bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Life’s Essential 8 with Cardiovascular Events and Mortality: The Cardiovascular Disease Lifetime Risk Pooling Project (LRPP)
Authors: Ning Hongyan , Perak Amanda M. , Siddique Juned , Wilkins John T , Lloyd-Jones Donald M. , Allen Norrina B. 
Published: August 2023

AbstractBackgroundThe American Heart Association (AHA) recently launched updated cardiovascular health (CVH) metrics, termed Life’s Essential 8 (LE8). Compared to Life’s Simple 7 (LS7), the new approach added sleep health as an eighth metric and updated the remaining 7 metrics. Whether the updated LE8 score outperforms the original LS7 score in predicting cardiovascular disease (CVD) is not known. We examined the association of LE8 scores with CVD, subtype CVD events and all-cause mortality.MethodsWe pooled individual-level data from 6 contemporary US-based cohorts from the Cardiovascular Lifetime Risk Pooling Project (LRPP). Total LE8 score (0-100 points), LE8 score without sleep (0-100 points), as well as prior LS7 scores (0-14 points), were calculated separately. We used multivariable-adjusted Cox models to evaluate the association of LE8 with CVD, CVD subtypes, and all-cause mortality among younger, middle, and older aged adult participants. Reclassification was defined based on the concordant/discordant categories of LS7 and LE8 scores quartile rankings across age groups.ResultsOur sample consisted of 32,896 US adults (7836 [23.8%] Black; 14941 [45.4%] men) followed for 642,000 person-years; of whom 9,391 developed CVD events. Each 10-point higher overall LE8 score was associated with 23-40% lower CVD risk across age groups. Reclassification of CVH from LS7 to LE8 was related to heath behaviors as well as health factors and was significantly associated with CVD risk.ConclusionsThese findings support the improved utility of the LE8 algorithm for assessing overall cardiovascular health and future CVD risk.
Non-Stationary Dynamic Mode Decomposition
Authors: Ferré John , Rokem Ariel , Buffalo Elizabeth A. , Kutz J. Nathan , Fairhall Adrienne 
Published: August 2023

ABSTRACTMany physical processes display complex high-dimensional time-varying behavior, from global weather patterns to brain activity. An outstanding challenge is to express high dimensional data in terms of a dynamical model that reveals their spatiotemporal structure. Dynamic Mode Decomposition is a means to achieve this goal, allowing the identification of key spatiotemporal modes through the diagonalization of a finite dimensional approximation of the Koopman operator. However, DMD methods apply best to time-translationally invariant or stationary data, while in many typical cases, dynamics vary across time and conditions. To capture this temporal evolution, we developed a method, Non-Stationary Dynamic Mode Decomposition (NS-DMD), that generalizes DMD by fitting global modulations of drifting spatiotemporal modes. This method accurately predicts the temporal evolution of modes in simulations and recovers previously known results from simpler methods. To demonstrate its properties, the method is applied to multi-channel recordings from an awake behaving non-human primate performing a cognitive task.
Flicker and Ganzfeld induced visual hallucinations differ in frequency and content
Authors: Shenyan Oris , Lisi Matteo , Greenwood John A. , Skipper Jeremy I. , Dekker Tessa M. 
Published: August 2023

AbstractHallucinatory experiences, defined as perception in the absence of external stimuli, can occur in both pathological and non-pathological states and can be broadly phenomenologically divided into those of a simple and a complex nature. Non-pathological visual hallucinations can be induced experimentally using a variety of stimulation conditions. To assess whether these techniques drive a shared underlying hallucinatory mechanism, despite these differences, we compared two methods: flicker and perceptual deprivation (Ganzfeld). Specifically, we measured the frequency and complexity of the hallucinations produced by these techniques. We utilised button press, retrospective drawing, interviews, and questionnaires to quantify hallucinatory experience in 20 participants. With both experimental techniques, we found that simple hallucinations were more common than complex hallucinations. We also found that on average, flicker was more effective than Ganzfeld at eliciting a higher number of hallucinations, though Ganzfeld hallucinations were longer than flicker hallucinations. There was no interaction between experimental condition and hallucination complexity, suggesting that the increased bottom-up visual input in flicker increased both simple and complex hallucinations similarly. A correlation was observed between the total proportional time spent hallucinating in flicker and Ganzfeld, which was replicated in a retrospective questionnaire measure of experienced intensity, suggesting a shared hallucinatory mechanism between the two methodologies. We attribute these findings to a shared low-level core hallucinatory mechanism, such as excitability of visual cortex, which is amplified in flicker compared to Ganzfeld due to heightened bottom-up input.
Humans with Pulmonary Arterial Hypertension display a global hypermethylation signature that worsens in patients who have a mutation in the gene encoding the methylation eraser, Tet Methylcytosine Dioxygenase 2 (TET2)
Authors: Hindmarch Charles C.T , Potus François , Ruaa Al-Qazazi , Ring Brooke , Nichols William C , Rauh Michael J , Archer Stephen L 
Published: August 2023

AbstractEpigenetic changes in gene expression due to DNA methylation are important physiologic and pathologic regulators of pulmonary vascular structure and function. Genetic or acquired alterations in DNA methylation or demethylation have been associated with the development and progression of pulmonary arterial hypertension (PAH). However, the DNA methylome signature of human PAH and its consequences on the PAH transcriptome are unknown. Reduced Representation Bisulfite Sequencing (RRBS) was used for epigenome-wide mapping of DNA methylation in whole peripheral blood of 10 healthy people and 20 age/sex matched PAH patients. RNA deep sequencing was performed in parallel on the same samples. We used whole-exome sequencing to identify two PAH cohorts, one free of mutations in the genes know to be associated with PAH patients and the second had mutations ofTET2, a newly identified PAH gene that encodes an enzyme that mediates DNA demethylation. We report an increased in global DNA methylation in the blood of PAH patients compared to healthy controls. Patients carrying theTET2mutation had a further increase in DNA compared to mutation free PAH patients. We identified 1,069 unique Differentially Methylated Regions (DMR) in the blood of PAH patients with a TET2 mutation. When organized into functional groups, we observed an enrichment of genes involved in ‘immune’, ‘cell differentiation’, or ‘metabolic’. When we compared these genes to publicly available data from an independent study on blood from PAH patients compared to controls, we identified 218 mRNA transcripts that align with our data (e.g. are hypermethylated blood genes that are downregulated in PAH blood), and functional analysis of these genes reveals common enriched terms in ‘immune’, ‘cell differentiation’, or ‘metabolic’ function. We characterized DNA methylation changes associated with TET2 mutation in the blood of patients with PAH compared to controls. This data demonstrates that epigenetic regulation of genes by methylation is involved in altered immune function, cell differentiation and metabolism in PAH.
A sex-stratified analysis of the genetic architecture of human brain anatomy
Authors: Shafee Rebecca , Moraczewski Dustin , Liu Siyuan , Mallard Travis , Thomas Adam , Raznahan Armin 
Published: August 2023

AbstractLarge biobanks have dramatically advanced our understanding of genetic influences on human brain anatomy. However, most studies have combined rather than compared males and females - despite theoretical grounds for potential sex differences. By systematically screening for sex differences in the common genetic architecture of > 1000 neuroanatomical phenotypes in the UK Biobank, we establish a general concordance between males and females in heritability estimates, genetic correlations and variant-level effects. Notable exceptions include: higher mean h2in females for regional volume and surface area phenotypes; between-sex genetic correlations that are significantly below 1 in the insula and parietal cortex; and, a male-specific effect common variant mapping toRBFOX1 -a gene linked to multiple male-biased neuropsychiatric disorders. This work suggests that common variant influences on human brain anatomy are largely consistent between males and females, with a few exceptions that will guide future research as biobanks continue to grow in size.
WASH interventions and child diarrhea at the interface of climate and socioeconomic position in Bangladesh
Authors: Ante-Testard Pearl Anne , Rerolle Francois , Nguyen Anna T. , Ashraf Sania , Parvez Sarker Masud , Naser Abu Mohammed , Benmarhnia Tarik , Rahman Mahbubur , Luby Stephen P. , Benjamin-Chung Jade , Arnold Benjamin F. 
Published: August 2023

AbstractMany diarrhea-causing pathogens are climate-sensitive, and the poorest populations are often most vulnerable to climate-related transmission. Household Water, Sanitation, and Handwashing (WASH) interventions constitute one potential effective strategy to reduce diarrhea among children, especially among low-income households. Here, capitalizing on a cluster randomized trial population (360 clusters, 8,440 measurements among children < 3 years) in rural Bangladesh, one of the world’s most climate-sensitive regions regarding precipitation regimes, we show that improved WASH substantially reduces diarrhea risk with largest benefits among poorest children and during the monsoon season. We extrapolated trial results to rural Bangladesh regions using high-resolution geospatial layers to identify areas most likely to benefit. We estimated that a similar intervention at scale could prevent 734 cases per 1,000 children per month during the seasonal monsoon, with marked heterogeneity by region. The analysis demonstrates how to extend large-scale trials to inform WASH strategies among climate-sensitive and low-income populations.
Evidence that metastases arisede novoas new cancers from cells of target organs
Authors: Raghuram Gorantla V. , Pal Kavita , Shende Soniya , Khare Naveen Kumar , Jadhav Vishalkumar , Shinde Sushma , Prasad Ratnam , Wani Harshada , Mittra Indraneel 
Published: August 2023

AbstractIntroductionBased on our earlier finding that cell-free chromatin particles (cfChPs) released from dying cancer cells are potentially oncogenic, we hypothesised that metastases arise as new cancers from the cells of target organs transformed by cfChPs released from dying cancer cells.MethodsWe fluorescently dually-labelled MDA-MB-231 human breast cancer cells and A-375 human melanoma cells in their DNA with BrdU and in their histones with CellLight® Histone 2BGFP. One hundred thousand dually-labelled cells were intravenously injected into SCID mice. In other experiments unlabelled cells were injected for detection of lung metastasis. Also intravenously injected were 700 ng of purified cfChPs isolated from radiation-killed MDA-MB-231 cells.ResultsWe observed that the fluorescently dually-labelled MDA-MB-231 and A-375 cells died upon reaching the lungs and released dually-labelled fluorescent chromatin particles that accumulated in the nuclei of lung cells at 48 h. Injection of unlabelled cfChPs led to the activation of 10 hallmarks of cancer and immune checkpoints in lung cells at 72 h, suggesting that the lung cells had rapidly transformed into incipient cancer cells. Fluorescentin situhybridisation analysis of lung metastases that subsequently developed using mouse and human specific DNA probes revealed that the tumour cells contained both mouse and human DNA in almost equal proportions. Similarly, immune-fluorescence analysis using species specific mAbs revealed that the tumour cells co-expressed mouse and human specific proteins. Metaphase preparations and single-cell clones developed from cell cultures of lung metastases were found to contain chimeric chromosomes containing both mouse and human DNA, and the cells to co-express both human- and mouse-specific proteins. The Intravenously injected purified cfChPs isolated from radiation-killed MDA-MB-231 cells also induced lung metastasis which predominantly contained mouse DNA strongly suggesting that the metastatic tumours had arisen from the mouse lung cells.ConclusionThese results provide strong evidence that cfChPs released from dying cancer cells integrate into genomes of target lung cells to transform them into new cancers that masquerade as metastasis. They support our hypothesis that metastases arise from the cells of target organs and not from those of the primary tumour. These findings have implications for the principles of cancer therapy.
Multiplexed Digital Characterisation of Misfolded Protein Oligomers via Solid-State Nanopores
Authors: Sandler Sarah E. , Horne Robert I. , Rocchetti Sara , Novak Robert , Hsu Nai-Shu , Cruz Marta Castellana , Brotzakis Z. Faidon , Gregory Rebecca C. , Chia Sean , Bernardes Gonçalo J. L. , Keyser Ulrich F. , Vendruscolo Michele 
Published: August 2023

AbstractMisfolded protein oligomers are of central importance in both the detection and treatment of Alzheimer’s and Parkinson’s diseases. However, accurate high-throughput methods to identify and quantify oligomer populations are currently lacking. We present here a single-molecule approach for the detection of oligomeric species. The approach is based on the use of solid state nanopores and multiplexed DNA barcoding to identify and characterise oligomers from multiple samples. We study α-synuclein oligomers in the presence of several small molecule inhibitors of α-synuclein aggregation, as an illustration of the applicability of this method to assist the development of diagnostic and therapeutic methods for Parkinson’s disease.
Establishing conditions for the generation and maintenance of estrogen receptor-positive organoid models of breast cancer
Authors: Oliphant Michael UJ , Akshinthala Dipikaa , Muthuswamy Senthil K 
Published: August 2023

AbstractPatient-derived organoid models of estrogen receptor-positive (ER+) breast cancer would provide a much-needed tool to better understand drug resistance and disease progression. However, the establishment and long-term maintenance of ER expression, function, and response in vitro remains a significant challenge. Here, we report the development of an ER+ breast tumor organoid medium (BTOM-ER) that conserves ER expression, estrogen responsiveness, and dependence, as well as sensitivity to endocrine therapy of ER+ patient-derived xenograft organoids (PDXO). Our findings demonstrate the utility of subtype-specific culture conditions that better mimic the characteristics of the breast epithelial biology and microenvironment, providing a powerful platform for investigating therapy response and disease progression of ER+ breast cancer.
Chromosome-Level Genome Assembly of Navel orange cv. Gannanzao (Citrus sinensisOsbeck cv. Gannanzao)
Authors: Xiong Zhiwei , Yin Hui , Wang Nian , Gao Yuxia 
Published: August 2023

AbstractNavel orange cv. Gannanzao is a variant of the navel orange cv. Newhall (C. sinensisOsbeck cv. Newhall) that exhibits an earlier maturation, making it commercially valuable. However, the underlying mechanism underneath its early maturation remains unknown. To address this question, we conducted genome sequencing and de novo assembly of navel orange cv. Gannanzao. The assembled genome sequence is 334.57 Mb in length with a GC content of 31.48%. It comprises 318 contigs (N50 = 3.23 Mb) and 187 scaffolds (N50 = 31.86 Mb). The BUSCO test demonstrates 94.6% completeness. The annotation revealed 23,037 gene models, 164.95 Mb of repetitive sequences, and 2,554 ncRNA. Comparative analysis identified 323 fruit ripening-related genes in navel orange cv. Gannanzao genome, while navel orange cv. Newhall genome contained 345 such genes. These genes were organized into 320 orthologous gene families, with 30.3% of them exhibiting differences in gene copy numbers between the two genomes. Additionally, we identified 15 fruit ripening-related genes that have undergone adaptive evolution, suggesting their potential role in advancing fruit maturation in navel orange cv. Gannanzao. Whole genome sequencing and annotation of navel orange cv. Gannanzao provides a valuable resource to unravel the early maturation mechanism of citrus and enriches the genomic resources for citrus research.
Complete Suspension Differentiation of Human Pluripotent Stem Cells into Pancreatic Islets Using Vertical Wheel®Bioreactors
Authors: Dadheech Nidheesh , Bermúdez de León Mario , Cuesta-Gomez Nerea , Jasra Ila Tewari , Pawlick Rena , Marfil-Garza Braulio , Verhoeff Kevin , Sapkota Sandhya , Razavy Haide , Anwar Perveen , Lyon James , MacDonald Patrick , Gorman Doug O’ , Jickling Glen , Shapiro AM James 
Published: August 2023

AbstractAdvanced protocols to produce human pluripotent stem cell (SC)-derived islets show promise in functional, metabolic, and transcriptional maturation of cell therapy product to treat diabetes. Available protocols are either developed as complete planar (2D) or, in later stages, combined with suspension cultures (3D). Despite marked progress, both approaches have clear limitations for scalability, cell loss and batch to batch heterogeneity during differentiation. Using a Vertical Wheel®bioreactor system, we present a highly efficient and scalable complete suspension protocol across all stages for directed differentiation of human pluripotent stem cells into functional pancreatic islets. Here, we generate homogeneous, metabolically functional, and transcriptionally enriched SC-islets and compared against adult donor islets. Generated SC-islets showed enriched endocrine cell composition (∼63% CPEP+NKX6.1+ISL1+) and displayed functional maturity for glucose stimulated insulin secretion (∼5-fold) duringin vitroand post transplantation. Comprehensive stage-specific single-cell mass flow cytometry characterization with dimensional reduction analysis at stage-4 and -6 confirmed optimal maturation was achieved without heterogeneity. Notably, by 16-weeks transplantation follow-up, normal glycemic homeostasis was restored, and glucose responsive human c-peptide secretion response (2-fold) was achieved. Four months post engraftment, graft-harvested single cells displayed islet hormonal cell composition with flow cytometry, improved functional maturity byin vivoglucose-stimulated insulin secretion (GSIS) and enhanced transcriptional landscape with real-time expression that closely resembled patterns comparable to adult human islets. Our comprehensive evaluation of a complete suspension method applied across all stages using Vertical Wheel®bioreactors for SC-islets generation highlight progressive molecular and functional maturation of islets while reducing potential cell loss and cellular heterogeneity. Such a system could potentially be scaled to deliver clinical grade SC-islet products in a closed good manufacturing practice type environment.One Sentence SummaryThis study describes all-stages complete suspension protocol for SC-islets generation.
Rats Chasing the Dragon: A new heroin inhalation method
Authors: Gutierrez Arnold , Taffe Michael A. 
Published: August 2023

AbstractRationaleDespite extensive human use of the inhalation route for ingesting opioids, models in rodents have mostly been limited to parenteral injection and oral dosing. Methods using electronic drug delivery systems (EDDS; “e-cigarettes”) have shown efficacy in rodent models but these do not faithfully mimic the most popular human inhalation method of heating heroin to the point of vaporization.ObjectiveThis study was designed to determine if direct volatilization of heroin hydrochloride delivers effective heroin doses to rodents.MethodsMiddle aged rats were exposed to vapor created by direct heating of heroin HCl powder in a ceramic e-cigarette type atomizer. Efficacy was determined with a warm water tail withdrawal nociception assay, rectal temperature and self-administration.ResultsTen minutes of inhalation of vaporized heroin slowed response latency in a warm water tail withdrawal assay and increased rectal temperature in male rats, in a dose-dependent manner. Similar antinociceptive effects in female rats were attenuated by the opioid antagonist naloxone (1.0 mg/kg, s.c.). Female rats made operant responses for heroin vapor in 15-minute sessions, increased their response rate when the reinforcement ratio increased from FR1 to FR5, and further increased their responding when vapor delivery was omitted. Anti-nociceptive effects of self-administered volatilized heroin were of a similar magnitude as those produced by the 10-minute non-contingent exposure.ConclusionsThis study shows that “chasing the dragon” methods of inhalation of heroin can be modeled successfully in the rat. Inhalation techniques may be particularly useful for longer term studies deep into middle age of rat species.
Epigenetic Regulation of Endothelial Extracellular Matrix Components is Critical for Murine Lung Development
Authors: Wu Meng-Ling , Wheeler Kate , Silasi-Mansat Robert , Lupu Florea , Griffin Courtney T. 
Published: August 2023

ABSTRACTBackgroundThe chromatin remodeling enzymes BRG1 (brahma-related gene 1) and CHD4 (chromodomain helicase DNA binding protein 4) independently regulate transcription of genes critical for vascular development, but their coordinated impact on vessels in late- stage embryos has not been explored.MethodsIn this study we genetically deleted endothelialBrg1andChd4in mixed background mice (Brg1fl/fl;Chd4fl/fl;VE-Cadherin-Cre+), and littermates that were negative for Cre recombinase were used as controls. Perinatal lung tissue was analyzed by immunostaining, immunoblots, and flow cytometry. Quantitative reverse transcription PCR was used to determine gene expression, and chromatin immunoprecipitation revealed gene targets of BRG1 and CHD4 in cultured endothelial cells (ECs).ResultsWe found thatBrg1/Chd4double mutants died soon after birth with small and compact lungs. Despite having normal cellular composition, distal air sacs of the mutant lungs displayed diminished ECM (extracellular matrix) components and TGFβ (transforming growth factor beta) signaling, which typically promotes matrix synthesis. Transcripts for collagen- and elastin-related genes and the TGFβ ligandTgfb1were decreased in mutant lung ECs, but genetic deletion of endothelialTgfb1failed to recapitulate the small lungs and ECM defects seen inBrg1/Chd4mutants. We instead found several ECM genes to be direct targets of BRG1 and CHD4 in cultured ECs.ConclusionsCollectively, our data highlight essential roles for ECs in promoting ECM deposition at late stages of embryonic lung development. Moreover, this endothelial ECM production is epigenetically regulated.Abstract FigureHIGHLIGHTSGenetic deletion of the chromatin remodeling enzymes BRG1 and CHD4 in endothelial cells of late-stage mouse embryos (Brg1/Chd4-ECdko) results in small and compact lungs at birth.Mutant embryos display reduced collagen IV deposition, dysregulated elastin fibers, and diminished TGFβ1 in the distal air sacs.Our combined in vitro and in vivo analyses indicate that BRG1 and CHD4 epigenetically regulate collagen IV- and elastin-related gene expression in embryonic ECs to promote proper lung development.