bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptive radioresistance of Enterohemorrhagic Escherichia coli O157:H7 results in genomic loss of shiga toxin-encoding prophages
Authors: Gaougaou Ghizlane , Vincent Antony T. , Krylova Kateryna , Habouria Hajer , Bessaiah Hicham , Baraketi Amina , Veyrier Frédéric J. , Dozois Charles M. , Déziel Eric , Lacroix Monique 
Published: August 2022

AbstractEnterohemorragic Escherichia coli (EHEC) O157:H7 is a foodborne pathogen producing shiga toxins (Stx1 and Stx2), can cause hemorrhagic diarrhea, and life-threatening infections. O157:H7 strain EDL933 carries prophages CP-933V and BP-933W that encode shiga toxin genes (stx1 and stx2 respectively). The aim of this work was to investigate the mechanisms of adaptive resistance of EHEC strain EDL933 to a typically “lethal” dose of γ-irradiation (1.5 kGy). Adaptive selection through six passages of exposure to 1.5 kGy resulted in the loss of CP-933V and BP-933W prophages from the genome and mutations within three genes: wrbA, rpoA, and Wt_02639 (molY). Three selected EHEC clones that became irradiation-adapted to the 1.5 kGy dose (C1, C2 and C3) demonstrated increased resistance to oxidative stress, sensitivity to acid pH, and decreased cytotoxicity to Vero cells. To confirm that loss of prophages plays a role in increased radioresistance, C1 and C2 clones were exposed to bacteriophage containing lysates. Although, phage BP-933W could lysogenize C1, C2, and E.coli K-12 strain MG1655, it was not found to have integrated into the bacterial chromosome in C1-Φ and C2-Φ lysogens. Interestingly, for the E. coli K-12 lysogen (K12-Φ), BP-933W DNA had integrated at the wrbA gene (K12-Φ). Both C1-Φ and C2-Φ lysogens regained sensitivity to oxidative stress, were more effectively killed by a 1.5 kGy γ-irradiation dose and had regained cytotoxicity and acid resistance phenotypes. Further, the K12-Φ lysogen became cytotoxic, more sensitive to γ-irradiation and oxidative stress and slightly more acid resistant.ImportanceGamma (γ)-irradiation of food products can provide an effective means of eliminating bacterial pathogens such as enterohemorrhagic Escherichia coli (EHEC) O157:H7, a significant foodborne pathogen that can cause severe disease due to the production of Shiga toxins. To decipher the mechanisms of adaptive resistance of the O157:H7 strain EDL933, we evolved clones of this bacterium resistant to a lethal dose of γ-irradiation by repeatedly exposing bacterial cells to irradiation following a growth restoration over six successive passages. Our findings provide evidence that adaptive selection involved modifications in the bacterial genome including deletion of the CP-933V and BP-933W prophages. These mutations in EHAC O157:H7 resulted in loss of stx1, stx2, loss of cytotoxicity to epithelial cells and decreased resistance to acidity, critical virulence determinants of EHEC, concomitant with increased resistance to lethal irradiation and oxidative stress. These findings demonstrate that the potential adaptation of EHEC to high doses of radiation would involve elimination of the Stx encoding phages and likely lead to a substantial attenuation of virulence.
Variant-risk-exon interplay impacts circadian rhythm and dopamine signaling pathway in severe psychiatric disorders
Authors: Worf Karolina , Matosin Natalie , Gerstner Nathalie , Fröhlich Anna S. , Koller Anna C. , Degenhardt Franziska , Thiele Holger , Rietschel Marcella , Udawela Madhara , Scarr Elizabeth , Dean Brian , Theis Fabian J. , Knauer-Arloth Janine , Mueller Nikola S. 
Published: August 2022

ABSTRACTIn psychiatric disorders, common and rare genetic variants cause widespread dysfunction of cells and their interactions, especially in the prefrontal cortex, giving rise to psychiatric symptoms. To better understand these processes, we traced the effects of common and rare genetics, and cumulative disease risk scores, to their molecular footprints in human cortical single-cell types. We demonstrated that examining gene expression at single-exon resolution is crucial for understanding the cortical dysregulation associated with diagnosis and genetic risk derived from common variants. We then used disease risk scores to identify a core set of genes that serve as a footprint of common and rare variants in the cortex. Pathways enriched in these genes included dopamine regulation, circadian entrainment, and hormone regulation. Single-nuclei-RNA-sequencing pinpointed these enriched genes to excitatory cortical neurons. This study highlights the importance of studying sub-gene-level genetic architecture to classify psychiatric disorders based on biology rather than symptomatology, to identify novel targets for treatment development.
Gain and loss of function variants in EZH1 disrupt neurogenesis timing and cause overlapping neurodevelopmental disorders
Authors: Gracia-Diaz Carolina , Zhou Yijing , Yang Qian , Lee Chul-Hwan , Espana-Bonilla Paula , Zhang Shuo , Padilla Natàlia , Fueyo Raquel , Otrimski Garrett , Li Dong , Sheppard Sarah , Mark Paul , Harr Margaret H. , Hakonarson Hakon , Rodan Lance , Jackson Adam , Vasudevan Pradeep , Powel Corrina , Mohammed Shehla , Maddirevula Sateesh , Alzaidan Hamad , Faqeih Eissa A. , Efthymiou Stephanie , Turchetti Valentina , Rahman Fatima , Maqbool Shazia , Salpietro Vincenzo , Ibrahim Shahnaz H , di Rosa Gabriella , Houlden Henry , Estaras Conchi , Hurst Anna C.E. , Thompson Michelle L. , Chassevent Anna , Smith-Hicks Constance L. , de la Cruz Xavier , Holtz Alexander , Torti Erin , Hajianpour MJ , Rieubland Claudine , Braun Dominique , Banka Siddharth ,   Genomic England Research Consortium, Heller Elizabeth A. , Saade Murielle , Song Hongjun , Ming Guo-Li , Alkuraya Fowzan S. , Maroofian Reza , Agrawal Pankaj B. , Reinberg Danny , Bhoj Elizabeth J. , Martinez-Balbas Marian A. , Akizu Naiara 
Published: August 2022

AbstractGenetic disruption of chromatin regulators is frequently found in neurodevelopmental disorders (NDDs). While chromatin regulators are attractive therapeutic targets, studies to determine their implication in the etiology of NDDs are limited, preventing advances in diagnosis and treatment strategies. Here, we uncover pathogenic variants in the chromatin modifier Enhancer of Zeste Homologue 1 (EZH1) as the cause of overlapping recessive and dominant NDDs in 17 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 (K27) methyltransferases of the Polycomb Repressive Complex 2 (PRC2). Unlike the other PRC2 subunits, which are associated with the pathogenesis of human cancers and developmental disorders, the implication of EZH1 in human development and disease is largely unknown. Using cellular models and biochemical studies, we demonstrate that recessive variants cause EZH1 loss of function (LOF), while dominant variants are all missense mutations that modify the catalytic activity of EZH1, thus generating a gain of function (GOF) effect. Consistent with a pathogenic effect, depletion or overexpression of EZH1 perturbs neuronal differentiation in the developing chick embryo neural tube. Furthermore, using human pluripotent stem cell (hPSC) derived neural cultures and forebrain organoids, we show that EZH1 LOF and GOF variants respectively delay and accelerate the schedule of cortical projection neuron generation. Our work identifies EZH1 LOF and GOF variants as the genetic basis of previously undefined NDDs and uncovers an essential role of EZH1 in regulating the timing of neurogenesis.
Safety and Immunogenicity of Intradermal Administration of Fractional Dose CoronaVac®, ChAdOx1 nCoV-19 and BNT162b2 as Primary Series Vaccination
Authors: Chatsiricharoenkul Somruedee , Niyomnaitham Suvimol , Posen H. Joshua , Toh Zheng Quan , Licciardi Paul V , Wongprompitak Patimaporn , Duangchinda Thaneeya , Pakchotanon Pattarakul , Chantima Warangkana , Chokephaibulkit Kulkanya 
Published: August 2022

AbstractThere is a limited supply of COVID-19 vaccines, with less than 20% of eligible populations in low-income countries having received one dose. Intradermal delivery of fractional dose vaccines is one way to improve global vaccine access, but no studies have reported data on intradermal delivery of COVID-19 primary series vaccination. We conducted a pilot study to examine the safety and immunogenicity of three intradermal primary series regimens – heterologous regimen of CoronaVac and ChAdOx1 (CoronaVac-ChAdOx1), homologous regimen of ChAdOx1 (ChAdOx1-ChAdOx1), and homologous regimen of BNT162b2 (BNT162b2-BNT162b2). Each dose was 1/5th or 1/6th of the standard dose. Two additional exploratory arms of intradermal vaccination for the second dose following an intramuscular first dose of ChAdOx1 and BNT162b2 were included. Intradermal vaccination was found to be immunogenic and safe. The antibody responses generated by the intradermal primary series were highest in the BNT162b2 arms. The anti-receptor binding domain (anti-RBD) IgG concentration following fractional dose intradermal vaccination was similar to that of standard dose intramuscular vaccination of the same regimen, except for BNT162b2. The BNT162b2 intradermal series generated a lower antibody concentration than the reference intramuscular series, despite generating the highest antibody concentration of all three intradermal primary series regimens. Neutralizing antibody responses against the SARS-CoV-2 ancestral strain were consistent with what was observed for anti-RBD IgG, with lower titers for SARS-CoV-2 variants. The FRNT50 titers were lowest against the omicron variant, being undetectable (GMT≤10) in about a quarter of study participants. T-cell responses against spike- and nucleocapsid-membrane-open reading frame proteins were also detected following intradermal vaccination. Adverse effects following intradermal vaccination were generally comparable with post-intramuscular vaccination effects. Taken together, our data suggest that intradermal vaccination using 1/5th or 1/6th of standard COVID-19 intramuscular vaccination dosing generates similar immune responses with tendency of lower systemic adverse reactions than intramuscular vaccination. Our findings have implications in settings where COVID-19 vaccines are in shortage.
Portable nucleic acid tests for rapid detection of monkeypox virus
Authors: Bhadra Sanchita , Ellington Andrew D. 
Published: August 2022

ABSTRACTWe report two isothermal nucleic acid amplification assays for detection of monkeypox virus (MPXV) clades 2 and 3 that include the strains responsible for the current global outbreak of monkeypox. The assays use loop-mediated isothermal amplification (LAMP) to amplify two distinct sequences in the MPXV genome. Readout specificity is ensured by oligonucleotide strand displacement (OSD) probes integrated in one-pot LAMP-OSD reactions. OSD probes undergo toehold-mediated strand displacement hybridization to LAMP amplicon loop sequences derived from MPXV clades 2 and 3 resulting in fluorescence readable both in realtime and visually at endpoint. We also perform both assays on two different portable devices, the GeneTiger and the miniPCR, to exemplify compatibility with minimum infrastructure point-of-care (POC) testing in clinical and at-home settings. Both assays could readily detect single digit copies of MPXV synthetic double stranded DNA templates within 30 min.
Limbic progesterone receptors regulate spatial memory
Authors: Joshi Suchitra , Williams Cedric L , Kapur Jaideep 
Published: August 2022

ABSTRACTProgesterone and its receptors (PRs) participate in mating and reproduction, but their role in spatial declarative memory, is not understood. Male and female mice express PRs in regions that support spatial memory: the hippocampus and entorhinal cortex. PRs were predominantly expressed in excitatory neurons in Pgr-Cre mice injected with AAV-delivered flexed tdTomato. Furthermore, segesterone, a specific PR agonist, activated neurons in the entorhinal cortex (EC) and the hippocampus. We assessed the PR function in these spatial memory circuit neurons by examining the performance of mice lacking this receptor (PRKO) in novel object recognition, object placement, and Y-maze alternation tasks. In the recognition test, wild-type littermates spent significantly more time exploring the new object than male PRKO mice. The EC-specific deletion of PRs was sufficient to induce a deficit in detecting familiar versus never experienced or new objects. We confirmed deficits in spatial memory of PRKO mice by testing them on the Y-maze forced alternation task. In contrast to spatial tasks, PR removal did not alter the response to fear conditioning. PRs also support spatial memory in female mice. These studies provide novel insights into the role of PR in facilitating spatial, declarative memory in males and females, which may help with finding reproductive partners.SIGNIFICANCE STATEMENTBrain progesterone receptors play an essential role in facilitating mating and reproductive behaviors, but their role in spatial memory and, therefore, mate-finding is not described. Principal, excitatory neurons of the entorhinal cortex and hippocampus express progesterone receptors. These receptors facilitate spatial memory in male and female mice, which may enhance mate-finding reproductive function and food foraging.
Follicle-innervating Aδ-low threshold mechanoreceptors organize through a population-dependent mechanism
Authors: Pomaville Matthew B. , Wright Kevin M. 
Published: August 2022

AbstractThe mammalian somatosensory system is comprised of multiple neuronal populations that form specialized, highly organized sensory endings in the skin. The organization of somatosensory endings is essential to their functions, yet the mechanisms which regulate this organization remain unclear. Using a combination of genetic and molecular labeling approaches, we examined the development of mouse hair follicle-innervating low-threshold mechanoreceptors (LTMRs) and explored competition for innervation targets as a mechanism involved in the patterning of their receptive fields. We show that follicle innervating neurons are present in the skin at birth and that LTMR receptive fields gradually add follicle-innervating endings during the first two postnatal weeks. Using a constitutive Bax knockout to increase the number of neurons in adult animals, we show that two LTMR subtypes have differential responses to an increase in neuronal population size: Aδ-LTMR neurons shrink their receptive fields to accommodate the increased number of neurons innervating the skin, while C-LTMR neurons do not. Our findings suggest that competition for hair follicles to innervate plays a role in the patterning and organization of follicle-innervating LTMR neurons.Summary StatementAδ follicle-innervating low-threshold mechanoreceptor neurons form tiled receptive fields through competition for hair follicles during the early postnatal period.
Circadian ribosome profiling reveals a role for thePeriod2upstream open reading frame in sleep
Authors: Millius Arthur , Yamada Rikuhiro , Fujishima Hiroshi , Maeda Kazuhiko , Standley Daron M. , Sumiyama Kenta , Perrin Dimitri , Ueda Hiroki R. 
Published: August 2022

AbstractMany mammalian proteins have circadian cycles of production and degradation, and many of these rhythms are altered post-transcriptionally. We used ribosome profiling to examine post-transcriptional control of circadian rhythms by quantifying RNA translation in the liver over a 24-h period from circadian-entrained mice transferred to constant darkness conditions and by comparing ribosome binding levels to protein levels for 16 circadian proteins. We observed large differences in ribosome binding levels compared to protein levels, and we observed delays between peak ribosome binding and peak protein abundance. We found extensive binding of ribosomes to upstream open reading frames (uORFs) in circadian mRNAs, including the core clock genePeriod2 (Per2). An increase in the number of uORFs in the 5’UTR was associated with a decrease in ribosome binding in the main coding sequence and a reduction in expression of synthetic reporter constructs. Mutation of thePer2uORF increased luciferase and fluorescence reporter expression in 3T3 cells and increased luciferase expression in PER2:LUC MEF cells. Mutation of thePer2uORF in mice increasedPer2mRNA expression, enhanced ribosome binding onPer2, and reduced total sleep time compared to that in wild-type mice. These results suggest that uORFs affect mRNA post-transcriptionally, which can impact physiological rhythms and sleep.Significance StatementPeriod (Per)is an iconic gene in the field of circadian rhythms since its discovery in 1971 by Seymour Benzer and Ronald Konopka in fruit flies. The inhibitory feedback loop of PER protein drives circadian rhythms. We show thatPer2is regulated by an upstream open reading frame (uORF) in the 5’ untranslated region ofPeriod2mRNA. Mutation of thePer2uORF altered the amplitude of luciferase reporter expression in well-characterized cell culture models.Per2uORF mutant mice had significantly elevatedPer2mRNA levels and exhibited sleep loss, particularly during light-to-dark and dark-to-light transitions, which suggests a role for uORFs in modulating molecular and physiological circadian rhythms.
Effectiveness of anterior cruciate ligament injury prevention programmes in sport: a scoping review
Authors: Margelli Michele , De Mucci Francesco , Nadaletto Francesco , Manfroni Tommaso Marzi , Beccari Andrea 
Published: August 2022

AbstractBackgroundAnterior cruciate ligament injury is the most common ligament injury of the knee and one of the most serious and common injuries in sport. This injury causes a number of both short-term and longterm negative consequences that negatively impact both sports performance and quality of life in general. The literature has recognised the need to improve primary prevention with the aim of decreasing the ACL injury rate. For this reason, numerous ACL-specific prevention programmes have been proposed in recent years that include various types of exercises and different methods of administration. The main objective of this scoping will be to report what the literature tells us about these programmes and prevention for ACL injuries.Inclusion criteriaEvery study about prevention programmes for LCA injury on athletes of all ages participating in professional or amateur sports will be included. This scoping review will consider studies conducted in any context.MethodsThe proposed scoping review will be conducted in accordance with the Joanna Briggs Institute methodology (JBI) for scoping reviews.The search will be carried out on 6 databases:MEDLINE, Cochrane Central, Scopus, CINHAL, Embase, and PEDro.Selection and data extraction will be conducted by two blind independent researchers and inconsistencies will be resolved by a third reviewer.The results will be presented in a schematic, tabular and descriptive format that will line up with the objectives and scope of the review.ConclusionsThis review provides a comprehensive overview of prevention for ACL injuries in sport, in particular the effectiveness of existing prevention programmes. The information provided will be useful for physiotherapists and athletic trainers during the sports season and as a therapeutic education tool. The results of this research will be published in scientific research databases.
Parental Deprivation- and Threat-Based Factors Associated with Youth Emotion-Based Neurocircuitry and Externalizing Behavior: A Systematic Review
Authors: Feeney Kathleen E. , Lobo Rosario Pintos , Hare Megan M. , Morris Stephanie S.J. , Laird Angela R. , Musser Erica D. 
Published: August 2022

AbstractParental factors, including negative parenting practices (e.g., family conflict, low monitoring), parental depression, and parental substance use, are associated with externalizing behaviors in youth; however, the mediating role of youth’s neurocircuitry in explaining these associations has been less studied. Both the dimensional and stress acceleration models provide frameworks for understanding how frontolimbic and frontoparietal networks implicated in emotional attention and regulation processes may be associated with parental factors. The current review builds upon this work by examining how deprivation- and threat-based parental factors are associated with youth externalizing behaviors through youth neurocircuitry involved in emotional functioning. A systematic review using PRISMA guidelines was completed and included five studies assessing parenting behaviors, six studies assessing parental depressive symptoms and/or diagnosis, and 12 studies assessing parental history of substance use. Overall, reviewed studies provided support for the dimensional and stress acceleration models within the context of deprivation and threat. There was limited support for the proposed mediation model, as only six studies tested for mediation. Specific recommendations for future work include more deliberate planning related to sample composition, improved clarity related to parental constructs, and consistency in methodology in order to better understand associations between contextual parental influences and youth neural and behavioral functioning.
Single-cell Transcriptomics Reveal Different Maturation Stages and Sublineages Commitment of Human Thymic Invariant Natural Killer T cells
Authors: Maas-Bauer Kristina , Acharya Swati , Baker Jeanette , Lewis David B. , Negrin Robert S. , Simonetta Federico 
Published: August 2022

SummaryInvariant natural killer T (iNKT) cells are a subset of heterogenous T-cells with potent cytotoxic and immunomodulatory properties. During thymic development, murine iNKT cells go through different maturation stages and differentiate into distinct sublineages, namely iNKT1, iNKT2, and iNKT17 cells. To define maturation stages and to assess sublineage commitment of human iNKT cells during thymic development, we performed single-cell RNA sequencing analysis on human thymic iNKT cells. We show that these iNKT cells displayed heterogeneity and unsupervised analysis identified two clusters: one with an immature profile with high expression of genes that are important for iNKT cell development and enriched in cells expressing an iNKT2 signature, whereas a second cluster displayed a mature, terminally differentiated profile resembling murine iNKT1 cells. Trajectory analysis suggested an ontological relationship between the two clusters. Our work provides the first single cell transcriptomic analysis of thymic human iNKT cells offering new insights into their developmental process in humans.
Macrophage migrates on alternate non-adhesive surfaces
Authors: Xing Fulin , Dong Hao , Yang Jianyu , Fan Chunhui , Hou Mengdi , Zhang Ping , Hu Fen , Zhou Jun , Chen Liangyi , Pan Leiting , Xu Jingjun 
Published: August 2022

AbstractMacrophages migrate across tissues upon immune demand, but their motility on heterogeneous substrates remains unclear. Protein-repelling reagents, e.g., poly(ethylene) glycol (PEG), are routinely employed to resist cell adhering and migrating. Contrary to this perception, we discovered a unique locomotion of macrophages in vitro that they overcome non-adhesive PEG gaps to reach adhesive regions in a mesenchymal mode. Adhesion to adhesive regions was a prerequisite for macrophages to perform further locomotion on the PEG regions, or else they kept a suspended round shape. Podosomes were found highly enriched on the PEG region, which supported macrophage migration. Myosin IIA played a negative role in macrophage motility. Moreover, a developed cellular Potts model reproduced the experimental observations. These findings uncovered a new migratory behavior on non-adhesive surfaces in macrophages.One-Sentence SummaryMacrophages can migrate across non-adhesive surfaces that are absolute boundaries for other cell types.