bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bi-allelic loss of function variants in COX20 gene cause autosomal recessive sensory neuronopathy
Authors: Dong Hai-Lin , Ma Yin , Yu Hao , Wei Qiao , Li Jia-Qi , Liu Gong-Lu , Li Hong-Fu , Chen Lei , Chen Dian-Fu , Bai Ge , Wu Zhi-Ying 
Published: March 2021

Abstract
Sensory neuronopathies are a rare and distinct subgroup of peripheral neuropathies, characterized by degeneration of the dorsal root ganglia neurons. About 50% of sensory neuronopathies are idiopathic and genetic causes remain to be clarified. Through a combination of homozygosity mapping and whole exome sequencing, we linked an autosomal recessive sensory neuronopathy to pathogenic variants in the COX20 gene. We identified eight unrelated families from the eastern Chinese population carrying a founder variant c.41A&gt;G (p.Lys14Arg) within COX20 in either a homozygous or compound heterozygous state. All patients displayed sensory ataxia with a decrease in non-length-dependent sensory potentials. COX20 encodes a key transmembrane protein implicated in the assembly of mitochondrial complex IV. We showed that COX20 variants lead to reduction of COX20 protein in patient’s fibroblasts and transfected cell lines, consistent with a loss-of-function mechanism. Knockdown of COX20 expression in ND7/23 sensory neuron cells resulted in complex IV deficiency and perturbed assembly of complex IV, which subsequently compromised cell spare respiratory capacity and reduced cell proliferation under metabolic stress. Consistent with mitochondrial dysfunction in knockdown cells, reduced complex IV assembly, enzyme activity and oxygen consumption rate were also found in patients’ fibroblasts. We speculated that the mechanism of COX20 was similar to other causative genes (e.g. SURF1, COX6A1, COA3 and SCO2) for peripheral neuropathies, all of which are functionally important in the structure and assembly of complex IV. Our study identifies a novel causative gene for the autosomal recessive sensory neuronopathy, whose vital function in complex IV and high expression in the proprioceptive sensory neuron further underlines loss of COX20 contributing to mitochondrial bioenergetic dysfunction as a mechanism in peripheral sensory neuron disease.
Individualized brain development and cognitive outcome in infants with congenital heart disease
Authors: Bonthrone Alexandra F , Dimitrova Ralica , Chew Andrew , Kelly Christopher J , Cordero-Grande Lucilio , Carney Olivia , Egloff Alexia , Hughes Emer , Vecchiato Katy , Simpson John , Hajnal Joseph V , Pushparajah Kuberan , Victor Suresh , Nosarti Chiara , Rutherford Mary A , Edwards A David , O’Muircheartaigh Jonathan , Counsell Serena J 
Published: March 2021

Abstract
Infants with congenital heart disease are at risk of neurodevelopmental impairments, the origins of which are currently unclear. This study aimed to characterize the relationship between neonatal brain development, cerebral oxygen delivery and neurodevelopmental outcome in infants with congenital heart disease. A cohort of infants with serious or critical congenital heart disease (N = 66; N = 62 born ≥37 weeks) underwent brain MRI before surgery on a 3T scanner situated on the neonatal unit. T2-weighted images were segmented into brain regions using a neonatal-specific algorithm. We generated normative curves of typical volumetric brain development using a data-driven technique applied to 219 healthy infants from the Developing Human Connectome Project (dHCP). Atypicality indices, representing the degree of positive or negative deviation of a regional volume from the normative mean for a given gestational age, sex and postnatal age, were calculated for each infant with congenital heart disease. Phase contrast angiography was acquired in 53 infants with congenital heart disease and cerebral oxygen delivery was calculated. Cognitive and motor abilities were assessed at 22 months (N = 46) using the Bayley scales of Infant and Toddler Development–Third Edition. We assessed the relationship between atypicality indices, cerebral oxygen delivery and cognitive and motor outcome. Additionally, we examined whether cerebral oxygen delivery was associated with neurodevelopmental outcome through the mediating effect of brain volume. Negative atypicality indices in deep grey matter were associated with both reduced neonatal cerebral oxygen delivery and poorer cognitive abilities at 22 months across the whole sample. In infants with congenital heart disease born ≥37 weeks, negative cortical grey matter and total tissue volume atypicality indices, in addition to deep grey matter structures, were associated with poorer cognition. There was a significant indirect relationship between cerebral oxygen delivery and cognition through the mediating effect of negative deep grey matter atypicality indices across the whole sample. In infants born ≥37 weeks, cortical grey matter and total tissue volume atypicality indices were also mediators of this relationship. In summary, lower cognitive abilities in toddlers with congenital heart disease were associated with smaller grey matter volumes before cardiac surgery. The aetiology of poor cognition may encompass poor cerebral oxygen delivery leading to impaired grey matter growth. Interventions to improve cerebral oxygen delivery may promote early brain growth and improve cognitive outcomes in infants with congenital heart disease.
Gut microbiota dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of NLRP3-inflammasome
Authors: Zhang Yun , Zhang Song , Li Bolin , Luo Yingchun , Gong Yongtai , Jin Xuexin , Zhang Jiawei , Zhou Yun , Zhuo Xiaozhen , Wang Zixi , Zhao Xinbo , Han Xuejie , Gao Yunlong , Yu Hui , Liang Desen , Zhao Shiqi , Sun Danghui , Wang Dingyu , Xu Wei , Qu Guangjin , Bo Wanlan , Li Dan , Wu Yue , Li Yue 
Published: March 2021

Abstract

Aims
Ageing is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). The gut microbiota dysbiosis is involved in age-related diseases. However, whether the aged-associated dysbiosis contributes to age-related AF is still unknown. Direct demonstration that the aged gut microbiota is sufficient to transmit the enhanced AF susceptibility in a young host via microbiota-intestinal barrier-atria axis has not yet been reported. This study aimed to determine whether gut microbiota dysbiosis affects age-related AF.

Methods and results
Herein, by using a faecal microbiota transplantation (FMT) rat model, we demonstrated that the high AF susceptibility of aged rats could be transmitted to a young host. Specially, we found the dramatically increased levels of circulating lipopolysaccharide (LPS) and glucose led to the up-regulated expression of NOD-like receptor protein (NLRP)-3 inflammasome, promoting the development of AF, which depended on the enhanced atrial fibrosis in recipient host. Inhibition of inflammasome by a potent and selective inhibitor of the NLRP3 inflammasome, MCC950, resulted in a lower atrial fibrosis and AF susceptibility. Then, we conducted cross-sectional clinical studies to explore the effect of ageing on the altering trends with glucose levels and circulating LPS among clinical individuals in two China hospitals. We found that both of serum LPS and glucose levels were progressively increased in elderly patients as compared with those young. Furthermore, the ageing phenotype of circulating LPS and glucose levels, intestinal structure and atrial NLRP3-inflammasome of rats were also confirmed in clinical AF patients. Finally, aged rats colonized with youthful microbiota restored intestinal structure and atrial NLRP3-inflammasome activity, which suppressed the development of aged-related AF.

Conclusions
Collectively, these studies described a novel causal role of aberrant gut microbiota in the pathogenesis of age-related AF, which indicates that the microbiota-intestinal barrier-atrial NLRP3 inflammasome axis may be a rational molecular target for the treatment of aged-related arrhythmia disease.
A case report of inappropriate inhibition of ventricular pacing due to a unique pacemaker electrogram storage feature
Authors: Khan Habib R , Chan William K , Kanawati Juliana , Yee Raymond 
Published: March 2021

Abstract

Background
Modern permanent pacemakers (PPMs) have individual features designed to identify cardiac rhythm abnormalities and improve their performance. Inappropriate pacing inhibition may be an undesired outcome from these features and cause symptoms in patients who require frequent pacing, leading to dizziness, and syncope. Inappropriate inhibition can be difficult to identify in circumstances that are intermittent and difficult to reproduce.

Case summary
A 57-year-old female underwent a mitral valve replacement (MVR) for severe mitral stenosis. One month following MVR, she presented with symptomatic third-degree atrioventricular block, and a dual-chamber PPM (Advisa™, Medtronic, Minneapolis, USA) was implanted and programmed DDD 50–130 b.p.m. At the 3-month follow-up, she reported frequent episodes of lightheadedness. She was found to have intermittent ventricular pacing inhibition on a 48-h Holter monitor due to an internal function of the Advisa™ series of PPMs that attempts to store an electrogram (EGM) every 1 h and 30 s. During the EGM storage, an amplified signal from the storage capacitor can result in oversensing by the ventricular channel and inappropriate pacing inhibition.

Discussion
To rectify the issue, the ventricular lead sensitivity value was increased from 0.9 mV to 1.2 mV. No instances of inappropriate ventricular pacing inhibition were noted on follow-up. To our knowledge, this is a rare case of inappropriate ventricular pacing inhibition caused by a combination of PPM self-adjusting sensitivity algorithm and oversensing every 1 h and 30 s from an amplified storage capacitor. Physicians should be aware of this possible complication and differentiate it from device or lead malfunction.
Obesity is not a contraindication to veno-arterial extracorporeal life support
Authors: Salna Michael , Fried Justin , Kaku Yuji , Brodie Daniel , Sayer Gabriel , Uriel Nir , Naka Yoshifumi , Takeda Koji 
Published: March 2021

Abstract

OBJECTIVES
Obesity may complicate the peripheral cannulation and delivery of veno-arterial extracorporeal life support (ECLS). With rising global body mass indices (BMI), obesity is becoming increasingly prevalent in severe cardiogenic shock yet its impact on outcomes is not well described. This study sought to examine the relationship between BMI and veno-arterial ECLS outcomes to better inform clinical decision-making.

METHODS
All cardiogenic shock patients undergoing peripheral veno-arterial ECLS at our institution from March 2008 to January 2019 were retrospectively analysed (n = 431). Patients were divided into 4 groups, BMI 17.5–24.9, 25–29.9, 30–34.9 and ≥35 kg/m2, and compared on clinical outcomes. Multivariable logistic regression was performed to identify variables associated with survival to discharge, the primary outcome of interest.

RESULTS
The median BMI was 28.3 kg/m2 (interquartile range 24.8–32.6) with a range of 17.0–69.1 kg/m2. Obese patients achieved significantly lower percentages of predicted flow rates compared with BMI &lt; 25 kg/m2 patients though did not differ in their lactate clearances. Patients with BMI ≥35 kg/m2 had similar complication rates to the other cohorts but were more likely to require continuous veno-venous haemodialysis (51% vs 25–40% in other cohorts, P = 0.002). Overall survival to discharge was 48% (n = 207/431) with no differences between the cohorts (P = 0.92). Patients with BMI ≥35 kg/m2 had considerably lower survival (10%) in extracorporeal membrane oxygenation cardiopulmonary resuscitation compared with the other groups (P = 0.17). On multivariable logistic regression, BMI was not significantly associated with failure to survive to discharge.

CONCLUSIONS
In conclusion, with the rising global prevalence of obesity, the results of our study suggest that clinicians need not treat obesity as a negative prognostic factor in cardiogenic shock requiring ECLS.
Assessing the indirect effects of COVID-19 on healthcare delivery, utilization and health outcomes: a scoping review
Authors: Roy Charlotte M , Bollman E. Brennan , Carson Laura M , Northrop Alexander J , Jackson Elizabeth F , Moresky Rachel T 
Published: March 2021

AbstractBackgroundThe COVID-19 pandemic and global efforts to contain its spread, such as stay-at-home orders and transportation shutdowns, have created new barriers to accessing healthcare, resulting in changes in service delivery and utilization globally. The purpose of this study is to provide an overview of the literature published thus far on the indirect health effects of COVID-19 and to explore the data sources and methodologies being used to assess indirect health effects.MethodsA scoping review of peer-reviewed literature using three search engines was performed.ResultsOne hundred and seventy studies were included in the final analysis. Nearly half (46.5%) of included studies focused on cardiovascular health outcomes. The main methodologies used were observational analytic and surveys. Data were drawn from individual health facilities, multicentre networks, regional registries, and national health information systems. Most studies were conducted in high-income countries with only 35.4% of studies representing low- and middle-income countries (LMICs).ConclusionHealthcare utilization for non-COVID-19 conditions has decreased almost universally, across both high- and lower-income countries. The pandemic’s impact on non-COVID-19 health outcomes, particularly for chronic diseases, may take years to fully manifest and should be a topic of ongoing study. Future research should be tied to system improvement and the promotion of health equity, with researchers identifying potentially actionable findings for national, regional and local health leadership. Public health professionals must also seek to address the disparity in published data from LMICs as compared with high-income countries.
Collection and consumption of non-wood forest products in Europe
Authors: Lovrić Marko , Da Re Riccardo , Vidale Enrico , Prokofieva Irina , Wong Jennifer , Pettenella Davide , Verkerk Pieter Johannes , Mavsar Robert 
Published: March 2021

AbstractMany non-wood forest products (NWFPs) such as mushrooms and berries are collected and consumed in Europe; but both national statistical and scientific data on this topic are reported only for a limited number of countries, products and case-study areas. Without an adequate quantitative basis, their importance as source of food and income, their links to recreation and cultural heritage, are all under-valued in forest-focused and forest-related policies. In this study, we aimed to address this gap by assessing the consumption and collection of NWFPs through a statistically representative survey in 28 European countries with over 17 000 respondents. Our results show that 90 per cent of households consume NWFPs and about one-quarter collects them. The consumption and collection rates, as well as the number of collected products and their contribution to household income, increase from the west to east of Europe. The vast majority of collected products are consumed fresh. Households with higher income consume a more diverse range of NWFPs, especially in Western Europe. The relation between income and collection is more ambiguous, but there is some indication that the collection rate is higher than average among higher-income households in North and Western Europe and among lower-income households in Eastern and South-Eastern Europe. Households for which NWFP collection is the main income source are predominantly located in Eastern Europe, and they focus their activities on few key products. Our results also identify recreational, hobby and professional collectors whose characteristics vary across socio-economic variables and geographical gradient. Recreational collectors in Western and Southern Europe collect 8 kg of NWFPs from five different products, while recreational collectors in Central-Eastern and North-Baltic Europe collect about four times more from 10 different products. Hobby collectors collect ~100 kg of NWFP per year and professional collectors half a ton, where both groups focus on 8–12 different products. Professional collectors are predominantly located in Eastern and South-Eastern Europe. We end the study by pointing to future research directions and with a series of policy recommendations on how NWFPs could be addressed along the geographical, income and urban–rural gradient with respect to their role in forest recreation as a food and income source.
Efficient CRISPR/Cas9 mutagenesis for neurobehavioral screening in adult zebrafish
Authors: Klatt Shaw Dana , Mokalled Mayssa H 
Published: March 2021

Abstract
Adult zebrafish are widely used to interrogate mechanisms of disease development and tissue regeneration. Yet, the prospect of large-scale genetics in adult zebrafish has traditionally faced a host of biological and technical challenges, including inaccessibility of adult tissues to high-throughput phenotyping and the spatial and technical demands of adult husbandry. Here, we describe an experimental pipeline that combines high-efficiency CRISPR/Cas9 mutagenesis with functional phenotypic screening to identify genes required for spinal cord repair in adult zebrafish. Using CRISPR/Cas9 dual-guide ribonucleic proteins, we show selective and combinatorial mutagenesis of 17 genes at 28 target sites with efficiencies exceeding 85% in adult F0 “crispants”. We find that capillary electrophoresis is a reliable method to measure indel frequencies. Using a quantifiable behavioral assay, we identify seven single- or duplicate-gene crispants with reduced functional recovery after spinal cord injury. To rule out off-target effects, we generate germline mutations that recapitulate the crispant regeneration phenotypes. This study provides a platform that combines high-efficiency somatic mutagenesis with a functional phenotypic readout to perform medium- to large-scale genetic studies in adult zebrafish.
Proteasome Control of [URE3] Prion Propagation by Degradation of Anti-Prion Proteins Cur1 and Btn2 in Saccharomyces cerevisiae
Authors: Edskes Herman K , Stroobant Emily E , DeWilde Morgan P , Bezsonov Evgeny E , Wickner Reed B 
Published: March 2021

Abstract
[URE3] is a prion of the nitrogen catabolism controller, Ure2p, and [PSI+] is a prion of the translation termination factor Sup35p in S. cerevisiae. Btn2p cures [URE3] by sequestration of Ure2p amyloid filaments. Cur1p, paralogous to Btn2p, also cures [URE3], but by a different (unknown) mechanism. We find that an array of mutations impairing proteasome assembly or MG132 inhibition of proteasome activity result in loss of [URE3]. In proportion to their prion—curing effects, each mutation affecting proteasomes elevates the cellular concentration of the anti-prion proteins Btn2 and Cur1. Of &gt;4,600 proteins detected by SILAC, Btn2p was easily the most overexpressed in a pre9Δ (α3 core subunit) strain. Indeed, deletion of BTN2 and CUR1 prevents the prion—curing effects of proteasome impairment. Surprisingly, the 15 most unstable yeast proteins are not increased in pre9Δ cells suggesting altered proteasome specificity rather than simple inactivation. Hsp42, a chaperone that cooperates with Btn2 and Cur1 in curing [URE3], is also necessary for the curing produced by proteasome defects, although Hsp42p levels are not substantially altered by a proteasome defect. We find that pre9Δ and proteasome chaperone mutants that most efficiently lose [URE3], do not destabilize [PSI+] or alter cellular levels of Sup35p. A tof2 mutation or deletion likewise destabilizes [URE3], and elevates Btn2p, suggesting that Tof2p deficiency inactivates proteasomes. We suggest that when proteasomes are saturated with denatured/misfolded proteins, their reduced degradation of Btn2p and Cur1p automatically upregulates these aggregate-handling systems to assist in the clean-up.
De novo assembly and delivery to mouse cells of a 101 kb functional human gene
Authors: Mitchell Leslie A , McCulloch Laura H , Pinglay Sudarshan , Berger Henri , Bosco Nazario , Brosh Ran , Bulajić Milica , Huang Emily , Hogan Megan S , Martin James A , Mazzoni Esteban O , Davoli Teresa , Maurano Matthew T , Boeke Jef D 
Published: March 2021

Abstract
Design and large-scale synthesis of DNA has been applied to the functional study of viral and microbial genomes. New and expanded technology development is required to unlock the transformative potential of such bottom-up approaches to the study of larger mammalian genomes. Two major challenges include assembling and delivering long DNA sequences. Here, we describe a workflow for de novo DNA assembly and delivery that enables functional evaluation of mammalian genes on the length scale of 100 kilobase pairs (kb). The DNA assembly step is supported by an integrated robotic workcell. We demonstrate assembly of the 101 kb human HPRT1 gene in yeast from 3 kb building blocks, precision delivery of the resulting construct to mouse embryonic stem cells, and subsequent expression of the human protein from its full-length human gene in mouse cells. This workflow provides a framework for mammalian genome writing. We envision utility in producing designer variants of human genes linked to disease and their delivery and functional analysis in cell culture or animal models.
Flexibility of joint production in mixed fisheries and implications for management
Authors: Briton Florence , Thébaud Olivier , Macher Claire , Gardner Caleb , Little Lorne Richard 
Published: March 2021

Abstract
Over the past decade, efforts have been made to factor technical interactions into management recommendations for mixed fisheries. Yet, the dynamics underlying joint production in mixed fisheries are generally poorly captured in operational mixed fisheries models supporting total allowable catch advice. Using an integrated ecological–economic simulation model, we explore the extent to which fishers are likely to alter the species composition of their landings in a mixed fishery managed with individual transferable quotas, the Australian Southern and Eastern Scalefish and Shark Fishery. Our simulations capture three different types of joint production problems, highlighting the flexibility that exists in terms of achievable catch compositions when quota markets provide the economic incentives to adapt fishing practices to quota availability. These results highlight the importance of capturing the drivers of fishing choices when advising TAC decisions in mixed fisheries. We also identify a hierarchy of species in this fishery, with harvest targets set for primary commercial species determining most of its socio-economic performance.