bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interpretable Solutions for Stochastic Dynamic Programming
Authors: Ferrer-Mestres Jonathan , Dietterich Thomas G. , Buffet Olivier , Chadès Iadine 
Published: August 2024

AbstractIn conservation of biodiversity, natural resource management and behavioural ecology, stochastic dynamic programming, and its mathematical framework, Markov decision processes (MDPs), are used to inform sequential decision-making under uncertainty. Models and solutions of Markov decision problems should be interpretable to derive useful guidance for managers and applied ecologists. However, MDP solutions that have thousands of states are often difficult to understand. Difficult to interpret solutions are unlikely to be applied, and thus we are missing an opportunity to improve decision-making. One way of increasing interpretability is to decrease the number of states.Building on recent artificial intelligence advances, we introduce a novel approach to compute more compact representations of MDP models and solutions as an attempt at improving interpretability. This approach reduces the size of the number of states to a maximum numberKwhile minimising the loss of performance compared to the original larger number of states. The reduced MDP is called aK-MDP. We present an algorithm to computeK-MDPs and assess its performance on three case studies of increasing complexity from the literature. We provide the code as a MATLAB package along with a set of illustrative problems.We found thatK-MDPs can achieve a substantial reduction of the number of states with a small loss of performance for all case studies. For example, for a conservation problem involving Northern Abalone and Sea Otters, we reduce the number of states from 819 to 5 states while incurring a loss of performance of only 1%. For a dynamic reserve selection problem with seven dimensions, while an impressive reduction in the number of states was achieved, interpreting the optimal solutions remained challenging.Modelling problems as Markov decision processes requires experience. While several models may represent the same problem, reducing the number of states is likely to make solutions and models more interpretable and facilitate the extraction of meaningful recommendations. We hope that this approach will contribute to the uptake of stochastic dynamic programming applications and stimulate further research to increase interpretability of stochastic dynamic programming solutions.
Infants and adults neurally represent the perspective of others like their own perception
Authors: Tebbe Anna-Lena , Rothmaler Katrin , Köster Moritz , Grosse Wiesmann Charlotte 
Published: August 2024

AbstractPreverbal infants already seem to consider the perspective of others, even when it differs from their own. Similarly, adults take the perspective of others very quickly, in parallel to other cognitively demanding tasks. This raises the question of how multiple perspectives are processed efficiently, and even before higher cognitive capacities develop. To test whether and how others’ perspectives are neurally represented, we presented 12-14-months-old infants and adults with objects flickering at 4 Hz, which evoked neural oscillations at the exact same frequency. Remarkably, both in infants and adults, this same highly specific neural signature of visual object processing was also present when their view was blocked and only another observer saw the object. These results provide strong evidence that we process what others see as if we saw it ourselves, revealing a neural mechanism for efficient perspective taking, present from infancy.
Hybrid Protocells based on Coacervate-Templated Fatty Acid Vesicles combine Improved Membrane Stability with Functional Interior Protocytoplasm
Authors: Lee Jessica , Cakmak Fatma P. , Booth Richard , Keating Christine D. 
Published: August 2024

AbstractPrebiotically-plausible compartmentalization mechanisms include membrane vesicles formed by amphiphile self-assembly and coacervate droplets formed by liquid-liquid phase separation. Both types of structures form spontaneously and can be related to cellular compartmentalization motifs in today’s living cells. As prebiotic compartments, they have complementary capabilities, with coacervates offering excellent solute accumulation and membranes providing superior boundaries. Herein, we describe protocell models constructed by spontaneous encapsulation of coacervate droplets by mixed fatty acid/phospholipid and by purely fatty acid membranes. Coacervate-supported membranes formed over a range of coacervate and lipid compositions, with membrane properties impacted by charge-charge interactions between coacervates and membranes. Vesicles formed by coacervate-templated membrane assembly exhibited profoundly different permeability than traditional fatty acid or blended fatty acid/phospholipid membranes without coacervate interiors, particularly in the presence of Mg2+ions. While fatty acid and blended membrane vesicles were disrupted by addition of 25 mM MgCl2, the corresponding coacervate-supported membranes remained intact and impermeable to externally-added solutes even in the presence of MgCl2. With the more robust membrane, fluorescein diacetate (FDA) hydrolysis, which is commonly used for cell viability assays, could be performed inside the protocell model due to the simple diffusion of FDA and then following with the coacervate-mediated abiotic hydrolysis to fluorescein.
TBK1 and IKKε protect target cells from IFNγ-mediated T cell killing via an inflammatory apoptotic mechanism
Authors: Sun Nicholas D. , Carr Allison R. , Krogman Erica N. , Chawla Yogesh , Zhong Jun , Guttormson Matthew C. , Chan Mark , Hsu Michelle A. , Dong Haidong , Bogunovic Dusan , Pandey Akhilesh , Rogers Laura M. , Ting Adrian T. 
Published: August 2024

AbstractCytotoxic T cells produce interferon gamma (IFNγ), which plays a critical role in anti-microbial and anti-tumor responses. However, it is not clear whether T cell-derived IFNγ directly kills infected and tumor target cells, and how this may be regulated. Here, we report that target cell expression of the kinases TBK1 and IKKε regulate IFNγ cytotoxicity by suppressing the ability of T cell-derived IFNγ to kill target cells. In tumor targets lacking TBK1 and IKKε, IFNγ induces expression of TNFR1 and the Z-nucleic acid sensor, ZBP1, to trigger RIPK1-dependent apoptosis, largely in a target cell-autonomous manner. Unexpectedly, IFNγ, which is not known to signal to NFκB, induces hyperactivation of NFκB in TBK1 and IKKε double-deficient cells. TBK1 and IKKε suppress IKKα/β activity and in their absence, IFNγ induces elevated NFκB-dependent expression of inflammatory chemokines and cytokines. Apoptosis is thought to be non-inflammatory, but our observations demonstrate that IFNγ can induce an inflammatory form of apoptosis, and this is suppressed by TBK1 and IKKε. The two kinases provide a critical connection between innate and adaptive immunological responses by regulating three key responses: (1) phosphorylation of IRF3/7 to induce type I IFN; (2) inhibition of RIPK1-dependent death; and (3) inhibition of NFκB-dependent inflammation. We propose that these kinases evolved these functions such that their inhibition by pathogens attempting to block type I IFN expression would enable IFNγ to trigger apoptosis accompanied by an alternative inflammatory response. Our findings show that loss of TBK1 and IKKε in target cells sensitizes them to inflammatory apoptosis induced by T cell-derived IFNγ.Short SummaryIn the absence of TBK1 and IKKε, target cells are killed by T cells in an IFNγ-dependent manner. In TBK1 and IKKε-deficient cells, IFNγ induces RIPK1-dependent death, as well as hyper-induction of NFκB-dependent inflammatory genes. This suggests that any inhibition of TBK1/IKKε to block type I IFN expression will result in the demise of the cell accompanied by an alternate inflammatory program.Graphical Abstract
Optics-free Spatial Genomics for Mapping Mouse Brain Aging
Authors: Abdulraouf Abdulraouf , Jiang Weirong , Xu Zihan , Zhang Zehao , Isakov Samuel , Raihan Tanvir , Zhou Wei , Cao Junyue 
Published: August 2024

AbstractSpatial transcriptomics has revolutionized our understanding of cellular network dynamics in aging and disease by enabling the mapping of molecular and cellular organization across various anatomical locations. Despite these advances, current methods face significant challenges in throughput and cost, limiting their utility for comprehensive studies. To address these limitations, we introduceIRISeq(ImagingReconstruction using IndexedSequencing), a optics-free spatial transcriptomics platform that eliminates the need for predefined capture arrays or extensive imaging, allowing for the rapid and cost-effective processing of multiple tissue sections simultaneously. Its capacity to reconstruct images based solely on sequencing local DNA interactions allows for profiling of tissues without size constraints and across varied resolutions. ApplyingIRISeq, we examined gene expression and cellular dynamics in thirty brain regions of both adult and aged mice, uncovering region-specific changes in gene expression associated with aging. Further cell type-centric analysis further identified age-related cell subtypes and intricate changes in cell interactions that are distinct to certain spatial niches, emphasizing the unique aspects of aging in different brain regions. The affordability and simplicity ofIRISeqposition it as a versatile tool for mapping region-specific gene expression and cellular interactions across various biological systems.One Sentence Summary:IRISeq, an innovative optics-free spatial transcriptomics method, uncovers aging-related changes in spatial gene expression and focal cell interactions in brain aging.
Sertad1 is elevated and plays a necessary role in synaptic loss, neuron death and cognitive impairment in a model of Alzheimer’s disease
Authors: Ambareen Naqiya , Gharami Kusumika , Biswas Subhas C. 
Published: August 2024

ABSTRACTDysfunctional autophagy is a primary characteristic of Alzheimer’s disease (AD) pathogenesis. How autophagic impairment leads to cellular changes that contributes to AD pathogenesis remains unclear. To study this further, we assessed levels of autophagy related proteins in 5xFAD mice brain at different ages and found their robust upregulation in cortex and hippocampus suggesting increased induction of autophagy with disease progression but failed clearance. We have identified a transcriptional coregulator Sertad1, as a key mediator of dysfunctional autophagy in AD mice. We found a progressive elevation in Sertad1 levels in 5xFAD mice with age compared to wild-type (WT) mice. Sertad1 knockdown in 5xFAD mice brain lowered levels of autophagy related proteins and lysosome marker, LAMP1 suggesting its role in autophagy flux modulation. FoxO3a is an important transcriptional regulator of the autophagy network and lies at the nexus of autophagy-apoptosis cross-talk. We found that Sertad1 knockdown blocked nuclear translocation of FoxO3a along with a restoration in Akt activity. Further, we showed that knockdown of Sertad1 in 5xFAD mice brain improved cognitive functions along with a remarkable restoration in synaptic health and dendritic spine density. Taken together, our results demonstrated that autophagy is robustly induced with disease progression but it is impaired; Sertad1 knockdown restored autophagy defects, synaptic loss and improved learning and memory in AD models. Thus, we propose that Sertad1 acts in a multimodal manner regulating crucial cell death pathways including apoptosis and autophagy and could be an excellent target for therapeutic intervention to combat a multifactorial disorder such as AD.
Machine learning, molecular docking and simulation studies reveal Lomitapide, Lodipamide, Zafirlukast, Netupitant and Salmon Calcitonin as potent drug molecules against Chagas disease
Authors: Singh Kavya , Kaur Navjeet , Prabhu Ashish 
Published: August 2024

ABSTRACTTrypanosoma cruzi(T.cruzi), a protozoan parasite, is the pathogen that causes the hazardous disease Chagas, sometimes referred to as American trypanosomiasis. Currently, there are just two drugs commercially available to treat this fatal condition. So, there is an urgent requirement to create novel, safer and efficient anti-Tc drugs. In this study, we introduce a robust experimental strategy that integrates machine learning with molecular docking and simulation studies to identify the most potential drug candidates from the DrugBank dataset for treating the Chagas disease. In a machine learning method, different classifiers (Naïve Bayes, Random Forest, SMO, and C4.5) were used to train the model on the PubChem dataset and the most effective model (C4.5 algorithm) was then chosen and tested on the DrugBank dataset (containing FDA-approved and investigational drugs). The C4.5 algorithm-based machine learning model with an accuracy of 65% predicts the possible drug candidates (a total of 280 drugs were predicted). AutoDock4.2 software was then used to dock the predicted compounds that had a confidence interval of 80% and above. As a result, 47 predicted drugs were docked, and the best of the 5 drugs based on their docking score were chosen for performing the MD simulation studies. MD simulations (100 ns) were conducted for each of the protein-ligand complexes, which produces an average RMSD score (2.23 Å). The RMSF value of the cruzain (Cys25) binding pocket, after interaction with the five compounds were found to be less than 3.0 Å. Therefore, based on the molecular docking and simulation studies, we found out that Lomitapide, Lodipamide, Zafirlukast, Netupitant and Salmon Calcitonin have shown a stronger binding affinity with the crystal structure of cruzain (Cyst25) molecule, making them potential effective inhibitors. Hence, we could anticipate that our five computationally validated drugs will soon be available at the clinical trial stage and eventually be made accessible to the necessary Chagas disease patients.
Immunological response against bovine viral diarrhoea virus (BVDV) types 1 and 2 after vaccination with DIVENCE®, measured by ELISA and serum neutralisation on serum and milk samples
Authors: Montbrau C. , Gibert M. , Taberner E. , Tapiolas M. , Teixeira R. , Prenafeta A. 
Published: August 2024

AbstractBackgroundA novel subunit vaccine, DIVENCE®, comprises different bovine respiratory and reproductive antigens, including BVDV-1 E2 recombinant glycoprotein and BVDV-2 E2 recombinant glycoprotein. This study evaluated the immune response against BVDV-1 and 2 generated by DIVENCE® over the long term in different strains.MethodsTwo different studies were conducted to assess the immune response induced by DIVENCE®. In the first study, 20 seronegative young calves (55-104 days of age) were randomly distributed into the vaccinated or control group. All animals were given four intramuscular doses (D0, D21, D204 and D570) of 2 mL DIVENCE® or phosphate-buffered saline (PBS). Blood samples were collected to assess BVDV serum antibodies (ELISA) and neutralising antibodies (SN) against BVDV-1 and BVDV-2. In the second trial, heifers (from 10 months of age until calving) and cows (between first and seventh calving) were included and assigned to the vaccinated and control groups. Three different farms were enrolled in the study. The administration regimen was the same as described in the first study. Blood samples were collected from 32 random animals on each farm (16 vaccinated and 16 control animals). Additionally, bulk tank milk samples from each farm were obtained at different time-points and individual milk samples were obtained from vaccinated and control animals. The immune response against BVDV was analysed in serum and milk samples using different ELISA kits. Neutralising antibodies induced by DIVENCE® against different BVDV isolates from Europe and the Americas were also assessed in this trial.ResultsOverall, DIVENCE® induced high levels of total antibodies (ELISA) and neutralising antibodies against BVDV-1 and BVDV-2. These values were significantly (p<0.05) greater than the control group from 21 days after the second dose (D42) until the end of the study (D591). The high antibody levels, particularly after the third dose, were similar to those that described efficacy against experimental challenges of BVDV-1 and 2 in pregnant animals. In the field trial, similar results were observed in terms of total antibodies (ELISA) against BVDV, and no induction of anti-p80 antibodies was observed in vaccinated animals at any time. Additionally, analyses on individual and bulk tank milk samples also confirmed that no anti-p80 antibodies were induced in vaccinated animals. Furthermore, high levels of neutralising antibodies were observed against different BVDV isolates from Europe and the Americas.ConclusionThe DIVENCE® vaccine induced a strong immune response against BVDV-1 and BVDV-2, and this response allows infected and vaccinated animals to be differentiated (DIVA vaccine).
Repeated activation of preoptic area-recipient neurons in posterior paraventricular nucleus mediates chronic heat-induced negative emotional valence and hyperarousal states
Authors: Cao Zhiping , Yung Wing-Ho , Ke Ya 
Published: August 2024

AbstractMental and behavioral disorders are associated with extended period of hot weather as found in heatwaves, but the underlying neural circuit mechanism is poorly known. The posterior paraventricular thalamus (pPVT) is a hub for emotional processing and receives inputs from the hypothalamic preoptic area (POA), the well-recognized thermoregulation center. The present study was designed to explore whether chronic heat exposure leads to aberrant activities in POA recipient pPVT neurons and subsequent changes in emotional states. By devising an air heating paradigm mimicking the condition of heatwaves and utilizing emotion-related behavioral tests, viral track tracing,in vivocalcium recordings, optogenetic manipulations and electrophysiological recordings, we found that chronic heat exposure for 3 weeks led to negative emotional valence and hyperarousal states in mice. The pPVT neurons receive monosynaptic excitatory and inhibitory innervations from the POA. These neurons exhibited a persistent increase in neural activity following chronic heat exposure, which was essential for chronic heat-induced emotional changes. Notably, these neurons were also prone to display stronger neuronal activities associated with anxiety responses to stressful situations. Furthermore, we observed saturated neuroplasticity in the POA-pPVT excitatory pathway after chronic heat exposure that occluded further potentiation. Taken together, long-term aberration in the POA to pPVT pathway offers a neurobiological mechanism of emotional and behavioral changes seen in extended periods of hot weather like heatwaves.
Nano-org, a functional resource for single-molecule localisation microscopy data
Authors: Shirgill S. , Nieves D.J. , Pike J.A. , Ahmed M.A. , Baragilly M.H.H. , Savoye K. , Worboys J. , Hazime K.S. , Garcia A. , Williamson D.J. , Rubin-Delanchy P. , Peters R. , Davis D.M. , Henriques R. , Lee S.F. , Owen D.M. 
Published: August 2024

ABSTRACTWe present a publicly accessible, curated, and functional resource, termed “nano-org”, containing single-molecule localisation microscopy (SMLM) data representing the nanoscale distributions of proteins in cells. Nano-org is searchable by comparing the statistical similarity of the datasets it contains. This unique functionality allows the resource to be used to understand the relationships of nanoscale architectures between proteins, cell types or conditions, enabling a new field of spatial nano-omics.
Single-nucleus transcriptomics resolves differentiation dynamics between shoot stem cells and primary stem
Authors: Moreno Sebastián R. , Lenz Martin O. , Meyerowitz Elliot M , Locke James CW , Jönsson Henrik 
Published: August 2024

ABSTRACTThe shoot apical meristem (SAM), located at the plant apex, is accountable for the formation of above-ground organs such as leaves, stem and flowers. Although transcriptional profiling has elucidated some cell-types observed within stems or flowers, the differentiation transcriptional dynamics from shoot stem cells to multiple cell identities remain unknown. We employed a single-nucleus RNA-sequencing approach to assess the transcriptional heterogeneity and cell differentiation processes within the SAM. By collecting dissected inflorescence meristems, we constructed an inflorescence single-nucleus SAM atlas fromArabidopsis thaliana. Our analysis unveiled regulatory elements for most previously known cell types such as the boundary domain, vasculature, early primordia, epidermis and internal stem cells. We also identified previously unobserved transcriptional profiles, revealing that the stem cortex is defined early within forming primordia. Moreover, trajectory inference analysis allowed us to capture spatial control of S-phase machinery by floral homeotic genes and differentiation gene expression dynamics from internal shoot stem cells toward internal layers such as cortex, cambium, xylem and phloem. The results advance our understanding of the cellular and transcriptional heterogeneity underlying the cell-fate transcriptional dynamics shaping shoot organs and architecture.
Ecosystem dynamics in wet heathlands: spatial and temporal effects of environmental drivers on the vegetation
Authors: Damgaard Christian 
Published: August 2024

AbstractTo understand and estimate the effects of environmental drivers on wet heathland vegetation, pin-point cover data from 42 sites sampled during a 15-year period was regressed onto environmental variables (nitrogen deposition, soil pH, soil C-N ratio, soil type, precipitation and grazing) in a spatio-temporal structural equation model using a Bayesian hierarchical model structure with latent variables to model the effect of measurement and sampling uncertainties.The results suggest that the modelled environmental variables have various regulating effects on the large-scale spatial variation as well as plant community dynamics in wet heathlands. Most noticeably, nitrogen deposition and yearly precipitation had relatively large and opposite effects on the characteristic speciesErica tetralixandMolinia caerulea, where nitrogen deposition had negative effects onE. tetralixand positive effects onM. caerulea. The results of this study differed in important qualitative aspects from the findings of an earlier study where comparable data from a shorter time-series (7 years instead of 15 years) were analyzed with a similar model, which suggests that relatively long time-series are needed for studying ecosystem dynamics. Furthermore, it was concluded that the effect of nitrogen deposition on plant community dynamics mainly was through direct effects, whereas the effect of soil type on plant community dynamics was both direct and indirect mediated by the effect of soil type on soil pH.It was concluded that the modeled environmental variables are sufficient for predicting theaverageplant community dynamics of wet heathlands. However, caution are required if the fitted model is used for generating local ecological predictions as input to a process of generating adaptive management plans for specific wet heathland sites. Moreover, the results suggest that the ratio between the two speciesE. tetralixandM. caeruleamay be used as an indicator for the conservation status of wet heathlands.