bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cracking Controls ATP Hydrolysis in the catalytic domain of a P-ATPase
Authors: Placenti M. Agueda , Martinez-Gache Santiago A. , González-Lebrero Rodolfo M. , Wolynes Peter G. , González Flecha F. Luis , Roman Ernesto A. 
Published: January 2025

AbstractMembrane transporters are essential for cell homeostasis. Among them P-type ATPases, which couple ATP hydrolysis to solute transport, play a key role. Despite extensive research, the fine mechanisms by which this coupling occurs are not completely understood. In this work, we analyzed the effect of substrate, temperature, and urea on the steady state ATPase activity, tryptophan fluorescence and far-UV ellipticity of the catalytic domain of a thermophilic Cu(I) transport ATPase. Through local frustration analysis in combination with AlphaFold2 prediction, we identified a novel conformation, enabling molecular dynamics simulations of an open/close transition. Our results revealed a “cracking” mechanism as a key step in the catalytic cycle. Furthermore, we developed a model that fully describes all the experimental observations. These findings reinforce the idea that local unfolding is involved in enzyme catalysis and suggest a key role in the regulation of enzyme activity.
A Cooperative Model for Symmetric Ligand Binding to Protein Fibrils
Authors: Smith Matthew S. , DeGrado William F. , Grabe Michael , Shoichet Brian K. 
Published: January 2025

AbstractA hallmark of neurodegenerative diseases like Alzheimer’s Disease (AD) and chronic traumatic encephalopathy (CTE) is the presence of toxic protein aggregates in neurons. In AD and CTE specifically, the protein tau forms insoluble fibrils that are hundreds of nanometers in length. Intriguingly, recent experimental structures suggest that tau ligands like the disaggregator EGCG and positron emission tomography (PET) tracers like GTP-1 and MK-6240 bind to tau fibrils in long stacks reflecting the symmetry of the protein across many binding sites. In these stacks, each ligand makes more contact with its symmetry mates than it does with the protein. To interpret the binding of these molecules and new ligands, we must understand the effects of the cooperativity between sites and the entropy coming from the number of sites. Here, we investigate a nearest-neighbors model of cooperativity and use statistical mechanics to derive binding isotherms for saturation and competition experiments. This model allows us to relate measuredEC50soIC50and so values to the intrinsic binding affinity to a single site and to cooperativity across sites in ways resembling the Cheng-Prusoff Equation. Depending on the degree of cooperativity between molecular species, this model permits solutions that lack the steep binding curves expected from cooperative systems and even solutions resembling 2-site systems. We finally consider conditions for a fibril’s detection in a PET scan and practical matters of fitting this model’s parameters to data.
Microglial plasticity governed by state-specific enhancer landscapes
Authors: Hamagami Nicole , Kapadia Dvita , Abduljawad Nora , Cheng Zuolin , McLaughlin Liam , Singhania Darsh , Barclay Kia M. , Yang Jin , Sun Zhixin , Bayguinov Peter , Yu Guoqiang , Gabel Harrison W. , Li Qingyun 
Published: January 2025

SUMMARYSingle-cell transcriptomic studies have identified distinct microglial subpopulations with shared and divergent gene signatures across development, aging and disease. Whether these microglial subsets represent ontogenically separate lineages of cells, or they are manifestations of plastic changes of microglial states downstream of some converging signals is unknown. Furthermore, despite the well-established role of enhancer landscapes underlying the identity of microglia, to what extent histone modifications and DNA methylation regulate microglial state switches at enhancers have not been defined. Here, using genetic fate mapping, we demonstrate the common embryonic origin of proliferative-region-associated microglia (PAM) enriched in developing white matter, and track their dynamic transitions into disease-associated microglia (DAM) and white matter-associated microglia (WAM) states in disease and aging contexts, respectively. This study links spatiotemporally discrete microglial states through their transcriptomic and epigenomic plasticity, while revealing state-specific histone modification profiles that govern state switches in health and disease.
Do monkeys see the way we do? Qualitative similarities and differences between monkey and human perception
Authors: Cherian Thomas , Jacob Georgin , Arun S.P. 
Published: January 2025

ABSTRACTMonkeys are widely used as model organisms for human vision and cognition. While their anatomy and physiology strongly correspond to humans, it is unclear to what extent their perception matches with ours. Previous studies have evaluated specific aspects of perception, after extensive training on customized tasks that could have altered their perception. To resolve these issues, we trained monkeys to perform an oddball visual search task on natural images, tested them on carefully controlled images to detect a variety of perceptual phenomena, and compared them with humans. This revealed a number of qualitative similarities and differences. Like humans, monkeys showed similar object relations, Weber’s law and amodal completion. However, unlike humans, monkeys did not show mirror confusion or a global advantage. These findings represent a first comprehensive evaluation of visual perception in monkeys and humans, revealing the limitations of monkeys as a model organism for human vision.SIGNIFICANCE STATEMENTMonkeys are widely used to study for vision and cognition, but is their perception like ours? Most previous studies have tested only single aspects of perception in monkeys, often after extensive training which could have altered their perception. Here, we overcame these limitations by training monkeys on a highly general oddball visual search task, testing them on many perceptual phenomena and comparing them with humans on the same tasks. Our results show that monkeys do indeed see the way we do, but with important differences that highlight their limitations as a model for human vision.
An improved catalogue for whole-genome sequencing prediction of bedaquiline resistance inM. tuberculosisusing a reproducible algorithmic approach
Authors: Adlard Dylan , Joseph Lavania , Webster Hermione , O’Reilly Ailva , Knaggs Jeffrey , Peto Tim EA , Crook Derrick W , Omar Shaheed V , Fowler Philip W 
Published: January 2025

AbstractBedaquiline (BDQ) has only been approved for use for a little over a decade yet is a key drug for treating multi-drug resistant tuberculosis, however rising levels of resistance threaten to reduce its effectiveness. Catalogues of mutations associated with resistance to bedaquiline are key to detecting resistance genetically for either diagnosis or surveillance. At present building catalogues requires considerable expert knowledge, often requires the use of complex grading rules, and is an irreproducible process. We developed an automated method, catomatic, that associates genetic variants with resistance (or susceptibility) using a two-tailed binomial test with a stated background rate and applied it to a dataset of 11,867Mycobacterium tuberculosissamples with whole genome and bedaquline susceptibility testing data. Using this framework we investigated how to best classify variants and the phenotypic significance of minor alleles. The genesmmpS5andmmpL5are not directly associated with bedaquline resistance, and our catalogue ofRv0678,atpE, andpepQvariants attains a cross-validated sensitivity and specificity of 79.4 ± 1.8 % and 98.5 ± 0.3%, respectively, for 94 ± 0.4% of samples. Identifying samples with subpopulations containingRv0678variants improves sensitivity, and detection thresholds in bioinformatic pipelines should therefore be lowered. By using a more permissive and deterministic algorithm trained on a sufficient number of resistant samples we have reproducibly constructed an AMR catalogue for BDQ resistance-associated variants that is comprehensive and accurate.Impact StatementBedaquiline has recently received global endorsement for tuberculosis treatment, yet the genetic determinants of antimicrobial resistance remain incompletely understood. Existing gold-standard methods for building mutation catalogs lack public accessibility and reproducibility. We introduce catomatic, a reproducible and publicly available method that employs simpler statistics to increase sensitivity to resistance-associated variants. This approach has enabled investigations into mechanisms of resistance, the significance of genetic subpopulations, and key data attributes that influence the ease of classifying effects and the accuracy of BDQ resistance phenotype prediction in clinical samples. We strongly emphasise the utility in using reproducible statistics and sustainably developed software in genetics-focussed microbiology.
Characterization of conformational dynamics and allostery of the catalytic domain of human mitochondrial YME1L protease
Authors: Black Megan K. , Kim Angelina S. , Chen Ching Y. , Goncalves Monica M. , Waseem Simrah , Vahidi Siavash , Huang Rui 
Published: January 2025

AbstractMitochondrial proteostasis is essential to maintain cellular function and survival. YME1L protease is an important contributor to proteostasis which belongs to the AAA+ (ATPasesAssociated with diverse cellularActivities) protease family and is anchored to the inner mitochondrial membrane. YME1L plays a pivotal role in mitochondrial protein quality control by selectively degrading misfolded and native proteins. The precise mechanisms by which nucleotide binding and hydrolysis influence YME1L’s conformational dynamics, proteolytic activity, and stability remain unclear. Here we characterize the conformational dynamics and allosteric regulation of the YME1L catalytic domain. Using a hexameric soluble YME1L construct, we employ hydrogen/deuterium exchange mass spectrometry (HDX-MS) and nuclear magnetic resonance (NMR) spectroscopy to demonstrate that nucleotide binding reduces the backbone flexibility and modulates the side-chain dynamics of the AAA+ domain, while Zn²⁺ binding stabilizes the protease domain. We also reveal novel long-range allostery between the AAA+ and protease domains of YME1L, mediated by a critical salt bridge on the inter-domain interface. We show the importance of the salt bridge in facilitating ATP-dependent substrate degradation by YME1L. Additionally, we show that ATP binding stabilizes the structure of the catalytic domain of YME1L and protects it from chemical modification- and heat-induced aggregation. These findings explain the nucleotide-driven regulation of YME1L and provide novel insights into understanding its proteolytic activity and structural stability under physiological and stress conditions.
Microbial functional guilds respond cohesively to rapidly fluctuating environments
Authors: Crocker Kyle , Skwara Abigail , Kannan Rathi , Murugan Arvind , Kuehn Seppe 
Published: January 2025

AbstractMicrobial communities experience environmental fluctuations across timescales from rapid changes in moisture, temperature, or light levels to long-term seasonal or climactic variations. Understanding how microbial populations respond to these changes is critical for predicting the impact of perturbations, interventions, and climate change on communities. Since communities typically harbor tens to hundreds of distinct taxa, the response of microbial abundances to perturbations is potentially complex. However, while taxonomic diversity is high, in many communities taxa can be grouped into functional guilds of strains with similar metabolic traits. These guilds effectively reduce the complexity of the system by providing a physiologically motivated coarse-graining. Here, using a combination of simulations, theory, and experiments, we show that the response of guilds to nutrient fluctuations depends on the timescale of those fluctuations. Rapid changes in nutrient levels drive cohesive, positively correlated abundance dynamics within guilds. For slower timescales of environmental variation, members within a guild begin to compete due to similar resource preferences, driving negative correlations in abundances between members of the same guild. Our results provide a route to understanding the relationship between functional guilds and community response to changing environments, as well as an experimental approach to discovering functional guilds via designed nutrient perturbations to communities.
IonBench: a benchmark of optimisation strategies for mathematical models of ion channel currents
Authors: Owen Matt J. , Mirams Gary R. 
Published: January 2025

AbstractIon channel models present many challenging optimisation problems. These include unidentifiable parame- ters, noisy data, unobserved states, and a combination of both fast and slow timescales. This can make it difficult to choose a suitable optimisation routinea priori. Nevertheless, many attempts have been made to design optimisation routines specifically for ion channel models, however, little work has been done to compare these optimisation approaches. We have developed ionBench, an open-source optimisation bench- marking framework, to evaluate and compare these approaches against a standard set of ion channel optimisation problems. We included implementations of thirty-four unique optimisation approaches that have been previously applied to ion channel models and evaluated them against the ionBench test suite, consisting of five parameter optimisation problems derived from the cardiac ion channel literature. Each optimisation approach was initiated from multiple starting parameters and tasked with reproducing a problem-specific simulated dataset. Through ionBench, we tracked and evaluated the performance of these optimisations, identifying the expected run time until a successful optimisation for each approach, which was used for comparisons. Finally, we used these results, in addition to other literature results, to identify a new efficient approach. Its use could reduce computation time by multiple orders of magnitude, while also improving the reliability of ion channel parameter optimisation.
Chaetognaths exhibit the most extensive repertoire of Hox genes among protostomes
Authors: Ordoñez June F. , Wollesen Tim 
Published: January 2025

1.AbstractThe evolutionary origins and body plan diversification within bilaterians hinge on our understanding of conserved developmental gene networks across diverse taxa. While significant advances have been made in elucidating the anterior-posterior (AP) axis patterning across well-studied bilaterian lineages, our understanding of the conservation of AP-patterning gene expression in underexplored protostomes with a phylogenetically informative position remains limited. Chaetognaths, a group of marine invertebrates, form a clade with Gnathifera as a sister to the remaining Lophotrochozoa, occupying an early-diverging branch of the spiralian lineage. Their phylogenetic position provides potentially valuable evolutionary insights into whether the AP patterning reflects conserved bilaterian mechanisms or reveals distinct lineage-specific adaptations. Here, we investigate the expression patterns of anterior nervous system markers (otx,nk2.1,six3/6) and Hox genes in post-embryonic stages of the chaetognathSpadella cephalopterausing fluorescence whole-mountin situhybridization. We identify expression domains of anterior-patterning genes in the cerebral ganglion and head structures, consistent with their conserved role in anterior central nervous system (CNS) specification in bilaterians. Additionally, we describe a staggered expression pattern of Hox genes, including previously undescribed central (Sce-med6) and posterior class (Sce-postCandSce-postD), along the ventral nerve cord (VNC) and post-anal tail. Our results demonstrate that chaetognaths exhibit the most extensive repertoire of Hox genes among protostomes, within metazoans only surpassed by chordates. All AP patterning genes are expressed in a staggered manner, with Hox gene expression absent in the head region. This pattern resembles the conserved expression profile inferred for the last common bilaterian ancestor and is only rudimentarily visible in other spiralians, including annelids and mollusks. Posterior Hox genes including the newly discoveredpostCandpostDgenes are absent in the hitherto investigated gnathiferan sister groups such as rotifers. The absence of a postanal tail in rotifers and other gnathiferans, combined with the expression of posterior Hox genes in the elongated postanal tail region, suggests their involvement in the formation of this unique chaetognath structure. Posterior flexibility of Hox genes, as previously hypothesized for chordates, likely contributed to the formation of the chaetognath tail during the early Cambrian period.
Green giants: how high–tech manufacturers in China foster supplier green innovativeness for sustainable development
Authors: Xin Chong , Wang Qi , Chen Ting ting 
Published: January 2025

Purpose
Based on the social exchange theory, this study aims to investigate the influence of green supplier development (GSD) on supplier green innovativeness (SGI), the mediating role of buyer–supplier cooperation and the moderating role of preferred customer status (PCS).

Design/methodology/approach
This study uses stratified regression analysis to test the hypothesized relationships with data collected from 385 Chinese high-tech manufacturing enterprises.

Findings
The results of regression analysis show that GSD has a significant positive effect on buyer–supplier cooperation and SGI; buyer–supplier cooperation plays a partially mediating role between GSD and SGI; PCS strengthens the positive relationship between buyer–supplier cooperation and SGI and enhances the mediating role of buyer–supplier cooperation between GSD and SGI.

Practical implications
Supplier participation in green innovation is of great significance to the green development transformation of China’s manufacturing industry. This study reveals the positive impact of GSD on enhancing SGI and provides specific suggestions for manufacturing enterprises to realize efficient supplier management and build mutually beneficial and win-win cooperative relationships.

Originality/value
This study enriches and expands the related research on SGI antecedents and reveals the mediating mechanism and boundary conditions therein, which better makes up for the lack of attention to GSD in the existing research on supplier management and can provide lessons and references for the subsequent related researches targeting the enhancement and utilization of SGI.
Pleasurable emotional states in health-care organizations: the mediation role of employee wellbeing on transformational leadership and job satisfaction
Authors: Kyambade Mahadih , Namatovu Afulah 
Published: January 2025

Purpose
This study aims to examine the association between transformational leadership, employee well-being and job satisfaction, focusing on the mediating role of employee well-being in the association between transformational leadership and job satisfaction.

Design/methodology/approach
Data for this purpose were gathered by the authors through a questionnaire survey, with 180 employees at health center IV hospitals in Uganda serving as the sample. To test the theoretical model, a PROCESS Model Type 4 mediation analysis was performed.

Findings
The findings demonstrate a slightly favorable association between transformational leadership and job satisfaction, transformational leadership is positively related to employee well-being as well as a positive association between employee well-being and job satisfaction. Moreover, the outcomes of the mediation analysis verify that employee well-being acts as a mediator in the association between transformational leadership and job satisfaction.

Practical implications
Health-care organizations should invest in leadership training programs that develop transformational leadership skills. Leaders, who can inspire, intellectually stimulate and provide individualized consideration can significantly enhance employee well-being, which in turn boosts job satisfaction. Establish ongoing development initiatives to ensure that leadership skills remain sharp and evolve with changing health-care demands.

Originality/value
This study adds to the body of knowledge in organizational behavior by examining the relationship in detail between transformational leadership, employee well-being and job satisfaction. In addition, this study was carried out in a developing nation, which might usually produce results that differ from those of studies carried out in developed nations.
Decline in plant species richness with a chronic decrease of precipitation: The mediating role of the dominant species
Authors: Ónodi Gábor , Kertész Miklós , Bede‐Fazekas Ákos , Batáry Péter , Kröel‐Dulay György , Botta‐Dukát Zoltán 
Published: January 2025

Abstract

Despite the increased frequency and severity of droughts in many regions and declining biodiversity, existing experimental evidence for changes in plant species richness associated with altered water availability is limited. The growing extent of drylands highlights the need to predict precipitation‐related changes in species richness, which requires a better understanding of the mechanisms.

We carried out a field experiment applying a single extreme drought event and combined it with subsequent chronic alteration of summer precipitation for 7 years in a water‐limited temperate grassland. We assessed how altered precipitation regimes and a previous extreme drought affect species richness. We compared a simple analysis assuming only the net effect of precipitation on species richness to a complex approach by structural equation modelling that included both the direct effects of precipitation and indirect effects through the biomass of dominant grass species.

Using simple analysis, we found significant positive and nonsignificant precipitation–species richness relationships in the presence and absence of extreme drought, respectively. The complex analysis disentangled direct and indirect pathways between precipitation and species richness. The indirect pathway acted only in the absence of drought. In this case, increasing precipitation increased the biomass of dominant species, which, in turn, decreased species richness, acting as a mediator variable. The direct relationship was positive, independent of the presence of drought.

Synthesis. Consistent with the global relationship between water availability and species richness, we experimentally showed that decreasing precipitation decreases species richness. Furthermore, we found that increasing precipitation may also decrease plant species richness via an indirect pathway acting through the biomass of the dominant species. Our results highlight that species richness can become more sensitive to changes in precipitation after extreme drought events that eliminate or set back dominant species.