bluuebunny/crossref_metadata_2025 huggingface dataset:
Parallel evolution ofLRP2gene mediating telescope-eye and celestial-eye in goldfish
Authors: Li Rongni , Zhang Bo , Sun Yansheng , Li Jingyi
Published: January 2025

After the intensive artificial selection, the development of celestial-eye in goldfish involves the protuberating and turning upwards of eyeballs, and also degeneration of the retinal. Thus, the celestial-eye goldfish provides an excellent model for both evolutionary and human ocular disease studies. Here, two mapping populations with segregating eye phenotypes in the offspring goldfish were constructed. Though whole genome sequencing using individual samples from the parents and pooled samples from the offspring, and RNA-seq for eyeball samples from pure goldfish lines, a premature stop codon in Exon 38 ofLRP2gene was identified as the top candidate mutation that is responsible for celestial-eye in goldfish. Fatty acid metabolisms and epidermal cells, especially keratocytes related functions were inhibited in the eyeballs of celestial-eye, while inflammatory reactions and extracellular matrix secreting were stimulated. These suggest the dysfunction of cornea in the celestial-eye, and same for retinal, which could be the results of the truncated LRP2 protein. Besides, evidence was provided that not all the goldfish lines share the same causal mutation for celestial-eye, while the same geneLRP2is in charge of the similar phenotypes (celestial-eye and telescope-eye) in goldfish but no shared mutation. Therefore, those mutations and the associated phenotypes exhibit parallel evolutions in molecular level under artificial selections. Overall, the candidate mutation for celestial-eye in goldfish was identified by this study, and further analyses provide insights into the developmental and evolutionary processes of morphological changes in the eyes of goldfish.

Author Summary

As the first domesticated ornamental fish, goldfish is now worldwide spread and has undergone intensively artificial selections for morphological variations. Among them, celestial-eye is one of the most unique traits for goldfish, which consists of enlarged and protuberant eyes while the eyeballs turning upwards and thus suitable for top viewing in pots. In this study, we have identified that a single nucleotide mutation resulting in disrupted function ofLRP2gene, is responsible for the celestial-eye phenotype. Together with our transcriptome analysis, the genetic and cellular mechanisms for celestial-eye in goldfish were reported for the first time, which provides fundamental knowledge for further studies about the development of eyes in fish and also for ophthalmic diseases in humans. In the aspect of evolution, our study and previous studies reported different truncated LRP2 proteins in charge of celestial-eye and telescope-eye, respectively, which are excellent materials to understand the mechanisms of parallel evolution in molecular level, i.e., independent artificial selections resulting in mutations of the same gene.
Upright stance is controlled close to critical stability across different postures
Authors: Geng Yang , Bruijn Sjoerd M. , van Dieen Jaap H.
Published: January 2025

Feedback stabilization of upright standing postures should be reflected by a time-lagged relationship between the ground reaction force (GRF) and the center of mass (COM) state. In this study, we propose a model relating corrective ground reaction forces (Fcorr) to preceding COM position (PCOM) and velocity (VCOM). We first checked the model’s validity by simulating an inverted pendulum model with known intrinsic and feedback parameters, to see if we could identify the feedback parameters. Next, we tested this model in 14 young adult volunteers standing in different postures.

Our model effectively reconstructedFcorrin both simulations (R2: 0.50∼0.99) and human experimental data (R2: 0.76∼0.99). Strikingly, estimated position and velocity gains were similar across postures even between bipedal and unipedal standing, with the position gain slightly above critical stiffness. The estimated delay in normal standing (246±21ms) was significantly larger than that in unipedal standing and step posture (204±24ms and 193±29ms, respectively).

In conclusion, our results support that an estimate of the COM state is used to generate corrective ground reaction forces to stabilize upright posture, and our feedback model can be used to characterize this control mechanism. The proposed model requires only easily measurable inputs which may yield value in assessment of balance disorders. Notably, our results showed that stability of upright stance is achieved by maintaining feedback gains at levels just above critical stability.
A delivered DNase toxin creates population heterogeneity through transient intoxication of siblings
Authors: Eriksson Hanna , Schlegel Susan , Kjellin Jonas , Koskiniemi Sanna
Published: January 2025

Population heterogeneity is important for multicellular behavior and division of labor. Bacterial toxin delivery has been implicated in generating population heterogeneity, but the molecular mechanisms behind this are not well understood. Here we investigatehowCdiA toxins generate heterogeneity in isogenic populations. Using a DNase toxin as proxy, we find thatE. colipopulations able to deliver the toxin show a heterogeneous expression of the SOS-response genesulA. Heterogeneity results from excessive delivery of toxin into some cells, which become intoxicated due to insufficient immunity. Intoxication is transiently reversible, and intoxicated cells can be rescued byde novosynthesis of cognate immunity protein. Expression ofsulAis regulated by both DNA damage and redox status. Interestingly, kin-delivery changes redox status, whereas intoxicated non-kin cells induce the SOS DNA damage response. The former results in changed expression of metabolic genes whereas the latter induces prophage excision, which may promote horizontal gene transfer. In conclusion, we identify a molecular mechanism by which heterogeneity is generated through toxin delivery among kin, and the consequences of said heterogeneity.

Significance statement

Bacteria communicate through secretion of chemical signaling molecules to perform multicellular behavior. Recent advances suggest that contact-mediated toxin delivery allow bacteria to participate also in direct cell-cell communication. How such toxin-mediated communication would work mechanistically is however unclear. Here we elucidate a molecular mechanism of a toxin-mediated communication, where kin-cells transiently intoxicate each other, resulting in physiological changes. These changes depend on the toxic activity, i.e. other toxins with different activities are likely to give rise to other responses. Thus, the arsenal of toxins that a bacterium harbors could affect their ability to communicate. Understanding the molecular mechanism of how toxins could mediate polyphenism is important for our understanding of what this signaling is used for.
Systematic functional assessment of antiphage systems in their native host
Authors: David Ellie , Plantady Clarisse , Poissonnier Sophiane , Le Boulch Justine , Gutierrez Arnaud , Chevallereau Anne
Published: January 2025

Bacterial resistance to bacteriophages (phages) relies on two primary strategies: preventing phage attachment and blocking post-attachment steps. These latter mechanisms are mediated by defence systems, including DNA-degrading systems such as Restriction- Modification (RM) and CRISPR-Cas, as well as abortive infection systems that induce cell death or dormancy. Computational studies suggest that bacterial genomes encode several defence systems, which may act synergistically to enhance phage resistance. However, the regulation, interactions, and ecological roles of these systems in native hosts remain poorly understood. This study explored the role of eight predicted defence systems in the clinical isolate NILS69 ofE. coliby testing its susceptibility to 93 phages. Infectivity and adsorption assays using mutants defective in these systems revealed that only PD-T4-3 and RM systems restricted phages able to adsorb. The RM system acted via a predicted Type IV endonuclease and was also able to limit plasmid conjugation if the plasmid was transferred from a donor strain lacking a methylase, which is the hallmark of Type I, II or III RM systems. Other defence systems showed no detectable activity, likely due to phage specificity, environmental regulation, or cofactor requirements. These findings underscore the need for further studies to investigate the regulation and ecological roles of bacterial defence systems in their native host contexts.
The Septin Cytoskeleton is a Novel Regulator of Intestinal Epithelial Barrier Integrity and Mucosal Inflammation
Authors: Naydenov Nayden G. , Hu Gaizun , Zafar Atif , Robak Dominik , Makhmudova Khosiyat , Lechuga Susana , Ohno Yuta , Sagwan Naseer , Bandyopadhyay Saikat , Musich Ryan , Jeffery Erin , Sun Lei , Marino-Melendez Armando , Rieder Florian , Sheynkman Gloria , Ivanov Andrei I. , Ebrahim Seham
Published: January 2025

Background and Aims

Intestinal epithelial barrier-integrity is essential for human health, and its disruption induces and exacerbates intestinal inflammatory disorders. While the cytoskeleton is critical for maintaining gut barrier-integrity, the role of the septins- the newest family of cytoskeletal proteins- is unknown. To address this knowledge gap, we evaluate the role of SEPT9- a critical component of the septin-cytoskeleton- in intestinal epithelial cell (IEC) barrier permeability and inflammation.

Methods

We developed SEPT9-NeonGreen knockin mice, inducible intestinal epithelial cell (IEC)-specific SEPT9 knockout (KO) mice, and SEPT9-KO human IEC lines. SEPT9 localization was analyzed using super-resolution microscopy. Barrier-integrity was assessed via transepithelial electrical resistance, FITC-dextran flux, and visualization of tight junction (TJ) and adherens junction (AJ) proteins. Dextran sodium sulfate-induced experimental colitis was evaluated in control and KO mice through measuring cytokine expression, immune cell infiltration, and IEC death. SEPT9 expression was examined in intestinal tissue of IBD patients.

Results

SEPT9 overlapped with TJs and AJs at IEC apical junctions. SEPT9 loss resulted in a leaky epithelial barrier due to mislocalization of junctional proteins. SEPT9 interacted with non-muscle myosin IIC (NMIIC) at the IEC apical-junctional actomyosin belt, and its ablation displaced NMIIC from IEC junctions. Loss of NMIIC also caused barrier disruption. SEPT9 KO mice exhibited increased susceptibility to experimental-colitis. SEPT9 expression was significantly reduced in intestinal mucosa of IBD patients.

Conclusion

SEPT9 regulates intestinal barrier integrity, supporting TJ and AJ assembly through NMIIC recruitment to the actomyosin belt. SEPT9 safeguards the intestinal mucosa during acute inflammation, and its reduced expression in IBD suggests a loss of this protective function.

Graphical Abstract
Parp7 generates an ADP-ribosyl degron that controls negative feedback of androgen signaling
Authors: Wierbiłowicz Krzysztof , Yang Chun-Song , Almaghasilah Ahmed , Wesołowski Patryk A. , Pracht Philipp , Dworak Natalia M. , Masur Jack , Wijngaarden Sven , Filippov Dmitri V. , Wales David J. , Kelley Joshua B. , Ratan Aakrosh , Paschal Bryce M.
Published: January 2025

Abstract

The androgen receptor (AR) tranduces the effects of circulating and tumor-derived androgens to the nucleus through ligand-induced changes in protein conformation, localization, and engagement with chromatin binding sites. Understanding these events and their integration with signal transduction is critical for defining how AR drives prostate cancer and unveiling pathway features that are amenable to therapeutic intervention. Here, we describe a novel post-transcriptional mechanism that controls AR protein levels on chromatin and associated gene output which is based on a highly selective, inducible degradation mechanism. We find that the mono-ADP-ribosyltransferase PARP7 generates an ADP-ribosyl degron on a single cysteine within the DNA binding domain of AR, which is then recognized by the ADP- ribose reader domain in the ubiquitin E3 ligase DTX2 and degraded by the proteasome. Mathematical modeling of the pathway suggested that PARP7 ADP-ribosylates chromatin-bound AR, a prediction that was validated in cells using an AR mutant that undergoes nuclear import but fails to bind DNA. Lysine- independent, non-conventional ubiquitin conjugation to ADP-ribosyl-cysteine and AR degradation by the proteasome forms the basis of a negative feedback loop that regulates specific modules of AR target genes. Our data expand the repertoire of mono-ADP-ribosyltransferase enzymes to include gene regulation based on highly selective protein degradation.

One Sentence Summary

PARP7 mono-ADP-ribosylates the androgen receptor on Cys620 to mark the androgen receptor for ubiquitin conjugation by an E3 ligase with ADP-ribose reader function, resulting in in negative feedback of AR-dependent gene expression.
Unicore Enables Scalable and Accurate Phylogenetic Reconstruction with Structural Core Genes
Authors: Kim Dongwook , Park Sukhwan , Steinegger Martin
Published: January 2025

The analysis of single-copy core genes, common to most members of a clade, is important for key tasks in biology including phylogenetic reconstruction and assessing genome quality. Core genes are traditionally identified by the analysis of amino acid similarities among proteomes, but can also be defined using structures, which bear potential in deep clades beyond the twilight zone of amino acids. Despite breakthroughs in accurate AI-driven protein structure prediction, obtaining full 3D structural models on a proteomic scale is still prohibitively slow. Here, we present Unicore, a novel method for identifying structural core genes at a scale suitable for downstream phylogenetic analysis. By applying the ProstT5 protein language model to the input proteomes to obtain their 3Di structural strings, Unicore saves over three orders of magnitude in runtime compared to a full 3D prediction. Using Foldseek clustering, Unicore identifies single-copy structures universally present in the species and aligns them using Foldmason. These structural core gene alignments are projected back to amino acid information for downstream phylogenetic analysis. We demonstrate that this approach defines core genes with linear run-time scaling over the number of species, up to 56 times faster than OrthoFinder, while reconstructing phylogenetic relationships congruent with conventional approaches. Unicore is universally applicable to any given set of taxa, even spanning superkingdoms and overcoming limitations of previous methods requiring orthologs of fixed taxonomic scope, and is available as a free and open source software athttps://github.com/steineggerlab/unicore.
Click-linking: a cell-compatible protein crosslinking method based on click chemistry
Authors: Amaral Bruno C. , Michael Andrew R.M. , Brodie Nicholas I. , Crowder D. Alex , Eiriksson Kristen H. , Schriemer David C.
Published: January 2025

Crosslinking mass spectrometry (XL-MS) has the potential to map the human interactome at high resolution and with high fidelity, replacing indirect, error prone sampling methods such as affinity pulldown MS. However, the sampling depth of XL-MS remains stubbornly low. We present a novel crosslinking strategy that splits the crosslinking reaction into two sequential and orthogonal coupling events. The method involves pre-stabilizing the spatial proteome with a fixation protocol inspired by immunofluorescence imaging, followed by a stepwise process that begins with extensively labeling surface-accessible lysines in the cell with N-hydroxysuccinimide (NHS)-modified click reagents. We show that a subsequent copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction of the installed precursors generates crosslinks at levels approaching 30% of the total signal, as demonstrated by a subtractive approach. The method generates no detectable side reactions or obvious distortions of the spatial proteome. Protein-protein interactions (PPIs) are detected at levels approximately 20 times higher than a conventional DSS-based method, outperforming even enrichable crosslinkers.
Agent-based modeling reveals impacts of cell adhesion and matrix remodeling on cancer collective cell migration phenotypes
Authors: Benson Temitope O. , Islam Mohammad Aminul , Liu Kailei , Ford Versypt Ashlee N.
Published: January 2025

Understanding the phenotypic transitions of cancer cells is crucial for elucidating tumor progression mechanisms, particularly the transition from a non-invasive spheroid phenotype to an invasive network phenotype. We developed an agent-based model (ABM) using Compucell3D, an open-source biological simulation software, to investigate how varying biophysical and biochemical parameters influence emerging properties of cellular communities, including cell growth, division, and migration. Our focus was on cell-cell contact adhesion and matrix remodeling effects on cancer cell migration.

We simplified enzymatic remodeling of the extracellular matrix and the subsequent enhancements to cellular chemotaxis or durotaxis as a combined effect of localized cellular secretion of a chemoattractant. By varying the chemoattractant secretion rate and contact adhesion energy, we simulated their effects on cellular behavior and driving the transition from a spheroid phenotype to a network phenotype. The model serves as a digital twin for 3D cancer cell culture, simulating cancer cell growth, division, and invasion over 1 week, validated against published data. The simulations track the emergent morphological and collective phenotype changes using key metrics such as cell circularity and invasion. Our findings indicate that increased chemoattractant secretion enhances the invasiveness of the collective cells, promoting the transition to a network phenotype. Additionally, changing cell-cell contact energy from a strong cell-cell adhesion to a weak cell-cell adhesion affects the compactness of the spheroids, resulting in lower circularity and increased collective cell invasion. Our work advances the understanding of tumor progression by providing insights into the biophysical mechanisms behind invasive cancer cell phenotypic transitions.
Missense mutations: Backbone structure positional effects
Authors: Perez Ivan , Stege Ulrike , Jabbari Hosna
Published: January 2025

Human diversity often manifests through single nucleotide polymorphisms (SNPs). Among these, missense mutations, or SNPs that alter amino acids, can modify a protein’s three-dimensional (3D) structure. This impacts its function and can potentially elicit diseases or affect drug interactions. Thus, understanding protein single point mutations is crucial for precision medicine, as it helps tailor treatments based on individual genetic variations. As atomic locations can be susceptible to any number of changes that might or might not affect function, we focus on the secondary structure to provide concrete results on possible protein structural deformation that may occur from missense mutations.

We assess state-of-the-art structure prediction methods regarding backbone deformations caused by missense mutations. We categorize these deformations aslocal, distant, orglobalbased on the proximity of structural changes to the mutation site. Our analysis utilizes a diverse dataset from the Protein Data Bank, comprising over 500 protein clusters with experimentally determined structures and documented mutations.

Our findings indicate that missense mutations can significantly affect the accuracy of structure prediction methods. These mutations often lead to predicted structural changes even when the actual secondary structures remain unchanged, suggesting that current methods overestimate the impact of missense mutations. This issue is particularly evident in advanced prediction algorithms, which struggle to accurately model proteins with stable mutations. We also found that the addition of low-performing prediction methods during structural analysis can positively impact the results on some proteins, particularly those with low homology. Furthermore, proteins that form complexes or bind ligands—such as membrane and transport proteins—are inaccurately predicted due to the absence of extra-molecular interaction data in the models, highlighting how missense mutations can complicate accurate structure prediction. All code and data are available athttps://github.com/ivanpmartell/pdb-sam.
Tracking Progress: Trends in Surgical Indicator Reporting in the World Development Indicators
Authors: Torres Perez-Iglesias Carolina , Jensen Kennedy , Raguveer Vanitha , Hyman Gabriella Y. , Suzuki Emi , Meara John G. , Raykar Nakul P.
Published: January 2025

Background

The Lancet Commission on Global Surgery (LCoGS) emphasized the need for six core indicators to track progress toward safe, affordable, and timely surgical care. In 2016, four of these indicators were integrated into the World Development Indicators (WDI) to facilitate global tracking of surgical system performance. However, the impact of these indicators relies on the accuracy and frequency of the reported data. We aimed to analyze trends in the reporting of the WDI surgical indicators and evaluate trends in the context of countries undertaking National Surgical Plans (NSPs).

Methods

Data were extracted from the World Bank WDI database and analyzed by WHO region from 2015-2020. Countries were categorized based on their engagement with NSPs. Trends in reporting for the four surgical indicators—surgical case volume (SV), surgical workforce density (SW), catastrophic health expenditure (CHE), and impoverishing expenditure (IE)—were assessed. Correlations between NSP implementation and reporting completeness were explored.

Results

From 2015 to 2020, reporting rates for the modeled indicators CHE and IE remained stable, with an average annual reporting rate of 62% for both. In contrast, the reporting of non-modeled indicators (SV, SW) declined over the study period. SV reporting dropped from 12% in 2015 to 0% in 2020, and SW reporting decreased from 18% to 0%. Regional disparities were significant: the European region had the highest reporting rates for non-modeled indicators, with 13.3% for SW and 3.7% for SV, while the African region reported only 5.4% for SW and 1.8% for SV. No significant correlation was found between NSP implementation and reporting rates (R² = 0.00014, p = 0.986).

Conclusions

Despite integrating surgical indicators into the WDI, reporting rates remain low, particularly for non-modeled indicators. Strengthening data collection and reporting systems, particularly in low-resource settings, is essential for improving surgical care monitoring and addressing global disparities.
Genetic Insight into the Paradoxical Relationship among Diabetes, Coronary Artery Disease, and Abdominal Aortic Aneurysm
Authors: Zheng Shufen , Wu Yonglin , Li Aijie , Wu Zhuoyi , Liu Zhen , Wang Huawei , Jia Xiaoyan , Tsao Philip S. , Pan Cuiping
Published: January 2025

Type 2 diabetes (T2D) increases the risk of coronary artery disease (CAD) but decreases that for abdominal aortic aneurysm (AAA), forming an intriguing diabetes-atherosclerosis paradox. We investigate its genetic basis employing techniques such as genetic correlation, colocalization, gene annotation, functional enrichment, and pathway pairing on GWAS datasets. We discover a strong and positive correlation between T2D and CAD throughout the genome, with shared enrichment in immune signaling. The genetic correlation between CAD and AAA is weaker, with shared genetic components related to lipid metabolism. Conversely, T2D and AAA show the weakest genetic correlation, counter-balanced by two-thirds of genes and chromosomal segments with positive correlations and one-third with negative correlations. The positive correlations entail immune signaling, whereas the negative correlations are characteristic of beta-cell function and lipid metabolism. Our study suggests immune signaling contributes to the synergy between diabetes and atherosclerosis. By decoding the genetic interplay underlying these diseases, our findings provide a foundation for improving treatment strategies and advancing precision medicine.
The dark side of streaking: Examining the backfire potential of run streaking in recreational runners who broke a long-term streak
Authors: Ingalls Erin E. , Larade Nicholas , Ozakinci Gozde , Tymowski-Gionet Gabriela , Fleig Lena , Dombrowski Stephan U.
Published: January 2025

Background

Run streaking is running on consecutive days for a minimum of one mile per day. Despite its benefits for supporting habit formation and long-term behaviour change, some streak runners report potential unintended negative consequences of run streaking. The aim of the study is to examine the backfire potential of run streaking in recreational runners who ended a long-term streak.

Methods

Qualitative semi-structured interviews with 17 recreational adult runners (10 male, 6 female, 1 other gender). All runners ended a run streak of ≥100 consecutive days. Transcripts were analyzed using a hybrid deductive–inductive thematic analysis.

Results

Prior to streak cessation, some runners felt streak-related inconveniences and ran with injury to prolong the streak. Immediate consequences following the end of a streak included feelings of sadness, anger, disappointment and relief. Several run streakers described a ‘grieving process’ in the weeks and months following streak cessation. Unintended negative consequences were amplified in runners with higher levels of streak attachment. All physically capable runners continued to run regularly with most starting a new streak and all voiced positive views towards run streaking despite their streak ending.

Conclusion

Run streaking as a behaviour change technique has small backfire potential in some runners. Ending a long-term run streak can lead to short-term negative affect which can develop into experiences of grief, particularly in those with high levels of streak attachment. No long-term negative consequences were reported. All participants perceived run streaking as positive overall and remained physically active following the end of their long-term streak.
Development and clinical validation of a cross-sex translator of ECG drug responses
Authors: Shetty Roshni , Morotti Stefano , Sobota Vladimír , Bayer Jason D. , Ni Haibo , Grandi Eleonora
Published: January 2025

Sex differences in cardiac electrophysiology are a crucial factor affecting arrhythmia risk and treatment responses. It is well-documented that females are at a higher risk of drug-induced Torsade de Pointes and sudden cardiac death, largely due to longer QTc intervals compared to males. However, the underrepresentation of females in both basic and clinical research introduces biases that hinder our understanding of sex-specific arrhythmia mechanisms, risk metrics, disease progression, treatment strategies, and outcomes. To address this problem, we developed a quantitative tool that predicts ECG features in females based on data from males (and vice versa) by combining detailed biophysical models of human ventricular excitation-contraction coupling and statistical regression models. We constructed male and female ventricular tissue models incorporating transmural heterogeneity and sex-specific parameterizations and derived pseudo-ECGs from these models. Multivariable lasso regression was employed to generate sets of regression coefficients (a cross-sex translator) that map male ECG features to female ECG features. The predictive ability of the translator was evaluated using an independent dataset that simulates the effects of various drugs and pharmacological agents at different concentrations on male and female models. Furthermore, we demonstrated a proof-of-concept clinical application using ECG data from age-matched subjects of both sexes under various drug regimens. We propose our cross-sex ECG translator as a novel digital health tool that can facilitate sex-specific cardiac safety assessments, ensuring that pharmacotherapy is safe and effective for both sexes, which is a major step forward in addressing disparities in cardiac treatment for females.

One Sentence Summary:We used biophysical and regression models for predicting ECG features across sexes to address disparities in sex-specific cardiac drug responses
Horizontal gene transfer rates decrease during transitions to new ecosystems
Authors: Mishra Swastik , Lercher Martin J.
Published: January 2025

Horizontal gene transfer (HGT) is a major driver of bacterial evolution, allowing bacteria to acquire new traits from other organisms. It enables the transfer of advantageous traits, such as antibiotic resistance, which can rapidly spread across bacterial populations, affecting public health. Several studies have estimated how widespread HGT can be and suggested that environmental changes are associated with changes in the rate of HGT. It is often considered that environmental changes lead to an increase in HGT rates due to the adaptive benefits of HGT. However, previous studies have been limited to one or a few species and have often focused on specific genes of interest. Here, we systematically investigate the effect of environmental changes on the rate of HGT in a large number of bacterial genomes along a deep phylogeny. We extend the scope of use of existing state-of -the -art methods for HGT inference to infer the transition into new ecosystems and the gain of pathogenicity. Transitions to new environments are associated with a decrease in the rate of HGT, along with the strengthening of purifying selection. This decrease in HGT rates is consistent regardless of genomic relatedness between the donor and recipient. Our results are robust to the use of different methodological frameworks and have implications for understanding the evolution of bacteria and HGT rates in natural microbial communities.
Trisomy 21 impairs synchronized activity and connectivity in developing human down syndrome cortical excitatory neuron networks
Authors: Peter Manuel , Real Raquel , Strano Alessio , Robinson Hugh P.C. , Smith Mark A. , Barnes Samuel J. , de Paola Vincenzo , Livesey Frederick J.
Published: January 2025

Down syndrome (DS) is the most common genetic cause of intellectual disability, affecting one in 700 live births worldwide, and is caused by trisomy of the human chromosome 21 (Hsa21). Here, we investigated whether trisomy 21 alters the development of human excitatory cortical neuronal networks, and whether that could contribute to the neurodevelopmental phenotypes of DS. By recapitulating cerebral cortex development in vitro with Trisomy 21 and control isogenic and non-isogenic human induced pluripotent stem cells (hiPSC), we assessed the impact of Hsa21 triplication on activity and connectivity in developing excitatory cortical neural networks. Our analysis revealed a significant decrease in neuronal activity in TS21 neurons early in development. Unlike euploid cortical excitatory neurons, TS21 neurons failed to develop synchronised bursting activity in vitro and in vivo following transplantation into the mouse forebrain. Viral transynaptic tracing identified significant reduction of neuronal connectivity in TS21 neuronal networks in vitro, suggesting that reduced network connectivity contributes to the reduction of synchronised bursting. Furthermore, TS21 neurons displayed significantly reduced expression of voltage-gated potassium channels, with single-neuron recordings confirming the absence of hyperpolarization-activated currents. This points to a functional loss of the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in TS21 neurons. Together, these findings indicate that Hsa21 trisomy leads to alterations in ion channel composition, spontaneous synchronised activity, and neuronal connectivity in cortical excitatory neuron networks, which likely contribute to the neurodevelopmental features of DS.
Absolute abundance unveilsBasidiobolusas a cross-domain bridge indirectly bolstering gut microbiome homeostasis
Authors: Ghotbi Mitra , Stajich Jason E. , Dallas Jason , Rurik Alexander , Cummins Chloe , Vargas-Gastélum Lluvia , Ghotbi Marjan , Spatafora Joseph W. , Kelly Kian , Alexander N. Reed , Moe Kylie C. , Syring Kimberly C. , Shadmani Leila , Perez-Marron Julissa , Walker Donald M.
Published: January 2025

The host microbiome is integral to metabolism, immune function, and resilience against pathogens. However, reliance on relative abundance (RA) to estimate host-associated microbiomes introduces compositional biases, while limited tools for absolute abundance (AA) quantification hinder broader applications. To address these challenges, we developed DspikeIn (https://github.com/mghotbi/DspikeIn), an R package paired with a versatile wet-lab methodology for AA quantification. Using RA and AA to compare core microbiome distributions across herpetofauna orders and their natural histories revealed starkly distinct results, driven by aggregate effects, including inherited compositional biases in RA and additional multifactorial influences. Focusing on two closely relatedDesmognathusspecies demonstrated that AA quantification enhanced resolution in differential abundance analyses and minimized false discovery rates (FDR) when identifying enriched taxa in their gut microbiomes. Keystone taxa identified through network associations also differed between RA and AA data. For example,LactococcusandCetobacteriumwere core members in Anura and Caudata, whileBasidiobolusandMortierellawere core to Chelonia and Squamata, facilitating host adaptation to diverse environments, insights undetectable with RA data. AA-based network analysis further revealed that removing theBasidiobolussubnetwork increased negative interactions, highlighting its role in promoting gut homeostasis through cross-domain connectivity. Despite low redundancy, theBasidiobolusnode exhibited high betweenness, efficiency, and degree, serving as a critical bridge linking disconnected nodes or modules and indirectly supporting microbiome stability, consistent with Burt’s structural hole theory. DspikeIn represents a transformative tool for microbiome research, enabling the transition from RA to AA quantification and delivering more accurate, consistent, and comparable results across studies.

Graphical abstract DspikeIn cheatsheet
Stick together: Isolation and characterization of exopolysaccharide producing bacteria from degraded permafrost soils
Authors: Waqas Muhammad , Zelenková Simona , Vogel Cordula , Rühmann Broder , Varsadiya Milan , Liebmann Patrick , Wang Haitao , Shibistova Olga , Urich Tim , Guggenberger Georg , Bárta Jiří
Published: January 2025

Permafrost thaw can result in two distinct environmental landscapes (i.e. “wet condition” soils rich in ice wedges and low drainage, and “dry condition” well-drained areas with higher evapotranspiration). These different conditions influence the bacterial communities and may impact their capacity to produce exopolysaccharides (EPSs), which are crucial for bacterial survival and adaptation. This study aimed to isolate and characterize EPSs-producing bacteria from the active layer of two permafrost degrading landscapes and from undisturbed permafrost soil. A total of 54 bacterial isolates were obtained, representing three phyla: Firmicutes, Actinomycetota, and Pseudomonadota. EPSs production was assessed by determining the polysaccharide content measured as glucose equivalent, and 26 isolates were identified as potential EPSs-producers. Among the isolates,Curtobacterium oceanosedimentum, Frigoribacterium faeni,Streptomycesstrains,Neobacillus bataviensisandMesobacillus subterraneushad the highest polysaccharide yield. They were also found inhabiting in the different horizons of degraded permafrost soil and undisturbed permafrost soil, by determining their relative proportion within the total bacterial community based on 16S rRNA gene sequences similarities.
Topical application of carbon dots and mesoporous silica nanoparticle-derived dsRNA-nanocomposites for the control of beet curly top virus and turnip mosaic virus
Authors: Zarrabi Sara , Rangel Carmen , Martínez-Campos Emanuel , Delgado-Martín Josemaría , Arpanaei Ayyoob , Shams-bakhsh Masoud , Velasco Leonardo
Published: January 2025

The management of emerging phytoviruses in current agriculture confronts many challenges, including the appearance of new strains or the arrival of new species, requiring a multidisciplinary approach. The usual methods for the control of these pathogens are based on management practices, vector control, seed control, etc., and the introgression of genetic resistance in cultivars. But the development of resistances by classical genetic methods is a costly and time-consuming process. A promising alternative is the control of these pathogens by means of the so-called SIGS (Spray-Induced Gene Silencing) that consists of topical treatments with specific molecules derived from the viruses as double-stranded RNA (dsRNA), triggering the plant defense mechanisms. In this work, we show the control of two viruses, the potyvirus turnip mosaic virus (TuMV) and the curtovirus beet curly top virus (BCTV) by dsRNA nanocomposites with carbon dots or mesoporous silica nanoparticles inNicotiana benthamiana. In the case of TuMV, the disease was significantly reduced in terms of plant photosynthetic capacity and viral titers, in the dsRNA treated plants. Moreover, when the treatments were carried out with dsRNAs as nanocomposites, the differences were even more noticeable with respect to untreated inoculated plants. In the case of BCTV, a significant delay in symptoms appearance was observed after the treatments with the dsRNA nanocomposites, but not with the naked dsRNAs. Viral titers were reduced either with the naked or the nanoparticle-delivered dsRNAs. The increased efficiency of dsRNA for virus control when supplied with the nanoparticles can be related with the enhanced dsRNA delivery reported in this work.
Identification of QTL-by-Environment Interaction by Controlling Polygenic Background Effect
Authors: Zhao Fuping , Wang Lixian , Xu Shizhong
Published: January 2025

The QTL by environment interaction (Q×E) effect is hard to detect because there are no effective ways to control the genomic background. In this study, we propose a novel linear mixed model that simultaneously analyzes data from multiple environments to detect Q×E interactions. This model incorporates two different kinship matrices derived from the genome-wide markers to control both main and interaction polygenic background effects. Simulation studies demonstrated that our approach was more powerful than the meta-analysis and inclusive composite interval mapping methods. We further analyzed four agronomic traits of rice across four environments. A main effect QTL was identified for 1000-grain weight (KGW), while no QTLs were found for tiller number. Additionally, a large QTL with a significant Q×E interaction was detected on chromosome 7 affecting grain number, yield and KGW. This region harbored two important genes,PROG1andGhd7. Furthermore, we applied our mixed model to analyze lodging in barley across six environments. The six regions exhibiting Q×E interaction effects identified by our approach overlapped with the SNPs previously identified using EM and MCMC-based Bayesian methods, further validating the robustness of our approach. Both simulation studies and empirical data analyses showed that our method outperformed all other methods compared.
Effectiveness of COVID-19 vaccines against SARS-CoV-2 infection and symptomatic infection in the England Winter Coronavirus (COVID-19) Infection Study cohort
Authors: Abdul Aziz Nurin , Andrews Nick , Rawlinson Christopher , Buckley Andrew , Allen Alexander
Published: January 2025

Background

The Winter Coronavirus (COVID-19) Infection Study (WCIS) was a sample-based household study in England and Scotland aiming to inform COVID-19-related epidemiology and health pressures over the 2023-2024 winter period. We aim to estimate vaccine effectiveness (VE) against both SARS-CoV-2 infection in general and specifically symptomatic infection (COVID-19) within the WCIS cohort in England.

Methods

Data from self-reported lateral flow device (LFD) tests for SARS-CoV-2 were collected from participants alongside self-completed questionnaires from November 2023 to March 2024. A test-negative case-control design was used to estimate VE of the Autumn 2023 COVID-19 boosters against SARS-CoV-2 infection and symptomatic infection compared with being unboosted, regardless of previous vaccination history. Symptomatic infection as an outcome was restricted to participants who reported an ARI symptom associated with their test. Logistic regression was used to calculate VE, with LFD test result as the outcome, vaccination status as primary exposure variable, and adjustment for covariates. Analyses were also stratified by bivalent BA4/5 and monovalent XBB vaccines to assess VE of individual vaccine types.

Results

The analysis included 109,929 English residents primarily in the 60-80 age range (54%), of White ethnic background (95%), and in the least deprived quintile (31%). Participants contributed 114,066 eligible tests in the analysis, of which 42,340 were associated with a symptomatic outcome. VE against infection peaked at 49% (95% Confidence Interval (CI): 35-60%) at 2-4 weeks post-vaccination, with waning to a null effect occurring after 10 weeks (VE: 5% (95% CI: -5-14%)). Similarly, VE against symptomatic infection peaked at 49% (95% CI: 32-63%) after 2-4 weeks, waning after 10 weeks (VE: 5% (95% CI: -7-16%)). The bivalent vaccine showed low and mainly non-significant evidence of protection against either outcome, whereas the monovalent vaccine showed a peak VE of 49% (95% CI: 34-60%) at 2-4 weeks against infection and 49% (95% CI: 31-63%) at 2-4 weeks against symptomatic infection.

Conclusions

The Autumn 2023 COVID-19 vaccine campaign provided moderate protection against infection and symptomatic infection during the 2023 winter period, with a differential effect between vaccine type. Household studies such as WCIS are useful to understand impacts of vaccination campaigns within the community, especially in the post-pandemic period where testing capacity is restricted to hospital settings.
YnaI exemplifies the diversity of structural gating mechanisms in mechanosensitive channels of small conductance
Authors: Flegler Vanessa J. , Rasmussen Akiko , Hedrich Rainer , Rasmussen Tim , Böttcher Bettina
Published: January 2025

Osmotically varying environments are challenging for bacterial cells. Sudden drops in osmolytes cause an increased membrane tension and rupture the cells in the absence of protective mechanisms. One family of protective proteins are mechanosensitive channels of small conductance that open in response to membrane tension. Although these channels have a common architecture, they vary widely in the number of transmembrane helices, conductivity, and gating characteristics. Despite of several structures of channels in the open and closed state, the underlying common principles of the gating mechanism are not well understood. Here we show that YnaI opens by radial relocation of the transmembrane sensor paddles together with a shortening of the pore. This contrasts the prototypic smaller MscS which tilts the sensor paddles and retains the pore length. A chimera of both channels with the YnaI sensor paddles and the pore containing C-terminal part of MscS has the conductivity of the pore donor and the tension response of the paddle donor together with the conformational changes of the respective donor. Our research shows that elements with different types of structural rearrangements can be mixed and matched within one channel as long as they support the common area expansion on the periplasmic side.
Exploring the effects of metformin on the body by urine proteome
Authors: Chen Yuzhen , Wang Haitong , Yang Minhui , Shen Ziyun , Gao Youhe
Published: January 2025

Metformin is the first-line medication for treating type 2 diabetes mellitus (T2DM), with over 200 million patients taking it daily. Its effects are extensive and play a positive role in multiple areas. Can we explore its effects and potential mechanisms by urine proteome? In this study, a total of 166 differential proteins were identified after rats were given a dose of 150 mg/(kg·d) of metformin for 5 consecutive days, including complement component C6, pyruvate kinase, coagulation factor X, growth differentiation factor 15 (GDF15), carboxypeptidase A4, chymotrypsin-like elastase family member 1, and L-lactate dehydrogenase C chain (LDH-C). Several of these proteins have been reported to be directly affected by metformin or associated with the effects of metformin. Several biological pathways enriched by the differential proteins or proteins where the differentially modified peptides are located have been reported to be associated with metformin, including glutathione metabolic process, negative regulation of gluconeogenesis, and renin-angiotensin system. Additionally, some significantly enriched biological pathways that have not been reported to be related to the effects of metformin may provide clues for the study of metformin’s potential mechanisms. In conclusion, the application of urine proteome offers a comprehensive and systematic approach to exploring both the known and unknown effects of drugs, thus opening a new window to study the mechanisms of metformin.
Does non-Mendelian chromosome transmission and unusual sex determination affect male mate choice in the flyBradysia coprophila?
Authors: Hodson Christina N , Baird Robert , Hodgemen Maddy , Dury Shona , Ross Laura
Published: January 2025

Mate quality and the cost of mating affect the evolution of mating preferences and is one reason females often show stronger mate preferences than males. Fungus gnats in the family Sciaridae (Diptera) are a family in which we might expect to see the evolution of strong male mate preferences. Many Sciaridae species are monogenic, where females exclusively produce offspring of one sex. Sciaridae species also exhibit paternal genome elimination, a reproductive system where males only transmit maternally inherited chromosomes to offspring. Therefore, Sciaridae males would benefit from exhibiting mating preferences for females that produce female offspring, as a male’s genes are only transmitted to future generations through his daughters, not his sons. We explore male mate choice in the sciarid flyBradysia(formerlySciara)coprophila. We find that mating is costly, as males become sperm limited through multiple matings, and that males exhibit preferences for larger females, suggesting that males are selected to be choosy. However, we do not find male preferences for females that produce female offspring, instead we find that males prefer mating with females that produce male offspring. We speculate that this seemingly maladaptive behaviour may be due to female receptivity rather than male preference, or that males are unable to distinguish between females of different types, which is perhaps surprising since these females differ genetically by 1000s of genes (through a large paracentric inversion on the X chromosome). Together we show how the interplay between unusual genetics and sex determining systems may affect mating system evolution.

Summary statement

In the fungus gnatBradysia coprophilafemales are genetically predetermined to produce broods of just one sex and males only transmit maternally inherited genes to offspring. These factors suggest males should have strong mating preferences for females that produce daughters, which we explore. We find that while males would benefit from being “choosy”, they appear unable to distinguish the two female types, possibly because females are selected to hide their sex determining phenotype.