bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrating Dynamic Network Analysis with AI for Enhanced Epitope Prediction in PD-L1:Affibody Interactions
Authors: Gomes Diego E.B. , Yang Byeongseon , Vanella Rosario , Nash Michael A. , Bernardi Rafael C.
Published: February 2024

Understanding binding epitopes involved in protein-protein interactions and accurately determining their structure is a long standing goal with broad applicability in industry and biomedicine. Although various experimental methods for binding epitope determination exist, these approaches are typically low throughput and cost intensive. Computational methods have potential to accelerate epitope predictions, however, recently developed artificial intelligence (AI)-based methods frequently fail to predict epitopes of synthetic binding domains with few natural homologs. Here we have developed an integrated method employing generalized-correlation-based dynamic network analysis on multiple molecular dynamics (MD) trajectories, initiated from AlphaFold2 Multimer structures, to unravel the structure and binding epitope of the therapeutic PD-L1:Affibody complex. Both AlphaFold2 and conventional molecular dynamics trajectory analysis alone each proved ineffectual in differentiating between two putative binding models referred to as parallel and perpendicular. However, our integrated approach based on dynamic network analysis showed that the perpendicular mode was significantly more stable. These predictions were validated using a suite of experimental epitope mapping protocols including cross linking mass spectrometry and next-generation sequencing-based deep mutational scanning. Our research highlights the potential of deploying dynamic network analysis to refine AI-based structure predictions for precise predictions of protein-protein interaction interfaces.
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

Patients 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

The 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

Genomic 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

Climate 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 Summary

Climate 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

Background

Irritable 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.

Methods

We 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.

Results

Our 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.

Conclusion

The 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

The 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

Cognitive 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

The 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

The 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

Inwardly 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

Parkinson’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

During 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.
“Evaluating the Benefits and Limits of Multiple Displacement Amplification with Whole-Genome Oxford Nanopore Sequencing”
Authors: Dadzie Fiifi A. , Beaudry Megan S. , Deyanov Alex , Slanis Haley , Duong Minh Q. , Turner Randi , Khan Asis , Arias Cesar A. , Kissinger Jessica C. , Glenn Travis C. , de Paula Baptista Rodrigo
Published: February 2024

Multiple Displacement Amplification (MDA) outperforms conventional PCR in long fragment and whole genome amplification which makes it attractive to couple with long-read sequencing of samples with limited quantities of DNA to obtain improved genome assemblies. Here, we explore the efficacy and limits of MDA for genome sequence assembly using Oxford Nanopore Technologies (ONT) rapid library preparations and minION sequencing. We successfully generated almost complete genome sequences for all organisms examined, includingCryptosporidium meleagridis,Staphylococcus aureus,Enterococcus faecium, andEscherichia coli,with the ability to generate high-quality data from samples starting with only 0.025 ng of total DNA. Controlled sheared DNA samples exhibited a distinct pattern of size-increase after MDA, which may be associated with the amplification of long, low-abundance fragments present in the assay, as well as generating concatemeric sequences during amplification. To address concatemers, we developed a computational pipeline (CADECT: Concatemer Detection Tool) to identify and remove putative concatemeric sequences. This study highlights the efficacy of MDA in generating high-quality genome assemblies from limited amounts of input DNA. Also, the CADECT pipeline effectively mitigated the impact of concatemeric sequences, enabling the assembly of contiguous sequences even in cases where the input genomic DNA was degraded. These results have significant implications for the study of organisms that are challenging to culturein vitro, such asCryptosporidium, and for expediting critical results in clinical settings with limited quantities of available genomic DNA.
Global niche partitioning of purine and pyrimidine cross-feeding among ocean microbes
Authors: Braakman Rogier , Satinsky Brandon , O’Keefe Tyler J. , Longnecker Krista , Hogle Shane L. , Becker Jamie W. , Li Robert C. , Dooley Keven , Arellano Aldo , Soule Melissa C. Kido , Kujawinski Elizabeth B. , Chisholm Sallie W.
Published: February 2024

Cross-feeding involves microbes consuming the exudates of other surrounding microbes, mediating elemental cycling. Characterizing the diversity of cross-feeding pathways in ocean microbes illuminates evolutionary forces driving self-organization of ocean ecosystems. Here, we uncover a purine and pyrimidine cross-feeding network in globally abundant groups. The cyanobacteriumProchlorococcusexudes both compound classes, which metabolic reconstructions suggest follows synchronous daily genome replication. Co-occurring heterotrophs differentiate into purine– and pyrimidine-using generalists, or specialists that use compounds for different purposes. The most abundant heterotroph, SAR11, is a specialist that uses purines as sources of energy, carbon and/or nitrogen, with subgroups differentiating along ocean-scale gradients in the supply of energy and nitrogen, in turn producing putative cryptic nitrogen cycles that link many microbes. Finally, in a SAR11 subgroup that dominates whereProchlorococcusis abundant, adenine additions to cultures inhibit DNA synthesis, poising cells for replication. We argue this subgroup uses inferred daily adenine pulses fromProchlorococcusto synchronize to the daily photosynthate supply from surrounding phytoplankton.
High-throughput phenotyping reveals multiple drought responses of wild and cultivated Phaseolinae beans
Authors: Verheyen Jon , Dhondt Stijn , Abbeloos Rafael , Eeckhout Joris , Janssens Steven , Leyns Frederik , Scheldeman Xavier , Storme Veronique , Vandelook Filip
Published: February 2024

Crop production worldwide is increasingly affected by drought stress. Although drought tolerance of a plant may be achieved through morphological, structural, physiological, cellular, and molecular adaptations, most studies remain limited to quantifying the effect of drought on biomass yield. Using a high-throughput phenotypic imaging system, we evaluated the drought tolerance of 151 bean accessions (Phaseolinae; Fabaceae) by quantifying five different traits simultaneously: biomass, water use efficiency, relative water content, chlorophyll content, and root/shoot ratio. Since crop wild relatives are important resources for breeding programmes, both wild and cultivated accessions were analyzed, the majority never evaluated for drought tolerance before. We demonstrate that the five traits are affected very differently by drought in the studied accessions, although a cluster analysis grouped the accessions into five distinct clusters with similar responses. We correlated the results for each accession to local climate variables at their original collection sites. Except for the root/shoot ratio, the results of all indicators were related to precipitation data, confirming that drought tolerant accessions grow in arid environments. This broader knowledge on the complex responses of plants to drought stress may prove an invaluable resource for future crop production.

Highlight

This study presents an innovative approach for the fast evaluation of different drought tolerance traits of legumes. Multiple responses to drought were observed in the economically important Phaseolinae beans.
Age-Related Dynamics of Methanogenic Archaea in the Human Gut Microbiome: Implications for Longevity and Health
Authors: Mohammadzadeh Rokhsareh , Mahnert Alexander , Shinde Tejus , Kumpitsch Christina , Weinberger Viktoria , Schmidt Helena , Moissl-Eichinger Christine
Published: February 2024

The reciprocal relationship between aging and alterations in the gut microbiota is a subject of ongoing research. While the role of bacteria in the gut microbiome is well-documented, specific changes in the composition of methanogens during extreme aging and the impact of high methane production in general on health remain unclear. To address these questions, we analyzed metagenomic data from the stool samples of young adults (n=127, Age: 19-59 y), older adults (n=86), and centenarians (n=34, age: 100-109 years).

Our findings reveal a compelling link between age and the prevalence of high methanogen phenotype, while overall archaeal diversity diminishes. Surprisingly, the archaeal composition of methanogens in the microbiome of centenarians appears more akin to that of younger adults, showing an increase inMethanobrevibacter smithii, rather thanCa.M. intestini. Remarkably,Ca.M. intestini emerged as a central player in the network stability of adults, paving the way forM. smithiiin older adults and centenarians. Notably, centenarians exhibit a highly complex and stable network of these two methanogens with other bacteria. Furthermore, the mutual exclusion between Lachnospiraceae and these methanogens throughout all age groups suggests that these archaeal communities may compensate for the age-related drop in Lachnospiraceae by co-occurring with butyrate-producing Oscillospiraceae.

This study underscores the crucial role of the archaeal microbiome in human physiology and aging. It highlights age-related shifts in methanogen composition, emphasizing the significance ofCa.M. intestini and the partnership between methanogens and specific butyrate-producing bacteria for enhanced health and potential longevity.
NCLX controls hepatic mitochondrial Ca2+extrusion and couples hormone-mediated mitochondrial Ca2+oscillations with gluconeogenesis
Authors: Taha Mahmoud , Assali Essam A. , Stuzmann Grace E. , Shirihai Orian S. , Hershfinkel Michal , Sekler Israel
Published: February 2024

Hepatic Ca2+signaling is emerging as a key factor in mediating gluconeogenesis. However, the identity of the hepatic mitochondrial Ca2+transporter is controversial and the role of mitochondria in controlling hormonal Ca2+signaling and linking them to metabolic activity is poorly understood. We first interrogated the role of the mitochondrial Na+/Ca2+exchanger NCLX by triggering cytosolic Ca2+purinergic signaling in primary hepatocytes, and Ca2+responses in isolated mitochondria from WT, global NCLX KO, and conditional hepatic NCLX KO mice models. We monitored a higher rate of Na+-dependent mitochondrial Ca2+efflux in NCLX-expressing hepatocytes, indicating that it constitutes the major Ca2+efflux pathway. We then asked if NCLX is controlling the hormone-dependent mitochondrial Ca2+oscillations by employing physiological concentrations of glucagon and vasopressin. Consistent with previous studies, hormone applications triggered mitochondrial Ca2+oscillations in WT hepatocytes. In NCLX KO hepatocytes the cytosolic oscillations persisted, however, the mitochondrial Ca2+oscillations were suppressed. To further understand the metabolic role of NCLX in the hepatic system, we examined gluconeogenic function in vivo and ex vitro by monitoring hepatic glucose production. We found that blood glucose dropped faster in the conditional KO mice and their hepatic glucagon-dependent glucose production was reduced, indicating that gluconeogenesis was impaired in hepatic conditional NCLX KO mice. Taken together, our results indicate that NCLX is the primary Ca2+extruder in hepatocytes and is required for mediating the hormone-dependent mitochondrial Ca2+oscillations and gluconeogenesis.

Significance

Hepatic Ca2+signaling is crucial for gluconeogenesis, but the mitochondrial control of this process is not resolved. This study identifies the mitochondrial transporter, NCLX, as a critical link between hormonal-dependent mitochondrial Ca2+oscillations and gluconeogenesis. We first show that NCLX is the major hepatic mitochondrial efflux pathway. We then demonstrate that NCLX is required for glucagon-dependent mitochondrial Ca2+oscillations and the acceleration of mitochondrial oxidative function. Using a conditional hepatic NCLX-null mouse model, we show that NCLX is required for maintaining hepatic glucose production during fasting and in response to glucagon stimulation. Overall, the study identifies NCLX as the integrator of hepatic mitochondrial Ca2+signaling, required for gluconeogenesis.
Spatial transcriptomics reveals focal induction of molecular responses and cellular interactions in the small intestine duringHeligmosomoides polygyrusInfection
Authors: Campillo Poveda Marta , Laidlaw Ross F , Hardy Olympia , Otto Thomas D , Maizels Rick M
Published: February 2024

The infective L3 larvae ofHeligmosomoides polygyrusmigrate to the small intestine where they take up residence in the submucosa, triggering the formation of complex granulomas around the parasite. Here, we employ spatial transcriptomics to elucidate the transcriptional intricacies and cell-cell interactions of the murine small intestine under both steady-state conditions and in response toH. polygyrusinfection. Our findings unveil distinct transcriptional signatures in the crypt zone, villi, and granulomas, providing nuanced insights into the molecular dynamics of the host response to parasitic infection. Molecular characterization ofH. polygyrusgranulomas reveals unique cellular compositions within distinct clusters, shedding light on localized immune activation and cellular dynamics. Utilizing deconvolution techniques, we uncovered common and infection-specific signatures of cell type colocalization, and identified potential ligand-receptor pairs that may mediate communication between the granuloma tissue and the epithelial crypt cells. Additionally, our study highlights the upregulation of genes such asCcl9, Fcer1gandTmsb4xwithin granulomas, suggesting roles in type 2 inflammation, and genes (e.gReg3bandMxra7) associated with wound healing and tissue repair. These results not only enhance our understanding of the murine small intestine’s transcriptional landscape but also provide a platform for exploring host-pathogen interactions. The comprehensive analysis presented here contributes to a holistic comprehension of tissue-specific responses during parasitic infections, offering valuable insights for targeted therapeutic interventions.
Insights from Genetic Studies: SNP Analyses Confirm White Clover Naturalization in Brazil
Authors: Alencar Amanda S , Suyama Yoshishisa , Takahashi Daiki , Mansano Vidal de F , Lira Catarina da F
Published: February 2024

White clover (Trifolium repens) is a stoloniferous legume herb native to Eurasia, which had been introduced and spread globally. In Brazil, it was introduced as forage crop. While previous studies focused mainly on its agricultural benefits, much remains unclear about its territorial dynamics, introduction process and potential threats in Brazil. This study aims to estimate the genetic diversity of naturalized white clover populations in Brazil and assess the influence of cultivars into these populations’ diversity. Through MIG-Seq analysis, 1097 SNPs show that Brazilian populations have 94% within-population variation. Additionally, two mountainous areas clustered together, while rural and urban areas formed a second cluster. Cultivars are less diverse and have 27% of their genetic variability between them. We found that some populations admixture with cultivated varieties, while more isolated mountainous populations were singular in their genetic background. We can conclude that it is possible that parts of the populations are originally native, brought during European immigration, while others appear to have similar cultivar ancestry, indicating possible biological escapes from cultivars into naturalized populations. Considering ecological data and our genetic findings, it is confirmed that white clover is indeed naturalized in Brazil.
Investigating the performance of foundation models on human 3’UTR sequences
Authors: Vilov Sergey , Heinig Matthias
Published: February 2024

Foundation models, such as DNABERT and Nucleotide Transformer have recently shaped a new direction in DNA research. Trained in an unsupervised manner on a vast quantity of genomic data, they can be used for a variety of downstream tasks, such as promoter prediction, DNA methylation prediction, gene network prediction or functional variant prioritization. However, these models are often trained and evaluated on entire genomes, neglecting genome partitioning into different functional regions. In our study, we investigate the efficacy of various unsupervised approaches, including genome-wide and 3’UTR-specific foundation models on human 3’UTR regions. Our evaluation includes downstream tasks specific for RNA biology, such as recognition of binding motifs of RNA binding proteins, detection of functional genetic variants, prediction of expression levels in massively parallel reporter assays, and estimation of mRNA half-life. Remarkably, models specifically trained on 3’UTR sequences demonstrate superior performance when compared to the established genome-wide foundation models in three out of four downstream tasks. Our results underscore the importance of considering genome partitioning into functional regions when training and evaluating foundation models.
The genome ofPasteuria ramosareveals a high turnover rate of collagen-like genes
Authors: Thivolle Alix , Paljakka Marjut , Ebert Dieter , Fields Peter D.
Published: February 2024

Collagen-like proteins (CLP) are commonly found in many pathogenic bacteria where they serve as adhesins to attach to host tissue. The repetition of the amino-acid pattern (Gly-Xaa-Yaa)nis the major feature of collagen and is essential to the formation of its stable triple helical structure. In theDaphnia magna–Pasteuria ramosasystem, a model system for studying antagonistic coevolution, a specific CLP in the virulent parasiteP. ramosaplays a pivotal role in host attachment, regulated by matching allele model. Recognizing the crucial role of CLPs in the infection process, we aimed to enhance our understanding ofP. ramosa-CLPs by sequencing high-quality genomes of two isolates, using long-read technology. An analysis of a CLP gene tree of representativeBacillotaspecies revealed a clear radiation of these genes inP. ramosa, which was not found in the closely relatedPasteuria penetrans. A comparison of the isolates reveals a high synteny, with the exception of a few duplications and inversions, mainly involving CLPs or transposases. Across isolates, we observed a recent burst of transposases as well as duplications of CLP genes. On average, CLP genes are well conserved between isolates, but the presence/absence of individual CLP genes is not fully shared, with 39 and 43 genes in the two isolates. Our findings suggest a rapid radiation of CLP genes combined with a birth and death process of the largeP. ramosa-CLP gene family, possibly driven by transposition and coevolution.

Importance

Although the host–pathogenDaphnia magna–Pasteuria ramosasystem has served as a model for coevolution, we have, to date, lacked high-quality genomic resources for the parasite, as is the case for many such systems. By presenting a complete assembly of two distinctP. ramosaisolates, our study addresses this lack and provides deeper insights into theP. ramosaCollagen Like Protein (CLP) family, essential proteins involved in attachment to the host. We discover that the rapid radiation of CLP genes inP. ramosaappears to be driven by transposition and coevolution, enabling the parasite to adapt to host resistance mechanisms. These insights improve our understanding of host–parasite interactions and pave the way for comparative genomic analyses to better understand the evolution of these genes. They also have broader implications for disease control and therapeutic development targeting pathogenic bacteria adhesion mechanisms.
Automated 3D Landmarking of the Skull: A Novel Approach for Craniofacial Analysis
Authors: Wilke Franziska , Matthews Harold , Herrick Noah , Dopkins Nichole , Claes Peter , Walsh Susan
Published: February 2024

Automatic dense 3D surface registration is a powerful technique for comprehensive 3D shape analysis that has found a successful application in human craniofacial morphology research, particularly within the mandibular and cranial vault regions. However, a notable gap exists when exploring the frontal aspect of the human skull, largely due to the intricate and unique nature of its cranial anatomy. To better examine this region, this study introduces a simplified single-surface craniofacial bone mask comprising 9,999 quasi-landmarks, which can aid in the classification and quantification of variation over human facial bone surfaces.

Automatic craniofacial bone phenotyping was conducted on a dataset of 31 skull scans obtained through cone-beam computed tomography (CBCT) imaging. The MeshMonk framework facilitated the non-rigid alignment of the constructed craniofacial bone mask with each individual target mesh. To gauge the accuracy and reliability of this automated process, 20 anatomical facial landmarks were manually placed three times by three independent observers on the same set of images. Intra- and inter-observer error assessments were performed using root mean square (RMS) distances, revealing consistently low scores.

Subsequently, the corresponding automatic landmarks were computed and juxtaposed with the manually placed landmarks. The average Euclidean distance between these two landmark sets was 1.5mm, while centroid sizes exhibited noteworthy similarity. Intraclass coefficients (ICC) demonstrated a high level of concordance (>0.988), and automatic landmarking showing significantly lower errors and variation.

These results underscore the utility of this newly developed single-surface craniofacial bone mask, in conjunction with the MeshMonk framework, as a highly accurate and reliable method for automated phenotyping of the facial region of human skulls from CBCT and CT imagery. This craniofacial template bone mask expansion of the MeshMonk toolbox not only enhances our capacity to study craniofacial bone variation but also holds significant potential for shedding light on the genetic, developmental, and evolutionary underpinnings of the overall human craniofacial structure.
Advancements in monitoring: a comparison of traditional and application-based tools for measuring outdoor recreation
Authors: Capdevila Talia Vilalta , McLellan Brynn A. , Loosen Annie , Forshner Anne , Pigeon Karine , Jacob Aerin L. , Wright Pamela , Ehlers Libby
Published: February 2024

Outdoor recreation has experienced a boom in recent years. While outdoor recreation provides wide-ranging benefits to human well-being and is an important feature of many protected and non-protected areas, there are growing concerns about the sustainability of recreation with the increased pressures placed on ecological systems and visitor experiences. These concerns emphasize the need for managers to access accurate and timely recreation data at scales that match the growing recreation footprint. Here, we compare spatial and temporal patterns of winter and summer recreation use using traditional and application-based tools across the Columbia and Canadian Rocky Mountains of western Canada. We demonstrate how recreation use can be estimated using traditional and application-based tools, although their accuracy and utility varies across space, season and activity type. Cameras and counters captured similar broad-scale patterns in count estimates of pedestrians and all recreation activities. Application-based data provided detailed spatiotemporal information on recreation use, but datasets were biased towards specific recreation types and did not represent the full recreation population. For instance, Strava Metro data was more suited for capturing broad-scale spatial patterns in biking than pedestrian recreation. Traditional tools including aerial surveys and participatory mapping captured coarser information on the intensity and extent of recreation, with the former tool capturing areas with low recreation intensity and the latter tool suited for capturing recreation information across large spatial and temporal scales. Application-based data should be supplemented with data from traditional tools including cameras or trail counters to identify biases in data and fill in data gaps. We provide a comparison of each tool for measuring recreation use, highlight each tools’ strengths and limitations, and suggest how to use these tools to address real-world monitoring and management scenarios. Our research contributes towards a better understanding of what tools are available to measure recreation and can help direct managers in selecting which tool, or combinations of tools, to use that can expand the rigor and scope of recreation research. This information can support decision-making and lead to the protection of ecological systems while allowing for high-quality recreation experiences.

GRAPHICAL ABSTRACT