bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fundamental equations linking methylation dynamics to maximum lifespan in mammals
Authors: Horvath Steve , Zhang Joshua , Haghani Amin , Lu Ake T. , Fei Zhe 
Published: May 2023

AbstractWe establish the mathematical foundation that links the rate of change in any molecular biomarker to species lifespan. Specifically, we propose a robust approach that identifies the strong inverse relationship for certain biomarkers using two comprehensive methylation datasets. After examining 54 chromatin states, we found the rates of change of CpG sites in bivalent chromatin states are negatively associated to the lifespans of 90 dog breeds in the first dataset, and the discoveries are further strengthened with 125 mammalian species in the second dataset. Our research leads to three key findings: First, a reciprocal relationship exists between the average rate of methylation change (AROCM) in bivalent promoter regions and maximum lifespan: AROCM ∝ 1/MaxLifespan. Second, the correlation between age and average methylation bears no relation to maximum lifespan, Cor(Methly,Age) ⊥ MaxLifespan. Third, the rate of methylation change in young animals is related to that in old animals: Young animals’ AROCM ∝ Old AROCM. These findings hinge on the chromatin context, as different results emerge when defining AROCM using different chromatin states. Our analytical framework is versatile and readily extendable to a broad range of other molecular assessments. Overall, our study demonstrates that epigenetic aging rates in specific chromatin states exhibit an inverse relationship with maximum lifespan in mammals.
P53 and BCL-2 family proteins PUMA and NOXA define competitive fitness in Pluripotent Cells
Authors: Valverde-Lopez Jose A. , Li-Bao Lin , Díaz-Díaz Covadonga , Sierra Rocío , Santos Elisa , Giovinazzo Giovanna , Torres Miguel 
Published: May 2023

ABSTRACTCell Competition is a process by which neighboring cells compare their fitness. As a result, viable but suboptimal cells are selectively eliminated in the presence of fitter cells. In the early mammalian embryo, epiblast pluripotent cells undergo extensive Cell Competition, which prevents suboptimal cells from contributing to the newly forming organism. While competitive ability is regulated by MYC in the epiblast, the mechanisms that contribute to competitive fitness in this context are largely unknown. Here, we report that P53 and its pro-apoptotic targets PUMA and NOXA regulate apoptosis susceptibility and competitive fitness in pluripotent cells. PUMA is widely expressed specifically in pluripotent cellsin vitroandin vivo. We show that the p53-PUMA/NOXA pathway regulates mitochondrial membrane potential and oxidative status. We found that P53 regulates MYC levels in pluripotent cells, which connects these two Cell competition pathways, however, MYC and PUMA/NOXA levels are independently regulated by P53. We propose a model that integrates a bifurcated P53 pathway regulating both MYC and PUMA/NOXA levels and determines competitive fitness through regulation of mitochondrial activity.
Development of a non-infectious control for viral hemorrhagic fever PCR assays
Authors: Knox Matthew A , Bromhead Collette , Hayman David TS 
Published: May 2023

AbstractAssay validation is an essential component of disease surveillance but can be problematic in low resource settings where access to positive control material is limited and a safety risk for handlers. Here we describe techniques for validating the PCR based detection ofCrimean-Congo hemorrhagic fever orthonairovirus, Ebola virus, Lassa virus, Marburg virus andRift Valley Fever phlebovirus. We designed non-infectious synthetic DNA oligonucleotide sequences incorporating primer binding sites suitable for multiple assays, and a T7 promotor site which was used to transcribe the sequence. Transcribed RNA was used as template in a dilution series, extracted and amplified with RT-PCR and RT-qPCR to demonstrate successful recovery and determine limits of detection in a range of laboratory settings. Our results are adaptable to any assay requiring validation of nucleic acid extraction and/or amplification, particularly where sourcing reliable, safe material for positive controls is infeasible.Author SummaryThe majority of zoonoses originate in wildlife and tend to emerge from biodiverse regions in low to middle income countries, frequently among deprived populations of at-risk people with a lack of access to diagnostic capacity or surveillance. Diseases such as Crimean-Congo Hemorrhagic Fever, Rift Valley Fever, Ebola Virus Disease, Marburg Virus Disease and Lassa Fever are viral hemorrhagic fevers (VHFs) and among the most neglected and serious threats to global public health. This threat is partly due to the severity of disease caused by these pathogens, but also because their geographical distribution is close to human populations with often limited access to medical or diagnostic laboratory services. In our study we describe and validate techniques for PCR based detection of five VHF viruses using a synthetic, multi-target non-infectious positive control. Our work has applications in assay design and optimization, particularly where access to source material is problematic or requires high level biosafety containment, as is the case with VHF viruses. This approach can help learners train in techniques used in nucleic acid extraction, amplification, and sequencing of VHF viruses, but can be used for any targets, with potential for multiplexing from a single positive control.
The significance of mitochondrial haplogroups in preeclampsia risk
Authors: Olsen Kristina Wendelboe , Hedley Paula L. , Hagen Christian M. , Rode Line , Placing Sophie , Wøjdemann Karen R , Shalmi Anne-Cathrine , Sundberg Karin , Nørremølle Anne , Tabor Ann , Elson Joanna L. , Christiansen Michael 
Published: May 2023

ObjectiveTo determine whether mitochondrial haplogroups function as disease-modifiers or as susceptibility factors in preeclampsia using a traditional haplogroup association model.MethodsThis retrospective study haplotyped 235 control and 78 preeclamptic pregnancies from Denmark using either real-time PCR or Sanger sequencing depending on the rarity of the haplogroup.ResultsNo significant association between haplogroups and the risk of preeclampsia was found, nor was any role for haplogroups in disease severity uncovered.ConclusionMitochondrial haplogroups are not associated with preeclampsia or the severity of preeclampsia in the Danish population. However, this study cannot exclude a role for less common mtDNA variation. Models that can examine these should be applied in preeclamptic patients.Graphical Abstract
Epigenomic profiling of the infrapatellar fat pad in osteoarthritis
Authors: Kreitmaier Peter , Park Young-Chan , Swift Diane , Gilly Arthur , Wilkinson J Mark , Zeggini Eleftheria 
Published: May 2023

AbstractOsteoarthritis is a prevalent, complex disease of the joints, and affects multiple intra-articular tissues. Here, we have examined genome-wide DNA methylation profiles of primary infrapatellar fat pad and matched blood samples from 70 osteoarthritis patients undergoing total knee replacement surgery. Comparing the DNA methylation profiles between these tissues reveal widespread epigenetic differences. We produce the first genome-wide methylation quantitative trait locus (mQTL) map of fat pad, and make the resource available to the wider community. Using two-sample Mendelian randomization and colocalization analyses, we resolve osteoarthritis GWAS signals and provide insights into the molecular mechanisms underpinning disease aetiopathology. Our findings provide the first view of the epigenetic landscape of infrapatellar fat pad primary tissue in osteoarthritis.
Modulation of visually induced self-motion illusions by α transcranial electric stimulation over the superior parietal cortex
Authors: Harquel Sylvain , Cian Corinne , Torlay Laurent , Cousin Emilie , Barraud Pierre-Alain , Bougerol Thierry , Guerraz Michel 
Published: May 2023

AbstractGrowing popularity of virtual reality systems has led to a renewed interest in understanding the neurophysiological correlates of the illusion of self-motion (vection), a phenomenon that can be both intentionally induced or avoided in such systems, depending on the application. Recent research has highlighted the modulation of α power oscillations over the superior parietal cortex during vection, suggesting the occurrence of inhibitory mechanisms in the sensorimotor and vestibular functional networks to resolve the inherent visuo-vestibular conflict. The present study aims to further explore this relationship and investigate whether neuromodulating these waves could causally affect the quality of vection. In a crossover design, 22 healthy volunteers received 13 minutes of high-amplitude, focused α-tACS over the superior parietal cortex while experiencing visually induced vection triggered by optokinetic stimulation. The tACS was tuned to each participant’s individual α peak frequency, with θ-tACS and sham stimulation serving as controls. Overall, participants experienced better quality vection during α-tACS compared to control θ-tACS and sham stimulations, as quantified by the intensity of vection. The observed neuromodulation supports a causal relationship between parietal α oscillations and visually induced self-motion illusions, with their entrainment triggering over-inhibition of the conflict within the sensorimotor and vestibular functional networks. These results confirm the potential of non-invasive brain stimulation for modulating visuo-vestibular conflicts, which could help to enhance the sense of presence in virtual reality environments.
Nighthawk: acoustic monitoring of nocturnal bird migration in the Americas
Authors: Van Doren Benjamin M. , Farnsworth Andrew , Stone Kate , Osterhaus Dylan M. , Drucker Jacob , Van Horn Grant 
Published: May 2023

AbstractAnimal migration is one of nature’s most spectacular phenomena, but migratory animals and their journeys are imperiled across the globe. Migratory birds are among the most well-studied animals on Earth, yet relatively little is known about in-flight behavior during nocturnal migration. Because many migrating bird species vocalize during flight, passive acoustic monitoring shows great promise for facilitating widespread monitoring of bird migration.Here, we present Nighthawk, a deep learning model designed to detect and identify the vocalizations of nocturnally migrating birds. We trained Nighthawk on the in-flight vocalizations of migratory birds using a diverse dataset of recordings from across the Americas.Our results demonstrate that Nighthawk performs well as a nocturnal flight call detector and classifier for dozens of avian taxa, both at the species level and for broader taxonomic groups (e.g., orders and families). The model accurately quantified nightly nocturnal migration intensity and species phenology and performed well on data from across North America. Incorporating modest amounts of additional annotated audio (50-120 h) into model training yielded high performance on target datasets from both North and South America.By monitoring the vocalizations of actively migrating birds, Nighthawk provides a detailed window onto nocturnal bird migration that is not presently attainable by other means (e.g., radar or citizen science). Scientists, managers, and practitioners could use acoustic monitoring with Nighthawk for a number of applications, including: monitoring migration passage at wind farms; studying airspace usage during migratory flights; monitoring the changing migrations of species susceptible to climate change; and revealing previously unknown migration routes and behaviors. Overall, this work will empower diverse stakeholders to efficiently monitor migrating birds across the Western Hemisphere and collect data in aid of science and conservation. Nighthawk is freely available athttps://github.com/bmvandoren/Nighthawk.
Urothelium-specific expression of mutationally activatedPik3cainitiates early lesions of non-invasive bladder cancer
Authors: Shuman Lauren , Pham Jonathan , Wildermuth Thomas , Wu Xue-Ru , Walter Vonn , Warrick Joshua I. , DeGraff David J. 
Published: May 2023

AbstractDespite the fact that ∼70% of bladder cancers are non-invasive and have high recurrence rates, early stage disease is understudied. The relative lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. While mutations inPIK3CAare frequent in human bladder cancer, anin vivomodel for understanding their contribution to bladder tumorigenesis is unavailable. Therefore, aUpk2-Cre/Pik3caH1047Rmouse model expressing one or twoR26-Pik3caH1047Ralleles in a urothelium-specific manner was created.Pik3caH1047Rfunctionality was confirmed by quantifying Akt phosphorylation and mice were characterized by assessing urothelial thickness, nuclear atypia, and expression of luminal and basal markers at 6 and 12 months of age. At 6 months,Pik3caH1047Rmice developed increased urothelial thickness and nuclear atypia, however, at 12 months,Pik3caH1047Rmice did not exhibit progressive disease. Immunohistochemistry shows urothelium maintained luminal differentiation characterized by high Foxa1 and Pparγ expression. In addition, mice were subjected to low-dose carcinogen exposure (N-Butyl-N-(4-hydroxybutyl)nitrosamine (BBN)). Surprisingly,Pik3caH1047Rmice exhibited no significant differences after exposure relative to mice without exposure. Furthermore, ssGSEA analysis of invasive human tumors showed those with mutantPIK3CAdo not exhibit significantly increased PI3K/AKT pathway activity compared to wildtypePIK3CAtumors. Overall, these data suggest thatPik3caH1047Rcan elicit early tumorigenic changes in the urothelium, but progression to invasion may require additional genetic alterations.
A genome catalog of the early-life human skin microbiome
Authors: Shen Zeyang , Robert Lukian , Stolpman Milan , Che You , Walsh Audrey , Saffery Richard , Allen Katrina J. , Eckert Jana , Young Angela , Deming Clay , Chen Qiong , Conlan Sean , Laky Karen , Li Jenny Min , Chatman Lindsay , Kashaf Sara Saheb ,   NISC Comparative Sequencing Program, Kong Heidi H. , Frischmeyer-Guerrerio Pamela A. , Perrett Kirsten P. , Segre Julia A. 
Published: May 2023

AbstractMetagenome-assembled genomes have greatly expanded the reference genomes for skin microbiome. However, the current reference genomes are largely based on samples from adults in North America and lack representation from infants and individuals from other continents. Here we used ultra-deep shotgun metagenomic sequencing to profile the skin microbiota of 215 infants at age 2-3 months and 12 months who were part of the VITALITY trial in Australia as well as 67 maternally-matched samples. Based on the infant samples, we present the Early-Life Skin Genomes (ELSG) catalog, comprising 9,194 bacterial genomes from 1,029 species, 206 fungal genomes from 13 species, and 39 eukaryotic viral sequences. This genome catalog substantially expands the diversity of species previously known to comprise human skin microbiome and improves the classification rate of sequenced data by 25%. The protein catalog derived from these genomes provides insights into the functional elements such as defense mechanisms that distinguish early-life skin microbiome. We also found evidence for vertical transmission at the microbial community, individual skin bacterial species and strain levels between mothers and infants. Overall, the ELSG catalog uncovers the skin microbiome of a previously underrepresented age group and population and provides a comprehensive view of human skin microbiome diversity, function, and transmission in early life.
Reintroduction of resistant frogs facilitates landscape-scale recovery in the presence of a lethal fungal disease
Authors: Knapp Roland A. , Wilber Mark Q. , Byrne Allison Q. , Joseph Maxwell B. , Smith Thomas C. , Rothstein Andrew P. , Grasso Robert L. , Rosenblum Erica Bree 
Published: May 2023

Vast alteration of the biosphere by humans is causing a sixth mass extinction, driven in part by an increase in emerging infectious diseases. The emergence of the lethal fungal pathogen (Batrachochytrium dendrobatidis; “Bd”) has devastated global amphibian biodiversity, with hundreds of species experiencing declines or extinctions. With no broadly applicable methods available to reverse these impacts in the wild, the future of many amphibians appears grim. The once-common mountain yellow-legged (MYL) frog is emblematic of amphibians threatened by Bd. Although most MYL frog populations are extirpated following disease outbreaks, some persist and eventually recover. Frogs in these recovering populations have increased resistance against Bd infection, consistent with evolution of resistant genotypes and/or acquired immunity. We conducted a 15-year landscape-scale reintroduction study and show that frogs collected from recovering populations and reintroduced to vacant habitats can reestablish populations despite the presence of Bd. In addition, results from viability modeling suggest that many reintroduced populations have a low probability of extinction over 50 years. To better understand the role of evolution in frog resistance, we compared the genomes of MYL frogs from Bd-naive and recovering populations. We found substantial differences between these categories, including changes in immune function loci that may confer increased resistance, consistent with evolutionary changes in response to Bd exposure. These results provide a rare example of how reintroduction of resistant individuals can allow the landscape-scale recovery of disease-impacted species. This example has broad implications for the many taxa worldwide that are threatened with extinction by novel pathogens.Significance StatementUnderstanding how species persist despite accelerating global change is critical for the conservation of biodiversity. Emerging infectious diseases can have particularly devastating impacts, and few options exist to reverse these effects. We used large-scale reintroductions of disease-resistant individuals in an effort to recover a once-common frog species driven to near-extinction by a disease that has decimated amphibian biodiversity. Introduction of resistant frogs allowed reestablishment of viable populations in the presence of disease. In addition, resistance may be at least partially the result of natural selection at specific immune function genes, which show evidence for selection in recovering populations. The evolution of resistance and reintroduction of resistant individuals could play an important role in biodiversity conservation in our rapidly changing world.
Synaptic turnover promotes efficient learning in bio-realistic spiking neural networks
Authors: Malakasis Nikos , Chavlis Spyridon , Poirazi Panayiota 
Published: May 2023

AbstractWhile artificial machine learning systems achieve superhuman performance in specific tasks such as language processing, image and video recognition, they do so use extremely large datasets and huge amounts of power. On the other hand, the brain remains superior in several cognitively challenging tasks while operating with the energy of a small lightbulb. We use a biologically constrained spiking neural network model to explore how the neural tissue achieves such high efficiency and assess its learning capacity on discrimination tasks. We found that synaptic turnover, a form of structural plasticity, which is the ability of the brain to form and eliminate synapses continuously, increases both the speed and the performance of our network on all tasks tested. Moreover, it allows accurate learning using a smaller number of examples. Importantly, these improvements are most significant under conditions of resource scarcity, such as when the number of trainable parameters is halved and when the task difficulty is increased. Our findings provide new insights into the mechanisms that underlie efficient learning in the brain and can inspire the development of more efficient and flexible machine learning algorithms.
A CRISPR-induced DNA break can trigger crossover, chromosomal loss and chromothripsis-like rearrangements
Authors: Samach Aviva , Mafessoni Fabrizio , Gross Or , Melamed-Bessudo Cathy , Filler-Hayut Shdema , Dahan-Meir Tal , Amsellem Ziva , Pawlowski Wojciech P. , Levy Avraham A. 
Published: May 2023

AbstractThe fate of DNA double-strand breaks (DSBs) generated by the Cas9 nuclease has been thoroughly studied. Repair via non-homologous end-joining (NHEJ) or homologous recombination (HR) is the common outcome. However, little is known about unrepaired DSBs and the type of damage they can trigger in plants. In this work, we designed a new assay that detects loss of heterozygosity (LOH) in somatic cells, enabling the study of a broad range of DSB-induced genomic events. The system relies on a mapped phenotypic marker which produces a light purple color (Betalain pigment) in all plant tissues. Plants with sectors lacking the Betalain marker upon DSB induction between the marker and the centromere were tested for LOH events. Using this assay we detected a flower with a twin yellow and dark purple sector, corresponding to a germinally transmitted somatic crossover event. We also identified instances of small deletions of genomic regions spanning the T-DNA and whole chromosome loss. In addition, we show that major chromosomal rearrangements including loss of large fragments, inversions, and translocations were clearly associated with the CRISPR-induced DSB. Detailed characterization of complex rearrangements by whole genome sequencing, molecular, and cytological analyses, supports a model in which breakage-fusion-bridge cycle followed by chromothripsis-like rearrangements had been induced. Our LOH assay provides a new tool for precise breeding via targeted crossover detection. It also uncovers CRISPR mediated chromothripsis-lke events that had not been previously identified in plants.
CLICK- chemoproteomics and molecular dynamics simulation reveals pregnenolone targets and their binding conformations in Th2 cells
Authors: Roy Sougata , Roy Sudeep , Mahata Bidesh , Pramanik Jhuma , Hennrich Marco L. , Gavin Anne-Claude , Teichmann Sarah A. 
Published: May 2023

AbstractPregnenolone (P5) is synthesized as the first bioactive steroid in the mitochondria from cholesterol. CD4+ and CD8+ immune cells synthesize P5de novo, P5 in turn play important role in immune homeostasis and regulation. However, P5’s biochemical mode of action in immune cells is still emerging. We envisage that revealing the complete spectrum of P5-target proteins in immune cells would have multifold applications, not only in basic understanding of steroids biochemistry in immune cells but also in developing new therapeutic applications. We employed a CLICK-enabled probe to capture P5-binding proteins in live Th2 cells. Subsequently, using high-throughput quantitative proteomics we identified the P5-interactome in CD4+ Th2 cells. Our study revealed P5’s conserved mode of action in CD4+ and CD8+ immune cells. We identified novel proteins from mitochondrial and endoplasmic reticulum membranes to be the primary mediators of P5’s biochemistry in CD4+ and CD8+ immune cells. Applying advanced computational algorithms, we were able to generate near-native maps of P5-protein key molecular interactions that can lead to successful designing of novel molecular therapeutics strategies.