bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hereditary Pancreatitis—25 Years of an Evolving Paradigm
Authors: Sahin-Tóth Miklós 
Published: June 2022

Abstract
The identification of the genetic basis of hereditary pancreatitis in 1996 confirmed the critical role of trypsinogen in this disease and opened a new avenue of research on pancreatitis-associated genetic risk factors and their mechanism of action. Through the following 25 years, the ensuing discoveries fundamentally changed our understanding of pancreatitis pathogenesis, clarified the role of trypsinogen autoactivation in disease onset and progression, and set the stage for future therapeutic interventions. This Frank Brooks Memorial Lecture was delivered on November 4, 2021, at the 52nd Annual Meeting of the American Pancreatic Association, held in Miami Beach, Florida.
Feasibility and Satisfaction of Using NET VITALS Self-assessment Tool Among Patients With Neuroendocrine Tumors
Authors: Li Daneng , Imbesi Giovanna J. , Yen Lisa , Kim Heeyoung , Sun Can-Lan , Crook Christiana J. , Ballena Richard , Zhang Ya-Han , Allen Rebecca , Sedrak Mina , Singh Gagandeep 
Published: June 2022

Objectives
There is a lack of effective patient education regarding diagnosis/treatment of neuroendocrine tumors (NETs), possibly related to their rare incidence.

Methods
In this cross-sectional survey study, NET patients attending the 2019 Annual Los Angeles NET Education Conference were approached to complete NET VITALS, a self-assessment tool gauging patients’ perception/awareness of their NET diagnosis/treatment, and a satisfaction survey. Feasibility of NET VITALS, patient satisfaction with NET VITALS, and patients’ perception/awareness of their NET diagnosis/treatment were evaluated.

Results
This analysis included 68 patients (median age, 63 years; 47.1% gastrointestinal NETs; 88.2% metastatic disease). Participation was 88.3% (68/77), with a median of 85.7% of items completed (range, 61.9%–100.0%). More than 30% of the patients answered “Don't know/Not familiar”/left blank questions related to tumor characteristics, years of symptoms, and liver-directed therapies. In addition, 69.5% of the patients did not feel sufficient information about NETs was provided at diagnosis. Overall, 67.8% of the patients felt that NET VITALS provides topics to discuss with providers and 76.3% would recommend NET VITALS to others.

Conclusions
NET VITALS is a feasible and acceptable self-assessment tool to potentially help patients improve communication about their NET diagnosis/treatment with their physician. Further studies will examine NET VITALS’ generalizability and discuss its incorporation into clinical care.
The Cohesin ATPase cycle is mediated by specific conformational dynamics and interface plasticity of SMC1A and SMC3 ATPase domains
Authors: Gomes Marina Vitoria , Landwerlin Pauline , Diebold-Durand Marie-Laure , Shaik Tajith B. , Durand Alexandre , Troesch Edouard , Weber Chantal , Brillet Karl , Lemée Marianne , Decroos Christophe , Dulac Ludivine , Antony Pierre , Watrin Erwan , Ennifar Eric , Golzio Christelle , Romier Christophe 
Published: June 2022

SummaryCohesin is key to eukaryotic genome organization and acts throughout the cell cycle in an ATP- dependent manner. The molecular mechanisms underlying the Cohesin ATPase activity are poorly understood. Here, we have characterized distinct steps of the human Cohesin ATPase cycle and show that the SMC1A and SMC3 ATPase domains undergo specific but concerted structural rearrangements along this cycle. Specifically, while the proximal coiled coil of the SMC1A ATPase domain remains conformationally stable, that of SMC3 displays an intrinsic flexibility. The ATP-dependent formation of the heterodimeric SMC1A/SMC3 ATPase module (engaged state) favours this flexibility, while it is counteracted by binding of NIPBL and DNA (clamped state). Opening of the SMC3/RAD21 interface (open-engaged state) leads to a stiffening of the SMC3 proximal coiled coil that constricts, together with that of SMC1A, the DNA binding chamber of the ATPase module. Our results reveal that the plasticity of the ATP-dependent interface between the SMC1A and SMC3 ATPase domains enables the structural rearrangements occurring between the engaged, clamped and open-engaged states, while keeping the ATP gate shut.
CARD8 negatively regulates NLRP1 inflammasome activation level by interaction with NLRP1
Authors: Xu Zhihao , Deng Shasha , Huang Yuluo , Yang Yunru , Sun Liangqi , Liu Hanyuan , Zhao Dan , Zeng Weihong , Yin Xueying , Zheng Peiyi , Liu Muziying , Zhao Weidong , Zhou Ying , Jin Tengchuan 
Published: June 2022

AbstractNLRP1 inflammasome functions as canonical cytosolic sensor in response to intracellular infections and is implicated in auto-inflammatory diseases. But the regulation and signal transduction mechanisms of NLRP1 are incompletely understood. Here, we show that the T60 variant of CARD8, but not the canonical T48 isoform, negatively regulates NLRP1 inflammasome activation by directly interacting with the receptor molecule NLRP1 and inhibiting inflammasome assembly. Furthermore, our results suggest that the different ASC preference in three types of inflammasomes, namely ASC-indispensable NLRP1 inflammasome, ASC-dispensable mNLRP1b inflammasome and ASC-independent CARD8 inflammasome, is mainly caused by the CARD domain, not the UPA subdomain. Based on the systematic site-directed mutagenesis and structural analysis, we find that the signal transduction of NLRP1 inflammasome relies on multiple interaction surfaces on its death domain superfamily member CARD domain. Finally, our results partly explain the mechanism of the NLRP1 mutation-derived auto-inflammatory diseases caused by the overactivation of the NLRP1 inflammasome. In conclusion, our study not only reveals how CARD8 downregulates NLRP1 inflammasome activation, but also provides insights into the mechanisms of CARD-containing inflammasome assembly.
YAP and collagen remodelling support cell proliferation and tumour aggressiveness in uterine leiomyosarcoma
Authors: Gonzalez-Molina Jordi , Hahn Paula , Falcão Raul Maia , Gultekin Okan , Kokaraki Georgia , Zanfagnin Valentina , Petta Tirzah Braz , Lehti Kaisa , Carlson Joseph W. 
Published: June 2022

AbstractFibrillar collagen deposition, stiffness, and downstream signalling support the development of leiomyomas (LM), common benign mesenchymal tumours of the uterus, and are associated with aggressiveness in multiple carcinomas. Compared to epithelial carcinomas, however, the impact of fibrillar collagens on malignant mesenchymal tumours, including uterine leiomyosarcoma (LMS), remains elusive. In this study, we analyse the network morphology and density of fibrillar collagens combined with the gene expression of LMS, LM and normal myometrium (MM). We find that, in contrast to LM, LMS tumours present low collagen density and increased expression of collagen-remodelling genes, features associated with tumour aggressiveness. Using collagen-based 3D matrices, we show that the activity of MMP14, a central protein with collagen-remodelling functions particularly overexpressed in LMS, is necessary for LMS cell proliferation. In addition, we find that, unlike MM and LM cells, LMS proliferation and migration are not affected by collagen substrate stiffness. We demonstrate that LMS cell growth in low matrix adhesion microenvironments is supported by an enhanced basal YAP activity. Altogether, our results indicate that LMS cells acquire high collagen remodelling capabilities and are adapted to grow and migrate in low collagen and soft microenvironments. These results further suggest that matrix remodelling and YAP are potential therapeutic targets for this deadly disease.
Cytoarchitectonic, receptor distribution and functional connectivity analyses of the macaque frontal lobe
Authors: Rapan Lucija J. , Froudist-Walsh Sean , Niu Meiqi , Xu Ting , Zhao Ling , Funck Thomas , Wang Xiao-Jing , Amunts Katrin , Palomero-Gallagher Nicola 
Published: June 2022

AbstractBased on quantitative cyto- and receptor architectonic analyses, we identified 35 prefrontal areas and introduced a novel subdivision of Walker’s areas 10, 9, 8B and 46. Statistical analysis of receptor densities revealed regional differences in lateral and ventrolateral prefrontal cortex. Since structural and functional organization of subdivisions encompassing areas 46 and 12 demonstrated significant differences in the interareal levels of α2 receptors. Furthermore, multivariate analysis included receptor fingerprints of previously identified 16 motor areas in the same macaque brains, and revealed five clusters encompassing frontal lobe areas. Based on the functional connectivity analysis, clustered areas showed similar connectivity distribution pattern. In particular, rostrally located areas (in clusters 1-2) were characterized by bigger fingerprints, i.e., higher receptor densities, and stronger regional interconnections. Whereas, more caudal areas (in clusters 3-5) had smaller fingerprints, but showed a widespread connectivity pattern with distant cortical regions. Taken together, present study provides a comprehensive insight into the molecular structure underlying the functional organization of the cortex and, thus, reconcile discrepancies between the structural and functional hierarchical organization of the primate frontal lobe. Finally, our data are publicly available via the EBRAINS and BALSA repositories for the entire scientific community.
Mitochondrial network structure controls cell-to-cell mtDNA variability generated by cell divisions
Authors: Glastad Robert C. , Johnston Iain G. 
Published: June 2022

AbstractMitochondria are highly dynamic organelles, containing vital populations of mitochondrial DNA (mtDNA) distributed throughout the cell. Mitochondria form diverse physical structures in different cells, from cell-wide reticulated networks to fragmented individual organelles. These physical structures are known to influence the genetic makeup of mtDNA populations between cell divisions, but their influence on the inheritance of mtDNA at divisions remains less understood. Here, we use statistical and computational models of mtDNA content inside and outside the reticulated network to quantify how mitochondrial network structure can control the variances of inherited mtDNA copy number and mutant load. We assess the use of moment-based approximations to describe heteroplasmy variance and identify several cases where such an approach has shortcomings. We show that biased inclusion of one mtDNA type in the network can substantially increase heteroplasmy variance (acting as a genetic bottleneck), and controlled distribution of network mass and mtDNA through the cell can conversely reduce heteroplasmy variance below a binomial inheritance picture. Network structure also allows the generation of heteroplasmy variance while controlling copy number inheritance to sub-binomial levels, reconciling several observations from the experimental literature. Overall, different network structures and mtDNA arrangements within them can control the variances of key variables to suit a palette of different inheritance priorities.
AGO1 and HSP90 buffer different genetic variants in Arabidopsis thaliana
Authors: Lemus Tzitziki , Mason G. Alex , Bubb Kerry L. , Alexandre Cristina M. , Queitsch Christine , Cuperus Josh T. 
Published: June 2022

AbstractArgonaute 1 (AGO1), the principal protein component of microRNA-mediated regulation, plays a key role in plant growth and development. AGO1 physically interacts with the chaperone HSP90, which buffers cryptic genetic variation in plants and animals. We sought to determine whether genetic perturbation of AGO1 in Arabidopsis thaliana would also reveal cryptic genetic variation, and if so, whether AGO1-dependent loci overlap with those dependent on HSP90. To address these questions, we introgressed a hypomorphic mutant allele of AGO1 into a set of mapping lines derived from the commonly used Arabidopsis strains Col-0 and Ler. Although we identified several cases in which AGO1 buffered genetic variation, none of the AGO1-dependent loci overlapped with those buffered by HSP90 for the traits assayed. We focused on one buffered locus where AGO1 perturbation uncoupled the traits days to flowering and rosette leaf number, which are otherwise closely correlated. Using a bulk segregant approach, we identified a non-functional Ler hua2 mutant allele as the causal AGO1-buffered polymorphism. Introduction of a non-functional hua2 allele into a Col-0 ago1 mutant background recapitulated the Ler-dependent ago1 phenotype, implying that coupling of these traits involves different molecular players in these closely related strains. Taken together, our findings demonstrate that even though AGO1 and HSP90 buffer genetic variation in the same traits, these robustness regulators interact epistatically with different genetic loci, suggesting that higher-order epistasis is uncommon.Article SummaryArgonaute 1 (AGO1), a key player in plant development, interacts with the chaperone HSP90 which buffers environmental and genetic variation. We found that AGO1 buffers environmental and genetic variation in the same traits; however, AGO1-dependent and HSP90-dependent loci do not overlap. Detailed analysis of a buffered locus found that a non-functional HUA2 allele decouples days to flowering and rosette leaf number in an AGO1-dependent manner, suggesting the AGO1-dependent buffering acts at the network level.
mBAT-combo: a more powerful test to detect gene-trait associations from GWAS data
Authors: Li Ang , Liu Shouye , Bakshi Andrew , Jiang Longda , Chen Wenhan , Zheng Zhili , Sullivan Patrick F. , Visscher Peter M. , Wray Naomi R. , Yang Jian , Zeng Jian 
Published: June 2022

AbstractGene-based association tests aggregate multiple SNP-trait associations into sets defined by gene boundaries. Since genes have a direct biological link to downstream function, gene-based test results are widely used in post-GWAS analysis. A common approach for gene-based tests is to combine SNPs associations by computing the sum of χ2 statistics. However, this strategy ignores the directions of SNP effects, which could result in a loss of power for SNPs with masking effects (e.g., when the product of the effects of two SNPs and their linkage disequilibrium (LD) correlation is negative). Here, we introduce “mBAT-combo”, a new set-based test that is better powered than other methods to detect multi-SNP associations in the context of masking effects. We validate the method through simulations and applications to real data. We find that of 35 blood and urine biomarker traits in the UK Biobank, 34 traits show evidence for masking effects in a total of 4,175 gene-trait pairs, indicating that masking effects in complex traits is common. We further validate the improved power of our method in height, body mass index and schizophrenia with different GWAS sample sizes and show that on average 95.7% of the genes detected only by mBAT-combo with smaller sample sizes can be identified by the single-SNP approach with larger sample sizes (average sample size increased by 1.7-fold). For instance, LRRC4B is significant only in our method for schizophrenia, which has been shown to play a role in presynaptic pathology using genetic fine-mapping and evidence-based synaptic annotations. As a more powerful gene-based method, mBAT-combo is expected to improve the downstream pathway analysis or tissue and cell-type enrichment analysis that takes genes identified from GWAS data as input to understand the biological mechanisms of the trait or disease. Despite our focus on genes in this study, the framework of mBAT-combo is general and can be applied to any set of SNPs to refine trait-association signals hidden in genomic regions with complex LD structures.
Natural products lysobactin and sorangicin A show in vitro activity against Mycobacterium abscessus complex
Authors: Sullivan Jaryd R. , Yao Jacqueline , Courtine Christophe , Lupien Andréanne , Herrmann Jennifer , Müller Rolf , Behr Marcel A. 
Published: June 2022

AbstractThe prevalence of lung disease caused by Mycobacterium abscessus is increasing among patients with cystic fibrosis. M. abscessus is a multidrug resistant opportunistic pathogen that is notoriously difficult to treat due to a lack of efficacious therapeutic regimens. Currently, there are no standard regimens, and treatment guidelines are based empirically on drug susceptibility testing. Thus, novel antibiotics are required. Natural products represent a vast pool of biologically active compounds that have a history of being a good source of antibiotics. Here, we screened a library of 517 natural products purified from fermentations of various bacteria and fungi against M. abscessus ATCC 19977. Lysobactin and sorangicin A were active against the M. abscessus complex and drug resistant clinical isolates. These natural products merit further consideration to be included in the M. abscessus drug pipeline.
Effectiveness of vaccines in preventing hospitalization due to COVID-19: A multicenter hospital-based case-control study, Germany, June 2021 to January 2022
Authors: Stoliaroff-Pepin Anna , Peine Caroline , Herath Tim , Lachmann Johannes , Perriat Delphine , Dörre Achim , Nitsche Andreas , Michel Janine , Grossegesse Marica , Hofmann Natalie , Rinner Thomas , Kohl Claudia , Brinkmann Annika , Meyer Tanja , Dorner Brigitte G. , Stern Daniel , Treindl Fridolin , Hein Sascha , Werel Laura , Hildt Eberhard , Gläser Sven , Schühlen Helmut , Isner Caroline , Peric Alexander , Ghouzi Ammar , Reichardt Annette , Janneck Matthias , Lock Guntram , Schaade Lars , Wichmann Ole , Harder Thomas 
Published: June 2022

AbstractWe included 852 patients in a prospectively recruiting multicenter matched case-control study in Germany to assess vaccine effectiveness (VE) in preventing COVID-19-associated hospitalization (Delta-variant dominance). Two-dose VE was 89% (95%CI 84-93%) overall, 79% in patients with >2 comorbidities and 77% in adults aged 60-75 years. A third dose increased VE to >93% in all patient-subgroups.
Maternal diagnoses around pregnancy and risk of autism spectrum disorder – A population-based study
Authors: Khachadourian Vahe , Arildskov Elias , Grove Jakob , O’Reilly Paul F , Kodesh Arad , Levine Stephen Z , Buxbaum Joseph D , Reichenberg Abraham , Croen Lisa A. , Schendel Diana , Sandin Sven , Hansen Stefan Nygaard , Janecka Magdalena 
Published: June 2022

ABSTRACTBackgroundThere is growing interest in the potential effects of maternal health in pregnancy on the risk for autism spectrum disorder (ASD) in the offspring. Studies to date have examined only a few maternal diagnoses in pregnancy and did not account for the potential effects of co-occurring conditions. This study systematically investigates the associations between maternal diagnoses in pregnancy and the risk of ASD in the offspring, addressing comorbidity and familial confounding.MethodsThe study sample included all children born in Denmark in 1998-2007 (N=653,580) and their mothers. We fitted Cox proportional hazard regression models to estimate the risk of ASD associated with maternal chronic and non-chronic ICD-10 diagnoses. We further examined the evidence for potential familial confounding using discordant sibling and negative control designs.ResultsThe analytic sample included 7,866 ASD cases (1.2%) and 645,714 controls, born to 425,399 mothers. We tested 241 non-chronic, and 90 chronic maternal conditions for an association with ASD. In a multivariable model, adjusting for maternal comorbidities, 15 of the non-chronic and 5 of the chronic diagnoses were significantly associated with ASD after correcting for multiple testing. Pregnancy complications and injuries accounted for a major portion of the non-chronic maternal diagnoses associated with risk of ASD (e.g., diabetes mellitus in pregnancy: HR=1.27, 95%CI: 1.07-1.51; fracture of skull and facial bones: HR=1.61, 95%CI: 1.09-2.38), and maternal psychiatric diagnoses were most strongly associated with ASD among the chronic conditions (e.g., major depressive disorder: HR=1.89, 95%CI: 1.39, 2.56). Results from negative control (timing of diagnosis, before vs. during pregnancy) and sibling analyses provide limited evidence for the role of familial confounding in the observed associations.ConclusionsOur findings highlight the potential relevance of maternal health around pregnancy for offspring long-term neurodevelopmental outcomes and offer insights into the ASD etiology – necessitating further dissection of the mechanisms underlying the observed associations.
Multiple Long-Term Conditions (MLTC) and the environment: A scoping review
Authors: Dambha-Miller Hajira , Cheema Sukhmani , Saunders Nile , Simpson Glenn 
Published: June 2022

ABSTRACTBackgroundMultiple Long Term conditions (MLTC), the coexistence of two or more health conditions, is a major health care challenge associated with high service utilisation and expenditure. Once established, the trajectory to an increased number and severity of conditions, hospital admission, increased social care need and mortality is multifactorial. The role of wider environmental determinants in the MLTC sequelae is unclear.AimThe aim of this review was to summarise and collate existing evidence on environmental determinants on established MLTC.MethodsA comprehensive search of Medline, Embase, Cochrane, CINAHL and Bielefeld Academic Search Engine (BASE) from inception to 4th June 2022 in addition to grey literature. Two authors independently screened and extracted papers. Disagreements were resolved with a third author.ResultsThe search yielded 9,079 articles of which 12 were included. Five studies considered the effect of urban built environments and neighbourhood characteristics on MLTC. Two studies examined both the built and social environments. The social environment was considered by four studies. One study examined the natural environment. Evidence of correlations between some environmental determinants and increased or decreased risks of MLTC were found, including the quality of internal housing/living environments, exposure to airborne environmental hazards and a beneficial association with socially cohesive, accessible and greener neighbourhood environments.ConclusionsOnly 12 relevant papers were identified, with the majority focused on the built and social environments. Overall, the review uncovered very limited evidence and this finding indicates a need for further research to understand the role of environmental determinants in MLTC.