bluuebunny/crossref_metadata_2025_split huggingface dataset:
Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression
Authors: Nshanian Michael , Gruber Joshua J. , Geller Benjamin S. , Chleilat Faye , Lancaster Samuel , White Shannon M. , Alexandrova Ludmila , Camarillo Jeannie Marie , Kelleher Neil L. , Zhao Yingming , Snyder Michael P. 
Published: January 2024

ABSTRACTThe short-chain fatty acids (SCFA) propionate and butyrate have beneficial health effects, are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. In order to better understand the function of these modifications we used ChIP-seq to map the genome-wide location of four short-chain acyl histone marks H3K18pr, H3K18bu, H4K12pr and H4K12bu in treated and untreated colorectal cancer (CRC) and normal cells, as well as in mouse intestinesin vivo. We correlate these marks with open chromatin regions along with gene expression to access the function of the target regions. Our data demonstrate that propionate and butyrate bind and act as promoters of genes involved in growth, differentiation as well as ion transport. We propose a mechanism involving direct modification of specific genomic regions, by SCFA resulting in increased chromatin accessibility, and in case of butyrate, opposing effects on the proliferation of normal versus CRC cells.
Genomic database furnishes a spontaneous example of a functional Class II glycyl-tRNA synthetase urzyme
Authors: Patra Sourav Kumar , Douglas Jordan , Wills Peter R. , Bouckeart Remco , Betts Laurie , Qing Tang Guo , Carter Charles W. 
Published: January 2024

AbstractThe chief barrier to studies of how genetic coding emerged is the lack of experimental models for ancestral aminoacyl-tRNA synthetases (AARS). We hypothesized that conserved core catalytic sites could represent such ancestors. That hypothesis enabled engineering functional “urzymes” from TrpRS, LeuRS, and HisRS. We describe here a fourth urzyme, GlyCA, detected in an open reading frame from the genomic record of the arctic fox,Vulpes lagopus. GlyCA is homologous to a bacterial heterotetrameric Class II GlyRS-B. Alphafold2 predicted that the N-terminal 81 amino acids would adopt a 3D structure nearly identical to the HisRS urzyme (HisCA1). We expressed and purified that N-terminal segment. Enzymatic characterization revealed a robust single-turnover burst size and a catalytic rate for ATP consumption well in excess of that previously published for HisCA1. Time-dependent aminoacylation of tRNAGlyproceeds at a rate consistent with that observed for amino acid activation. In fact, GlyCA is actually 35 times more active in glycine activation by ATP than the full-length GlyRS-B α-subunit dimer. ATP-dependent activation of the 20 canonical amino acids favors Class II amino acids that complement those favored by HisCA and LeuAC. These properties reinforce the notion that urzymes represent the requisite ancestral catalytic activities to implement a reduced genetic coding alphabet.
Chromosome-levelde novogenome unveils the evolution ofGleditsia sinensisand thorns development
Authors: Xiao Dandan , Liu Jiahao , Wang Jing , Yang Yuzhang , Yang Xiaoqian , Yu Ruen , Wang Chun , Wang Yanwei , Liu Yanping , Fan Dingchen , Lin Furong 
Published: January 2024

AbstractGleditsiaLinn is widely distributed in the world andGleditsia sinensisas an important Leguminosae specie, especially its thorns, has been used in the Chinese medicine as a chief ingredient for centuries. While the lack of genome database limits its in-depth research, especially genetic regulation and molecular developmental mechanism. In this investigation, a chromosome-levelde novogenome ofG. sinensiswas assembled through PacBio HiFi, Illumina sequencing as well as those from Hi-C, genetic mapping and K-mer analysis. TheG. sinensisharbors 786.13 Mb sized genome (contig N50=1.58 Mb, scaffold N50=51.53 Mb, 2n=28) with 36, 408 protein-coding genes. The full-length transcriptome sequencing of diverse tissues was performed to assist genome functional annotation. The comparative and evolutionary analysis unveiled thatG. sinensisdiverged from the Cretaceous period approximately 76.31 million years ago (Mya) and the close relationship betweenG. sinensisand other 8 Leguminosae species. The whole-genome duplication (WGD) analysis indicatedG. sinensisunderwent three WGD events and might go through another WGD event after differentiating from other Leguminosae plants. The Weighted Gene Coexpression Network Analysis based on phenotype and differentially expressed genes further demonstrated thatGsinMYBshould be involved in the development of thorns via regulating late thorn differentiation. This investigation provides a high level genome ofGleditsiafor Leguminosae species evolution comparison and functional elucidation and also key insights for further study on the molecular regulation mechanisms of the thorns development as a special abnormal stem organ in plants and the molecular breeding ofG. sinensis.
Delayed Healthcare Seeking and Associated Factors for Common Childhood Illnesses among Caregivers with Under-Five Children in Southwestern Ethiopia, 2023
Authors: Hunde Gamechu Atomsa , Fikadu Kalkidan , Demeke Tigist 
Published: January 2024

AbstractBackgroundFor under-five children, receiving timely and appropriate medical attention is crucial in preventing serious and fatal complications. Unfortunately, evidence shows that parents of young children frequently delay seeking care, contributing to the death of many kids before they even get to a medical facility.ObjectivesThe study aimed to assess delay in healthcare seeking and associated factors for common childhood illnesses among caregivers with under-five children visiting Yem special woreda public health facilities, 2023.MethodsA facility-based cross-sectional study was conducted among 333 caregivers of under-five children diagnosed with common childhood illnesses visiting Yem special woreda public health facilities. Systematic random sampling was employed and data collection was carried out using an interviewer-administered questionnaire. Delay was characterized as a long time (typically >24 hours) between disease onset and start of the necessary treatment. Data was entered using Epi Data version 4.7 and exported to Statistical Package for the Social Sciences version 25.0. Bi-variable and multivariable logistic regression analyses were conducted to identify the factors that influence the delay in healthcare seeking. Adjusted odds ratios with a 95% confidence interval were used to determine the associations. Statistically significant variables were identified based on a p-value < 0.05.ResultsA total of 326 caregivers participated in the study with a response rate of 98%. The proportion of delayed health care seeking was 74.5%. Child ≥ 12 months (AOR =1.99, 95% CI: 1.11-3.57), rural residence (AOR = 2.41, 95% CI: 1.35-4.28), no community health insurance (AOR = 1.91, 95% CI: 1.07-3.42), traditional treatment (AOR = 2.98, 95% CI: 1.46- 6.10), and self-medication at home first (AOR = 2.73, 95% CI: 1.32-5.63) and perceiving illness as mild (AOR= 2.64, 95% CI: 1.28-5.42) were factors associated with delayed healthcare seeking.Conclusion and recommendationThe study showed delay in health care seeking for common childhood illnesses among caregivers was high. Hence, reducing delays necessitates the implementation of public education campaigns, collaboration with local organizations, and the provision of counseling for caregivers regarding childhood illnesses.
Effect of the Healing Fit program on sleep quality, stress, and concentration: a randomized controlled study
Authors: Kim Wonjong , Bae Iklyul , Kim Kiyong , Ju Wonheo 
Published: January 2024

ABSTRACTThis study examined the usefulness for improving sleep quality of the Healing Fit program, which provides micro-electrical stimulation of the brain (transcranial electrical stimulation) and music therapy, in healthy adults who experienced sleep deprivation. A randomized controlled pretest–posttest design was used to evaluate effects on sleep quality, stress, and concentration. The study began after approval from the Institutional Review Board of Eulji University before conducting the study (EU22-90). Healing Fit was applied to the experimental group (n = 25) at a volume of 50 dB (about the level of normal conversation) for 30 min. Transcranial electrical stimulation intensity was set individually from 1 to 10 to the extent that the participant had no pain. Afterwards, interventions corresponding to learning, healing, and sleep music within Healing Fit were applied three times a day (30 min per session) for 14 days while participants continued their normal daily routines. The 25 control participants rested without any treatment for 30 min. Subjective/objective sleep quality, subjective/objective stress, concentration, and general characteristics were measured on day 1 of the experiment in both groups. Objective/subjective sleep quality was measured on day 7 and objective/subjective sleep quality, objective/subjective stress, and concentration were measured on day 14. The total sleep time, waking time after sleep onset, sleep efficiency, deep sleep, and subjective sleep quality were significantly better in the experimental group than in the control group. Objective and subjective stress decreased significantly in the experimental group compared to the control group, but there were no significant differences in autonomic nervous system activity. However, sympathetic and parasympathetic nervous system activity was balanced when Healing Fit was applied. There were no significant differences in concentration between groups; however, concentration tended to increase over time in the experimental group.Clinical Trial RegistrationClinical Research Information Service (https://cris.nih.go.kr/; KCT0009045).
Insulin resistance assessed by short insulin tolerance test and its association with obesity and insulin resistance-related parameters in humans: A randomized trial
Authors: Hayashishita Akiko , Watanabe Taku , Suzuki Naoko , Nakaya Toshitaka , Sugimoto Ayako , Yokota Isao , Ohira Hiroshi , Nishimura Masaharu , Tsujino Ichizo 
Published: January 2024

AbstractThe aim of this study was to examine the association of insulin resistance (evaluated by the short insulin tolerance test [SITT]) with parameters related to obesity and insulin resistance. We prospectively recruited controls and patients with type 2 diabetes mellitus (T2DM), subjected them to the SITT, and calculated the K indices of the intravenous insulin tolerance test (KITT(iv)) and the subcutaneous insulin tolerance test (KITT(sc)). We compared KITT(iv) between the volunteers and patients, and examined its correlation with KITT(sc). We also examined the association of KITT(iv) with obesity, insulin resistance-related parameters, and the insulin dose required for glycemic control. A total of 24 participants (seven controls and 17 patients with T2DM) were studied. The mean KITT(iv) was significantly lower in patients with T2DM than in the controls (2.5%±2.1% vs. 4.5%±1.8%). In all participants, KITT(iv) was significantly correlated with the HOMA-IR values (r=−0.601, p<0.05) but not with KITT(sc) (p=0.62). KITT(iv) was correlated positively with the serum adiponectin concentration, but negatively with the visceral fat area and serum concentrations of tumor necrosis factor-α and branched-chain amino acids. In patients with T2DM, KITT(iv) and HOMA-IR values were significantly correlated with the total insulin dose required for glycemic control. Insulin resistance evaluated using intravenous insulin (KITT(iv)) was correlated with the HOMA-IR values, but not with the resistance evaluated using subcutaneous insulin (KITT(sc)). The degree of insulin resistance was associated with biomarkers, such as adiponectin, and with the dose of insulin required for glycemic control.
Contribution of parasite and host genotype to immunopathology of schistosome infections
Authors: Jutzeler Kathrin S. , Le Clec’h Winka , Chevalier Frédéric D. , Anderson Timothy J.C. 
Published: January 2024

AbstractBackgroundThe role of pathogen genotype in determining disease severity and immunopathology has been studied intensively in microbial pathogens including bacteria, fungi, protozoa, and viruses, but is poorly understood in parasitic helminths. The medically important blood flukeSchistosoma mansoniis an excellent model system to study the impact of helminth genetic variation on immunopathology. Our laboratory has demonstrated that laboratory schistosome populations differ in sporocyst growth and cercarial production in the intermediate snail host and worm establishment and fecundity in the vertebrate host. Here, we (i) investigate the hypothesis that schistosome genotype plays a significant role in immunopathology and related parasite life history traits in the vertebrate mouse host and (ii) quantify the relative impact of parasite and host genetics on infection outcomes.MethodsWe infected BALB/c and C57BL/6 mice with four different laboratory schistosome populations from Africa and the Americas. We quantified disease progression in the vertebrate host by measuring body weight and complete blood count (CBC) with differential over an infection period of 12 weeks. On sacrifice, we assessed parasitological (egg and worm counts, fecundity), immunopathological (organ measurements and histopathology), and immunological (CBC with differential and cytokine profiles) characteristics to determine the impact of parasite and host genetics.ResultsWe found significant variation between parasite populations in worm numbers, fecundity, liver and intestine egg counts, liver and spleen weight, and fibrotic area, but not in granuloma size. Variation in organ weight was explained by egg burden and by intrinsic parasite factors independent of egg burden. We found significant variation between infected mouse lines in cytokines (IFN-γ, TNF-α), eosinophil, lymphocyte, and monocyte counts.ConclusionsThis study showed that both parasite and host genotype impact the outcome of infection. While host genotype explains most of the variation in immunological traits, parasite genotype explains most of the variation in parasitological traits, and both host and parasite genotype impact immunopathology outcomes.
Delineation of signaling routes that underlie differences in macrophage phenotypic states
Authors: Totu Tiberiu , Bossart Jonas , Hast Katharina , Li Chen , Rottmar Markus , Sobottka Bettina , Yu Guocan , Ayala-Nunez Vanesa , Buljan Marija 
Published: January 2024

AbstractMacrophages represent a major immune cell type in tumor microenvironments, they exist in multiple functional states and are of a strong interest for therapeutic reprogramming. While signaling cascades defining pro-inflammatory macrophages are better characterized, pathways that drive polarization in immunosuppressive macrophages are incompletely mapped. Here, we performed an in-depth characterization of signaling events in primary human macrophages in different functional states using mass spectrometry-based proteomic and phosphoproteomic profiling. Analysis of direct and indirect footprints of kinase activities has suggested PAK2 and PKCα kinases as important regulators ofin vitroimmunosuppressive macrophages (IL-4/IL-13 or IL-10 stimulated). Network integration of these data with the corresesponding transcriptome profiles has further highlighted FOS and NCOR2 as central transcription regulators in immunosuppressive states. Furthermore, we retrieved single cell sequencing datasets for tumors from cancer patients and found that the unbiased signatures identified here through proteomic analysis were able to successfully separate pro-inflammatory macrophage populations in a clinical setting and could thus be used to expand state-specific markers. This study contributes to in-depth multi-omics characterizations of macrophage phenotypic landscapes, which could be valuable for assisting future interventions that therapeutically alter immune cell compartments.Abstract FigureHighlightsGlobal proteomic characterization of primary human macrophages in different statesMapping of main signaling events through in-depth data analysisPKCα and PAK2 kinases are important regulators of immunosuppressive macrophagesProteomic signatures enable accurate detection of pro-inflammatory macrophages in patient tumors
Long-Term Potentiation Produces a Sustained Expansion of Synaptic Information Storage Capacity in Adult Rat Hippocampus
Authors: Samavat Mohammad , Bartol Thomas M. , Bromer Cailey , Hubbard Dusten D. , Hanka Dakota C. , Kuwajima Masaaki , Mendenhall John M. , Parker Patrick H. , Bowden Jared B. , Abraham Wickliffe C. , Sejnowski Terrence J. , Harris Kristen M. 
Published: January 2024

AbstractLong-term potentiation (LTP) has become a standard model for investigating synaptic mechanisms of learning and memory. Increasingly, it is of interest to understand how LTP affects the synaptic information storage capacity of the targeted population of synapses. Here, structural synaptic plasticity during LTP was explored using three-dimensional reconstruction from serial section electron microscopy. Storage capacity was assessed by applying a new analytical approach, Shannon information theory, to delineate the number of functionally distinguishable synaptic strengths. LTP was induced by delta-burst stimulation of perforant pathway inputs to the middle molecular layer of hippocampal dentate granule cells in adult rats. Spine head volumes were measured as predictors of synaptic strength and compared between LTP and control hemispheres at 30 min and 2 hr after the induction of LTP. Synapses from the same axon onto the same dendrite were used to determine the precision of synaptic plasticity based on the similarity of their physical dimensions. Shannon entropy was measured by exploiting the frequency of spine heads in functionally distinguishable sizes to assess the degree to which LTP altered the number of bits of information storage. Outcomes from these analyses reveal that LTP expanded storage capacity; the distribution of spine head volumes was increased from 2 bits in controls to 3 bits at 30 min and 2.7 bits at 2 hr after the induction of LTP. Furthermore, the distribution of spine head volumes was more uniform across the increased number of functionally distinguishable sizes following LTP, thus achieving more efficient use of coding space across the population of synapses.SignificanceEstablishing relationships between structure, function, and information storage capacity provides a new approach to assessing network strength from structural measurements. Long term potentiation (LTP) is a standard model for investigating synaptic mechanisms of learning and memory. Information is a retrievable quantity that is being stored in synapses as synaptic strength and is correlated with multiple structural components of synaptic strength. Structural synaptic plasticity was measured in 3D reconstructions from serial section electron microscopy of spine head volume, as a proxy for synapse strength, at 30 min and 2 hr after LTP induction. Outcomes indicate that LTP enhances information storage capacity for at least 2 hr by increasing the precision of the synaptic structure and expanding the range of synapse sizes.
Microsatellite break-induced replication generates highly mutagenized extrachromosomal circular DNAs
Authors: Gadgil Rujuta Yashodhan , Rider S. Dean , Shrestha Resha , Alhawach Venicia , Hitch David C. , Leffak Michael 
Published: January 2024

AbstractExtrachromosomal circular DNAs (eccDNAs) are produced from all regions of the eucaryotic genome. In tumors, highly transcribed eccDNAs have been implicated in oncogenesis, neoantigen production and resistance to chemotherapy. Here we show that unstable microsatellites capable of forming hairpin, triplex, quadruplex and AT-rich structures generate eccDNAs when integrated at a common ectopic site in human cells. These non-B DNA prone microsatellites form eccDNAs by replication-dependent mechanisms. The microsatellite-based eccDNAs are highly mutagenized and display template switches to sister chromatids and to nonallelic chromosomal sites. High frequency mutagenesis occurs within the eccDNA microsatellites and extends bidirectionally for several kilobases into flanking DNA and nonallelic DNA. Mutations include mismatches, short duplications, longer nontemplated insertions and large deletions. Template switching leads to recurrent deletions and recombination domains within the eccDNAs. Template switching events are microhomology-mediated, but do not occur at all potential sites of complementarity. Each microsatellite exhibits a distinct pattern of recombination, microhomology choice and base substitution signature. Depletion of Rad51, the COPS2 signalosome subunit or POLη alter the eccDNA mutagenic profiles. We propose an asynchronous capture model based on break-induced replication from microsatellite-induced DNA breaks for the generation and circularization of mutagenized eccDNAs and genomic homologous recombination deficiency (HRD) scars.
Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling
Authors: Mori Mateus Prates , Lozoya Oswaldo , Brooks Ashley M. , Grenet Dagoberto , Nadalutti Cristina A. , Ryback Birgitta , Huang Kai Ting , Hasan Prottoy , Hajnóczky Gyӧrgy , Santos Janine H. 
Published: January 2024

SummaryMaintenance of the mitochondrial inner membrane potential (ΔΨM) is critical for many aspects of mitochondrial function, including mitochondrial protein import and ion homeostasis. While ΔΨM loss and its consequences are well studied, little is known about the effects of increased ΔΨM. In this study, we used cells deleted ofATPIF1, a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of mitochondrial hyperpolarization. Our data show that chronic ΔΨM increase leads to nuclear DNA hypermethylation, regulating transcription of mitochondria, carbohydrate and lipid metabolism genes. Surprisingly, remodeling of phospholipids, but not metabolites or redox changes, mechanistically links the ΔΨM to the epigenome. These changes were also observed upon chemical exposures and reversed by decreasing the ΔΨM, highlighting them as hallmark adaptations to chronic mitochondrial hyperpolarization. Our results reveal the ΔΨM as the upstream signal conveying the mitochondrial status to the epigenome to regulate cellular biology, providing a new framework for how mitochondria can influence health outcomes in the absence of canonical dysfunction.HighlightsMitochondria hyperpolarization leads to nuclear DNA hypermethylationDNA methylation regulates expression of mitochondrial and lipid metabolism genesPhospholipid remodeling mediates the epigenetic effects of mitochondrial hyperpolarization