bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ribosome-rescuer PELO catalyzes the oligomeric assembly of NLR family proteins via activating their ATPase
Authors: Wu Xiurong , Yang Zhang-Hua , Wu Jianfeng , Han Jiahuai 
Published: October 2022

SUMMARYNOD-like receptors (NLRs) are pattern recognition receptors for diverse innate immune responses. Self-oligomerization after engagement with a ligand was a generally accepted model for the activation of each NLR. We report here that a catalyzer is required for the self-oligomerization. Protein pelota homolog (PELO, Dom34 in yeast), a well-known surveillance factor in translational quality control/ribosome rescue, interacts with all cytosolic NLRs and activates their ATPase. In the case of flagellin-initiated NLRC4 inflammasome activation, flagellin-bound NAIP5 recruits the first NLRC4 and then PELO is required for correctly assembling the rest of NLRC4s into the NLRC4 complex one by one by activating the NLRC4 ATPase. Stoichiometric and functional data revealed that PELO cannot be a structural constituent of NLRC4 inflammasome but a powerful catalyzer for its assembly. The catalytic role of PELO in the activation of cytosolic NLRs is unexpected and may break new ground for future studies of NLR family members.
Eliminating mother-to-child transmission of HIV in Tanzania calls for efforts to address factors associated with a low confirmatory test
Authors: Morris Baraka M. , Nyamhagata Mukome , Tarimo Edith , Sunguya Bruno 
Published: October 2022

AbstractBackgroundOption B+ approach for prevention of mother-to-child transmission (PMTCT) has demonstrated the potential to eliminate pediatric HIV infections. Its success depends on early infant diagnosis (EID) of HIV among the exposed infants within the first 6 weeks, and a subsequent confirmatory HIV test at the 18th month. However, most mothers enrolled in the PMTCT-option B+ cascade of services in Tanzania do not turn-up for such confirmatory tests. We examined factors associated with the turning-up of mother-baby pairs on the PMTCT program for confirmatory HIV testing 18 months post-delivery in Tanzania.MethodsThis study utilized longitudinal data collected between 2015 and 2017 from 751 mother-baby pairs enrolled in the PMTCT-Option B+ approach in 79 health facilities from the 12 regions of Tanzania-mainland. Analysis was conducted using descriptive statistics to characterize the proportion of mother-baby pairs turning up for a confirmatory test and logistic regression analysis to examine factors associated with turning up for a confirmatory HIV testing at the 18th month.ResultsA total of 751 mother-baby records were observed only and 44.2% (95% CI: 40.7 – 47.8) of them received the HIV confirmatory test at 18 months. Mothers aged 25 years or above (adults’ mothers) were 1.44 more likely to turn up for confirmatory HIV-testing than young mothers; mothers with partners tested for HIV were 1.74 more likely to have confirmatory HIV-testing compared with partners not tested for HIV; newly HIV-positive mothers diagnosed on enrolment were 28% less likely to turn up their babies for confirmatory HIV-testing compared to known HIV-positive mothers; mothers with treatment supporters were 1.58 more likely to receive confirmatory HIV-testing compared to mothers without one, and mothers with babies whose DBS-PCR-1 was collected were 3.61 more likely to have confirmatory HIV-testing than those who didn’t collect DBS-PCR-1.ConclusionThis study reveals that the turn-up for confirmatory HIV testing at 18 months among mother-baby pairs enrolled in the Option B+ approach is still low in Tanzania. This turn-up is associated with low maternal age, having a male partner who has not tested for HIV, lack of experience with HIV services, lack of treatment supporters, and failure to take the first DBS-PCR HIV test within the first two months post-delivery.
The ZMYND8 chromatin factor protects cardiomyocyte identity and function in the mouse heart
Authors: Kekūpaʻa Knutson Andrew , Avelar Abigail , Shohet Ralph V. 
Published: October 2022

ABSTRACTAppropriate gene expression within cardiomyocytes is coordinated by chromatin factors and is essential for heart function. We investigated the role of the chromatin reader ZMYND8 in the mouse heart using null and conditional knockouts (Zmynd8-cKO). While full-lengthZmynd8is not required for cardiomyocyte development,Zmynd8-cKOmice develop cardiomegaly, decreased cardiac function, and premature death compared to controls. Transcriptome analysis ofZmynd8-cKOcardiomyocytes reveals illegitimate expression of transcripts normally limited to skeletal muscle. Additionally, we observe integration of TNNI2 skeletal troponin into cardiac sarcomeres of mutant mice. We conclude that ZMYND8 is necessary to maintain appropriate cardiomyocyte gene expression and cardiac function.
The X-factor in ART: does the use of Assisted Reproductive Technologies influence DNA methylation on the X chromosome?
Authors: Romanowska Julia , Nustad Haakon E. , Page Christian M. , Denault William R.P. , Bohlin Jon , Lee Yunsung , Magnus Maria C. , Haftorn Kristine L. , Gjerdevik Miriam , Novakovic Boris , Saffery Richard , Gjessing Håkon K. , Lyle Robert , Magnus Per , Håberg Siri E. , Jugessur Astanand 
Published: October 2022

AbstractBackgroundAssisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother-father-newborn trios of ART and non-ART (natural) conceptions to date to investigate DNAm differences on the X chromosome.Materials and MethodsThe discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). The replication cohort consisted of 149 ART and 58 non-ART neonates from the Australian “Clinical review of the Health of adults conceived following Assisted Reproductive Technologies” (CHART) study. The Illumina EPIC array was used to measure DNA methylation (DNAm) in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies (“XWASs” hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. For replication purposes, we ran an analogous model to our main model on the CHART dataset.Results and conclusionsIn the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted even after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental infertility as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was inUBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were inEIF2S3andAMOT. These three loci also displayed differential DNAm in the CHART cohort. Overall, genes that co-localized with the significant CpGs and DMRs are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism. These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to naturally-conceived.
Losses resulting from deliberate exploration trigger beta oscillations in frontal cortex
Authors: Chernyshev Boris V. , Pultsina Kristina I. , Tretyakova Vera D. , Miasnikova Aleksandra S. , Prokofyev Andrey O. , Kozunova Galina L. , Stroganova Tatiana A. 
Published: October 2022

AbstractWe examined the neural signature of directed exploration by contrasting MEG beta (16-30 Hz) power changes between disadvantageous and advantageous choices in the two-choice probabilistic reward task. We analyzed the choices made after the participants have learned the probabilistic contingency between choices and their outcomes, i.e., acquired the inner model of choice values. Therefore, rare disadvantageous choices might serve explorative, environment-probing purposes. The study brought two main findings. Firstly, decision making leading to disadvantageous choices took more time and evidenced greater large-scale suppression of beta oscillations than its advantageous alternative. Additional neural resources recruited during disadvantageous decisions strongly suggest their deliberately explorative nature. Secondly, an outcome of disadvantageous and advantageous choices had qualitatively different impact on feedback-related beta oscillations. After the disadvantageous choices, only losses – but not gains – were followed by late beta synchronization in frontal cortex. Our results are consistent with the role of frontal beta oscillations in the stabilization of neural representations for selected behavioral rule when explorative strategy conflicts with value-based behavior. Punishment for explorative choice being congruent with its low value in the reward history is more likely to strengthen, through punishment-related beta oscillations, the representation of exploitative choices consistent with the inner utility model.
Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice
Authors: Green Cara L. , Trautman Michaela E. , Babygirija Reji , Jain Raghav , Chaiyakul Krittisak , Pak Heidi H. , Bleicher Anneliese , Novak Grace , Sonsalla Michelle M. , Yeh Chung-Yang , Calubag Mariah F. , Liu Teresa T. , Flores Victoria , Newman Sarah , Ricke Will A. , Matkowskyj Kristina A. , Ong Irene M. , Simcox Judith , Lamming Dudley W. 
Published: October 2022

AbstractLow protein (LP) diets promote health and longevity in diverse species. Although the precise components of an LP diet that mediate its beneficial effects have not been defined, reducing dietary levels of the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine promotes metabolic health in both sexes, and increases lifespan while reducing frailty in male, but not female, C57BL/6J mice. Each BCAA has unique metabolic effects, and we recently showed that restriction of isoleucine is both sufficient to promote metabolic health and required for the metabolic benefits of an LP diet in male C57BL/6J mice. Here, we tested the hypothesis that specifically restricting isoleucine could promote healthy aging in genetically heterogenous UM-HET3 mice. We find that a reduced isoleucine diet improves the metabolic health of both young and old HET3 mice, promoting leanness and glycemic control. Restriction of isoleucine starting in adult, 6 month old HET3 mice reprograms hepatic metabolism in a way distinct from an LP diet. Finally, we find that a reduced isoleucine diet reduces frailty and extends the lifespan of both male and female HET3 mice, but to a much greater degree in males. Our results demonstrate that restricting dietary isoleucine can increase health span and longevity in a genetically diverse population of mice, and suggests that reducing dietary levels of isoleucine may have great potential as a geroprotective intervention.
HIV-1 neutralization tiers are not relevant for inhibitors targeting the pre-hairpin intermediate
Authors: Bell Benjamin N. , Bruun Theodora U. J. , Friedland Natalia , Kim Peter S. 
Published: October 2022

AbstractHIV-1 strains are categorized into one of three neutralization tiers based on the relative ease by which they are neutralized by plasma from HIV-1 infected donors not on antiretroviral therapy; tier-1 strains are particularly sensitive to neutralization while tier-2 and tier-3 strains are increasingly difficult to neutralize. Most broadly neutralizing antibodies (bnAbs) previously described target the native prefusion conformation of HIV-1 Envelope (Env), but the relevance of the tiered categories for inhibitors targeting another Env conformation, the pre-hairpin intermediate, is not well understood. Here we show that two inhibitors targeting distinct highly-conserved regions of the pre-hairpin intermediate have strikingly consistent neutralization potencies (within ∼100-fold for a given inhibitor) against strains in all three neutralization tiers of HIV-1; in contrast, best-in-class bnAbs targeting diverse Env epitopes vary by more than 10,000-fold in potency against these strains. Our results indicate that antisera-based HIV-1 neutralization tiers are not relevant for inhibitors targeting the pre-hairpin intermediate and highlight the potential for therapies and vaccine efforts targeting this conformation.
Cell division history encodes directional information of fate transitions
Authors: Wang Kun , Hou Liangzhen , Lu Zhaolian , Wang Xin , Zi Zhike , Zhai Weiwei , He Xionglei , Curtis Christina , Zhou Da , Hu Zheng 
Published: October 2022

AbstractSingle-cell RNA-sequencing (scRNA-seq) enables systematic mapping of cellular differentiation trajectories. However, inferring the cell-fate transitions under diseases or perturbations is still challenging due to the high cellular plasticity. Here, we demonstrate that monotonically expressed genes (MEGs) along cell divisions record the directions of state transitions regardless of the cellular processes. We developed a computational framework (PhyloVelo) to identify MEGs and reconstruct a novel transcriptomic velocity field by leveraging both scRNA-seq and phylogenetic information. PhyloVelo accurately recovered linear, bifurcated and convergent differentiations in simulations and C. elegans. It outperformed current approaches for delineating cellular trajectories in embryo development and tumor evolution through analysis of five CRISPR/Cas9-based lineage tracing datasets. Together, our study unveils an internal cellular clock and provides a powerful method for cellfate analysis in diverse biological contexts.
Proximity Analysis of Native Proteomes Reveals Interactomes Predictive of Phenotypic Modifiers of Autism and Related Neurodevelopmental Conditions
Authors: Gao Yudong , Trn Matthew , Shonai Daichi , Zhao Jieqing , Soderblom Erik J. , Garcia-Moreno S. Alexandra , Gersbach Charles A. , Wetsel William C. , Dawson Geraldine , Velmeshev Dmitry , Jiang Yong-hui , Sloofman Laura G. , Buxbaum Joseph D. , Soderling Scott H. 
Published: October 2022

AbstractOne of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving high specificity spatial interactomes compared to prior methods. The resulting native proximity interactomes are enriched for human genes dysregulated in the brain of autistic individuals and reveal unexpected and highly significant interactions with other lower-confidence autism risk gene products, positing new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the condition. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two autism models, demonstrating functional interactions that modulate mechanisms of their dysregulation. Together, these results reveal native proteome networksin vivorelevant to autism, providing new inroads for understanding and manipulating the cellular drivers underpinning its etiology.
CBD resistantSalmonellastrains are susceptible to Epsilon 34 phage tailspike protein
Authors: Ibrahim Iddrisu , Ayariga Joseph Atia , Xu Junhuan , Adebanjo Ayomide , Samuel-Foo Michelle , Ajayi Olufemi S. 
Published: October 2022

AbstractThe rise of antimicrobial resistance is a global public health crisis that threatens the effective control and prevention of infections. Due to the emergence of pandrug-resistant bacteria, most antibiotics have lost their efficacy. Meanwhile, the development of new antimicrobials has stagnated, which leads to the creation of new and unconventional treatments. Bacteriophages or their components are known to target bacterial cell walls, cell membranes, and lipopolysaccharides (LPS) and hydrolyze them. Bacteriophages being the natural predators of pathogenic bacteria, are inevitably categorized as “human friends”, thus fulfilling the adage that “the enemy of my enemy is my friend”. Leveraging on their lethal capabilities against pathogenic bacteria, researchers are searching for more ways to overcome the current antibiotic resistance challenge. Bacteriophages are considered to be one of the most effective alternative therapies for multidrug resistant bacteria. In this study, we expressed and purified epsilon 34 phage tailspike protein (E34 TSP) from the E34 TSP gene which was previously cloned into a pET30a-LIC vector, then assessed the ability of this bacteriophage protein in the killing of two CBD-resistant strains ofSalmonellaspp. We observed that the combined treatment of CBD-resistant strains ofSalmonellawith CBD and E34 TSP showed poor killing ability whereas the monotreatment with E34 TSP showed considerably higher killing efficiency.
The Human Pangenome’s sequence conservation reveals a landscape of polymorphic structural variations
Authors: Lee HoJoon , Greer Stephanie U. , Pavlichin Dmitri S. , Hughes Christopher R. , Zhou Bo , Weissman Tsachy ,   Human Pangenome Reference Consortium, Ji Hanlee P. 
Published: October 2022

ABSTRACTThe Human Pangenome is a new reference build that addresses many of the limitations of the current reference. The first release is based on 94 high-quality haploid assemblies from individuals with diverse backgrounds. To facilitate the Pangenomes adoption in the wider research community, we conducted a multiple genome comparative analysis against the current GRCh38 reference. We applied a k-mer indexing strategy to identify highly conserved sequences that are omnipresent across all Pangenome assemblies, the reference and CHM13, a reference assembly with telomere-to-telomere chromosomes. Pan-conserved tag segments provided an informative set of universally conserved sequences. Examining the intervals between pairs of these segments defined highly conserved segments of the genome versus ones that have structurally related polymorphisms. We identified a Pangenome landscape of 60,764 polymorphic intervals with unique and geo-ethnic features. Overall, this study of the Pangenome revealed the conserved versus divergent features including the landscape of polymorphic structural variants.
Assessment of the Feasibility of Remote Training, At-Home Testing, and Test-Retest Variability of Clustered Virtual Reality Perimetry
Authors: Chia Zer Keen , Kong Alan W. , Turner Marcus L. , Saifee Murtaza , Damato Bertil E. , Backus Benjamin T. , Blaha James J. , Schuman Joel S. , Deiner Michael , Ou Yvonne 
Published: October 2022

AbstractObjectiveTo assess the feasibility of remotely training glaucoma patients to take a ten-session clustered virtual reality (VR) visual field test (VVP-10) at home, analyze results for test-retest variability, and assess correspondence with conventional perimetry.DesignCross-sectional study.Subjects21 subjects with glaucoma were enrolled and included in the feasibility assessment of remote training. 36 eyes were used for test-retest analysis and determination of concordance with Humphrey Visual Field (HVF) testing.MethodsSubjects were provided with a mobile VR headset containing the VVP-10 test software and trained remotely via video conferencing. Subjects were instructed to complete ten sessions over a 14-day period.Main Outcome MeasuresFeasibility was determined by the number of subjects who were able to independently complete VVP-10 over the 14-day period after one remote training session. Intraclass correlation coefficient (ICC) of average fraction seen across ten sessions and standard error (SE) for the mean were primary outcome measures for assessing test-retest variability. Correlation with HVF mean sensitivity (MS) across eyes, was a secondary outcome measure.Results20 subjects (95%) successfully completed the VVP-10 test series after one training session. ICC of VVP-10 was 0.95 (95% CI [0.92, 0.97]). Mean SE in units of fraction seen was 0.012. The Spearman correlations of VVP-10 average fraction seen versus HVF MS were 0.88 (95% CI [0.66, 0.99]) for moderate to advanced glaucoma eyes, and decreased to 0.68 (95% CI [0.29, 0.94]) when all eyes were included.ConclusionsRemote training of patients at home is feasible and subsequent remote clustered visual field testing using VVP-10 by patients on their own without any further interactions with caregivers or study staff was possible. At-home VVP-10 results demonstrated low test-retest variability. Future studies must be conducted to determine if VVP-10, taken at home as convenient for the patient, may be a viable supplement to provide equivalent or complementary results to that of standard in-clinic assessment of visual function in glaucoma.
Body Composition, Cardiometabolic Risk Factors and Comorbidities in Psoriasis and the Effect ofHLA-C*06:02Status: The HUNT Study, Norway
Authors: Solvin Åshild Ø. , Bjarkø Vera V. , Thomas Laurent F. , Berrospi Patricia , Hveem Kristian , Saunes Marit , Åsvold Bjørn O. , Løset Mari 
Published: October 2022

ABSTRACTPsoriasis has been associated with increased adiposity measures driving systemic inflammation, which may lead to metabolic dysfunction and comorbidities. In this population-based, cross-sectional study, we used data from 56 042 individuals in the fourth wave of the Trøndelag Health Study (HUNT4), to investigate the associations between psoriasis and body composition measures assessed using bioelectrical impedance analysis, cardiometabolic risk factors, and comorbidities. Further, we investigated the associations betweenHLA-C*06:02status, a potential clinical biomarker for a distinct psoriasis endotype, and these outcomes. Psoriasis was associated with increased adiposity measures, including increased body and visceral fat, and lower levels of skeletal muscle and soft lean mass, as well as higher prevalence of cardiovascular, respiratory and endocrine disorders.HLA-C*06:02-positive individuals with psoriasis had lower levels of hsCRP, increased prevalence of atrial fibrillation and decreased prevalence of migraine. Our results point to altered body composition in psoriasis with increased levels of fat, and particularly metabolically active visceral fat, and provide support for a broad clinical approach to psoriatic patients in a general population.