bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural evolution of trypsinogen gene redundancy confers risk for pancreas diseases
Authors: Lou Haiyi , Wang Yimin , Xie Bo , Bai Xinyue , Gao Yang , Zhang Rui , Xu Shuhua 
Published: August 2022

AbstractTrypsin is an important enzyme secreted by the pancreas for digesting proteins. The precursors of major human trypsin are encoded by trypsinogen genes PRSS1 and PRSS2. Here, we leveraged multi-omic data to study their evolutionary and functional impact. We estimated that the primate trypsinogen gene was duplicated from a single copy to multiple-copy 24-34 million years ago (Mya). Compared to six protein-coding genes in non-human great apes, the human ancestral state was a 5-copy with three being pseudogenized. Interestingly, a derived 3-copy form emerged in Africans ∼260 Kya and dominated in non-Africans as one of the two major haplotypes. Although no longer encoding proteins, the pseudogene enhancers still function on pancreatic PRSS2 expression, leading to ∼15% up-regulation for the 5-copy than the 3-copy haplotype. Notably, the 3-copy structure was under positive selection in East Asians, where lower trypsin might be adaptive during high-starch diet shift for protecting the pancreas from autodigestion, as also supported by the identified causality of the haplotype structure to pancreatitis risk. Our efforts in elucidating the structural evolution of trypsinogen genes advance our understanding of the genetic basis and molecular mechanism of human pancreas diseases.
A study to assess the impact of cobas Liat point-of-care PCR assays (SARS-CoV-2 and Influenza A/B) on patient clinical management in the emergency department of the University of California at Davis Medical Center
Authors: May Larissa , Robbins Elissa M. , Canchola Jesse A. , Chugh Kamal , Tran Nam K. 
Published: August 2022

AbstractBackgroundRapid detection of SARS-CoV-2 is crucial for reduction of transmission and clinical decision-making. The cobas® SARS-CoV-2 & Influenza A/B nucleic acid test for use on the cobas Liat® System is a rapid (20 minutes) point-of-care (POC) polymerase chain reaction (PCR) method.MethodsThis unblinded, pre-post study enrolled consecutive patients with symptoms/signs consistent with SARS-CoV-2 infection presenting to the University of California, Davis emergency department (ED). Outcomes following implementation of the cobas Liat SARS-CoV-2 & Influenza A/B test (intervention period: December 2020–May 2021) were compared with previous standard-of-care using centralized laboratory PCR methods (control period: April 2020–October 2020).ResultsElectronic health records of 8879 symptomatic patients were analyzed, comprising 4339 and 4540 patient visits and 538 and 638 positive SARS-CoV-2 PCR test results in the control and intervention periods, respectively. Compared with the control period, turnaround time (TAT) was shorter in the intervention period (median 0.98 vs 12.3 hours; p<0.0001). ED length of stay (LOS) was generally longer in the intervention period compared with the control period, but for those SARS-CoV-2-negative who were admitted, ED LOS was shorter (median 12.53 vs 17.93 hours; p<0.0001). Overall, the rate of anti-infective prescribing was also lower in the intervention period than in the control period (antibiotics only: 38.11% vs 44.55%; p<0.0001 and antivirals only: 3.13% vs 0.94%; p<0.0001).ConclusionThis real-world study confirms faster TAT with a POC PCR method in an emergency care setting and highlights the importance of rapid SARS-CoV-2 detection to aid patient management and inform treatment decisions.Clinical RelevanceThis study reports data collected from a quasi-experimental pre-post study using the electronic health records of patients presenting to the emergency department (ED) of the University of California at Davis Medical Center with symptoms or signs consistent with SARS-CoV-2 infection during their ED visit. The primary objective of this study was to determine if implementation of the point-of-care (POC) cobas® Liat® SARS-CoV-2 & Influenza A/B test for use on the cobas Liat System reduced the diagnostic turnaround time and/or length of stay for ED patients with suspected SARS-CoV-2 infection compared with the previous standards of care (batch-wise diagnostic testing using the cobas 6800 System and on-demand urgent testing on the GenMark Dx® ePlex® system in a centralized clinical laboratory). Ultimately, these data help to inform how implementation of POC molecular testing methods impact patient management.
Outcomes of a resource-adapted Wilms tumor treatment protocol in Lilongwe, Malawi, 2016-2021: successes and enduring barriers to cure
Authors: Holmes David M. , Matatiyo Apatsa , Mpasa Atupele , Huibers Minke H. W. , Manda Geoffrey , Tomoka Tamiwe , Mulenga Maurice , Namazzi Ruth , Mehta Parth , Zobeck Mark , Mzikamanda Rizine , Chintagumpala Murali , Allen Carl , Nuchtern Jed G. , Borgstein Eric , Aronson Daniel C. , Ozuah Nmazuo , Nandi Bip , McAtee Casey L. 
Published: August 2022

AbstractPurposeWilms tumor is a common renal cancer of childhood with long-term survival rates exceeding 80% in high-resource countries, yet survival remains below 50% in the low-resource settings of Africa. We assessed outcomes of a resource-adapted treatment protocol at a Malawian hospital to identify actionable factors affecting survival.MethodsWe assessed clinical outcomes with a single-center retrospective cohort study of children diagnosed between 2016 and 2021 in Lilongwe, Malawi.FindingsWe identified 136 patients with Wilms tumor, most commonly with stage III (25.7%) or IV disease (25.7%). Two-year overall survival (OS) was: Stage I, 78%; Stage II, 27%; Stage III, 62%; Stage IV, 23%, Stage V, 0%. Event-free survival (EFS) was: Stage I, 60%; Stage II, 0%; Stage III, 51%; Stage IV, 13%; Stage V, 0%. After death, treatment abandonment was the most common event comprising EFS, occurring in 26.5% of patients. Among 43% of patients who completed therapy, 2-year OS was 80% and EFS was 69%. Relapse was documented in 9.6% of patients. Radiotherapy was indicated for 40.4% patients, among whom only three received it due to regional unavailability. Factors associated with OS were severe acute malnutrition (Hazard ratio, HR, 1.9), increasing tumor stage (HR, 1.5), and inferior vena cava involvement (HR, 2.7). On multivariable analysis, only tumor stage remained associated with outcome.InterpretationImplementing a curative resource-adapted treatment protocol in an extremely resourced-constrained environment was feasible in Malawi and resulted in relatively favorable outcomes in low-stage disease, particularly among those who completed therapy. However, factors such as late-stage disease, frequent abandonment, and absent radiotherapy represent ongoing implementation barriers that should be the focus of continued research funding and intervention in Africa.
Trends in psychological distress in Great Britain, 1991-2019: evidence from three representative surveys
Authors: Zhang Anwen , Gagne Thierry , Walsh David , Ciancio Alberto , Proto Eugenio , McCartney Gerry 
Published: August 2022

AbstractBackgroundPreviously improving UK mortality trends stalled around 2012 due to economic policy changes. This paper examines whether trends in psychological distress across three population surveys show similar trends.MethodsWe report the percentages reporting psychological distress (4+ in the 12-item General Health Questionnaire (GHQ-12)) from Understanding Society (Great Britain, 1991-2019), Scottish Health Survey (SHeS, 1995-2019) and Health Survey for England (HSE, 2003-2018) for the population overall, and stratified by sex, age and area deprivation. Summary inequality indices were calculated and segmented regressions fitted to identify turning points after 2010.ResultsPsychological distress was higher in Understanding Society than in the SHeS or HSE. There was a slight improvement between 1992 and 2015 in Understanding Society (with prevalence declining from 20.6% to 18.6%) with some fluctuations. After 2015 there is some evidence of an overall deterioration in psychological distress across surveys. Prevalence worsened notably among those aged 16-34 years after 2010 (all three surveys), and aged 35-64 years in Understanding Society and SHeS after 2015. In contrast, the prevalence declined in those aged 65+ years in Understanding Society after around 2008, with less clear trends in the other surveys. The prevalence was around twice as high in the most deprived compared to the least deprived areas, and higher in women, with trends by deprivation and sex similar to the populations overall.ConclusionPsychological distress worsened amongst working-age adults after around 2015 across British population surveys, mirroring the mortality trends. This indicates a widespread health crisis that pre-dates the COVID-19 pandemic.
The microtubule-associated protein SlMAP70 interacts with SlIQD21 and regulates fruit shape formation in tomato
Authors: Bao Zhiru , Guo Ye , Deng Yaling , Zang Jingze , Zhang Junhong , Ouyang Bo , Qu Xiaolu , Bürstenbinder Katharina , Wang Pengwei 
Published: August 2022

AbstractThe shape of tomato fruits is closely correlated to microtubule organization and the activity of microtubule associated proteins (MAP), but insights into the mechanism from a cell biology perspective are still largely elusive. Analysis of tissue expression profiles of different microtubule regulators revealed that functionally distinct classes of MAPs are highly expressed during fruit development. Among these, several members of the plant-specific MAP70 family are preferably expressed at the initiation stage of fruit development. Transgenic tomato lines overexpressing SlMAP70 produced elongated fruits that show reduced cell circularity and microtubule anisotropy, while SlMAP70 loss-of-function mutant showed an opposite effect with flatter fruits. Microtubule anisotropy of fruit endodermis cells exhibited dramatic rearrangement during tomato fruit development, and SlMAP70-1 is likely implicated in cortical microtubule organization and fruit elongation throughout this stage by interacting with SUN10/SlIQD21a. The expression of SlMAP70 (or co-expression of SlMAP70 and SUN10/SlIQD21a) induces microtubule stabilization and prevents its dynamic rearrangement, both activities are essential for fruit shape establishment after anthesis. Together, our results identify SlMAP70 as a novel regulator of fruit elongation, and demonstrate that manipulating microtubule stability and organization at the early fruit developmental stage has a strong impact on fruit shape.
Optical O2 sensors also respond to redox active molecules commonly secreted by bacteria
Authors: Flamholz Avi I. , Saccomano Samuel , Cash Kevin , Newman Dianne K. 
Published: August 2022

AbstractFrom a metabolic perspective, molecular oxygen (O2) is arguably the most significant constituent of Earth’s atmosphere. Nearly every facet of microbial physiology is sensitive to the presence and concentration of O2, which is the most favorable terminal electron acceptor used by biological organisms and also a dangerously reactive oxidant. As O2 has such sweeping implications for physiology, researchers have developed diverse approaches to measure O2 concentrations in natural and laboratory settings. Recent improvements to phosphorescent O2 sensors piqued our interest due to the promise of optical measurement of spatiotemporal O2 dynamics. However, we found that our preferred bacterial model, Pseudomonas aeruginosa PA14, secretes more than one molecule that quenches such sensors, complicating O2 measurements in PA14 cultures and biofilms. Assaying supernatants from cultures of 9 bacterial species demonstrated that this phenotype is common: all supernatants quenched a soluble O2 probe substantially. Phosphorescent O2 probes are often embedded in solid support for protection, but an embedded probe called O2NS was quenched by most supernatants as well. Measurements using pure compounds indicated that quenching is due to interactions with redox-active small molecules including phenazines and flavins. Uncharged and weakly-polar molecules like pyocyanin were especially potent quenchers of O2NS. These findings underscore that optical O2 measurements made in the presence of bacteria should be carefully controlled to ensure that O2, and not bacterial secretions, is measured, and motivate the design of custom O2 probes for specific organisms to circumvent sensitivity to redox-active metabolites.ImportanceWhen they are closely-packed, as in biofilms, colonies, and soils, microbes can consume O2 faster than it diffuses. As such, O2 concentrations in natural environments can vary greatly over time and space, even on the micrometer scale. Wetting soil, for example, slows O2 diffusion higher in the soil column, which, in concert with microbial respiration, greatly diminishes [O2] at depth. Given that variation in [O2] has outsized implications for microbial physiology, there is great interest in measuring the dynamics of [O2] in microbial cultures and biofilms. We demonstrate that certain classes of bacterial metabolites frustrate optical measurement of [O2] with phosphorescent sensors, but also that some species (e.g. E. coli) do not produce problematic secretions under the conditions tested. Our work therefore offers a strategy for identifying organisms and culture conditions in which optical quantification of spatiotemporal [O2] dynamics with current sensors is feasible.
SARS-CoV-2 genomic diversity in households highlights the challenges of sequence-based transmission inference
Authors: Bendall Emily , Paz-Bailey Gabriela , Santiago Gilberto A. , Porucznik Christina A. , Stanford Joseph B. , Stockwell Melissa S. , Duque Jazmin , Jeddy Zuha , Veguilla Vic , Major Chelsea , Rivera-Amill Vanessa , Rolfes Melissa A. , Dawood Fatimah S. , Lauring Adam S. 
Published: August 2022

ABSTRACTBackgroundThe reliability of sequence-based inference of SARS-CoV-2 transmission is not clear. Sequence data from infections among household members can define the expected genomic diversity of a virus along a defined transmission chain.MethodsSARS-CoV-2 cases were identified prospectively among 2,369 participants in 706 households. Specimens with an RT-PCR cycle threshold ≤30 underwent whole genome sequencing. Intrahost single nucleotide variants (iSNV) were identified at ≥5% frequency. Phylogenetic trees were used to evaluate the relationship of household and community sequences.ResultsThere were 178 SARS-CoV-2 cases in 706 households. Among 147 specimens sequenced, 106 yielded a whole genome consensus with coverage suitable for identifying iSNV. Twenty-six households had sequences from multiple cases within 14 days. Consensus sequences were indistinguishable among cases in 15 households, while 11 had ≥1 consensus that differed by 1-2 mutations. Sequences from households and the community were often interspersed on phylogenetic trees. Identification of iSNV improved inference in 2 of 15 households with indistinguishable consensus sequences and 6 of 11 with distinct ones.ConclusionsIn multiple infection households, whole genome consensus sequences differed by 0-1 mutations. Identification of shared iSNV occasionally resolved linkage, but the low genomic diversity of SARS-CoV-2 limits the utility of “sequence-only” transmission inference.SummaryHigh depth of coverage whole genome sequencing can identify SARS-CoV-2 transmission chains in settings where there is strong epidemiologic linkage but is not reliable as a stand-alone method for transmission inference.
Patient Reported Outcomes of Medical Cannabis for Managing Pain in Charcot-Marie-Tooth Disease
Authors: Canals Priscilla C. , Aguilar Alexia G. , Carter Gregory T. , Shields C. Miyabe , Westerkamp Andrew , D’Elia Meg , Aldrich Joy , Moore Robert N. , Moore Allison T. , Piper Brian J. 
Published: August 2022

AbstractBackground and aimsChronic pain is a major part of the disease burden in Charcot-Marie-Tooth (CMT) disease. Current pharmacotherapies to manage symptoms of CMT disease, particularly pain, are inadequate. This exploratory study examined the patient reported efficacy of medical cannabis among CMT patients.MethodsParticipants (N = 56; 71.4% female; Age = 48.9, SD = 14.6; 48.5% CMT1) were recruited though the Hereditary Neuropathy Foundation’s Global Registry for Inherited Neuropathies. The online survey contained 52 multiple choice questions about demographics, medical cannabis use, symptomology, efficacy, and adverse effects.ResultsWhen asked about how much relief they experience from using cannabis as a method of symptom relief, respondents reported an average of 69.6% (SEM + 2.6). Women were more likely to report experiencing pain than men (p < .05). Participants who perceived support from their providers were more likely to inform them of their cannabis use (p < .05).InterpretationPatients reported that cannabis was effective to manage symptoms. More prospective and controlled research needs to be conducted to better serve and optimize the potential use of cannabis to treat CMT.Graphical AbstractPatient Reported Outcomes of Medical Cannabis for Managing Pain in Patients with Charcot-Marie-Tooth DiseasePriscilla C. Canals, Alexia G. Aguilar, Gregory T. Carter, Marion McNabb, Andrew M. Westerkamp, Miyabe Shields, Meg D’Elia, Joy Aldrich, Robert N. Moore, Allison T. Moore, Brian J. Piper*There is no prior research of medical cannabis experiences among Charcot-Marie-Tooth (CMT) patients.CMT patients (N=56) were recruited though the Hereditary Neuropathy Foundation’s Global Registry for Inherited Neuropathies and completed an online survey.Symptom relief from using cannabis was moderately-high (70% + 3).CMT patients that received support from their providers were significantly more likely to inform them of their cannabis use.These descriptive results should be verified using prospective and randomized controlled trials.
ProteasomeID: quantitative mapping of proteasome interactomes and substrates forin vitroandin vivostudies
Authors: Bartolome Aleksandar , Heiby Julia C. , Fraia Domenico Di , Heinze Ivonne , Knaudt Hannah , Späth Ellen , Omrani Omid , Minetti Alberto , Hofmann Maleen , Kirkpatrick Joanna M. , Dau Therese , Ori Alessandro 
Published: August 2022

SUMMARYProteasomes are essential molecular machines responsible for the degradation of proteins in eukaryotic cells. Altered proteasome activity has been linked to neurodegeneration, auto-immune disorders and cancer. Despite the relevance for human disease and drug development, no method currently exists to monitor proteasome composition and interactionsin vivoin animal models. To fill this gap, we developed a strategy based on tagging of proteasomes with promiscuous biotin ligases and generated a new mouse model enabling the quantification of proteasome interactions by mass spectrometry. We show that biotin ligases can be incorporated in fully assembled proteasomes without negative impact on their activity. We demonstrate the utility of our method by identifying novel proteasome-interacting proteins, charting interactomes across mouse organs, and showing that proximity-labeling enables the identification of both endogenous and small molecule-induced proteasome substrates.
Structural Basis of Mammalian Respiratory Complex I Inhibition by Medicinal Biguanides
Authors: Bridges Hannah R. , Blaza James N. , Yin Zhan , Chung Injae , Pollak Michael N. , Hirst Judy 
Published: August 2022

AbstractThe molecular mode of action of metformin, a biguanide used widely in the treatment of diabetes, is incompletely characterized. Here we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We explain the unique selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel and an additional binding site is in a pocket on the intermembrane space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable rational design of novel medicinal biguanides.One-Sentence SummaryBiguanides inhibit complex I by binding in the quinone channel, and exert an independent localized chaotropic effect.
Human brain organoid model of maternal immune activation identifies radial glia cells as selectively vulnerable
Authors: Sarieva Kseniia , Kagermeier Theresa , Khakipoor Shokoufeh , Atay Ezgi , Yentür Zeynep , Becker Katharina , Mayer Simone 
Published: August 2022

AbstractMaternal immune activation (MIA) during the critical windows of gestation is correlated with long- term neurodevelopmental deficits in the offspring, including increased risks for autism spectrum disorder (ASD) in humans. Interleukin 6 (IL-6) derived from the gestational parent is one of the major molecular mediators, by which MIA alters the developing brain. In this study, we established a human three-dimensional (3D) in vitro model of MIA by treating induced pluripotent stem cell- derived dorsal forebrain organoids with a constitutively active form of IL-6, Hyper-IL-6. We validated our model by showing that dorsal forebrain organoids express the molecular machinery necessary for responding to Hyper-IL-6 and activate STAT signaling upon Hyper-IL-6 treatment. RNA sequencing analysis revealed the upregulation of major histocompatibility complex class I (MHCI) genes, which have been implicated with ASD. Immunohistochemical analysis as well as single-cell RNA-sequencing revealed a small increase in the proportion of radial glia cells. Single-cell transcriptomic analysis revealed the highest number of differentially expressed genes in radial glia cells with downregulation of genes related to protein translation in line with data from mouse models of MIA. Additionally, we identified differentially expressed genes not found in mouse models of MIA which might drive species-specific responses to MIA. Together, we establish a human 3D model of MIA, which can be used to study the cellular and molecular mechanisms underlying the increased risk for developing disorders such as ASD.
A truncating mutation of Magel2 in the rat modelled for the study of Schaaf-Yang and Prader-Willi syndromes alters select behavioral and physiological outcomes
Authors: Reznik Derek L , Yang Mingxiao V , de la Haza Pedro Albelda , Jain Antrix , Spanjaard Melanie , Theiss Susanne , Schaaf Christian P , Malovannaya Anna , Strong Theresa V , Veeraragavan Surabi , Samaco Rodney C 
Published: August 2022

ABSTRACTTruncating mutations of the maternally imprinted, paternally expressed MAGEL2 gene are the predicted genetic cause of several rare neurodevelopmental disorders including Schaaf-Yang (SYS), Chitayat-Hall and Opitz Trigonocephaly C syndromes. MAGEL2 is also deleted or inactivated in Prader-Willi syndrome (PWS). Previous studies in mice have utilized Magel2 gene deletion models to examine the consequences of its absence. In this study, we report the generation, molecular validation, and phenotypic characterization of a novel rat model with a truncating Magel2 mutation generating a mutant peptide sequence more closely modeling variants associated with SYS-causing mutations. Within the hypothalamus, a brain region wherein mouse and human MAGEL2 is paternally-expressed, we demonstrate at the level of transcript and peptide detection that Magel2 in the rat exhibits a paternal, parent-of-origin effect. In the evaluation of behavioral features across several domains, juvenile Magel2 mutant rats display select alterations in anxiety-like behavior and sociability measures. Moreover, the analysis of peripheral organ systems detected alterations in body composition, cardiac structure and function, and breathing irregularities in Magel2 mutant rats. Several of these findings are concordant with reported mouse phenotypes, signifying the conservation of MAGEL2 function across rodent species for specific behavioral outcome measures. We conclude that our comprehensive analysis demonstrating impairments across multiple domains demonstrates the tractability of this model system for the study of truncating MAGEL2 mutations.