bluuebunny/crossref_metadata_2025 huggingface dataset:
Changing of therapeutic trends between the 1st and 2nd wave did not reduce COVID-19 related mortality of renal transplant recipients: a national registry study
Authors: Berger Bastien , Hazzan Marc , Kamar Nassim , Francois Hélène , Matignon Marie , Greze Clarisse , Gatault Philippe , Frimat Luc , Westeel Pierre F , Goutaudier Valentin , Snanoudj Renaud , Colosio Charlotte , Sicard Antoine , Bertrand Dominique , Mousson Christiane , Bamoulid Jamal , Thierry Antoine , Anglicheau Dany , Couzi Lionel , Chemouny Jonathan M , Duveau Agnes , Moal Valerie , Le Meur Yannick , Blancho Gilles , Tourret Jérôme , Malvezzi Paolo , Mariat Christophe , Rerolle Jean-Philippe , Bouvier Nicolas ,   the French SOT COVID Registry, Caillard Sophie , Thaunat Olivier
Published: December 2021

SARS-CoV-2 pandemic evolved in two consecutive waves over 2020 (for France: 1st wave from March 1 to July 31; and 2nd wave from August 1 to December 31). Improvements in the management of COVID-19 led to a reduction of mortality rates in hospitalized patients during the second wave. Whether this progress also benefited to kidney transplant recipients (KTR), a population particularly vulnerable to severe COVID-19, remained unclear.

In France, 957 KTR were hospitalized for COVID-19 in 2020 and their data were prospectively collected in the French SOT COVID registry. The presentation, management, and outcomes of the 359 KTR diagnosed during the 1st wave were compared to those of the 598 of the 2nd wave. Baseline comorbidities were largely similar between KTR of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs 58.4%, p<0.001) or CNI (32.1% vs 16.6%, p<0.001) was less frequent during the 2nd wave. Hydroxychloroquine and azithromycin that were commonly used during the 1st wave (21.7% and 30.9%, respectively) were almost abandoned during the 2nd. In contrast, the use of high dose corticosteroids doubled (19.5% vs. 41.6%, p<0.001). Despite these changing trends in COVID-19 management, 60-day mortality was not statistically different between the 2 waves (25.3% vs. 23.9%; Log Rank, p=0.48).

We conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality in KTR. Our data indirectly support the importance of vaccination and monoclonal neutralizing anti-SARS-CoV-2 antibodies to protect KTR from severe COVID-19.
Patterns of convergence and divergence between bipolar disorder type I and type II: evidence from integrative genomic analyses
Authors: Huang Yunqi , Liu Yunjia , Wu Yulu , Tang Yiguo , Liu Siyi , Xiao Liling , Zhang Mengting , Tao Shiwan , Xie Min , Dai Minhan , Li Mingli , Gui Hongsheng , Wang Qiang
Published: December 2021

Genome-wide association studies (GWAS) analyses have revealed genetic evidence of bipolar disorder (BD), but little is known about genetic structure of BD subtypes. We aimed to investigate genetic overlap and distinction of bipolar type I (BDI) & type II (BDII) by conducting integrative post-GWAS analyses. This study utilized single nucleotide polymorphism (SNP)-level approaches to uncover correlated and distinct genetic loci. Transcriptome-wide association analyses (TWAS) were then approached to pinpoint functional genes expressed in specific brain tissues and blood. Next, we performed cross-phenotype analysis including exploring the potential causal associations between BDI & II and drug responses and comparing the difference of genetic structures among four different psychiatric traits. Our results find SNP-level evidence revealed three genomic loci, SLC25A17, ZNF184 and RPL10AP3 shared by BDI & II, while one locus (i.e., MAD1L1) and significant gene sets involved in calcium channel activity, neural and synapsed signals that distinguished two subtypes. TWAS data implicated different genes effecting BDI & II through expression in specific brain regions (e.g., nucleus accumbens for BDI). Cross-phenotype analyses indicated that BDI & II share continuous genetic structures with schizophrenia (SCZ) and major depression disorder (MDD), which help fill the gaps left by the dichotomy of mental disorder. These combined evidences illustrate genetic convergence and divergence between BDI & II and provide an underlying biological and trans-diagnostic insight into major psychiatric disorders.
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

Prader-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

Importance

Epidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring.

Objective

To 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.

Design

Retrospective cohort

Participants

Live offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems.

Exposure

SARS-CoV-2 infection confirmed by PCR during pregnancy

Main Outcome and Measures

Neurodevelopmental 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.

Results

The 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 Relevance

Our 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 Registration

NA

Key Points

Question

Does COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life?

Findings

In 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.

Meaning

These 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

Many 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

The 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

BACKGROUND

It is unclear how strong and long lasting the effects of (recurring) COVID-19 restrictions are on older adults’ loneliness.

METHODS

469 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.

RESULTS

The 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.

CONCLUSIONS

More 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

The 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

Introduction

Determining 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.

Methods

An 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.

Results

26,399 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).

Discussion

Telemedicine 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

Indigenous 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

Here, 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

Chromosomes 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

Recent 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

Cry11Aa 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

Magic 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.

TOC

Molecular fishing: a family of trifunctional photoaffinity capture compounds enables the identification of Magic Spot Nucleotide receptors by a chemoproteomics approach.
Non-random organization of flux control mechanisms in yeast central metabolic pathways
Authors: Yu Rosemary , Vorontsov Egor , Sihlbom Carina , Nielsen Jens
Published: December 2021

Metabolic flux can be regulated by a variety of different mechanisms, but the organization of these mechanisms within the metabolic network has remained unknown. Here we test the hypothesis that flux control mechanisms are not distributed randomly in the metabolic network, but rather organized according to pathway. Combining proteomics, phosphoproteomics, and metabolic modeling, we report the largest collection of flux-enzyme-phosphoenzyme relationships to date in Saccharomyces cerevisiae. In support of the hypothesis, we show that (i) amino acid metabolic pathways are predominantly regulated by enzyme abundance stemming from transcriptional regulation; (ii) upper glycolysis and associated pathways, by inactivating enzyme phosphorylation; (iii) lower glycolysis and associated pathways, by activating enzyme phosphorylation; and (iv) glycolipid/glycophospholipid pathways, by a combination of enzyme phosphorylation and metabolic compartmentalization. We delineate the evolutionary history for the observed organization of flux control mechanisms in yeast central metabolic pathways, furthering our understanding of the regulation of metabolism and its evolution.
Polymorphism-aware estimation of species trees and evolutionary forces from genomic sequences with RevBayes
Authors: Borges Rui , Boussau Bastien , Höhna Sebastian , Pereira Ricardo J. , Kosiol Carolin
Published: December 2021

The availability of population genomic data through new sequencing technologies gives unprecedented opportunities for estimating important evolutionary forces such as genetic drift, selection, and mutation biases across organisms. Yet, analytical methods that can handle polymorphisms jointly with sequence divergence across species are rare and not easily accessible to empiricists.

We implemented polymorphism-aware phylogenetic models (PoMos), an alternative approach for species tree estimation, in the Bayesian phylogenetic software RevBayes. PoMos naturally account for incomplete lineage sorting, which is known to cause difficulties for phylogenetic inference in species radiations, and scale well with genome-wide data. Simultaneously, PoMos can estimate mutation and selection biases.

We have applied our methods to resolve the complex phylogenetic relationships of a young radiation of Chorthippus grasshoppers, based on coding sequences. In addition to establishing a well-supported species tree, we found a mutation bias favoring AT alleles and selection bias promoting the fixation of GC alleles, the latter consistent with GC-biased gene conversion. The selection bias is two orders of magnitude lower than genetic drift, validating the critical role of nearly neutral evolutionary processes in species radiation.

PoMos offer a wide range of models to reconstruct phylogenies and can be easily combined with existing models in RevBayes — e.g., relaxed clock and divergence time estimation — offering new insights into the evolutionary processes underlying molecular evolution and, ultimately, species diversification.
ZEB2 transduces HIF1α dependent regulation of Transglutaminase 2 in glomerular podocytes
Authors: Kolligundla Lakshmi P , Singh Ashish K , Kavvuri Rajesh , Pasupulati Anil K
Published: December 2021

Glomerular podocytes are instrumental in ensuring glomerular permselectivity and regulating the integrity of glomerular biology. However, podocytes are vulnerable to various noxious stimuli such as hypoxia, and podocyte injury presented with glomerulosclerosis and impaired kidney function. The mechanism of hypoxia-induced podocyte injury vis-a-vis glomerulosclerosis has remained enigmatic. Hypoxia inducible factor 1α (HIF1α) that transduces hypoxic adaptations, induces Transglutaminase 2 (TG2), a calcium dependent enzyme that catalyzes intramolecular ε-(γ-glutamyl) lysine cross-links of extracellular matrix (ECM) proteins. In this study, we investigated the mechanism of regulation of TG2 by HIF1α. Stabilization of HIF1α by FG4592 (Roxadustat) and physiological hypoxia, resulted in elevated expression of ZEB2 (zinc-finger E-box-homeobox 2) and its downstream target TRPC6 (transient receptor potential channel 6). ZEB2 transcriptionally activates TG2 expression, whereas, via TRPC6, it induces calcium influx, inturn it increases the TG2 activity. Blocking the TRPC6 action or suppressing its expression only partially attenuated FG4592 induced TG2 activity, whereas suppression of ZEB2 expression significantly abolished TG2 activity. This study demonstrates that stabilization of HIF1α stimulates both TG2 expression and activity, whereas abrogation of HIF1α by metformin prevented HIF1α regulated TG2 and consequent glomerular injury.
GiPS: Genomics-informed parent selection uncovers the breeding value of wheat genetic resources
Authors: Schulthess Albert W. , Kale Sandip M. , Liu Fang , Zhao Yusheng , Philipp Norman , Rembe Maximilian , Jiang Yong , Beukert Ulrike , Serfling Albrecht , Himmelbach Axel , Fuchs Jörg , Oppermann Markus , Weise Stephan , Boeven Philipp H. G. , Schacht Johannes , Longin C. Friedrich H. , Kollers Sonja , Pfeiffer Nina , Korzun Viktor , Lange Matthias , Scholz Uwe , Stein Nils , Mascher Martin , Reif Jochen C.
Published: December 2021

The great efforts spent in the maintenance of past diversity in genebanks are rationalized by the potential role of plant genetic resources in future crop improvement – a concept whose practical implementation has fallen short of expectations. Here, we implement genomics-informed parent selection to expedite pre-breeding without discriminating against non-adapted germplasm. We collect dense genetic profiles for a large winter wheat collection and evaluate grain yield and resistance to yellow rust in representative coresets. Genomic prediction within and across genebanks identified the best parents for PGR x elite derived crosses that outyielded current elite cultivars in multiple field trials.
Metabolic alterations in a Drosophila model of Parkinson’s disease based on DJ-1 deficiency
Authors: Solana-Manrique Cristina , Sanz Francisco José , Torregrosa Isabel , Palomino-Schätzlein Martina , Hernández-Oliver Carolina , Pineda Antonio , Paricio Nuria
Published: December 2021

Parkinson’s disease (PD) is the second most common neurodegenerative disorder whose physiopathology is still unclear. Besides, it is urgent to discover new biomarkers and therapeutic targets to facilitate its diagnosis and treatment. Previous studies performed in PD models and samples from PD patients already demonstrated that metabolic alterations were associated with this disease. In this context, the aim of this study is to give a better understanding of metabolic disturbances underlying PD pathogenesis. To achieve this goal, we used a Drosophila PD model based on inactivation of the DJ-1β gene (ortholog of human DJ-1). Metabolomic analyses were performed in 1-day-old and 15-day-old DJ-1β mutants and control flies using 1H nuclear magnetic resonance spectroscopy, combined with expression and enzymatic activity assays of proteins implicated in altered pathways. Our results showed that PD model flies exhibit protein metabolism alterations, a shift from tricarboxylic acid cycle to glycolytic pathway to obtain ATP, together with an increase in the expression of some urea cycle enzymes. Thus, these metabolic changes could be contributing to PD pathogenesis and might constitute possible therapeutic targets and/or biomarkers for this disease.
Regulation of effector gene expression as concerted waves inLeptosphaeria maculans: a two-players game
Authors: Clairet C. , Gay E.J. , Porquier A. , Blaise F. , Marais C.L. , Balesdent M.-H. , Rouxel T. , Soyer J.L. , Fudal I.
Published: December 2021

During infection, plant pathogenic fungi secrete a set of molecules collectively known as effectors, involved in overcoming the host immune system and in disease establishment. Effector genes are concertedly expressed as waves all along plant pathogenic fungi lifecycle. However, little is known about how coordinated expression of effector genes is regulated. Since many effector genes are located in repeat-rich regions, the role of chromatin remodeling in the regulation of effector expression was recently investigated. InLeptosphaeria maculans, causing stem canker of oilseed rape, we established that the repressive histone modification H3K9me3 (trimethylation of Lysine 9 of Histone H3), deposited by the histone methyltransferase KMT1, was involved in the regulation of expression of genes highly expressed during infection, including effectors. Nevertheless, inactivation ofKMT1did not induce expression of these genes at the same level as observed during infection of oilseed rape, suggesting that a second regulator, such as a transcription factor (TF), might be involved. Pf2, a TF belonging to the Zn2Cys6 fungal specific TF family, was described in several Dothideomycete species as essential for pathogenicity and effector gene expression. We identified the orthologue of Pf2 inL. maculans, LmPf2, and investigated the role of LmPf2 together with KMT1, by inactivating and over-expressingLmPf2in a wild type (WT) strain and aΔkmt1mutant. Functional analyses of the corresponding transformants highlighted an essential role of LmPf2 in the establishment of pathogenesis. Transcriptomic analyses during axenic growth showed that LmPf2 is involved in the control of effector gene expression. We observed an enhanced effect of the over-expression ofLmPf2on effector gene expression in aΔkmt1background, suggesting an antagonist role between KMT1 and LmPf2.
Insulin exposed endometrial epithelial cells cultured in a microfluidic device alters transcripts involved in translation that may contribute to reduced implantation capacity of the endometrium
Authors: Baik Soo Young , Tinning Haidee , Wang Dapeng , Forde Niamh
Published: December 2021

Obesity is a rapidly growing public health issue among women of reproductive age. It is also associated with decreased reproductive function including implantation failure. Implantation failure can result from a myriad of factors including impaired gametes and endometrial dysfunction. The mechanisms of how obesity-related hyperinsulinaemia disrupts endometrial function and implantation are poorly understood. Our study aims to investigate potential mechanisms by which insulin alters endometrial transcript expression, which may affect endometrial receptivity. Ishikawa cells mimicking human endometrial epithelium were seeded into a microfluidics organ-on-chip device to produce anin vitroendometrium. Syringe pump was attached to the microfluidics device to deliver three varying treatments into Ishikawa cells: 1) media control 2) vehicle control (PBS acidified to pH3 with acetic acid) 3) Insulin (2mg/mL) at a constant flow rate of 1uL/min for 24 hours to mimic secretionin vivo. Three biological replicates were obtained. Insulin-induced transcriptomic response of thein vitroendometrium was quantified via RNA sequencing, and subsequently analysed using DAVID and Webgestalt to identify Gene Ontology (GO) terms and signalling pathways. A Total of 29 transcripts showed differential expression levels across two comparison groups (control v vehicle control; vehicle control v insulin). There were nine transcripts significantly differentially expressed in vehicle control v insulin group (p<0.05). Functional annotation analysis of transcripts altered by insulin (n=9) identified three significantly enriched GO terms: SRP-dependent cotranslational protein targeting to membrane, poly(A) binding, and RNA binding (p<0.05). Over-representation analysis found three significantly enriched signalling pathways relating to insulin-induced transcriptomic response: protein export, glutathione metabolism, and ribosome pathways (p<0.05). Insulin-induced dysregulation of biological functions and pathways highlight potential mechanisms by which high insulin concentrations within maternal circulation may perturb endometrial receptivity.
Detecting and quantifying clonal selection in somatic stem cells
Authors: Körber Verena , Ansari-Pour Naser , Jakobsen Niels Asger , Moore Rachel , Claudino Nina , Metzner Marlen , Hörsch Franziska , Usukhbayar Batchimeg , Salazar Mirian Angulo , Newman Simon , Kendrick Benjamin JL , Taylor Adrian H , Afinowi-Luitz Rasheed , Gundle Roger , Watkins Bridget , Wheway Kim , Beazley Debra , Dakin Stephanie G , Carr Andrew J , Vyas Paresh , Höfer Thomas
Published: December 2021

As DNA variants accumulate in somatic stem cells, become selected or evolve neutrally, they may ultimately alter tissue function. When, and how, selection occurs in homeostatic tissues is incompletely understood. Here, we introduce SCIFER, a scalable method that identifies selection in an individual tissue, without requiring knowledge of the underlying driver event. Moreover, SCIFER infers the self-renewal and mutation dynamics of the tissue’s stem cells, and, if selection is present, the size and growth rate of the largest selected clone. We benchmark SCIFER with published data and then probe bone marrow of 22 non-leukemic individuals for clonal hematopoiesis (CH), identifying CH with known and unknown driver events. Unexpectedly, we find accelerated division of all stem cells in CH, compared to age-matched non-CH individuals, suggesting that the bone marrow environment alters stem cell dynamics in individuals with CH. SCIFER is broadly applicable to renewing somatic tissues to detect and quantify selection.
Non-invasive Chromatin Deformation and Measurement of Differential Mechanical Properties in the Nucleus
Authors: Seelbinder B. , Jain M. , Erben E. , Klykov S. , Stoev I. D. , Kreysing M.
Published: December 2021

The nucleus is highly organized to facilitate coordinated gene transcription. Measuring the rheological properties of the nucleus and its sub-compartments will be crucial to understand the principles underlying nuclear organization. Here, we show that strongly localized temperature gradients (approaching 1°C /μm) can lead to substantial intra-nuclear chromatin displacements (>1 μm), while nuclear area and lamina shape remain unaffected. Using particle image velocimetry (PIV), intra-nuclear displacement fields can be calculated and converted into spatio-temporally resolved maps of various strain components. Using this approach, we show that chromatin displacements are highly reversible, indicating that elastic contributions are dominant in maintaining nuclear organization on the time scale of seconds. In genetically inverted nuclei, centrally compacted heterochromatin displays high resistance to deformation, giving a rigid, solid-like appearance. Correlating spatially resolved strain maps with fluorescent reporters in conventional interphase nuclei reveals that various nuclear compartments possess distinct mechanical identities. Surprisingly, both densely and loosely packed chromatin showed high resistance to deformation, compared to medium dense chromatin. Equally, nucleoli display particularly high rigidity and strong local anchoring to heterochromatin. Our results establish how localized temperature gradients can be used to drive nuclear compartments out of mechanical equilibrium to obtain spatial maps of their material responses.

Main Findings

Novel non-invasive active micro-rheology method to probe spatial intranuclear material responses, unhindered by the nuclear lamina, using strongly localized temperature gradients

Chromatin shows both elastic and viscous properties at the mesoscale with a retardation time of τ ∼ 1s

Compacted heterochromatin in a model of nuclear inversion shows high resistance to deformation, suggesting dominantly solid-like behavior

The nucleus displays spatially distinct material properties for different compartments

The nucleolus shows high resistance to deformation on the time scale of seconds

Immobile nucleoli appear solidly anchored to and retain the deformation of surrounding chromatin
Soluble MAC is primarily released from MAC-resistant bacteria that potently convert complement component C5
Authors: Doorduijn Dennis J. , Lukassen Marie V. , van ’t Wout Marije F.L. , Franc Vojtech , Ruyken Maartje , Bardoel Bart W. , Heck Albert J.R. , Rooijakkers Suzan H. M.
Published: December 2021

The Membrane Attack Complex (MAC or C5b-9) is an important effector of the immune system to kill invading microbes. MAC is formed when complement enzymes on the bacterial surface convert complement component C5 into C5b. Although the MAC is a membrane-inserted complex, soluble forms of MAC (sMAC, or terminal complement complex (TCC)) are often detected in sera of patients suffering from infections. Consequently, sMAC has been proposed as a biomarker, but it remains unclear when and how it is formed during infections. Here, we studied mechanisms of MAC formation on bacteria and found that sMAC is primarily formed in human serum by bacteria resistant to MAC-dependent killing. Surprisingly, C5 was converted into C5b more potently by MAC-resistant compared to MAC-sensitiveEscherichia colistrains. Both the increase in C5 conversion and sMAC generation were linked to the expression of lipopolysaccharide (LPS) O-Antigen in the bacterial outer membrane. In addition, we found that MAC precursors are released from the surface of MAC-resistant bacteria during MAC assembly. Release of MAC precursors from bacteria induced lysis of bystander human erythrocytes in the absence of other serum components. However, serum regulators vitronectin (Vn) and clusterin (Clu) can prevent this bystander lysis. Combining size exclusion chromatography with mass spectrometry profiling, we show that sMAC released from bacteria in serum is a heterogeneous mixture of complexes composed of C5b-8, up to 3 copies of C9 and multiple copies of Vn and Clu. Altogether, our data provide molecular insight into how sMAC is generated during bacterial infections. This fundamental knowledge could form the basis for exploring the use of sMAC as biomarker.
Comprehensive Benchmarking of CITE-seq versus DOGMA-seq Single Cell Multimodal Omics
Authors: Xu Zhongli , Heidrich-O’Hare Elisa , Chen Wei , Duerr Richard H.
Published: December 2021

The recently developed transcription, epitopes, and chromatin accessibility by sequencing (TEA-seq) and similar DOGMA-seq single-cell trimodal omics assays provide unprecedented opportunities for understanding cell biology, but independent optimization, benchmarking and evaluation are lacking. We explored the utility, pros and cons of DOGMA-seq compared to the bimodal cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) assay in activated and stimulated human peripheral blood T cells. We identified an optimal incubation time and concentration of digitonin (DIG) for cell permeabilization and found that single-cell trimodal omics measurements after DIG permeabilization were generally better than after an alternative “low-loss lysis” (LLL) permeabilization condition. Next, we found that DOGMA-seq with optimized DIG permeabilization and its ATAC library provides more information, even though its mRNA and cell surface protein antibody-derived tag (ADT) libraries have slightly inferior quality, compared to CITE-seq. Finally, we recognized the additional value of DOGMA-seq for studying lineage-specific T helper cells.