bluuebunny/crossref_metadata_2025_split huggingface dataset:
Localized high-risk prostate cancer harbors an androgen receptor low subpopulation susceptible to HER2 inhibition
Authors: Wilkinson Scott , Ku Anson T. , Lis Rosina T. , King Isaiah M. , Low Daniel , Trostel Shana Y. , Bright John R. , Terrigino Nicholas T. , Baj Anna , Fenimore John M. , Li Chennan , Vo BaoHan , Jansen Caroline S. , Ye Huihui , Whitlock Nichelle C. , Harmon Stephanie A. , Carrabba Nicole V. , Atway Rayann , Lake Ross , Kissick Haydn T. , Pinto Peter A. , Choyke Peter L. , Turkbey Baris , Dahut William L. , Karzai Fatima , Sowalsky Adam G. 
Published: February 2024

ABSTRACTPatients diagnosed with localized high-risk prostate cancer have higher rates of recurrence, and the introduction of neoadjuvant intensive hormonal therapies seeks to treat occult micrometastatic disease by their addition to definitive treatment. Sufficient profiling of baseline disease has remained a challenge in enabling the in-depth assessment of phenotypes associated with exceptional vs. poor pathologic responses after treatment. In this study, we report comprehensive and integrative gene expression profiling of 37 locally advanced prostate tumors prior to six months of androgen deprivation therapy (ADT) plus the androgen receptor (AR) inhibitor enzalutamide prior to radical prostatectomy. A robust transcriptional program associated with HER2 activity was positively associated with poor outcome and opposed AR activity, even after adjusting for common genomic alterations in prostate cancer includingPTENloss and expression of the TMPRSS2:ERG fusion. Patients experiencing exceptional pathologic responses demonstrated lower levels of HER2 and phospho-HER2 by immunohistochemistry of biopsy tissues. The inverse correlation of AR and HER2 activity was found to be a universal feature of all aggressive prostate tumors, validated by transcriptional profiling an external cohort of 121 patients and immunostaining of tumors from 84 additional patients. Importantly, the AR activity-low, HER2 activity-high cells that resist ADT are a pre-existing subset of cells that can be targeted by HER2 inhibition alone or in combination with enzalutamide. In summary, we show that prostate tumors adopt an AR activity-low prior to antiandrogen exposure that can be exploited by treatment with HER2 inhibitors.ClinicalTrials.govregistration:NCT02430480.
A cross-country analysis of episodic memory and (potentially) modifiable risk factors of dementia
Authors: Knapp David , Kapteyn Arie , Giambrone Alessandro , Ozawa Tabasa 
Published: February 2024

AbstractThe widely cited Lancet Commission concluded that 40% of dementia cases may be preventable through interventions targeting what they refer to as modifiable risk factors. These risk factors have been widely studied individually, but rarely investigated collectively and across many countries. If these factors are “true” (i.e., impactful) modifiable risk factors, then their independent relationship should be robust across countries and comorbidities. We analyze the cross-country consistency of relationships between these modifiable risk factors and episodic memory, a common predictor of cognition and dementia. Using internationally comparable aging studies in 31 countries including the United States, England and Europe, we estimate regressions of combined immediate and delayed word recall with modifiable risk factors and demographic characteristics. Cross-country differences in culture, policies, economy, and other collective experiences lead to significant variation in lifecycle outcomes, including cognitive decline and modifiable risk factors. Our approach does not conclusively affirm a causal relationship but can identify relationships that are weak or nonexistent. We find a limited number of robust relations: education, depression, and hearing loss show clear, consistent associations with our cognition measure. The evidence for other factors, including obesity, smoking, diabetes, and hypertension is weaker and becomes almost non-existent when correcting for multiple hypotheses testing. The inconsistent relationships across countries between episodic memory and obesity, smoking, diabetes, and hypertension suggest the lack of a causal mechanism leading to cognitive decline – a necessary condition for these risk factors to be modifiable and effective targets for policy interventions aimed at controlling dementia prevalence and cost.
Genomics reveals heterogeneousPlasmodium falciparumtransmission and population differentiation in Zambia and bordering countries
Authors: Fola Abebe A. , He Qixin , Xie Shaojun , Thimmapuram Jyothi , Bhide Ketaki P. , Dorman Jack , Ciubotariu Ilinca I. , Mwenda Mulenga C. , Mambwe Brenda , Mulube Conceptor , Hawela Moonga , Norris Douglas E. , Moss William J. , Bridges Daniel J. , Carpi Giovanna 
Published: February 2024

AbstractGenomic surveillance plays a critical role in monitoring malaria transmission and understanding how the parasite adapts in response to interventions. We conducted genomic surveillance of malaria by sequencing 241Plasmodium falciparumgenomes from regions with varying levels of malaria transmission across Zambia. We found genomic evidence of high levels of within-host polygenomic infections, regardless of epidemiological characteristics, underscoring the extensive and ongoing endemic malaria transmission in the country. We identified country-level clustering of parasites from Zambia and neighboring countries, and distinct clustering of parasites from West Africa. Within Zambia, our identity by descent (IBD) relatedness analysis uncovered spatial clustering of closely related parasite pairs at the local level and rare cases of long-distance sharing. Genomic regions with large shared IBD segments and strong positive selection signatures identified genes involved in sulfadoxine-pyrimethamine and artemisinin combination therapies drug resistance, but no signature related to chloroquine resistance. Together, our findings enhance our understanding ofP. falciparumtransmission nationwide in Zambia and highlight the urgency of strengthening malaria control programs and surveillance of antimalarial drug resistance.
Ecological impacts of climate change will transform public health priorities for zoonotic and vector-borne disease
Authors: Redding David W. , Gibb Rory , Jones Kate E. 
Published: February 2024

AbstractClimate change impacts on zoonotic/vector-borne diseases pose significant threats to humanity1but these links are, in general, poorly understood2. Here, we project present and future geographical risk patterns for 141 infectious agents to understand likely climate change impacts, by integrating ecological models of infection hazard (climate-driven host/vector distributions and dispersal3,4) with exposure (human populations) and vulnerability (poverty prevalence). Projections until 2050, under a medium climate change (Representative Concentration Pathway (RCP) 4.5), show a 9.6% mean increase in endemic area size for zoonotic/vector-borne diseases globally (n=101), with expansions common across continents and priority pathogen groups. Range shifts of host and vector animal species appear to drive higher disease risk for many areas near the poles by 2050 and beyond. Projections using lower climate change scenarios (RCP 2.6 & 4.5) indicated similar or slightly worse future population exposure trends than higher scenarios (RCP 6.0 & 8.5), possibly due to host and vector species being unable to track faster climatic changes. Socioeconomic development trajectories, Shared Socioeconomic Pathways (SSPs), mediate future risk through a combination of climate and demographic change, which will disrupt current, regional patterns of disease burden. Overall, our study suggests that climate change will likely exacerbate global animal-borne disease risk, emphasising the need to consider climate change as a health threat.One Sentence SummaryClimate change and socio-economic development dictate future geographical areas at risk of zoonotic and vector-borne diseases.
Genetic Insights into the Relationship Between Psychiatric Disorders and Irritable Bowel Syndrome: A Mendelian Randomization Analysis
Authors: Omar Mahmud , Omar Mohammad , Agbareia Reem , Nassar Saleh 
Published: February 2024

AbstractBackgroundIrritable Bowel Syndrome (IBS) is often accompanied by psychiatric conditions, yet the causal relationship remains uncertain. This study leverages Mendelian Randomization to explore the genetic basis of the association between IBS and various psychiatric disorders.MethodsWe analyzed GWAS data to assess the causal effects of Major Depressive Disorder (MDD), Anxiety, and other psychiatric disorders on Irritable Bowel Syndrome (IBS). Stringent criteria were used to select genetic instrumental variables, and we applied multiple Mendelian Randomization (MR) methods, including a reverse MR analysis, to investigate the impacts comprehensively.ResultsOur study found a significant causal relationship between IBS and MDD (IVW OR: 1.328, 95% CI: 1.122, 1.572, P=0.001) and a slight but significant link with Anxiety Disorders (IVW OR: 1.0611, 95% CI: 1.0184, 1.1056, P=0.0046). Bipolar Disorder, Schizophrenia, OCD, ADHD, Anorexia Nervosa, and Insomnia did not show significant causal connections with IBS. The reverse MR analysis demonstrated a positive correlation between IBS and MDD (IVW OR: 1.522) and a negative one with ADHD (IVW OR: 0.866), while findings for Schizophrenia and other disorders were not significant.ConclusionThe study confirms a unidirectional causal relationship between IBS and certain psychiatric disorders, highlighting the relevance of the gut-brain axis. These insights contribute to the understanding of IBS pathophysiology and underscore the need for considering mental health in IBS management.
WAVELET-BASED AUTOMATIC PECTORAL MUSCLE SEGMENTATION FOR MAMMOGRAMS
Authors: White Basel , Harrow Amy , Cinelli Christina , Batchelder Kendra , Khalil Andre 
Published: February 2024

ABSTRACTThe computational analysis to assist radiologists in the interpretation of mammograms usually requires a pre-processing step where the image is converted into a black and white mask to separate breast tissue from the pectoral muscle and the image background. The manual delineation of the breast tissue from the mammogram image is subjective and time-consuming. The 2D Wavelet Transform Modulus Maxima (WTMM) segmentation method, a powerful and versatile multi-scale edge detection approach, is adapted and presented as a novel automated breast tissue segmentation method. The algorithm computes the local maxima of the modulus of the continuous Gaussian wavelet transform to produce candidate edge detection lines called maxima chains. These maxima chains from multiple wavelet scales are optimally sorted to produce a breast tissue segmentation mask. The mammographic mask is quantitatively compared to a manual delineation using the Dice-Sorenson Coefficient (DSC). The adaptation of the 2D WTMM segmentation method produces a median DSC of 0.9763 on 1042 mediolateral oblique (MLO) 2D Full Field Digital mammographic views from 82 patients obtained from the MaineHealth Biobank (Scarborough, Maine, USA). Our proposed approach is evaluated againstOpenBreast, an open-source automated analysis software in MATLAB, through comparing each approach’s masks to the manual delineations.OpenBreastproduces a lower median DSC of 0.9710. To determine statistical significance, the analysis is restricted to 82 mammograms (one randomly chosen per patient), which yields DSC medians of 0.9756 for the WTMM approach vs. 0.9698 forOpenBreast(p-value = 0.0067 using a paired Wilcoxon Rank Sum test). Thus, the 2D WTMM segmentation method can reliably delineate the pectoral muscle and produce an accurate segmentation of whole breast tissue in mammograms.
The relationship between cognitive abilities and mental health as represented by cognitive abilities at the neural and genetic levels of analysis
Authors: Wang Yue , Anney Richard , Pat Narun 
Published: February 2024

AbstractCognitive abilities are often associated with mental health across different disorders, beginning in childhood. However, the extent to which the relationship between cognitive abilities and mental health is represented in part by different neurobiological units of analysis, such as multimodal neuroimaging and polygenic scores (PGS), remains unclear. Using large-scale data from the Adolescent Brain Cognitive Development (ABCD) Study, we first quantified the relationship between cognitive abilities and mental health in children aged 9-10. Our multivariate models revealed that mental health variables could predict cognitive abilities with an out-of-sample correlation of approximately .4. In a series of separate commonality analyses, we found that this relationship between cognitive abilities and mental health was primarily represented by multimodal neuroimaging (66%) and, to a lesser extent, by polygenic scores (PGS) (21%). This multimodal neuroimaging was based on multivariate models predicting cognitive abilities from 45 types of brain MRI (such as, task fMRI contrasts, resting-state fMRI, structural MRI, and diffusion tensor imaging), while the PGS was based on previous genome-wide association studies on cognitive abilities. Additionally, we also found that environmental factors accounted for 63% of the variance in the relationship between cognitive abilities and mental health. These environmental factors included socio-demographics (e.g., parent’s income and education), lifestyles (e.g., extracurricular activities, sleep) and developmental adverse events (e.g., parental use of alcohol/tobacco, pregnancy complications). The multimodal neuroimaging and PGS then explained 58% and 21% of the variance due to environmental factors, respectively. Notably, these patterns remained stable over two years. Accordingly, our findings underscore the significance of neurobiological units of analysis for cognitive abilities, as measured by multimodal neuroimaging and PGS, in understanding a) the relationship between cognitive abilities and mental health and b) the variance in this relationship that was shared with environmental factors.
A mechanistic statistical approach to infer invasion characteristics of human-dispersed species with complex life cycle
Authors: Goel Nikunj , Liebhold Andrew M. , Bertelsmeier Cleo , Hooten Mevin B. , Korolev Kirill S. , Keitt Timothy H. 
Published: February 2024

AbstractThe rising introduction of invasive species through trade networks threatens biodiversity and ecosystem services. Yet, we have a limited understanding of how transportation networks determine patterns of range expansion. This is partly because current analytical models fail to integrate the invader’s life-history dynamics with heterogeneity in human-mediated dispersal patterns. And partly because classical statistical methods often fail to provide reliable estimates of model parameters due to spatial biases in the presence-only records and lack of informative demographic data. To address these gaps, we first formulate an age-structured metapopulation model that uses a probability matrix to emulate human-mediated dispersal patterns. The model reveals that an invader spreads along the shortest network path, such that the inter-patch network distances decrease with increasing traffic volume and reproductive value of hitchhikers. Next, we propose a Bayesian statistical method to estimate model parameters using presence-only data and prior demographic knowledge. To show the utility of the statistical approach, we analyze zebra mussel (Dreissena polymorpha) expansion in North America through the commercial shipping network. Our analysis underscores the importance of correcting spatial biases and leveraging priors to answer questions, such as where and when the zebra mussels were introduced and what life-history characteristics make these mollusks successful invaders.
Identification of leukemia stem cell subsets with distinct transcriptional, epigenetic and functional properties
Authors: Boutzen Héléna , Murison Alex , Wang Jean C. Y. , Arlidge Christopher , Lupien Mathieu , Kaufmann Kerstin B. , Dick John E. 
Published: February 2024

AbstractThe leukemia stem cell (LSC) compartment is a complex reservoir fueling disease progression in acute myeloid leukemia (AML). The existence of heterogeneity within this compartment is well documented but prior studies have focused on genetic heterogeneity without being able to address functional heterogeneity. Understanding this heterogeneity is critical for the informed design of therapies targeting LSC, but has been hampered by LSC scarcity and the lack of reliable cell surface markers for viable LSC isolation. To overcome these challenges, we turned to the patient-derived OCI-AML22 cell model. This model includes functionally, transcriptionally and epigenetically characterized LSC broadly representative of LSC found in primary AML samples. Focusing on the pool of LSC, we used an integrated approach combining xenograft assays with single-cell analysis to identify two LSC subtypes with distinct transcriptional, epigenetic and functional properties. These LSC subtypes differed in depth of quiescence, differentiation potential and repopulation capacity and could be isolated based on CD112 expression. A majority of AML patient samples had transcriptional signatures reflective of either LSC subtype, and some even showed coexistence within an individual sample. This work provides a framework for further investigation of the LSC compartment in AML.
Biochemical, biophysical, and structural investigations of two mutants (C154Y and R312H) of the human Kir2.1 channel involved in the Andersen-Tawil syndrome
Authors: Zuniga Dania , Zoumpoulakis Andreas , Veloso Rafael F. , Peverini Laurie , Shi Sophie , Pozza Alexandre , Kugler Valérie , Bonneté Françoise , Bouceba Tahar , Wagner Renaud , Corringer Pierre-Jean , Fernandes Carlos A. H. , Vénien-Bryan Catherine 
Published: February 2024

AbstractInwardly rectifying potassium (Kir) channels play a pivotal role in physiology by establishing, maintaining, and regulating the resting membrane potential of the cells, particularly contributing to the cellular repolarization of many excitable cells. Dysfunction in Kir2.1 channels is implicated in several chronic and debilitating human diseases for which there are currently no effective treatments. Specifically, Kir2.1-R312H and Kir2.1-C154Y mutations are associated with Andersen-Tawil syndrome (ATS) in humans. We have investigated the impact of these two mutants in the trafficking of the channel to the cell membrane and function inXenopus laevisoocytes. Despite both mutations being successfully trafficked to the cell membrane and capable of binding PIP2(phosphatidylinositol-4,5- bisphosphate), the main modulator for channel activity, they resulted in defective channels that do not display K+current, albeit through different molecular mechanisms. Co-expression studies showed that R312H and C154Y are expressed and associated with the WT subunits. While WT subunits could rescue R312H dysfunction, the presence of a unique C154Y subunit disrupts the function of the entire complex, which is a typical feature of mutations with a dominant-negative effect. Molecular dynamics simulations showed that Kir2.1-C154Y mutation induces a loss in the structural plasticity of the selectivity filter, impairing the K+flow. In addition, the cryo-EM structure of the Kir2.1-R312H mutant has been reconstructed. This study identified the molecular mechanisms by which two ATS-causing mutations impact Kir2.1 channel function and provide valuable insights that can guide potential strategies for the development of future therapeutic interventions for ATS.
PINK1 is a target of T cell responses in Parkinson’s disease
Authors: Williams Gregory P. , Michaelis Tanner , Lima-Junior João Rodrigues , Frazier April , Tran Ngan K. , Phillips Elizabeth J. , Mallal Simon A. , Litvan Irene , Goldman Jennifer G. , Alcalay Roy N. , Sidney John , Sulzer David , Sette Alessandro , Lindestam Arlehamn Cecilia S. 
Published: February 2024

AbstractParkinson’s disease (PD) is associated with autoimmune T cells that recognize the protein alpha-synuclein in a subset of individuals. Multiple neuroantigens are targets of autoinflammatory T cells in classical central nervous system autoimmune diseases such as multiple sclerosis (MS). Here, we explored whether additional autoantigenic targets of T cells in PD. We generated 15-mer peptide pools spanning several PD-related proteins implicated in PD pathology, including GBA, SOD1, PINK1, parkin, OGDH, and LRRK2. Cytokine production (IFNγ, IL-5, IL-10) against these proteins was measured using a fluorospot assay and PBMCs from patients with PD and age-matched healthy controls. This approach identified unique epitopes and their HLA restriction from the mitochondrial-associated protein PINK1, a regulator of mitochondrial stability, as an autoantigen targeted by T cells. The T cell reactivity was predominantly found in male patients with PD, which may contribute to the heterogeneity of PD. Identifying and characterizing PINK1 and other autoinflammatory targets may lead to antigen-specific diagnostics, progression markers, and/or novel therapeutic strategies for PD.
Phospho-KNL-1 recognition by a TPR domain targets the BUB-1–BUB-3 complex toC. eleganskinetochores
Authors: Houston Jack , Vissotsky Clémence , Deep Amar , Hakozaki Hiro , Crews Enice , Oegema Karen , Corbett Kevin D. , Lara-Gonzalez Pablo , Kim Taekyung , Desai Arshad 
Published: February 2024

ABSTRACTDuring mitosis, the Bub1-Bub3 complex concentrates at kinetochores, the microtubule-coupling interfaces on chromosomes, where it contributes to spindle checkpoint activation, kinetochore-spindle microtubule interactions, and protection of centromeric cohesion. Bub1 has a conserved N-terminal tetratricopeptide (TPR) domain followed by a binding motif for its conserved interactor Bub3. The current model for Bub1-Bub3 localization to kinetochores is that Bub3, along with its bound motif from Bub1, recognizes phosphorylated “MELT” motifs in the kinetochore scaffold protein Knl1. Motivated by the greater phenotypic severity of BUB-1 versus BUB-3 loss inC. elegans, we show that the BUB-1 TPR domain directly recognizes a distinct class of phosphorylated motifs in KNL-1 and that this interaction is essential for BUB-1–BUB-3 localization and function. BUB-3 recognition of phospho-MELT motifs additively contributes to drive super-stoichiometric accumulation of BUB-1–BUB-3 on its KNL-1 scaffold during mitotic entry. Bub1’s TPR domain interacts with Knl1 in other species, suggesting that collaboration of TPR-dependent and Bub3-dependent interfaces in Bub1-Bub3 localization and functions may be conserved.