bluuebunny/crossref_metadata_2025_split huggingface dataset:
Doublet decoding of tRNASer3demonstrates plasticity of ribosomal decoding center
Authors: Krishnaswamy Shruthi , Akbar Shirin , Larsson Daniel S. D. , Chen Yang , Selmer Maria 
Published: December 2024

AbstractFrameshifts can be caused by specific combinations of tRNA and mRNA. The wildtype AGC-decodingE. colitRNASer3GCUwas in the 1980s shown to induce -1 ribosomal frameshifting on GCA alanine codons, and proposed to read a two-base codon instead of a canonical triplet. It has remained unclear whether this type of non-cognate decoding can be accommodated by the ribosome. We here performed single-particle cryo-EM reconstructions onE. coli70S ribosomes with the frameshift-inducing tRNASer3bound to the non-cognate GCA codon or the cognate AGC codon in the ribosomal A site. The structures demonstrate that doublet-decoding is made possible when A1493, the conserved monitoring base in 16S rRNA, mimics a first codon base, forming a Hoogsteen base pair with U36 from the anticodon and stacking with the mRNA. This interaction pushes the first two bases of the A-site codon in position for base pairing with C35 and G34 of the anticodon.
EnzymeCAGE: A Geometric Foundation Model for Enzyme Retrieval with Evolutionary Insights
Authors: Liu Yong , Hua Chenqing , Zeng Tao , Rao Jiahua , Zhang Zhongyue , Wu Ruibo , Coley Connor W , Zheng Shuangjia 
Published: December 2024

AbstractEnzyme catalysis is fundamental to life, driving the chemical transformations that sustain biological processes and support industrial applications. However, unraveling the intertwined relationships between enzymes and their catalytic reactions remains a significant challenge. Here, we present EnzymeCAGE, a catalytic-specific geometric foundation model trained on approximately 1 million structure-informed enzyme-reaction pairs, spanning over 2,000 species and encompassing an extensive diversity of genomic and metabolic information. EnzymeCAGE features a geometry-aware multi-modal architecture coupled with an evolutionary information integration module, enabling it to effectively model the nuanced relationships between enzyme structure, catalytic function, and reaction specificity. EnzymeCAGE supports both experimental and predicted enzyme structures and is applicable across diverse enzyme families, accommodating a broad range of metabolites and reaction types. Extensive evaluations demonstrate EnzymeCAGE’s state-of-the-art performance in enzyme function prediction, reaction de-orphaning, catalytic site identification, and biosynthetic pathway reconstruction. These results highlight its potential as a transformative foundation model for understanding enzyme catalysis and accelerating the discovery of novel biocatalysts.
Higher-Order Interactions in Neuronal Function: From Genes to Ionic Currents in Biophysical Models
Authors: Reva Maria , Arnaudon Alexis , Zbili Michael , Markram Henry , Goaillard Jean-Marc , Van Geit Werner 
Published: December 2024

AbstractNeuronal firing patterns are the consequence of precise variations in neuronal membrane potential, which are themselves shaped by multiple ionic currents. In this study, we use biophysical models, statistical methods, and information theory to explore the interaction between these ionic currents and neuron electrophysiological phenotype. We created numerous electrical models with diverse firing patterns using Monte Carlo Markov Chain methods. By analyzing these models, we identified intricate relationships between model parameters and electrical features. Our findings show that neuronal features are often influenced by multiple ionic currents sharing synergistic relationships. We also applied our methods to single-cell RNAseq data, discovering gene expression modules specific to certain interneuron types. This research sheds light on the complex links between biophysical parameters and neuronal phenotypes.
No time to waste: A synthesis of evidence on time reallocation following water, sanitation and hygiene interventions
Authors: Sharma Waddington Hugh , Dickin Sarah K , Basak Kishore , Mohandas Saranya , Macura Biljana 
Published: December 2024

AbstractLarge amounts of time are wasted globally by households who need access to improved water for domestic uses and sanitation. The burden of inadequate access mainly affects women and girls in low- and middle-income countries. We conducted a systematic review and meta-analysis based on evidence mapping initiatives. The evidence synthesis found mean reductions of 15 minutes per trip for water supply, and 3 minutes per trip for sanitation interventions, adding up to around 8 hours per week and 3.5 hours per week respectively at the household level. Time savings from improvements in water supplies were very large, whether improved water supplies were provided at the household or community level. In contrast, studies on water treatment reported small time increases, and there were no studies that reported time following hygiene interventions. We found limited evidence on time reallocation to other activities, but disaggregated data showed girls were significantly more likely to attend school following WASH interventions. This policy-relevant evidence synthesis contributes to the case for increasing investments in appropriate water supply and sanitation interventions.
Large language models for conducting systematic reviews: on the rise, but not yet ready for use – a scoping review
Authors: Lieberum Judith-Lisa , Töws Markus , Metzendorf Maria-Inti , Heilmeyer Felix , Siemens Waldemar , Haverkamp Christian , Böhringer Daniel , Meerpohl Joerg J. , Eisele-Metzger Angelika 
Published: December 2024

ABSTRACTBackgroundMachine learning (ML) promises versatile help in the creation of systematic reviews (SRs). Recently, further developments in the form of large language models (LLMs) and their application in SR conduct attracted attention.ObjectiveTo provide an overview of ML and specifically LLM applications in SR conduct in health research.Study designWe systematically searched MEDLINE, Web of Science, IEEEXplore, ACM Digital Library, Europe PMC (preprints), Google Scholar, and conducted an additional hand search (last search: 26 February 2024). We included scientific articles in English or German, published from April 2021 onwards, building upon the results of a mapping review with a related research question. Two reviewers independently screened studies for eligibility; after piloting, one reviewer extracted data, checked by another.ResultsOur database search yielded 8054 hits, and we identified 33 articles from our hand search. Of the 196 included reports, 159 described more traditional ML techniques, 37 focused on LLMs. LLM approaches covered 10 of 13 defined SR steps, most frequently literature search (n=15, 41%), study selection (n=14, 38%), and data extraction (n=11, 30%). The mostly recurring LLM was GPT (n=33, 89%). Validation studies were predominant (n=21, 57%). In half of the studies, authors evaluated LLM use as promising (n=20, 54%), one quarter as neutral (n=9, 24%) and one fifth as non-promising (n=8, 22%).ConclusionsAlthough LLMs show promise in supporting SR creation, fully established or validated applications are often lacking. The rapid increase in research on LLMs for evidence synthesis production highlights their growing relevance.HIGHLIGHTSMachine learning (ML) offers promising support for systematic review (SR) creation.GPT was the most commonly used large language model (LLM) to support SR production.LLM application included 10 of 13 defined SR steps, most often literature search.Validation studies predominated, but fully established LLM applications are rare.LLM research for SR conduct is surging, highlighting the increasing relevance.
Release strategies affect the freshwater residence and survival of hatchery-reared juvenile Chinook Salmon
Authors: Balfour Thomas J. B. , Hurwitz David J. A. , Atkinson Jamieson B. , Martins Eduardo G. 
Published: December 2024

AbstractObjectiveThis study investigated the effects of size, location and timing of release on the freshwater residence and survival hatchery-reared Chinook Salmon (Oncorhynchus tshawytscha) in the Toquaht River, BC.MethodsJuvenile salmon were PIT tagged and released on three separate dates (May 23, June 9 and 19, 2021) and three distinct locations within the river (lower river [below lake], lake, and upper river [above lake]). Fish were detected near the river mouth using a PIT array, and detection data were analyzed with an integrated model of freshwater residence and capture-recapture using Bayesian inference.ResultThe median duration of freshwater residence was 13.8 days and was longer for fish released in the lake and upper river earlier in the study. The median survival probability was 0.35 and it was higher for fish released in the lake and upper river later in the study. Both freshwater residence time and survival declined with fish size at release.ConclusionThese findings highlight that hatchery release strategies can significantly influence survival and freshwater residence times, underscoring the need for adaptable management practices.Impact statementJuvenile Chinook Salmon survival during freshwater residence and outmigration is strongly influenced by hatchery release strategies, thus optimizing these strategies is key for hatcheries to support the recovery of salmon populations.
Phage-displayed synthetic library and screening platform for nanobody discovery
Authors: Xia Baolong , Kim Ah-Ram , Liu Feimei , Han Myeonghoon , Stoneburner Emily , Makdissi Stephanie , Cara Francesca Di , Mohr Stephanie E. , Ring Aaron M. , Perrimon Norbert 
Published: December 2024

AbstractNanobodies, single-domain antibodies derived from camelid heavy-chain antibodies, are known for their high affinity, stability, and small size, which make them useful in biological research and therapeutic applications. However, traditional nanobody generation methods rely on camelid immunization, which can be costly and time- consuming, restricting their practical feasibility. In this study, we present a phage- displayed synthetic library for nanobody discovery. To validate this approach, we screened nanobodies targeting variousDrosophilasecreted proteins. The nanobodies identified were suitable for applications such as immunostaining and immunoblotting, supporting the phage-displayed synthetic library as a versatile platform for nanobody development. To address the challenge of limited accessibility to high-quality synthetic libraries, this library will be openly available for non-profit use.
Understanding genetic architecture overcomes tradeoffs between seed quality and insect resistance
Authors: White Joseph R. , McNellie James P. , Keepers Kyle G. , Smart Brian C. , Portlas Zoe M. , Marcus Zach E. , Kane Nolan C. , Prasifka Jarrad R. , Hulke Brent S. 
Published: December 2024

AbstractThe sunflower (Helianthus annuus) pericarp protects the seed within from both abiotic and biotic stresses. Achenes with stronger pericarps are less susceptible to damage from insect feeding. Complicating the genetic improvement of pericarp strength is the negative correlation between pericarp thickness (a component of strength) and oil content. As breeding efforts have increased oil content, there has been a concomitant decrease in pericarp thickness. A logical sunflower improvement goal is to improve oil content while preserving pericarp strength through genetic mechanisms independent of the tradeoffs with pericarp thickness. To determine the genetic basis of oil content, pericarp strength, and thickness, we identified QTL in two populations; the Sunflower Association Mapping panel (Mandel et al., 2011) and a recombinant inbred line (RIL) population derived from a thin pericarp oilseed inbred (HA 467) crossed to a thick pericarp open pollinated variety from Türkiye (PI 170415). A region on chromosome 15 was associated with neighboring QTL for banded moth resistance, oil content, and pericarp thickness, partially underlying the trade-offs among these traits. Additional QTL on chromosome 5 and 14 for pericarp strength provide fewer trade-offs with oil content. QTL for pericarp strength on chromosome 5 and pericarp thickness on chromosome 16 were associated with large structural variants, with candidate gene presence/absence variation between the haplotypes on chromosome 5. Understanding the origin and nature of phenotypic tradeoffs is beneficial to plant biologists and sunflower breeders as they seek to understand the origin and genetic architecture of adaptive and maladaptive traits.
A single main-chain hydrogen bond required to keep GABAAreceptors closed
Authors: Borghese Cecilia M. , Galpin Jason D. , Lidbrink Samuel Eriksson , Zhuang Yuxuan , Desai Netrang G. , Howard Rebecca J. , Lindahl Erik , Ahern Christopher A. , Goldschen-Ohm Marcel P. 
Published: December 2024

AbstractGABAAreceptors are the primary inhibitory neurotransmitter receptors throughout the central nervous system. Despite significant progress understanding their three-dimensional structure, a critical gap remains in determining the molecular basis for channel gating. We recently identified M2-M3 linker mutations that suggest linker flexibility has asymmetric subunit-specific correlations with channel opening. Here we use non-canonical amino acids (ncAAs) to investigate the role of main-chain H-hydrogen bonds (H-bonds) that may stabilize the M2-M3 linkers. We show that a single main-chain H-bond within the β2 subunit M2-M3 linker inhibits pore opening and is required to keep the unliganded channel closed. Furthermore, breaking this H-bond during channel opening accounts for approximately one third of the activation energy derived from GABA binding. In contrast, the analogous H-bond in the α1 subunit has no effect on gating. Our observations suggest that channel opening involves state-dependent breakage/disruption of a specific main-chain H-bond within the β2 subunit M2-M3 linker.
Distinct cortical populations drive multisensory modulation of segregated auditory sources
Authors: Cai Huaizhen , Shirley Harry , Escabí Monty A. , Cohen Yale E. 
Published: December 2024

AbstractAuditory perception can be modulated by other sensory stimuli. However, we do not fully understand the neural mechanisms that support multisensory behavior. Here, we recorded spiking activity from the primary auditory cortex (A1) in non-human primates, while they detected a target vocalization that was embedded in a background chorus of vocalizations. We found that a congruent video of a monkey eliciting a vocalization improved the monkeys’ behavior, relative to their performance when we only presented a static image of the monkey. As a proxy for the functional organization of A1, we compared the contribution of neurons with significant spectrotemporal response fields (STRFs) with those that had non-significant STRFs (nSTRFs). Based on spike-waveform shape and functional connectivity, STRF and nSTRF neurons appeared to belong to distinct neural populations. Consistent with this, we found that although STRF neurons encoded stimulus information through synchronized activity, the population of nSTRF neurons encoded task-related information in the primate A1 more as a structured dynamic process. Together, these findings demonstrate a functional distinction between the behavioral contributions of nSTRF and STRF neurons.
Estimation of fluid flow velocities in cortical brain tissue driven by the microvasculature
Authors: Koch Timo , Mardal Kent-André 
Published: December 2024

AbstractWe present a modelling framework for describing bulk fluid flow in brain tissue. Within this framework, using computational simulation, we estimate bulk flow velocities in the gray matter parenchyma due to static or slowly varying water potential gradients—hydrostatic pressure gradients and osmotic pressure gradients. Working with the situation that experimental evidence and some model parameter estimates, as we point out, are presently insufficient to estimate velocities precisely, we explore feasible parameter ranges resulting in a range of estimates. We consider the effect of realistic microvascular architecture (extracted from mouse cortical gray matter). Although the estimated velocities are small in magnitude (e.g. in comparison to blood flow velocities), the passive transport of solutes with the bulk fluid can be a relevant process when considering larger molecules transported over larger distances. We compare velocity magnitudes resulting from filtration and pulsations. Filtration can lead to continuous directed fluid flow in the parenchyma, while pulsation-driven flow is (at least partly) reversible. For the first time, we consider the effect of the vascular architecture on the velocity distribution in a tissue sample of ca. 1 mm3cortical gray matter tissue. We conclude that both filtration and pulsations are potentially potent drivers for fluid flow.Summary (lay abstract)Fluid transport through brain tissue is dynamic, but the basic properties of this flow and its variability are poorly characterised. Disturbed fluid transport was linked to Alzheimer’s disease. Moreover, fluid flow may be exploited to administer drugs to the brain. Using computer simulations, we estimate bulk flow velocities in the gray matter functional brain tissue due to changes in blood pressure and solute concentrations in unseen detail. We show that microvessel pulsations as filtration across the blood capillaries are potentially potent drivers of fluid flow in brain tissue.
Activity-Dependent Localization and Heterogeneous Dynamics of STIM1 and STIM2 at ER-PM contacts in Hippocampal Neurons
Authors: Chhikara Arun , Maciąg Filip , Sorush Nasrin , Heine Martin 
Published: December 2024

AbstractStromal interaction molecules (STIMs) are calcium sensors integral to store-operated calcium entry (SOCE), a process critical for non-excitable cells and contributing to homeostatic functions in neurons. Upon depletion of Ca2+from the endoplasmic reticulum (ER), STIMs translocate to ER-plasma membrane (PM) junctions to contact the inner leaflet of the plasma membrane. Using single-particle tracking (SPT), we characterized the dynamic properties of neuronal STIM1 and STIM2 in hippocampal neurons.Our data reveal that STIMs exhibit heterogenous dynamics in dendrites and axons, while only transiently visiting synaptic compartments. A substantial fraction of STIM2 proteins define ER-PM contacts under resting conditions, whereas STIM1 proteins are recruited to ER-PM junctions during strong activation of glutamatergic synapses. Junctions organized by KV2.1 channels are not particularly enriched with STIM proteins. Activity-dependent confinement of STIM proteins is not influenced by L-type calcium channel (CaV1.2) activity. We propose that STIM proteins predominantly regulate the contact area and frequency of contacts between ER and PM.
Virus-free continuous directed evolution in human cells using somatic hypermutation
Authors: Bram Stanley , Quenneville Jordan , Lindsey Graeme , Leach Sarah , Guthmiller Jenna J. , Mehta Angad P. 
Published: December 2024

AbstractRandom mutations followed by natural selection is one of the key mechanisms during natural evolution that results in the generation of new functions. This process is typically slow in nature because of low mutational frequency. In contrast, the B cells of mammalian immune systems have evolved somatic hypermutation (SHM) mechanisms that introduce mutations at the immunoglobulin genomic loci at a significantly higher frequency than the rest of the genome. SHM allows B cells to rapidly evolve new antibody sequences without compromising their fitness as a consequence of genome-wide mutations. In this work, we developed a continuous directed evolution platform in human B cell lines (CODE-HB) that recruits and repurposes the SHM mechanisms to rapidly evolve reporter proteins like the Green Fluorescent Protein. This approach uses a stable, non-immunoglobulin locus within the genomes of human B cell lines. To comprehensively characterize the mutational profile and breadth of this strategy, we performed single-molecule sequencing experiments. We illustrate the utility of the platform by rapidly evolving antibody fragments in a continuous manner by B cell surface display targeting avian subtypes of influenza hemagglutinin (e.g., H5) from emerging strains.
Alternating hemiplegia of childhood associated mutations inAtp1a3reveal diverse neurological alterations in mice
Authors: Terrey Markus , Krivoshein Georgii , Adamson Scott I. , Arystarkhova Elena , Anderson Laura , Szwec John , McKee Shelby , Jones Holly , Perkins Sara , Selvam Vijay , Piec Pierre-Alexandre , Chhaya Dweet , Dehn Ari , Zuberi Aamir , Murray Stephen A. , Morsci Natalia S. , Sweadner Kathleen J. , Knowles David A. , Tolner Else A. , van den Maagdenberg Arn M.J.M. , Lutz Cathleen M. 
Published: December 2024

AbstractPathogenic variants in the neuronal Na+/K+ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most commonde novopathogenic variants in AHC are p.D801N (∼40% of patients) and p.E815K (∼25% of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then, performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of two most common AHC patient observed variants in theAtp1a3gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815K variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.
Governing relationships: the direct and interactive role of perceived fairness in distribution channels
Authors: Trada Sandip , Singh Baljeet 
Published: December 2024

PurposeThis research aims to analyse the potential role of perceived fairness as a complete governance mechanism in distribution channels. In doing so, this study examines the direct impact of perceived fairness on governance costs and its interactive effect on the driver (i.e. relationship-specific investments (RSIs) and deterrent (i.e. communication) of suppliers’ governance costs.Design/methodology/approachThis research used a structural modelling approach to analyse the matched data collected from 241 pharmaceutical suppliers and distributors and test the proposed model.FindingsThe findings reveal that perceived fairness directly reduces governance costs in distribution channels. Further, they suggest that perceived fairness weakens the positive impact of suppliers’ RSIs and strengthens the negative effects of communication on suppliers’ governance costs.Research limitations/implicationsThis study suggests that perceived fairness is a novel and effective way to govern distribution channels. These findings provide a holistic understanding of how perceived fairness reduces governance costs, directly and indirectly.Practical implicationsThe findings suggest managers should design fair channel policies and train sales personnel to emphasise fairness during channel interactions. This would foster an equitable channel climate that safeguards investments and reduces governance efforts.Originality/valuePrior literature has mostly overlooked the potential role of perceived fairness in distribution channels; however, this study addresses this gap and highlights the dual role of perceived fairness in channel governance.