bluuebunny/crossref_metadata_2025 huggingface dataset:
The public health impact of poor sleep on severe COVID-19, influenza and upper respiratory infections
Authors: Jones Samuel E. , Maisha Fahrisa I. , Strausz Satu J. , Cade Brian E. , Tervi Anniina M. , Helaakoski Viola , Broberg Martin E. , Lammi Vilma ,   FinnGen, Lane Jacqueline M. , Redline Susan , Saxena Richa , Ollila Hanna M.
Published: February 2022

Background

Poor sleep is associated with an increased risk of infections and all-cause mortality, and acute sleep loss and disruption have been linked with inflammation and poorer immune control. Previous studies, however, have been unable to evidence causality between the chronic effects of poor sleep and respiratory infection risk. In light of the ongoing COVID-19 pandemic and potential future disease outbreaks, understanding the risk factors for these infections is of great importance.

Aim

Our goal was to understand if chronic poor sleep could be identified as a causal risk factor for respiratory infections including influenza, upper respiratory infections and COVID-19.

Methods

We used population cohorts from the UK Biobank (N ≈ 231,000) and FinnGen (N ≈ 327,000) with ICD-10 based electronic health records and obtained diagnoses of insomnia, influenza and upper respiratory infections (URIs) from primary care and hospital settings. We computed logistic regression to assess association between poor sleep and infections, disease free survival hazard ratios, and used summary statistics from genome-wide association studies of insomnia, influenza, URI and COVID-19 to perform Mendelian randomization analyses and assess causality.

Findings

Utilizing 23 years of registry data and follow-up, we saw that insomnia diagnosis associated with increased risk for infections in FinnGen and in UK Biobank (FinnGen influenza HR = 5.32 [4.09, 6.92], P = 1.02×10−35, UK Biobank influenza HR = 1.54 [1.37, 1.73], P = 2.49×10−13). Mendelian randomization indicated that insomnia causally predisposed to influenza (OR = 1.59, P = 6.23×10−4), upper respiratory infections (OR = 1.71, P = 7.60×10−13), COVID-19 infection (OR = 1.08, P = 0.037) and risk of hospitalization from COVID-19 (OR = 1.47, P = 4.96×10−5).

Conclusions

Our findings indicate that chronic poor sleep is a causal risk factor for contracting respiratory infections, and in addition contributes to the severity of respiratory infections. These findings highlight the role of sleep in maintaining sufficient immune response against pathogens as suggested by earlier work. As the current COVID-19 pandemic has increased the number of people suffering from poor sleep, safe interventions such as sleep management and treating individuals with insomnia could be promoted to reduce infections and save lives.
Association between sexual and reproductive health knowledge and protective sexual behaviors among young women in Nigeria
Authors: Okunola David Aduragbemi , Alawode Oluwatobi Abel , Ajayi Anthony Idowu
Published: February 2022

Background

While the literature is replete with studies on young people’s risky sexual behaviors and their effects on HIV and STI acquisition, unintended pregnancy, and unsafe abortion, few studies have explored the practice of protective sexual behaviors and its association with sexual and reproductive health knowledge. We examined the association between sexual and reproductive health knowledge and protective sexual behaviors using data of young women in Nigeria.

Methods

Data of 8,995 young women (aged 15-24) who were neither married nor living with a partner were obtained from the 2018 Nigeria Demographic and Health Survey (NDHS) and analyzed in this study. Protective sexual behaviors were measured using questions exploring sexual fidelity, condom use, having multiple partners, and abstinence, while sexual and reproductive health knowledge was measured with questions on fertility, fecundity, contraceptives, and HIV prevention. We fitted multinomial logistic regression to examine the association between sexual and reproductive health knowledge and protective sexual behaviors.

Results

The median score on sexual and reproductive health knowledge was five. The majority of the sample (71.5%) had no sexual experience, 6.6% abstained from sex in the past year, 7.2% used condoms and practiced sexual fidelity, 1.0% used condoms but did not practice sexual fidelity, 12.7% did not practice sexual fidelity but used condoms while 0.8% neither used condom nor practiced sexual fidelity. After controlling for important covariates, sexual and reproductive health knowledge was positively associated with “condom use and sexual fidelity” (uRRR = 1.28; CI = 1.04-1.60) relative to “not using condoms nor practicing sexual fidelity.” However, the association between sexual and reproductive health knowledge and other categories of protective sexual behaviors, such as no sexual experience, abstinence in the past year, and sexual fidelity but no condom use, did not reach a significant level.

Conclusion

We found a high prevalence of protective sexual behavior among young women in Nigeria. Our study provides evidence in support of the association between sexual and reproductive health knowledge and a higher likelihood of practicing protective sexual behaviors. Intervention efforts can focus on providing sexual and reproductive health education to young people to equip them with information to safeguard their sexual health.
A novel SEIR-e model for disease transmission and pathogen exposure
Authors: Tambyah Tamara A. , Testolin Matthew J. , Hill Alexander M.
Published: February 2022

In this study, we couple compartment models for indoor air quality and disease transmission to develop a novel SEIR-e model for disease transmission and pathogen exposure. In doing so, we gain insight into the contribution of people–people and people–pathogen interactions to the spread of transmissible diseases. A general modelling framework is used to assess the risk of infection in indoor environments due to people–pathogen interactions via inhalation of viral airborne aerosols, and contact with contaminated surfaces. We couple the indoor environment model with a standard disease transmission model to investigate how both people–people and people–pathogen interactions result in disease transmission. The coupled model is referred to as the SEIR-e model. To demonstrate the applicability of the SEIR-e model and the novel insights it can provide into different exposure pathways, parameter values which describe exposure due to people–people and people–pathogen interactions are inferred using Bayesian techniques and case data relating to the 2020 outbreak of COVID-19 in Victoria (Australia).
Analytical Sensitivity of the SalivaDirect™ Assay on the Liberty16 for detecting SARS-CoV-2 B.1.1.529 (“Omicron”)
Authors: Tan Yen Pei , Al-Halbouni Mila , Chen Ching-Huan , Hirst David B. , Pickering Paul J.
Published: February 2022

The newly emerged Omicron variant of SARS-CoV-2 has numerous mutations that are not found in other variants of concern (VOCs). Despite acquiring extended functions in adapting to the host-cell environment, the viral genetic variation exerts a potential negative impact on a molecular test, which in turn, compromises public health and safety. The Liberty16 has been clinically validated as a flexible and accessible device system for running the affordable SalivaDirect™ real time PCR detection assay for SARS-CoV-2 especially in low resource settings. Preliminary, based on in-silico sequence analysis, we found that Omicron’s mutation at position 28,311 overlaps with the CDC 2019-nCoV_N1 probe binding region. In order to verify the performance of CDC 2019-nCoV-N1 primers-probe set in detecting the Omicron variant of SARS-CoV-2, plasmids containing Wuhan/WH01/2019 (wild-type) and B.1.1.529 (Omicron) sequences were serially diluted and subsequently directed for SalivaDirect™ RT-qPCR detection on Liberty16 using commercially procured reagents. Our findings provide analytical support for reports that the mutations in the Omicron variant have little or no impact on SalivaDirect™ assay in terms of amplification efficiency and detection sensitivity using either standard and the recently reported fast Liberty16 SalivaDirect™ thermal cycling protocols.
Decision formation in parietal cortex transcends a fixed frame of reference
Authors: So NaYoung , Shadlen Michael N
Published: February 2022

Neurons in the lateral intraparietal cortex (area LIP) represent the formation of a decision when it is linked to a specific action, such as an eye movement to a choice target. However, these neurons should be unable to represent a decision that transpires across actions that would disrupt this linkage. We investigated this limitation by recording simultaneously from many neurons. While intervening actions disrupt the representation by single neurons, the ensemble achieves continuity of the decision process by passing information from currently active neurons to neurons that will become active after the action. In this way, the representation of an evolving decision can be generalized across actions and transcends the frame of reference that specifies the neural response fields. The finding extends previous observations of receptive field remapping, thought to support the stability of perception across eye movements, to the continuity of a thought process, such as a decision.
TraDIS-validate: a method for curating ordered gene-replacement libraries
Authors: Goodall Emily C. A. , Morris Faye C. , McKeand Samantha A. , Sullivan Rudi , Warner Isabel A. , Sheehan Emma , Boelter Gabriela , Icke Christopher , Cunningham Adam F. , Cole Jeffrey A. , Banzhaf Manuel , Bryant Jack A. , Henderson Ian R.
Published: February 2022

In recent years the availability of genome sequence information has grown logarithmically resulting in the identification of a plethora of uncharacterised genes. To address this gap in functional annotation, many high-throughput screens have been devised with the goal of uncovering novel gene functions. Gene-replacement libraries are one such tool that can be screened in a high-throughput way to link genotype and phenotype and are key community resources. However, for a phenotype to be attributed to a specific gene, there needs to be confidence in the genotype. Construction of large libraries can be laborious and occasionally errors will arise. Here, we present a rapid and accurate method for the validation of any ordered gene-replacement library. We applied our method (TraDIS-Validate) to the well-known Keio library of Escherichia coli gene-deletion mutants. Our method identified 3,718 constructed mutants out of a total of 3,728 confirmed isolates. TraDIS-validate therefore had a success rate of 99.7% for identifying the correct kanamycin cassette position. This dataset provides a benchmark for the purity of the Keio mutants and a screening method for mapping the position of an antibiotic resistance cassette in any ordered library.
HIV-1 preintegration complex preferentially integrates the viral DNA into nucleosomes containing trimethylated histone 3-lysine 36 modification
Authors: Sapp Nicklas , Burge Nathaniel , Cox Khan , Thapa Santosh , Prakash Prem , Balasubramaniam Muthukumar , Christenson Devin , Li Min , Linderberger Jared , Kvaratskhelia Mamuka , Pandhare Jui , Craigie Robert , Sundquist Wesley , Poirier Michael G , Dash Chandravanu
Published: February 2022

HIV-1 DNA integration into the host chromosomes is carried out by the preintegration complex (PIC). The PIC contains the viral DNA, virally encoded integrase enzyme and other critical viral/host factors. The PIC-associated viral DNA is preferentially integrated into gene bodies of actively transcribing genes. Here, we identify a biochemical mechanism underlying the preference of PIC-mediated viral DNA integration (PIC-VDI). Specifically, we observed that the PIC-VDI into human chromatin is preferred over the genomic DNA. Surprisingly, nucleosome core particles without any histone modifications were not preferred for PIC-VDI when compared to the analogous naked DNA. However, PIC-VDI was markedly enhanced with nucleosomes containing the trimethylated histone 3 lysine 36 (H3K36me3), an epigenetic mark linked to HIV-1 DNA integration preference. Interestingly, we observed that nucleosomes with flanking linker DNA promoted PIC-VDI in the presence of LEDGF/p75. We also discovered that nucleosomes with linker DNA and H3K36me3 served as the optimal substrate for PIC-VDI. Mapping of the integration sites within these substrates identified preference of specific regions of the nucleosome core DNA for integration. Finally, we provide biochemical and genetic evidence that histone H1 protein, that condenses the chromatin, negatively regulates HIV-1 DNA integration, consistent with the integration preference for open chromatin structure. Collectively, these results identify the role of specific chromatin marks that drive HIV-1 integration preference and define the optimal substrate requirement for efficient DNA integration by the PIC.
Autophagy promotes organelle clearance and organized cell separation of living root cap cells in Arabidopsis thaliana
Authors: Goh Tatsuaki , Sakamoto Kaoru , Wang Pengfei , Kozono Saki , Ueno Koki , Miyashima Shunsuke , Toyokura Koichi , Fukaki Hidehiro , Kang Byung-Ho , Nakajima Keiji
Published: February 2022

The root cap is a multi-layered tissue covering the tip of a plant root that directs root growth through its unique functions such as gravity-sensing and rhizosphere interaction. To prevent damages from the soil environment, cells in the root cap continuously turn over through balanced cell division and cell detachment at the inner and the outer cell layers, respectively. Upon displacement toward the outermost layer, columella cells at the central root cap domain functionally transition from gravity-sensing cells to secretory cells, but the mechanisms underlying this drastic cell fate transition are largely unknown. By using live-cell tracking microscopy, we here show that organelles in the outermost cell layer undergo dramatic rearrangements, and at least a part of this rearrangement depends on spatiotemporally regulated activation of autophagy. Notably, this root cap autophagy does not lead to immediate cell death, but rather is necessary for organized separation of living root cap cells, highlighting a previously undescribed role of developmentally regulated autophagy in plants.

Summary statement

Time-lapse microscope imaging revealed spatiotemporal dynamics of intracellular reorganization associated with functional transition and cell separation in the Arabidopsis root cap and the roles of autophagy in this process.
Target-enrichment sequencing yields valuable genomic data for difficult-to-culture bacteria of public health importance
Authors: Dennis Tristan P. W. , Mable Barbara K. , Brunelle Brian , Devault Alison , Carter Ryan , Ling Clare L. , Mmbaga Blandina T. , Halliday Jo E. B. , Oravcova Katarina , Forde Taya L.
Published: February 2022

Genomic data contribute invaluable information to the epidemiological investigation of pathogens of public health importance. However, whole genome sequencing (WGS) of bacteria typically relies on culture, which represents a major hurdle for generating such data for a wide range of species for which culture is challenging. In this study, we assessed the use of culture-free target-enrichment sequencing as a method for generating genomic data for two bacterial species: 1) Bacillus anthracis, which causes anthrax in both people and animals and whose culture requires high level containment facilities; and 2) Mycoplasma amphoriforme, a fastidious emerging human respiratory pathogen. We obtained high quality genomic data for both species directly from clinical samples, with sufficient coverage (>15X) for confident variant calling over at least 80% of the baited genomes for over two thirds of the samples tested. Higher qPCR cycle threshold (Ct) values (indicative of lower pathogen concentrations in the samples), pooling libraries prior to capture, and lower captured library concentration were all statistically associated with lower capture efficiency. The Ct value had the highest predictive value, explaining 52% of the variation in capture efficiency. Samples with Ct values ≤ 30 were over 6 times more likely to achieve the threshold coverage than those with a Ct > 30. We conclude that target-enrichment sequencing provides a valuable alternative to standard WGS following bacterial culture and creates opportunities for an improved understanding of the epidemiology and evolution of many clinically important pathogens for which culture is challenging.

Data summary

The authors confirm all supporting data, code and protocols have been provided within the article or through supplementary data files. Scripts used in this study can be accessed on GitHub at https://github.com/tristanpwdennis/bactocap. All sequence data generated during this study have been deposited in the European Nucleotide Archive (ENA) Sequence Read Archive (SRA) under project accession numbers PRJEB46822 (B. anthracis) and PRJEB50216 (M. amphoriforme). Accession numbers for individual samples, along with metadata, laboratory parameters and sequence quality metrics, are available at the University of Glasgow’s data repository, Enlighten, at http://dx.doi.org/10.5525/gla.researchdata.1249.
Autism is associated with inter-individual variations of gray and white matter morphology
Authors: Mei Ting , Forde Natalie J. , Floris Dorothea L. , Dell’Acqua Flavio , Stones Richard , Ilioska Iva , Durston Sarah , Moessnang Carolin , Banaschewski Tobias , Holt Rosemary J. , Baron-Cohen Simon , Rausch Annika , Loth Eva , Oakley Bethany , Charman Tony , Ecker Christine , Murphy Declan G. M. ,   the EU-AIMS LEAP group, Beckmann Christian F. , Llera Alberto , Buitelaar Jan K.
Published: February 2022

Background

Although many studies have explored atypicalities in gray and white matter (GM, WM) morphology of autism, most of them rely on unimodal analyses that do not benefit from the likelihood that different imaging modalities may reflect common neurobiology. We aimed to establish multimodal brain patterns that differentiate between autism and typically developing (TD) controls and explore associations between these brain patterns and clinical measures.

Methods

We studied 183 individuals with autism and 157 TD individuals (6-30 years) in a large deeply phenotyped autism dataset (EU-AIMS LEAP). Linked Independent Component Analysis was utilized to link all participants’ GM and WM images, and group comparisons of modality shared variances were examined. Subsequently, we performed a canonical correlation analysis to explore the aggregated effects between all multimodal GM-WM covariations and clinical profiles.

Results

One multimodal pattern was significantly related to autism. This pattern was primarily associated with GM in bilateral insula, frontal, pre- and post-central, cingulate, and caudate areas, and co-occurred with altered WM features in the superior longitudinal fasciculus. The canonical analysis showed a significant multivariate correlation primarily between multimodal brain patterns that involved variation of corpus callosum, and symptoms of social affect in the autism group.

Conclusions

Our findings demonstrate the assets of integrated analyses of GM and WM alterations to study the brain mechanisms that underpin autism, and show that the complex clinical autism phenotype can be interpreted by multimodal brain patterns that are spread across the brain involving both cortical and subcortical areas.
Xist expression impacts chromatin structure and YY1 mediated transcription of X-linked genes in hematopoietic progenitor cells
Authors: Yang Tianqi , Ou Jianhong , Yildirim Eda
Published: February 2022

X chromosome inactivation (XCI) is a dosage compensation phenomenon that occurs in females. Initiation of XCI depends on Xist RNA, which triggers silencing of one of the two X chromosomes, except for genes that escape XCI. This inactive state is propagated during cell divisions with continuous Xist expression. How Xist impacts XCI maintenance remains an open question. Here, we delete Xist in hematopoietic cells of mice and report increased fraction of cycling hematopoietic progenitors and differentiation defects during hematopoiesis. Xist loss results in upregulation of a subset of X-linked genes, several of which escape XCI and have functions in hematopoiesis and immunity. We find that the underlying mechanism of transcriptional upregulation involves reduced H3K27me3 occupancy and increased chromatin accessibility which accommodate binding of YY1 transcription factor (TF). We propose that XCI maintenance defects in Xist deficient mice rely on the landscape of open chromatin sites, TF availability, and cell cycle stress in specific cellular context during hematopoiesis.
Targeting the fronto-parietal network using multifocal personalized transcranial alternating current stimulation to enhance motor sequence learning in healthy older adults
Authors: Draaisma L.R. , Wessel M.J. , Moyne M. , Morishita T. , Hummel F.C.
Published: February 2022

Background

Healthy older adults show a decrease in motor learning capacity as well as in working memory (WM) performance. WM has been suggested to be involved in motor learning processes, such as sequence learning. Correlational evidence has shown the involvement of the fronto-parietal network (FPN), a network underlying WM processes, in motor sequence learning. However, causal evidence is currently lacking. Non-invasive brain stimulation (NIBS) studies have focused so far predominantly on motor related areas to enhance motor sequence learning while areas associated with more cognitive aspects of motor learning have not yet been addressed.

Hypothesis

In this study, we aim to provide causal evidence for the involvement of WM processes and the underlying FPN in successful motor sequence learning by using a theta transcranial alternating current stimulation (tACS) paradigm targeting the FPN during motor sequence learning.

Methods

In a cohort of 20 healthy older adults, we applied bifocal tACS in the theta range to the FPN during a sequence learning task. With the use of a double-blind, cross-over design, we tested the efficacy of active compared with sham stimulation. Two versions of the motor task were used: one with high and one with low WM load, to explore the efficacy of stimulation on tasks differing in WM demand. Additionally, the effects of stimulation on WM performance were addressed using an N-back task. The tACS frequency was personalized by means of EEG measuring the individual theta peak frequency during the N-back task.

Results

The application of personalized theta tACS to the FPN improved performance on the motor sequence learning task with high WM load (p <.001), but not with low WM load. Active stimulation significantly improved both speed (p <.001), and accuracy (p =.03) during the task with high WM load. In addition, the stimulation paradigm improved performance on the N-back task for the 2-back task (p = .013), but not for 1-back and 3-back.

Conclusion

Motor sequence learning can be enhanced with the use of personalized bifocal theta tACS to the FPN when WM load is high. This indicates that the efficacy of this stimulation paradigm is dependent on the cognitive demand during the learning task and provides further causal evidence for the critical involvement of WM processes and the FPN in motor sequence learning in healthy older adults. These findings open new exciting possibilities to counteract the age-related decline in motor learning capacity and WM performance.
Vps60 initiates formation of alternative membrane-bound ESCRT-III filaments
Authors: Pfitzner Anna-Katharina , Zivkovic Henry , Humbert Frédéric , Roux Aurélien
Published: February 2022

Endosomal sorting complex required for transport-III (ESCRT-III)-driven membrane remodeling participates in many crucial cellular functions, from cell division to endosome maturation, and occurs on essentially all cellular organelles. In eukaryotes, ESCRT-III displays a remarkable molecular diversity in its subunits which may have been acquired through evolution to perform novel cellular functions. Here, we describe and characterize a novel ESCRT-III polymer initiated by the subunit Vps60. Membrane-bound Vps60 polymers recruit ESCRT-III subunits Vps2, Vps24, Did2 and Ist1, and undergo polymer turnover powered by the ATPase Vps4. Snf7- and Vps60 filaments can coexist on membranes without interacting. Their nucleation, polymerization and recruitment of downstream subunits remains unaffected by the presence of the respective other polymer. Taken together, our results suggest Vps60 and Snf7 form distinct ESCRT-III polymers, which overall, supports the notion of evolutionary diversification of ESCRT-III assemblies to perform specific cellular functions.
Comparisons of cell proliferation and cell death across life histories in the hemichordate Schizocardium californicum
Authors: Bump Paul , Khariton Margarita , Stubbert Clover , Moyen Nicole E. , Yan Jia , Wang Bo , Lowe Christopher J.
Published: February 2022

Background

There are a wide range of developmental strategies in animal phyla, but most insights into adult body plan formation come from direct-developing species. For indirect-developing species, there are distinct larval and adult body plans that are linked together by metamorphosis. Some outstanding questions in indirect-developing organisms include the extent to which larval tissue undergoes cell death during the process of metamorphosis and when the tissue that will give rise to the adult originates. Here we present patterns of cell proliferation and cell death during larval development, metamorphosis, and adult body plan formation, in the hemichordate Schizocardium californium to answer these questions.

Results

We identified distinct patterns of cell proliferation between larval and adult body plan formation of S. californicum. We found that some adult tissues proliferate prior to the start of any morphological metamorphosis. Additionally, we describe a genetic signature of proliferative cells with an irradiation approach that revealed markers shared between the life history states and others that are unique to larvae or juveniles. Finally, we observed that cell death is minimal in larval stages but begins with the onset of metamorphosis.

Conclusions

Cell proliferation during the development of S. californicum has distinct patterns in the formation of larval and adult body plans. However, cell death is very limited in larvae and begins during the onset of metamorphosis and into early juvenile development in specific domains. The populations of cells that proliferate and give rise to the larva and juvenile have a genetic signature that is more suggestive of a heterogeneous pool of proliferative progenitors versus a population of pluripotent set-aside cells. Taken together, we propose that S. californicum has a transformative metamorphosis that may be more representative of the development strategies that characterize metamorphosis in many metazoan animals.
Hypoxic response is driven by the BAF form of SWI/SNF
Authors: Tran Kathleen Diep , Chakravarty Tomali , Garzon Jada Lauren , Saraf Anita , Florens Laurence , Washburn Michael P. , Dutta Arnob
Published: February 2022

SWI/SNF has been shown to have important functions in hypoxia-mediated gene expression through roles of its catalytic and core subunits. Since SWI/SNF exists as three distinct assemblies, and usage of complex specific subunits of the complex can be expected to vary within a given cell under changing environmental conditions. It remains an open question as to the compositional makeup of SWI/SNF and the roles of individual complexes in gene expression and cell viability in a hypoxic environment. In our current study, we find that hypoxia regulates levels of unique subunits that define each complex. Protein levels of ARID2 and PBRM1, members of PBAF and BRD9, a member of ncBAF, are downregulated in hypoxic cells, while members of BAF complex are retained. Our studies further show that loss of ARID1A, ARID1B and DPF2, which are unique subunits of BAF, reduces induction of HIF target genes and ARID1A or DPF2 are important for cell survival during hypoxia. Collectively, our results provide evidence that levels of SWI/SNF forms are not static within cells, but can be dynamically altered as a response to environmental changes.
Synaptic basis of a sub-second representation of time
Authors: Barri A. , Wiechert M. T. , Jazayeri M. , DiGregorio D. A.
Published: February 2022

Temporal sequences of neural activity are essential for driving well-timed behaviors, but the underlying cellular and circuit mechanisms remain elusive. We leveraged the well-defined architecture of the cerebellum, a brain region known to support temporally precise actions, to explore theoretically whether the experimentally observed diversity of short-term synaptic plasticity (STP) at the input layer could generate neural dynamics sufficient for subsecond temporal learning. Simulated synaptic input generated a diverse set of transient, firing patterns in granule cells (GCs) that provided a temporal basis set for learning precisely timed pauses of Purkinje cell activity associated with delayed eyelid conditioning and Bayesian interval estimation. The learning performance across time intervals was influenced by the temporal bandwidth of the GC basis, which was determined by the input layer synaptic properties. The ubiquity of STP throughout the brain positions it as a general, tunable cellular mechanism for sculpting neural dynamics and fine-tuning behavior.
A single 2’-O-methylation of ribosomal RNA gates assembly of a functional ribosome
Authors: Yelland James N. , Bravo Jack P.K. , Black Joshua J. , Taylor David W. , Johnson Arlen W.
Published: February 2022

RNA modifications are widespread in biology, and particularly abundant in ribosomal RNA. However, the significance of these modifications is not well understood. We show that methylation of a single universally conserved nucleotide, in the catalytic center of the large subunit, gates ribosome assembly. Massively parallel mutational scanning of the essential nuclear GTPase Nog2 identified important interactions with ribosomal RNA helix 92, particularly with the methylated A-site base Gm2922. We found that 2’-O-methylation of G2922 is needed for efficient nuclear export of the large subunit. Critically, we identified single amino acid changes in Nog2 that completely bypass its dependence on G2922 methylation. By solving the cryo-EM structure of the unmodified nascent subunit, we reveal how methylation flips Gm2922 into the active site channel of Nog2. This work demonstrates that a single RNA modification is a critical checkpoint in ribosome biogenesis, and suggests that RNA modifications can play an important role in regulation and assembly of macromolecular machines.
Modeling exercise using optogenetically contractible Drosophila larvae
Authors: Ghosh Arpan C. , Liu Yifang , Tattikota Sudhir Gopal , Hu Yanhui , Perrimon Norbert
Published: February 2022

The pathophysiological effects of a number of metabolic and age-related disorders can be prevented to some extent by exercise and increased physical activity. However, the molecular mechanisms that contribute to the beneficial effects of muscle activity remain poorly explored. Availability of a fast, inexpensive, and genetically tractable model system for muscle activity and exercise will allow the rapid identification and characterization of molecular mechanisms that mediate the beneficial effects of exercise. Here, we report the development and characterization of an optogenetically-inducible muscle contraction (OMC) model in Drosophila larvae that we used to study acute exercise-like physiological responses. To characterize muscle-specific transcriptional responses to acute exercise, we performed bulk mRNA-sequencing, revealing striking similarities between acute exercise-induced genes in flies and those previously identified in humans. Our larval muscle contraction model opens a path for rapid identification and characterization of exercise-induced factors.
GSK3 inhibition improves skeletal muscle function and whole-body metabolism in the severe DBA/2Jmdxmouse model
Authors: Marcella Bianca M. , Hockey Briana L. , Braun Jessica L. , Whitley Kennedy C. , Geromella Mia S. , Baranowski Ryan W. , Watson Colton J.F. , Silvera Sebastian , Hamstra Sophie I. , Wasilewicz Luc J. , Crozier Robert W.E. , Marais Amelie , Vandenboom Rene , Roy Brian D. , MacNeil Adam J. , MacPherson Rebecca E.K. , Fajardo Val A.
Published: February 2022

Introductory paragraph

Duchenne muscular dystrophy (DMD) is a severe X-linked muscle wasting disorder that affects 1 in 5,000 males worldwide1. It is caused by the absence of functional dystrophin, which compromises muscle integrity, leading to progressive muscle wasting and weakness2. Glucocorticoids are the standard of care for patients with DMD as they delay the loss of ambulation by an average of 3 years3; however, they are also associated with adverse effects such as insulin resistance and increased risk of type 2 diabetes4. Thus, alternative therapeutic options should be explored. Here, we show that treating the DBA/2Jmdxmouse with the glycogen synthase kinase 3 (GSK3) inhibitor, tideglusib, improved skeletal muscle function and insulin sensitivity, while also attenuating the hypermetabolic phenotype previously observed in these mice5. Furthermore, treatingmdxmice with the GSK3 inhibitor, lithium, augmented the benefits of voluntary wheel running on insulin sensitivity and skeletal muscle function despite running half of the total distance compared to control-treatedmdxmice. This is important given that some patients with DMD may not be able to engage in adequate amounts of physical activity. Thus, GSK3 inhibition alone or in combination with exercise can enhance skeletal muscle function and insulin sensitivity inmdxmice.
Postnatal environmental enrichment enhances memory by shaping hippocampal-prefrontal theta and gamma rhythms in diploid and trisomic female mice
Authors: Alemany-González Maria , Vilademunt Marta , Gener Thomas , Nebot Pau , Puig M. Victoria
Published: February 2022

Rich social, physical, and cognitively stimulating lifestyles have powerful effects on cognitive abilities, especially when they are experienced early in life. Cognitive therapies are widely used to attenuate cognitive impairment due to intellectual disability, but also aging and neurodegeneration, however the underlying neural mechanisms are poorly understood. Here we investigated the neural substrates of memory amelioration induced by postnatal environmental enrichment (EE) in diploid female mice and Ts65Dn female mice with partial trisomy of genes ortholog to human chromosome 21, a standard model of Down syndrome (DS, trisomy 21). We recorded neural activities in two brain structures key for cognitive function, the hippocampus and the prefrontal cortex, during rest, sleep and memory performance in mice reared in standard or enriched environments for 7 weeks post-weaning. We found that EE shaped hippocampal- prefrontal neural dynamics in diploid mice and rescued the same disrupted pathways in Ts65Dn mice. The neural activity changes detected in EE-reared wild-type mice combined task-independent adjustments (augmented hippocampal pyramidal activity and gamma synchrony across different brain states) and memory-dependent adjustments (enhanced theta-gamma coupling and ripples in the HPC). Therefore, both brain state adjustments and memory-associated adjustments are good candidates to underlie the beneficial effects of EE on cognition in diploid female mice. Concomitantly, EE attenuated hippocampal and prefrontal hypersynchrony in trisomic females, suggesting distinct neural mechanisms for the generation and rescue of healthy and pathological brain synchrony, respectively, by EE. These results put forward hippocampal hypersynchrony and hippocampal-prefrontal miscommunication as major neural mechanisms underlying the beneficial effects of EE for intellectual disability in DS.
Bioinformatic analysis of B and T cell epitopes from SARS-CoV-2 Spike, Membrane and Nucleocapsid proteins as a strategy to assess possible cross-reactivity between emerging variants, including Omicron, and other human coronaviruses
Authors: Pacheco-Olvera Diana Laura , Remy-Hernández Stephanie Saint , García-Valeriano María Guadalupe , Rivera-Hernández Tania , López-Macías Constantino
Published: February 2022

The COVID-19 pandemic caused by SARS-CoV-2 produced a global health emergency since December 2019, that up to the end of January 2022 had caused the death of more than 5.6 million people worldwide. Despite emergence of new variants of concern, vaccination remains one of the most important tools to control the pandemic. All approved vaccines and most of the vaccine candidates use the spike protein of the virus as a target antigen to induce protective immune responses. Several variants of the virus present key mutations in this protein which render the virus, at different rates, to evade the neutralizing antibody response. Although experimental evidence suggests that cross-reactive responses between coronaviruses are present in the population, it is unknown which potential antigens shared between different coronaviruses could be responsible for these responses. This study provides predictions of new potential B and T cell epitopes within SARS-CoV-2 Spike (S), Membrane (M) and Nucleocapsid (N) proteins together with a review of the reported B epitopes of these proteins. We also analyse amino acid changes present in the epitopes of variants of concern (VOC) and variants being monitored (VBM), and how these might affect the immune response, as these changes may alter the peptides’ immunogenicity index and the antigen presentation by related HLA alleles. Finally, given these observations, we performed an identity analysis between the repertoire of potential epitopes of SARS-CoV-2 and other human coronaviruses to identify which are conserved among them.

The results shown here together with the published experimental evidence, allow us to support the hypothesis that antibody and T cell cross-reactive responses to common coronaviruses epitopes, could contribute to broaden the protective response to SARS-CoV-2 and its variants. This evidence could help not only to understand cross-reactive responses among coronaviruses but also contribute to elucidate their role in immunity to SARS-CoV-2 induced by infection and/or vaccination. Finally, these findings could promote targeted analysis of antigen-specific immune responses and might orient and drive the rational development of new SARS-CoV-2 vaccines including candidates that ideally provide “universal” protection against other coronaviruses relevant to human health.
Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells
Authors: Gerdes Patricia , Lim Sue Mei , Ewing Adam D. , Larcombe Michael R. , Chan Dorothy , Sanchez-Luque Francisco J. , Walker Lucinda , Carleton Alexander L. , James Cini , Knaupp Anja S. , Carreira Patricia E. , Nefzger Christian M. , Lister Ryan , Richardson Sandra R. , Polo Jose M. , Faulkner Geoffrey J.
Published: February 2022

Induced pluripotent stem cells (iPSCs) can in principle differentiate into any cell of the body, and have revolutionized biomedical research and regenerative medicine. Unlike their human counterparts, mouse iPSCs (miPSCs) are reported to silence transposable elements (TEs) and prevent TE-mediated mutagenesis. Here we applied short-read or Oxford Nanopore Technologies (ONT) long-read genome sequencing to 38 bulk miPSC lines reprogrammed from 10 parental cell types, and 18 single-cell miPSC clones. While single nucleotide variants and structural variants restricted to miPSCs were rare, we found 83de novoTE insertions, including examples intronic toBrca1andDmd. LINE-1 (L1) retrotransposons were profoundly hypomethylated in miPSCs, beyond other TEs and the genome overall, and harbored alternative protein-coding gene promoters. Treatment with the L1 inhibitor lamivudine did not hinder reprogramming and efficiently blocked endogenous retrotransposition, as detected by ONT sequencing. These experiments reveal the complete spectrum and potential significance of mutations acquired by miPSCs.
Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity
Authors: Guo Heyun , Stamper Ericca L. , Sato-Carlton Aya , Shimazoe Masa A. , Li Xuan , Zhang Liangyu , Stevens Lewis , Jacky Tam KC , Dernburg Abby F. , Carlton Peter M.
Published: February 2022

In the first meiotic cell division, proper segregation of chromosomes in most organisms depends on chiasmata, exchanges of continuity between homologous chromosomes that originate from the repair of programmed double-strand breaks (DSBs) catalyzed by the Spo11 endonuclease. Since DSBs can lead to irreparable damage in germ cells, while chromosomes lacking DSBs also lack chiasmata, the number of DSBs must be carefully regulated, so as to be neither too high nor too low. Here, we show that in Caenorhabditis elegans, meiotic DSB levels are controlled by the phosphoregulation of DSB-1, a homolog of the yeast Spo11 cofactor Rec114, by the opposing activities of PP4PPH-4.1 phosphatase and ATRATL-1 kinase. Increased DSB-1 phosphorylation in pph-4.1 mutants correlates with reduction in DSB formation, while prevention of DSB-1 phosphorylation drastically increases the number of meiotic DSBs both in pph-4.1 mutants as well as in the wild type background. C. elegans and its close relatives also possess a diverged paralog of DSB-1, called DSB-2, and loss of dsb-2 is known to reduce DSB formation in oocytes with increasing age. We show that the proportion of the phosphorylated, and thus inactivated, form of DSB-1 increases with age and also upon loss of DSB-2, while non-phosphorylatable DSB-1 rescues the age-dependent decrease in DSBs in dsb-2 mutants. These results suggest that DSB-2 evolved in part to compensate for the inactivation of DSB-1 through phosphorylation, to maintain levels of DSBs in older animals. Our work shows that PP4PPH-4.1, ATRATL-1, and DSB-2 act in concert with DSB-1 to promote optimal DSB levels throughout the reproductive lifespan.
The acute lag effects of elevated ambient air pollution on stillbirth risk in Ulaanbaatar, Mongolia
Authors: Enebish Temuulen , Warburton David , Habre Rima , Breton Carrie , Tuvshindorj Nomindelger , Tumur Gantuya , Munkhuu Bayalag , Franklin Meredith
Published: February 2022

Ulaanbaatar city (UB), the capital and the home to half of Mongolia’s total population, has experienced extreme seasonal air pollution in the past two decades with levels of fine particulate matter with an aerodynamic diameter less than 2.5 micrometers (PM2.5) exceeding 500 μg/m3 during winter. Based on monitoring data, (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and carbon monoxide (CO) exposures were estimated for residential areas across UB using Random Forest models. We collected individual-level data on 1093 stillbirths from UB hospital records (2010-2013) and a surveillance database (2014-2018). Using a time-stratified case-crossover design, we investigated whether short-term increases in daily ambient air pollutants with different exposure lags (2 to 6 days) before delivery were associated with stillbirth. We estimated associations using conditional logistic regression and examined individual-level characteristics for effect modification. During the cold season (Oct-Mar) we observed significantly elevated relative odds of stillbirth per interquartile range increase in mean concentrations of PM2.5 (odds ratio [OR]=1.35, 95% confidence interval [CI]=1.07-1.71), SO2 (OR=1.71, 95% CI=1.06-2.77), NO2 (OR=1.30, 95% CI=0.99-1.72), and CO (OR=1.44, 95% CI=1.17-1.77) 6 days before delivery after adjusting for apparent temperature with a natural cubic spline. The associations of pollutant concentrations with stillbirth were significantly stronger among those younger than 25, nulliparous, and without comorbidities or pregnancy complications during stratified analyses. There was a clear pattern of increased risk for women living in areas of lower socioeconomic status. We conclude that acute exposure to ambient air pollution before delivery may trigger stillbirth, and this risk is higher for certain subsets of women.
A systematic review of previous MRI studies demonstrating the relationship between season and brain volume
Authors: Majrashi Naif A. , Alyami Ali S.
Published: February 2022

Introduction

Specific diseases such as Alzheimer’s, schizophrenia and multiple sclerosis have been associated with environmental changes, including changes in season. The relationship between changes in season or photoperiod and brain volume has been widely studied in animals. However, the relationship between changes in season and brain volume in humans is not yet well established. Here, we aim to provide a comprehensive and systematic review of magnetic resonance imaging (MRI) studies examining the effects of changes in season or photoperiod on brain volume.

Methods

We used a systematic review approach to study reports on the relationship between changes in season or photoperiod and brain volume using MRI. PubMed database and Google Scholar search engines were used to locate appropriate. PRISMA was used in selection of appropriate studies on season or photoperiod and brain volume using MRI.

Results

Five studies were included in the current review: three examined the relationship between changes in photoperiod and brain volumes while two studies examined the relationship between changes in season and brain volume.

Conclusion

When studying other variables like changes in temperature and humidity on how they affect brain volume, no effect was observed. It was, however, observed from studies that hydration status changed brain volumes when measured using MRI. Overall, we found evidence demonstrating differences in human brain volumes across different seasons. We suggest future longitudinal research to prove changes in brain volume across different seasons.
Brain regional identity and cell type specificity landscape of human cortical organoid models
Authors: Magni M. , Bossi B. , Conforti P. , Galimberti M. , Dezi F. , Lischetti T , He X. , Barker R.A. , Zuccato C. , Espuny-Camacho I. , Cattaneo E.
Published: February 2022

In vitro models of corticogenesis using mouse and human pluripotent stem cells (PSC) have greatly improved our understanding of human brain development and disease. Among these, 3D cortical organoid systems are able to recapitulate some aspects of in vivo cytoarchitecture of the developing cortex.

Here, we tested three cortical organoid protocols for brain regional identity, cell type-specificity and neuronal maturation. Overall all protocols gave rise to organoids that displayed a time-dependent expression of neuronal maturation genes such as those involved in the establishment of synapses and neuronal function. We showed that three months old cortical organoids showed a pattern of gene expression that resembled late human embryonic cortex. Comparatively, directed differentiation methods without WNT activation gave rise to the highest degree of cortical regional identity in brain organoids. Whereas, default “intrinsic” brain organoid differentiation produced the broadest range of cell types such as neurons, astrocytes and hematopoietic-lineage derived microglia cells of the brain. These results suggest that cortical organoid models produce diverse outcomes in terms of brain regional identity and cell type specificity and emphasize the importance of selecting the correct model for the right application.