bluuebunny/crossref_metadata_2025 huggingface dataset:
Health aspects of vegan diets among children and adolescents: a systematic review and meta-analyses
Authors: Koller Alina , Rohrmann Sabine , Wakolbinger Maria , Gojda Jan , Selinger Eliska , Cahova Monika , Svetnicka Martin , Haider Sandra , Schlesinger Sabrina , Kuhn Tilman , Keller Jeffrey
Published: May 2023

Health effects of vegan diets among children are a controversial public health topic. Thus, we evaluated a broad range of health outcomes among vegan children and adolescents aged 0 to 18 years by a systematic review and meta-analyses. 17 studies met the inclusion criteria (16 cross-sectional studies, one randomized trial). Meta-analyzes showed lower intakes of protein (%E MD[95%CI]: −3.54 [−5.08, −2.00]) and higher intakes of fiber (g/1000kcal MD[95%CI]: 8.01 [6.96, 9.06]) in vegans compared to omnivores. Non-meta-analyzable studies showed lower calorie, vitamin B12 (when not using supplements) and selenium intakes, as well as lower blood levels of ferritin and vitamin B12. By contrast, vegans had significantly higher intakes of folate, vitamin C and iron. Levels of several cardiometabolic biomarkers (cholesterol, LDL) and indicators of bone health (vitamin D and calcium intake, vitamin D blood levels, bone mineral density) were lower in vegans. Risk of Bias was rated as high or very high in seven out of 17 primary studies. The Certainty of the Evidence was low or very low in all meta-analyses. Vegan children and adolescents following a vegan diet may have a beneficial cardiovascular risk profile but may be at risk for impaired bone health.
Diffusion-limited O2release in human kidneys perfused with stored blood
Authors: Dumbill Richard , Rabcuka Julija , Knight Simon , Hunter James , Fallon John , Voyce Daniel , Barrett Jacob , Ellen Matt , Weissenbacher Annemarie , Kurniawan Tetuko , Blonski Slawomir , Korczyk Piotr , Ploeg Rutger , Coussios Constantin , Friend Peter , Swietach Pawel
Published: May 2023

A central dogma in physiology is that oxygen release at tissues is not diffusion-limited because gas exchange at capillaries is rapid. This assertion has influenced clinical care, which focuses on optimising oxygen delivery through improving blood flow and oxygen content, rather than oxygen unloading from red blood cells (RBCs). Since storage of blood causes profound changes that slow oxygen release from RBCs, transfusions could compromise tissue respiration. We investigated this in transplant human kidneys normothermically perfused with stored blood. During perfusions, renal respiration was measured from blood gases and RBCs were analysed for oxygen-unloading kinetics. Respiratory rate did not correlate significantly with the standard definition of oxygen delivery based on blood flow and oxygen content. However, a strong correlation was obtained after introducing a factor describing oxygen release from RBCs. Oxygen release to tissues can become diffusion-limited with transfused blood, and therefore the kinetic quality of RBCs should be considered.
HIV burden and the global fast-track targets progress among pregnant women in Tanzania calls for intensified case finding: Analysis of 2020 antenatal clinics HIV sentinel site surveillance
Authors: Mboya Erick , Mizinduko Mucho , Balandya Belinda , Mushi Jeremiah , Sabasaba Amon , Amani Davis Elias , Kamori Doreen , Ruhago George , Faustine Prosper , Maokola Werner , Sambu Veryeh , Nyamuhagata Mukome , Jullu Boniphace S. , Juya Amiri , Rugemalila Joan , Mgomella George , Asiimwe Sarah , Pembe Andrea B. , Sunguya Bruno
Published: May 2023

Background

For successful HIV response, updated information on the burden and progress towards elimination targets are required to guide programmatic interventions. We used data from the 2020 HIV sentinel surveillance to update on the burden, HIV status awareness, ART coverage, and factors associated with HIV infection among pregnant women in Tanzania mainland.

Methodology

We conducted the ANC surveillance in 159 ANC sites from all 26 regions of Tanzania’s mainland from September to December 2020. This cross-sectional study included all pregnant women (≥15 years) on their first ANC visit in the current pregnancy during the survey period. Routine HIV counseling and testing were done at the facility. Multivariable logistic regression model was used to examine factors associated with HIV infections.

Results

A total of 38,783 pregnant women were enrolled (median age (IQR) =25 (21–30) years). HIV prevalence was 5.9% (95%CI: 5.3% - 6.6%), ranging from 1.9% in Manyara region to 16.4% in Njombe region. Older age, lower and no education, not being in marital union, and living in urban or semi-urban areas was associated with higher odds of HIV infection. HIV status awareness among women who tested positive was 70.9% (95% CI: 67.5%- 74.0%). ART coverage among those aware of their status was 91.6% (86.5%- 94.9%). Overall, 66.6% (95% CI: 62.4%- 70.6%) of all pregnant women tested positive for HIV knew their HIV status and were on ART.

Conclusion

HIV is increasingly prevalent among pregnant women in Tanzania especially among older, those with lower or no formal education, those outside marital union and pregnant women living in urban and semi-urban areas. Behind the global fast-target to end HIV/ AIDS, about a third of pregnant women living with HIV initiating ANC were not on ART. Interventions to increase HIV testing and linkage to care among women of reproductive age should be intensified.
Relationship between prokaryotic GC content and environmental salinity
Authors: Hu En-Ze , Sun Shen , Niu Deng-Ke
Published: May 2023

Background

The correlation between GC content and halophilicity has received limited attention, despite the numerous environmental factors associated with GC content evolution. While higher GC content has been linked to halophiles in some archaeal cases, it is widely believed that selective pressure from high-intensity ultraviolet radiation in halophilic archaea drives GC content increase, as it prevents DNA photoproduct formation. However, this assumption has not been statistically analyzed in a phylogenetically independent manner prior to our study.

Results

Using phylogenetic generalized least squares, we investigated the relationship between GC content and halophilicity in 1226 bacteria and 181 archaea. Our analysis found significant positive correlations in bacteria but not in archaea. Resampling analysis indicates that the absence of significant correlation in archaea may be due to the relatively small sample size. We also observed that the strength of the correlation is negatively influenced by the functional constraint of genomic components. Additionally, we found that halophilic bacteria and archaea do not have lower photoreactivity (a measure of DNA vulnerability to ultraviolet radiation) than the photoreactivity expected from their GC contents.

Conclusions

In contrast to previous assumptions, we did not find evidence to support the widespread photoprotection hypothesis or another hypothesis that high GC content in halophiles stabilizes nucleic acid structures. Instead, our findings align with a nonadaptive hypothesis. Halophilic prokaryotes likely evolved high GC content due to frequent GC-biased gene conversion in response to DNA double-strand breaks induced directly or indirectly by high salt concentrations.
Redefining Pleiotropic Drug Resistance in a Pathogenic Yeast: Pdr1 Functions as a Sensor of Cellular Stresses inCandida glabrata
Authors: Gale Andrew N. , Pavesic Matthew W. , Nickels Timothy J. , Xu Zhuwei , Cormack Brendan P. , Cunningham Kyle W.
Published: May 2023

Candida glabratais a prominent opportunistic fungal pathogen of humans. The increasing incidence ofC. glabratainfections is attributed to both innate and acquired resistance to antifungals. Previous studies suggest the transcription factor Pdr1 and several target genes encoding ABC transporters are critical elements of pleiotropic defense against azoles and other antifungals. This study utilizesHermestransposon insertion profiling to investigate Pdr1-independent and Pdr1-dependent mechanisms that alter susceptibility to the frontline antifungal fluconazole. Several new genes were found to alter fluconazole susceptibility independent of Pdr1 (CYB5,SSK1,SSK2,HOG1,TRP1). A bZIP transcription repressor of mitochondrial function (CIN5) positively regulated Pdr1 while hundreds of genes encoding mitochondrial proteins were confirmed as negative regulators of Pdr1. The antibiotic oligomycin activated Pdr1 and antagonized fluconazole efficacy likely by interfering with mitochondrial processes inC. glabrata. Unexpectedly, disruption of many 60S ribosomal proteins also activated Pdr1, thus mimicking the effects of the mRNA translation inhibitors. Cycloheximide failed to fully activate Pdr1 in a cycloheximide-resistant Rpl28-Q38E mutant. Similarly, fluconazole failed to fully activate Pdr1 in a strain expressing a low-affinity variant of Erg11. Fluconazole activated Pdr1 with very slow kinetics that correlated with the delayed onset of cellular stress. These findings are inconsistent with the idea that Pdr1 directly senses xenobiotics and support an alternative hypothesis where Pdr1 senses cellular stresses that arise only after engagement of xenobiotics with their targets.

Importance

Candida glabratais an opportunistic pathogenic yeast that causes discomfort and death. Its incidence has been increasing because of natural defenses to our common antifungal medications. This study explores the entire genome for impacts on resistance to fluconazole. We find several new and unexpected genes can impact susceptibility to fluconazole. Several antibiotics can also alter the efficacy of fluconazole. Most importantly, we find that Pdr1 – a key determinant of fluconazole resistance – is not regulated directly through binding of fluconazole and instead is regulated indirectly by sensing the cellular stresses caused by fluconazole blockage of sterol biosynthesis. This new understanding of drug resistance mechanisms could improve the outcomes of current antifungals and accelerate the development of novel therapeutics.
CrOssing fiber Modeling in the Peritumoral Area using dMRI (COMPARI)
Authors: Golkar Ehsan , Parker Drew , Brem Steven , Almairac Fabien , Verma Ragini
Published: May 2023

Visualization of fiber tracts around the tumor is critical for neurosurgical planning and preservation of crucial structural connectivity during tumor resection. Biophysical modeling approaches estimate fiber tract orientations from differential water diffusivity information of diffusion MRI. However, the presence of edema and tumor infiltration presents a challenge to visualize crossing fiber tracts in the peritumoral region. Previous approaches proposed free water modeling to compensate for the effect of water diffusivity in edema, but those methods were limited in estimating complex crossing fiber tracts. We propose a new cascaded multi-compartment model to estimate tissue microstructure in the presence of edema and pathological contaminants in the area surrounding brain tumors. In our model (COMPARI), the isotropic components of diffusion signal, including free water and hindered water, were eliminated, and the fiber orientation distribution (FOD) of the remaining signal was estimated. In simulated data, COMPARI accurately recovered fiber orientations in the presence of extracellular water. In a dataset of 23 patients with highly edematous brain tumors, the amplitudes of FOD and anisotropic index distribution within the peritumoral region were higher with COMPARI than with a recently proposed multi-compartment constrained deconvolution model. In a selected patient with metastatic brain tumor, we demonstrated COMPARI’s ability to effectively model and eliminate water from the peritumoral region. The white matter bundles reconstructed with our model were qualitatively improved compared to those of other models, and allowed the identification of crossing fibers. In conclusion, the removal of isotropic components as proposed with COMPARI improved the bio-physical modeling of dMRI in edema, thus providing information on crossing fibers, thereby enabling improved tractography in a highly edematous brain tumor. This model may improve surgical planning tools to help achieve maximal safe resection of brain tumors.
Preparing correctional settings for the next pandemic: a modelling study of COVID-19 outbreaks in two high-income countries
Authors: Kwon Jisoo A. , Bretaña Neil A. , Kronfli Nadine , Dussault Camille , Grant Luke , Galouzis Jennifer , Hoey Wendy , Blogg James , Lloyd Andrew R. , Gray Richard T.
Published: May 2023

Correctional facilities are high-priority settings for coordinated public health responses to the COVID-19 pandemic. These facilities are at high risk of disease transmission due to close contacts between people in prison and with the wider community. People in prison are also vulnerable to severe disease given their high burden of co-morbidities. We developed a mathematical model to evaluate the effect of various public health interventions, including vaccination, on the mitigation of COVID-19 outbreaks, applying it to prisons in Australia and Canada. We found that, in the absence of any intervention, an outbreak would occur and infect almost 100% of people in prison within 20 days of the index case. However, the rapid rollout of vaccines with other non-pharmaceutical interventions would almost eliminate the risk of an outbreak. Our study highlights that high vaccination coverage is required for variants with high transmission probability to completely mitigate the outbreak risk in prisons.

Article Summary Line

High vaccination coverage is required to eliminate the risk of an outbreak in prisons
C-type natriuretic peptide improves maternally aged oocytes quality by inhibiting excessive PINK1/Parkin-mediated mitophagy
Authors: Zhang Hui , Li Chan , Liu Qingyang , Li Jingmei , Wu Hao , Xu Rui , Sun Yidan , Cheng Ming , Zhao Xiaoe , Pan Menghao , Wei Qiang , Ma Baohua
Published: May 2023

The overall oocyte quality declines with ageing, and this effect is strongly associated with a higher reactive oxygen species (ROS) level and the resultant oxidative damage. C-type natriuretic peptide (CNP) is a well-characterized physiological meiotic inhibitor that has been successfully used to improve immature oocyte quality during in vitro maturation (IVM). However, the underlying roles of CNP in maternally aged oocytes have not been reported. Here, we found that the age-related reduction in the serum CNP concentration was highly correlated with decreased oocyte quality. Treatment with exogenous CNP promoted follicle growth and ovulation in aged mice and enhanced meiotic competency and fertilization ability. Interestingly, the cytoplasmic maturation of aged oocytes was thoroughly improved by CNP treatment, as assessed by spindle/chromosome morphology and redistribution of organelles (mitochondria, the endoplasmic reticulum [ER], cortical granules [CGs], and the Golgi apparatus). CNP treatment also ameliorated DNA damage and apoptosis caused by ROS accumulation in aged oocytes. Importantly, oocyte RNA-seq revealed that the beneficial effect of CNP on aged oocytes was mediated by restoration of mitochondrial oxidative phosphorylation, eliminating excessive mitophagy. CNP reversed the defective phenotypes in aged oocytes by alleviating oxidative damage and suppressing excessive PINK1/Parkin-mediated mitophagy. Mechanistically, CNP functioned as a cAMP/PKA pathway modulator to decrease PINK1 stability and inhibit Parkin recruitment. In summary, our results demonstrated that CNP supplementation constitutes an alternative therapeutic approach for advanced maternal age-related oocyte deterioration and may improve the overall success rates of clinically assisted reproduction in older women.
Mathematical modeling of clonal interference by density-dependent selection in heterogeneous cancer cell lines
Authors: Veith Thomas , Alahmari Saeed , Schultz Andrew , Johnson Joseph , Maksin Konstantin , Andor Noemi
Published: May 2023

Many cancer cell lines are aneuploid and heterogeneous, with multiple karyotypes co-existing within the same cell line. Karyotype heterogeneity has been shown to manifest phenotypically, affecting how cells respond to drugs or to minor differences in culture media. Knowing how to interpret karyotype heterogeneity phenotypically, would give insights into cellular phenotypes before they unfold temporally. Here we reanalyze single cell RNA (scRNA)- and scDNA sequencing data from eight stomach cancer cell lines by placing gene expression programs into a phenotypic context. We quantify differences in growth rate and contact inhibition between the eight cell lines using live-cell imaging, and use these differences to prioritize transcriptomic biomarkers of growth rate and carrying capacity. Using these biomarkers, we find significant differences in the predicted growth rate or carrying capacity between multiple karyotypes detected within the same cell line. We use these predictions to simulate how the clonal composition of a cell line will change depending on the timing of splitting cells. Once validated, these models can aid the design of experiments that steer evolution with density dependent selection.
The spatiotemporal richness of hummingbird wing deformations
Authors: Skandalis Dimitri A. , Baliga Vikram B. , Goller Benjamin , Altshuler Douglas A.
Published: May 2023

Animals exhibit an abundant diversity of forms, and this diversity is even more evident when considering animals that can change shape on demand. The evolution of flexibility contributes to aspects of performance from propulsive efficiency to environmental navigation. It is, however, challenging to quantify and compare body parts that, by their nature, dynamically vary in shape over many time scales. Commonly, body configurations are tracked by labelled markers and quantified parametrically through conventional measures of size and shape (descriptor approach) or non-parametrically through data-driven analyses that broadly capture spatiotemporal deformation patterns (shape variable approach). We developed a weightless marker tracking technique and combined these analytic approaches to study wing morphological flexibility in hoverfeeding Anna’s hummingbirds (Calypte anna). Four shape variables explained >95% of typical stroke cycle wing shape variation and were broadly correlated with specific conventional descriptors like wing twist and area. Moreover, shape variables decomposed wing deformations into pairs of in- and out-of-plane components at integer multiples of the stroke frequency. This property allowed us to identify spatiotemporal deformation profiles characteristic of hoverfeeding with experimentally imposed kinematic constraints, including through shape variables explaining <10% of typical shape variation. Hoverfeeding in front of a visual barrier restricted stroke amplitude and elicited increased stroke frequencies together with in- and out-of-plane deformations throughout the stroke cycle. Lifting submaximal loads increased stroke amplitudes at similar stroke frequencies together with prominent in-plane deformations during the upstroke and pronation. Our study highlights how spatially and temporally distinct changes in wing shape can contribute to agile fluidic locomotion.

Hummingbirds exhibit complex wing deformations throughout the stroke cycle, and the timing and origin of these deformations differs between hoverfeeding behaviours.
Sex and dominance status affect allogrooming in free-ranging feral cattle
Authors: Hodgson George M. W. , Flay Kate J. , Perroux Tania A. , Chan Wai Yan , McElligott Alan G.
Published: May 2023

Social interactions are fundamental properties of gregarious species, helping to establish dominance hierarchies and maintain social bonds within groups, thus having significant effects on fitness. Cattle (Bos taurus) are social ungulates which engage in affiliative and agonistic relationships with other individuals. Although there are approximately 1.5 billion cattle on the planet, the opportunity to research cattle behaviour in free-ranging groups is rare, as there are few feral populations worldwide. Cattle engage in positive social behaviours such as allogrooming, where one individual licks the body of another. The relationship between affiliative behaviours and other individual characteristics (such as sex and dominance status) are frequently studied in other gregarious species, but are largely undetermined in cattle. To investigate the relationships between sex, dominance status and allogrooming, we observed a mixed-sex feral cattle herd in Hong Kong, recording dominance interactions and allogrooming events. We found that dominant females received more allogrooming than subordinate females, but subordinate females did not perform more than dominant ones. Males performed allogrooming more towards females than other males, but females groomed both sexes equally. Sex affected dominance position, with males obtaining higher status than females, but not all females were subordinate to males. These preferential allogrooming patterns improve our knowledge of sex-specific interactions, and help us to understand the dynamics of agonistic and affiliative behaviours in multi-male, multi-female ungulate groups. Studying a free-ranging feral population provides us with a unique insight into ungulate behavioural patterns and the evolution of cattle social behaviours.
Pseudoirreversible inhibition elicits persistent efficacy of a sphigosine-1-phosphate receptor-1 antagonist
Authors: Maruyama Yuya , Ohsawa Yusuke , Suzuki Takayuki , Yamauchi Yuko , Ohno Kohsuke , Inoue Hitoshi , Yamamoto Akitoshi , Hayashi Morimichi , Okuhara Yuji , Muramatsu Wataru , Namiki Kano , Hagiwara Naho , Miyauchi Maki , Miyao Takahisa , Ishikawa Tatsuya , Horie Kenta , Hayama Mio , Akiyama Nobuko , Hirokawa Takatsugu , Akiyama Taishin
Published: May 2023

Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. We synthesized a competitive antagonist, KSI-6666, that persistently inhibits S1PR1 activity and effectively suppresses pathogenic inflammation. Metadynamics simulation proposed that the interaction of KSI-6666 with a methionine residue in the ligand-binding pocket of S1PR1 may inhibit the dissociation of KSI-6666 from S1PR1. Consistently, in vitro functional and mutational analyses revealed that KSI-6666 causes pseudoirreversible inhibition of S1PR1, dependent on the methionine residue of the protein and substituents on the distal benzene ring of KSI-6666. Moreover, in vivo study suggested that this pseudoirreversible inhibition is responsible for the persistent activity of KSI-6666. In this study, we discover that KSI-6666 is a potent S1PR1 antagonist, achieving pseudoirreversible inhibition of S1PR1 activity through interacting with a specific methionine residue.
Adopting Duplex Sequencing™ Technology for Genetic Toxicity Testing: A Proof-of-Concept Mutagenesis Experiment with N-Ethyl-N-Nitrosourea (ENU)-Exposed Rats
Authors: Smith-Roe Stephanie L. , Hobbs Cheryl A. , Hull Victoria , Auman J. Todd , Recio Leslie , Streicker Michael A. , Rivas Miriam V. , Pratt Gabriel A. , Lo Fang Yin , Higgins Jacob E. , Schmidt Elizabeth K. , Williams Lindsey N. , Nachmanson Daniela , Valentine Charles C. , Salk Jesse J. , Witt Kristine L.
Published: May 2023

Duplex sequencing (DuplexSeq) is an error-corrected next-generation sequencing (ecNGS) method in which molecular barcodes informatically link PCR-copies back to their source DNA strands, enabling computational removal of errors by comparing grouped strand sequencing reads. The resulting background of less than one artifactual mutation per 107nucleotides allows for direct detection of somatic mutations. TwinStrand Biosciences, Inc. has developed a DuplexSeq-based mutagenesis assay to sample the rat genome, which can be applied to genetic toxicity testing. To evaluate this assay for early detection of mutagenesis, a time-course study was conducted using male Hsd:Sprague Dawley SD rats (3 per group) administered a single dose of 40 mg/kg N-ethyl-N-nitrosourea (ENU) via gavage, with mutation frequency (MF) and spectrum analyzed in stomach, bone marrow, blood, and liver tissues at 3 h, 24 h, 7 d, and 28 d post-exposure. Significant increases in MF were observed in ENU-exposed rats as early as 24 h for stomach (site of contact) and bone marrow (a highly proliferative tissue) and at 7 d for liver and blood. The canonical, mutational signature of ENU was established by 7 d post-exposure in all four tissues. Interlaboratory analysis of a subset of samples from different tissues and time points demonstrated remarkable reproducibility for both MF and spectrum. These results demonstrate that MF and spectrum can be evaluated successfully by directly sequencing targeted regions of DNA obtained from various tissues, a considerable advancement compared to currently usedin vivogene mutation assays.

HIGHLIGHTS

DuplexSeq is an ultra-accurate NGS technology that directly quantifies mutations

ENU-dependent mutagenesis was detected 24 h post-exposure in proliferative tissues

Multiple tissues exhibited the canonical ENU mutation spectrum 7 d after exposure

Results obtained with DuplexSeq were highly concordant between laboratories

The Rat-50 Mutagenesis Assay is promising for applications in genetic toxicology
Phenology and social status of the endemic Sable Island Sweat Bee,Lasioglossum sablense
Authors: Richards Miriam H , Lucas Zoe , Proulx Alex , Corbin Lyllian A-J , Jacks Frederica , Kehler Dan
Published: May 2023

The Sable Island Sweat Bee (Lasioglossum (Dialictus) sablenseGibbs, 2010) is endemic to Sable Island, an isolated sandbar located about 160 km east of Nova Scotia.L. sablenseis classified as Threatened due to its restricted geographic distribution, so promoting its conservation requires detailed information about nesting phenology and behaviour. We combined measurements and dissections of adult females collected in 2016 and 2017 with behavioural observations of nests and foragers on the grounds of the Sable Island Station in 2019 and 2022, to compile the first description of flight phenology and social status. Like many members of its subgenus,L. sablenseexhibits a diphasic life history. Phase 1 begins when large adult females emerge from hibernation, begin burrow and brood cell construction, and forage to provision Brood 1, which comprises both daughters and sons. Most, but not all, nests initiated during Phase 1, reactivate during Phase 2, as adult Brood 1 daughters emerge from their nests and initiate foraging to provision Brood 2. This suggests a mix of univoltine (single generation) and bivoltine (two generation) reproductive strategies. Behavioural observations at nest entrances demonstrated that during Phase 2, reactivated nests sometimes contained multiple adult females, suggesting the potential for colonies to become social. Comparisons of body size and ovarian status of Phase 1 and 2 females collected from flowers, showed Phase 2 foragers were significantly smaller than Phase 1 foragers and had somewhat lower levels of ovarian development, as expected if Phase 2 females were workers from eusocial nests. However, five large females collected during Phase 2, which had high levels of wear, likely were Phase 1 foundresses that resumed foraging during Phase 2. Taken together, these observations suggest a mix of phenological and social strategies, including both univoltine and bivoltine life histories, and a mix of solitary and social behaviour among reactivated colonies in Phase 2.
Dynamic PRC1-CBX8 stabilizes a porous structure of chromatin condensates
Authors: Uckelmann Michael , Levina Vita , Taveneau Cyntia , Ng Xiao Han , Pandey Varun , Martinez Jasmine , Mendiratta Shweta , Houx Justin , Boudes Marion , Venugopal Hari , Trépout Sylvain , Zhang Qi , Flanigan Sarena , Li Minrui , Sierecki Emma , Gambin Yann , Das Partha Pratim , Bell Oliver , de Marco Alex , Davidovich Chen
Published: May 2023

The compaction of chromatin is a prevalent paradigm in gene repression. Chromatin compaction is commonly thought to repress transcription by restricting chromatin accessibility. However, the spatial organisation and dynamics of chromatin compacted by gene-repressing factors are unknown. Using cryo-electron tomography, we solved the three-dimensional structure of chromatin condensed by the Polycomb Repressive Complex 1 (PRC1) in a complex with CBX8. PRC1-condensed chromatin is porous and stabilised through multivalent dynamic interactions of PRC1 with chromatin. Mechanistically, positively charged residues on the internally disordered regions (IDRs) of CBX8 mask negative charges on the DNA to stabilize the condensed state of chromatin. Within condensates, PRC1 remains dynamic while maintaining a static chromatin structure. In differentiated mouse embryonic stem cells, CBX8-bound chromatin remains accessible. These findings challenge the idea of rigidly compacted polycomb domains and instead provides a mechanistic framework for dynamic and accessible PRC1-chromatin condensates.
The genomic landscape of transposable elements in yeast hybrids is shaped by structural variation and genotype-specific modulation of transposition rate
Authors: Hénault Mathieu , Marsit Souhir , Charron Guillaume , Landry Christian R.
Published: May 2023

Transposable elements (TEs) are major contributors to structural genomic variation by creating interspersed duplications of themselves. In return, structural variants (SVs) can affect the genomic distribution of TE copies and shape their load. One long-standing hypothesis states that hybridization could trigger TE mobilization and thus increase TE load in hybrids. We previously tested this hypothesis by performing a large-scale evolution experiment by mutation accumulation (MA) on multiple hybrid genotypes within and between wild populations of the yeastsSaccharomyces paradoxusandSaccharomyces cerevisiae. Using aggregate measures of TE load with short-read sequencing, we found no evidence for TE load increase in hybrid MA lines. Here, we resolve the genomes of the hybrid MA lines with long-read phasing and assembly to precisely characterize the role of SVs in shaping the TE landscape. Highly contiguous phased assemblies of 127 MA lines revealed that SV types like polyploidy, aneuploidy and loss of heterozygosity have large impacts on the TE load. We characterized 18 de novo TE insertions, indicating that transposition only has a minor role in shaping the TE landscape in MA lines. Because the scarcity of TE mobilization in MA lines provided insufficient resolution to confidently dissect transposition rate variation in hybrids, we adapted an in vivo assay to measure transposition rates in variousS. paradoxushybrid backgrounds. We found that transposition rates are not increased by hybridization, but are modulated by many genotype-specific factors including initial TE load, TE sequence variants and mitochondrial DNA inheritance. Our results show the multiple scales at which TE load is shaped in hybrid genomes, being highly impacted by SV dynamics and finely modulated by genotype-specific variation in transposition rates.
Adherence to the Eatwell Guide and cardiometabolic, cognitive and neuroimaging parameters: An analysis from the PREVENT Dementia study
Authors: Gregory Sarah , Griffiths Alex , Jennings Amy , Malcolmson Fiona , Matu Jamie , Minihane Anne Marie , Muniz-Terrera Graciela , Ritchie Craig W. , Parra-Soto Solange , Stevenson Emma , Townsend Rebecca , Ward Nicola , Shannon Oliver M
Published: May 2023

Background: The Eatwell guide reflects the UK governments recommendations for a healthy and balanced diet. Previous research has identified associations between healthy eating patterns and both cardiovascular and brain health, although there is little evidence specifically focusing on the Eatwell Guide. To date no research has investigated associations between the Eatwell Guide and risk for future dementia. Methods: Data from the PREVENT dementia cohort study baseline visit was used in this analysis. Binary and graded Eatwell Guide scores (BEWG, GEWG) were created from a self-reported Food Frequency Questionnaire. The CAIDE score was included as the primary outcome measure to represent risk for future Alzheimers disease. Secondary outcome measures included cardiometabolic health measures and brain health measures. Generalised additive models were run in R. Results: A total of 517 participants were included in the analysis, with a mean BEWG score of 4.39 (1.66) (out of a possible 12 points) and GEWG score of 39.88 (6.19) (out of a possible 60 points). There was no significant association between either Eatwell Guide score and the CAIDE score (BEWG B: 0.07, 95% confidence interval (CI): -0.07, 0.22; GEWG B: 0.02, 95% CI: -0.02, 0.06) or any measures of brain health. There was a significant association between higher GEWG score and lower systolic and diastolic blood pressure and body mass index (BMI) (systolic B: -0.24, 95% CI: -0.45, -0.03; diastolic B: -0.16, 95% CI: -0.29, -0.03; BMI B: -0.09, 95% CI: -0.16, -0.01). Conclusions: Although not directly associated with the CAIDE score, the Eatwell Guide dietary pattern may be beneficial for dementia prevention efforts through the modification of hypertension and obesity, which are both known risk factors for dementia. Future work could replicate these findings in other UK-based cohorts as well as further development of Eatwell Guide scoring methodologies.
World Health Organization Danger Signs to predict bacterial sepsis in newborns: A pragmatic prospective cohort study
Authors: Akinseye Omolabake , Popescu Constantin R. , Chiume-Kayuni Msandeni , Irvine Michael A. , Lufesi Norman , Mvalo Tisungane , Kissoon Niranjan , Wiens Matthew O. , Lavoie Pascal M.
Published: May 2023

Background

The World Health Organization (WHO) has developed danger signs (DS) to help front-line health workers triage interventions in children with severe illnesses. Our objective was to evaluate the extent to which DS predict bacterial sepsis in young infants presenting with acute illness.

Methodology/Principal Findings

This prospective study evaluated nine DS in infants younger than 3 months with suspected sepsis in a large regional hospital in Lilongwe, Malawi, between June 2018 and April 2020. The main outcomes were positive blood or cerebrospinal fluid (CSF) cultures and mortality. Blood (n=85/401) and CSF (n=2/204) cultures were positive in 21.2% and 1% of infants, respectively (N=401; gestational age mean ± SD: 37.1±3.3 weeks, birth weight 2865±785 grams). In-hospital deaths occurred in 9.7% (N=39/401) of infants (61.5% within 48h of admission). In univariate analyses, all DS were associated with mortality except for temperature instability and tachypnea, whereas “infant was unable to feed” was the only DS significantly associated with bacterial sepsis.

After co-variable adjustments, number of DS predicted mortality (OR: 1.75; 95%CI: 1.43–2.16; p<0.001; AUC-ROC: 0.756) but not positive cultures (OR 1.08; 95%CI: 0.92–1.30; p=0.336). Whether potential bacterial contaminants were included or not did not change results meaningfully.

Conclusion/Significance

DS predicted fatal outcomes but not positive cultures in a large regional hospital setting. These data imply that the incidence of bacterial sepsis and attributable mortality are unlikely to be accurate based on clinical signs alone, in infants in LMIC settings.
Integration of leaf spectral reflectance variability facilitates identification of plant leaves at different taxonomic levels
Authors: Quinteros Casaverde Natalia L. , Serbin Shawn P. , Daly Douglas C.
Published: May 2023

Plant identification is crucial to the conservation and management of natural areas. The shortwave spectral reflectance of leaves is a promising tool for rapidly identifying species at different taxonomic ranks. However, the spectral reflectance of leaves changes in response to biotic and abiotic conditions. This investigation asked how this variability affects the accuracy of methods used to predict plant taxonomies and what factors most influence the spectral signature of leaves. To answer these questions, we measured the reflectance of leaves of 62 woody species from the living collection at the NYBG twice in two pairwise samplings. We found that PLS-DA accuracy improved when we used a larger sample of natural variance in the classification model. Finally, to evaluate whether there was an influence of the species’ relatedness or the growing environment on structural and biochemical traits predicted from the leaf reflectance, we ran a phylogenetic signal analysis and a series of mixed effects model analyses that showed no phylogenetic but an environmental influence. We found that the increase in temperature and relative humidity variability explained the increment of predicted carotene and the decrease of Nitrogen content for the first pairwise analysis. For the second pairwise analysis, we found that the reduction of relative humidity variability explained leaf water and Nitrogen content decrease, and relative humidity decrease combined with day length decrease explained a decline in LMA.
A deep catalog of protein-coding variation in 985,830 individuals
Authors: Sun Kathie Y. , Bai Xiaodong , Chen Siying , Bao Suying , Kapoor Manav , Zhang Chuanyi , Backman Joshua , Joseph Tyler , Maxwell Evan , Mitra George , Gorovits Alexander , Mansfield Adam , Boutkov Boris , Gokhale Sujit , Habegger Lukas , Marcketta Anthony , Locke Adam , Kessler Michael D. , Sharma Deepika , Staples Jeffrey , Bovijn Jonas , Gelfman Sahar , Gioia Alessandro Di , Rajagopal Veera , Lopez Alexander , Varela Jennifer Rico , Alegre Jesus , Berumen Jaime , Tapia-Conyer Roberto , Kuri-Morales Pablo , Torres Jason , Emberson Jonathan , Collins Rory ,   Regeneron Genetics Center,   RGC-ME Cohort Partners, Cantor Michael , Thornton Timothy , Kang Hyun Min , Overton John , Shuldiner Alan R. , Cremona M. Laura , Nafde Mona , Baras Aris , Abecasis Goncalo , Marchini Jonathan , Reid Jeffrey G. , Salerno William , Balasubramanian Suganthi
Published: May 2023

Coding variants that have significant impact on function can provide insights into the biology of a gene but are typically rare in the population. Identifying and ascertaining the frequency of such rare variants requires very large sample sizes. Here, we present the largest catalog of human protein-coding variation to date, derived from exome sequencing of 985,830 individuals of diverse ancestry to serve as a rich resource for studying rare coding variants. Individuals of African, Admixed American, East Asian, Middle Eastern, and South Asian ancestry account for 20% of this Exome dataset. Our catalog of variants includes approximately 10.5 million missense (54% novel) and 1.1 million predicted loss-of-function (pLOF) variants (65% novel, 53% observed only once). We identified individuals with rare homozygous pLOF variants in 4,874 genes, and for 1,838 of these this work is the first to document at least one pLOF homozygote. Additional insights from the RGC-ME dataset include 1) improved estimates of selection against heterozygous loss-of-function and identification of 3,459 genes intolerant to loss-of-function, 83 of which were previously assessed as tolerant to loss-of-function and 1,241 that lack disease annotations; 2) identification of regions depleted of missense variation in 457 genes that are tolerant to loss-of-function; 3) functional interpretation for 10,708 variants of unknown or conflicting significance reported in ClinVar as cryptic splice sites using splicing score thresholds based on empirical variant deleteriousness scores derived from RGC-ME; and 4) an observation that approximately 3% of sequenced individuals carry a clinically actionable genetic variant in the ACMG SF 3.1 list of genes. We make this important resource of coding variation available to the public through a variant allele frequency browser. We anticipate that this report and the RGC-ME dataset will serve as a valuable reference for understanding rare coding variation and help advance precision medicine efforts.
NGBO: Introducing -omics metadata to biobanking ontology
Authors: Alghamdi Dalia , Dooley Damion M. , Samman Mannar , Hsiao William W.L.
Published: May 2023

Background

With improvements in high throughput sequencing technologies and the constant generation of large biomedical datasets, biobanks increasingly take on the role of managing and delivering not just specimens but also data. However, re-using data from different biobanks is challenged by incompatible data representations. Contextual data describing biobank digital resources often contain unstructured textual information incompatible with computational processes such as automated data discovery and integration. Therefore, a consistent and comprehensive contextual data framework is needed to increase discovery, reusability, and integrability across data sources.

Methods

Based on available genomics standards (e.g., Minimum information about a microarray experiment (MIAME)), the College of American Pathologists (CAP) laboratory accreditation requirements, and the Open Biological and Biomedical Ontologies Foundry principles, we developed the Next Generation Biobanking Ontology (NGBO). In addition, we created new terms and re-used concepts from the Ontology for Biomedical Investigations (OBI) and the Ontology for Biobanking (OBIB) to build NGBO.

Results

The Next Generation Biobanking Ontologyhttps://www.ebi.ac.uk/ols4/ontologies/ngbois an open application ontology representing omics contextual data, licensed under the Apache License 2.0. The ontology focuses on capturing information about three main activities: wet bench analysis used to generate omics data, bioinformatics analysis used to process and interpret data, and data management. In this paper, we demonstrated the use of the NGBO to add semantic statements to real-life use cases and query data previously stored in unstructured textual format.
Molecular signatures associated with successful implantation of the human blastocyst
Authors: Chousal Jennifer N. , Srinivasan Srimeenakshi , Lee Katherine , To Cuong , Cho Kyucheol , Zhang Wei , Yeo Ana Lisa , Garzo V. Gabriel , Parast Mana M. , Laurent Louise C. , Cook-Andersen Heidi
Published: May 2023

Embryo implantation in humans is remarkably inefficient for reasons that remain largely unexplained, and high rates of implantation failure remain one of the greatest obstacles in treating infertility. The volume of gene expression data available from human embryos has rapidly accumulated in recent years. However, prioritization of these data to identify the subset of genes that determine successful implantation remains a challenge, in part, because comprehensive analyses cannot be performed on the same embryos that are transferred. Here, we leverage clinical morphologic grading—known for decades to correlate with implantation potential—and transcriptome analyses of matched embryonic and abembryonic samples to identify genes and cell-cell interactions enriched and depleted in human blastocysts of good and poor morphology, genome-wide. Unexpectedly, we discovered that the greatest molecular difference was in the state of the extraembryonic primitive endoderm (PrE), with relative deficiencies in PrE development in embryos of poor morphology at the time of embryo transfer. Together, our results support a model in which implantation success is most strongly reflected by factors and signals from the embryonic compartment and suggest that deficiencies in PrE development, in particular, are common among embryos with reduced implantation potential. Our study provides a valuable resource for those investigating the markers and mechanisms of human embryo implantation.
The Development of Resistance to an Inhibitor of a Cellular Protein Reveals a critical interaction between the enterovirus protein 2C and a small GTPase Arf1
Authors: Viktorova Ekaterina G. , Gabaglio Samuel , Moghimi Seyedehmahsa , Zimina Anna , Wynn Bridge G. , Sztul Elizabeth , Belov George A.
Published: May 2023

The cellular protein GBF1, an activator of Arf GTPases (ArfGEF: Arf guanine nucleotide exchange factor), is recruited to the replication organelles of enteroviruses through interaction with the viral protein 3A, and its ArfGEF activity is required for viral replication. Here, we investigated the development of resistance of poliovirus, a prototype enterovirus, to increasing concentrations of brefeldin A (BFA), an inhibitor of GBF1. High level of resistance required a gradual accumulation of multiple mutations in the viral protein 2C. The 2C mutations conferred BFA resistance even in the context of a 3A mutant previously shown to be defective in the recruitment of GBF1 to replication organelles, and in cells depleted of GBF1, suggesting a GBF1-independent replication mechanism. Still, activated Arfs accumulated on the replication organelles of this mutant even in the presence of BFA, its replication was inhibited by a pan-ArfGEF inhibitor LM11, and the BFA-resistant phenotype was compromised in Arf1-knockout cells. Importantly, the mutations strongly increased the interaction of 2C with the activated form of Arf1. Analysis of other enteroviruses revealed a particularly strong interaction of 2C of human rhinovirus 1A with activated Arf1. Accordingly, the replication of this virus was significantly less sensitive to BFA than that of poliovirus. Thus, our data demonstrate that enterovirus 2Cs may behave like Arf1 effector proteins and that GBF1 but not Arf activation can be dispensable for enterovirus replication. These findings have important implications for the development of host-targeted anti-viral therapeutics.
Dissecting the impact of somatic hypermutation on SARS-CoV-2 neutralization and viral escape
Authors: Korenkov Michael , Zehner Matthias , Cohen-Dvashi Hadas , Borenstein-Katz Aliza , Kottege Lisa , Janicki Hanna , Vanshylla Kanika , Weber Timm , Gruell Henning , Koch Manuel , Diskin Ron , Kreer Christoph , Klein Florian
Published: May 2023

Somatic hypermutation (SHM) drives affinity maturation and continues over months in SARS-CoV-2 neutralizing antibodies. Yet, several potent SARS-CoV-2 antibodies carry no or only few mutations, leaving the question of how ongoing SHM affects neutralization. Here, we reverted variable region mutations of 92 antibodies and tested their impact on SARS-CoV-2 binding and neutralization. Reverting higher numbers of mutations correlated with decreasing antibody functionality. However, some antibodies, including the public clonotype VH1-58, remained unaffected for Wu01 activity. Moreover, while mutations were dispensable for Wu01-induced VH1-58 antibodies to neutralize Alpha, Beta, and Delta variants, they were critical to neutralize Omicron BA.1/BA.2. Notably, we exploited this knowledge to convert the clinical antibody tixagevimab into a BA.1/BA.2-neutralizer. These findings substantially broaden our understanding of SHM as a mechanism that not only improves antibody responses during affinity maturation, but also counteracts antigenic imprinting through antibody diversification and thus increases the chances of neutralizing viral escape variants.
Phase-dependent stimulation response is shaped by the brain’s transient collective dynamics
Authors: Benitez Stulz Sophie , Gutkin Boris , Gilson Matthieu , Battaglia Demian
Published: May 2023

Exogenous stimulation is a promising tool for investigating and altering cognitive processes in the brain, with potential clinical applications. Following experimental observations, we hypothesise that the effect of stimulation crucially depends on the endogenous dynamics of the brain. Our study explores how local and global dynamical properties, like the stimulation phase of regional oscillatory activity and the transient network states, modulate the effect of single pulse stimulation in a large-scale network. Our findings demonstrate that the effect of stimulation strongly depends on the interplay between stimulated phase, transient network state, and brain region. Importantly, we show that stimulation is not only state-dependent but can also induce global state switching. Lastly, predicting the effect of stimulation by using machine learning shows that state-aware measures can increase the performance by up to 40%. Our results suggest that a fine characterisation of the complex brain dynamics in experimental setups is essential for improving the reliability of exogenous stimulation.