bluuebunny/crossref_metadata_2025_split huggingface dataset:
Noradrenergic signaling controls Alzheimer’s disease pathology via activation of microglial β2 adrenergic receptors
Authors: Le L. , Feidler A.M. , Li H. , Kara-Pabani K. , Lamantia C. , O’Banion M.K. , Majewska K. A 
Published: December 2023

AbstractIn Alzheimer’s disease (AD) pathophysiology, plaque and tangle accumulation trigger an inflammatory response that mounts positive feed-back loops between inflammation and protein aggregation, aggravating neurite damage and neuronal death. One of the earliest brain regions to undergo neurodegeneration is the locus coeruleus (LC), the predominant site of norepinephrine (NE) production in the central nervous system (CNS). In animal models of AD, dampening the impact of noradrenergic signaling pathways, either through administration of beta blockers or pharmacological ablation of the LC, heightened neuroinflammation through increased levels of pro-inflammatory mediators. Since microglia are the resident immune cells of the CNS, it is reasonable to postulate that they are responsible for translating the loss of NE tone into exacerbated disease pathology. Recent findings from our lab demonstrated that noradrenergic signaling inhibits microglia dynamics via β2 adrenergic receptors (β2ARs), suggesting a potential anti-inflammatory role for microglial β2AR signaling. Thus, we hypothesize that microglial β2 adrenergic signaling is progressively impaired during AD progression, which leads to the chronic immune vigilant state of microglia that worsens disease pathology. First, we characterized changes in microglial β2AR signaling as a function of amyloid pathology. We found that LC neurons and their projections degenerate early and progressively in the 5xFAD mouse model of AD; accompanied by mild decrease in the levels of norepinephrine and its metabolite normetanephrine. Interestingly, while 5xFAD microglia, especially plaque-associated microglia, significant downregulatedβ2ARgene expression early in amyloid pathology, they did not lose their responsiveness to β2AR stimulation. Most importantly, we demonstrated that specific microglial β2AR deletion worsened disease pathology while chronic β2AR stimulation resulted in attenuation of amyloid pathology and associated neuritic damage, suggesting microglial β2AR might be used as potential therapeutic target to modify AD pathology.
Contrasting Sequence with Structure: Pre-training Graph Representations with PLMs
Authors: Robinson Louis , Atkinson Timothy , Copoiu Liviu , Bordes Patrick , Pierrot Thomas , Barrett Thomas D. 
Published: December 2023

AbstractUnderstanding protein function is vital for drug discovery, disease diagnosis, and protein engineering. While Protein Language Models (PLMs) pre-trained on vast protein sequence datasets have achieved remarkable success, equivalent Protein Structure Models (PSMs) remain underrepresented. We attribute this to the relative lack of high-confidence structural data and suitable pre-training objectives. In this context, we introduce BioCLIP, a contrastive learning framework that pre-trains PSMs by leveraging PLMs, generating meaningful per-residue and per-chain structural representations. When evaluated on tasks such as protein-protein interaction, Gene Ontology annotation, and Enzyme Commission number prediction, BioCLIP-trained PSMs consistently outperform models trained from scratch and further enhance performance when merged with sequence embeddings. Notably, BioCLIP approaches, or exceeds, specialized methods across all benchmarks using its singular pre-trained design. Our work addresses the challenges of obtaining quality structural data and designing self-supervised objectives, setting the stage for more comprehensive models of protein function. Source code is publicly available2.
Genome-wide SNP data reveal recent population structure ofHuidobria fruticosa(Loasaceae), a paleo-endemic lineage from the Atacama Desert
Authors: Merklinger Felix F. , Zheng Yichen , Böhnert Tim , Luebert Federico , Harpke Dörte , Stoll Alexandra , Wiehe Thomas , Koch Marcus , Quandt Dietmar 
Published: December 2023

ABSTRACTThe Atacama Desert is a biodiversity hotspot of neo-endemic radiation, where long-term aridity and complex physiographic processes create a unique environmental setting. Current species assemblages are mainly concentrated in highly patchy loma formations, and plant populations occurring in these are often geographically isolated from each other. Despite a general consensus on long-term aridity in the Atacama, climatological and geological evidence points to repeated climate change, making the Atacama Desert an ideal system for studying population genetic processes in highly unstable habitats. We are analyzing the genetic structure within and between populations ofHuidobria fruticosa, a paleo-endemic lineage of the Atacama Desert, to shed new light on its biogeographic history and broaden our understanding of the evolution of life in extreme aridity, as well as plant evolution in response to a changing environment. To do this, we analyzed SNP data from genotyping-by-sequencing of 354 individuals from 21 populations. Our results suggest that, despite being an ancient lineage, the current population structure ofHuidobria fruticosaonly reflects changing abiotic conditions over the last 2 million years. We therefore conclude that the present distribution, together with the evolutionary processes documented here, is the result of climatic fluctuations and prolonged periods of hyperaridity during the Pleistocene. Building on this understanding, our findings contribute to a global narrative that highlights the complex interplay between climate change and evolutionary dynamics, and emphasize the importance of deserts as living laboratories for deciphering how species have historically adapted to some of the most extreme habitats on Earth.
Innate extracellular Hsp70 inflammatory properties are mediated by the interaction of Siglec-E and LOX-1 receptors
Authors: Borges Thiago J. , Lima Karina , Murshid Ayesha , Lape Isadora T. , Zhao Yunlong , Rigo Maurício M. , Lang Benjamin J. , Siddiqui Shoib S. , Hui Enfu , Riella Leonardo V. , Bonorino Cristina , Calderwood Stuart K 
Published: December 2023

AbstractInnate immune responses to cell damage-associated molecular patterns induce a controlled degree of inflammation, ideally avoiding the promotion of intense unwanted inflammatory adverse events. When released by damaged cells, Hsp70 can stimulate different responses that range from immune activation to immune suppression. The effects of Hsp70 are mediated through innate receptors expressed primarily by myeloid cells, such as dendritic cells (DCs). The regulatory innate receptors that bind to extracellular mouse Hsp70 (mHsp70) are not fully characterized, and neither are their potential interactions with activating innate receptors. Here, we describe that extracellular mHsp70 interacts with a receptor complex formed by inhibitory Siglec-E and activating LOX-1 on DCs. We also find that this interaction takes place within lipid microdomains, and Siglec-E acts as a negative regulator of LOX-1-mediated innate activation upon mHsp70 or oxidized LDL binding. Thus, HSP70 can both bind to and modulate the interaction of inhibitory and activating innate receptors on the cell surface. These findings add another dimension of regulatory mechanism to how self-molecules contribute to dampening of exacerbated inflammatory responses.
Differences in stomatal sensitivity to CO2and light influences variation in water use efficiency and leaf carbon isotope composition in two genotypes of the C4plantZea mays
Authors: Crawford Joseph D , Twohey Robert J. , Pathare Varsha S. , Studer Anthony J. , Cousins Asaph B. 
Published: December 2023

AbstractThe ratio of net CO2uptake (Anet) and stomatal conductance (gs) is an intrinsic measurement of leaf water use efficiency (WUEi) however its measurement can be challenging for large phenotypic screens. Measurements of leaf carbon isotope composition (δ13Cleaf) may be a scalable tool to approximateWUEifor screening because it in part reflects the competing influences ofAnetandgson the CO2partial pressure (pCO2) inside the leaf over time. However, in C4photosynthesis the CO2concentrating mechanism complicates the relationship between δ13CleafandWUEi. Despite this complicated relationship, several studies have shown genetic variation in δ13Cleafacross C4plants. Yet there has not been a clear demonstration of whetherAnetorgsare the causal mechanisms controllingWUEiand δ13Cleaf. Our approach was to characterize leaf photosynthetic traits of twoZea maysrecombinant inbred lines (Z007E0067 and Z007E0150) which consistently differ for δ13Cleafeven though they have minimal confounding genetic differences. We demonstrate that these two genotypes contrasted inWUEidriven by differences in the speed of stomatal responses to changes inpCO2and light that lead to unproductive leaf water loss. These findings provide support that differences in δ13Cleafin closely related genotypes do reflect greaterWUEiand further suggests that differences in stomatal kinetic response to changing environmental conditions is a key target to improveWUEi.
Remote memory engrams are controlled by encoding-specific tau phosphorylation
Authors: Stefanoska Kristie , Prikas Emmanuel , Lin Yijun , Kosonen Renée , Ittner Arne 
Published: December 2023

AbstractThe engram represents the physical trace that encodes a specific memory and enables its recall1–4. Functional failure of the engram is linked to the progressive memory decline in Alzheimer’s disease5. However, it is unknown whether the microtubule-associated protein tau, a central factor in Alzheimer’s6,7, has a direct function in the engram. Here, we demonstrate that tau and encoding-associated tau phosphorylation are critical for robust remote memory engrams. Tau is required specifically during memory formation for remote, yet not proximal recall in memory paradigms in mice. Controlled expression of tau exclusively during memory entrainment is necessary and sufficient to restore remote memory deficits intauknockout mice. Tau is phosphorylated at specific sites during encoding. Gene editing to ablate site-specific phosphorylation at threonine-205 (T205) lowers precision of engram cell recruitment and precludes efficient remote recall. Vector-based engineering of engram cells reveals that T205 phosphorylation of tau is required to engrain memory for recall at remote timepoints. Notably, in the absence oftau, memory is recalled from latency by direct optogenetic activation of engram cells at distal time points but not when natural cues are used, revealing an association-specific gatekeeper function of tau during encoding. Our work delineates a physiologic role of site-specific tau phosphorylation at the inception of episodic memory to support an enduring engram and enable efficient remote recall. Thus, encoding-associated phosphorylation of tau is proximal to the elusive substrate of remote memory and may connect to the basis of amnesia in Alzheimer’s disease.
Improved Peptide Docking with Privileged Knowledge Distillation using Deep Learning
Authors: Zhang Zicong , Verburgt Jacob , Kagaya Yuki , Christoffer Charles , Kihara Daisuke 
Published: December 2023

AbstractProtein-peptide interactions play a key role in biological processes. Understanding the interactions that occur within a receptor-peptide complex can help in discovering and altering their biological functions. Various computational methods for modeling the structures of receptor-peptide complexes have been developed. Recently, accurate structure prediction enabled by deep learning methods has significantly advanced the field of structural biology. AlphaFold (AF) is among the top-performing structure prediction methods and has highly accurate structure modeling performance on single-chain targets. Shortly after the release of AlphaFold, AlphaFold-Multimer (AFM) was developed in a similar fashion as AF for prediction of protein complex structures. AFM has achieved competitive performance in modeling protein-peptide interactions compared to previous computational methods; however, still further improvement is needed. Here, we present DistPepFold, which improves protein-peptide complex docking using an AFM-based architecture through a privileged knowledge distillation approach. DistPepFold leverages a teacher model that uses native interaction information during training and transfers its knowledge to a student model through a teacher-student distillation process. We evaluated DistPepFold’s docking performance on two protein-peptide complex datasets and showed that DistPepFold outperforms AFM. Furthermore, we demonstrate that the student model was able to learn from the teacher model to make structural improvements based on AFM predictions.
Soil stockpile age does not impact vegetation establishment in a cold, arid natural gas field
Authors: Curran Michael F. , Sorenson Joshua R. , Robinson Timothy J. 
Published: December 2023

AbstractLand reclamation is critical to ensure surface disturbance associated with natural gas development is not permanent. Soil management is critical to reclamation success, especially in environments which are challenged by aridity. Typically, natural gas well pad construction involves stripping topsoil to allow for equipment to be on level ground and placing it into a stockpile. After well pad construction is complete, soil is respread and seeded across a large portion of the initial disturbance to initiate interim reclamation. With the advent of new extraction technologies (e.g., directional drilling), it is not always known how many individual wells will be placed on a given well pad until results from exploratory tests are examined. Previous research has shown soil disturbance during natural gas well pad construction and subsequent reclamation in cold, arid environments is highest at the stripping and respreading phases, with minimal soil activity occurring during the stockpile phase. Other research has shown that additional soil disturbances after reclamation is initiated may exacerbate soil damage, limiting revegetation potential. However, no studies have been conducted to determine if soil stockpile age impacts vegetation emergence. Here, we examine soil stockpiles which are 1-7 years old in the Jonah Infill natural gas field for vegetation emergence and vegetation cover using an image analysis software called SamplePoint. In a ten-week greenhouse experiment, we found vegetation cover across stockpile age-classes increased uniformly during the study period but that there was no significant difference in rate of vegetation cover increase or percent vegetation cover over time. These findings suggest it may be better to keep soil stockpiled in cold, arid natural gas fields when it is uncertain if additional construction activities will be required on a well pad location rather than respreading soil with a chance that redisturbance is necessary.
Inflammatory dietary potential is associated with vitamin depletion and gut microbial dysbiosis in early pregnancy
Authors: Alvernaz Suzanne A. , Wenzel Elizabeth S. , Nagelli Unnathi , Pezley Lacey B. , LaBomascus Bazil , Gilbert Jack A. , Maki Pauline M. , Tussing-Humphreys Lisa , Bernabé Beatriz Peñalver 
Published: December 2023

AbstractBackgroundPregnancy alters many physiological systems, including the maternal gut microbiota. Diet is a key regulator of this system and can alter the host immune system to promote inflammation. Multiple perinatal disorders have been associated with inflammation, maternal metabolic alterations, and gut microbial dysbiosis, including gestational diabetes mellitus, preeclampsia, preterm birth, and mood disorders. However, the effects of high inflammatory diets on the gut microbiota during pregnancy have yet to be fully explored.ObjectiveTo use a systems-based approach to characterize associations among dietary inflammatory potential, a measure of diet quality, and the gut microbiome during pregnancy.MethodsForty-nine pregnant persons were recruited prior to 16 weeks of gestation. Participants completed a food frequency questionnaire (FFQ) and provided fecal samples. Dietary inflammatory potential was assessed using the Dietary Inflammatory Index (DII) from FFQ data. Fecal samples were analyzed using 16S rRNA amplicon sequencing. Differential taxon abundance with respect to DII score were identified, and microbial metabolic potential was predicted using PICRUSt2.ResultsInflammatory diets were associated with decreased vitamin and mineral intake and dysbiotic gut microbiota structure and predicted metabolism. Gut microbial compositional differences revealed a decrease in short chain fatty acid producers such asFaecalibacterium,and an increase in predicted vitamin B12 synthesis, methylglyoxal detoxification, galactose metabolism and multi drug efflux systems in pregnant individuals with increased DII scores.ConclusionsDietary inflammatory potential was associated with a reduction in the consumption of vitamins & minerals and predicted gut microbiota metabolic dysregulation.
Structure-based virtual screening and Molecular Dynamic Simulations identified FDA-approved molecules as potential inhibitors against the surface proteins of H1N1
Authors: Bordoloi Sukanya , Prasad Roshny , Lakshmi VS , Chandramohanadas Rajesh , Natarajan Kathiresan , Nelson-Sathi Shijulal 
Published: December 2023

AbstractH1N1, a subtype of influenza A virus, remains a global concern due to its ability to cause highly contagious, and fatal infections of the respiratory tract that can lead to seasonal pandemics. Factors such as genetic reassortment and antigenic shift due to the segmented nature of its RNA genome, lead to its rapid evolution that impacts drug and vaccine interactions. Thus, there is growing interest in identifying small-molecules against H1N1 to address the challenges posed by its ever-changing nature and enhance ability to combat the virus. By targeting the surface proteins crucial in the viral life cycle and interactions with host cells, we conducted structure-based virtual screening of 2,471 FDA-approved small molecules against H1N1’s hemagglutinin (HA) and neuraminidase (NA) using molecular docking, and molecular dynamic simulations. A binding pocket for HA was identified at the interface of the three protomers, close to the fusion peptide, while in the case of NA the co-crystal ligand binding site was targeted. We identified 5 molecules, namely Econazole, Butoconazole, Miconazole, Isoconazole, and Tioconazole with higher binding affinity to HA and 4 molecules, namely Acarbose, Rutin, Paromomycin, and Idarubicin showing superior binding affinity to NA. Further molecular dynamic simulation of these molecules bound with HA and NA reaffirm the stability of the complexes. These molecules are known to have antifungal and antiviral properties. Thus, this study elucidates the importance of targeting HA and NA and paves the way for repurposing existing antivirals, antibacterials, and antifungals as inhibitors of the H1N1 viral entry into host cells.
Genetic load, eco-evolutionary feedback and extinction in metapopulations
Authors: Olusanya Oluwafunmilola , Khudiakova Ksenia , Sachdeva Himani 
Published: December 2023

AbstractHabitat fragmentation poses a significant risk to population survival, causing both demographic stochasticity and genetic drift within local populations to increase, thereby increasing genetic load. Higher load causes population numbers to decline, which reduces the efficiency of selection and further increases load, resulting in a positive feedback which may drive entire populations to extinction. Here, we investigate this eco-evolutionary feedback in a metapopulation consisting of local demes connected via migration, with individuals subject to deleterious mutation at a large number of loci. We first analyse the determinants of load under soft selection, where population sizes are fixed, and then build upon this to understand hard selection, where population sizes and load co-evolve. We show that under soft selection, very little gene flow (less than one migrant per generation) is enough to prevent fixation of deleterious alleles. By contrast, much higher levels of migration are required to mitigate load and prevent extinction when selection is hard, with critical migration thresholds for metapopulation persistence increasing sharply as the genome-wide deleterious mutation rate becomes comparable to the baseline population growth rate. Moreover, critical migration thresholds are highest if deleterious mutations have intermediate selection coefficients, but lower if alleles are predominantly recessive rather than additive (due to more efficient purging of recessive load within local populations). Our analysis is based on a combination of analytical approximations and simulations, allowing for a more comprehensive understanding of the factors influencing load and extinction in fragmented populations.
Remodeling of the protein ubiquitylation landscape in the aging vertebrate brain
Authors: Marino Antonio , Fraia Domenico Di , Panfilova Diana , Sahu Amit Kumar , Ori Alessandro 
Published: December 2023

ABSTRACTPost-translational modifications (PTMs) regulate protein homeostasis and function. How aging affects the landscape of PTMs remains largely elusive. Here, we reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the aging brain of mice. We show that aging has a major impact on protein ubiquitylation and that 29% of the ubiquitylation sites are affected independently of protein abundance, indicating altered PTM stoichiometry. We found a subset of these sites to be also affected in the brain of the short-lived killifishNothobranchius furzeri, highlighting a conserved aging phenotype. Furthermore, we estimated that over 35% of ubiquitylation changes observed in old mouse brains derive from partial proteasome inhibition, a well-established hallmark of brain aging. Our findings provide evidence of an evolutionarily conserved ubiquitylation signature of the aging brain and establish a causal link between proteasome inhibition and age-related remodeling of the ubiquitylome.
Temporal Tracking of Plasma Cellsin vivoUsing J-chain CreERT2 Reporter System
Authors: Borbet Timothy C. , Zaldaña Kimberly , Zavitsanou Anastasia-Maria , Hines Marcus J. , Bajwa Sofia , Morrison Tate , Boehringer Thomas , Hallisey Victoria M. , Cadwell Ken , Koralov Sergei B. 
Published: December 2023

AbstractPlasma cells (PCs) are essential for humoral immunity, as they are responsible for the production of antibodies and contribute to immunological memory. Despite their importance, differentiating between long-lived and short-lived PCsin vivoremains a challenge due to a lack of specific markers to distinguish these populations. Addressing this gap, our study introduces a novel J-chain CreERT2 GFP allele (IgJCreERT2) for precise genetic studies of PCs. This model takes advantage of PC-restricted expression of the J-chain gene, enabling temporal and cell-specific tracking of PCs utilizing a tamoxifen-inducible Cre recombinase. Ourin vitroandin vivovalidation studies of the inducible Cre allele confirmed the fidelity and utility of this model and demonstrated the model’s ability to trace the long-lived PC populationin vivofollowing immunization. The IgJCreERT2model allowed for detailed analysis of surface marker expression on PCs, revealing insights into PC heterogeneity and characteristics. Our findings not only validate the IgJCreERT2mouse as a reliable tool for studying PCs but also facilitate the investigation of PC dynamics and longevity, particularly in the context of humoral immunity and vaccine responses. This model represents a significant advancement for the in-depth study of PCs in health and disease, offering a new avenue for the exploration of PC biology and immunological memory.