bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chrom-Lasso: a lasso regression-based model to detect functional interactions using Hi-C data
Authors: Lu Jingzhe , Wang Xu , Sun Keyong , Lan Xun 
Published: April 2021

Abstract
Hi-C is a genome-wide assay based on Chromosome Conformation Capture and high-throughput sequencing to decipher 3D chromatin organization in the nucleus. However, computational methods to detect functional interactions utilizing Hi-C data face challenges including the correction for various sources of biases and the identification of functional interactions with low counts of interacting fragments. We present Chrom-Lasso, a lasso linear regression model that removes complex biases assumption-free and identifies functional interacting loci with increased power by combining information of local reads distribution surrounding the area of interest. We showed that interacting regions identified by Chrom-Lasso are more enriched for 5C validated interactions and functional GWAS hits than that of GOTHiC and Fit-Hi-C. To further demonstrate the ability of Chrom-Lasso to detect interactions of functional importance, we performed time-series Hi-C and RNA-seq during T cell activation and exhaustion. We showed that the dynamic changes in gene expression and chromatin interactions identified by Chrom-Lasso were largely concordant with each other. Finally, we experimentally confirmed Chrom-Lasso’s finding that Erbb3 was co-regulated with distinct neighboring genes at different states during T cell activation. Our results highlight Chrom-Lasso’s utility in detecting weak functional interaction between cis-regulatory elements, such as promoters and enhancers.
Assessing the performance of computational predictors for estimating protein stability changes upon missense mutations
Authors: Iqbal Shahid , Li Fuyi , Akutsu Tatsuya , Ascher David B , Webb Geoffrey I , Song Jiangning 
Published: April 2021

Abstract
Understanding how a mutation might affect protein stability is of significant importance to protein engineering and for understanding protein evolution genetic diseases. While a number of computational tools have been developed to predict the effect of missense mutations on protein stability protein stability upon mutations, they are known to exhibit large biases imparted in part by the data used to train and evaluate them. Here, we provide a comprehensive overview of predictive tools, which has provided an evolving insight into the importance and relevance of features that can discern the effects of mutations on protein stability. A diverse selection of these freely available tools was benchmarked using a large mutation-level blind dataset of 1342 experimentally characterised mutations across 130 proteins from ThermoMutDB, a second test dataset encompassing 630 experimentally characterised mutations across 39 proteins from iStable2.0 and a third blind test dataset consisting of 268 mutations in 27 proteins from the newly published ProThermDB. The performance of the methods was further evaluated with respect to the site of mutation, type of mutant residue and by ranging the pH and temperature. Additionally, the classification performance was also evaluated by classifying the mutations as stabilizing (∆∆G ≥ 0) or destabilizing (∆∆G &lt; 0). The results reveal that the performance of the predictors is affected by the site of mutation and the type of mutant residue. Further, the results show very low performance for pH values 6–8 and temperature higher than 65 for all predictors except iStable2.0 on the S630 dataset. To illustrate how stability and structure change upon single point mutation, we considered four stabilizing, two destabilizing and two stabilizing mutations from two proteins, namely the toxin protein and bovine liver cytochrome. Overall, the results on S268, S630 and S1342 datasets show that the performance of the integrated predictors is better than the mechanistic or individual machine learning predictors. We expect that this paper will provide useful guidance for the design and development of next-generation bioinformatic tools for predicting protein stability changes upon mutations.
Circles of Peace. A Video Analysis of Situational Group Formation and Collective Third-Party Intervention in Violent Incidents
Authors: Weenink Don , Dhattiwala Raheel , van der Duin David 
Published: April 2021

AbstractWe seek to understand collective third-party intervention in violent incidents. Based on analyses of 131 video clips captured on mobile phones, we argue that bodily alignment between bystanders creates situational groups that encourage collective de-escalatory action. Qualitative analysis reveals that third parties generate situational groups when they create circular formations, providing greater opportunities to notice each other’s monitoring of the situation while separating those focused on the incident from others just passing by. Statistical analysis shows that the formation of situational groups facilitates the collectivization of de-escalatory action. In contrast to popular but outdated ideas about the dangerous influence of assemblies on individual behaviour (allegedly leading to disorder or apathy), our findings emphasize the self-regulatory, defusing capacity of gatherings.
An in vivo Caenorhabditis elegans model for therapeutic research in human prion diseases
Authors: Bizat Nicolas , Parrales Valeria , Laoues Sofian , Normant Sébastien , Levavasseur Etienne , Roussel Julian , Privat Nicolas , Gougerot Alexianne , Ravassard Philippe , Beaudry Patrice , Brandel Jean-Philippe , Laplanche Jean-Louis , Haïk Stéphane 
Published: April 2021

Abstract
Human prion diseases are fatal neurodegenerative disorders that include sporadic, infectious and genetic forms. Inherited Creutzfeldt-Jakob disease due to the E200K mutation of the prion protein-coding gene is the most common form of genetic prion disease. The phenotype resembles that of sporadic Creutzfeldt-Jakob disease at both the clinical and pathological levels, with a median disease duration of 4 months. To date, there is no available treatment for delaying the occurrence or slowing the progression of human prion diseases. Existing in vivo models do not allow high-throughput approaches that may facilitate the discovery of compounds targeting pathological assemblies of human prion protein or their effects on neuronal survival.
Here, we generated a genetic model in the nematode Caenorhabditis elegans, which is devoid of any homologue of the prion protein, by expressing human prion protein with the E200K mutation in the mechanosensitive neuronal system.
Expression of E200K prion protein induced a specific behavioural pattern and neurodegeneration of green fluorescent protein-expressing mechanosensitive neurons, in addition to the formation of intraneuronal inclusions associated with the accumulation of a protease-resistant form of the prion protein. We demonstrated that this experimental system is a powerful tool for investigating the efficacy of anti-prion compounds on both prion-induced neurodegeneration and prion protein misfolding, as well as in the context of human prion protein. Within a library of 320 compounds that have been approved for human use and cross the blood–brain barrier, we identified five molecules that were active against the aggregation of the E200K prion protein and the neurodegeneration it induced in transgenic animals.
This model breaks a technological limitation in prion therapeutic research and provides a key tool to study the deleterious effects of misfolded prion protein in a well-described neuronal system.
Plasma amyloid-β ratios in autosomal dominant Alzheimer’s disease: the influence of genotype
Authors: O'Connor Antoinette , Pannee Josef , Poole Teresa , Arber Charles , Portelius Erik , Swift Imogen J , Heslegrave Amanda J , Abel Emily , Willumsen Nanet , Rice Helen , Weston Philip S J , Ryan Natalie S , Polke James M , Nicholas Jennifer M , Mead Simon , Wray Selina , Chávez-Gutiérrez Lucía , Frost Chris , Blennow Kaj , Zetterberg Henrik , Fox Nick C 
Published: April 2021

AbstractIn vitro studies of autosomal dominant Alzheimer’s disease implicate longer amyloid-β peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-β (Aβ)42:38, Aβ42:40 and Aβ38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-β processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-β between genotypes: higher Aβ42:38 in PSEN1 versus APP (P &lt; 0.001) and non-carriers (P &lt; 0.001); higher Aβ38:40 in APP versus PSEN1 (P &lt; 0.001) and non-carriers (P &lt; 0.001); while Aβ42:40 was higher in both mutation groups compared to non-carriers (both P &lt; 0.001). Amyloid-β profiles were reasonably consistent in plasma and cell lines. Within the PSEN1 group, models demonstrated associations between Aβ42:38, Aβ42:40 and Aβ38:40 ratios and parental age at onset. In vivo differences in amyloid-β processing between PSEN1 and APP carriers provide insights into disease pathophysiology, which can inform therapy development.
Impaired sensory evidence accumulation and network function in Lewy body dementia
Authors: O’Callaghan Claire , Firbank Michael , Tomassini Alessandro , Schumacher Julia , O’Brien John T , Taylor John-Paul 
Published: April 2021

Abstract
Deficits in attention underpin many of the cognitive and neuropsychiatric features of Lewy body dementia. These attention-related symptoms remain difficult to treat and there are many gaps in our understanding of their neurobiology. An improved understanding of attention-related impairments can be achieved via mathematical modelling approaches, which identify cognitive parameters to provide an intermediate level between observed behavioural data and its underlying neural correlate. Here, we apply this approach to identify the role of impaired sensory evidence accumulation in the attention deficits that characterize Lewy body dementia. In 31 people with Lewy body dementia (including 13 Parkinson’s disease dementia and 18 dementia with Lewy bodies cases), 16 people with Alzheimer’s disease, and 23 healthy controls, we administered an attention task whilst they underwent functional 3 T MRI. Using hierarchical Bayesian estimation of a drift-diffusion model, we decomposed task performance into drift rate and decision boundary parameters. We tested the hypothesis that the drift rate—a measure of the quality of sensory evidence accumulation—is specifically impaired in Lewy body dementia, compared to Alzheimer’s disease. We further explored whether trial-by-trial variations in the drift rate related to activity within the default and dorsal attention networks, to determine whether altered activity in these networks was associated with slowed drift rates in Lewy body dementia. Our results revealed slower drift rates in the Lewy body dementia compared to the Alzheimer’s disease group, whereas the patient groups were equivalent for their decision boundaries. The patient groups were reduced relative to controls for both parameters. This highlights sensory evidence accumulation deficits as a key feature that distinguishes attention impairments in Lewy body dementia, consistent with impaired ability to efficiently process information from the environment to guide behaviour. We also found that the drift rate was strongly related to activity in the dorsal attention network across all three groups, whereas the Lewy body dementia group showed a divergent relationship relative to the Alzheimer’s disease and control groups for the default network, consistent with altered default network modulation being associated with impaired evidence accumulation. Together, our findings reveal impaired sensory evidence accumulation as a specific marker of attention problems in Lewy body dementia, which may relate to large-scale network abnormalities. By identifying impairments in a specific sub-process of attention, these findings will inform future exploratory and intervention studies that aim to understand and treat attention-related symptoms that are a key feature of Lewy body dementia.
Musical Expertise Is Associated with Improved Neural Statistical Learning in the Auditory Domain
Authors: Pesnot Lerousseau Jacques , Schön Daniele 
Published: April 2021

Abstract

It is poorly known whether musical training is associated with improvements in general cognitive abilities, such as statistical learning (SL). In standard SL paradigms, musicians have shown better performances than nonmusicians. However, this advantage could be due to differences in auditory discrimination, in memory or truly in the ability to learn sequence statistics. Unfortunately, these different hypotheses make similar predictions in terms of expected results. To dissociate them, we developed a Bayesian model and recorded electroencephalography (EEG). Our results confirm that musicians perform approximately 15% better than nonmusicians at predicting items in auditory sequences that embed either low or high-order statistics. These higher performances are explained in the model by parameters governing the learning of high-order statistics and the selection stage noise. EEG recordings reveal a neural underpinning of the musician’s advantage: the P300 amplitude correlates with the surprise elicited by each item, and so, more strongly for musicians. Finally, early EEG components correlate with the surprise elicited by low-order statistics, as opposed to late EEG components that correlate with the surprise elicited by high-order statistics and this effect is stronger for musicians. Overall, our results demonstrate that musical expertise is associated with improved neural SL in the auditory domain.

Significance statement
It is poorly known whether musical training leads to improvements in general cognitive skills. One fundamental cognitive ability, SL, is thought to be enhanced in musicians, but previous studies have reported mixed results. This is because such musician’s advantage can embrace very different explanations, such as improvement in auditory discrimination or in memory. To solve this problem, we developed a Bayesian model and recorded EEG to dissociate these explanations. Our results reveal that musical expertise is truly associated with an improved ability to learn sequence statistics, especially high-order statistics. This advantage is reflected in the electroencephalographic recordings, where the P300 amplitude is more sensitive to surprising items in musicians than in nonmusicians.
Design of Multidrug-Resistant Tuberculosis Treatment Regimens Based on DNA Sequencing
Authors: Grobbel Hans-Peter , Merker Matthias , Köhler Niklas , Andres Sönke , Hoffmann Harald , Heyckendorf Jan , Reimann Maja , Barilar Ivan , Dreyer Viola , Hillemann Doris , Kalsdorf Barbara , Kohl Thomas A , Sanchez Carballo Patricia , Schaub Dagmar , Todt Katharina , Utpatel Christian , Maurer Florian P , Lange Christoph , Niemann Stefan 
Published: April 2021

Abstract

Background
Comprehensive and reliable drug susceptibility testing (DST) is urgently needed to provide adequate treatment regimens for patients with multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). We determined whether next-generation sequencing (NGS) analysis of Mycobacterium tuberculosis complex isolates and genes implicated in drug resistance can guide the design of effective MDR/RR-TB treatment regimens.

Methods
NGS-based genomic DST predictions of M. tuberculosis complex isolates from MDR/RR-TB patients admitted to a TB reference center in Germany between 1 January 2015 and 30 April 2019 were compared with phenotypic DST results of mycobacteria growth indicator tubes (MGIT). Standardized treatment algorithms were applied to design individualized therapies based on either genomic or phenotypic DST results, and discrepancies were further evaluated by determination of minimal inhibitory drug concentrations (MICs) using Sensititre MYCOTBI and UKMYC microtiter plates.

Results
In 70 patients with MDR/RR-TB, agreement among 1048 pairwise comparisons of genomic and phenotypic DST was 86.3%; 76 (7.2%) results were discordant, and 68 (6.5%) could not be evaluated due to the presence of polymorphisms with yet unknown implications for drug resistance. Importantly, 549 of 561 (97.9%) predictions of drug susceptibility were phenotypically confirmed in MGIT, and 27 of 64 (42.2%) false-positive results were linked to previously described mutations mediating a low or moderate MIC increase. Virtually all drugs (99.0%) used in combination therapies that were inferred from genomic DST were confirmed to be susceptible by phenotypic DST.

Conclusions
NGS-based genomic DST can reliably guide the design of effective MDR/RR-TB treatment regimens.
Efficacy and Safety of Tofacitinib Re-treatment for Ulcerative Colitis After Treatment Interruption: Results from the OCTAVE Clinical Trials
Authors: Panés Julian , Vermeire Séverine , Dubinsky Marla C , Loftus Edward V , Lawendy Nervin , Wang Wenjin , Salese Leonardo , Su Chinyu , Modesto Irene , Guo Xiang , Colombel Jean-Frederic 
Published: April 2021

Abstract

Background and Aims
Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. Here, we evaluate the efficacy and safety of tofacitinib re-treatment following treatment interruption in patients with ulcerative colitis.

Methods
Here, patients with clinical response to tofacitinib 10 mg b.d. induction therapy were randomised to receive placebo in OCTAVE Sustain. Those experiencing treatment failure after Week 8 of OCTAVE Sustain entered OCTAVE Open and re-initiated tofacitinib 10 mg b.d. [re-treatment subpopulation]; efficacy and safety data are presented up to Month 36 of OCTAVE Open.

Results
Median time to treatment failure following interruption was 169 (95% confidence interval [CI], 94.0–179.0) and 123 [95% CI, 91.0–168.0] days for induction remitters, and induction responders but non-remitters, respectively. Following re-treatment with tofacitinib, rates (non-responder imputation after a patient discontinued; latest observation carried forward imputation after a patient advanced to a subsequent study [NRI-LOCF]) of clinical response, remission, and endoscopic improvement were 74.0%, 39.0%, and 55.0% at Month 2, and 48.5%, 37.4%, and 42.4% at Month 36, respectively. Among induction remitters and induction responders but non-remitters, clinical response rates at Month 36 were 60.6% and 42.4% [NRI-LOCF], respectively. Efficacy was recaptured regardless of prior tumour necrosis factor inhibitor failure status. The safety profile of tofacitinib 10 mg b.d. re-treatment was consistent with the overall cohort and demonstrated no new safety risks associated with exposure of ≤36 months.

Conclusions
Median time to treatment failure was numerically higher in induction remitters versus induction responders but non-remitters. Following treatment interruption, efficacy was safely and successfully recaptured with tofacitinib 10 mg b.d. re-treatment in a substantial proportion of patients [ClinicalTrials.gov:NCT01458574;NCT01470612].
Long-term mortality in patients with ischaemic heart failure revascularized with coronary artery bypass grafting or percutaneous coronary intervention: insights from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR)
Authors: Völz Sebastian , Redfors Björn , Angerås Oskar , Ioanes Dan , Odenstedt Jacob , Koul Sasha , Valeljung Inger , Dworeck Christian , Hofmann Robin , Hansson Emma , Venetsanos Dimitrios , Ulvenstam Anders , Jernberg Tomas , Råmunddal Truls , Pétursson Pétur , Fröbert Ole , Erlinge David , Jeppsson Anders , Omerovic Elmir 
Published: April 2021

Abstract

Aims
To compare coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for treatment of patients with heart failure due to ischaemic heart disease.

Methods and results
We analysed all-cause mortality following CABG or PCI in patients with heart failure with reduced ejection fraction and multivessel disease (coronary artery stenosis &gt;50% in ≥2 vessels or left main) who underwent coronary angiography between 2000 and 2018 in Sweden. We used a propensity score-adjusted logistic and Cox proportional-hazards regressions and instrumental variable model to adjust for known and unknown confounders. Multilevel modelling was used to adjust for the clustering of observations in a hierarchical database. In total, 2509 patients (82.9% men) were included; 35.8% had diabetes and 34.7% had a previous myocardial infarction. The mean age was 68.1 ± 9.4 years (47.8% were &gt;70 years old), and 64.9% had three-vessel or left main disease. Primary designated therapy was PCI in 56.2% and CABG in 43.8%. Median follow-up time was 3.9 years (range 1 day to 10 years). There were 1010 deaths. Risk of death was lower after CABG than after PCI [odds ratio (OR) 0.62; 95% confidence interval (CI) 0.41–0.96; P = 0.031]. The risk of death increased linearly with quintiles of hospitals in which PCI was the preferred method for revascularization (OR 1.27, 95% CI 1.17–1.38, P trend &lt; 0.001).

Conclusion
In patients with ischaemic heart failure, long-term survival was greater after CABG than after PCI.
Salt reduction to prevent hypertension: the reasons of the controversy
Authors: He Feng J , Campbell Norm R C , Woodward Mark , MacGregor Graham A 
Published: April 2021

Abstract
There is a causal relationship between dietary salt intake and blood pressure. A reduction in salt intake from the current world average of ∼10 g/day to the WHO recommended level of &lt;5 g/day, lowers blood pressure and reduces the risk of cardiovascular disease and all-cause mortality. However, a few cohort studies have claimed that there is a J-shaped relationship between salt intake and cardiovascular risk, i.e. both high and low salt intakes are associated with an increased risk. These cohort studies have several methodological problems, including reverse causality, and inaccurate and biased estimation of salt intake, e.g. from a single spot urine sample with formulas. Recent studies have shown that the formulas used to estimate salt intake from spot urine cause a spurious J-curve. Research with inappropriate methodology should not be used to refute the robust evidence on the enormous benefits of population-wide reduction in salt intake. Several countries, e.g. Finland, the UK, have successfully reduced salt intake, which has resulted in falls in population blood pressure and deaths from stroke and ischaemic heart disease. Every country should develop and implement a coherent, workable strategy to reduce salt intake. Even a modest reduction in salt intake across the whole population will lead to a major improvement in public health, along with huge cost-savings to the healthcare service.