO (MKO) and Floxed mice were subjected to Chow diet, HFD or HFD combined with exercise training (HFD ExTr) for 16 weeks. Hepatic phosphoenolpyruvate carboxykinase (PEPCK) protein content decreased with both HFD and HFD ExTr in Floxed mice, but increased in IL‐6 MKO mice on HFD. In addition, the intrahepatic glucose concentration was in IL‐6 MKO mice higher in HFD than chow. Within HFD ExTr mice, hepatic glucose‐6‐phosphatase (G6Pase) 36 kDa protein content was higher in IL‐6 MKO than Floxed mice. Hepatic pyruvate dehydrogenase kinase (PDK) 4 and PDK2 protein content was in Floxed mice lower in HFD ExTr than Chow. In addition, hepatic ACC1‐phosphorylation was higher and ACC1 protein lower in HFD. Together this suggests that SkM IL‐6 regulates hepatic glucose metabolism, but does not seem to be of major importance for the regulation of oxidative capacity or lipogenesis in liver during HFD or HFD combined with exercise training.
Effect of a Novel Clinical Decision Support Tool on the Efficiency and Accuracy of Treatment Recommendations for Cholesterol Management

Summary Background: The 2013 American College of Cardiology / American Heart Association Guidelines for the Treatment of Blood Cholesterol emphasize treatment based on cardiovascular risk. But finding time in a primary care visit to manually calculate cardiovascular risk and prescribe treatment based on risk is challenging. We developed an informatics-based clinical decision support tool, MayoExpertAdvisor, to deliver automated cardiovascular risk scores and guideline-based treatment recommendations based on patient-specific data in the electronic heath record. Objective: To assess the impact of our clinical decision support tool on the efficiency and accuracy of clinician calculation of cardiovascular risk and its effect on the delivery of guideline-consistent treatment recommendations. Methods: Clinicians were asked to review the EHR records of selected patients. We evaluated the amount of time and the number of clicks and keystrokes needed to calculate cardiovascular risk and provide a treatment recommendation with and without our clinical decision support tool. We also compared the treatment recommendation arrived at by clinicians with and without the use of our tool to those recommended by the guidelines. Results: Clinicians saved 3 minutes and 38 seconds in completing both tasks with MayoExpertAd-visor, used 94 fewer clicks and 23 fewer key strokes, and improved accuracy from the baseline of 60.61% to 100% for both the risk score calculation and guideline-consistent treatment recommendation. Conclusion: Informatics solution can greatly improve the efficiency and accuracy of individualized treatment recommendations and have the potential to increase guideline compliance.
ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis

Initially identified in DNA damage repair, ATM-interactor (ATMIN) further functions as a transcriptional regulator of lung morphogenesis. Here we analyse three mouse mutants, Atmingpg6/gpg6, AtminH210Q/H210Q and Dynll1GT/GT, revealing how ATMIN and its transcriptional target dynein light chain LC8-type 1 (DYNLL1) are required for normal lung morphogenesis and ciliogenesis. Expression screening of ciliogenic genes confirmed Dynll1 to be controlled by ATMIN and further revealed moderately altered expression of known intraflagellar transport (IFT) protein-encoding loci in Atmin mutant embryos. Significantly, Dynll1GT/GT embryonic cilia exhibited shortening and bulging, highly similar to the characterised retrograde IFT phenotype of Dync2h1. Depletion of ATMIN or DYNLL1 in cultured cells recapitulated the in vivo ciliogenesis phenotypes and expression of DYNLL1 or the related DYNLL2 rescued the effects of loss of ATMIN, demonstrating that ATMIN primarily promotes ciliogenesis by regulating Dynll1 expression. Furthermore, DYNLL1 as well as DYNLL2 localised to cilia in puncta, consistent with IFT particles, and physically interacted with WDR34, a mammalian homologue of the Chlamydomonas cytoplasmic dynein 2 intermediate chain that also localised to the cilium. This study extends the established Atmin-Dynll1 relationship into a developmental and a ciliary context, uncovering a novel series of interactions between DYNLL1, WDR34 and ATMIN. This identifies potential novel components of cytoplasmic dynein 2 and furthermore provides fresh insights into the molecular pathogenesis of human skeletal ciliopathies.
Paired-pulse transcranial magnetic stimulation reveals probability-dependent changes in functional connectivity between right inferior frontal cortex and primary motor cortex during go/no-go performance

The functional role of the right inferior frontal cortex (rIFC) in mediating human behavior is the subject of ongoing debate. Activation of the rIFC has been associated with both response inhibition and with signaling action adaptation demands resulting from unpredicted events. The goal of this study is to investigate the role of rIFC by combining a go/no-go paradigm with paired-pulse transcranial magnetic stimulation (ppTMS) over rIFC and the primary motor cortex (M1) to probe the functional connectivity between these brain areas. Participants performed a go/no-go task with 20% or 80% of the trials requiring response inhibition (no-go trials) in a classic and a reversed version of the task, respectively. Responses were slower to infrequent compared to frequent go trials, while commission errors were more prevalent to infrequent compared to frequent no-go trials. We hypothesized that if rIFC is involved primarily in response inhibition, then rIFC should exert an inhibitory influence over M1 on no-go (inhibition) trials regardless of no-go probability. If, by contrast, rIFC has a role on unexpected trials other than just response inhibition then rIFC should influence M1 on infrequent trials regardless of response demands. We observed that rIFC suppressed M1 excitability during frequent no-go trials, but not during infrequent no-go trials, suggesting that the role of rIFC in response inhibition is context dependent rather than generic. Importantly, rIFC was found to facilitate M1 excitability on all low frequent trials, irrespective of whether the infrequent event involved response inhibition, a finding more in line with a predictive coding framework of cognitive control.
Biomonitoring of blood cholinesterases and acylpeptide hydrolase activities in rural inhabitants exposed to pesticides in the Coquimbo Region of Chile

In Chile, agriculture is a relevant economic activity and is concomitant with the use of pesticides to improve the yields. Acute intoxications of agricultural workers occur with some frequency and they must be reported to the surveillance system of the Ministry of Health. However the impacts of chronic and environmental pesticide exposure have been less studied. Among pesticides frequently used in Chile for insects control are organophosphates (OP) and carbamates (CB). They are inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In this study we determined the pattern of both biomarkers activity in three populations with different type of chronic exposure to OP/CB: environmentally exposed (EE), occupationally exposed (OE) and a reference group (RG) without exposure. Besides this, we also measured the activity of acylpeptide hydrolase (APEH), an enzyme involved in relevant functions in the central synapses that is also expressed in erythrocytes and previously reported to be highly inhibited by some OP. A baseline measurement was done in both exposure groups and then a second measurement was done during the spraying season. The RG was measured only once at any time of the year. Our results indicate that people under chronic OP/CB exposure showed an adaptive response through an increase of basal BChE activity. During the spray season only BChE activity was decreased in the EE and OE groups (p<0.05 and p<0.01, respectively) and the higher magnitude of BChE inhibition was observed in the EE group. The analysis of the frequencies of inhibition above 30% (biological tolerance limit declared by Chilean legislation) indicated that BChE was most frequently inhibited in the EE group (53% of the individuals displayed inhibition) and AChE in the OE group (55% of the individuals displayed AChE inhibition). APEH activity showed the highest frequency of inhibition in the EE group independent of its magnitude (64%). Our results demonstrate that the rural population living nearby agricultural settings displays high levels of environmental exposure. APEH activity seems to be a sensitive biomarker for acute low-level exposure and its usefulness as a routine biomarker must to be explored in future studies. Systematic biomonitoring and health outcomes studies are necessary as well as obtaining the baseline for BChE and AChE activity levels with the aim to improve environmental and occupational health policies in Chile.
Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10−35 and <10−8 respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10−6). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10−20) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.
A Bacterial Analysis Platform: An Integrated System for Analysing Bacterial Whole Genome Sequencing Data for Clinical Diagnostics and Surveillance

Recent advances in whole genome sequencing have made the technology available for routine use in microbiological laboratories. However, a major obstacle for using this technology is the availability of simple and automatic bioinformatics tools. Based on previously published and already available web-based tools we developed a single pipeline for batch uploading of whole genome sequencing data from multiple bacterial isolates. The pipeline will automatically identify the bacterial species and, if applicable, assemble the genome, identify the multilocus sequence type, plasmids, virulence genes and antimicrobial resistance genes. A short printable report for each sample will be provided and an Excel spreadsheet containing all the metadata and a summary of the results for all submitted samples can be downloaded. The pipeline was benchmarked using datasets previously used to test the individual services. The reported results enable a rapid overview of the major results, and comparing that to the previously found results showed that the platform is reliable and able to correctly predict the species and find most of the expected genes automatically. In conclusion, a combined bioinformatics platform was developed and made publicly available, providing easy-to-use automated analysis of bacterial whole genome sequencing data. The platform may be of immediate relevance as a guide for investigators using whole genome sequencing for clinical diagnostics and surveillance. The platform is freely available at: https://cge.cbs. dtu.dk/services/CGEpipeline-1.1 and it is the intention that it will continue to be expanded with new features as these become available.
Mechanisms Underlying Alcohol-Approach Action Tendencies: The Role of Emotional Primes and Drinking Motives

The tendency to approach alcohol-related stimuli is known as the alcohol-approach bias and has been related to heavy alcohol use. It is currently unknown whether the alcohol-approach bias is more pronounced after emotional priming. The main aim of this study was to investigate whether positive and negative emotional primes would modulate the alcohol-approach bias. For this purpose, a new contextual emotional prime-approach avoidance task was developed, containing both negative and positive emotional primes. Explicit coping drinking motives were expected to be related to an increased alcohol-approach bias after negative primes. Results of 65 heavy and 50 occasional drinkers showed that the alcohol-approach bias was increased in both groups during negative emotional priming. This appeared to be due to slower alcohol avoidance rather than faster alcohol approach. This change in alcohol-approach bias was positively related to explicit enhancement drinking motives and negatively related to alcohol use-related problems. A stronger alcohol-approach bias in heavy compared to occasional drinkers could not be replicated here, and coping drinking motives were not related to the alcohol-approach bias in any of the emotional contexts. The current findings suggest that both occasional and heavy drinkers have a selective difficulty to avoid alcohol-related cues in a negative emotional context. Negative reinforcement may therefore be involved in different types of drinking patterns. The influence of emotional primes on alcohol-related action tendencies may become smaller when alcohol use becomes more problematic, which is in line with habit accounts of addiction.
Edinburgh Research Explorer Challenges in microbial ecology: building predictive understanding of community function and dynamics

The importance of microbial communities (MCs) cannot be overstated. MCs underpin the biogeochemical cycles of the earth ’ s soil, oceans and the atmosphere, and perform ecosystem functions that impact plants, animals and humans. Yet our ability to predict and manage the function of these highly complex, dynamically changing communities is limited. Building predictive models that link MC composition to function is a key emerging challenge in microbial ecology. Here, we argue that addressing this challenge requires close coordination of experimental data collection and method development with mathematical model building. We discuss specific examples where model – experiment integration has already resulted in important insights into MC function and structure. We also highlight key research questions that still demand better integration of experiments and models. We argue that such integration is needed to achieve significant progress in our understanding of MC dynamics and function, and we make specific practical suggestions as to how this could be achieved.
Re-wiring of energy metabolism promotes viability during hyperreplication stress in E. coli

Chromosome replication in Escherichia coli is initiated by DnaA. DnaA binds ATP which is essential for formation of a DnaA-oriC nucleoprotein complex that promotes strand opening, helicase loading and replisome assembly. Following initiation, DnaAATP is converted to DnaAADP primarily by the Regulatory Inactivation of DnaA process (RIDA). In RIDA deficient cells, DnaAATP accumulates leading to uncontrolled initiation of replication and cell death by accumulation of DNA strand breaks. Mutations that suppress RIDA deficiency either dampen overinitiation or permit growth despite overinitiation. We characterize mutations of the last group that have in common that distinct metabolic routes are rewired resulting in the redirection of electron flow towards the cytochrome bd-1. We propose a model where cytochrome bd-1 lowers the formation of reactive oxygen species and hence oxidative damage to the DNA in general. This increases the processivity of replication forks generated by overinitiation to a level that sustains viability.