bluuebunny/crossref_metadata_2025 huggingface dataset:
Nurturing future leaders for nature: the example of the UK's National Education Nature Park
Authors: Hazell Jonny , Clarke Edward
Published: April 2024

This piece reviews the evidence on the effect that engaging with nature has on school-age children's future attitudes and behaviour towards nature. It also looks into the impact engaging with nature has on children and young people's physical, mental and personal development and the evidence on how much time children in England are spending in natural environments. It then presents a UK Government project, the National Education Nature Park (NENP), intended to increase children in England's access to nature by developing nature spaces within the grounds of educational institutions. It concludes with suggestions for how the implementation of the NENP could be used to learn more about the effect that engaging with nature has on children alongside understanding how school-based nature projects could benefit the local environment.

This article is part of the theme issue ‘Bringing nature into decision-making’.
Clinician Insights into Effective Components, Delivery Characteristics, and Implementation Strategies of Ambulatory Palliative Care for People with Heart Failure: A Qualitative Analysis
Authors: Feder Shelli , Iannone Lynne , Lendvai Dora , Zhan Yan , Akgün Kathleen , Ersek Mary , Luhrs Carol , Allen Larry A. , Bekelman David B. , Goldstein Nathan , Kavalieratos Dio
Published: April 2024

Objectives

To elicit perspectives from specialist palliative care (SPC) and cardiology clinicians on the necessary components, delivery characteristics, and implementation strategies of successful ambulatory SPC for people with heart failure (HF).

Background

Palliative care is a recommended component of guideline-directed care for people with HF. However, optimal strategies to implement SPC within ambulatory settings are unknown.

Methods

Following a positive deviance frame, we conducted a qualitative study comprising interviews with SPC and cardiology clinicians at Veterans Affairs Medical Centers (VAMCs) with the highest number of ambulatory SPC consultations within the VA system among people with HF from 2021-2022. Clinicians were asked how they provided ambulatory SPC and what they felt were the necessary components, delivery characteristics, and implementation strategies of care delivery. Interviews were analyzed using content analysis.

Results

We interviewed 14 SPC clinicians and 9 cardiology clinicians at seven national VAMCs; 43% were physicians 48% were advanced practice registered nurses/physician associates, and 10% were psychologists or social workers. Discussion of goals of care (e.g., prognosis, advance directives) and connecting patients/caregivers to resources (e.g., homecare) were essential components of ambulatory SPC provided at participating facilities. Clinicians preferred and used integrated (i.e., embedded) approaches to SPC delivery, employed standardized patient selection and referral procedures, and formalized procedures for handoffs to and from SPC. Necessary strategies to address barriers to ambulatory SPC implementation included deploying palliative champions, educating non-SPC clinicians on the value of ambulatory SPC for people with HF, and developing ambulatory models through leadership support.

Conclusions/Implications

Facilitating the broader adoption of ambulatory SPC may be achieved by prioritizing these mutually valued and necessary features of delivery.
Exploring Barriers to Parent-Adolescent Sexual-Risk Communication among Adolescents in Port Harcourt Nigeria: Adolescents’ and Parents’ Perspective
Authors: Chidinma Okpalaku Joycelyn , Ogubuike Chigozirim
Published: April 2024

Background

Adolescent risky sexual behaviour is a public health problem with its deleterious outcomes. Parents are the most influential source of sexuality education to adolescent, yet adolescents lack sexuality education. The study explored barriers in parent-adolescent sexual-risk communication from both perspectives in Port-Harcourt LGA, Rivers State, Nigeria.

Materials and Method

A cross-sectional study design using explanatory sequential mixed methods approach was implemented. Three hundred and twenty nine in-school adolescents participated in the quantitative study and recruited using multi-stage sampling technique while 9 parents of adolescents and 16 adolescents participated in the qualitative study. A semi-structured administered questionnaire was used to elicit information from the adolescents while an FGD and IDI guide was used to elicit information from in-school adolescents and parents respectively. The qualitative data was analysed using descriptive statistics and chi-square while the qualitative data was subjected to thematic analysis.

Results

The mean age of the adolescents was 16.0±1.1 years and 55% were males. A quarter (21%) of the parents had never discussed sex with their adolescents. The barriers identified from the adolescents’ perspective were parental factors (parents being too busy, judgmental, low knowledge), individual factors (discomfort to initiate communication, lack of trust), religious and cultural factors. The barriers from the parents’ perspective were shame to initiate communication, fear of outcome, feeling children are too young and lack of accurate information.

Conclusion

The barriers to parent-adolescent communication featured interplay of parental, individual, cultural and religious factors. Parents should be trained to initiate timely and accurate sexuality education to the adolescent to curb adolescent risky sexual exploitations.
Automated detection of Bornean white-bearded gibbon (Hylobates albibarbis) vocalisations using an open-source framework for deep learning
Authors: Owens A. F. , Hockings Kimberley J. , Imron Muhammed Ali , Madhusudhana Shyam , Mariaty  , Setia Tatang Mitra , Sharma Manmohan , Maimunah Siti , Van Veen F. J. F. , Erb Wendy M.
Published: April 2024

Passive acoustic monitoring is a promising tool for monitoring at-risk populations of vocal species, yet extracting relevant information from large acoustic datasets can be time-consuming, creating a bottleneck at the point of analysis. To address this, we adapted an open-source framework for deep learning in bioacoustics to automatically detect Bornean white-bearded gibbon (Hylobates albibarbis) “great call” vocalisations in a long-term acoustic dataset from a rainforest location in Borneo. We describe the steps involved in developing this solution, including collecting audio recordings, developing training and testing datasets, training neural network models, and evaluating model performance. Our best model performed at a satisfactory level (F score = 0.87), identifying 98% of the highest-quality calls from 90 hours of manually-annotated audio recordings and greatly reduced analysis times when compared to a human observer. We found no significant difference in the temporal distribution of great call detections between the manual annotations and the model’s output. Future work should seek to apply our model to long-term acoustic datasets to understand spatiotemporal variations in H. albibarbis’ calling activity. Overall, we present a roadmap for applying deep learning to identify the vocalisations of species of interest which can be adapted for monitoring other endangered vocalising species.
NAB2-STAT6 drives an EGR1-dependent neuroendocrine program in Solitary Fibrous Tumors
Authors: Hill Connor M , Indeglia Alexandra , Picone Francis , Murphy Maureen E. , Cipriano Cara , Maki Robert G. , Gardini Alessandro
Published: April 2024

The pathogenesis of many rare tumor types is poorly understood, preventing the design of effective treatments. Solitary fibrous tumors (SFTs) are neoplasms of mesenchymal origin that affect 1/1,000,000 individuals every year and are clinically assimilated to soft tissue sarcomas. SFTs can arise throughout the body and are usually managed surgically. However, 30-40% of SFTs will relapse local-regionally or metastasize. There are no systemic therapies with durable activity for malignant SFTs to date. The molecular hallmark of SFTs is a gene fusion between theNAB2andSTAT6loci on chromosome 12, resulting in a chimeric protein of poorly characterized function called NAB2-STAT6. We use primary samples and an inducible cell model to discover that NAB2-STAT6 operates as a transcriptional coactivator for a specific set of enhancers and promoters that are normally targeted by the EGR1 transcription factor. In physiological conditions, NAB2 is primarily localized to the cytoplasm and only a small nuclear fraction is available to operate as a co-activator of EGR1 targets. NAB2-STAT6 redirects NAB1, NAB2, and additional EGR1 to the nucleus and bolster the expression of neuronal EGR1 targets. The STAT6 moiety of the fusion protein is a major driver of its nuclear localization and further contributes to NAB2’s co-activating abilities. In primary tumors, NAB2-STAT6 activates a neuroendocrine gene signature that sets it apart from most sarcomas. These discoveries provide new insight into the pathogenesis of SFTs and reveal new targets with therapeutic potential.
Fibre tracing in biomedical images: An objective comparison between seven algorithms
Authors: Arafat Youssef , Cuesta-Apausa Cristina , Castellano Esther , Reyes-Aldasoro Constantino Carlos
Published: April 2024

Obtaining the traces and the characteristics of elongated structures is an important task in computer vision pipelines. In biomedical applications, the analysis of traces of vasculature, nerves or fibres of the extracellular matrix can help characterise processes like angiogenesis or the effect of a certain treatment. This paper presents an objective comparison of six existing methodologies (Edge detection, CT Fire, Scale Space, Twombli, U-Net and Graph Based) and one new approach calledTrace Ridgesto trace biomedical images with fibre-like structures. Trace Ridges is a fully automatic and fast algorithm that combines a series of image-processing algorithms including filtering, watershed transform and edge detection to obtain an accurate delineation of the fibre-like structures in a rapid time. To compare the algorithms, four biomedical data sets with very different characteristics were selected. Ground truth was obtained by manual delineation of the fibre-like structures. Three pre-processing filtering options were used as a first step: no filtering, Gaussian low-pass and DnCnn, a deep-learning filtering. Three distance error metrics (total, average and maximum distance from the obtained traces to the ground truth) and processing time were calculated. It was observed that no single algorithm outperformed the others in all metrics. For the total distance error, which was considered the most significative, Trace Ridges ranked first, followed by Graph Based, U-Net, Twombli, Scale Space, CT Fire and Edge Detection. In terms of speed, Trace Ridges ranked second only slightly slower than Edge Detection. Code is freely available atgithub.com/youssefarafat/Trace Ridges.
Swimming kinematics of rainbow trout behind cylinder arrays: the effect of vortex street periodicity and turbulence kinetic energy
Authors: Sparks David M. , Rajeev Edwin , Canestrelli Alberto , Liao James C.
Published: April 2024

Fish in the wild often contend with complex flows that are produced by natural and artificial structures. Research into fish interactions with turbulence often investigates metrics such as turbulence kinetic energy (TKE) or fish positional location, with less attention paid to the specific interactions between vortex organization and body swimming kinematics. Here we compare the swimming kinematics of rainbow trout (Oncorhynchus mykiss) holding station in flows produced by two different 3 x 5 cylinder arrays. We systematically utilized computational fluid dynamics to generate one array that produced a Kármán vortex street with high vortex periodicity and TKE (KVS array), and another that produced low periodicity and TKE, similar to a parallel vortex street (PVS array). The only difference in swimming kinematics between cylinder arrays was an increased tail beat amplitude in the KVS array. In both cylinder arrays, the tail beat frequency decreased and snout amplitude increased compared with the freestream.

The center of mass amplitude was greater in the PVS array than in only the freestream, however, suggesting some buffeting of the body by the fluid. Notably, we did not observe Kármán gaiting in the KVS array as in previous studies. We hypothesize that this is because (1) vorticity was dissipated in the region where fish held station in this study and (2) cylinder arrays produced vortices that were in-line rather than staggered. These results are the first to quantify the kinematics and behavior of fishes swimming in the wake of multiple cylinder arrays, which has important implications for biomechanics, fluid dynamics, and fisheries management.

SUMMARY STATEMENT

The swimming kinematics of rainbow trout are largely preserved across two, 3 x 5 cylinder array treatments that differed in vortex periodicity and turbulence kinetic energy.
The ERK1/2-Elk1, JNK-cJun, and JAK-STAT Transcriptional Axes as Potential Bortezomib Resistance Mediators in Prostate Cancer
Authors: Kalampounias Georgios , Zafeiropoulou Kalliopi , Androutsopoulou Theodosia , Alexis Spyridon , Symeonidis Argiris , Katsoris Panagiotis
Published: April 2024

The effectiveness of proteasome inhibitors against solid tumors is limited as the emergence of resistance is rapid. Although many mechanisms have been proposed and verified, no definite answer has been given, highlighting the complexity of the resistant phenotype. In this study, a Bortezomib-resistant prostate cancer cell line is created, and a broad-spectrum signaling pathway analysis is performed to identify differences and adaptations the resistant cells exhibit. Our findings highlight the upregulation and activation of Nf-κB, STAT3, cJun, and Elk1 transcription factors in the resistant cells and the subsequent evasion of apoptosis and induction of autophagy, which is constantly activated and substitutes the role of the ubiquitin-proteasome system (UPS). Additionally, assessment of the intracellular reactive oxygen species in resistant cells confirms their downregulation, which is theorized to be a consequence of metabolic changes, increased autophagic flux, and antioxidative enzyme action. The results of this study highlight the potential therapeutic targeting of key kinases and transcription factors, participating in the main signaling pathways and gene regulation of Bortezomib-resistant cells, that could re-sensitize the cells to proteasome inhibitors, thus surpassing the current limitations.
Overcoming Limitations to Deep Learning in Domesticated Animals with TrioTrain
Authors: Kalleberg Jenna , Rissman Jacob , Schnabel Robert D.
Published: April 2024

Variant calling across diverse species remains challenging as most bioinformatics tools default to assumptions based on human genomes. DeepVariant (DV) excels without joint genotyping while offering fewer implementation barriers. However, the growing appeal of a “universal” algorithm has magnified the unknown impacts when used with non-human genomes. Here, we use bovine genomes to assess the limits of human-genome-trained models in other species. We introduce the first multi-species DV model that achieves a lower Mendelian Inheritance Error (MIE) rate during single-sample genotyping. Our novel approach, TrioTrain, automates extending DV for species without Genome In A Bottle (GIAB) resources and uses region shuffling to mitigate barriers for SLURM-based clusters. To offset imperfect truth labels for animal genomes, we remove Mendelian discordant variants before training, where models are tuned to genotype the offspring correctly. With TrioTrain, we use cattle, yak, and bison trios to build 30 model iterations across five phases. We observe remarkable performance across phases when testing the GIAB human trios with a mean SNP F1 score >0.990. In HG002, our phase 4 bovine model identifies more variants at a lower MIE rate than DeepTrio. In bovine F1-hybrid genomes, our model substantially reduces inheritance errors with a mean MIE rate of 0.03 percent. Although constrained by imperfect labels, we find that multi-species, trio-based training produces a robust variant calling model. Our research demonstrates that exclusively training with human genomes restricts the application of deep-learning approaches for comparative genomics.
ModDotPlot - Rapid and interactive visualization of complex repeats
Authors: Sweeten Alexander P. , Schatz Michael C. , Phillippy Adam M.
Published: April 2024

MotivationA common method for analyzing genomic repeats is to produce a sequence similarity matrix visualized via a dot plot. Innovative approaches such as StainedGlass have improved upon this classic visualization by rendering dot plots as a heatmap of sequence identity, enabling researchers to better visualize multi-megabase tandem repeat arrays within centromeres and other heterochromatic regions of the genome. However, computing the similarity estimates for heatmaps requires high computational overhead and can suffer from decreasing accuracy.ResultsIn this work we introduce ModDotPlot, an interactive and alignment-free dot plot viewer. By approximating average nucleotide identity via ak-mer-based containment index, ModDotPlot produces accurate plots orders of magnitude faster than StainedGlass. We accomplish this through the use of a hierarchical modimizer scheme that can visualize the full 128 Mbp genome ofArabidopsis thalianain under 5 minutes on a laptop. ModDotPlot is implemented in Python with a graphical user interface supporting real-time interactive navigation of entire chromosomes.Availability and ImplementationModDotPlot is available at https://github.com/marbl/ModDotPlot.
Habitat fragmentation mediates the mechanisms underlying long-term climate-driven thermophilization in birds
Authors: Liu Juan , Tingley Morgan , Wu Qiang , Ren Peng , Jin Tinghao , Ding Ping , Si Xingfeng
Published: April 2024

Climatic warming can shift community composition driven by the colonization-extinction dynamics of species with different thermal preferences; but simultaneously, habitat fragmentation can mediate species' responses to warming. As this potential interactive effect has proven difficult to test empirically, we collected data on birds over 10 years of climate warming in a reservoir subtropical island system that was formed 65 years ago. We investigated how the mechanisms underlying climate-driven directional change in community composition were mediated by habitat fragmentation. We found thermophilization driven by increasing warm-adapted species and decreasing cold-adapted species in terms of trends in colonization rate, extinction rate, occupancy rate and population size. Critically, colonization rates of warm-adapted species increased faster temporally on smaller or less isolated islands; cold-adapted species generally were lost more quickly temporally on closer islands. This provides support for dispersal limitation and microclimate buffering as primary proxies by which habitat fragmentation mediates species range shift. Overall, this study advances our understanding of biodiversity responses to interacting global change drivers.
Assessment of the Degree of Coincidence between Differentially Expressed Genes in Pancreatic Cancer with and without CAR T Cell treatment
Authors: Luna-Alvear Alibeth E. , Suárez-Gómez Deiver , Sanchez-Castro Andrea A. , Rentas-Echeverria Alexandra C. , Cabrera-Ríos Mauricio , Isaza Clara E.
Published: April 2024

Treatment of cancer with CAR T Cells has steadily become a viable and promising cellular therapy approach in recent years. It is well known that liquid cancers are better suited for this kind of treatment, as opposed to solid cancers. This work focuses on contrasting lists of differentially expressed genes (DEGs) found in pancreatic cancer -a solid cancer-against lists of DEGs found in post-CAR T Cell treatment of pancreatic cancer. It is postulated that the degree of coincidence in these lists could positively correlate with treatment effectiveness. OBAMA, a proprietary mathematical optimization-based analysis pipeline that minimizes user selection bias is employed here to preserve objectivity. The study utilized publicly available microarray experiments. The results indicate overall low degrees of coincidence, which partially support the postulate of this work.
Estimation of Species Abundance Based on the Number of Segregating Sites using Environmental DNA (eDNA)
Authors: Ai Qiaoyun , Yuan Hao , Wang Ying , Li Chenhong
Published: April 2024

The advance of environmental DNA (eDNA) has enabled rapid and non-invasive species detection in aquatic environments. Although most studies focus on species detections, some recent studies explored the potential of using eDNA concentration to quantify species abundance. However, the differential individual DNA contribution to eDNA samples could easily obscure the concentration-species abundance relationship. We propose using the number of segregating sites as a proxy for estimating species abundance. Since segregating sites reflects the genetic diversity of the population, which is less sensitive to differential individual DNA contribution than eDNA concentration. We examined the relationship between the number of segregating sites and species abundance in silico, in vitro, and in situ using two brackish goby species,Acanthogobius hastaandTridentiger bifasciatus. Analyses of the simulated data and in vitro data with DNA mixed from a known number of individuals showed a strong correlation between the number of segregating sites and species abundance (R2> 0.9; P < 0.01). Results from the in situ experiment further validated the correlation (R2= 0.70, P < 0.01), and such correlation was not affected by biotic factors, including body size and feeding behavior (P > 0.05). Results of the cross-validation test also showed that the number of segregating sites predicted species abundance with less bias and variability than the eDNA concentration. Overall, the number of segregating sites correlates stronger with species abundance and also provides a better estimate than eDNA concentration. This advancement can significantly enhance the quantitative capabilities of eDNA technology.
Functional cardiac consequences of β-adrenergic stress-induced injury in themdxmouse model of Duchenne muscular dystrophy
Authors: Earl Conner C. , Javier Areli J. , Richards Alyssa M. , Markham Larry W. , Goergen Craig J. , Welc Steven S.
Published: April 2024

Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD), however, in themdxmouse model of DMD, the cardiac phenotype differs from that seen in DMD-associated cardiomyopathy. Although some have used pharmacologic stress to enhance the cardiac phenotype in themdxmodel, many methods lead to high mortality, variable cardiac outcomes, and do not recapitulate the structural and functional cardiac changes seen in human disease. Here, we describe a simple and effective method to enhance the cardiac phenotype model inmdxmice using advanced 2D and 4D high-frequency ultrasound to monitor cardiac dysfunction progressionin vivo. For our study,mdxand wild-type (WT) mice received daily low-dose (2 mg/kg/day) isoproterenol injections for 10 days. Histopathologic assessment showed that isoproterenol treatment increased myocyte injury, elevated serum cardiac troponin I levels, and enhanced fibrosis inmdxmice. Ultrasound revealed reduced ventricular function, decreased wall thickness, increased volumes, and diminished cardiac reserve in mdx mice compared to wild-type. Our findings highlight the utility of low-dose isoproterenol inmdxmice as a valuable model for exploring therapies targeting DMD-associated cardiac complications.

SUMMARY STATEMENT

This work introduces an improved method to model heart failure in mouse models of Duchenne muscular dystrophy and comprehensively describes underlying cellular and physiologic mechanisms using advanced imaging techniques.
Repair of leukemia-associated single nucleotide variants via interallelic gene conversion
Authors: Silver Alexander James , Brown Donovan J , Olmstead Sarah D , Watke Jackson M , Gorska Agnieszka E , Tanner Londa , Ramsey Haley E , Savona Michael R
Published: April 2024

CRISPR-Cas9 is a useful tool for inserting precise genetic alterations through homology-directed repair (HDR), although current methods rely on provision of an exogenous repair template. Here, we tested the possibility of repairing heterozygous single nucleotide variants (SNVs) using the cell′s own wild-type allele rather than an exogenous template. Using high-fidelity Cas9 to perform allele-specific CRISPR across multiple human leukemia cell lines as well as in primary hematopoietic cells from patients with leukemia, we find high levels of reversion to wild-type in the absence of exogenous template. Moreover, we demonstrate that bulk treatment to revert a truncating mutation inASXL1using CRISPR-mediated interallelic gene conversion (IGC) is sufficient to prolong survival in a human cell line-derived xenograft model (median survival 33 days vs 27.5 days; p = 0.0040). These results indicate that IGC can be applied to numerous types of leukemia and can meaningfully alter cellular phenotypes at scale. Because our method targets single-base mutations, rather than larger variants targeted by IGC in prior studies, it greatly expands the pool of risk-increasing genetic lesions which could potentially be targeted by IGC. This technique may reduce cost and complexity for experiments modeling phenotypic consequences of SNVs. The principles of SNV-specific IGC demonstrated in this proof-of-concept study could be applied to investigate the phenotypic effects of targeted clonal reduction of leukemogenic SNV driver mutations.
Loss of circulating CD8α+NK cells during humanMycobacterium tuberculosisinfection
Authors: Mehanna Nezar , Pradhan Atul , Kaur Rimanpreet , Kontopoulos Theodota , Rosati Barbara , Carlson David , Cheung Nai-Kong , Xu Hong , Bean James , Hsu Katherine , Luduec Jean-Benoit Le , Vorkas Charles Kyriakos
Published: April 2024

Natural Killer (NK) cells can recognize and killMtb-infected cells in vitro, however their role after natural human exposure has not been well-studied. To identifyMtb-responsive NK cell populations, we analyzed the peripheral blood of healthy household contacts of active Tuberculosis (TB) cases and source community donors in an endemic region of Port-au-Prince, Haiti by flow cytometry. We observed higher CD8α expression on NK cells in putative resistors (IGRA-contacts) with a progressive loss of these circulating cells during household-associated latent infection and disease. In vitro assays and CITE-seq analysis of CD8α+NK cells demonstrated enhanced maturity, cytotoxic gene expression, and response to cytokine stimulation relative to CD8α-NK cells. CD8α+NK cells also displayed dynamic surface expression dependent on MHC I in contrast to conventional CD8+T cells. Together, these results support a specialized role for CD8α+NK cell populations duringMtbinfection correlating with disease resistance.
Determining Interaction Directionality in Complex Biochemical Networks from Stationary Measurements
Authors: Leibovich Nava
Published: April 2024

Revealing interactions in complex systems from observed collective dynamics constitutes a fundamental inverse problem in science. Some methods may reveal undirected network topology, e.g., using node-node correlation. Yet, the direction of the interaction, thus a causal inference, remains to be determined - especially in steady-state observations. We introduce a method to infer the directionality within this network only from a “snapshot” of the abundances of the relevant molecules. We examine the validity of the approach for different properties of the system and the data recorded, such as the molecule’s level variability, the effect of sampling and measurement errors. Simulations suggest that the given approach successfully infer the reaction rates in various cases.
Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer’s Disease and Older Controls in Multi-Ethnic Populations
Authors: Reddy Joseph S. , Heath Laura , Linden Abby Vander , Allen Mariet , de Paiva Lopes Katia , Seifar Fatemeh , Wang Erming , Ma Yiyi , Poehlman William L. , Quicksall Zachary S. , Runnels Alexi , Wang Yanling , Duong Duc M. , Yin Luming , Xu Kaiming , Modeste Erica S. , Shantaraman Anantharaman , Dammer Eric B. , Ping Lingyan , Oatman Stephanie R. , Scanlan Jo , Ho Charlotte , Carrasquillo Minerva M. , Atik Merve , Yepez Geovanna , Mitchell Adriana O. , Nguyen Thuy T. , Chen Xianfeng , Marquez David X. , Reddy Hasini , Xiao Harrison , Seshadri Sudha , Mayeux Richard , Prokop Stefan , Lee Edward B. , Serrano Geidy E. , Beach Thomas G. , Teich Andrew F. , Haroutunian Varham , Fox Edward J. , Gearing Marla , Wingo Aliza , Wingo Thomas , Lah James J. , Levey Allan I. , Dickson Dennis W. , Barnes Lisa L. , De Jager Philip , Zhang Bin , Bennett David , Seyfried Nicholas T. , Greenwood Anna K. , Ertekin-Taner Nilüfer
Published: April 2024

INTRODUCTION

Multi-omics studies in Alzheimer’s disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD.

METHODS

To bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors.

RESULTS

We generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AAandLA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures.

DISCUSSION

Inclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.
JUND plays a genome-wide role in the quiescent to contractile switch in the pregnant human myometrium
Authors: Khader Nawrah , Dorogin Anna , Shynlova Oksana , Mitchell Jennifer A.
Published: April 2024

The myometrium, the muscular layer of the uterus, undergoes crucial transitions during pregnancy, maintaining quiescence throughout gestation, and generating coordinated contractions during labor. Dysregulation of this transition can lead to premature labor with serious complications for the infant. Despite extensive gene expression data available for varying myometrial states, the molecular mechanisms governing the increase in contraction- associated gene expression at labor onset remain unclear. Transcription factors, such as JUND and progesterone receptor (PR), play essential roles in regulating transcription of select myometrial contraction-associated genes, however, a broader understanding of their involvement in transcriptional regulation at a genome-wide scale is lacking. This study examines changes in transcription and JUND binding within human myometrial tissue during the transition from quiescence (term-not-in labor/TNIL) to contractility (term labor/TL). Total RNA- sequencing reveals a global increase in primary transcript levels at TL, with AP-1/JUND binding motifs overrepresented in the promoters of upregulated transcripts. Interestingly, ChIP-seq analysis demonstrates higher JUND enrichment in TNIL compared to TL tissues, suggesting its role in preparing the myometrium for labor onset. Integration of JUND and PR ChIP-seq data identifies over 10,000 gene promoters bound by both factors at TNIL and TL, including genes involved in labor-driving processes. Additionally, the study uncovers elevated levels of enhancer RNAs (eRNAs) at intergenic JUND peaks in laboring myometrial tissues, and implicates additional transcription factors, such as NFKB and ETS, in the regulatory switch from quiescence to contractility. In summary, this research enhances our understanding of the myometrial molecular regulatory network during pregnancy and labor, shedding light on the roles of JUND and PR in gene expression regulation genome-wide. These findings open avenues for further exploration, potentially leading to improved interventions for preventing premature labor and the associated complications.
Evaluation of multi-peptide sequences identifiedin silicofor the serological identification of antibodies against Vector-Borne Diseases
Authors: Peña-Bates Carlos A. , Lugo-Caballero Cesar I. , Pavía-Ruz Norma , Noh-Pech Henry R. , Omodior Oghenekaro , Puerto-Manzano Fernando I. , Dzul-Rosado Karla R.
Published: April 2024

The socio-ecological conditions of Mexican regions are conducive to the spread of vector-borne diseases. Although there are established treatment guidelines for dengue and rickettsiosis, diagnosis is complicated. The objective of this work was to identify epitopes ofRickettsiaand Dengue virus that could be used in serology screening against vector-borne diseases. For this, epitopes with high HLA-II binding efficiency of OmpB protein ofRickettsia rickettsiiand NS2B protein of dengue virus were identifiedin silicothrough a reverse vaccinology strategy. The selected epitopes were grouped into multi-peptide sequences that were synthesized and immobilized in a nitrocellulose membrane to evaluate the reactivity sera from patients previously infected with dengue orRickettsia. The evaluation of the sequences of the NS2B and OmpB proteins was performed with 60 sera previously diagnosed as positive or negative by the respective gold standard techniques. Thedot blottechnique was used for the antigenic evaluation of the peptides against these serum samples.Dot blotanalysis correctly identified 85% of sera positive for rickettsiosis and 75% of sera positive for dengue. Reverse vaccinology reduces the time and cost of antigen discovery. Experimental evidence from multi-peptide sequences suggests their potential use in the development of diagnostic tests for dengue and rickettsiosis.

Abstract Figure
WITHDRAWN: Proteonano™ coupled with Orbitrap Astral™: A robust and standardized workflow for large-cohort clinical plasma proteomics studies
Authors: Fan Chaoyang , Wang Yi , Huang Min , Cao Jianming , Li Xiangjun , Ouyang Xiehua , Wu Hao
Published: April 2024

Withdrawal Statement

The authors have withdrawn their manuscript owing to [INCOMPLETE DATA ANALYSIS]. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Zebrafish as a model to study PERK function in developmental diseases: implications for Wolcott-Rallison syndrome
Authors: Almeida Liliana M. , Lima Leonor Pereira , Oliveira Nuno A. S. , Silva Rui F. O. , Sousa Bruno , Bessa José , Pinho Brígida R. , Oliveira Jorge M. A.
Published: April 2024

Developmental diseases are challenging to investigate due to their clinical heterogeneity and relatively low prevalence. The Wolcott-Rallison Syndrome (WRS) is a rare developmental disease characterized by skeletal dysplasia and permanent neonatal diabetes due to loss-of-function mutations in the endoplasmic reticulum stress kinase PERK (EIF2AK3). The lack of efficient and less invasive therapies for WRS highlights the need for new animal models that replicate the complex pathological phenotypes, while preserving scalability for drug screening. Zebrafish exhibits high fecundity and rapid development that facilitate efficient and scalablein vivodrug testing. Here, we aimed to assess the potential of zebrafish to study PERK function and its pharmacological modulation, and as model organism of developmental diseases such as the WRS. Using bioinformatic analyses, we showed high similarity between human and zebrafish PERK. We used the pharmacological PERK inhibitor GSK2606414, which was bioactive in zebrafish, to modulate PERK function. Using transgenic zebrafish expressing fluorescent pancreatic markers and a fluorescent glucose probe, we observed that PERK inhibition decreasedβcell mass and disrupted glucose homeostasis. By combining behavioural and functional assays, we show that PERK-inhibited zebrafish present marked skeletal defects and defective growth, as well as neuromuscular and cardiac deficiencies, which are clinically relevant in WRS patients, while sparing parameters like otolith area and eye/body ratio which are not associated with WRS. These results show that zebrafish holds potential to study PERK function and its pharmacological modulation in developmental disorders like WRS, assisting research on their pathophysiology and experimental treatments.
Protein language models are performant in structure-free virtual screening
Authors: Lam Hilbert Yuen In , Guan Jia Sheng , Ong Xing Er , Pincket Robbe , Mu Yuguang
Published: April 2024

1.1

Hitherto virtual screening has been typically performed using a structure-based drug design paradigm. Such methods typically require the use of molecular docking on high-resolution three-dimensional structures of a target protein - a computationally-intensive and time-consuming exercise. This work demonstrates that by employing protein language models and molecular graphs as inputs to a novel graph-to-transformer cross-attention mechanism, a screening power comparable to state-of-the-art structure-based models can be achieved. The implications thereof include highly expedited virtual screening due to the greatly reduced compute required to run this model, and the ability to perform early stages of computer-aided drug design in the complete absence of 3D protein structure.
MedImg: a database for public medical image integration
Authors: Zhong Bitao , Fan Rui , Ji Xiangwen , Cui Qinghua , Cui Chunmei
Published: April 2024

The advancements of deep learning algorithms in medical image analysis has garnered tremendous attention in recent years. Several studies have reported that the models have achieved and even surpassed human performance, whereas the translation of these models into clinical practice is still accompanied by various challenges. A major challenge is the large-scale and well characterized dataset to validate the generalization of models. Therefore, we collected diverse medical image datasets from multiple public sources containing 103 datasets, 1,622,956 images. These images are derived from 14 modalities like XR, CT, MRI, OCT, ultrasound, and endoscopy, and from 9 organs such as lung, brain, eye, and heart. Subsequently, we constructed an online database, MedImg, which incorporates and hierarchically organizes medical images to facilitate data access. MedImg serves as an intuitive and open-access platform for contributing to deep learning-based medical image analysis, accessible athttps://www.cuilab.cn/medimg/.
Cytosolic Ribosomal Protein Haploinsufficiency affects Mitochondrial Morphology and Respiration
Authors: Surya Agustian , Bolton Blythe Marie , Rothe Reed , Mejia-Trujillo Raquel , Zhao Qiuxia , Leonita Amanda , Liu Yue , Rangan Rekha , Gorusu Yasash , Nguyen Pamela , Cenik Can , Cenik Elif Sarinay
Published: April 2024

The interplay between ribosomal protein composition and mitochondrial function is essential for sustaining energy homeostasis. Precise stoichiometric production of ribosomal proteins is crucial to maximize protein synthesis efficiency while reducing the energy costs to the cell. However, the impact of this balance on mitochondrial ATP generation, morphology and function remains unclear. Particularly, the loss of a single copy ribosomal protein gene is observed in Mendelian disorders like Diamond Blackfan Anemia and is common in somatic tumors, yet the implications of this imbalance on mitochondrial function and energy dynamics are still unclear. In this study, we investigated the impact of haploinsufficiency for four ribosomal protein genes implicated in ribosomopathy disorders (rps-10, rpl-5, rpl-33, rps-23) inCaenorhabditis elegansand corresponding reductions in human lymphoblast cells. Our findings uncover significant, albeit variably penetrant, mitochondrial morphological differences across these mutants, alongside an upregulation of glutathione transferases, and SKN-1 dependent increase in oxidative stress resistance, indicative of increased ROS production. Specifically, loss of a single copy ofrps-10inC. elegansled to decreased mitochondrial activity, characterized by lower energy levels and reduced oxygen consumption. A similar reduction in mitochondrial activity and energy levels was observed in human leukemia cells with a 50% reduction inRPS10transcript levels. Importantly, we also observed alterations in the translation efficiency of nuclear and mitochondrial electron transport chain components in response to reductions in ribosomal protein genes’ expression in bothC. elegansand human cells. This suggests a conserved mechanism whereby the synthesis of components vital for mitochondrial function are adjusted in the face of compromised ribosomal machinery. Finally, mitochondrial membrane and cytosolic ribosomal components exhibited significant covariation at the RNA and translation efficiency level in lymphoblastoid cells across a diverse group of individuals, emphasizing the interplay between the protein synthesis machinery and mitochondrial energy production. By uncovering the impact of ribosomal protein haploinsufficiency on the translation efficiency of electron transport chain components, mitochondrial physiology, and the adaptive stress responses, we provide evidence for an evolutionarily conserved strategy to safeguard cellular functionality under genetic stress.
Dynamic spatiotemporal activation of a pervasive neurogenic competence in striatal astrocytes supports continuous neurogenesis following injury
Authors: Fogli Marco , Nato Giulia , Greulich Philip , Pinto Jacopo , Peretto Paolo , Buffo Annalisa , Luzzati Federico
Published: April 2024

Adult brain neural stem cells (NSCs) are conventionally regarded as rare cells restricted to two niches: the subventricular zone (SVZ) and the subgranular zone. Parenchymal astrocytes can also contribute to neurogenesis after injury, however the prevalence, distribution, and behaviour of these latent NSCs remained elusive. To tackle these issues, we reconstructed the spatiotemporal pattern of striatal astrocytes neurogenic activation after excitotoxic lesion in mice. Our results indicate that a neurogenic potential is broadly distributed throughout the striatum but is focally activated at the lesion border. In this region, similarly to canonical niches, steady state neurogenesis is ensured by the continuous stochastic activation of local astrocytes. Activated astrocytes quickly return to quiescence, while their progeny locally proliferate for about 10 days following a stochastic behaviour that features an acceleration in differentiation propensity. Notably, striatal astrocytes activation rate matches that of SVZ astrocytes indicating a comparable prevalence of NSC potential.
Common viral infections inhibit egg laying in honey bee queens and are linked to premature supersedure
Authors: Chapman Abigail , McAfee Alison , Tarpy David R. , Fine Julia , Rempel Zoe , Peters Kira , Currie Rob , Foster Leonard J.
Published: April 2024

With their long lives and extreme reproductive output, social insect queens have escaped the classic trade-off between fecundity and lifespan but evidence for a trade-off between fecundity and immunity has been inconclusive. This is in part because pathogenic effects are seldom decoupled from effects of immune induction. We conducted parallel, blind virus infection experiments in the laboratory and in the field to interrogate the idea of a reproductive immunity trade-off and better understand how these ubiquitous honey bee stressors affect queen health. We found that queens injected with infectious virus had smaller ovaries and were less likely to recommence egg-laying than controls, while queens injected with UV-inactivated virus displayed an intermediate phenotype. In the field, heavily infected queens had smaller ovaries and infection was a meaningful predictor of whether supersedure cells were observed in the colony. Immune responses in queens receiving live virus were similar to queens receiving inactivated virus, and several of the same immune proteins were negatively associated with ovary mass in the field. This work solidifies the relationship between virus infection and symptoms associated with queen failure and suggests that a reproductive-immunity trade-off is partially, but not wholly responsible for these effects.
Organelle-targeted Laurdans measure heterogeneity in subcellular membranes and their responses to saturated lipid stress
Authors: Wong Adrian M. , Budin Itay
Published: April 2024

Cell organelles feature characteristic lipid compositions that lead to differences in membrane properties. In living cells, membrane ordering and fluidity are commonly measured using the solvatochromic dye Laurdan, whose fluorescence is sensitive to membrane packing. As a general lipophilic dye, Laurdan stains all hydrophobic environments in cells, so it is challenging to characterize membrane properties in specific organelles or assess their responses to pharmacological treatments in intact cells. Here, we describe the synthesis and application of Laurdan-derived probes that read out membrane packing of individual cellular organelles. The set of Organelle-targeted Laurdans (OTL) localizes to the ER, mitochondria, lysosomes and Golgi compartments with high specificity, while retaining the spectral resolution needed to detect biological changes in membrane packing. We show that ratiometric imaging with OTL can resolve membrane heterogeneity within organelles, as well as changes in membrane packing resulting from inhibition of lipid trafficking or bioenergetic processes. We apply these probes to characterize organelle-specific responses to saturated lipid stress. While ER and lysosomal membrane fluidity is sensitive to exogenous saturated fatty acids, that of mitochondrial membranes is protected. We then use differences in ER membrane fluidity to sort populations of cells based on their fatty acid diet, highlighting the ability of organelle-localized solvatochromic probes to distinguish between cells based on their metabolic state. These results expand the repertoire of targeted membrane probes and demonstrate their application to interrogating lipid dysregulation.