bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glutamatergic and GABAergic neurons mediate distinct neurodevelopmental phenotypes of STXBP1 encephalopathy
Authors: Kim Joo Hyun , Chen Wu , Chao Eugene S. , Chen Hongmei , Xue Mingshan 
Published: July 2021

AbstractHeterozygous pathogenic variants in syntaxin-binding protein 1 (STXBP1, also known as MUNC18-1) cause STXBP1 encephalopathy and are among the most frequent causes of developmental and epileptic encephalopathies and intellectual disabilities. STXBP1 is an essential protein for presynaptic neurotransmitter release, and its haploinsufficiency impairs glutamatergic and GABAergic neurotransmission. However, the mechanism underlying the broad spectrum of neurological phenotypes is poorly understood. Here we show that glutamatergic and GABAergic neurons mediate distinct disease features with few overlaps. Glutamatergic and GABAergic neurons-specific Stxbp1 haploinsufficient mice exhibit different subsets of the cognitive and seizure phenotypes observed in the constitutive Stxbp1 haploinsufficient mice. Developmental delay and most of the motor and psychiatric phenotypes are only recapitulated by GABAergic Stxbp1 haploinsufficiency. Thus, the contrasting roles of excitatory and inhibitory signaling in STXBP1 encephalopathy identify GABAergic dysfunction as a main disease mechanism and reveal the possibility to selectively modulate disease phenotypes by targeting specific neurotransmitter systems.
Pfam domain adaptation profiles reflect plant species’ evolutionary history
Authors: Jensen Sarah E. , Buckler Edward S. 
Published: July 2021

AbstractThe increase in global temperatures predicted by climate change models presents a serious problem for agriculture because high temperatures reduce crop yields. Protein biochemistry is at the core of plant heat stress response, and understanding the interactions between protein biochemistry and temperature will be key to developing heat-tolerant crop varieties. Current experimental studies of proteome-wide plant thermostability are limited by the complexity of plant proteomes: evaluating function for thousands of proteins across a variety of temperatures is simply not feasible with existing technologies. In this paper, we use homologous prokaryote sequences to predict plant Pfam temperature adaptation and gain insights into how thermostability varies across the proteome for three species: maize, Arabidopsis, and poplar. We find that patterns of Pfam domain adaptation across organelles are consistent and highly significant between species, with cytosolic proteins having the largest range of predicted Pfam stabilities and a long tail of highly-stable ribosomal proteins. Pfam adaptation in leaf and root organs varies between species, and maize root proteins have more low-temperature Pfam domains than do Arabidopsis or poplar root proteins. Both poplar and maize populations have an excess of low-temperature mutations in Pfam domains, but only the mutations identified in poplar accessions have a negative effect on Pfam temperature adaptation overall. These Pfam domain adaptation profiles provide insight into how different plant structures adapt to their surrounding environment and can help inform breeding or protein editing strategies to produce heat-tolerant crops.
A genetic toolkit for investigating Clavibacter: markerless deletion, permissive site identification and an integrative plasmid
Authors: Stevens Danielle M. , Tang Andrea , Coaker Gitta 
Published: July 2021

AbstractThe development of knockout mutants and expression variants are critical for understanding genotype-phenotype relationships. However, advancements of these techniques in Gram-positive actinobacteria have stagnated over the last decade. Actinobacteria in the Clavibacter genus are composed of diverse crop pathogens which cause a variety of wilt and cankering diseases. Here, we present a suite of tools for genetic manipulation in the tomato pathogen C. michiganensis including a markerless deletion system, an integrative plasmid, and an R package for identification of permissive sites for plasmid integration. The vector pSelAct-KO is a recombination based, markerless knockout system that uses dual selection to engineer seamless deletions of a region of interest, providing opportunities for repeated higher-order genetic knockouts. The efficacy of pSelAct-KO was demonstrated in C. michiganensis and confirmed using whole genome sequencing. We developed permissR, an R package to identify permissive sites for chromosomal integration, which can be used in conjunction with pSelAct-Express, a non-replicating integrative plasmid that enables recombination into a permissive genomic location. Expression of eGFP by pSelAct-Express was verified in two candidate permissive regions predicted by permissR in C. michiganensis. These molecular tools are essential advancements for investigating Gram-positive actinobacteria, particularly for important pathogens in the Clavibacter genus.
Use of 1-MNA to Improve Exercise Tolerance and Fatigue in Patients After COVID-19
Authors: Chudzik Michał , Kapusta Joanna , Burzyńska Monika 
Published: July 2021

AbstractBackgroundCoronavirus disease 2019 (COVID-19) is a serious respiratory disease that results from infection with a newly discovered coronavirus (SARS-COV-2). Unfortunately, COVID-19 is not only a short-term infection but that patients (pts) recovering from SARS-CoV2 infection complain of persisting symptoms including: fatigue, diffuse myalgia and weakness, which may lead to chronic fatigue syndrome. There is currently no evidence that nutritional supplements and/or physical exercise can assist in the recovery of pts with chronic fatigue syndrome. 1-Methylnicotinamide (1-MNA) is an endogenic substance that is produced in the liver when nicotinic acid is metabolized. 1-MNA demonstrates anti-inflammatory and anti-thrombotic properties. Therefore, we investigated whether 1-MNA supplements could improve exercise tolerance and decrease fatigue among patients recovering from SARS-CoV-2.MethodsThe study population was composed of pts after COVID-19, expressing subjective feelings of limited tolerance to exercise. The selected pts were randomized into two groups: GrM0 – without supplementation; GrM1 – with 1-MNA supplementation. At the beginning of the study (Phase 0), in both groups, a 6-minute walk test (6MWT) was carried out and fatigue assessment with Fatigue Severity Scale (FSS) was performed. After 1 month (Phase 1), a follow up FSS and 6MWT once more were performed in both groups.ResultsA significant improvement in the mean distance covered in the 6MWT was noted among the pts in GrM1, compared to those in GrM0. We also noted that in GrM1 the 6MWT distance was significantly higher after 1 month of supplementation with 1-MNA, compared to the beginning of the study (515.18 m in Phase 0 vs 557.8m in Phase 1; p = 0.000034). In GrM1, significantly more pts improved their distance in the 6MWT (23 out of 25 pts, equal to 92%), by a mean of 47 meters, compared to GrM0 (15 of 25 pts, equal to 60%) (p = 0.0061). After one month, significantly more patients in the group without 1-MNA had severe fatigue (FSS ≥ 4) compared to the group with supplementation (GrM1 = 5 pts (20%) vs GrM0 = 14pts (56%); p = 0.008).Conclusions1-MNA supplementation significantly improved physical performance in a 6-minute walk test and reduced the percentage of patients with severe fatigue after COVID-19. The comprehensive action of 1-MNA, including anti-inflammatory and anticoagulant effects, as well as activation of the SIRT1 enzyme, may be beneficial for the recovery of patients with persistent symptoms of fatigue and low tolerance to exercise after COVID-19.
Programmed axon death executor SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated by physiological levels of NMN, NAD, NADP and other metabolites
Authors: Angeletti Carlo , Amici Adolfo , Gilley Jonathan , Loreto Andrea , Trapanotto Antonio G. , Antoniou Christina , Coleman Michael P. , Orsomando Giuseppe 
Published: July 2021

ABSTRACTSARM1 is an NAD glycohydrolase and TLR adapter with an essential, prodegenerative role in programmed axon death (Wallerian degeneration). It has low basal NADase activity that becomes strongly activated by NAD precursor NMN. Very high levels of NAD oppose this activation, competing for the same allosteric site on SARM1’s regulatory ARM domain. Injury or diseases that deplete axons of NMNAT2, an essential enzyme converting NMN to NAD, cause SARM1 activation. The resulting NAD degradation by SARM1, combined with loss of NAD synthesis by NMNAT2, causes rapid depletion of axonal NAD. This NAD loss is widely assumed to mediate axon death and is consequently a key focus for therapeutic strategies for axonopathies. However, like other NAD(P) glycohydrolases, SARM1 has additional enzyme activities whose contributions, consequences and regulation need to be fully understood. Here, we compare the multiple actions and regulation of recombinant human SARM1 with those of two other NAD(P) glycohydrolases, human CD38 and Aplysia californica ADP ribosyl cyclase. We find that SARM1 has the highest transglycosidation (base exchange) activity of these enzymes at neutral pH and with some bases this dominates NAD(P) hydrolysis and cyclisation. Moreover, like its NADase and NADPase reactions, SARM1-mediated base exchange at neutral pH is activated by increases in the NMN:NAD ratio, which we show for the first time can act in the presence of physiological levels of both metabolites. We establish that SARM1 base exchange is the most likely physiological source of calcium mobilizing agent NaADP, and potentially of other NAD(P) analogues, which could contribute to axon and cell death. We also identify regulatory effects of free pyridine bases, of NADP and of nicotinic acid riboside (NaR) on SARM1 that represent further therapeutic opportunities. These data will help to pinpoint which of the multiple functions of SARM1 is responsible for axon degeneration and how it can be optimally targeted to block axon degeneration in disease.
RNase HI depletion strongly potentiates cell killing by rifampicin in mycobacteria
Authors: Al-Zubaidi Abeer , Cheung Chen-Yi , Cook Gregory M. , Taiaroa George , Mizrahi Valerie , Lott J. Shaun , Dawes Stephanie S. 
Published: July 2021

AbstractMultidrug resistant (MDR) tuberculosis (TB) is defined by the resistance of Mycobacterium tuberculosis, the causative organism, to the first-line antibiotics rifampicin and isoniazid. Mitigating or reversing resistance to these drugs offers a means of preserving and extending their use in TB treatment. R-loops are RNA/DNA hybrids that are formed in the genome during transcription, and can be lethal to the cell if not resolved. RNase HI is an enzyme that removes R-loops, and this activity is essential in M. tuberculosis: knockouts of rnhC, the gene encoding RNase HI, are non-viable. This essentiality supports it as a candidate target for the development of new antibiotics. In the model organism Mycolicibacterium smegmatis, RNase HI activity is provided by two RNase HI enzymes, RnhA and RnhC. We show that the partial depletion of RNase HI activity in M. smegmatis, by knocking out either of the genes encoding RnhA or RnhC, led to the accumulation of R-loops. The sensitivity of the knockout strains to the antibiotics moxifloxacin, streptomycin and rifampicin was increased, with sensitivity to the transcriptional inhibitor rifampicin strikingly increased by nearly 100-fold. We also show that R-loop accumulation accompanies partial transcriptional inhibition, suggesting a mechanistic basis for the synergy between RNase HI depletion and transcriptional inhibition. A model of how transcriptional inhibition can potentiate R-loop accumulation is presented. Finally, we identified four small molecules that inhibit recombinant RnhC activity and that also potentiated rifampicin activity in whole-cell assays against M. tuberculosis, supporting an on-target mode of action, and providing the first step in developing a new class of anti-mycobacterial drug.ImportanceThis study validates mycobacterial RNase HI as a druggable, vulnerable candidate for a new therapeutic treatment of M. tuberculosis with a novel mode of action. RNase HI depletion shows synergistic bacterial killing with some current first- and second-line antibiotics, suggesting that RNase HI inhibitors would combine well with these regimens, and could potentially accelerate the clearance of drug-sensitive strains. RNase HI inhibitors also have the potential to reduce the effective dose of rifampicin, with the comcommitant reduction in side effects. The potentiation of rifampicin efficacy conferred by RNase HI deficiency suggests that RNase HI inhibitors may be able to mitigate against development of rifampicin resistance. The synergy may also be able to reverse rifampicin resistance, rescuing this antibiotic for therapy. The surprising finding that low levels of transcriptional inhibition potentiate R-loop formation provides a key new insight into R-loop metabolism.
Systematic in vivo interrogation identifies novel enhancers and silencers associated to Atrial Fibrillation
Authors: Victorino Jesus , Rollan Isabel , Rouco Raquel , Adan Javier , Manzanares Miguel 
Published: July 2021

AbstractCis-regulatory elements control gene expression in time and space and their disruption can lead to pathologies. Reporter assays allow the functional validation of enhancers and other regulatory elements, and such assays by means of the generation of transgenic mice provide a powerful tool to study gene regulation in development and disease. However, these experiments are time-consuming and, thus, their performance is very limited. Here, we increase the throughput of in vivo mouse reporter assays by using a piggyBac transposon-based system, and use it to decode the regulatory landscape of atrial fibrillation, a prevalent cardiac arrhythmia. We systematically interrogated ten human loci associated to atrial fibrillation in the search for regulatory elements. We found five new cardiac-specific enhancers and implicated novel genes in arrhythmia through genome editing and three-dimensional chromatin analysis by 4C-seq. Of note, functional dissection of the 7q31 locus identified a bivalent regulatory element in the second intron of the CAV1 gene differentially acting upon four genes. Our system also detected negative regulatory elements thanks to which we identified a ubiquitous silencer in the 16q22 locus that regulates ZFHX3 and can outcompete heart enhancers. Our study characterizes the function of new genetic elements that might be of relevance for the better understanding of gene regulation in cardiac arrhythmias. Thus, we have .established a new framework for the efficient dissection of the genetic contribution to common human diseases.
The J domain of sacsin disrupts intermediate filament assembly
Authors: Dabbaghizadeh Afrooz , Paré Alexandre , Cheng-Boivin Zacharie , Dagher Robin , Minotti Sandra , Dicaire Marie-Josée , Bernard Brais , Young Jason C. , Durham Heather D. , Gentil Benoit J. 
Published: July 2021

AbstractAutosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS), is caused by loss of function mutations in the SACS gene, which encodes sacsin, a giant protein of 520 kDa. A key feature of the absence of sacsin in cells is the formation of abnormal bundles of intermediate filaments (IF) including neurofilaments (NF) in neurons and vimentin IF in fibroblasts, suggesting a role of sacsin in IF homeostasis. Sacsin contains a J domain (SacsJ) homologous to Hsp40, that can interact with Hsp70 chaperones. The SacsJ domain resolved NF bundles in cultured Sacs-/- neurons, however, its mechanism is still unclear. Here, we focused on the role of SacsJ in NF assembly. We report that the SacsJ domain directly interacts with NF proteins in vitro to disassemble NFL filaments, and to inhibit their initial assembly, in the absence of Hsp70. We generated a cell-penetrating peptide derived from this domain, SacsJ-myc-TAT, which was efficient in disassembling both vimentin IF and NF in cultured fibroblasts and Sacs+/+ motor neurons as well as NF bundles in cultured Sacs-/- motor neurons. Whereas a normal NF network was restored in Sacs-/- neurons treated with the SacsJ peptide, there was some loss of IF networks in Sacs+/+ fibroblasts or neurons. These results suggest that SacsJ is a key regulator of NF and IF networks in cells, with implications for its therapeutic use.
How far the Indian banking sectors are efficient?: An empirical investigation
Authors: Maity Sudarshan , Sahu Tarak Nath 
Published: July 2021

PurposeBank mobilizes savings and transforms it into credit for investments in various sectors, which helps the economy running. The purpose of this paper is to examine the efficiency of three bank groups in India with data spanning from 2009–2010 to 2018–2019.Design/methodology/approachThe study uses data envelopment analysis for measuring the efficiency of the selected banks. It measures the efficiency both from the revenue dimension and from the supply-side dimension of financial inclusion.FindingsThe study finds that foreign banks on average are working efficiently far better than the public-sector and private-sector banks. It indicates that foreign banks in India are operating at 92.53% efficiency level, whereas private- and public-sector banks are operating at 90.20 and 86.04% efficiency levels, respectively. Further, the result of the Friedman test reveals that there is no significant difference in efficiency scores amongst these three bank groups. As major challenges, non-performing assets of the banking industry to be reduced by 15% as radial and 53.18% as slack.Originality/valueOne of the notable innovativeness of this study is that, unlike most of the previous studies that are mostly selected few banks and specific group, the present study may place itself as a unique inquiry in the domain of technical efficiency in macro concept by considering three major bank groups operating in India. An important contribution of the study is the classification of reasons behind the inefficiency, i.e. managerial or inappropriate scale size and further projections of input factors for the same level of output.
The productivity of the agricultural sector and industrial sector as a driving force of economic growth and community welfare in Indonesia
Authors: Salendu Salendu 
Published: July 2021

Purpose This study aims to examine the effect of trade liberalization on welfare, directly or indirectly, through the productivity of the agricultural sector and the productivity of the industrial sector, which affects economic growth and the welfare of the community.Design/methodology/approach This study is explanatory as it looks at causal relationships between one variable with another (causality relationship). The data used in this study are secondary data from various sources, such as the International Financial Statistics (IFS) from the International Monetary Fund (IMF), World Bank, Bank Indonesia reports, Central Bureau of Statistics and several other sources. All data used in this study is annual data for each research variable from 1986 to 2016.Findings Based on the results of the analysis, there is a significant direct and negative influence of the agricultural sector productivity on economic growth, a significant direct and negative influence of the industrial sector productivity on economic growth.Originality/value Considering the diverse effects of trade liberalization both on economic growth and people's welfare in developing countries, the researcher was interested in knowing how trade liberalization affects Indonesia. This study tries to observe and analyze those relations.
The critical factors shaping customer shopping experiences with innovative technologies
Authors: Ylilehto Marianne , Komulainen Hanna , Ulkuniemi Pauliina 
Published: July 2021

PurposeThe purpose of this study is to explore the customer shopping experience in the innovative technology setting. Specifically, the purpose is to understand how do innovative technologies influence the customer shopping experience?Design/methodology/approachThis qualitative, explorative study has characteristics of a phenomenological research strategy. The data were collected from four focus groups and ten in-depth interviews with consumers. Abductive approach with an implementation of content analysis was used as a method of analysis.FindingsThe results show that there are three critical factors in customer's shopping experience in the context of innovative technologies; (1) channel choice, (2) value dimensions related to convenience and enjoyment, and (3) social interaction. All factors are highly intertwined and influence each other.Originality/valueThis study contributes to customer experience literature by offering a framework for understanding customer shopping experiences in the innovative technology setting. These findings have important implications for retail managers seeking to enhance customer experience and achieve a competitive advantage by utilizing innovative technology.
Corporate governance and risk-taking of Islamic banks: evidence from OIC countries
Authors: Aslam Ejaz , Haron Razali 
Published: July 2021

Purpose
This paper aims to investigate the impact of corporate governance and other related factors on the risk-taking of Islamic banks. Risk-taking is defined according to credit risk, liquidity risk and operational risk.

Design/methodology/approach
The study uses the two step system generalized method of moment (2SYS-GMM) estimation technique by using a panel data set of 129 Islamic banks (IBs) from 29 countries in the Middle East, South Asia and the Southeast Asia regions covering from 2008 to 2017. Governance variables incorporated include board size, board independence, chief executive officer (CEO) power, Shariah board and audit committee, as well as other control variables.

Findings
This study provides evidence that board size and Shariah board are positively and significantly related to credit and liquidity risk. Board independence and CEO power are negative and significantly associated with credit and liquidity risk, but the audit committee has a mixed relationship with bank risk. Male CEOs take more risk compared to the female and more board meeting has an inverse relationship with Islamic banks risk. Bank size, however, does not influence the level of risk in Islamic banks, but leverage has an inverse relationship with bank risk.

Research limitations/implications
The present study sheds light on the risk-taking behaviour of the board of IBs, particularly the board independence and CEO power reducing the level of risk in IBs thereby contributing to the agency theory. Therefore, regulators and policymakers can use the findings of this study to strengthen the internal corporate governance mechanism to protect IBs at a time of financial distress. Moreover, it increases the trust of the shareholders and stakeholders in the effectiveness of governance reforms that have been pursued to reap long-term benefits.

Originality/value
To the best of the knowledge, this research is preliminary in examining the board behaviour on risk-taking of IBs from four different regions. The results are robust and suggest that the board of directors mitigate the level of risk in IBs.