bluuebunny/crossref_metadata_2025_split huggingface dataset:
The utility of explainable A.I. for MRI analysis: Relating model predictions to neuroimaging features of the aging brain
Authors: Hofmann Simon M. , Goltermann Ole , Scherf Nico , Müller Klaus-Robert , Löffler Markus , Villringer Arno , Gaebler Michael , Witte A. Veronica , Beyer Frauke 
Published: October 2024

AbstractIntroductionDeep learning models highly accurately predict brain-age from MRI but their explanatory capacity is limited. Explainable A.I. (XAI) methods can identify relevant voxels contributing to model estimates, yet, they do not reveal which biological features these voxels represent. In this study, we closed this gap by relating voxel-based contributions to brain-age estimates, extracted with XAI, to human-interpretable structural features of the aging brain.MethodsTo this end, we associated participant-level XAI-based relevance maps extracted from two ensembles of 3D-convolutional neural networks (3D-CNN) that were trained on T1-weighted and fluid attenuated inversion recovery images of 2016 participants (age range 18-82 years), respectively, with regional cortical and subcortical gray matter volume and thickness, perivascular spaces (PVS) and water diffusion-based fractional anisotropy of main white matter tracts.ResultsWe found that all neuroimaging markers of brain aging, except for PVS, were highly correlated with the XAI-based relevance maps. Overall, the strongest correlation was found between ventricular volume and relevance (r= 0.69), and by feature, temporal-parietal cortical thickness and volume, cerebellar gray matter volume and frontal-occipital white matter tracts showed the strongest correlations with XAI-based relevance.ConclusionOur ensembles of 3D-CNNs took into account a plethora of known aging processes in the brain to perform age prediction. Some age-associated features like PVS were not consistently considered by the models, and the cerebellum was more important than expected. Taken together, we highlight the ability of end-to-end deep learning models combined with XAI to reveal biologically relevant, multi-feature relationships in the brain.
Effect of differential protection regimes on the diversity and composition of woody plants in the Western Ghats
Authors: Shigwan Bhushan K. , Kulkarni Aboli , Smirthy Vijayan , Page Navendu V. , Shetti Rohan , Datar Mandar N. 
Published: September 2024

AbstractHuman interference in forests is inevitable, and despite significant conservation efforts, many forest areas continue to suffer from anthropogenic pressures. The forests of the Northern Western Ghats (NWG) exhibit varying degrees of protection, including private, community, and legal frameworks. However, the tree diversity within these protection regimes remains underexplored. This study aims to assess tree diversity, composition, and structure across four protection regimes using a transect-cum-quadrat method, with four quadrats (20×20 m) along a single transect line. Data collected included species richness, individual counts, girth at breast height (GBH), basal area, and a combined disturbance index (CDI). Approximately 50% commonality was observed among sites across the four protection regimes. Protected Areas (PA) and Reserved Forests (RF) exhibited higher tree densities compared to Sacred Groves (SG) and Private Forests (PV). Notably, Sacred Groves, despite experiencing high disturbance levels, displayed a similar tree variety to PAs and RFs. While species composition across the four regimes was comparable, structural elements such as tree density and basal area varied significantly. Sacred Groves were predominantly characterized by older trees, whereas RFs and PAs were primarily populated by younger trees. These findings underscore the critical need for targeted conservation strategies that address the unique challenges faced by each protection regime. Enhanced conservation planning is essential to mitigate the impacts of disturbances, such as climate change and land use changes, which threaten the biodiversity of these forests. The study highlights the importance of preserving Sacred Groves and emphasizes the role of community involvement in conservation efforts to safeguard endemic species and maintain ecological balance in the NWG.
Positive and Negative Retinotopic Codes in the Human Hippocampus
Authors: Angeli Peter A. , Steel Adam , Silson Edward H. , Robertson Caroline E. 
Published: September 2024

AbstractThe hippocampus is thought to coordinate sensory-mnemonic information streams in the brain, representing both the apex of the visual processing hierarchy and the central hub of mnemonic processing. Yet, the mechanisms underlying sensory-mnemonic interactions in the hippocampus are poorly understood. Recent work in cortex suggests that a retinotopic code – typically thought to be exclusive to visual areas – may help organize internal and external information at the cortical apex via opponent interactions. Here, we leverage high-resolution 7T functional MRI to test whether a bivalent retinotopic code structures activity within the human hippocampus and mediates hippocampal-cortical interactions. In seven densely-sampled individuals, we defined the retinotopic preferences of individual voxels within the hippocampus and cortex during a visual mapping task, as well as their functional connectivity during independent runs of resting-state fixation. Our findings reveal a robust retinotopic code in the hippocampus, characterized by stable population receptive fields (pRFs) with consistent preferred visual field locations across experimental runs. Notably, this retinotopic code is comprised of roughly equal proportions of positive and negative pRFs, aligning with the hypothesized role of negative pRFs in mnemonic processing. Finally, the signed amplitude of hippocampal pRFs predicts functional connectivity between retinotopic hippocampal and cortical voxels. Taken together, these results suggest that retinotopic coding may scaffold internal mnemonic and external sensory information processing within the hippocampus, and across hippocampal-cortical interactions.
The Haemagglutinin Gene of Bovine Origin H5N1 Influenza Viruses Currently Retains an Avian Influenza Virus phenotype
Authors: Yang Jiayun , Qureshi Mehnaz , Kolli Reddy , Peacock Thomas P. , Sadeyen Jean-Remy , Carter Toby , Richardson Samuel , Daines Rebecca , Barclay Wendy S. , Brown Ian , Iqbal Munir 
Published: September 2024

AbstractClade 2.3.4.4b H5N1 high pathogenicity avian influenza virus (HPAIV) has caused a panzootic affecting all continents except Australia, expanding its host range to several mammalian species. In March 2024, H5N1 HPAIV was first detected in dairy cattle and goats in the United States. Since then, over 230 dairy farms across 14 states have tested positive, with zoonotic infections reported among dairy workers. This raises concerns about the virus undergoing evolutionary changes in cattle that could enhance its zoonotic potential. The Influenza glycoprotein haemagglutinin (HA) facilitates entry into host cells through receptor binding and pH-induced fusion with cellular membranes. Adaptive changes in HA modulate virus-host cell interactions. This study compared the HA genes of cattle and goat H5N1 viruses with the dominant avian-origin clade 2.3.4.4b H5N1 in the United Kingdom, focusing on receptor binding, pH fusion, and thermostability. All the tested H5N1 viruses showed binding exclusively to avian-like receptors, with a pH fusion of 5.9, outside the pH range associated with efficient human airborne transmissibility (pH 5.0 to 5.5). We further investigated the impact of emerging HA substitutions seen in the ongoing cattle outbreaks, but saw little phenotypic difference, with continued exclusive binding to avian-like receptor analogues and pHs of fusion above 5.8. This suggests that the HA genes from the cattle and goat outbreaks do not pose an enhanced threat compared to circulating avian viruses. However, given the rapid evolution of H5 viruses, continuous monitoring and updated risk assessments remain essential to understanding virus zoonotic and pandemic risks.
The Neural Blueprint of Stress Susceptibility: Brain-wide neuronal activity associated with the consequences of stress
Authors: Dirven Bart C.J. , Negwer Moritz , Botan Andriana , Maas Riv , van Melis Lennart , Merjenburgh Sanne , van Rijn Rebecca , Grandjean Joanes , Homberg Judith R. , Kozicz Tamas , Henckens Marloes J.A.G. 
Published: September 2024

AbstractUnderstanding the neurobiological mechanisms of stress susceptibility is key to advancing our insight into stress-related psychopathology like post-traumatic stress disorder (PTSD). Preclinical animal models however typically lack translationally relevant brain readouts. Here, we used a mouse model for severe stress, segregating mice into stress-susceptible and resilient groups. We analyzed and contrasted their whole-brain neuronal activity pre-, peri- and post-stress exposure and compared functional connectivity of the salience (SN), default mode (DMN) and executive control network (lateral cortical network (LCN) in rodents). We found that stress-susceptible mice exhibited pre-existing hyperactivity in the lateral orbital area, a potential risk factor for stress vulnerability, and heightened retrosplenial cortex activity peri- and post-stress, potentially contributing to maladaptive fear memory. Upon stress exposure, susceptible mice showed strong recruitment of visual and memory-related areas, whereas resilient mice displayed marked reductions in retrosplenial activity and increased activation in the agranular insula and ventral striatum. Observations of enhanced intra-SN and SN-DMN connectivity in susceptible mice mirrored those observed in individuals with PTSD. Moreover, susceptible mice displayed aberrant DMN-LCN network pre- and peri-stress. These findings highlight the importance of dynamic network interactions in stress susceptibility and suggest novel brain region targets for (early) intervention.
Specific growth rates and growth stoichiometries of Saccharomycotina yeasts on ethanol as sole carbon and energy substrate
Authors: Warmerdam Marieke , Vieira-Lara Marcel A. , Mans Robert , Daran Jean Marc , Pronk Jack T. 
Published: September 2024

AbstractEmerging low-emission production technologies make ethanol an interesting substrate for yeast biotechnology, but information on growth rates and biomass yields of yeasts on ethanol is scarce. Strains of 52 Saccharomycotina yeasts were screened for growth on ethanol. The 21 fastest strains, among which representatives of the Phaffomycetales order were overrepresented, showed specific growth rates in ethanol-grown shake-flask cultures between 0.12 and 0.46 h-1. Seven strains were studied in aerobic, ethanol-limited chemostats (dilution rate 0.10 h-1).Saccharomyces cerevisiaeandKluyveromyces lactis, whose genomes do not encode Complex-I-type NADH dehydrogenases, showed biomass yields of 0.59 and 0.56 gbiomassg-1, respectively. Different biomass yields were observed among species whose genomes do harbour Complex-I genes:Phaffomyces thermotolerans(0.58 g g-1),Pichia ethanolica(0.59 g g-1),Saturnispora dispora(0.66 g g-1),Ogataea parapolymorpha(0.67 g g-1), andCyberlindnera jadinii(0.73 g g-1). The biomass yield ofC. jadinii, which also showed the highest biomass protein content of these yeasts, corresponded to 88% of the theoretical maximum achieved when growth is limited by assimilation rather than by energy availability. This study indicates that energy coupling of mitochondrial respiration and its regulation are key factors for selecting and improving yeast strains for ethanol-based processes.
Mapping herpesvirus-driven impacts on the cellular milieu and transcriptional profile of Kaposi sarcoma in patient-derived mouse models
Authors: Li Xiaofan , Ohler Zoë Weaver , Day Amanda , Bassel Laura , Grosskopf Anna , Afsari Bahman , Tagawa Takanobu , Custer Wendi , Mangusan Ralph , Lurain Kathryn , Yarchoan Robert , Ziegelbauer Joseph , Ramaswami Ramya , Krug Laurie T. 
Published: September 2024

AbstractKaposi sarcoma (KS) is defined by aberrant angiogenesis driven by Kaposi sarcoma herpesvirus (KSHV)-infected spindle cells with endothelial characteristics. KS research is hindered by rapid loss of KSHV infection upon explant culture of tumor cells. Here, we establish patient-derived KS xenografts (PDXs) upon orthotopic implantation of cutaneous KS biopsies in immunodeficient mice. KS tumors were maintained in 27/28 PDX until experimental endpoint, up to 272 days in the first passage of recipient mice. KSHV latency associated nuclear antigen (LANA)+ endothelial cell density increased by a mean 4.3-fold in 14/15 PDX analyzed by IHC at passage 1 compared to respective input biopsies, regardless of implantation variables and clinical features of patients. The Ki-67 proliferation marker colocalized with LANA more frequently in PDXs. Spatial transcriptome analysis revealed increased expression of viral transcripts from latent and lytic gene classes in the PDX. The expanded KSHV+ regions of the PDX maintained signature gene expression of KS tumors, with enrichment in pathways associated with angiogenesis and endothelium development. Cells with characteristics of tumor-associated fibroblasts derived from PDX were propagated for 15 passages. These fibroblast-like cells were permissive forde novoKSHV infection, and one lineage produced CXCL12, a cancer-promoting chemokine. Spatial analysis revealed that fibroblasts are a likely source of CXCL12 signaling to CXCR4 that was upregulated in KS regions. The reproducible expansion of KSHV-infected endothelial cells in PDX from multiple donors and recapitulation of a KS tumor gene signature supports the application of patient-derived KS mouse models for studies of pathogenesis and novel therapies.One Sentence SummaryTumor virus-driven expansion of endothelial cells with a transcriptional signature of Kaposi sarcoma in a large cohort of patient-derived xenografts provides a platform to discover cell communications within the tumor microenvironment.
A novel degenerate primer set for eDNA metabarcoding of amphibians, turtles and fish
Authors: Rodgers Torrey W. , Olson John R. , Hawkins Charles P , Mock Karen E. 
Published: October 2024

AbstractMetabarcoding of environmental DNA (eDNA) has revolutionized the detection of aquatic species across large geographic scales. However, the effectiveness of eDNA metabarcoding across taxa is marker-dependent, often requiring multiple markers to detect divergent taxonomic groups. Here, we introduce a novel metabarcoding marker designed to simultaneously detect amphibians, turtles, and fish from eDNA samples. We initially optimized this marker to match species from central and southern California, USA, and conducted validation on 525 field-collected eDNA samples from central California, while also testing an existing published amphibian marker from the literature. Additionally, we assessed the global applicability of the marker within-silicoanalysis through comparison with 11,350 amphibian, turtle, and fish mitochondrial genomes downloaded from GenBank. Field validation demonstrated the markers robustness in detecting aquatic vertebrates, outperforming the published marker in sensitivity, particularly for turtles and fish. In-silico evaluation demonstrated the potential for global use of this marker, indicating broad applicability for amplifying eDNA from amphibians, turtles, and fish worldwide. Our findings highlight the utility of this novel marker for monitoring of aquatic vertebrate communities, with implications for conservation, management, and ecological research.
Single cell variation and rapid emergence of phenotypic heterogeneity in cell lines- a cautionary tale for devotees of CRISPR-Cas9
Authors: Bradley Hayley , Barr John N , Stacey Martin 
Published: September 2024

AbstractThe use and publication of research utilising CRISPR/cas9 in gene editing and knock outs (KOs) within cell lines is now widespread and has proved extremely powerful in the interrogation of gene function. However, the potential of experimental artefacts resulting from the need to generate single cell clones post gene-manipulation has been somewhat overlooked. In this study, we show that the commonly used pulmonary cell line A549 displays significant heterogeneity in terms of their gene expression, and that individual cells from a population exhibit dramatically different susceptibility to viral infection from a range of viruses including respiratory syncytial virus (RSV), influenza A virus (IAV), Hazara virus (HAZV), lymphocytic choriomeningitis virus (LCMV) and Bunyamwera virus (BUNV). Moreover, we demonstrate the rapid re-emergence of phenotypic heterogeneity even after cloning. These results demonstrate the need for caution in interpreting results from CRISPR screens and CRISPR-KO validation studies, especially in the study of viral infection.
Activation of group I mGluRs is required for heterosynaptic priming of long-term potentiation in mouse hippocampus
Authors: Koek Laura A. , Sanderson Thomas M. , Georgiou John , Collingridge Graham L. 
Published: September 2024

ABSTRACTMetaplasticity involves changes in the state of neurons or synapses that influence their ability to generate synaptic plasticity. One form of heterosynaptic metaplasticity, known as synaptic tagging and capture (STC), has been intensively studied but the underlying mechanisms are not fully understood. In experiments using hippocampal slices prepared from C57BL/6J mice, we have examined the role of group I metabotropic glutamate receptors (mGluRs) in STC. We used a version of STC where a strong theta-burst stimulus (TBS), delivered to one set of Schaffer collateral-commissural pathway inputs to CA1, preceded a weak TBS delivered to a second independent set of inputs. We observed that, firstly, dual inhibition of mGluR1 and mGluR5, using YM 298198 and MTEP respectively, did not affect a form of protein synthesis-independent LTP (LTP1), but substantially inhibited a form of protein synthesis-dependent LTP (LTP2). Secondly, these inhibitors prevented the small heterosynaptic potentiation, which is often associated with LTP2. Thirdly, STC was abolished when these antagonists were applied either during the strong (priming) TBS or during the subsequent weak TBS at the independent pathway. It is proposed that the activation of group I mGluRs serves as a trigger for local protein synthesis both during the strong and weak TBS and, as such, are an integral part of the STC process. STC is involved in associative learning and memory, a cognitive function that is disrupted in many brain disorders including Alzheimer’s disease.
Millisecond-scale motor coding precedes sensorimotor learning in songbirds
Authors: Pascual Leila May M. , Vusirikala Aanya , Nemenman Ilya M. , Sober Samuel J. , Pasek Michael 
Published: September 2024

AbstractA key goal of the nervous system in young animals is to learn motor skills. Songbirds learn to sing as juveniles, providing a unique opportunity to identify the neural correlates of skill acquisition. Prior studies have shown that spike rate variability in vocal motor cortex decreases substantially during song acquisition, suggesting a transition from rate-based neural control to the millisecond-precise motor codes known to underlie adult vocal performance. By distinguishing how the ensemble of spike patterns fired by cortical neurons (the “neural vocabulary”) and the relationship between spike patterns and song acoustics (the “neural code”) change during song acquisition, we quantified how vocal control changes across learning in juvenile Bengalese finches. We found that despite the expected drop in rate variability (a learning-related change in spike vocabulary), the precision of the neural code in the youngest singers is the same as in adults, with 1–2 ms variations in spike timing transduced into quantifiably different behaviors. In contrast, fluctuations in firing rates on longer timescales fail to affect the motor output in both juvenile and adult animals. The consistent presence of millisecond-scale motor coding during changing levels of spike rate and behavioral variability suggests that learning-related changes in cortical activity reflect the brain’s changing its spiking vocabulary to better match the underlying motor code, rather than a change in the precision of the code itself.
Context-Dependent Interaction Between Goal-Directed and Habitual Control Under Time Pressure
Authors: Frölich Sascha , Wagner Ben J. , Smolka Michael N. , Kiebel Stefan J. 
Published: October 2024

AbstractHabits are an important aspect of human behaviour. Habits are reflexive, inflexible, and fast, in contrast to goal-directed behaviour which is reflective, flexible, and slow. Current theories assume that habits and goal-directed actions are controlled by two separate but interacting systems. However, it is not clear how these two systems interact when actions must be made under time pressure. Here we use a task which induces habitual behaviour in the form of action sequences, while concurrently requiring participants to perform goal-directed actions that are either congruent or incongruent with the habit. This task thus allows for concurrent measurement of both goal-directed and habitual behaviour, thereby permitting a nuanced analysis of the interaction between these two control modes. Using computational modelling, we find that models where the influence of the habit depends on the number of repetitions, explain participant behaviour better than models that assume the habit to be constant. We further show that roughly half of the participants modulate their use of the habit depending on the context, i.e. they selectively inhibit the habit’s influence when it is incongruent to their explicit goals, but not when both are congruent and the influence of the habit is adaptive. Additional drift-diffusion modelling of choice and reaction time data shows that proactive control is mobilized in the congruent task context whereas reactive control is mobilized in the incongruent task context. The present study thus indicates that habitual control is context-dependent and can be adaptively deployed via proactive and reactive control, rather than being a fixed or isolated mechanism.
Concentration dependent CsrA regulation of theuxuBtranscript leads to development of post-transcriptional BANDPASS Filter
Authors: Rojano-Nisimura Alejandra M. , Simmons Trevor R. , Lukasiewicz Alexandra J. , Buchser Ryan , Ruzek Josie S. , Avila Jacqueline L. , Contreras Lydia M. 
Published: October 2024

AbstractPost-transcriptional control systems offer new avenues to design synthetic circuits that offer reduced burden and less synthetic regulatory components compared to transcriptionally based tools. Herein, we repurpose a newly identified post-transcriptional interaction between theuxuBleader sequence and theE. coliCsrA regulatory protein to design a biological post-transcriptional BANDPASS filter. In this work, we characterizethe uxuBmRNA as heterogenous target of the Carbon Storage Regulatory A (CsrA) protein, where the protein can both activate and repressuxuBactivity depending on its intracellular concentration. We leverage this interaction to implement a novel strategy of regulation within the 5’UTR of an mRNA. Specifically, we report a hierarchical binding strategy that may be leveraged by CsrA withinuxuBto result in a dose- dependent response in regulatory outcomes. In our semi-synthetic circuit, theuxuBmRNA leader sequence is used as a scaffold that is fused to a gene of interest, which allows the circuit to transition between ON/OFF states based on a range of free native concentration of the CsrA regulatory protein. Notably, this system exerts regulation comparable to previously developed transcriptional BANDPASS filters while reducing the number of circuit components and can be used in concert with additional controlled circuits to achieve complex multi-signal control. We anticipate that future characterization of native regulatory RNA-protein systems will allow for development of more complex RNP-based circuits for synthetic biology applications.Abstract Figure