bluuebunny/crossref_metadata_2025 huggingface dataset:
Helicobacter turcicus sp. nov., a catalase-negative new member of the Helicobacter genus, isolated from Anatolian Ground Squirrel (Spermophilus xanthoprymnus) in Turkey
Authors: Aydin Fuat , Karakaya Emre , Kayman Tuba , Abay Secil , Saticioglu Izzet Burcin
Published: May 2022

Eleven Gram-negative, curved and S-shaped, oxidase activity positive, catalase activity negative bacterial isolates recovered from faeces of Anatolian ground squirrel (Spermophilus xanthoprymnus) in the city of Kayseri, Turkey, were subjected to a polyphasic taxonomic study. Results of a genus-specific PCR revealed that these isolates belonged to the genus

Helicobacter

. The 16S rRNA gene sequence analysis revealed that the 11 isolates had over 99 % sequence identity with each other and were most closely related to

Helicobacter ganmani

CMRI H02T with 97.0–97.1 % identity levels and they formed a novel phylogenetic line within the genus

Helicobacter

. Faydin-H64 and Faydin-H70T strains were subjected to gyrA and atpA gene and whole genome sequence analyses. These two

Helicobacter

strains formed separate phylogenetic clades, divergent from other known

Helicobacter

species. The DNA G+C content and genome size of the strain Faydin-H70T were 35.3 mol% and 1.7 Mb, respectively. Average nucleotide identity (ANI) and digital DNA–DNA hybridization (dDDH) values between strain Faydin-H70T and its close phylogenetic neighbour H. winghamensis ATCC BAA-430T were determined as 81.7 and 34.9 %, respectively. Pairwise sequence comparison showed that it was closely related to

H. ganmani

CMRI H02T however it shared the highest ANI and dDDH values with H. winghamensis ATCC BAA-430T. The data obtained from the polyphasic taxonomy approach, including phenotypic characterization and whole-genome sequences, revealed that these strains represent a novel species within the genus

Helicobacter

, for which the name Helicobacter turcicus sp. nov., is proposed with Faydin-H70T as the type strain (=DSM 112556T=LMG 32335T).
Marinifilum caeruleilacunae sp. nov., isolated from Yongle Blue Hole in the South China Sea
Authors: Dai Wei , Sun Wen , Fu Tianyu , Jia Chao , Cui Hongchang , Han Yanqiong , Shi Xiaochong , Zhang Xiao-Hua
Published: May 2022

A Gram-stain-negative, non-motile, facultatively anaerobic and non-flagellated marine bacterium, designated JC070T was isolated from the Yongle Blue Hole in the South China Sea. The temperature, pH and NaCl ranges for growth of strain JC070T were 4–37 °C (optimum, 16 °C), pH 6.0–9.0 (optimum, pH 7.0) and 1.0 –6.0% (w/v; optimum, 3.0%). The predominant isoprenoid quinone of strain JC070T was identified as menaquinone-7. The dominant fatty acids (>10%) were iso-C15:0 (59.6%) and iso-C17:0 3-OH (17.2%). The major polar lipids were aminophospholipid, aminolipid, two unknown phospholipids and two unidentified lipids. The genomic DNA G+C content was determined to be 37.0 mol%. Based on the results of polyphasic analysis, a new species, named Marinifilum caeruleilacunae sp. nov., within the genus

Marinifilum

was proposed. The type strain is JC070T (= JCM 39045T=MCCC 1K03774T).
Serum and cerebrospinal fluid phosphorylated neurofilament heavy subunit as a marker of neuroaxonal damage in tick-borne encephalitis
Authors: Fortova Andrea , Hönig Vaclav , Palus Martin , Salat Jiri , Pychova Martina , Krbkova Lenka , Vyhlidalova Tereza , Kriha Michal F. , Chrdle Ales , Ruzek Daniel
Published: May 2022

Extensive axonal and neuronal loss is the main cause of severe manifestations and poor outcomes in tick-borne encephalitis (TBE). Phosphorylated neurofilament heavy subunit (pNF-H) is an essential component of axons, and its detection in cerebrospinal fluid (CSF) or serum can indicate the degree of neuroaxonal damage. We examined the use of pNF-H as a biomarker of neuroaxonal injury in TBE. In 89 patients with acute TBE, we measured CSF levels of pNF-H and 3 other markers of brain injury (glial fibrillary acidic protein, S100B and ubiquitin C-terminal hydrolase L1) and compared the results to those for patients with meningitis of other aetiology and controls. Serum pNF-H levels were measured in 80 patients and compared with findings for 90 healthy blood donors. TBE patients had significantly (P<0.001) higher CSF pNF-H levels than controls as early as hospital admission. Serum pNF-H concentrations were significantly higher in samples from TBE patients collected at hospital discharge (P<0.0001) than in controls. TBE patients with the highest peak values of serum pNF-H, exceeding 10 000 pg ml−1, had a very severe disease course, with coma or tetraplegia. Patients requiring intensive care had significantly higher serum pNF-H levels than other TBE patients (P<0.01). Elevated serum pNF-H values were also observed in patients with incomplete recovery (P<0.05). Peak serum pNF-H levels correlated positively with the duration of hospitalization (P=0.005). Measurement of pNF-H levels in TBE patients might be useful for assessing disease severity and determining prognosis.
Monthly excess mortality across counties in the United States during the Covid-19 pandemic, March 2020 to February 2022
Authors: Paglino Eugenio , Lundberg Dielle J. , Zhou Zhenwei , Wasserman Joe A. , Raquib Rafeya , Luck Anneliese N. , Hempstead Katherine , Bor Jacob , Preston Samuel H. , Elo Irma T. , Stokes Andrew C.
Published: May 2022

Excess mortality is the difference between expected and observed mortality in a given period and has emerged as a leading measure of the overall impact of the Covid-19 pandemic that is not biased by differences in testing or cause-of-death assignment. Spatially and temporally granular estimates of excess mortality are needed to understand which areas have been most impacted by the pandemic, evaluate exacerbating and mitigating factors, and inform response efforts, including allocating resources to affected communities. We estimated all-cause excess mortality for the United States from March 2020 through February 2022 by county and month using a Bayesian hierarchical model trained on data from 2015 to 2019. An estimated 1,159,580 excess deaths occurred during the first two years of the pandemic (first: 620,872; second: 538,708). Overall, excess mortality decreased in large metropolitan counties, but increased in nonmetro counties, between the first and second years of the pandemic. Despite the initial concentration of mortality in large metropolitan Northeast counties, beginning in February 2021, nonmetro South counties had the highest cumulative relative excess mortality. These results highlight the need for investments in rural health as the pandemic’s disproportionate impact on rural areas continues to grow.
Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology
Authors: Bhatia Himanshi , Larsson Alex T. , Calizo Ana , Pollard Kai , Zhang Xiaochun , Conniff Eric , Tibbitts Justin F. , Osum Sara H. , Williams Kyle B. , Crampton Ali L. , Jubenville Tyler , Schefer Daniel , Yang Kuangying , Lyu Yang , Bade Jessica , Pino James C. , Gosline Sara J.C. , Pratilas Christine A. , Largaespada David A. , Wood David K. , Hirbe Angela C.
Published: May 2022

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1-MPNST), but can occur sporadically. Through a multi-institution collaboration, we have developed 13 NF1-associated MPNST patient-derived xenografts (PDX). Genomic analysis of the PDX-tumor pairs identified somatic mutations in NF1 (61%), SUZ12 (61%), EED (15%), and TP53 (15%), and chromosome 8 (Chr8) gain (77%), consistent with published data. Pre-clinical models that capture this molecular heterogeneity are needed to identify and prioritize effective drug candidates for clinical translation. Here, we describe the successful development of a medium-throughput ex vivo 3D microtissue model with several advantages over 2D cell line growth, which can be utilized to predict drug response in vivo. Herein, we present proof-of-principle of this PDX-to-microtissue system, using four genomically representative MPNST and three drugs. This work highlights the development of a novel ex vivo to in vivo preclinical platform in MPNST that successfully captures the genomic diversity observed in patients and represents a resource to identify future therapeutic strategies.
Mortality during inpatient admissions for Takotsubo cardiomyopathy: can mortality be predicted with a scoring system?
Authors: Loomba Rohit S.
Published: May 2022

Introduction

This study aims to identify which comorbidities and demographic characteristics increase the inpatient mortality rate of patients with TCM and to establish a simple scoring system to help identify those at high risk for mortality.

Methods

A retrospective cross-sectional study using the Nationwide Inpatient Sample was conducted. Admissions with and without inpatient mortality were then compared. Univariate analyses were conducted to compare admission characteristics with and without inpatient mortality. A logistic regression analysis was conducted with inpatient mortality as the dependent variability and various admission characteristics as the independent variables in order to develop a model to predict inpatient mortality. The model was then used to calculate a score, the TCM mortality score, for each admission. A receiver operator curve analysis was conducted to determine the sensitivity, specificity, negative predictive value, and positive predictive value of the TCM mortality score in prediction of inpatient mortality.

Results

A total of 19,454 admissions were included in the final analyses. Inpatient mortality was greater in patients that were older, males, Hispanics or Asian Pacific Islanders, and those with Medicare/Medicaid. In regards to comorbidities, inpatient mortality was greater in those with heart failure, arrhythmia, and acute kidney injury. Those with mortality were also more likely to have had an intra-aortic balloon pump or having had to be placed on extracorporeal membrane oxygenation. A mortality score was found to be 4.4 in the mortality group as compared to 1.6 for those in the non-mortality group.

Conclusion

Inpatient mortality with Takotsubo cardiomyopathy is approximately 4.0% and those presenting with certain demographic characteristics and comorbidities are at an increased risk for mortality. A simple scoring system can help identify those at high risk for mortality.
PathGPS: Discover shared genetic architecture using biobank data
Authors: Gao Zijun , Hastie Trevor , Zhao Qingyuan
Published: May 2022

The increasing availability and scale of Genome Wide Association Studies (GWAS) bring new horizons for understanding biological mechanisms. PathGPS is an exploratory method that discovers genetic architecture using GWAS summary data. It can separate genetic components from unobserved environmental factors and extract clusters of genes and traits associated with the same biological pathways. When applying to a metabolomics dataset and the UK Biobank, PathGPS confirms several known gene-trait clusters and suggest many new hypotheses for future investigations.
SARS-CoV-2 outbreaks in secondary school settings in the Netherlands during fall 2020; silent circulation
Authors: Jonker Lotte , Linde Kimberly J , de Hoog Marieke LA , Sprado Robin , Huisman Robin C , Molenkamp Richard , Oude Munnink Bas B , Dohmen Wietske , Heederik Dick JJ , Eggink Dirk , Welkers Matthijs RA , Vennema Harry , Fraaij Pieter LA , Koopmans Marion PG , Wouters Inge M , Bruijning-Verhagen Patricia CJL
Published: May 2022

Background

In fall 2020 when schools in the Netherlands operated under a limited set of COVID-19 measures, we conducted outbreaks studies in four secondary schools to gain insight in the level of school transmission and the role of SARS-CoV-2 transmission via air and surfaces.

Methods

Outbreak studies were performed between 11 November and 15 December 2020 when the wild-type variant of SARS-CoV-2 was dominant. Clusters of SARS-CoV-2 infections within schools were identified through a prospective school surveillance study. All school contacts of cluster cases, irrespective of symptoms, were invited for PCR testing twice within 48 hrs and 4-7 days later. Combined NTS and saliva samples were collected at each time point along with data on recent exposure and symptoms. Surface and active air samples were collected in the school environment. All samples were PCR-tested and sequenced when possible.

Results

Out of 263 sampled school contacts, 24 tested SARS-CoV-2 positive (secondary attack rate 9.1%), of which 62% remained asymptomatic and 42% had a weakly positive test result. Phylogenetic analysis on 12 subjects from 2 schools indicated a cluster of 8 and 2 secondary cases, respectively, but also other distinct strains within outbreaks. Of 51 collected air and 53 surface samples, none were SARS-CoV-2 positive.

Conclusion

Our study confirmed within school SARS-CoV-2 transmission and substantial silent circulation, but also multiple introductions in some cases. Absence of air or surface contamination suggests environmental contamination is not widespread during school outbreaks.
H3AGWAS : A portable workflow for Genome Wide Association Studies
Authors: Brandenburg Jean-Tristan , Clark Lindsay , Botha Gerrit , Panji Sumir , Baichoo Shakuntala , Fields Christopher , Hazelhurst Scott
Published: May 2022

Background

Genome-wide association studies (GWAS) are a powerful method to detect associations between variants and phenotypes. A GWAS requires several complex computations with large data sets, and many steps may need to be repeated with varying parameters. Manual running of these analyses can be tedious, error-prone and hard to reproduce.

Results

The H3AGWAS workflow from the Pan-African Bioinformatics Network for H3Africa is a powerful, scalable and portable workflow implementing pre-association analysis, implementation of various association testing methods and postassociation analysis of results.

Conclusions

The workflow is scalable — laptop to cluster to cloud (e.g., SLURM, AWS Batch, Azure). All required software is containerised and can run under Docker on Singularity.
GraphPred: An approach to predict multiple DNA motifs from ATAC-seq data using graph neural network and coexisting probability
Authors: Zhang Shuangquan , Yang Lili , Wu Xiaotian , Sheng Nan , Fu Yuan , Ma Anjun , Wang Yan
Published: May 2022

Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) utilizes hyperactive Tn5 transposase to cut open chromatin and reveal chromatin accessibility at a genome-wide level. ATAC-seq can reveal more kinds of transcription factor binding regions than Chromatin immunoprecipitation sequencing (ChIP-seq) and DNase I hypersensitive sites sequencing (DNase-seq). Transcription factor binding sites (TFBSs) prediction is a crucial step to reveal the functions of TFs from the high throughput sequencing data. TFBSs of the same TF tend to be conserved in the sequence level, which is named motif. Several deep learning models based on the convolutional neural networks are used to find motifs from ATAC-seq data. However, these methods didn’t take into account that multiple TFs bind to a given sequence and the probability that a fragment of a given sequence is a TFBS. To find binding sites of multiple TFs, we developed a novel GNN model named GraphPred for TFBSs prediction and finding multiple motifs using the coexisting probability of k-mers. In the light of the experiment results, GraphPred can find more and higher quality motifs from 88 ATAC-seq datasets than comparison tools. Meanwhile, GraphPred achieved an area of eight metrics radar (AEMR) score of 2.31.
Taxonbridge: an R package to create custom taxonomies based on the NCBI and GBIF taxonomies
Authors: Veldsman Werner P. , Campli Giulia , Dind Sagane , de Laval Valentine Rech , Drage Harriet B. , Waterhouse Robert M. , Robinson-Rechavi Marc
Published: May 2022

Biological taxonomies establish conventions by which researchers can catalogue and systematically compare their work using nomenclature such as species binomial names and reference identifiers. The ideal taxonomy is unambiguous and exhaustive; however, no such single taxonomy exists, partly due to continuous changes and contributions made to existing taxonomies. The degree to which a taxonomy is useful furthermore depends on context provided by such variables as the taxonomic neighbourhood of a species (e.g., selecting arthropod or vertebrate species) or the geological time frame of the study (e.g., selecting extinct versus extant species). Collating the most relevant taxonomic information from multiple taxonomies is hampered by arbitrarily defined identifiers, ambiguity in scientific names, as well as duplicated and erroneous entries. The goal of taxonbridge is to provide tools for merging the Global Biodiversity Information Facility (GBIF) Backbone Taxonomy and the United States National Center for Biotechnology Information (NCBI) Taxonomy in order to create consistent, deduplicated and disambiguated custom taxonomies that reference both extant and extinct species.

Availability

Taxonbridge is available as a package in the Comprehensive R Archive Network (CRAN) repository: https://CRAN.R-project.org/package=taxonbridge.

Contact

wernerpieter.veldsman@unil.ch
Robust associations between white matter microstructure and general intelligence
Authors: Stammen Christina , Fraenz Christoph , Grazioplene Rachael G. , Schlüter Caroline , Merhof Viola , Johnson Wendy , Güntürkün Onur , DeYoung Colin G. , Genç Erhan
Published: May 2022

Early research on the neural correlates of human intelligence was almost exclusively focused on gray matter properties. The advent of diffusion-weighted imaging led to an exponential growth of white matter brain imaging studies. However, this line of research has yielded mixed observations, especially about the relations between general intelligence and white matter microstructure. We used a multi-center approach to identify white matter regions that show replicable structure-function associations, employing data from four independent samples comprising over 2000 healthy participants. We used tract-based spatial statistics to examine associations between g factor scores and white matter microstructure and identified 188 voxels which exhibited positive associations between g factor scores and fractional anisotropy in all four data sets. Replicable voxels formed three clusters: one located around the forceps minor, crossing with extensions of the anterior thalamic radiation, the cingulum-cingulate gyrus, and the inferior fronto-occipital fasciculus in the left hemisphere, one located around the left-hemispheric superior longitudinal fasciculus, and one located around the left-hemispheric cingulum-cingulate gyrus, crossing with extensions of the anterior thalamic radiation and the inferior fronto-occipital fasciculus. Our results indicate that individual differences in general intelligence are robustly associated with white matter organization in specific fiber bundles.
Abrupt transitions and its indicators in mutualistic meta-networks: effects of network topology, size of metacommunities and species dispersal
Authors: Baruah Gaurav
Published: May 2022

Gradual changes in the environment could cause dynamical ecological networks to abruptly shift from one state to an alternative state. When this happens ecosystem functions and services provided by ecological networks get disrupted. We, however, know very little about how the topology of such interaction networks can play a role in the transition of ecological networks at spatial scales. In the event of such unwanted transitions, little is known about how statistical metrics used to inform such impending transitions, measured at the species-level or at the community-level could relate to network architecture and the scale of spatial interactions such as the size of the metacommunity. Here, using hundred and one empirical plant-pollinator networks in a spatial setting, I evaluated the impact of network topology and spatial scale of species interactions on abrupt transitions, and on statistical metrics used as predictors to forecast such abrupt transitions. Using generalized Lotka-Volterra equations in a meta-network framework, I show that species dispersal rate and the size of the metacommunity can impact when an abrupt transition can occur. In addition, forecasting such unwanted abrupt transitions of meta-networks using statistical metrics of instability was also consequently dependent on the topology of the network, species dispersal rate, and the size of the metacommunity. The results indicated that the plant-pollinator meta-networks that could exhibit stronger statistical signals before collapse than others were dependent on their network architecture and on the spatial scale of species interactions.
Gestational day 12 moderate prenatal alcohol exposure produces sex-specific social impairments and attenuates prelimbic excitability and amygdala-cortex modulation of adult social behavior
Authors: Przybysz Kathryn R. , Spodnick Mary B. , Johnson Julia M. , Varlinskaya Elena I. , Diaz Marvin R.
Published: May 2022

Lifelong social impairments are common in individuals with prenatal alcohol exposure (PAE), and preclinical studies have identified gestational day (G)12 as a vulnerable timepoint for producing social deficits following binge-level PAE. While moderate (m)PAE also produces social impairments, the long-term neuroadaptations underlying them are poorly understood. Activity of the projection from the basolateral amygdala to the prelimbic cortex (BLA→PL) leads to social avoidance, and the PL alone is implicated in negative social behaviors, making each of these potential candidates for the neuroadaptations underlying mPAE-induced social impairments. To examine this, we first established that G12 mPAE produced sex-specific social impairments lasting into adulthood. We then chemogenetically inhibited the BLA→PL using Clozapine N-Oxide (CNO) during adult social testing. This revealed that CNO reduced social investigation in control males, but had no effect on mPAE males or females of either exposure, indicating that mPAE attenuated the role of this projection in regulating male social behavior and highlighting one potential mechanism by which mPAE affects male social behavior more severely. Using whole-cell electrophysiology, we also examined mPAE-induced changes to PL pyramidal cell physiology and determined that mPAE reduced the excitability of these cells, likely due to increased suppression by inhibitory interneurons. Overall, this work identified two mPAE-induced neuroadaptations that last into adulthood and which may underlie the sexspecific vulnerability to mPAE-induced social impairments. Future research is necessary to expand upon how these circuits modulate both normal and pathological social behavior, and to identify sex-specific mechanisms leading to differential vulnerability in males and females.
The role of geology in creating stream climate-change refugia along climate gradients
Authors: Ishiyama Nobuo , Sueyoshi Masanao , Jorge García Molinos , Iwasaki Kenta , Negishi N Junjiro , Koizumi Itsuro , Nagayama Shigeya , Nagasaka Akiko , Nagasaka Yu , Nakamura Futoshi
Published: May 2022

Identifying climate-change refugia is a key adaptation strategy for reducing global warming impacts. Knowledge of the effects of underlying geology on thermal regime along climate gradients and the ecological responses to the geology-controlled thermal regime is essential to plan appropriate climate adaptation strategies. The dominance of volcanic rocks in the watershed is used as a landscape-scale surrogate for cold groundwater inputs to clarify the importance of underlying geology. Using statistical models, we explored the relationship between watershed geology and the mean summer water temperature of mountain streams along climate gradients in the Japanese archipelago. Summer water temperature was explained by the interaction between the watershed geology and climate in addition to independent effects. The cooling effect associated with volcanic rocks was more pronounced in streams with less summer precipitation or lower air temperatures. We also examined the function of volcanic streams as cold refugia under contemporary and future climatic conditions. Community composition analyses revealed that volcanic streams hosted distinct stream communities composed of more cold-water species compared with non-volcanic streams. Scenario analyses revealed a geology-related pattern of thermal habitat loss for cold-water species. Non-volcanic streams rapidly declined in thermally suitable habitats for lotic sculpins even under the lowest emission scenario (RCP 2.6). In contrast, most volcanic streams will be sustained below the thermal threshold, especially for low and mid-level emission scenarios (RCP 2.6, 4.5). However, the distinct stream community in volcanic streams and geology-dependent habitat loss for lotic sculpins was not uniform and was more pronounced in areas with less summer precipitation or lower air temperatures. Although further studies are needed to understand underlying mechanisms of the interplay of watershed geology and climate, findings highlight that watershed geology, climate variability, and their interaction should be considered simultaneously for effective management of climate-change refugia in mountain streams.
ISG15 Monomer Promotes IFNα-mediated Antiviral Activity against Pseudorabies Virus by Facilitating phosphorylation of STAT1/STAT2
Authors: Liu Huimin , Li Chen , He Wenfeng , Chen Jing , Yang Guoqing , Chen Lu , Chang Hongtao
Published: May 2022

Pseudorabies virus (PRV), which presently lacks both an antiviral drug and a viable therapeutic option, is a major viral pathogen that poses a danger to the pig industry worldwide. Interferon-stimulated gene 15 (ISG15) is strongly upregulated during viral infections and has been reported to have proviral or antiviral properties, depending on the virus and host species. Our previous studies demonstrated ISG15 was remarkably upregulated during PRV infection, and the overexpression of ISG15 inhibited PRV replication. Nevertheless, the exact mechanism through which ISG15 influences PRV replication poorly understood unclear. Here, we demonstrate that ISG15 accumulation induced by PRV infection requires viral gene expression and viral growth. Conjugation inhibition assays showed that ISG15 imposes its antiviral effects via unconjugated (free) ISG15 and affects the viral release. In addition, we found ISG15 promoted IFNα-mediated antiviral activity against PRV by facilitating the phosphorylation of STAT1 and STAT2, along with an increase of ISGF3-induced ISRE promoter activity. Furthermore, we evaluated the role of ISG15 in host defense to control PRV infection by using ISG15-/- mice model. When challenged with PRV, ISG15-/- mice exhibited increased morbidity and mortality, as well as viral load compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the brains of ISG15-/- mice, along with the upregulation of the cytokines. Our findings establish the importance of ISG15 in IFNα-induced antiviral response and in the control of PRV infection.
Attention Deficit Hyperactivity Disorder Symptoms and Brain Morphology: Examining Confounding Bias
Authors: Dall’Aglio Lorenza , Kim Hannah H. , Lamballais Sander , Labrecque Jeremy , Muetzel Ryan L. , Tiemeier Henning
Published: May 2022

Background

Associations between attention-deficit/hyperactivity disorder (ADHD) and brain morphology have been reported, although with several inconsistencies. These may partly stem from confounding bias, which could distort associations and limit generalizability. We examined how associations between brain morphology and ADHD symptoms change with adjustments for potential confounders typically overlooked in the literature (aim 1), and for IQ, which is typically corrected for but plays an unclear role (aim 2).

Methods

Participants were 10-year-old children from the Adolescent Brain Cognitive Development (N=7,961) and Generation R (N=2,531) studies. Cortical area and volume were measured with MRI and ADHD symptoms with the Child Behavior Checklist. Surface-based cross-sectional analyses were run.

Results

ADHD symptoms related to widespread cortical regions when solely adjusting for demographic factors. Additional adjustments for socioeconomic and maternal behavioral confounders (aim 1) generally attenuated associations, as cluster sizes halved and effect sizes substantially reduced. Cluster sizes were further reduced when including IQ (aim 2), however, we argue that adjustments could have introduced bias (e.g., by conditioning on a collider).

Conclusions

Careful confounder selection and control can help identify more robust and specific regions of associations for ADHD symptoms, across two cohorts. We provided guidance to minimizing confounding bias in psychiatric neuroimaging.

Funding

Authors are supported by an NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200 to HT) for HT, LDA, SL, and the Sophia Foundation S18-20, and Erasmus University and Erasmus MC Fellowship for RLM.
Label-free imaging of large samples: 3D rendering and morphological analysis within histological workflows using serial block face imaging
Authors: Malloci Marine , de Villemagne Perrine , Dorval Paul , Feyeux Magalie , Blandin Stéphanie , Schmid Guillaume , Hulin Philippe , Gilloteaux Perrine Paul
Published: May 2022

Serial block face imaging (SFBI) is a method used to generate 3-dimensional (3D) reconstruction of a sample via serial image acquisition. Several SBFI approaches have been proposed for large samples, differing in the ability to generate contrast as well as in the nature of the detected signal. We propose a new system that detects the endogenous autofluorescence signal of paraffin-embedded samples. The sample preparation is simplified compared to other approaches, and adapted to be integrated into a routine histological preparation. More specifically, it was designed to limit reagent toxicity and to be compatible with downstream histological processing. We show the usefulness of the technique with a wide range of tissues based on the intrinsic autofluorescence signal. Optimization of quality section recovery offers the possibility to develop correlative approaches and multimodal analysis between the 3D dataset with the 2-dimensional (2D) sections. In addition, contrast and resolution of block-face images allow us to successfully perform post processing analysis and morphology quantifications. Overall, our methodology offers a simple, cost effective and rapid approach to obtain quantitative data on a large sample with no specific staining.
Extending the Boundaries of Cancer Therapeutic Complexity with Literature Data Mining
Authors: Niezni Danna , Taub-Tabib Hillel , Harris Yuval , Sason-Bauer Hagit , Amrusi Yakir , Azagury Dana , Avrashami Maytal , Launer-Wachs Shaked , Borchardt Jon , Kusold M , Tiktinsky Aryeh , Hope Tom , Goldberg Yoav , Shamay Yosi
Published: May 2022

Drug combination therapy is a main pillar of cancer therapy but the formation of an effective combinatorial standard of care (SOC) can take many years and its length of development is increasing with complexity of treatment. In this paper, we develop a path to extend the boundaries of complexity in combinatorial cancer treatments using text data mining (TDM). We first use TDM to characterize the current boundaries of cancer treatment complexity and find that the current complexity limit for clinical trials is 6 drugs per plan and for pre-clinical research is 10. We then present a TDM based assistive technology, cancer plan builder (CPB), which we make publicly available and allows experts to create literature-anchored high complexity combination treatment (HCCT) plans of significantly larger size. We develop metrics to evaluate HCCT plans and show that experts using CPB are able to create HCCT plans at much greater speed and quality, compared to experts without CPB. We hope that by releasing CPB we enable more researchers to engage with HCCT planning and demonstrate its clinical efficacy.
Probing single cell fermentation flux and intercellular exchange networks via pH-microenvironment sensing and inverse modeling
Authors: Onesto V. , Forciniti S. , Alemanno F. , Narayanankutty K. , Chandra A. , Prasad S. , Azzariti A. , Gigli G. , Barra A. , De Martino A. , De Martino D. , del Mercato L.L.
Published: May 2022

The homeostatic control of their environment is an essential task of living cells. It has been hypothesized that when microenvironmental pH inhomogeneities are induced by high cellular metabolic activity, diffusing protons act as signaling molecules, driving the establishment of cross-feeding networks sustained by the cell-to-cell shuttling of overflow products such as lactate. Despite their fundamental role, the extent and dynamics of such networks is largely unknown due to the lack of methods in single cell flux analysis. In this study we provide direct experimental characterization of such exchange networks. We devise a method to quantify single cell fermentation fluxes over time by integrating high-resolution pH microenvironment sensing via ratiometric nanofibers with constraint-based inverse modeling. We apply our method to cell cultures with mixed populations of cancer cells and fibroblasts. We find that the proton trafficking underlying bulk acidification is strongly heterogeneous, with maximal single cell fluxes exceeding typical values by up to 3 orders of magnitude. In addition, a crossover in time from a networked phase sustained by densely connected “hubs” (corresponding to cells with high activity) to a sparse phase dominated by isolated dipolar motifs (i.e. by pair-wise cell-to-cell exchanges) is uncovered, which parallels the time course of bulk acidification. Our method promises to shed light on issues ranging from the homeostatic function of proton exchange to the metabolic coupling of cells with different energetic demands, and paves the way for real-time non-invasive single cell metabolic flux analysis.
Nuclear receptor ligand screening in an iPSC-derived in vitro blood-brain barrier model identifies new contributors to leptin transport
Authors: Shi Yajuan , Kim Hyosung , Hamann Catherine A. , Rhea Elizabeth M. , Brunger Jonathan M. , Lippmann Ethan S.
Published: May 2022

Background

The peptide hormone leptin exerts its function in the brain to reduce food intake and increase energy expenditure to prevent obesity. However, most obese subjects reflect the resistance to leptin even with elevated serum leptin. Considering that leptin must cross the blood-brain barrier (BBB) in several regions to enter the brain parenchyma, altered leptin transport through the BBB might play an important role in leptin resistance and other biological conditions. Here, we report the use of a human induced pluripotent stem cell (iPSC)-derived BBB model to explore mechanisms that influence leptin transport.

Methods

iPSCs were differentiated into brain microvascular endothelial cell (BMEC)-like cells using standard methods. BMEC-like cells were cultured in Transwell filters, treated with ligands from a nuclear receptor agonist library, and assayed for leptin transport using an enzyme-linked immune sorbent assay. RNA sequencing was further used to identify differentially regulated genes and pathways. The role of a select hit in leptin transport was tested with the competitive substrate assay and after gene knockdown using CRISPR techniques.

Results

Following a screen of 73 compounds, 17β-estradiol was identified as a compound that could significantly increase leptin transport. RNA sequencing revealed many differentially expressed transmembrane transporters after 17β-estradiol treatment. Of these, cationic amino acid transporter-1 (CAT-1, encoded by SLC7A1) was selected for follow-up analyses due to its high and selective expression in BMECs in vivo. Treatment of BMEC-like cells with CAT-1 substrates, as well as knockdown of CAT-1 expression via CRISPR-mediated epigenome editing, yielded significant increases in leptin transport.

Conclusions

A major female sex hormone, as well as an amino acid transporter, were revealed as regulators of leptin BBB transport in the iPSC-derived BBB model. Outcomes from this work provide insights into regulation of peptide hormone transport across the BBB.
Mapping mechanical stress in curved epithelia of designed size and shape
Authors: Marín-Llauradó Ariadna , Kale Sohan , Ouzeri Adam , Sunyer Raimon , Torres-Sánchez Alejandro , Latorre Ernest , Gómez-González Manuel , Roca-Cusachs Pere , Arroyo Marino , Trepat Xavier
Published: May 2022

The function of organs such as lungs, kidneys and mammary glands relies on the three-dimensional geometry of their epithelium. To adopt shapes such as spheres, tubes and ellipsoids, epithelia generate mechanical stresses that are generally unknown. Here we engineered curved epithelial monolayers of controlled size and shape and mapped their state of stress. We designed pressurized epithelia with circular, rectangular and ellipsoidal footprints. We developed a computational method to map the stress tensor in these epithelia. This method establishes a direct correspondence between epithelial shape and mechanical stress without assumptions of material properties. In epithelia with spherical geometry spanning more than one order of magnitude in radius, we show that stress weakly increases with areal strain in a size-independent manner. In epithelia with rectangular and ellipsoidal cross-section we found pronounced stress anisotropies consistent with the asymmetric distribution of tractions measured at the cell-substrate contact line. In these anisotropic profiles, cell shape tended to align with the direction of maximum principal stress but this alignment was non-universal and depended on epithelial geometry. Besides interrogating the fundamental mechanics of epithelia over a broad range of sizes and shapes, our approach will enable a systematic study of how geometry and stress influence epithelial fate and function in three-dimensions.
Ability of the Ash dieback pathogen to reproduce and to induce damage on its host are controlled by different environmental parameters
Authors: Marçais Benoit , Giraudel Arnaud , Husson Claude
Published: May 2022

Ash dieback, induced by an invasive ascomycete,Hymenoscyphus fraxineus, has emerged in the last decade as a severe disease threatening ash populations in Europe. Future prospects for Ash are improved by the existence of individuals with natural genetic resistance to the disease and by limited disease impact in many environmental conditions where ashes are frequent. Nevertheless, it was suggested that even in those conditions, ash trees are infected and enable pathogen transmission. We studied the influence of climate and local environment on the ability ofH. fraxineusto infect, be transmitted and cause damage on its host. We showed that healthy carrier, i.e. asymptomatic individuals carryingH. fraxineus, exists and may play a significant role in ash dieback epidemiology. Environment strongly influencedH. fraxineuswith different parameters being important depending on the life cycle stage. The ability ofH. fraxineusto establish on ash leaves and to reproduce on the leaf debris in the litter (rachises) mainly depended on total precipitations in July-August and was not influenced by local tree cover. By contrast, damages to the host, and in particular shoot mortality was significantly reduced by high summer temperature in July-August and by high autumn average temperature. As a consequence, in many situations ash trees are infected and enableH. fraxineustransmission while showing limited or even no damages. We also observed a decreasing trend of severity (leaf necrosis and shoot mortality likelihood) with the time of disease presence in a plot that could be significant for the future of Ash dieback.
Viruses inhibit TIR gcADPR signaling to overcome bacterial defense
Authors: Leavitt Azita , Yirmiya Erez , Amitai Gil , Lu Allen , Garb Jeremy , Morehouse Benjamin R. , Hobbs Samuel J. , Kranzusch Philip J. , Sorek Rotem
Published: May 2022

The Toll/interleukin-1 receptor (TIR) domain is a key component of immune receptors that identify pathogen invasion in bacteria, plants, and animals. In the bacterial antiphage system Thoeris, as well as in plants, recognition of infection stimulates TIR domains to produce an immune signaling molecule whose molecular structure remained elusive. This molecule binds and activates the Thoeris immune effector, which then executes the immune function. We identified a large family of phage-encoded proteins, denoted here Thoeris anti-defense 1 (Tad1), that inhibit Thoeris immunity. We found that Tad1 proteins are “sponges” that bind and sequester the immune signaling molecule produced by TIR-domain proteins, thus decoupling phage sensing from immune effector activation and rendering Thoeris inactive. A high-resolution crystal structure of Tad1 bound to the signaling molecule revealed that its chemical structure is 1′–2′ glycocyclic ADPR (gcADPR), a unique molecule not previously described in other biological systems. Our results define the chemical structure of a central immune signaling molecule, and reveal a new mode of action by which pathogens can suppress host immunity.
Intermittent antibiotic treatment of bacterial biofilms favors the rapid evolution of resistance
Authors: Usui Masaru , Yoshii Yutaka , Thiriet-Rupert Stanislas , Ghigo Jean-Marc , Beloin Christophe
Published: May 2022

The rise of antibiotic resistance in bacterial pathogens is a major health concern and the determinants of this emergence are actively studied. By contrast, although biofilms are an important cause of infections due to their high tolerance to a broad range of antimicrobials, much less is known on the development of antibiotic resistance within the biofilm environment, an issue potentially aggravating the current antibiotic crisis. Here, we compared the occurrence of resistance mutations in pathogenic Escherichia coli planktonic and biofilm populations exposed to clinically relevant cycles of lethal treatments with the aminoglycoside antibiotic amikacin. This experimental evolution approach revealed that mutations in sbmA and fusA are rapidly selected in biofilm but not in planktonic populations. The apparition of these bona fide resistance —and not tolerance— mutations is favored by the biofilm preexisting tolerance and high mutation rate. Moreover, we showed that while fusA mutations displayed a high fitness cost in planktonic conditions, these mutations were maintained in biofilms, a phenomenon further possibly amplified by the selection of fimH mutations favoring biofilm formation itself. Our study therefore provides new insights into the dynamic evolution of antibiotic resistance in biofilms, which could lead to clinically practical antibiotic regimen limiting biofilm-associated infections, while mitigating the emergence of worrisome antibiotic resistance mutations.
Sensory responses in dorsolateral striatum are modulated by motor activity in a dopamine-dependent manner
Authors: de la Torre-Martinez Roberto , Ketzef Maya , Silberberg Gilad
Published: May 2022

The dorsolateral striatum (DLS) receives excitatory inputs from both sensory and motor cortical regions and is involved in sensory and motor functions. In cortical regions, sensory responses are altered by motor activity, however, it is not known if such sensorimotor interactions also occur in the striatum and how they are modulated by dopamine (DA). To determine the impact of motor activity on striatal sensory processing, we performed in vivo whole-cell recordings in the DLS of awake mice during the presentation of tactile stimuli. Striatal medium spiny neurons (MSNs) were activated by both whisker stimulation and spontaneous whisking, however, responses to whisker deflection during ongoing whisking were attenuated. DA depletion reduced the representation of whisking in direct-pathway MSNs, but not in those of the indirect-pathway. Furthermore, DA depletion impaired the discrimination between ipsi- and contralateral sensory stimulation in both direct- and indirect- pathway MSNs. Our results show that sensory responses in basal ganglia circuits are modulated by motor activity and that both processes are dopamine- and cell type-dependent.
State Dependent Coupling of Hippocampal Oscillations
Authors: Modi Brijesh , Guardamagna Matteo , Stella Federico , Griguoli Marilena , Cherubini Enrico , Battaglia Francesco P.
Published: May 2022

Oscillations occurring simultaneously in a given area represent a physiological unit of brain states. They allow for temporal segmentation of spikes and support distinct behaviors. To establish how multiple oscillatory components co-varies simultaneously and influence neuronal firing during sleep and wakefulness, we describe a multi-variate analytical framework for constructing the state space of hippocampal oscillations. Examining the co-occurrence patterns of oscillations on the state space, across species, uncovered the presence of network constraints and distinct set of cross-frequency interactions during wakefulness as compared to sleep. We demonstrated how the state space can be used as a canvas to map the neural firing and found that distinct neurons during navigation were tuned to different set of simultaneously occurring oscillations during sleep. This multivariate analytical framework provides a window to move beyond classical bivariate pipelines, for investigating oscillations and neuronal firing, thereby allowing to factor-in the complexity of oscillation-population interactions.
Protection from Omicron and other VOCs by Bivalent S-Trimer COVID-19 Vaccine
Authors: Su Danmei , Li Xinglin , Huang Xueqin , He Cui , Zeng Cheng , Wang Qiang , Qin Wenchang , Mu Zhongquan , Ambrosino Donna , Siber George , Clemens Ralf , Liang Joshua G. , Liang Peng , Jackson Nick , Xu Rong
Published: May 2022

The Omicron variant of SARS-COV-2 (GISAID GRA clade [B.1.1.529, BA.1 and BA.2]) is now the single dominant Variant of Concern (VOC). The high number of mutations in the Omicron Spike (S) protein promotes humoral immunological escape. Although a third homologous boost with S, derived from the ancestral strain, was able to increase neutralizing antibody titers and breadth including to Omicron, the magnitude of virus neutralization could benefit from further optimization. Moreover, combining SARS-COV-2 strains as additional valences may address the current antigenicity range occupied by VOCs.

Using Trimer-Tag™ platform we have previously demonstrated phase 3 efficacy and safety of a prototypic vaccine SCB-2019 in the SPECTRA trial and have submitted applications for licensure. Here, we successfully generated a bivalent vaccine candidate including both Ancestor and Omicron variant S-proteins. Preclinical studies demonstrate this SARS-CoV-2 bivalent S-Trimer subunit vaccine elicits high titers of neutralizing antibodies against all VOCs, with markedly enhanced Omicron specific neutralizing antibody responses.