bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alteration of serum leptin and LEP/LEPR promoter methylation in Prader-Willi syndrome
Authors: Wieting Jelte , Jahn Kirsten , Buchholz Vanessa , Lichtinghagen Ralf , Bleich Stefan , Eberlein Christian K. , Deest Maximilian , Frieling Helge 
Published: December 2021

ABSTRACTPrader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11-13. During child development, PWS usually results in insatiable appetite with subsequent obesity representing the major mortality factor. The neurobiological basis of PWS-typical hyperphagia has remained poorly understood. Many PWS-typical abnormalities are based on hypothalamic dysregulation, the region in which hunger and satiety are hormonally regulated, with the hormone leptin being a main long-term regulator of satiety. Previous studies in PWS have inconsistently shown leptin alterations solely in early childhood, without investigating the leptin system on an epigenetic level.The present study investigates serum leptin levels (S-leptin) and methylation of the leptin (LEP) and leptin receptor gene (LEPR) promoter in 24 individuals with PWS compared to 13 healthy controls matched for sex, age, and body mass index (BMI) and relates the results to the extent of hyperphagia in PWS.S-Leptin levels were obtained by Enzyme-linked Immunosorbent Assay. LEP/LEPR-promoter methylation was assessed by DNA-bisulfite-sequencing, hyperphagia by Hyperphagia Questionnaire for Clinical Trials (HQ-CT). PWS and control groups differed significantly in S-leptin levels with higher S-leptin in PWS. Methylation analysis showed significant differences in mean promoter methylation rate both for LEP and LEPR with a lower methylation rate in PWS. LEPR, but not LEP methylation correlated with S-leptin levels. S-leptin and both LEP and LEPR methylation did not correlate with HQ-CT scores in PWS.The present study is the first to show significantly elevated S-leptin levels in an adult PWS cohort combined with an altered, downregulated LEP and LEPR promoter methylation status compared to BMI-matched controls. Analogous to previous studies, no link to the behavioral dimension could be drawn. Overall, the results suggest an increased leptin dysregulation in PWS, whereby the findings partly mirror leptin resistance seen in non-syndromic obesity.
Neurodevelopmental outcomes at one year in offspring of mothers who test positive for SARS-CoV-2 during pregnancy
Authors: Edlow Andrea G. , Castro Victor M. , Shook Lydia L. , Kaimal Anjali J. , Perlis Roy H. 
Published: December 2021

AbstractImportanceEpidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring.ObjectiveTo determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth.DesignRetrospective cohortParticipantsLive offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems.ExposureSARS-CoV-2 infection confirmed by PCR during pregnancyMain Outcome and MeasuresNeurodevelopmental disorders determined from ICD-10 diagnostic codes over 12 months; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record.ResultsThe cohort included 7,772 live births (7,466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean maternal age of 32.9 years; offspring were 9.9% Asian, 8.4% Black, and 69.0% white; 15.1% were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers (14% versus 8.7%; p=.003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses (crude OR 2.17 [95% CI 1.24-3.79, p=0.006]) as well as models adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR 1.86 [95% CI 1.03-3.36, p=0.04]). Third-trimester infection was associated with effects of larger magnitude (adjusted OR 2.34, 95% CI 1.23-4.44, p=0.01)Conclusion and RelevanceOur results provide preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these effects.Trial RegistrationNAKey PointsQuestionDoes COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life?FindingsIn a cohort of babies delivered during COVID-19, those born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery.MeaningThese preliminary findings suggest that COVID-19 exposure may impact neurodevelopment, and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.
Rare genetic variants in dominant developmental disorder loci cause milder related phenotypes in the general population
Authors: Kingdom Rebecca , Tuke Marcus , Wood Andrew , Beaumont Robin N. , Frayling Timothy , Weedon Michael N. , Wright Caroline F. 
Published: December 2021

ABSTRACTMany rare diseases are known to be caused by deleterious variants in Mendelian genes, however the same variants can also be found in people without the associated clinical phenotypes. The penetrance of these monogenic variants is generally unknown in the wider population, as they are typically identified in small clinical cohorts of affected individuals and families with highly penetrant variants. Here, we investigated the phenotypic effect of rare, potentially deleterious variants in genes and loci that are known to cause monogenic developmental disorders (DD) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 dominant DD genes using whole exome sequencing data from ∼200,000 individuals, and rare copy number variants overlapping known DD loci using SNP-array data from ∼500,000 individuals. We found that individuals with these likely deleterious variants had a mild DD-related phenotype, including lower fluid intelligence, slower reaction times, lower numeric memory scores and longer pairs matching times compared to the rest of the UK Biobank cohort. They were also shorter, with a higher BMI and had significant socioeconomic disadvantages, being less likely to be employed or be able to work, and having a lower income and higher deprivation index. Our findings suggest that many monogenic DD genes routinely tested within paediatric genetics have intermediate penetrance and may cause lifelong milder, sub-clinical phenotypes in the general adult population.
Projected epidemiological consequences of the Omicron SARS-CoV-2 variant in England, December 2021 to April 2022
Authors: Barnard Rosanna C. , Davies Nicholas G. , Pearson Carl A. B. , Jit Mark , Edmunds W. John 
Published: December 2021

AbstractThe Omicron B.1.1.529 SARS-CoV-2 variant was first detected in late November 2021 and has since spread to multiple countries worldwide. We model the potential consequences of the Omicron variant on SARS-CoV-2 transmission and health outcomes in England between December 2021 and April 2022, using a deterministic compartmental model fitted to epidemiological data from March 2020 onwards. Because of uncertainty around the characteristics of Omicron, we explore scenarios varying the extent of Omicron’s immune escape and the effectiveness of COVID-19 booster vaccinations against Omicron, assuming the level of Omicron’s transmissibility relative to Delta to match the growth in observed S gene target failure data in England. We consider strategies for the re-introduction of control measures in response to projected surges in transmission, as well as scenarios varying the uptake and speed of COVID-19 booster vaccinations and the rate of Omicron’s introduction into the population. These results suggest that Omicron has the potential to cause substantial surges in cases, hospital admissions and deaths in populations with high levels of immunity, including England. The reintroduction of additional non-pharmaceutical interventions may be required to prevent hospital admissions exceeding the levels seen in England during the previous peak in winter 2020–2021.
The impact of COVID-19 restrictions on older adults’ loneliness: Evidence from high-frequency panel data in Austria
Authors: Stolz Erwin , Mayerl Hannes , Freidl Wolfgang 
Published: December 2021

AbstractBACKGROUNDIt is unclear how strong and long lasting the effects of (recurring) COVID-19 restrictions are on older adults’ loneliness.METHODS469 retired older Austrians (60+) provided 9,732 repeated observations of loneliness across 30 waves of the Austrian Corona Panel Project between March 2020 and March 2022. Ordinal mixed regression models were used to estimate the effect of the strictness of COVID-19 restrictions (stringency index, range=0-100) on older adult’s loneliness.RESULTSThe proportion of older adults who reported to be often lonely correlated (r=0.45) with the stringency index over time: both peaked during lock-downs (stringency index=82, often lonely=10-13%) and were lowest during the summer of 2020 (stringency index=36, often lonely=4-6%). Results from regression models indicate, that when the stringency index increased, loneliness also increased. In turn, as COVID-19 restrictions loosened, levels of loneliness decreased again. Older adults who lived alone were more affected in terms of loneliness by COVID-19 restriction measures compared to those living with others.CONCLUSIONSMore stringent COVID-19 restrictions were associated with an increased in (situational) loneliness among older adults in Austria, and this effect was stronger among those who lived alone. Efforts should be made to enable older adults, in particular those who live alone, to have save in-person contact during periods of strict pandemic restriction measures.
The Michigan Genomics Initiative: a biobank linking genotypes and electronic clinical records in Michigan Medicine patients
Authors: Zawistowski Matthew , Fritsche Lars G. , Pandit Anita , Vanderwerff Brett , Patil Snehal , Schmidt Ellen M. , VandeHaar Peter , Brummett Chad M. , Keterpal Sachin , Zhou Xiang , Boehnke Michael , Abecasis Gonçalo R. , Zöllner Sebastian 
Published: December 2021

AbstractThe recent wave of biobank repositories linking individual-level genetic data with dense clinical health history has introduced a dramatic paradigm shift in phenotyping for human genetic studies. The mechanism by which biobanks recruit participants can vary dramatically according to factors such as geographic catchment and sampling strategy. These enrollment differences leave an imprint on the cohort, defining the demographics and the utility of the biobank for research purposes. Here we introduce the Michigan Genomics Initiative (MGI), a rolling enrollment, single health system biobank currently consisting of >85,000 participants recruited primarily through surgical encounters at Michigan Medicine. A strong ascertainment effect is introduced by focusing recruitment on individuals in Southeast Michigan undergoing surgery. MGI participants are, on average, less healthy than the general population, which produces a biobank enriched for case counts of many disease outcomes, making it well suited for a disease genetics cohort. A comparison to the much larger UK Biobank, which uses population representative sampling, reveals that MGI has higher prevalence for nearly all diagnosis- code-based phenotypes, and larger absolute numbers of cases for many phenotypes. GWAS of these phenotypes replicate many known findings, validating the genetic and clinical data and their proper linkage. Our results illustrate that single health-system biobanks that recruit participants through opportunistic sampling, such as surgical encounters, produce distinct patient profiles that provide an ideal resource for exploring the genetics of complex diseases.
One year of child neurology telemedicine: a data-driven analysis of 14,820 encounters
Authors: Kaufman Michael C. , Xian Julie , Galer Peter D. , Parthasarathy Shridhar , Gonzalez Alexander K. , Helbig Katherine , McKeown Sarah , Prelack Marisa S. , Fitzgerald Mark P. , Craig Sansanee , Rametta Salvatore C. , Fridinger Sara E. , Sharif Uzma , Melamed Susan E. , DiGiovine Marissa , Fried Lawrence , Malcolm Marissa P. , Kessler Sudha Kilaru , Chadehumbe Madeline , Szperka Christina L. , Chuo John , Caffee Laurel , Stephenson Donna J. , Banwell Brenda L. , Goldberg Ethan , Abend Nicholas S. , Helbig Ingo 
Published: December 2021

AbstractIntroductionDetermining the long-term impact of telemedicine in care across the diagnostic and age spectrum of child neurology during the COVID-19 pandemic and with the re-opening of outpatient clinics.MethodsAn observational cohort study of 34,837 in-person visits and 14,820 telemedicine outpatient pediatric neurology visits between October 1, 2019 and April 9, 2021. We assessed differences in care across visit types, time-period observed, time between follow-ups, patient portal activation rates and demographic factors.Results26,399 patients were observed in this study (median age 11.4 years [interquartile range, 5.5-15.9]; 13,209 male). We observed a higher proportion of telemedicine for epilepsy (ICD10 G40: OR 1.4, 95% CI 1.3-1.5) and a lower proportion for movement disorders (ICD10 G25: OR 0.7, 95% CI 0.6-0.8; ICD10 R25: OR 0.7, 95% CI 0.6-0.9). Infants were more likely to be seen in-person after re-opening clinics than by telemedicine (OR 1.6, 95% CI 1.5-1.8) as were individuals with neuromuscular disorders (OR 0.6, 95% CI 0.6-0.7). Racial and ethnic minority populations and those with highest social vulnerability had lower rates of telemedicine participation throughout the pandemic (OR 0.8, 95% CI 0.8-0.8; OR 0.7, 95% CI 0.7-0.8).DiscussionTelemedicine implementation was followed by continued use even once in-person clinics were available. Pediatric epilepsy care can often be performed using telemedicine while young children and patients with neuromuscular disorders often require in-person assessment. Prominent barriers for socially vulnerable families and racial and ethnic minorities persist.
Epidemiological analysis of hospitalized cases of COVID-19 in in-digenous people in an Amazonian region: cross-sectional study with data from the surveillance of acute and severe respiratory syn-dromes in Brazil
Authors: Silva Ferreira Ana Lucia da , Sardinha Daniele Melo , El-Husny Claudia Ozela , de Sá Carmem Aliandra Freire , Conceição Emilyn Costa , Batista Lima Karla Valéria 
Published: December 2021

AbstractIndigenous people are considered more vulnerable to new infectious agents. In view of the novel coronavirus causing COVID-19, health authorities are concerned about the possible impact of the pandemic on reaching vulnerable populations, such as the indigenous people of the Brazilian Amazon. Thus, we aimed to carry out an epidemiological analysis of serious cases and deaths from COVID-19 in indigenous population in the state of Pará, Brazil. The data was obtained from the public Ministry of Health platform. Data analysis was performed using the Statistical Package for the Social Sciences 20, Chi-square of adherence, the independence test and G test. For spatial distribution was used ArcGIS. We observed 123 COVID-19 cases: 46 deaths (37.40%), male gender (76-61.79%), age above 60 years (61-49.6%), the most frequent risk factor was chronic cardiovascular disease (18-14.63%). The predictors of death were: invasive ventilation has (10.73) more chances for the outcome death, those not vaccinated against influenza have (3.41) and age (1.4). COVID-19 occurrence was higher in municipalities that have villages with health care or commerce, or with migrants from the Warao ethnic group. Notifications should take into consideration the specific issues of indigenous people so that effective control measures can be defined.
Development of a Natural Language Processing Algorithm for the Classification of Suspicious Liver Lesions from Radiology Reports
Authors: Johnson Jacob , Senevirathne Kaneel , Ngo Lawrence 
Published: December 2021

AbstractHere, we developed and validated a highly generalizable natural language processing algorithm based on deep-learning. Our algorithm was trained and tested on a highly diverse dataset from over 2,000 hospital sites and 500 radiologists. The resulting algorithm achieved an AUROC of 0.96 for the presence or absence of liver lesions while achieving a specificity of 0.99 and a sensitivity of 0.6.
The ParB clamp docks onto Smc for DNA loading via a joint-ParB interface
Authors: Bock Florian P. , Anchimiuk Anna , Diebold-Durand Marie-Laure , Gruber Stephan 
Published: December 2021

AbstractChromosomes readily unlink from one another and segregate to daughter cells during cell division highlighting a remarkable ability of cells to organize long DNA molecules. SMC complexes mediate chromosome folding by DNA loop extrusion. In most bacteria, SMC complexes start loop extrusion at the ParB/parS partition complex formed near the replication origin. Whether they are recruited by recognizing a specific DNA structure in the partition complex or a protein component is unknown. By replacing genes in Bacillus subtilis with orthologous sequences from Streptococcus pneumoniae, we show that the three subunits of the bacterial Smc complex together with the ParB protein form a functional module that can organize and segregate chromosomes when transplanted into another organism. Using chimeric proteins and chemical cross-linking, we find that ParB binds to the Smc subunit directly. We map a binding interface to the Smc joint and the ParB CTP-binding domain. Structure prediction indicates how the ParB clamp presents DNA to the Smc complex to initiate DNA loop extrusion.
Modeling the Three-Dimensional Chromatin Structure from Hi-C Data with Transfer Learning
Authors: Georges Tristan Meynier , Rapsomaniki Maria Anna 
Published: December 2021

AbstractRecent studies have revealed the importance of three-dimensional (3D) chromatin structure in the regulation of vital biological processes. Contrary to protein folding, no experimental procedure that can directly determine ground-truth 3D chromatin coordinates exists. Instead, chromatin conformation is studied implicitly using high-throughput chromosome conformation capture (Hi-C) methods that quantify the frequency of all pairwise chromatin contacts. Computational methods that infer the 3D chromatin structure from Hi-C data are thus unsupervised, and limited by the assumption that contact frequency determines Euclidean distance. Inspired by recent developments in deep learning, in this work we explore the idea of transfer learning to address the crucial lack of ground-truth data for 3D chromatin structure inference. We present a novel method, Transfer learning Encoder for CHromatin 3D structure prediction (TECH-3D) that combines transfer learning with creative data generation procedures to reconstruct chromatin structure. Our work outperforms previous deep learning attempts for chromatin structure inference and exhibits similar results as state-of-the-art algorithms on many tests, without making any assumptions on the relationship between contact frequencies and Euclidean distances. Above all, TECH-3D presents a highly creative and novel approach, paving the way for future deep learning models.
De novodetermination of mosquitocidal Cry11Aa and Cry11Ba structures from naturally-occurring nanocrystals
Authors: Tetreau Guillaume , Sawaya Michael R. , De Zitter Elke , Andreeva Elena A. , Banneville Anne-Sophie , Schibrowsky Natalie , Coquelle Nicolas , Brewster Aaron S. , Grünbein Marie Luise , Kovacs Gabriela Nass , Hunter Mark S. , Kloos Marco , Sierra Raymond G. , Schiro Giorgio , Qiao Pei , Stricker Myriam , Bideshi Dennis , Young Iris D. , Zala Ninon , Engilberge Sylvain , Gorel Alexander , Signor Luca , Teulon Jean-Marie , Hilpert Mario , Foucar Lutz , Bielecki Johan , Bean Richard , de Wijn Raphael , Sato Tokushi , Kirkwood Henry , Letrun Romain , Batyuk Alexander , Snigireva Irina , Fenel Daphna , Schubert Robin , Canfield Ethan J. , Alba Mario M. , Laporte Frédéric , Després Laurence , Bacia Maria , Roux Amandine , Chapelle Christian , Riobé François , Maury Olivier , Ling Wai Li , Boutet Sébastien , Mancuso Adrian , Gutsche Irina , Girard Eric , Barends Thomas R. M. , Pellequer Jean-Luc , Park Hyun-Woo , Laganowsky Arthur D. , Rodriguez Jose , Burghammer Manfred , Shoeman Robert L. , Doak R. Bruce , Weik Martin , Sauter Nicholas K. , Federici Brian , Cascio Duilio , Schlichting Ilme , Colletier Jacques-Philippe 
Published: December 2021

AbstractCry11Aa and Cry11Ba are the two most potent toxins produced by mosquitocidalBacillus thuringiensissubsp.israelensisandjegathesan, respectively. The toxins naturally crystallize within the host; however, the crystals are too small for structure determination at synchrotron sources. Therefore, we applied serial femtosecond crystallography at X-ray free electron lasers toin vivo-grown nanocrystals of these toxins. The structure of Cry11Aa was determinedde novousing the single-wavelength anomalous dispersion method, which in turn enabled the determination of the Cry11Ba structure by molecular replacement. The two structures reveal a new pattern forin vivocrystallization of Cry toxins, whereby each of their three domains packs with a symmetrically identical domain, and a cleavable crystal packing motif is located within the protoxin rather than at the termini. The diversity ofin vivocrystallization patterns suggests explanations for their varied levels of toxicity and rational approaches to improve these toxins for mosquito control.
Photoaffinity capture compounds to profile the Magic Spot Nucleotide interactomes
Authors: Haas Thomas M. , Laventie Benoît-Joseph , Lagies Simon , Harter Caroline , Prucker Isabel , Ritz Danilo , Batcha Raspudin Saleem , Qiu Danye , Hüttel Wolfgang , Andexer Jennifer , Jenal Urs , Jessen Henning J. 
Published: December 2021

ABSTRACTMagic Spot Nucleotides (MSN) regulate the stringent response, a highly conserved bacterial stress adaptation mechanism, enabling survival when confronted with adverse external challenges. In times of antibiotic crisis, a detailed understanding of the stringent response is of critical importance, as potentially new targets for pharmacological intervention could be identified. In this study, we delineate the MSN interactome in Escherichia coli and Salmonella typhimurium cell lysates applying a family of trifunctional photoaffinity capture compounds. We introduce different MSN probes covering diverse phosphorylation patterns, such as pppGpp, ppGpp, and pGpp. Our chemical proteomics approach provides datasets of diverse putative MSN receptors both from cytosolic and membrane fractions that, upon validation, unveil new MSN targets. We find, for example, that the dinucleoside polyphosphate hydrolase activity of the non-Nudix hydrolase ApaH is potently inhibited by pppGpp, which itself is converted to pGpp by ApaH. The photoaffinity capture compounds described herein will be useful to identify MSN interactomes under varying conditions and across bacterial species.TOCMolecular fishing: a family of trifunctional photoaffinity capture compounds enables the identification of Magic Spot Nucleotide receptors by a chemoproteomics approach.