bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metformin abrogates pathological TNF-α-producing B cells through mTOR-dependent metabolic reprogramming in polycystic ovary syndrome
Authors: Xiao Na , Wang Jie , Wang Ting , Xiong Xingliang , Zhou Junyi , Su Xian , Peng Jing , Yang Chao , Li Xiaofeng , Lin Ge , Lu Guangxiu , Gong Fei , Cheng Lamei 
Published: December 2021

AbstractB cells contribute to the pathogenesis of polycystic ovary syndrome (PCOS). Clinically, metformin is used to treat PCOS, but it is unclear whether metformin exerts its therapeutic effect by regulating B cells. Here, we showed that the expression level of TNF-α in peripheral blood B cells from PCOS patient was increased. Metformin used in vitro and in vivo was able to reduce the production of TNF-α in B cells from PCOS patient. Administration of metformin improved mouse PCOS phenotypes induced by dehydroepiandrosterone (DHEA) and also inhibited TNF-α expression in splenic B cells. Further, metformin induced metabolic reprogramming of B cells in PCOS patients, including the alteration in mitochondrial morphology, the decrease in mitochondrial membrane potential, ROS production and glucose uptake. In DHEA-induced mouse PCOS model, metformin altered metabolic intermediates in splenic B cells. Moreover, the inhibition of TNF-α expression and metabolic reprogramming in B cells of PCOS patients and mouse model by metformin were associated with decreased mTOR phosphorylation. Together, TNF-α-producing B cells are involved in the pathogenesis of PCOS, and metformin inhibits mTOR phosphorylation and affects metabolic reprogramming, thereby inhibiting TNF-α expression in B cells, which may be a new mechanism of metformin in the treatment of PCOS.
High Throughput Characterization of V(D)J Recombination Signal Sequences Redefines the Consensus Sequence
Authors: Hoolehan Walker , Harris Justin C. , Byrum Jennifer N. , Rodgers Karla K. 
Published: December 2021

ABSTRACTIn the adaptive immune system, V(D)J recombination initiates the production of a diverse antigen receptor repertoire in developing B and T cells. Recombination activating proteins, RAG1 and RAG2 (RAG1/2), catalyze V(D)J recombination by cleaving adjacent to recombination signal sequences (RSSs) that flank antigen receptor gene segments. Previous studies defined the consensus RSS as containing conserved heptamer and nonamer sequences separated by a less conserved 12 or 23 base-pair spacer sequence. However, many RSSs deviate from the consensus sequence. Here, we developed a cell-based, massively parallel V(D)J recombination assay to evaluate RAG1/2 activity on thousands of RSSs. We focused our study on the RSS heptamer and adjoining spacer region, as this region undergoes extensive conformational changes during RAG-mediated DNA cleavage. While the consensus heptamer sequence (CACAGTG) was marginally preferred, RAG1/2 was highly active on a wide range of non-consensus sequences. RAG1/2 generally preferred select purine/pyrimidine motifs that may accommodate heptamer unwinding in the RAG1/2 active site. Our results suggest RAG1/2 specificity for RSS heptamers is primarily dictated by DNA structural features dependent on purine/pyrimidine pattern, and to a lesser extent, RAG:RSS base-specific interactions. Further investigation of RAG1/2 specificity using this new approach will help elucidate the genetic instructions guiding V(D)J recombination.Summary StatementPartially conserved recombination signal sequences (RSSs) govern antigen receptor gene assembly during V(D)J recombination. Here, a massively parallel analysis of randomized RSSs reveals key attributes that allow DNA sequence diversity in the RAG1/2 active site and that contribute to the differential utilization of RSSs in endogenous V(D)J recombination. Overall, these results will assist identification of RAG1/2 off-target sites, which can drive leukemia cell transformation, as well as characterization of bona fide RSSs used to generate antigen receptor diversity.
Modelling of filamentous phage-induced antibiotic tolerance of P.aeruginosa
Authors: van Rossem Maria , Wilks Sandra , Kaczmarek Malgosia , Secor Patrick R. , D’Alessandro Giampaolo 
Published: December 2021

AbstractFilamentous molecules tend to spontaneously assemble into liquid crystalline droplets with a tactoid morphology in the environments with the high concentration on non-adsorbing molecules. Tactoids of filamentous Pf bacteriophage, such as those produced by Pseudomonas aeruginosa, have been linked with increased antibiotic tolerance. We modelled this system and show that tactoids, composed of filamentous Pf virions, can lead to antibiotic tolerance by acting as an adsorptive diffusion barrier. The continuum model, reminiscent of descriptions of reactive diffusion in porous media, has been solved numerically and good agreement was found with the analytical results, obtained using a homogenisation approach. We find that the formation of tactoids significantly increases antibiotic diffusion times leading to stronger antibiotic resistance.
Methylation pattern of polymorphically imprinted nc886 is not conserved across mammalia
Authors: Kostiniuk Daria , Tamminen Hely , Mishra Pashupati P. , Marttila Saara , Raitoharju Emma 
Published: December 2021

AbstractBackgroundIn humans, the nc886 locus is a polymorphically imprinted metastable epiallele. Periconceptional conditions have an effect on the methylation status of nc886, and further, this methylation status is associated with health outcomes in later life, in line with the Developmental Origins of Health and Disease (DOHaD) hypothesis. Animal models would offer opportunities to study the associations between periconceptional conditions, nc886 methylation status and metabolic phenotypes further. Thus, we set out to investigate the methylation pattern of the nc886 locus in non-human mammals.DataWe obtained DNA methylation data from the data repository GEO for mammals, whose nc886 gene included all three major parts of nc886 and had sequency similarity of over 80% with the human nc886. Our final sample set consisted of DNA methylation data from humans, chimpanzees, bonobos, gorillas, orangutangs, baboons, macaques, vervets, marmosets and guinea pigs.ResultsIn human data sets the methylation pattern of nc886 locus followed the expected bimodal distribution, indicative of polymorphic imprinting. In great apes, we identified a unimodal DNA methylation pattern with 50% methylation level in all individuals and in all subspecies. In Old World monkeys, the between individual variation was greater and methylation on average was close to 60%. In guinea pigs the region around the nc886 homologue was non-methylated. Results obtained from the sequence comparison of the CTCF binding sites flanking the nc886 gene support the results on the DNA methylation data.ConclusionsOur results indicate that unlike in humans, nc886 is not a polymorphically imprinted metastable epiallele in non-human primates or in guinea pigs, thus implying that animal models are not applicable for nc886 research. The obtained data suggests that the nc886 region may be classically imprinted in great apes, and potentially also in Old World monkeys, but not in guinea pigs.
What can cold-induced transcriptomes of Arctic Brassicaceae tell us about the evolution of cold tolerance?
Authors: Birkeland Siri , Slotte Tanja , Brysting Anne K. , Gustafsson A. Lovisa S. , Hvidsten Torgeir R. , Brochmann Christian , Nowak Michael D. 
Published: December 2021

AbstractLittle is known about the evolution of cold tolerance in polar plant species and how they differ from their temperate relatives. To gain insight into their biology and the evolution of cold tolerance, we compared the molecular basis of cold response in three Arctic Brassicaceae species.We conducted a comparative time series experiment to examine transcriptional responses to low temperature. RNA was sampled at 22 °C, and after 3h, 6h, and 24h at 2 °C. We then identified sets of genes that were differentially expressed in response to cold and compared them between species, as well as to published data from the temperate Arabidopsis thaliana.Most differentially expressed genes were species-specific, but a significant portion of the cold response was also shared among species. Among thousands of differentially expressed genes, ∼200 were shared among the three Arctic species and A. thaliana, while ∼100 were exclusively shared among the three Arctic species.Our results show that cold response differs markedly between Arctic Brassicaceae species, but likely builds on a conserved basis found across the family. They also confirm that highly polygenic traits such as cold tolerance may show little repeatability in their patterns of adaptation.
Large genetic divergence underpins cryptic local adaptation across ecological and evolutionary gradients
Authors: Sparks Morgan M. , Kraft Joshua C. , Subida Blackstone Kliffi M. , McNickle Gordon G. , Christie Mark R. 
Published: December 2021

AbstractEnvironmentally covarying local adaptation is a form of cryptic local adaptation in which the covariance of the genetic and environmental effects on a phenotype obscures the divergence between locally adapted genotypes. Here, we systematically document the magnitude and drivers of the genetic effect (VG) for two forms of environmentally covarying local adaptation: counter- and cogradient variation. Using a hierarchical Bayesian meta-analysis, we calculated the overall effect size of VG as 1.05 and 2.13 for populations exhibiting countergradient or cogradient variation, respectively. These results indicate that the genetic contribution to phenotypic variation represents a 1.05 to 2.13 standard deviation change in trait value between the most disparate populations depending on if populations are expressing counter- or cogradient variation. We also found that while there was substantial variance among abiotic and biotic covariates, the covariates with the largest mean effects were temperature (2.41) and gamete size (2.81). Our results demonstrate the pervasiveness and large genetic effects underlying environmentally covarying local adaptation in wild populations and highlights the importance of accounting for these effects in future studies.
Structure-based discovery of small molecule inhibitors of the autocatalytic proliferation of α-synuclein aggregates
Authors: Chia Sean , Brotzakis Z. Faidon , Horne Robert I. , Possenti Andrea , Mannini Benedetta , Cataldi Rodrigo , Nowinska Magdalena , Staats Roxine , Linse Sara , Knowles Tuomas P. J. , Habchi Johnny , Vendruscolo Michele 
Published: December 2021

AbstractThe presence of amyloid fibrils of α-synuclein is closely associated with Parkinson’s disease and related synucleinopathies. It is still very challenging, however, to systematically discover small molecules that prevent the formation of these aberrant aggregates. Here, we describe a structure-based approach to identify small molecules that specifically inhibit the surface-catalyzed secondary nucleation step in the aggregation of α-synuclein by binding to the surface of the amyloid fibrils. The resulting small molecules are screened using a combination of kinetic and thermodynamic assays for their ability to bind α-synuclein fibrils and prevent the further generation of toxic oligomers. This study demonstrates that the combination of structure-based and kinetic-based drug discovery methods can lead to the identification of small molecules that selectively inhibit the autocatalytic proliferation of α-synuclein aggregates.
Mosquito excreta reveals circulation of West Nile virus and its underlying ecosystem
Authors: L’Ambert Grégory , Gendrot Mathieu , Briolant Sébastien , Nguyen Agnès , Pages Sylvain , Bosio Laurent , Palomo Vincent , Gomez Nicolas , Benoit Nicolas , Savini Hélène , Pradines Bruno , Durand Guillaume André , Leparc-Goffart Isabelle , Grard Gilda , Fontaine Albin 
Published: December 2021

AbstractEmerging and endemic mosquito-borne viruses can be difficult to detect and monitor because they often cause asymptomatic infections in human or vertebrate animals or cause nonspecific febrile illness with a short recovery waiting period. Cases’ detection in vertebrate hosts can be complemented by entomological surveillance, but this method is not adapted to low infection rates in mosquito populations that typically occur in low or non-endemic areas. We identified West Nile Virus circulation in Camargue, a wetland area in South of France, using a cost effective innovative xenomonitoring method based on the molecular detection of virus in excreta from trapped mosquitoes. We also succeeded at identifying the mosquito community diversity dynamic on several sampling sites, together with the vertebrate hosts on which they fed prior to be captured using amplicon-based metagenomic on mosquito excreta without processing any mosquito. Mosquito excreta-based virus surveillance can be considered as a cost-effective and non-invasive strategy that offers the additional asset to reveal the ecological network underlying arbovirus circulation.
Barrier mitigation measures trigger the rapid recovery of genetic connectivity in five freshwater fish species
Authors: Prunier Jérôme G. , Loot Géraldine , Veyssiere Charlotte , Poulet Nicolas , Blanchet Simon 
Published: December 2021

ABSTRACTRivers are heavily fragmented by man-made instream barriers such as dams and weirs. This hyper-fragmentation is a major threat to freshwater biodiversity and restoration policies are now adopted worldwide to mitigate these impacts. However, there is surprisingly little feedback on the efficiency of barrier mitigation measures in restoring riverine connectivity, notably for non-migratory fish species. Here, we implemented a “before-after genetic monitoring” of the restoration of 11 weirs in France using a dedicated genetic index of fragmentation (the FINDEX), with a focus on five fish species from two genera. We found that most obstacles actually had a significant impact on connectivity before restoration, especially the highest and steepest ones, with an overall barrier effect of about 51% of the maximal theoretical impact. Most importantly, we demonstrated for the first time that mitigation measures such as dam removal or fish pass creation significantly and rapidly improved connectivity, with –for some barriers-a complete recovery of the genetic connectivity in less than twelve months. Our study provides a unique and strong proof-of-concept that barrier removal is an efficient strategy to restore riverine connectivity and that molecular tools can provide accurate measures of restoration efficiency within a few months.Graphical Abstract
Biofilm Growth Under Elastic Confinement
Authors: Fortune George T. , Oliveira Nuno M. , Goldstein Raymond E. 
Published: December 2021

AbstractBacteria often form surface-bound communities, embedded in a self-produced extracellular matrix, called biofilms. Quantitative studies of their growth have typically focused on unconfined expansion above solid or semi-solid surfaces, leading to exponential radial growth. This geometry does not accurately reflect the natural or biomedical contexts in which biofilms grow in confined spaces. Here we consider one of the simplest confined geometries: a biofilm growing laterally in the space between a solid surface and an overlying elastic sheet. A poroelastic framework is utilised to derive the radial growth rate of the biofilm; it reveals an additional self-similar expansion regime, governed by the stiffness of the matrix, leading to a finite maximum radius, consistent with our experimental observations of growing Bacillus subtilis biofilms confined by PDMS.
Germline mosaicism of a missense variant in KCNC2 in a multiplex family with autism and epilepsy
Authors: Mehinovic Elvisa , Gray Teddi , Campbell Meghan , Ekholm Jenny , Wenger Aaron , Rowell William , Grudo Ari , Grimwood Jane , Korlach Jonas , Gurnett Christina , Constantino John N. , Turner Tychele N. 
Published: December 2021

ABSTRACTCurrently, protein-coding de novo variants and large copy number variants have been identified as important for ∼30% of individuals with autism. One approach to identify relevant variation in individuals who lack these types of events is by utilizing newer genomic technologies. In this study, highly accurate PacBio HiFi long-read sequencing was applied to a family with autism, treatment-refractory epilepsy, cognitive impairment, and mild dysmorphic features (two affected female full siblings, parents, and one unaffected sibling) with no known clinical variant. From our long-read sequencing data, a de novo missense variant in the KCNC2 gene (encodes Kv3.2 protein) was identified in both affected children. This variant was phased to the paternal chromosome of origin and is likely a germline mosaic. In silico assessment of the variant revealed it was in the top 0.05% of all conserved bases in the genome, and was predicted damaging by Polyphen2, MutationTaster, and SIFT. It was not present in any controls from public genome databases nor in a joint-call set we generated across 49 individuals with publicly available PacBio HiFi data. This specific missense mutation (Val473Ala) has been shown in both an ortholog and paralog of Kv3.2 to accelerate current decay, shift the voltage dependence of activation, and prevent the channel from entering a long-lasting open state. Seven additional missense mutations have been identified in other individuals with neurodevelopmental disorders (p = 1.03 × 10−5). KCNC2 is most highly expressed in the brain; in particular, in the thalamus and is enriched in GABAergic neurons. Long-read sequencing was useful in discovering the relevant variant in this family with autism that had remained a mystery for several years and will potentially have great benefits in the clinic once it is widely available.
A hybrid ant colony–particle swarm optimization method (ACOPSO) for aerospace propulsion systems
Authors: Piskin Altug , Baklacioglu Tolga , Turan Onder 
Published: December 2021

Purpose
The purpose of this paper is to introduce a hybrid, metaheuristic, multimodal and multi-objective optimization tool that is needed for aerospace propulsion engineering problems.

Design/methodology/approach
Multi-objective hybrid optimization code is integrated with various benchmark and test functions that are selected suitable to the difficulty level of the aero propulsion performance problems.

Findings
Ant colony and particle swarm optimization (ACOPSO) has performed satisfactorily with benchmark problems.

Research limitations/implications
ACOPSO is able to solve multi-objective and multimodal problems. Because every optimization problem has specific features, it is necessary to search their general behavior using other algorithms.

Practical implications
In addition to the optimization solving, ACOPSO enables an alternative methodology for turbine engine performance calculations by using generic components maps. The user is flexible for searching various effects of component designs along with the compressor and turbine maps.

Originality/value
A hybrid optimization code that has not been used before is introduced. It is targeted use is propulsion systems optimization and design such as Turboshaft or turbofan by preparing the necessary engine functions. A number of input parameters and objective functions can be modified accordingly.
Financial statement analysis: a review and current issues
Authors: Jackson Andrew B. 
Published: December 2021

PurposeThe literature on financial statement analysis attempts to improve fundamental analysis and to identify market inefficiencies with respect to financial statement information.Design/methodology/approachIn this paper, the author reviews the extant research on financial statement analysis.FindingsThe author then provides some preliminary evidence using Chinese data and offer suggestions for future research, with a focus on utilising unique features of the Chinese business environment as motivation.Originality/valueThe author notes that there has been no work that the author could locate specifically on Chinese FSA research. The unique business environment in China, relative to the US where the vast majority of this work has been conducted, should motivate any studies, especially given the author documents the robust finding in terms of the mean reversion in profitability.
Grey wolf optimizer algorithm for the performance predetermination of variable speed self-excited induction generators
Authors: R. Essaki Raj , Sridhar Sundaramoorthy 
Published: December 2021

Purpose
This paper aims to apply grey wolf optimizer (GWO) algorithm for steady state analysis of self-excited induction generators (SEIGs) supplying isolated loads.

Design/methodology/approach
Taking the equivalent circuit of SEIG, the impedances representing the stator, rotor and the connected load are reduced to a single loop impedance in terms of the unknown frequency, magnetizing reactance and core loss resistance for the given rotor speed. This loop impedance is taken as the objective function and minimized using GWO to solve for the unknown parameters. By including the value of the desired voltage as a constraint, the formulated objective function is also extended for estimating the required excitation capacitance.

Findings
The experimental results obtained on a three phase 415 V, 3.5 kW SEIG and the corresponding predetermined performance characteristics agree closely, thereby validating the proposed GWO method. Moreover, a comparative study of GWO with genetic algorithm and particle swarm optimization techniques reveals that GWO exhibits much quicker convergence of the objective function.

Originality/value
The important contributions of this paper are as follows: for the first time, GWO has been introduced for the SEIG performance predetermination and computation of the excitation capacitance for attaining the desired terminal voltage for the given load and speed; the predicted performance accuracy is improved by considering the variable core loss of the SEIG; and GWO does not require derivations of lengthy equations for calculating the SEIG performance.
Performance comparison between Islamic and conventional stocks: evidence from Pakistan's equity market
Authors: Jabeen Munazza , Kausar Saba 
Published: December 2021

PurposeThis paper aims to examine the performance of Islamic and conventional stocks listed at the Pakistan Stock Exchange by using both parametric and non-parametric approaches. The motivation is to do risk-return analysis of Islamic stock prices and conventional stock prices.Design/methodology/approachIt uses various measures of performance, e.g. Sharpe ratio, Treynor ratio, Jensen's alpha, beta, generalized auto-regressive conditional heteroskedasticity and stochastic dominance. Using the Karachi Meezan Index-30 (KMI-30) and the Karachi Stock Exchange Index-30 (KSE-30) as proxies for Islamic and conventional stock prices, respectively, it examines the performance of Islamic and conventional stocks. The daily data of KMI-30 and KSE-30, covering period from June 9, 2009 to June 20, 2020 are used.FindingsThe results show that the overall KMI-30 outperforms the KSE-30. The returns of the KMI-30 are greater than the KSE-30. However, the risk and volatility of the KMI-30 and KSE-30 are similar. Further, the KMI-30 has higher excess returns per unit of total risk than the KSE-30. But both indexes have similar excess returns per unit of systematic risk. Moreover, the KMI-30 returns have stochastically dominance over the KSE-30 returns. These results reveal that the Islamic index performs better than the conventional index.Practical implicationsThe findings provide several practical implications in financial and investment decisions making by investors, managers and policymakers such as strategies for asset allocation and investment. Further, in risk management, it provides guidance for allocating portfolios and managing risk. The investment in Islamic stocks may mitigate potential risk within asset portfolios.Originality/valueThis research is unique in its approach to the analysis of the performance comparison of conventional and Islamic stock by using comprehensive parametric and non-parametric estimation techniques. Such research has not been undertaken in the Pakistan's equity market since.