bluuebunny/crossref_metadata_2025_split huggingface dataset:
Force tuning explains changes in phasic dopamine signaling during stimulus-reward learning
Authors: Bakhurin Konstantin , Hughes Ryan N. , Jiang Qiaochu , Hossain Meghdoot , Gutkin Boris , Fallon Isabella P. , Yin Henry H. 
Published: April 2023

AbstractAccording to a popular hypothesis, phasic dopamine (DA) activity encodes a reward prediction error (RPE) necessary for reinforcement learning. However, recent work showed that DA neurons are necessary for performance rather than learning. One limitation of previous work on phasic DA signaling and RPE is the limited behavioral measures. Here, we measured subtle force exertion while recording and manipulating DA activity in the ventral tegmental area (VTA) during stimulus-reward learning. We found two major populations of DA neurons that increased firing before forward and backward force exertion. Force tuning is the same regardless of learning, reward predictability, or outcome valence. Changes in the pattern of force exertion can explain results traditionally used to support the RPE hypothesis, such as modulation by reward magnitude, probability, and unpredicted reward delivery or omission. Thus VTA DA neurons are not used to signal RPE but to regulate force exertion during motivated behavior.
Codon affinity in mitochondrial DNA shapes evolutionary and somatic fitness
Authors: Lareau Caleb A. , Yin Yajie , Gutierrez Jacob C. , Dhindsa Ryan S. , Gribling-Burrer Anne-Sophie , Hsieh Yu-Hsin , Nitsch Lena , Buquicchio Frank A. , Abay Tsion , Zielinski Sebastian , Stickels Robert R. , Ulirsch Jacob C. , Yan Patrick , Wang Fangyi , Miao Zhuang , Sandor Katalin , Daniel Bence , Liu Vincent , Wang Quanli , Hu Fengyuan , Smith Katherine R. , Deevi Sri V.V. , Maschmeyer Patrick , Petrovski Slavé , Smyth Redmond P. , Greenleaf William J. , Kundaje Anshul , Munschauer Mathias , Ludwig Leif S. , Satpathy Ansuman T. 
Published: April 2023

Summary ParagraphSomatic variation contributes to biological heterogeneity by modulating cellular proclivity to differentiate, expand, adapt, or die. While large-scale sequencing efforts have revealed the foundational role of somatic variants to drive human tumor evolution, our understanding of the contribution of mutations to modulate cellular fitness in non-malignant contexts remains understudied. Here, we identify a mosaic synonymous variant (m.7076A>G) in the mitochondrial DNA (mtDNA) encoded cytochrome c-oxidase subunit 1 gene (MT-CO1, p.Gly391=), which was present at homoplasmy in 47% of immune cells from a healthy donor. Using single-cell multi-omics, we discover highly specific selection against the m.7076G mutant allele in the CD8+effector memory T cell compartmentin vivo, reminiscent of selection observed for pathogenic mtDNA alleles1, 2and indicative of lineage-specific metabolic requirements. While the wildtype m.7076A allele is translated via Watson-Crick-Franklin base-pairing, the anticodon diversity of the mitochondrial transfer RNA pool is limited, requiring wobble-dependent translation of the m.7076G mutant allele. Notably, mitochondrial ribosome profiling revealed altered codon-anticodon affinity at the wobble position as evidenced by stalled translation of the synonymous m.7076G mutant allele encoding for glycine. Generalizing this observation, we provide a new ontogeny of the 8,482 synonymous variants in the human mitochondrial genome that enables interpretation of functional mtDNA variation. Specifically, via inter- and intra-species evolutionary analyses, population-level complex trait associations, and the occurrence of germline and somatic mtDNA mutations from large-scale sequencing studies, we demonstrate that synonymous variation impacting codon:anticodon affinity is actively evolving across the entire mitochondrial genome and has broad functional and phenotypic effects. In summary, our results introduce a new ontogeny for mitochondrial genetic variation and support a model where organismal principles can be discerned from somatic evolution via single-cell genomics.
Rapid quantitative assessment of small molecule leakage from microdroplets by flow cytometry and improvement of fluorophore retention in biochemical assays
Authors: Zinchenko Anastasia , Devenish Sean R. A. , Hollfelder Florian 
Published: April 2023

AbstractMicrodroplets are compartments made in the laboratory that allow the miniaturisation of chemical and biological experiments to the femto- to picolitre scale, replacing the classical test tube with a droplet. Ideally containment of the contents of individual droplets would be perfect, but in reality this situation rarely occurs. Instead the leaking of molecules even from intact droplets presents a challenge to the success of miniaturisation and must be assessed on a case-by-case basis. We now present a new method for quantitative determination of leakage: a sheath fluid-free flow cytometer (Guava EasyCyte) is used to directly determine the fluorescence of water-in-oil droplets as a function of time. We validate this method by demonstrating that this assessment of leakage provides a framework for experimental improvements that reduce the leakage of two widely used fluorophores. A 40-fold better retention compared to current protocols is achieved for resorufin with an optimized mix (oil: FC-70, surfactant: 0.1% w/w AZ900C, additive: 1% BSA) to maintain useful retention for up to 130 hours. Likewise leakage of the fluorophore methylumbelliferone is reduced by 75-fold. The availability of a method to quantitate leakage quickly for a variety of experimental conditions will facilitate future applications of droplet-based experiments (e.g. in directed evolution or diagnostics), aid miniaturisation of lab-scale assays into this format, and improve the degrees of freedom in setting up such ultrahigh-throughput experiments.
XIAP-mediated targeting of endolysosomes to stressed mitochondria occurs in a switch-like, global manner and results in autophagy-independent, sub-organelle level mitochondrial degradation
Authors: Wang Tim Sen , Coppens Isabelle , Brady Nathan Ryan , Hamacher-Brady Anne 
Published: April 2023

AbstractDamaged mitochondria can be subject to lysosomal degradation via mitophagy. However, whole-organelle degradation exhibits relatively slow kinetics and thus its impact may be limited in response to acute, fast-acting cellular stress. We previously reported that in Parkin-deficient cells endolysosomes directly target mitochondria when subjected to bioenergetic stress. Here, using high-resolutionlivecell imaging we reveal a striking level of dynamic targeting of Rab5+ early endosomes to stressed mitochondria, culminating in a switch-like accumulation in the entire mitochondrial population, independently of canonical autophagy. This process of rapid, largescale Rab5+ vesicle trafficking to mitochondria coincides with, and is mediated by, XIAP E3 ligase activated mitochondrial ubiquitylation and results in ultrastructural changes to, and degradation of, intra-mitochondrial components. Mitochondria-targeting vesicles include early endosomal subpopulations marked by Rab5 effector APPL1 and ubiquitin-binding endocytic adaptors OPTN, TAX1BP1 and Tollip, and Rab7-positive late endosomes/lysosomes. In Parkin expressing cells, XIAP- and Parkin-dependent mitochondrial targeting and resulting processing modes are competitively regulated. Together, our data suggest that XIAP-mediated targeting of endolysosomes to mitochondria functions as a stress-responsive, sub-organelle level mitochondrial processing mode that is distinct from, and competitive to, Parkin-mediated mitophagy.
Does a probiotic (L. reuteri) lozenge taken twice daily over 3-4 weeks reduce probing pocket depth in patients with chronic periodontitis after 3 months? A systematic review of clinical trials (Protocol)
Authors: Mickenautsch Steffen , Rupf Stefan , Yengopal Veerasamy 
Published: April 2023

AbstractIntroductionChronic periodontitis is a slow progressing, multifactorial inflammatory disease of the periodontium that may lead to its destruction, which is detectable as increasing probing pocket depth (PPD), subsequent tooth mobility and tooth loss. The purpose of this systematic review is to update and appraise the current trial evidence to the question do probiotic (L. reuteri) lozenge taken twice daily over 3-4 weeks reduce probing pocket depth in patients with chronic periodontitis after 3 months.Methods and analysisWe will conduct reference checks of previous systematic review and trial reports to the topic. PubMed, Scopus, Cochrane library and the Directory of Open Access Journals (DOAJ) will be searched. All selected trial reports will be independently appraised by two reviewers, using the CQS-2B trial appraisal tool. Meta-analysis will be conducted using a random effect model with inverse variance method, stratified according to CQS-2B corroboration levels (C1 – 4). The I2– test with 95% Confidence Interval will be used to establish whether any statistical heterogeneity between datasets exist. Sensitivity analysis will be conducted for meta-analysis results of trials that were rated with 1-score at all four CQS-2B appraisal criteria, by excluding trials in which: Patients were smokers; Patients were Type II diabetics; Adjunctive antibiotic therapy was provided. For meta-analyses including data of at least four trials, which have been rated with a 1-score for all four appraisal criteria, the results will be further statistically tested for possible selection bias. Publication bias risk will be quantitatively assessed by use of Egger’s regression.Ethics and disseminationEthical approval is not required for literature-based studies. The results will be disseminated as a prior preprint version and subsequent peer-reviewed publication.
Early-life socioeconomic circumstances and the comorbidity of depression and overweight in adolescence and young adulthood: a longitudinal study
Authors: Kilpi Fanny , Howe Laura D 
Published: April 2023

ABSTRACTBackgroundDepression and overweight both often emerge early in life and have been found to be associated, but few studies examine depression-overweight comorbidity and its social patterning early in the life course. This study investigates how different aspects of early-life socioeconomic circumstances are associated with depression-overweight comorbidity from adolescence to young adulthood exploring any differences by age and sex.MethodsDrawing on data from 4,948 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort from the UK, we estimated how parental education, social class and financial difficulties reported in pregnancy were associated with depression and overweight, and their comorbidity at approximately the ages 17 and 24 in males and females.ResultsThe results from multinomial logistic regression models showed that all three socioeconomic markers were associated with depression-overweight comorbidity and results were similar across age. Lower parental education (relative risk ratio (RRR) and 95% confidence interval (CI) of low education v high education: 3.61 (2.30-5.67) in females and 1.54 (1.14-2.07) in males) and social class (class IV/I v class I: 5.67 (2.48-12.94) in females and 3.11 (0.70-13.91) in males) had strong associations with comorbidity at age 17 relative to having neither depression or overweight. Financial difficulties were also a risk factor in females, with less clear results in males.ConclusionThe findings indicate that early socioeconomic circumstances are linked with the accumulation of mental and physical health problems already in adolescence, which has implications for life-long health inequalities.
Resistance and prevalence implications of doxycycline post-exposure prophylaxis for gonorrhea prevention in men who have sex with men: a modeling study
Authors: Reichert Emily , Grad Yonatan H. 
Published: April 2023

AbstractBackgroundDoxycycline post-exposure prophylaxis (DoxyPEP) has demonstrated efficacy for prevention of bacterial sexually transmitted infections. To inform policy decisions on the use of DoxyPEP for gonorrhea prevention, we used a mathematical model to investigate its impact on resistance dynamics and the burden of infection in men who have sex with men (MSM).Methods and FindingsUsing a deterministic compartmental model of gonorrhea transmission in an MSM population, we introduced DoxyPEP at various uptake levels (10-75%) and compared 20-year prevalence and resistance dynamics relative to those at baseline (i.e., no DoxyPEP introduction). Uptake of DoxyPEP resulted in initial drops in the prevalence and incidence of gonorrhea infection, but also accelerated the spread of doxycycline resistance, with increasing DoxyPEP use driving steeper initial declines followed by faster spread of resistance. This resulted in the total loss of DoxyPEP’s clinical efficacy within 1-2 decades in almost all scenarios explored. The magnitude by which DoxyPEP initially reduced the prevalence of infection was constrained by the extent of pre-existing doxycycline resistant strains in the population.De novoemergence of doxycycline resistance did not influence these dynamics. Additionally, the implementation of DoxyPEP had minimal impact on extending the clinically useful lifespan of ceftriaxone monotherapy.ConclusionsModel findings suggest DoxyPEP can be an effective but short-term solution for reducing the burden of gonorrhea infection, as its selection for doxycycline-resistant strains results in loss of its prophylaxis benefit. Increasing levels of DoxyPEP uptake and higher starting prevalence of doxycycline resistance resulted in faster loss of its efficacy and had little change on extending the clinical lifespan of ceftriaxone for treatment ofN. gonorrhoeaeinfections.
LONG-TERM PHYSICAL AND MENTAL HEALTH IMPACT OF COVID-19 ON ADULTS IN ENGLAND: FOLLOW UP OF A LARGE RANDOM COMMUNITY SAMPLE
Authors: Atchison Christina J , Davies Bethan , Cooper Emily , Lound Adam , Whitaker Matthew , Hampshire Adam , Azor Adriana , Donnelly Christl , Chadeau-Hyam Marc , Cooke Graham S , Ward Helen , Elliott Paul 
Published: April 2023

ABSTRACTBackgroundThe COVID-19 pandemic is having a lasting impact on health and well-being. We compare current self-reported health, quality of life and symptom profiles for people with ongoing symptoms following COVID-19 to those who have never had COVID-19 or have recovered.MethodsA cohort study was established with participants from the REACT programme. A sample (N=800,000) of adults were contacted between August and December 2022 to complete a questionnaire about their current health and COVID-19 history. We used logistic regression to identify predictors of persistent symptoms lasting ≥12 weeks following COVID-19. We fitted Accelerated Failure Time models to assess factors associated with rate of recovery from persistent symptoms.FindingsOverall, 276,840/800,000 (34.6%) of invited participants completed the questionnaire. Median duration of COVID-related symptoms (N=130,251) was 1.3 weeks (inter-quartile range 6 days to 2 weeks), with 7.5% and 5.2% reporting ongoing symptoms ≥12 weeks and ≥52 weeks respectively. Female sex, having ≥1 comorbidity, more severe symptoms at time of COVID-19 and being infected when Wild-type variant was dominant were associated with higher probability of symptoms lasting ≥12 weeks. Longer time to recovery in those with persistent symptoms was found for females, people with comorbidities, living in more deprived areas, current smokers and for Wild-type compared to later variants. Mental health and health-related quality of life were significantly worse among participants with ongoing persistent COVID-19 symptoms compared with those who had never had COVID-19 or had recovered.InterpretationAlthough COVID-19 is usually of short duration, some adults experience persistent and burdensome illness.FundingThis work is independent research funded by the National Institute for Health and Care Research (NIHR) (REACT Long COVID (REACT-LC) (COV-LT-0040)). This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (UKRI) (MC_PC_20029). The views expressed in this publication are those of the author(s) and not necessarily those of NIHR or UKRI.
Flow characterization of low sweep MULDICON wing at low speed
Authors: Haider Bilal , Mansor Shuhaimi , Mat Shabudin , Nasir Nazri 
Published: April 2023

Purpose
The flow topology for multi-disciplinary configuration (MULDICON) wing is very complicated and nonlinear at low to high angle of attack (AOA). This paper aims to provide the correlation between the unsteadiness and uncertainties of the flow topology and aerodynamic forces and moments above MULDICON WING at a medium to a higher AOA.

Design/methodology/approach
The experimental and computational fluid dynamics methods were used to investigate a generic MULDICON wing. During the experiment, the AOA were varied from α = 5° to 30°, whereas yaw angle varies between β = ±20° and Reynolds number between Re = 3.0 × 105 and Re = 4.50 × 105. During the experiments steady-state loading, dynamic loading and flow visualization wind tunnel methods were used.

Findings
The standard deviation quantified the unsteadiness and uncertainties of flow topology and predicted that they significantly affect the pitching moment (Cm) at medium to higher AOA. A strong correlation between flow topology and Cm was exhibited, and the experiment data was well validated by previous numerical work. The aerodynamic center was not fixed and shifted toward the wing apex when AOA is increasing. For a = 10°, the flow becomes more asymmetric. Power spectral densities plots quantify the flow separation (apex vortex, leading-edge vortex and vortex breakdown) over the MULDICON wing.

Originality/value
The application and comparison of steady-state and dynamic loading data to quantify the unsteadiness and uncertainties of flow topology above the MULDICON wing.
Usage of digital library services during COVID-19 pandemic: a study of Indian Institutes of Management (IIMs)
Authors: Ansari Anam Jamal , PM Naushad Ali 
Published: April 2023

Purpose
This paper aims to find out the digital services of management libraries provided during the library closure and the challenges and initiatives the libraries have taken up to fulfill the need of their user community during the pandemic crisis.

Design/methodology/approach
To meet the purpose of the study, the investigators have used a survey method. An online questionnaire was devised and administered among the Indian Institutes of Management (IIMs) librarians using Microsoft Forms.

Findings
The study's findings suggested that all the libraries under investigation must avail of various digital library services in the wake of the coronavirus pandemic. Further, the investigators recommend that libraries formulate a disaster preparedness and management plan in the wake of the COVID-19 pandemic so that libraries can prepare themselves for the future.

Originality/value
The pandemic has affected every aspect of life and changed the digital library services scenario. Thus, it is essential to examine the role libraries have played during the COVID-19 pandemic and distinguish the challenges and initiatives libraries have taken to tackle the problems they faced. This study has been conducted on the digital library services that were provided by the libraries of IIMs.
Does digital transformation increase firms' productivity perception? The role of technostress and work engagement
Authors: Picazo Rodríguez Beatriz , Verdú-Jover Antonio Jose , Estrada-Cruz Marina , Gomez-Gras Jose Maria 
Published: April 2023

PurposeTo understand how organizations, public or private, must increase their productivity perception (PP), independently of the sector. This article aims to analyze PP in the digital transformation (DT) process to determine how it is affected by technostress (TS) and work engagement (WE), two concepts that seem to be forces opposing PP.Design/methodology/approachThe authors use data from a questionnaire addressed to personnel in two organizations (public and private). The analysis applies partial least squares technique to the 505 valid responses obtained from these organizations. This analysis is based not on representativeness but on uniqueness.FindingsThe results suggest a positive, significant relationship between DT and PP. This article integrates DT and its effects on aspects of people's health, PP and WE. The model thus includes interactions of technology with human elements. In both business and administrative environments, PP is key to optimizing resources and survival of organizations.Research limitations/implicationsDT processes are different and complex because every organization is different. The authors recommend expanding this study to other sectors in both spheres, public and private. Aligning the objectives of the institutions for aid with DT is also quite complicated.Practical implicationsThis study contributes to improving participating organizations. It also provides government institutions with a clear foundation from which to encourage actions that promote the health and WE of their workforce without reducing productivity. In addition, this study adds novelty to the research line.Originality/valueThe authors have deepened this line of research by developing fuller knowledge of the relationships among novel and necessary variables in organizations. The authors provide complementary, different and inspiring value in addressing this line of research.