bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying Adolescent and Young Adults’ Preferences for Oncology Symptom Management Clinical Trial Participation
Authors: Knoerl Robert , Smener Liat , Grandinetti Katherine , Fecher Leslie A. , Henry N. Lynn , Karimi Yasmin , Pettit Kristen , Schuetze Scott , Walling Emily , Zhang Anao , Barton Debra
Published: January 2025

Background

Most studies to date exploring facilitators and barriers to adolescent and young adults’ (AYAs’) participation in clinical trials have been focused on external factors to AYAs’ participation or recruitment strategies.

Objective

The purpose of this mixed-methods study was to determine AYA cancer survivors’ preferences for oncology symptom management clinical trial participation.

Methods

Semistructured interviews and conjoint analysis were conducted to clarify potential attributes (eg, characteristics) and levels (eg, value of the characteristic) that may be important to AYA cancer survivors when considering clinical trial participation (n = 19). The final list of attributes and levels was administered within a choice-based conjoint analysis survey (n = 52). The utility score for each level was analyzed using hierarchical Bayes estimation, and the feature importance for each attribute was quantified.

Results

The type of new treatment (22.9%) and perceived importance of study topic (19.5%) were the most important attributes identified by participants. The levels with the highest utility scores within each attribute included prescription medicine treatment with mild side effects, electronic surveys, under-30-minute study visits, no follow-up visits, 4-week treatment period, and once-a-week treatment frequency.

Conclusion

The data support that study designs with low participant burden, interventions with few side effects, and the involvement of AYAs in determining the priority of the research topic are appealing to AYAs when considering participation in symptom management trials.

Implications for Practice

AYA participation in clinical trials is necessary to develop new symptom management modalities. Clinicians may use the results to introduce clinical trials containing trial characteristics that appeal to AYA cancer survivors.
Staphylococcus lugdunensis does not exert competitive exclusion on human corneocytes
Authors: Zhang Tianqi , Luo Ran , Ehrström Marcus , Melican Keira
Published: January 2025

Human skin is our primary physical barrier and largest immune organ, and it also hosts a protective microbiota. Staphylococci are prominent members of the skin microbiota, including the ubiquitous coagulase-negative staphylococci (CoNS). The coagulase-positive Staphylococcus aureus is found as part of the microbiota, but it poses clinical concern due to its potential pathogenicity and antibiotic resistance. Recently, a CoNS, Staphylococcus lugdunensis, has been shown to inhibit S. aureus growth via the production of a novel antibiotic, lugdunin. In this study, we use human skin models to understand the spatial relationships between the CoNS Staphylococcus epidermidis and S. lugdunensis with S. aureus during colonization of human skin. We investigated the attachment patterns of the bacteria, both individually and in competition. Surprisingly, we found that attachment did not always correlate with colonization ability. S. lugdunensis exhibited significantly reduced attachment to human skin stratum corneum but was an efficient longer-term colonizer. S. lugdunensis had a distinct attachment pattern on human corneocytes, with no significant overlap, or competitive exclusion, with the other strains. S. lugdunensis is a potential probiotic strain, with a proven ability to suppress S. aureus. Before this potential can be realized, however, further research is needed to understand how this strain adheres and interacts with other bacteria in the human skin microenvironment.
Multi-ancestry meta-analysis of keloids uncovers novel susceptibility loci in diverse populations
Authors: Greene Catherine A. , Hampton Gabrielle , Jaworski James , Shuey Megan M. , Khan Atlas , Luo Yuan , Jarvik Gail P. , Namjou-Khales Bahram , Edwards Todd L. , Velez Edwards Digna R. , Hellwege Jacklyn N.
Published: January 2025

Keloids are raised scars that grow beyond original wound boundaries, resulting in pain and disfigurement. Reasons for keloid development are not well-understood, and current treatment options are limited. Keloids are more likely to occur in darker-skinned individuals of African and Asian descent than in Europeans. We performed a genome-wide association study (GWAS) examining keloid risk across and within continental ancestry groups, incorporating 7,837 cases and 1,593,009 controls. We detected 21 novel independent loci in the multi-ancestry analysis, including several previously associated with fibroproliferative disorders. Heritability estimates were 6%, 21%, and 34% for the European, East Asian, and African ancestry analyses, respectively. Genetically predicted gene expression and colocalization analyses identified 27 gene-tissue pairs, including nine in skin and fibroblasts. Pathway analysis implicated integrin signaling and upstream regulators involved in cancer, fibrosis, and sex hormone signaling. This investigation nearly quintuples the number of keloid-associated risk loci, illuminating biological processes in keloid pathology.
Larger fish upstream in a small stream: what are the causes of this longitudinal pattern?
Authors: Wolf Pedro , Marques Piatã , Mazzoni Rosana
Published: January 2025

Stream fishes often display distinct spatial patterns in size distribution, with one possible pattern being larger individuals dominating the headwaters. This “larger fish upstream pattern” (LFUP) has been widely documented, yet the ecological drivers remain unclear. We investigated factors contributing to LFUP in the fish community of a South American stream. Using historical data (1994–1998) from electrofishing surveys across six sites, we analyzed size distribution across eight species, with predictors including upstream distance, food availability, predation pressure, and intraspecific competition. Linear mixed models indicated that four species exhibit consistent LFUP, primarily driven by upstream distance or food availability. Species with pelagic or lithopelagic spawning displayed LFUP, supporting the hypothesis that LFUP is linked to reproductive strategies requiring upstream movement to maintain population stability. Our findings support that habitat connectivity and complexity are crucial for conserving small pelagic and lithopelagic fish species, as suggested in previous works. This study contributes to the field by highlighting mobile behavior in small tropical stream fishes and underscores the need for conservation strategies that account for movement patterns and habitat requirements in stream systems worldwide.
Nuclear Import Defects Drive Cell Cycle Dysregulation in Neurodegeneration
Authors: Plessis-Belair Jonathan , Russo Taylor , Riessland Markus , Sher Roger B
Published: January 2025

Neurodegenerative diseases (NDDs) and other age-related disorders have been classically defined by a set of key pathological hallmarks. Two of these hallmarks, cell cycle dysregulation (CCD) and nucleocytoplasmic transport (NCT) defects, have long been debated as being either causal or consequential in the pathology of accelerated aging. Specifically, aberrant cell cycle activation in post-mitotic neurons has been shown to trigger neuronal cell death pathways and cellular senescence. Additionally, NCT has been observed to be progressively dysregulated during aging and in neurodegeneration, where the increased subcellular redistribution of nuclear proteins such as TAR DNA-Binding Protein-43 (TDP43) to the cytoplasm is a primary driver of many NDDs. However, the functional significance of NCT defects as either a primary driver or consequence of pathology, and how the redistribution of cell cycle machinery contributes to neurodegeneration, remains unclear. Here, we describe that pharmacological inhibition of importin-β nuclear import is capable of perturbing cell cycle machinery both in mitotic neuronal cell lines and post-mitotic primary neuronsin vitro. OurNemfR86Smouse model of motor neuron disease, characterized by nuclear import defects, further recapitulates the hallmarks of CCD in mitotic cell lines and in post-mitotic primary neuronsin vitro, and in spinal motor neuronsin vivo. The observed CCD is consistent with the transcriptional and phenotypical dysregulation observed in neuronal cell death and cellular senescence in NDDs. Together, this evidence suggests that impairment of nuclear import pathways resulting in CCD may be a common driver of pathology in neurodegeneration.

Graphical Abstract

Graphical Abstract:

Overview of Dysregulated Cell Cycle Mechanisms in Neuronal Cells. A nuclear import block drives cell cycle re-entry from G0, culminating in cell cycle arrest at G1/S. This cell cycle arrest is associated with activation of CKIs from the INK locus (p15, p16, p18, p19) and Cip/Kip (p21, p27) which act on specific CDK/Cyclin complexes. This activity is further associated with the G1/S downregulation E2F and stathmins, resulting in microtubule dysregulation and cell cycle arrest.
Accurate quantification of spliced and unspliced transcripts for single-cell RNA sequencing with tidesurf
Authors: Schleicher Jan T. , Claassen Manfred
Published: January 2025

Motivation

Single-cell RNA sequencing (scRNA-seq) allows for the detailed analysis of dynamic cellular processes. In particular, this has been enabled by the estimation of RNA velocity, the derivative of gene expression, from separate count matrices for different splice states, which provides information about a cell’s immediate future even in snapshot data. Useful velocity estimates strongly depend on accurate counts for spliced and unspliced transcripts. Velocyto remains the standard tool for spliced and unspliced mRNA molecule quantification. However, despite considerable advances in scRNA-seq protocols, velocyto has not been updated to account for peculiarities of new protocols, such as popular approaches based on 5’ chemistry.

Results

To address this shortcoming, we present tidesurf, a command line tool for the quantification of spliced and unspliced transcript molecules from scRNA-seq libraries. Employing it on four different publicly available 10x Genomics Chromium datasets, we show the accuracy on various datasets generated with either 3’ or 5’ chemistry, whereas velocyto’s results are highly erroneous for the latter. Considering broader applicability, our results highlight tidesurf as a potential replacement for velocyto.

Availability and implementation

A Python implementation of tidesurf is available from PyPI and atgithub.com/janschleicher/tidesurf. Code for reproducing the analyses is available at github.com/janschleicher/tidesurf projects.
Theoretical and Empirical Performance of Pseudo-likelihood-based Bayesian Inference of Species Trees under the Multispecies Coalescent
Authors: Sapoval Nicolae , Liu Zejian , Tamiji Mehrdad , Li Meng , Nakhleh Luay
Published: January 2025

Likelihood-based inference under the multispecies coalescent provides accurate estimates of species trees. However, maximum likelihood and Bayesian inference are both computationally very demanding. Pseudo-likelihood has been previously proposed as a computationally efficient alternative to full phylogenetic likelihood calculations in the context of maximum likelihood estimation. However, theoretical and practical aspects of pseudo-likelihood in the context of Bayesian inference have not been explored. In this work, we provide strong theoretical guarantees and an empirical evaluation of pseudo-likelihood-based Bayesian inference of species trees under the multispecies coalescent. Our contributions are threefold. First, we prove a bound on the convergence rate for species tree topology inference and a Bernstein-von Mises result for branch lengths under model misspecification. Second, we provide an empirical comparison of full- and pseudo-likelihood-based Bayesian inference on synthetic data. Finally, we demonstrate the practical scalability of pseudo-likelihood-based inference by analyzing two biological datasets.
ShapeME: A tool and web front-end for de novo discovery of structural motifs underpinning protein-DNA interactions
Authors: Schroeder Jeremy W. , Wolfe Michael B. , Freddolino Lydia
Published: January 2025

Determining where transcriptional regulators bind within a genome is paramount to understanding how gene expression is regulated. Historically, position weight matrices (PWMs) have been used to define the binding preferences of DNA binding proteins1. However, PWMs treat the identity of each base in a sequence as an independent and additive measure of binding preference, which can limit their utility2. Models that consider higher order interactions between nearby bases yield greater success in predicting proteins’ binding to DNA, but for many proteins there is still substantial room for improvement in predicting and understanding the determinants of proteins’ binding to DNA3. In addition to DNA sequence motifs, structural motifs (e.g., a narrow minor groove width) are important determinants of binding for some DNA-binding proteins4. Despite the initial success of algorithms using structural features of DNA to predict binding properties of proteins from either ChIP-seq or SELEX data5–8, there remains a need for ade novostructural motif discovery framework which can be applied to data from a variety of experimental designs. Here, we present a unified workflow, capable of utilizing virtually any type of data representing sequence coverage or enrichment (e.g. ChIP-seq, RNA-seq, SELEX, etc.), to discover short structural motifs with explanatory power for a protein’s DNA binding preference. We couple the DNAshapeR algorithm9with our own information-theoretic approach tode novomotif discovery, and wrap shape and sequence motif inference and model selection into a single tool called ShapeME. Application of our structural motif discovery algorithm to proteins with ChIP-seq data in ENCODE datasets reveals a subset of proteins where short structural motifs outperform the best PWM for that protein as determined from the JASPAR database, or as identified by the sequence motif elicitation tool STREME. Our approach offers a powerful and versatile framework for inferring structural DNA binding motifs, and will complement current sequence-based motif elicitation tools in discovery of protein-DNA interaction principles. A web-based interface to ShapeME is available athttps://seq2fun.dcmb.med.umich.edu/shapeme, with full source code available athttps://github.com/freddolino-lab/ShapeME.
Lower corticalFKBP5DNA methylation at key enhancer sites is associated with older age and higher gene expression in schizophrenia
Authors: Edmond Katrina Z. , Kaul Dominic , Yusupov Natan , Ködel Maik , Sauer Susann , Fröhlich Anna S. , Tao Ran , Kleinman Joel E. , Weinberger Daniel R. , Hyde Thomas M. , Czamara Darina , Binder Elisabeth B. , Matosin Natalie
Published: January 2025

An increasingly compelling body of literature indicates the glucocorticoid receptor cochaperone FK506-binding protein 51 (FKBP51) is a promising target for novel psychiatric therapeutics. However, the mechanisms regulating the correspondingFKBP5gene directly in the human brain remain largely unknown yet are needed to facilitate the development of precise mechanism-based treatment approaches. Here, we examinedFKBP5DNA methylation patterns in postmortem human brain samples from the dorsolateral prefrontal cortex of individuals who lived with a major psychiatric disorder (schizophrenia, major depression, or bipolar disorder; n=329) and controls n=231. We identified that cytosine-phosphate-guanine-dinucleotide (CpG) specificFKBP5DNA methylation is altered in psychiatric disorders across theFKBP5locus, and that these changes are differentially associated with age and genotype (rs1360780 CCvsCT/TT). Individuals with schizophrenia had significantly lower levels of DNA methylation in the proximal enhancer ofFKBP5, which also negatively correlated withFKBP5gene expression. These changes were also associated with predicted glucocorticoid response elements (GREs) in the proximal enhancer, but not other transcription factor binding sites. This evidence supports that in the human cortex,FKBP5DNA methylation is associated with both genetic and ageing effects, and that the associations between these factors vary at a diagnosis-specific level in psychopathology. This may have implications for developingFKBP5-targeted therapeutics and defining a subgroup of patients who will benefit from such treatments.
How peak knee loads are affected by changing the mass of lower-limb body segments during walking
Authors: Miller Delaney Elyssa , Brown Ashley E , Bianco Nicholas A , Bhise Rucha , Delp Scott L , Collins Steven H
Published: January 2025

For individuals with knee osteoarthritis, increased knee loading is linked to disease progression and pain. Some approaches to treating osteoarthritis, such as specialized footwear, braces, and powered exoskeletons, also increase the mass of the lower limbs, which could lead to increases in knee loads. Prior studies have investigated the effect of changes in torso mass and total body mass on peak knee contact forces, but the effects of increased leg mass remain unclear. In this study, we created musculoskeletal simulations informed by experimental data to estimate tibiofemoral knee contact force under different lower-limb segment mass conditions. The mass of the foot, shank, and thigh were varied by adding weights to each segment, separately and concurrently, as healthy young adults (N = 10) walked on a treadmill. Kinematics, kinetics, and muscle activity were recorded. Our simulations used an optimal control framework that enforced experimental kinematics while minimizing a combination of net joint moment errors and mismatch between measured and estimated muscle activity. The simulations revealed that adding mass to the lower-limb segments linearly increased early- and late-stance peaks in knee contact force, but that the slope of this relationship was different for each peak and each mass placement location. For each 1% of body weight (BW) added per limb (2% BW total) at the thigh, shank, and foot, early-stance peak knee contact force increased by 1.5%, 2.1%, and 5.9%, while late-stance peak contact force increased by 1.6%, 0.9% and 3.0%, respectively. Adding mass to the thigh and shank increases peak contact force at or below the rate of increase in body mass, while adding mass to the foot disproportionately increases peak knee contact force. These detrimental effects should be considered when designing interventions for osteoarthritis.
The Effects of Pressure and Temperature on the Thermodynamics of α-Helices
Authors: Makhatadze George I. , Moustouka Caitlyn , Coffin Carleton , Tzul Franco O.
Published: January 2025

In light of the recent realization that a large fraction of microbial biomass lives under high hydrostatic pressure, there is a renewed interest in understanding molecular details by which proteins in these organisms modulate their functional native state. The effects of pressure on protein stability are defined by the volume changes between native and denatured states. The conformational ensemble of the denatured state can depend on several extrinsic variables, such as pH and ionic strength of solvent, temperature, and pressure. The effect of the latter on the elements of the secondary structures, and α-helical structures has been inconclusive. This has been largely due to the inherent difficulties of high-pressure experiments. Here, we adapted the method of choice, circular dichroism spectroscopy, on a well-established series of model peptides to study helical structure formation, while focusing on the pressure and temperature dependencies of the helix-coil transition. We find that at low temperatures, pressure stabilizes the helical structure, suggesting that the volume of the helix-coil transition is positive. However, at higher temperatures (>40°C), the volume changes become negative, and pressure destabilizes the helical structure.
Genomic and Transcriptomic Characterization of Carbohydrate-Active Enzymes in the Anaerobic FungusNeocallimastix camerooniivar. constans
Authors: Blair Elaina M. , Navaratna Tejas A. , Ahern Colleen B. , Ragunathan Ramya , Brown Jennifer L. , Mondo Stephen J. , Lipzen Anna , Hanafy Radwa A. , LaButti Kurt , Talag Jayson , Barry Kerrie , Chovatia Mansi , Wang Mei , Gonzalez Jessy , Peng Xuefeng , Grigoriev Igor V. , O’Malley Michelle A.
Published: January 2025

Anaerobic gut fungi effectively degrade lignocellulose in the guts of large herbivores, but there remains a limited number of isolated, publicly available, and sequenced strains that impede our understanding of the role of anaerobic fungi within microbial communities. We isolated and characterized a new fungal isolate,Neocallimastix camerooniivar. constans, providing a transcriptomic and genomic understanding of its ability to degrade diverse carbohydrates. This anaerobic fungal strain was stably cultivated for multiple yearsin vitroamong members of an initial enrichment microbial community derived from goat feces, and it demonstrated the ability to pair with other microbial members, namely archaeal methanogens to produce methane from lignocellulose. Genomic analysis revealed a higher number of predicted carbohydrate-active enzymes encoded in theN. camerooniivar. constans genome compared to most other sequenced anaerobic fungi. The carbohydrate-active enzyme profile for this isolate contained 660 glycoside hydrolases, 160 carbohydrate esterases, 194 glycosyltrasferases, and 85 polysaccharide lyases. Differential gene expression analysis showed the upregulation of thousands of genes (including predicted carbohydrate-active enzymes) whenN. camerooniivar. constans was grown on lignocellulose (reed canary grass) compared to less complex substrates, such as cellulose (filter paper), cellobiose, and glucose. AlphaFold was used to predict functions of transcriptionally active yet poorly annotated genes, revealing feruloyl esterases that likely play an important role in lignocellulose degradation by anaerobic fungi. The combination of this strain’s genomic and transcriptomic characterization, omics-informed structural prediction, and robustness in microbial co-culture make it a well-suited platform to conduct future investigations into bioprocessing and enzyme discovery.
Biomarkers of pesticide exposure predict Depressive Symptoms in rural and urban workers of the Maule Region, Chile
Authors: Lucero Boris , Muñoz-Quezada María Teresa , Canales-Johnson Andrés , Carrasco Cynthia , Rodríguez María Victoria , Reid Tannelle , Méndez Pablo , Adonis Jandy , Bekinschtein Tristan A.
Published: January 2025

Background

Agricultural workers are routinely exposed to pesticides, which are associated with a range of adverse health outcomes, including potential impacts on mental health such as depressive symptoms. In the Maule region of Chile, an area characterized by intensive pesticide use, this study investigates the association between exposure to organophosphate (OP) pesticides and the prevalence of depressive symptoms among agricultural workers.

Methods

We conducted a longitudinal study with 78 participants, comprising agricultural workers occupationally exposed to pesticides and nearby urban non-agricultural workers. Pesticide exposure was assessed through six dialkyl phosphate (DAP) metabolites in four repeated urine samples over two years. Depressive symptoms were evaluated using the CES-D scale and affect using the PANAS scale. Sociodemographic, health, and exposure-related variables were included as covariates. Generalized Estimating Equations (GEE) were employed to investigate dose-response relationships between pesticide exposure and depressive symptoms.

Results

No reliable differences in urinary DAP, DEAP, and DMP metabolite concentrations were observed directly when testing between rural and urban workers, however, dose-response analyses revealed that cumulative exposure to diethyl alkyl phosphates (DEAPs) was associated with depressive symptoms (CI=0.0003–0.0127, p = 0.040). Over time, positive affect increased among rural workers, whereas urban workers reported significantly lower negative affect in 2023. Further analyses showed problematic alcohol consumption (CI=0.018–3.707, p = 0.048) as a predictor of depressive symptoms.

Conclusions

Pesticide exposure extends beyond occupational settings to include environmental sources or food residues, as shown by comparable exposure levels in rural and urban participants and consistent measurements over two years. Chronic exposure to DEAPs was predictive of depressive symptoms, emphasizing the importance of biomarkers for assessing cumulative exposure. Public health interventions, stricter regulations, and awareness programs are needed to address the mental health risks of pesticide exposure. Further research should explore genetic and environmental factors influencing susceptibility to mental health.
SHINE: SERS-based Hepatotoxicity detection using Inference from Nanoscale Extracellular vesicle content
Authors: Parlatan Ugur , Boudreau Luke , Torun Hulya , Fan Letao , Aygun Ugur , Gokaltun Ayse Aslihan , Akin Demir , Usta O. Berk , Demirci Utkan
Published: January 2025

Extracellular vesicles (EV) are becoming crucial tools in liquid biopsy, diagnostics, and therapeutic applications, yet their nanoscale characterization remains challenging. In this context, the detection of drug-induced liver injury,i.e., hepatotoxicity, through extracellular vesicle molecular content remains an unexplored frontier. To this end, we present a label-free surface-enhanced Raman (SERS) spectroscopy approach, which provides rapid EV content analysis under ten minutes and requires only 1.3 microliters of sample. Using hepatic cultures as a model, our platform captures distinct and reproducible EV molecular changes in response to acetaminophen-induced hepatoxicity. Our platform achieves exceptional accuracy with root mean squared error values as low as 3.80%, establishing strong correlations between EV spectra and conventional toxicity biomarkers. Unlike previous EV-SERS studies limited to vesicle identification and disease markers, this approach reveals EV drug-response signatures strongly correlated with conventional toxicity markers. These findings establish EVs as dynamic reporters of cellular drug responses and demonstrate use of SERS-based EV detection of hepatotoxicity.
Aβ-induced distress of astrocytes triggers Alzheimer disease pathology through non-canonical δ secretase activity
Authors: Schmidt Vanessa , Ziemlinska Ewelina , Obrebski Tomasz , Zurawska-Plaksej Ewa , Cendrowski Jaroslaw , Hempstead Barbara L , Willnow Thomas E , Malik Anna R
Published: January 2025

The importance of astrocytes for Alzheimer disease (AD) pathology is increasingly appreciated, yet the mechanisms whereby this cell type impacts neurodegenerative processes remain elusive. In a genetic mouse model with diminished astrocyte stress response, even low levels of amyloid-β trigger astrocyte reactivity, resulting in brain inflammation and massive amyloid and tau pathologies. This dysfunctional response of astrocytes to amyloid-β acts through activation of δ secretase, a stress-induced protease implicated in both amyloid and tau-related proteolytic processing. Our findings identify a failed astrocyte stress response to amyloid-β as an early inducer of amyloid and tau co-morbidity, a noxious process in AD acting through a unique non-canonical secretase pathway.
Gene regulatory mechanisms underlying evolutionary adaptations of homologous neuronal cell types
Authors: Millán-Trejo Andrea , Mora-Martínez Carlos , Tarazona-Sánchez Adrián , Lloret-Fernández Carla , Alis Rafael , Jordán Antonio , Barrios Arantza , Flames Nuria
Published: January 2025

How nervous systems coordinate the generation of specific neuron types with gene expression plasticity and how these mechanisms impact cell type evolution is unknown. Here we useCaenorhabditisspecies to study neuron-type robustness, plasticity and evolution, using VC4 and VC5 cholinergic motoneurons as models. InC. elegans, we found that epigenetic silencing through histone 3 lysine 9 methylation (H3K9me) is necessary to suppress the expression of the serotonin reuptake genemod-5/Sert and a serotonergic phenotype in these cells. In contrast, we observed that VC4 and VC5 neurons in theAngariagroup of species of theCaenorhabditisgenus have evolved an intense serotonergic staining. This phenotype is caused by the emergence of a new enhancer in themod-5/Sert locus, which has been recruited to the ancestral neuron-type gene regulatory network. Enhancer transfer fromC. angariais sufficient to impose a constitutive serotonergic fate inC. elegans. Remarkably, acquiring this new trait modulates egg-laying responses to high levels of exogenous serotonin, which can be found in specific environments. Finally, we discovered that the repression of the serotonergic fate inC. elegansVC4 and VC5 neurons is indeed a plastic trait that can be adjusted in specific environmental growth conditions to elicit egg-laying behaviours similar to those observed inAngariaspecies. Our work identifies gene regulatory mechanisms that coordinate the generation of robust neuron-type-specific programs with plastic gene expression responses. These findings identify a gene regulatory framework underlying the evolution of neuron-type-specific features and the emergence of novel behaviours.
Mapping of Quorum Sensing Landscape of Commensal and Pathogenic Staphylococci Reveals a Largely Inhibitory Interaction Network
Authors: Gless Bengt H. , Sereika-Bejder Benjamin S. , Jensen Iben , Bojer Martin S. , Tsiko Katerina , Schmied Sabrina H. , Vitolo Ludovica , Toledo-Silva Bruno , De Vliegher Sarne , Ingmer Hanne , Olsen Christian A.
Published: January 2025

Staphylococci utilize secreted autoinducing peptides (AIPs) to regulate group behaviour through a process called quorum sensing (QS). For staphylococcal pathogens such asS. aureus, QS regulates expression of major virulence factors and QS inhibition has been proposed as an alternative to antibiotics for treatment of infections with methicillin resistantS. aureus(MRSA). Here, we surveyed the interaction map between QS systems of the pathogensStaphylococcus aureus, Staphylococcus epidermidis, andStaphylococcus lugdunensisand the 36 currently known AIPs from 22 staphylococcal species. We identified seven of these ribosomally synthesized and post-translationally modified peptides (RiPPs) in this study and all synthetic peptides were assessed for their ability to modulate QS. The mapped interactions of >280 native QS pairings were divided into human- and animal-associated staphylococci showing substantial differences in inhibitory potencies between the groups. In particular, AIPs of the bovine-associated speciesS. simulansdisplayed potential as QS inhibitors in the strains investigated in this study and were therefore chosen as starting point for a structure–activity relationship study. This study provides insights into the requirements for QS interference, yielding the most potent inhibitors reported to date forS. epidermidisandS. lugdunensis. Further, we tested anS. simulansAIP as anti-virulence agent in an assay to assess risk of acquired suppression of the inhibitory effect, and we established an assay set-up to successfully monitoragrdeactivation of virulent MRSA by the QS inhibitor. Finally, a peptide was shown to attenuate skin infection caused by MRSA in a mouse model. Our results reveal a complex network of staphylococcal interactions and provide further impetus for the development of therapeutic strategies, based on QS modulation to target antibiotic-resistant pathogens.

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Emergence of binding and catalysis from a designed generalist binding protein
Authors: Chen Yuda , Bhattacharya Sagar , Bergmann Lena , Correy Galen J. , Tan Sophia , Hou Kaipeng , Biel Justin , Lu Lei , Bakanas Ian , Polizzi Nicholas F. , Fraser James S. , DeGrado William F.
Published: January 2025

The evolution of proteins that bind to small molecules and catalyze chemical transformations played a central role in the emergence of life. While natural proteins have finely tuned affinity for their primary ligands, they also often have weak affinities for other molecules. These interactions serve as starting points for the evolution of new specificities and functions. Inspired by this concept, we determined the ability of a simplede novoprotein to bind a set of diverse small molecules (< 300 Da) by crystallographic fragment screening. We then used this information to design one variant that binds fluorogenic molecule and another that acts as a highly efficient Kemp eliminase enzyme. Collectively, our work illuminates how the evolution of novel protein functions can emerge from existing proteins.
Intense oocyte competition builds the female reproductive reserve in mice
Authors: Zhang Yan , Bo Yingnan , Cheng Kaixin , Mu Lu , Liang Jing , Li Lingyu , Hu Xindi , Wang Ge , Geng Kaiying , Yang Xuebing , Wang Wenji , Jia Longzhong , Xu Xueqiang , Hu Jingmei , Wang Chao , Ke Yuwen , Xia Guoliang , Zhang Hua
Published: January 2025

During the process of ovariogenesis, more than two-thirds of germ cells are sacrificed to enhance the quality of the remaining oocytes. But the detail process of selection is not completely understood in mammals. Here, by creating a high resolution 4- dimensional ovariogenesis imaging system, we recorded the progress of oocyte fate determination in live mouse ovaries, and discovered an oocyte competition mechanism that determines the survival of oocytes. We found that dominant oocytes catch and absorb the cell debris from sacrificed oocytes to enrich their cytoplasm for survival. Single-cell sequencing demonstrated that this competition follows a classic autophagy- driven model. Blocking competition by suppressing autophagy resulted in an enlarged pool of survived oocytes. However, these oocytes lacking competition were unable to fully develop and contribute to fertility. Our study suggests that mammals have evolved a unique intensive competition system to enhance oocyte quality, necessary to support their long reproductive lifespan.
Proteomic Ligandability Maps of Phosphorus(V) Stereoprobes Identify Covalent TLCD1 Inhibitors
Authors: Sharma Hayden A. , Bielecki Michael , Holm Meredith A. , Thompson Ty M. , Yin Yue , Cravatt Jacob B. , Ware Timothy B. , Reed Alex , Nassir Molham , Ewing Tamara El-Hayek , Melillo Bruno , Bazan J Fernando , Baran Phil S. , Cravatt Benjamin F.
Published: January 2025

Activity-based protein profiling (ABPP) of stereoisomerically defined sets of electrophilic compounds (‘stereoprobes’) offers a versatile way to discover covalent ligands for proteins in native biological systems. Here we report the synthesis and chemical proteomic characterization of stereoprobes bearing a P(V)-oxathiaphospholane (OTP) reactive group. ABPP experiments identified numerous proteins in human cancer cells that showed stereoselective reactivity with OTP stereoprobes, and we confirmed several of these liganding events with recombinant proteins. OTP stereoprobes engaging the poorly characterized transmembrane protein TLCD1 impaired the incorporation of monounsaturated fatty acids into phosphatidylethanolamine lipids in cells, a lipidomic phenotype that mirrored genetic disruption of this protein. Using AlphaFold2, we found that TLCD1 structurally resembles the ceramide synthase and fatty acid elongase families of coenzyme A-dependent lipid processing enzymes. This structural similarity included conservation of catalytic histidine residues, the mutation of which blocked the OTP stereoprobe reactivity and lipid remodeling activity of recombinant TLCD1. Taken together, these data indicate that TLCD1 acts as a lipid acyltransferase in cells, and that OTP stereoprobes function as inhibitors of this enzymatic activity. Our findings thus illuminate how the chemical proteomic analysis of electrophilic compounds can facilitate the functional annotation and chemical inhibition of a key lipid metabolic enzyme in human cells.
Identification of the shortest species-specific oligonucleotide sequences
Authors: Mouratidis Ioannis , Konnaris Maxwell A. , Chantzi Nikol , Chan Candace S.Y. , Patsakis Michail , Provatas Kimonas , Montgomery Austin , Baltoumas Fotis A. , Sha Congzhou M. , Mareboina Manvita , Pavlopoulos Georgios A. , Chartoumpekis Dionysios V. , Georgakopoulos-Soares Ilias
Published: January 2025

Despite the exponential increase in sequencing information driven by massively parallel DNA sequencing technologies, universal and succinct genomic fingerprints for each organism are still missing. Identifying the shortest species-specific nucleotide sequences offers insights into species evolution and holds potential practical applications in agriculture, wildlife conservation, and healthcare. We propose a new method for sequence analysis termed nucleic “quasi-primes,” the shortest occurring sequences in each of 45,076 organismal reference genomes, present in one genome and absent from every other examined genome. In the human genome, we find that the genomic loci of nucleic quasi-primes are most enriched for genes associated with brain development and cognitive function. In a single-cell case study focusing on the human primary motor cortex, nucleic quasi-prime genes account for a significantly larger proportion of the variation based on average gene expression. Nonneuronal cell types, including astrocytes, endothelial cells, microglia perivascular-macrophages, oligodendrocytes, and vascular and leptomeningeal cells, exhibit significant activation of quasi-prime-containing gene associations related to cancer, whereas simultaneously suppressing quasi-prime-containing genes are associated with cognitive, mental, and developmental disorders. We also show that human disease–causing variants, eQTLs, mQTLs, and sQTLs are 4.43-fold, 4.34-fold, 4.29-fold, and 4.21-fold enriched at human quasi-prime loci, respectively. These findings indicate that nucleic quasi-primes are genomic loci linked to the evolution of species-specific traits, and in humans, they provide insights in the development of cognitive traits and human diseases, including neurodevelopmental disorders.
Flux Fractionalization Transition in Anisotropic
S=1
Antiferromagnets and Dimer-Loop Models
Authors: Kundu Souvik , Damle Kedar
Published: January 2025

We demonstrate that the low-temperature (T) properties of a class of anisotropic spin S=1 kagome (planar pyrochlore) antiferromagnets on a field-induced 13-magnetization (12-magnetization) plateau are described by a model of fully packed dimers and loops on the honeycomb (square) lattice, with a temperature-dependent relative fugacity w(T) for the dimers. The fully packed O(1) loop model (w=0) and the fully packed dimer model (w=∞) limits of this dimer-loop model are found to be separated by a phase transition at a finite and nonzero critical fugacity wc, with interesting consequences for the spin correlations of the frustrated magnet. The w>wc phase has short loops and spin correlations dominated by power-law columnar order (with subdominant dipolar correlations), while the w<wc phase has dominant dipolar spin correlations and long loops governed by a power-law distribution of loop sizes. Away from wc, both phases are described by a long-wavelength Gaussian effective action for a scalar height field that represents the coarse-grained electrostatic potential of fluctuating dipoles. The destruction of power-law columnar spin order below wc is driven by an unusual flux fractionalization mechanism, topological in character but quite distinct from the usual Kosterlitz-Thouless mechanism for such transitions: Fractional electric fluxes which are bound into integer values for w>wc, proliferate in the w<wc phase and destroy power-law columnar order.

Published by the American Physical Society
2025
Electron-density analysis of halide...halide through-space magnetic exchange
Authors: Scatena Rebecca , Manson Zachary E. , Manson Jamie L. , Allan David R. , Goddard Paul A. , Johnson Roger D.
Published: January 2025

We present a combined experimental and density functional theory study that characterizes the charge and spin density in NiX
2(3,5-lutidine)4 (X = Cl, Br and I). In this material, magnetic exchange interactions occur via Ni2+–halide...halide–Ni2+ pathways, forming one-dimensional chains. We find evidence for weak halide...halide covalency in the iodine system, which is greatly reduced when X = Br and is absent for X = Cl; this is consistent with the reported `switching-on' of magnetic exchange in the larger-halide cases. Our results are benchmarked against density functional theory calculations on [NiHF2(pyrazine)2]SbF6, in which the primary magnetic exchange is mediated by F–H–F bridging ligands. This comparison indicates that, despite the largely depleted charge density found at the centre of halide...halide bonds, these through-space interactions can support strong magnetic exchange gated by weak covalency and enhanced by significant electron density overlapping that of the transition metal centres.
Structure of Clostridium leptum carboxyspermidine decarboxylase and comparison to homologs prevalent within the human gut microbiome
Authors: Jones Savannah J. , Bell Dawson J. , McFarlane Jeffrey S.
Published: January 2025

Polyamines are key signalling and substrate molecules that are made by all organisms. The polyamine known as spermidine is typically made by spermidine synthase, but in many bacterial species, including 70% of human gut microbes, carboxyspermidine decarboxylase (CASDC) performs the terminal step in the production of spermidine. An X-ray crystal structure of CASDC from the human gut microbe Clostridium leptum has been solved by molecular replacement at a resolution of 1.41 Å. CASDC is a homodimer, with each monomer composed of two domains: a β/α-barrel pyridoxal 5′-phosphate-binding domain that forms most of the active site and a β-barrel domain that extends the dimeric interface and contributes to the active site of the opposing monomer. We performed a structural comparison of CASDC enzymes for 15 common genera within the human gut flora. This analysis reveals structural differences occurring in the β6/β7 loop that acts as a `flap' covering the active site and in the α9/β12 loop that is connected to the α9 helix which is thought to select substrates by their chain length. This structural analysis extends our understanding of a key enzyme in spermidine biosynthesis in many bacterial species.
Deconvoluting thermomechanical effects in X-ray diffraction data using machine learning
Authors: Lim Rachel E. , Shang Shun-Li , Chuang Chihpin , Phan Thien Q. , Liu Zi-Kui , Pagan Darren C.
Published: January 2025

X-ray diffraction is ideal for probing the sub-surface state during complex or rapid thermomechanical loading of crystalline materials. However, challenges arise as the size of diffraction volumes increases due to spatial broadening and because of the inability to deconvolute the effects of different lattice deformation mechanisms. Here, we present a novel approach that uses combinations of physics-based modeling and machine learning to deconvolve thermal and mechanical elastic strains for diffraction data analysis. The method builds on a previous effort to extract thermal strain distribution information from diffraction data. The new approach is applied to extract the evolution of the thermomechanical state during laser melting of an Inconel 625 wall specimen which produces significant residual stress upon cooling. A combination of heat transfer and fluid flow, elasto-plasticity and X-ray diffraction simulations is used to generate training data for machine-learning (Gaussian process regression, GPR) models that map diffracted intensity distributions to underlying thermomechanical strain fields. First-principles density functional theory is used to determine accurate temperature-dependent thermal expansion and elastic stiffness used for elasto-plasticity modeling. The trained GPR models are found to be capable of deconvoluting the effects of thermal and mechanical strains, in addition to providing information about underlying strain distributions, even from complex diffraction patterns with irregularly shaped peaks.
Cascading Effects of Anthropogenic Excess Food for Predators on a Peri‐Urban Population of an Endangered Ungulate
Authors: Arnon Amir , Wronski Torsten , Malkinson Dan , Izhaki Ido , Davis Miranda
Published: January 2025

A major side effect of urbanization is the increased availability of food for wildlife in peri‐urban areas. Most research has focused on highly adaptive exploiter species that thrive under such conditions, overlooking avoider species, which are often predated upon by exploiters. Moreover, peri‐urban areas are often grazed by livestock, mainly to reduce the frequency and intensity of fires, a practice that can also adversely affect vulnerable wildlife species. We examined the long‐term effects of excess food provided to discourage exploiter species, namely golden jackal (Canis aureus) and wild boar (Sus scrofa), from foraging on farmland and in human residencies. Both species prey on endangered mountain gazelles (Gazella gazella) in our peri‐urban study area, which is nested within a mosaic of settlements and agricultural lands in Mediterranean Israel. Because the park is routinely subjected to seasonal cattle ranching, we included cattle stocking rate (mean ± SD: 51.77 ± 18.21 cow grazing days/ha) as an alternative factor, into our analysis. We used Generalized Linear Mixed Models to analyze an extensive dataset, comprising 724 surveys conducted over 17 years, and modeled gazelle encounter rates in response to excess food and cattle ranching, while controlling for environmental factors. Our results suggest that anthropogenic excess food through diversionary feeding led to decreasing gazelle densities, probably through increased predation by exploiter species. When diversionary feeding ceased after 12 years, gazelle encounter rates increased. We argue that this increase corresponds to population recovery, although it could be consistent with alternative mechanisms such as altered space‐use and movement patterns. To conserve vulnerable and endangered wildlife species in urban and peri‐urban areas, managers should reduce the availability of anthropogenic food for predators and scavengers. Furthermore, moderate cattle ranching (i.e., seasonal with low stocking rates) could mitigate potential adverse impacts of cattle ranching on mountain gazelle populations.