bluuebunny/crossref_metadata_2025 huggingface dataset:
Using Coincidence Analysis to Identify Causal Chains of Factors Associated with Implementation and Optimization of Lynch Syndrome Tumor Screening Across Multiple Health care Systems
Authors: Cragun Deborah , Salvati Zachary M , Schneider Jennifer L , Burnett-Hartman Andrea N , Epstein Mara M , Hunter Jessica Ezzell , Liang Su-Ying , Lowery Jan , Lu Christine Y. , Pawloski Pamala A. , Schleider Victoria , Sharaf Ravi N , Williams Marc S , Rahm Alanna Kulchak
Published: December 2024

Purpose

This study of multiple case study compared Lynch syndrome universal tumor screening (UTS) to understand multi-level factors that may impact the successful implementation of complex programs.

Methods

Data from 66 stakeholder interviews were used to conduct multi-value coincidence analysis (mv-CNA) and identify key factors that consistently make a difference in whether UTS programs were implemented and optimized at the system level.

Results

The selected CNA model revealed combinations of conditions that distinguish 4 optimized UTS programs, 10 non-optimized programs, and 4 systems with no program. Fully optimized UTS programs had both a maintenance champion and a positive inner setting. Two independent paths were unique to non-optimized programs: 1) positive attitudes and a mixed inner setting, or 2) limited planning & engaging among stakeholders. Negative views about UTS evidence or lack of knowledge about UTS led to a lack of planning and engaging, which subsequently prevented program implementation.

Conclusion

The model improved our understanding of program implementation in health care systems and informed the creation of a toolkit to guide UTS implementation, optimization, and changes. Our findings and toolkit may serve as a use case to increase the successful implementation of other complex precision health programs.
CLUSTERING OF RARE VARIANTS FOR CAUSAL VARIANTS IDENTIFICATION AND EFFECT
DIRECTION CLASSIFICATION
Authors: Sun Xianbang , Liu Xue , Liu Chunyu
Published: December 2024

Several gene-based tests, e.g., sequence kernel association test, have been
developed for association testing of rare single nucleotide variants (SNVs) in
genomic regions with disease traits. A common limitation of these aggregate
methods is their inability to discriminate potentially causal variants from null
variants within the tested regions. We propose a novel clustering method to
classify rare variants into null and signal variant groups using summary
statistics from the gene-based tests based on a Gaussian mixture model (GMM). We
classify the signal variants into potentially risk and protective subgroups of
different effect sizes. We evaluate the performance of the proposed method by a
simulation study, considering several statistics such as the adjusted rand index
(ARI), mean square error (MSE), and accuracy in specifying the number of
clusters. We apply the proposed clustering method to identify possibly risk and
protective rare variants in six genes that are significantly associated with
blood pressure (BP) traits in the most recent large genomewide association study
(GWAS) and meta-analysis. This proposed method may facilitate the identification
of potentially causal rare variant clusters in genomic regions and ultimately
help understand the genetic architecture underlying human complex traits for the
discovery of drug target and the design of gene therapy.
Bilateral aldosterone production is most common in primary aldosteronism found by screening within primary care
Authors: Makhnov Nikita , Skov Jakob , Axling Fredrik , Andernord Daniel , Bergenheim Mikael , Waldén Mauritz , Hellman Per
Published: December 2024

OBJECTIVE

Primary aldosteronism (PA) is the most common cause of secondary hypertension, and implies high risk of cardiovascular complications. Previously, our group had screened 1181 unselected Swedish primary care hypertensive patients, to find PA prevalence of 4,5%. The current study describes results of further diagnostics and specific treatment of these PA patients.

DESIGN

Prospective evaluation of lateralization and treatment of patients with PA.

PATIENTS

Fifty-three individuals with PA diagnosed by screening carried out in strict accordance with the current guidelines.

MEASUREMENTS

All patients accepting possible surgery underwent adrenal venous sampling, complemented, if unsuccessful, by adrenal cortex-specific positron emission tomography. Lateralizing cases were advised laparoscopic adrenalectomy. Bilateral ones were treated by mineralocorticoid receptor antagonists. Treatment results were assessed by at least 6 - 12 months of follow-up.

RESULTS

Localizing studies were accepted by 45 patients, 8 patients declined. Lateralized disease was found in 14 cases. Of 11 operated cases 3 had adenoma (prevalence 7-13%). Remaining operated cases comprised micro- and macronodular pathology. Thirty-one patients had bilateral PA. Screening and specific PA treatment led to better blood pressure and raising renin signifying risk amelioration. Both surgical and conservative treatment were tolerated well even when mainly conducted at regional healthcare level.

CONCLUSIONS

Bilateral production of aldosterone is common in a patient cohort derived from screening within primary care. Lateralization may be due to either adenoma, which is very rare, or due to nodular forms of PA, and both are successfully treated with adrenalectomy.
A Population-Based Cross-Sectional Investigation of COVID-19 Hospitalizations and Mortality Among Autistic People
Authors: Nijhof Dewy , Sosenko Filip , Mackay Daniel , Fleming Michael , Jani Bhautesh D , Pell Jill , Hatton Chris , Cairns Deborah , Henderson Angela , Ward Laura , Rydzewska Ewelina , Gardani Maria , Millington Elliot , Melville Craig
Published: December 2024

Background

Current evidence suggests the possibility that autistic people may be at more risk of COVID-19 infection, hospitalisation, and mortality than the general population. Previous studies, however, are either limited in scale or do not investigate potential risk factors. Whilst many risk factors have been speculated to be responsible for severe COVID-19, this research has focused on general population samples.

Methods

Using data-linkage and a whole-country population, this study modelled associations between autism and COVID-19 hospitalisation and mortality risk in adults, investigating a multitude of clinical and demographic risk factors.

Results

Autistic adults had higher rates of hospitalisation, Standardised Incident Ratio 1.6 in 2020 and 1.3 in 2021, and mortality, Standardised Mortality Ratio 1.52 in 2020 and 1.34 in 2021, due to COVID-19 than the general population. In both populations, age, complex multimorbidity and vaccination status were the most significant predictors of COVID-19 hospitalisation and mortality. Effects of psychotropic medication varied by class.

Conclusions

Although similar factors exhibited a positive association with heightened risk of severe COVID-19 in both the autistic and general populations, with comparable effect sizes, mortality rates were elevated among the autistic population as compared to the general population. Specifically, the presence of complex multimorbidity and classification of prescribed medications may emerge as particularly significant predictors of severe COVID-19 among individuals within the autistic population due to higher prevalence of complex multimorbidity in the autistic population and variability in the association between medication classes and severe COVID-19 between both populations, though further research is needed.
Multi-ancestry Genome Wide Association Study Meta-analysis of Non-syndromic Orofacial Clefts
Authors: Jia Zhonglin , Mukhopadhyay Nandita , Yang Zhenglin , Butali Azeez , Sun Jialin , You Yue , Yao Meilin , Zhen Qi , Ma Jian , He Miao , Pan Yongchu , Alade Azeez , Wang Yirui , Olujitan Mojisola , Qi Mengchun , Adeyemo Wasiu Lanre , Buxó Carmen J. , Gowans Lord J.J , Eshete Mekonen , Huang Yongqing , Li Chenghao , Leslie Elizabeth J. , Wang Lin , Bian Zhuan , Carlson Jenna C. , Shi Bing , Weinberg Seth M. , Murray Jeffrey C. , Sun Liangdan , Marazita Mary L. , Freathy Rachel M. , Beaumont Robin N.
Published: December 2024

Non-syndromic orofacial clefts (NSOC) are common craniofacial birth defects, and result from both genetic and environmental factors. NSOC include three major sub-phenotypes: non-syndromic cleft lip with palate (NSCLP), non-syndromic cleft lip only (NSCLO) and non-syndromic cleft palate only (NSCPO), NSCLP and NSCLO are also sometimes grouped as non-syndromic cleft lip with or without cleft palate (NSCL/P) based on epidemiology. Currently known loci only explain a limited proportion of the heritability of NSOC. Further, differences in genetic susceptibility among the sub-phenotypes are poorly characterized. We performed a multi-ancestry GWAS meta-analysis on 44,094 individuals (9,381 cases, 28,510 controls, 2042 case-parent trios and 18 multiplex pedigrees) of East Asian, European, Latin and South American, and African ancestry for both NSOC and subtypes. We identified 50 loci, including 11 novel loci: four loci (CALD1,SHH,NRG1andLINC00320) associated with both NSOC and NSCL/P, two loci (NTRK1andRUNX1) only associated with NSOC, four loci (HMGCR,PRICKLE1,SOX9andMYH9) only associated with NSCL/P and one locus (ALX1) specifically associated with NSCLO. Five of the novel loci are located in regions containing genes associated with syndromic orofacial clefts (SHH,NTRK1, CALD1, ALX1andSOX9); seven of the novel loci are located in regions containing genes-implicated in craniofacial development (HMGCR, SHH, PRICKLE1, ALX1, SOX9, RUNX1, MYH9). Genetic correlation and colocalization analyses revealed an overlap between signals associated with NSCLO, NSCPO and NSCLP, but there were also notable differences, emphasizing the complexity of common and distinct genetic processes affecting lip and palate development.
Universal toolset for mass spectrometric analysis of intracellular peptidome and small protein fraction
Authors: Kote Sachin , Piróg Artur , Faktor Jakub , Dziadosz Alicja , Marek-Trzonkowska Natalia
Published: December 2024

The analysis of native intracellular peptidome has gained significant attention in recent years. However, there is still a need for more knowledge regarding various sample preparation methods that facilitate efficient and reproducible recovery of peptides, which can then be analyzed using quantitative liquid chromatography-mass spectrometry. A similar situation exists in small proteome research, typically defined as polypeptides with masses of less than 100 amino acids, often too long for easy identification without enzymatic digestion. In this context, we describe a set of methods that involve simple denaturation and solid-phase extraction of polypeptides, applicable for isolating short intracellular polypeptides within the desired length range. Our work demonstrates the efficiency and reproducibility of these methods for quantitative analysis of the peptidome in mammalian cells. Additionally, we investigated the flexibility of adjusting the mass range through ultrafiltration. We have shown that these methods can be adapted for highly efficient enrichment and fractionation of small proteins, resulting in polypeptide isolates suitable for tryptic digestion and intact protein analysis. Moreover, we describe the use of freely available computational tools that can effectively manage the analysis of the resulting data. The research presented here will benefit the global scientific community in both fundamental (protein turnover, proteolytic processing, non-canonical open reading frames,etc.) and applied sciences (bioactive/neuro peptide discovery, precision medicine, vaccines,etc.), and other areas that could benefit from selective analysis of short native polypeptides.
Modulation of all-transretinoic acid by light and dopamine in the murine eye
Authors: Talwar Sarah , Mazade Reece , Bentley-Ford Melissa , Yu Jianshi , Pilli Nageswara , Kane Maureen A , Ethier C Ross , Pardue Machelle T
Published: December 2024

Purpose

Ambient light exposure is linked to myopia development in children and affects myopia susceptibility in animal models. Currently, it is unclear which signals mediate the effects of light on myopia. All-transretinoic acid (atRA) and dopamine (DA) oppositely influence experimental myopia and may be involved in the retino-scleral signaling cascade underlying myopic eye growth. However, how ocular atRA responds to different lighting and whether atRA and DA interact remains unknown.

Methods

Dark-adapted C57BL/6J mice (29-31 days old) were exposed to Dim (1 lux), Mid (59 lux), or Bright (12,000 lux) ambient lighting for 5-60 minutes. Some mice were also systemically administered the DA precursor, LDOPA, or atRA prior to light exposure. After exposure, the retina and the back-of-the-eye (BOE) were collected and analyzed for levels of atRA, DA, and the DA metabolite, DOPAC.

Results

DA turnover (DOPAC/DA ratio) in the retina increased in magnitude after only five minutes of exposure to higher ambient luminance but was minimal in the BOE. In contrast, atRA levels in the retina and BOE significantly decreased with higher ambient luminance and longer duration exposure. Intriguingly, LDOPA-treated mice had a transient reduction in retinal atRA compared to saline-treated mice, whereas atRA treatment had no effect on ocular DA.

Conclusions

Ocular atRA was affected by the duration of exposure to different ambient lighting and retinal atRA levels decreased with increased DA. Overall, these data suggest specific interactions between ambient lighting, atRA, and DA that could have implications for the retino-scleral signaling cascade underlying myopic eye growth.
Seed dispersal disruption limits tropical forest regrowth
Authors: Fricke Evan C. , Cook-Patton Susan C. , Harvey Charles F. , Terrer César
Published: December 2024

Many trees depend on animals for seed dispersal, and human activities that disrupt seed dispersal by animals may impact forest regeneration and carbon storage. Yet whether expected negative impacts are observable across regrowing forests remains untested. We modeled seed dispersal disruption and its relationship to aboveground carbon accumulation observed across 3026 sites in the tropics, where most trees are animal dispersed. We found that seed dispersal disruption explains wide variation in local carbon accumulation rates. Across areas identified for restoration, we estimate that seed dispersal disruption reduces carbon accumulation rates by 57% on average. These results advance understanding of animal biodiversity’s impact on forest carbon and emphasize the need to address biodiversity loss and climate change together.
Alteration of skin fibroblast steady state contributes to healing outcomes
Authors: Huang Yaqing , Wang Nuoya , Xing Hao , Tian Jingru , Zhang Dingyao , Gao Daqian , Hsia Henry C. , Lu Jun , Raredon Micha Sam Brickman , Kyriakides Themis R.
Published: December 2024

Fibroblasts display complex functions associated with distinct gene expression profiles that influence matrix production and cell communications and the autonomy of tissue development and repair. Thrombospondin-2 (TSP-2), produced by fibroblasts, is a potent angiogenesis inhibitor and negatively associated with tissue repair. Single-cell (sc) sequencing analysis on WT and TSP2KO skin fibroblasts demonstrate distinct cell heterogeneity. Specifically, we found an enrichment of Sox10+ multipotent progenitor cells, identified as Schwann precursor cells, in TSP2KO fibroblasts, while fibrosis-related subpopulations decreased. Immunostaining of tissue and cells validated the increase of this Sox10+ population in KO fibroblasts. Furthermore, in silico analysis suggested enhanced pro-survival signaling, including WNT, TGF-β, and PDGF-β, alongside a reduced BMP4 response. Additionally, the creation of two TSP2KO NIH3T3 cell lines using the CRISPR/Cas9 technique allowed functional and signaling validation in a less complex system. Moreover, KO 3T3 cells exhibited enhanced migration and proliferation, with elevated levels of pro-regenerative molecules including TGF-β3 and Wnt4, and enrichment of nuclear β-catenin. These functional and molecular alterations likely contribute to improved healing and increased neurogenesis in TSP2-deficient wounds. Overall, our findings describe the heterogeneity of dermal fibroblasts and identify pro-regenerative features of TSP2KO fibroblasts.
Spatiotemporal dynamics of non-ecological speciation in rubyspot damselflies (Hetaerinaspp.)
Authors: Patterson C. , Brennan A. , Cowling H. , González-Rodríguez A. , Grether G.F. , Mendoza Cuenca L. , Springer M. , Vega-Sanchez Y. M. , Drury J.
Published: December 2024

Non-ecological speciation is a common mode of speciation which occurs when allopatric lineages diverge in the absence of pronounced ecological differences. Yet, relative to other speciation mechanisms, non-ecological speciation remains understudied. Numerous damselfly clades are characterized as non-adaptive radiations (the result of several rounds of non-ecological speciation), but there are few damselfly lineages for which we have a detailed understanding of the spatiotemporal dynamics of divergence. Recent phylogeographic analyses demonstrate that American rubyspot damselflies (Hetaerina americanasensu lato) actually comprise at least two cryptic lineages that coexist sympatrically across most of Mexico. To broaden our understanding of the dynamics of diversification to other rubyspot lineages, we investigated the phylogeographic history of smoky rubyspot damselflies (Hetaerina titia) using genomic data collected across Central and North America. Unexpectedly, we found evidence of reproductive isolation between the highly genetically differentiated Pacific and Atlantic lineages ofH. titiain a narrow secondary contact zone on the Isthmus of Tehuantepec, Mexico. We then fit models of historical demography to bothH. americanasensu lato andH. titiato place these comparisons in a temporal context. Our findings indicate that Pacific and Atlantic lineages ofH. titiasplit more recently than the broadly sympatric lineages withinH. americanasensu lato, supporting key assumptions of the non-ecological speciation model and demonstrating that these two pairs of sister lineages are at different stages of the speciation cycle.
Museum insights for conservation: Unraveling the Extinction Factors in the Jambato Harlequin Frog,Atelopus ignescens
Authors: Guerra Mónica A. , Gao Chengchen , Crickenberger Samuel , Vélez Michelle , Coloma Luis A. , Wang Silu
Published: December 2024

Natural history museums harbor invaluable resources for conserving endangered species by providing insights into the mechanism of historical population declines. Here we conducted data synthesis to better understand the extinction factors of the iconic Jambato Harlequin frog,Atelopus ignescens, which was widespread in the Ecuadorian Andes before 1985 but vanished in 1988. The mechanism of extinction remains elusive, as it was uncertain whetherBatrachochytrium dendrobatidis (Bd)fungus infection, climate change, or the interaction of the two factors primarily contributed to the rapid population decline. Here we synthesize historical data from natural history museums, the Global Biodiversity Information Facility (GBIF), and mitochondrial DNA sequences to uncover the factors that have potentially contributed to the extinction of the Jambato Harlequin frog. We found excessive rare alleles reflected in the negative Tajima’s D estimated from the mitochondrial DNA samples collected in 1984, which indicates a selective sweep or bottleneck in the population shortly before the historical extinction. There was a marginal effect of the time before versus duringBdepizootics on the body sizes of the adult males, which was relatively weaker than the sex effect and geographic effect. The body size of adult males, but not the females form a geographic cline where the individuals in the northeast were larger than the males in the southwest. Species distribution modeling based on temperature and precipitation accurately predicted the occupancy ofA. ignescensin 1960-69 (R2= 0.72, accuracy = 0.9). This model further predicted the rapid decline in species distribution over decades of climate change between 1970-2020, which could have contributed to the rapid population decline in the 1980s. Collectively, our data synthesis revealed a strong climate effect and a weak epizootics effect onA. ignescensextinction, which unravels the mysterious rapid population decline and informs ongoing conservation efforts. This investigation inspires future museum genomic studies to dissect the potential climatic maladaptation behind one of the most dramatic extinction events in modern history.
Generative AI-assisted Virtual Screening Pipeline for Generalizable and Efficient Drug Repurposing
Authors: Pham Phuc , Duy Nguyen Viet Thanh , Cho Kyu Hong , Hy Truong Son
Published: December 2024

Drug repurposing presents a valuable strategy to expedite drug discovery by identifying new therapeutic uses for existing compounds, especially for diseases with limited treatment options. We propose a Generative AI-assisted Virtual Screening Pipeline that combines generative modeling, binding pocket prediction, and similarity-based searches within drug databases to achieve a generalizable and efficient approach to drug repurposing. Our pipeline enables blind screening of any protein target without requiring prior structural or functional knowledge, allowing it to adapt to a wide range of diseases, including emerging health threats and novel targets where information is scarce. By rapidly generating potential ligands and efficiently identifying and ranking drug candidates, our approach accelerates the drug discovery process, broadening the scope and impact of repurposing efforts and offering new possibilities for therapeutic development. Detailed results and implementation can be accessed athttps://github.com/HySonLab/DrugPipe.
Molecular mechanisms of GSK3β-driven modulation of ABLIM1 and titin interactions in cardiac muscle
Authors: Sun Bin , Loftus Alec , Beh Goh Beh Brandon , Hepburn Aalaythia , Kekenes-Huskey Peter
Published: December 2024

The heart adapts to cardiac demand through a variety of mechanisms. Some of these adaptations include chemical modifications of myofilament proteins responsible for cell contraction. Interestingly, many of these chemical modifications, such as phosphorylation, are found in unstructured, or intrinsically disordered, regions of proteins. For these myofilament assoiciated proteins with intrinsic disorder (MAPIDs), it has been difficult to determine how their disordered regions influence the function of the intact protein or the myofilament as a whole. Given that cardiac dysfunction can be accompanied by dramatic shifts in post-translational modifications (PTMs) of myofilament proteins, assessment of these impacts in intrinsically disordered regions is important. We hypothesized that regulation of the actin-binding myofilament protein LIM protein 1, ABLIM1, through its IDRs occurs because PTMs, namely phosphorylation, alter their conformation ensembles. The change in conformations thereby toggles their availability for binding protein partners. To evaluate this hypothesis, we used molecular dynamics to simulate ABLIM1 and thereby determine its conformation ensemble before and after phosphorylation. In accordance with published phosphorylation data in GSK3β knockout models, our results indicate that local changes in the physicochemical properties of ABLIM1's IDRs via phosphorylation can influence its global ensemble properties, with the potential to impact its interaction with myofilament targets like titin. These findings provide important molecular-level insights into a mechanism of regulating cardiomyocyte contraction.
STING agonists drive recruitment and intrinsic type I interferon responses in monocytic lineage cells for optimal anti-tumor immunity
Authors: Girard Melanie , Yu Tianning , Batista Nathalia V , Yeung Karen K. M. , Lamorte Sara , Gao Wenting , Liu Miaoxi , McGaha Tracy L. , Watts Tania H.
Published: December 2024

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a sensor of cytosolic DNA, orchestrates the production of pro-inflammatory cytokines, chemokines, and type I interferons (IFN-I), thereby contributing to spontaneous tumor surveillance. Intratumoral delivery of synthetic STING agonists induces IFN-I dependent tumor regression in preclinical cancer models and is being tested clinically. In this study, we investigate the role of monocytic lineage (MCs) cells in response to STING agonist induced IFN-I signaling. We show that CCR2-deficient mice, lacking inflammatory MCs in the periphery, or Lyz2-Cre-IFNAR1fl/flmice in which IFN-I signaling in monocytes is reduced, exhibit impaired responses to STING agonist therapy of MC38 and/or B16F10 tumors. STING agonist treatment induced CCR5-dependent migration of MCs carrying tumor antigen from the tumor to the lymph nodes. Single-cell RNA sequencing of CD45+cells from lymph nodes and tumors of mice in which half the hematopoietic cells lack the interferon alpha/beta receptor 1 (IFNAR1) revealed that STING agonist therapy induces intrinsic IFNAR1-dependent acquisition of an inflammatory monocytic cell phenotype distinct from inflammatory cDC and a reduction in macrophages with a pro-tumor TGFβ/angiogenesis transcriptome. IL-18 - IL-18R1 interaction was the top predicted interaction between monocytic lineage cells and CD8+T cells or NK cells. Blocking IL-18 reduced the therapeutic efficacy of STING agonist treatment in CCR2+/+but not CCR2-/-mice, implicating IL-18 production by the monocytes in STING agonist therapy of melanoma. These findings support a pivotal role for IL-18 producing inflammatory monocytic lineage cells in tumor control following STING agonist treatment.
Enhancer heterogeneity in acute lymphoblastic leukemia drives differential gene expression between patients
Authors: Smith Alastair L. , Denny Nicholas , Chahrour Catherine , Sharp Kim , Elliott Natalina , Harman Joe , Jackson Thomas , Geng Huimin , Smith Owen , Bond Jonathan , Roberts Irene , Stam Ronald W. , Crump Nicholas T , Davies James O.J. , Roy Anindita , Milne Thomas A.
Published: December 2024

Genetic alterations alone cannot account for the diverse phenotypes of cancer cells. Even cancers with the same driver mutation show significant transcriptional heterogeneity and varied responses to therapy. However, the mechanisms underpinning this heterogeneity remain under-explored. Here, we find that novel enhancer usage is a common feature in acute lymphoblastic leukemia (ALL). In particular,KMT2A::AFF1ALL, an aggressive leukemia with a poor prognosis and a low mutational burden, exhibits substantial transcriptional heterogeneity between individuals. Using single cell multiome analysis and extensive chromatin profiling, we reveal that much transcriptional heterogeneity inKMT2A::AFF1ALL is driven by novel enhancer usage. Using high resolution Micro-Capture-C in primary patient samples, we also identify patient-specific enhancer activity at key oncogenes such asMEIS1andRUNX2, driving high levels of expression of both oncogenes in a patient-specific manner. Overall, our data show that enhancer heterogeneity is highly prevalent inKMT2A::AFF1ALL and may also be a mechanism that drives transcriptional heterogeneity in cancer more generally.

Key Points

Leukemia patients with the same driver mutations often display gene expression differences

Using chromatin profiling and high resolution 3C methods we show that enhancer heterogeneity drives gene expression differences
“Photosynthetic and Genetic Adaptations Underpinning the Resilience ofCistanthe longiscapain the Atacama Desert”
Authors: Sandoval-Ibáñez Omar , Tapia-Reyes Patricio , Riveros Aníbal , Yusta Ricardo , Chang Shengxin , Ossa Paulina , Nilo-Poyanco Ricardo , Moreno Adrián A. , Miquel Alvaro , Almeida Andrea Miyasaka , Zurita-Silva Andrés , Orellana Daniela , Baeza Carlos , Blanco-Herrera Francisca , Genova Alex Di , Allende Miguel L. , González Mauricio , Maass Alejandro , Montecino Martin , Gutiérrez Rodrigo A. , Bock Ralph , Meneses Claudio , Orellana Ariel
Published: December 2024

The Atacama Desert is one of the most hostile environments for life. However, the plant speciesCistanthe longiscapa(C. longiscapa) completes its life cycle in the Atacama Desert after sporadic rainfall.

Physiological analyses under controlled environmental conditions revealed superior photosynthetic performance, better light acclimation mechanisms, and larger accumulation of photosystem II inC. longiscapacompared to its mesophilic sister species.

C. longiscapashows evolutionary expansions in gene families related to DNA repair, photosynthesis, and protein homeostasis. In addition, we observed substantial gene duplication and polymorphic variations between coastal and inland populations in the Atacama Desert. Finally, our assembled mitochondrial genome provides genetic information for all DNA-containing compartments ofC. longiscapa.

Diurnal oscillations of malic acid and time-resolved transcriptome analyses of plants harvested in the Atacama Desert indicate thatC. longiscapaengages in CAM metabolism. We observed significant differences in transcripts encoding plastid-localized proteins, including those involved in carbon metabolism, light harvesting, and photoprotection, highlighting the critical role of chloroplasts in the adaptation ofC. longiscapato the Atacama Desert.

Our study provides physiological and genetic evidence for the adaptations ofC. longiscapaand advances our understanding of how plants can cope with extreme environmental conditions.
Preferential Release of microRNAs via Extracellular Vesicles is Associated with Ductal Carcinoma In Situ to Invasive Breast Cancer Progression
Authors: Elayapillai Sugantha Priya , Dogra Samrita , Lausen James , Bruns Matthew , Behbod Fariba , Hladik Cole , Gin Amy , Xu Chao , Zhang Roy , Ding Wei-Qun , Hannafon Bethany N.
Published: December 2024

Ductal carcinoma in situ (DCIS) is a benign “pre-cancer” that increases the risk of invasive breast cancer (IBC). Not all DCIS progress to IBC, and the primary factors driving progression remain unclear. Small extracellular vesicles (sEVs) or exosomes are known to play a role in advanced cancers, but their involvement in DCIS is poorly understood. This study examined the role of sEVs and their RNA content in DCIS progression. Rab27A, which regulates exosome release, is elevated in DCIS and IBC tissues compared with normal breast tissues. Inhibition of sEV release via Rab27A knockdown alters pro-invasive pathways and reduces invasion in a DCIS mouse model. Using the isogenic MCF10 breast cancer progression series, we found a significant increase in microRNAs (miRNAs) in sEVs from normal to malignant states, with the highest number of differentially expressed miRNAs in IBC sEVs compared with DCIS sEVs. In vivo, DCIS invasive progression elevated circulating sEV miRNA levels, which decreased upon Rab27A knockdown. Re-expression of miR-205, preferentially loaded into IBC sEVs, reduced proliferation, invasion, and EMT marker expression in DCIS cells. Combined Rab27A knockdown and miR-205 expression repressed TGF-β signaling, activated p38, and induced cell cycle arrest and cell death. These findings illustrate that sEVs and their miRNAs promote DCIS progression, and the reintroduction of miR-205 in DCIS cells can inhibit invasive progression.
Sexual reproduction is controlled by successive transcriptomic waves inPodospora anserina
Authors: Bidard Frédérique , Grognet Pierre , Lelandais Gaëlle , Imbeaud Sandrine , Muchielli Marie-Hélène , Debuchy Robert , Berteaux-Lecellier Véronique , Malagnac Fabienne
Published: December 2024

Despite the inherent challenge of finding suitable mating partners, most eukaryotes use sexual reproduction to produce offspring endowed with increase genetic diversity and fitness. The persistence of this mode of reproduction is a key question in evolutionary biology. Fungi offer valuable insights into this question, due to their diversity and short lifecycle. This study focuses onPodospora anserina, a pseudohomothallic ascomycete fungus that bypasses self-sterility by maintaining two compatible nuclei in one mycelium. We performed genome-wide gene expression profiling during ten stages ofP. anserinasexual reproduction and identified five major expression patterns. Our expert annotation approaches identified differentially expressed genes related to secondary metabolite production, fungal vegetative incompatibility, programmed cell death, and epigenetic regulation. In addition, master transcriptional regulators and their target networks were uncovered. This study provides a comprehensive database for future functional genomics experiments and novel pathway characterization during sexual reproduction.
Variance inC. elegansgut bacterial load suggests complex host-microbe dynamics
Authors: Boddu Satya Spandana , Martini K. Michael , Nemenman Ilya , Vega Nic M.
Published: December 2024

Variation in bacterial composition inside a host is a result of complex dynamics of microbial community assembly, but little is known about these dynamics. To deconstruct the factors that contribute to this variation, we used a combination of experimental and modeling approaches. We found that demographic stochasticity and stationary heterogeneity in the host carrying capacity or bacterial growth rate are insufficient to explain quantitatively the variation observed in our empirical data. Instead, we found that the data can be understood if the host-bacteria system can be viewed as stochastically switching between high and low growth rates phenotypes. This suggests the dynamics significantly more complex than logistic growth used in canonical models of microbiome assembly. We develop mathematical models of this process that can explain various aspects of our data. We highlight the limitations of snapshot data in describing variation in host-associated communities and the importance of using time-series data along with mathematical models to understand microbial dynamics within a host.
Modernizing histopathological analysis: a fully automated workflow for the digital image analysis of the intestinal microcolony survival assay
Authors: Baikalov Alexander , Wang Ethan , Neill Denae , Shetty Nihar , Waldrop Trey , Liu Kevin , Delahousessaye Abagail , Aguilar Edgardo , Mims Nefetiti , Bartzsch Stefan , Schüler Emil
Published: December 2024

Background

Manual analysis of histopathological images is often not only time-consuming and painstaking but also prone to error from subjective evaluation criteria and human error. To address these issues, we created a fully automated workflow to enumerate jejunal crypts in a microcolony survival assay to quantify gastrointestinal damage from radiation.

Methods and Materials

After abdominal irradiation of mice, jejuna were obtained and prepared on histopathologic slides, and crypts were counted manually by trained individuals. The automated workflow (AW) involved obtaining images of jejunal slices from the irradiated mice, followed by cropping and normalizing the individual slice images for resolution and color; using deep learning-based semantic image segmentation to detect crypts on each slice; using a tailored algorithm to enumerate the crypts; and tabulating and saving the results. A graphical user interface (GUI) was developed to allow users to review and correct the automated results.

Results

Crypts counted manually exhibited a mean absolute percent deviation of (34 ± 26)% between individuals vs the group mean across counters, which was reduced to (11 ± 6)% across the 3 most-experienced counters. The AW processed a sample image dataset from 60 mice in a few hours and required only a few minutes of active user effort. AW counts deviated from experts’ mean counts by (10 ± 8)%. The AW thereby allowed rapid, automated evaluation of the microcolony survival assay with accuracy comparable to that of trained experts and without subjective inter-observer variation.

Highlights

We fully automated the digital image analysis of a microcolony survival assay

Analyzing 540 images takes a few hours with only minutes of active user effort

The automated workflow (AW) is just as accurate as trained experts

The AW eliminates subjective inter-observer variation and human error

Human review possible with built-in graphical user interface

Graphical Abstract
Cardiac tissue perfusion at rest correlates with systemic microvascular function in those with and without atherosclerotic coronary artery disease; a cross-sectional study
Authors: Wilcox Joshua , Gosling Oliver , Casanova Francesco , He Jingzhou , Gooding Kim M , Pitt Andrew , Ball Claire , Morgan-Hughes Gareth , Bellenger Nick , Shore Angela C , Strain W David
Published: December 2024

Background

Coronary microvascular disease is often defined by symptoms in the absence of epicardial coronary artery stenosis. There is, however, a growing interest in exploring the vascular physiology of patients with chest pain syndromes who have been confirmed to have unobstructed coronary arteries. As it is known that people with microvascular coronary disease have an additive poor prognosis, we aimed to determine whether this was part of a systemic microvascular dysregulation. As such, we explored the correlations between cardiovascular magnetic resonance (CMR) myocardial perfusion with cutaneous maximal hyperaemic response (MHR) and post-occlusive reactive hyperaemia (PORH), as assessed by laser Doppler fluximetry, in patients with known coronary anatomy determined via computed tomography coronary angiography (CTCA).

Methods

MHR was measured in response to local heating to 42°C and PORH was measured in response to a 4-minute ischaemic stimulus in 102 participants with and without diabetes and/or coronary artery disease, defined as coronary artery calcification of >0 Agatston units. Subepicardial and subendocardial perfusion at rest and in response to adenosine stress was measured via CMR.

Results

Out of 102 participants, 47 (45.1%) had diabetes, and 59 (57.8%) had coronary artery disease, with 32 (31.4%) having both. MHR and PORH were attenuated in participants with diabetes. Resting, but not stressed, CMR perfusion in all subepicardial and subendocardial territories was proportionately impaired in those with attenuated MHR. This association was independent of conventional risk factors including age, sex, blood pressure, glycaemia, coronary artery disease and body habitus (standardised beta 0.315, p=0.012). Conversely, PORH did not correlate with CMR perfusion at rest or after stress.

Conclusions

Maximal hyperaemic response is associated with resting CMR perfusion independent of conventional risk factors. This suggests that cardiac microvascular dysfunction may represent a manifestation of wider microcirculatory derangements. Further research is required to determine whether interventions that improve systemic vascular disturbances may improve cardiac microcirculation.

Translational Perspective

It is recognised that coronary microvascular dysfunction is associated with residual symptoms in people with angina, after the correction of occlusive coronary arterial disease. As such it is a promising target for symptom control, however development of proof-of-concept trials is limited by the ability to monitor the coronary microcirculation in those trials.

This manuscript identifies an appropriate surrogate endpoint that can be easily and non-invasively monitored and validates it against MRI imaging of the coronary microcirculation.
Genetic Nurture: Estimating the direct genetic effects of pediatric anthropometric traits
Authors: Ghatan Samuel , de Vries Jard , Pingault Jean-Baptiste , Jaddoe Vincent W , Cecil Charlotte , Felix Janine F , Rivadeneira Fernando , Medina-Gomez Carolina
Published: December 2024

Parental genetic variants can indirectly influence the traits of their child through the environment, a concept termed "genetic nurture", or indirect genetic effects (IGE). This study estimated the direct genetic effects (DGE), via direct allelic transmission, and IGE shaping height, body mass index (BMI), and bone mineral density (BMD) in a multi-ethnic Dutch pediatric cohort, examining children with repeated measurements at ages six, nine, and thirteen. We imputed missing parental alleles from the phased haplotypes of 1,931,478 variants (MAF >1%), utilizing snipar (single nucleotide imputation of parents). We constructed polygenic risk scores (PRSs) and jointly regressed the proband’s trait on their own PRS, while controlling for the proband’s maternal and paternal PRSs. A total of 4,488 probands, with genetic data, underwent at least one of the three specified measurements. We found statistically significant DGE estimates for the three traits across ages six, nine and thirteen. For instance, 71-77% of the BMI variance explained by the BMI-PRS can be attributed solely to the DGE. IGE estimates reached significance only for BMI measured at ages nine (Beta: 0.05, 95%CI: 0.01-0.09) and thirteen (Beta: 0.05, 95%CI: 0.01-0.09). Maternal and paternal IGE were of a similar magnitude in all our analyses. Our findings indicate that genetic nurture has limited influence on anthropometric traits during formative years. In addition, we do not observe differences between the maternal and paternal indirect contributions to these traits, opposite to the stronger maternal nurturing effect reported for other traits.
Simulate Scientific Reasoning with Multiple Large Language Models: An Application to Alzheimer’s Disease Combinatorial Therapy
Authors: Xu Qidi , Liu Xiaozhong , Jiang Xiaoqian , Kim Yejin
Published: December 2024

Motivation

This study aims to develop an AI-driven framework that leverages large language models (LLMs) to simulate scientific reasoning and peer review to predict efficacious combinatorial therapy when data-driven prediction is infeasible.

Results

Our proposed framework achieved a significantly higher accuracy (0.74) than traditional knowledge-based prediction (0.52). An ablation study highlighted the importance of high quality few-shot examples, external knowledge integration, self-consistency, and review within the framework. The external validation with private experimental data yielded an accuracy of 0.82, further confirming the framework’s ability to generate high-quality hypotheses in biological inference tasks. Our framework offers an automated knowledge-driven hypothesis generation approach when data-driven prediction is not a viable option.

Availability and implementation

Our source code and data are available athttps://github.com/QidiXu96/Coated-LLM
Circulating microRNA profiles in early-stage osteoarthritis and rheumatoid arthritis
Authors: Baghel Madhu , Wilson Thomas , Ormseth Michelle , Yousif Patrick , Alkhatib Ayad , Meysami Alireza , Davis Jason , Moutzouros Vasilios , Ali Shabana Amanda
Published: December 2024

Background

Osteoarthritis (OA) and rheumatoid arthritis (RA) are prevalent forms of arthritis. Early detection of OA and RA is challenging with existing methods, which can delay effective management. MicroRNAs are small molecules that have emerged as promising disease biomarkers with the potential to improve early detection and differentiation of arthritis subtypes. In this study we aimed to identify distinct circulating microRNAs in plasma from individuals with early OA and early RA, using an unbiased microRNA-sequencing approach.

Methods

Plasma samples were collected from three study groups including: (a) early OA (N=20), individuals with knee OA symptoms and radiographic Kellgren-Lawrence grade 0 or 1; (b) early RA (N=12), treatment-naïve individuals with <6 months of RA symptoms in any joint; and (c) non-OA/RA (N=44), individuals with no history of arthritis. Of these, N=62 samples were subjected to microRNA-sequencing and analysis using a previously optimized pipeline. Exploratory analyses were followed by a stepwise filtering approach to shortlist both known (documented in miRBase v22.1) and novel (predicted using bioinformatics) microRNAs. Prioritized microRNAs were then validated via real-time qPCR (RT-qPCR) in N=14 independent samples.

Results

Principal component analyses revealed clustering of early OA versus both early RA and non-OA/RA groups, but not between early RA and non-OA/RA. In early OA, n=170 differentially expressed (DE) microRNAs were identified compared to both early RA and non-OA/RA, while no significant differences were found between early RA and non-OA/RA. Of these DE microRNAs, stepwise filtering and RT-qPCR validation identified dysregulation of six known microRNAs between early OA and early RA. Of these six microRNAs, two were upregulated in early OA, including hsa-miR-16-5p and hsa-miR-29c-3p, and four were upregulated in early RA, including hsa-miR-744-5p, hsa-miR-382-5p, hsa-miR-3074-5p, and hsa-miR-11400. Additionally, one novel microRNA sequence was found to be enriched in early OA and four in early RA.

Conclusion

We identified a total of six known and five novel circulating microRNAs that differ between early OA and early RA individuals. Validation of these microRNAs in independent cohorts is warranted to establish their biomarker potential for distinguishing individuals with early OA versus early RA.
Rapid NGS Analysis on Google Cloud Platform: performance benchmark and user tutorial
Authors: Franzoso Eugenio , Santorsola Mariangela , Lescai Francesco
Published: December 2024

Next-Generation Sequencing (NGS) is being increasingly adopted in clinical settings as a tool to increase diagnostic yield in genetically determined pathologies. However, for patients in critical conditions the time-to-results of data analysis is crucial for a rapid diagnosis and response. Sentieon DNASeq and Clara Parabricks Germline are two widely used pipelines for ultra-rapid NGS analysis, but their high computational demands often exceed the resources available in many healthcare facilities. Cloud platforms, like Google Cloud Platform (GCP), offer scalable solutions to address these limitations. Yet, setting up these pipelines in a cloud environment can be complex. This work provides a benchmark of the two solutions, and offers a comprehensive tutorial aimed at easing their implementation on GCP by healthcare bioinformaticians. Additionally, it presents a valuable cost guidance to healthcare managers who consider implementing cloud-based NGS processing. Using five publicly available exome (WES) and five genome (WGS) samples, we benchmarked both pipelines on GCP in terms of runtime, cost, and resource utilisation. Our results show that Sentieon and Parabricks perform comparably. Both pipelines are viable options for rapid, cloud-based NGS analysis, enabling healthcare providers to access advanced genomic tools without the need for extensive local infrastructure.
FaDAM3andFaDAM4are candidate genes for the regulation of seasonal dimorphism in cultivated strawberry
Authors: David Stephan , Han Jielyu , Marcelis Leo F.M. , Verdonk Julian C.
Published: December 2024

Cultivated strawberry (Fragaria ananassa) exhibits seasonal dimorphism between the summer and winter seasons. Under the influence of short day conditions, the winter morphology is induced, which includes shorter petioles, smaller and thicker leaves with higher concentrations of chlorophyll and higher density of trichomes. In peach (Prunus persica) the Dormancy-Associated MADS-box (DAM) gene family is involved in the regulation of winter dormancy, which closely resembles strawberry seasonal dimorphism in terms of timing and environmental regulation. In strawberry, six genes exist with close homology to the peachDAMgenes. We analyzed the amino acid and coding sequences of these genes, and designated themFaDAM1-4andFaSVP1-2.We found that there are three pairs of highly similar paralogs within the strawberry genome that exhibit similar expression patterns, although expression levels vary.FaDAM3andFaDAM4exhibit expression patterns that are consistent with seasonal dimorphism. We conclude thatFaDAM3andFaDAM4are candidate genes for the regulation of seasonal dimorphism in strawberry.