bluuebunny/crossref_metadata_2025_split huggingface dataset:
An automated and fast sample preparation workflow for laser microdissection guided ultrasensitive proteomics
Authors: Makhmut Anuar , Qin Di , Hartlmayr David , Seth Anjali , Coscia Fabian 
Published: December 2023

ABSTRACTSpatial tissue proteomics integrating whole-slide imaging, laser microdissection and ultrasensitive mass spectrometry is a powerful approach to link cellular phenotypes to functional proteome states in (patho)physiology. To be applicable to large patient cohorts and low sample input amounts, including single-cell applications, loss-minimized and streamlined end-to-end workflows are key. We here introduce an automated sample preparation protocol for laser microdissected samples utilizing the cellenONE® robotic system, which has the capacity to process 192 samples in three hours. Following laser microdissection collection directly into the proteoCHIP LF 48 or EVO 96 chip, our optimized protocol facilitates lysis, formalin de-crosslinking and tryptic digest of low-input archival tissue samples. The seamless integration with the Evosep ONE LC system by centrifugation allows ‘on-the-fly’ sample clean-up, particularly pertinent for laser microdissection workflows. We validate our method in human tonsil archival tissue, where we profile proteomes of spatially-defined B-cell, T-cell and epithelial microregions of 4,000 µm2to a depth of ∼2,000 proteins and with high cell type specificity. We finally provide detailed equipment templates and experimental guidelines for broad accessibility.
Metabolic abnormalities in the bone marrow cells of young offspring born to obese mothers
Authors: Phillips Elysse , Alharithi Yem , Kadam Leena , Coussens Lisa M. , Kumar Sushil , Maloyan Alina 
Published: December 2023

ABSTRACTIntrauterine metabolic reprogramming occurs in obese mothers during gestation, putting the offspring at high risk of developing obesity and associated metabolic disorders even before birth. We have generated a mouse model of maternal high-fat diet-induced obesity that recapitulates the metabolic changes seen in humans. Here, we profiled and compared the metabolic characteristics of bone marrow cells of newly weaned 3-week-old offspring of dams fed either a high-fat (Off-HFD) or a regular diet (Off-RD). We utilized a state-of-the-art targeted metabolomics approach coupled with a Seahorse metabolic analyzer. We revealed significant metabolic perturbation in the offspring of HFD-fed vs. RD-fed dams, including utilization of glucose primarily via oxidative phosphorylation, and reduction in levels of amino acids, a phenomenon previously linked to aging. Furthermore, in the bone marrow of three-week-old offspring of high-fat diet-fed mothers, we identified a unique B cell population expressing CD19 and CD11b, and found increased expression of Cyclooxygenase-2 (COX-2) on myeloid CD11b, and on CD11bhiB cells, with all the populations being significantly more abundant in offspring of dams fed HFD but not a regular diet. Altogether, we demonstrate that the offspring of obese mothers show metabolic and immune changes in the bone marrow at a very young age and prior to any symptomatic metabolic disease.
Altered Glia-Neuron Communication in Alzheimer’s Disease Affects WNT, p53, and NFkB Signaling Determined by snRNA-seq
Authors: Soelter Tabea M. , Howton Timothy C. , Clark Amanda D. , Oza Vishal H. , Lasseigne Brittany N. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease is the most common cause of dementia and is characterized by amyloid-β plaques, tau neurofibrillary tangles, and neuronal loss. Although neuronal loss is a primary hallmark of Alzheimer’s disease, it is known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk. Many signaling pathways have been proposed to be dysregulated in Alzheimer’s disease, including WNT, TGFβ, p53, mTOR, NFkB, and Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia and neurons.MethodsUsing public snRNA-sequencing data generated from postmortem human prefrontal cortex, we predicted altered cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells) and neurons (excitatory and inhibitory). We confirmed interactions in a second and third independent orthogonal dataset. We determined cell-type-specificity using Jaccard Similarity Index and investigated the downstream effects of altered interactions in inhibitory neurons through gene expression and transcription factor activity analyses of signaling mediators. Finally, we determined changes in pathway activity in inhibitory neurons.ResultsCell-cell communication between glia and neurons is altered in Alzheimer’s disease in a cell-type-specific manner. As expected, ligands are more cell-type-specific than receptors and targets. We identified ligand-receptor pairs in three independent datasets and found involvement of the Alzheimer’s disease risk genesAPPandAPOEacross datasets. Most of the signaling mediators of these interactions were not differentially expressed, however, the mediators that are also transcription factors had differential activity between AD and control. Namely,MYCandTP53, which are associated with WNT and p53 signaling, respectively, had decreased TF activity in Alzheimer’s disease, along with decreased WNT and p53 pathway activity in inhibitory neurons. Additionally, inhibitory neurons had both increased NFkB signaling pathway activity and increased TF activity ofNFIL3, an NFkB signaling-associated transcription factor.ConclusionsCell-cell communication between glia and neurons in Alzheimer’s disease is altered in a cell-type-specific manner involving Alzheimer’s disease risk genes. Signaling mediators had altered transcription factor activity suggesting altered glia-neuron interactions may dysregulate signaling pathways including WNT, p53, and NFkB in inhibitory neurons.
Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Mice Consuming Alcohol Attenuates Glycolysis
Authors: Ehinger Yann , Laguesse Sophie , Phamluong Khanhky , Salvi Alexandra , Sei Yoshitaka J. , Hoisington Zachary W. , Soneja Drishti , Gunasekaran Sowmya , Nakamura Ken , Ron Dorit 
Published: December 2023

AbstractmTORC1 promotes protein translation, learning and memory, and neuroadaptations that underlie alcohol use and abuse. We report that activation of mTORC1 in the nucleus accumbens (NAc) of mice consuming alcohol promotes the translation of microRNA (miR) machinery components and the upregulation of microRNAs (miRs) expression including miR-34a-5p. In parallel, we detected a paradoxical mTORC1-dependent repression of translation of transcripts including Aldolase A, an essential glycolytic enzyme. We found that miR-34a-5p in the NAc targets Aldolase A for translation repression and promotes alcohol intake. Our data further suggest that glycolysis is inhibited in the NAc manifesting in an mTORC1-dependent attenuation of L-lactate, the end product of glycolysis. Finally, we show that systemic administration of L-lactate attenuates mouse excessive alcohol intake. Our data suggest that alcohol promotes paradoxical actions of mTORC1 on translation and glycolysis which in turn drive excessive alcohol use.
MolPad: An R-Shiny Package for Cluster Co-Expression Analysis in Longitudinal Microbiomics
Authors: Ma Kaiyan , Thairu Margaret W. , Sankaran Kris 
Published: December 2023

SummaryThe R-Shiny package MolPad provides an interactive dashboard for understanding the dynamics of longitudinal molecular co-expression in microbiomics. The main idea for addressing the issue is first to use a network to overview major patterns among their predictive relationships and then zoom into specific clusters of interest. It is designed with a focus-plus-context analysis strategy and automatically generates links to online curated annotations. The dashboard consists of a cluster-level network, a bar plot of taxonomic composition, a line plot of data modalities, and a table for each pathway. Further, the package includes functions that handle the data processing for creating the dashboard. This makes it beginner-friendly for users with less R programming experience. We illustrate these methods with a case study on a longitudinal metagenomics analysis of the cheese microbiome.
Metabolic imprints in the hydrogen isotopes ofArchaeoglobus fulgidustetraether lipids
Authors: Rhim Jeemin H. , Kopf Sebastian , McFarlin Jamie , Maloney Ashley E. , Batther Harpreet , Harris Carolynn M. , Zhou Alice , Feng Xiahong , Weber Yuki , Hoeft-McCann Shelley , Pearson Ann , Leavitt William D. 
Published: December 2023

AbstractThe stable hydrogen isotope composition of archaeal lipids is emerging as a potential paleoenvironmental proxy, adding to the well-established application of plant leaf wax-derivedn-alkanes in paleohydrological reconstruction. A handful of studies reported relatively invariant and depleted hydrogen isotope compositions for archaeal lipids despite the range of different organisms and growth conditions explored. However, how modes of metabolism and physiological state (growth phase) affect the hydrogen isotope signatures of archaeal lipids remains poorly understood, limiting our ability to interpret archaeal lipid biomarker records from the environment. Here we conducted water isotope label experiments with a metabolically flexible and well-studied model archaeonArchaeoglobus fulgidusand quantified the hydrogen isotope fractionation between lipids and water in response to different carbon substrates and electron donor-acceptor pairs. The2H/1H fractionation between lipids and water (εL/W) was overall negative, ranging from –280 to –226 ‰, and overlapped with the ranges observed for other archaea in previous studies. Isotope flux-balance model results suggest that ≥80 % and ≥50 % of lipid-bound H inA. fulgiduscultures directly reflect water isotope compositions (i.e., not via organic substrate or H2) during autotrophy and heterotrophy, respectively. The model results also suggest the final saturation during isoprenoid lipid biosynthesis catalyzed by a flavoenzyme geranylgeranyl reductase likely contributes to the large2H/1H fractionation observed in this study, consistent with previous isotope flux-balance model results for a different archaeon. Finally, we synthesized available data to compare εL/Wpatterns across all three domains of life: Bacteria, Archaea and Eukarya. Emerging patterns between archaeal and eukaryotic lipids are consistent with the notion of highly fractionating geranylgeranyl reductase, and the patterns between archaeal and bacterial lipids suggest that the general state of energy limitation may also contribute to large, negative values of εL/Wobserved in prokaryotic lipids. Altogether, these findings lend further support for the potential of archaeal lipid εL/Was a paleohydrological proxy and provide a broader insight into the2H/1H fractionation mechanisms potentially shared among prokaryotic and eukaryotic lipid biomarkers.
Dynamics of drug delivery determines course of evolution of antibiotic responses in bacteria
Authors: Crow John C. , Geng Hao , Sullivan Timothy J. , Soucy Shannon M. , Schultz Daniel 
Published: December 2023

AbstractTo adjust to sudden shifts in conditions, microbes possess regulated genetic mechanisms that sense environmental challenges and induce the appropriate responses. The initial evolution of microbes in new environments is thought to be driven by regulatory mutations, but it is not clear how this evolution is affected by how quickly conditions change (i.e. dynamics). Here, we perform experimental evolution on continuous cultures of tetracycline resistantE. coliin different dynamical regimens of drug administration. We find that cultures evolved under gradually increasing drug concentrations acquire fine-tuning mutations adapting an alternative efflux pump to tetracycline. However, cultures that are instead periodically exposed to large drug doses evolve transposon insertions resulting in loss of regulation of the main mechanism of tetracycline resistance. A mathematical model shows that sudden drug exposures overwhelm regulated responses, which cannot induce resistance fast enough. These results help explain the frequent loss of regulation of resistance in clinical pathogens.
Antiviral humoral immunity against SARS-CoV-2 Omicron subvariants induced by XBB.1.5 monovalent vaccine in infection-naïve and XBB-infected individuals
Authors: Kosugi Yusuke , Kaku Yu , Hinay Alfredo A , Guo Ziyi , Uriu Keiya , Kihara Minoru , Saito Fumitake , Uwamino Yoshifumi , Kuramochi Jin , Shirakawa Kotaro , Takaori-Kondo Akifumi ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Sato Kei 
Published: December 2023

AbstractTo control infection with SARS-CoV-2 Omicron XBB subvariants, the XBB.1.5 monovalent mRNA vaccine has been available since September 2023. However, we have found that natural infection with XBB subvariants, including XBB.1.5, does not efficiently induce humoral immunity against the infecting XBB subvariants. These observations raise the possibility that the XBB.1.5 monovalent vaccine may not be able to efficiently induce humoral immunity against emerging SARS-CoV-2 variants, including a variety of XBB subvariants (XBB.1.5, XBB.1.16, XBB.2.3, EG.5.1 and HK.3) as well as BA.2.86. To address this possibility, we collected two types of sera from individuals vaccinated with the XBB.1.5 vaccine; those who had not been previously infected with SARS-CoV-2 and those who had been infected with XBB subvariants prior to XBB.1.5 vaccination. We collected sera before and 3-4 weeks after vaccination, and then performed a neutralization assay using these sera and pseudoviruses.
Traumatic brain injury and Alzheimer’s Disease biomarkers: A systematic review of findings from amyloid and tau positron emission tomography (PET)
Authors: Dybing Kaitlyn M. , Vetter Cecelia J. , Dempsey Desarae A. , Chaudhuri Soumilee , Saykin Andrew J. , Risacher Shannon L. 
Published: December 2023

AbstractTraumatic brain injury (TBI) has been discussed as a risk factor for Alzheimer’s disease (AD) due to its association with dementia risk and earlier cognitive symptom onset. However, the mechanisms behind this relationship are unclear. Some studies have suggested TBI may increase pathological protein deposition in an AD-like pattern; others have failed to find such associations. This review covers literature that uses positron emission tomography (PET) of amyloid-β and/or tau to examine subjects with history of TBI who are at risk for AD due to advanced age. A comprehensive literature search was conducted on January 9, 2023, and 24 resulting citations met inclusion criteria. Common methodological concerns included small samples, limited clinical detail about subjects’ TBI, recall bias due to reliance on self-reported TBI, and an inability to establish causation. For both amyloid and tau, results were widespread but inconsistent. The regions which showed the most compelling evidence for increased amyloid deposition were the cingulate gyrus, cuneus/precuneus, and parietal lobe. Evidence for increased tau was strongest in the medial temporal lobe, entorhinal cortex, precuneus, and frontal, temporal, parietal, and occipital lobes. However, conflicting findings across most regions of interest in both amyloid- and tau-PET studies indicate the critical need for future work in expanded samples and with greater clinical detail to offer a clearer picture of the relationship between TBI and protein deposition in older subjects at risk for AD.
Population age as a key factor in the COVID-19 pandemic dynamics
Authors: Nesteruk Igor , Keeling Matt 
Published: December 2023

ABSTRACTThe population and governments of many countries are losing interest in the SARS-CoV-2 infection, the number of tests and the number of new cases detected is sharply decreasing. To compare the accumulated numbersCCof cases and deathsDCper million and to answer the question why the less vaccinated Africa has accumulated 36 times lowerCCvalues and 15 times lowerDCvalues than Europe, simple statistical analysis have been performed.CCandDCvalues demonstrated rather strong correlation with the median age of populations. One-year increment in the median year yields 12-18 thousand increase inCCvalues and 52-83 increase inDCvalues. Zero-COVID countries succeed to have much lower numbers of deaths per capita and case fatality ratiosDC/CC.
Inhibitory fear memory engram in the mouse central lateral amygdala
Authors: Hou Wen-Hsien , Jariwala Meet , Wang Kai-Yi , Seewald Anna , Lin Yu-Ling , Ricci Alessia , Ferraguti Francesco , Lien Cheng-Chang , Capogna Marco 
Published: December 2023

SUMMARYEngrams are cellular substrates of memory traces that have been identified in various brain areas, including the amygdala. Most engrams identified so far are formed by excitatory, glutamatergic neurons. However, little attention has been paid to defining GABAergic inhibitory engrams. Here, we report an inhibitory engram in the central lateral amygdala (CeL), a crucial area for Pavlovian fear conditioning. This engram is primarily composed of GABAergic somatostatin-expressing (SST+) and to a lesser extent of protein kinase C-δ-expressing [PKC-δ(+)] neurons. Fear memory is accompanied by a preferential enhancement of mIPSC frequency onto PKC-δ(+) neurons as well as a general increment of amplitude. Moreover, non-engram cells exhibit higher mIPSC frequency than engram cells. The inhibition of the CeL GABAergic engram disinhibits the activity of engram-targeted areas and increases selectively the encoded fear expression. Our data defines the behavioral function of an engram formed exclusively by GABAergic inhibitory neurons in the mammalian CNS.
Identifying Impacts of Contact Tracing on Epidemiological Inference from Phylogenetic Data
Authors: Kupperman Michael D. , Ke Ruian , Leitner Thomas 
Published: December 2023

AbstractRobust sampling methods are foundational to inferences using phylogenies. Yet the impact of using contact tracing, a type of non-uniform sampling used in public health applications such as infectious disease outbreak investigations, has not been investigated in the molecular epidemiology field. To understand how contact tracing influences a recovered phylogeny, we developed a new simulation tool called SEEPS (Sequence Evolution and Epidemiological Process Simulator) that allows for the simulation of contact tracing and the resulting transmission tree, pathogen phylogeny, and corresponding virus genetic sequences. Importantly, SEEPS takes within-host evolution into account when generating pathogen phylogenies and sequences from transmission histories. Using SEEPS, we demonstrate that contact tracing can significantly impact the structure of the resulting tree, as described by popular tree statistics. Contact tracing generates phylogenies that are less balanced than the underlying transmission process, less representative of the larger epidemiological process, and affects the internal/external branch length ratios that characterize specific epidemiological scenarios. We also examined real data from a 2007-2008 Swedish HIV-1 outbreak and the broader 1998-2010 European HIV-1 epidemic to highlight the differences in contact tracing and expected phylogenies. Aided by SEEPS, we show that the data collection of the Swedish outbreak was strongly influenced by contact tracing even after downsampling, while the broader European Union epidemic showed little evidence of universal contact tracing, agreeing with the known epidemiological information about sampling and spread. Overall, our results highlight the importance of including possible non-uniform sampling schemes when examining phylogenetic trees. For that, SEEPS serves as a useful tool to evaluate such impacts, thereby facilitating better phylogenetic inferences of the characteristics of a disease outbreak. SEEPS is available atgithub.com/MolEvolEpid/SEEPS.
Hepatic Vagal Afferents Convey Clock-Dependent Signals to Regulate Circadian Food Intake
Authors: Woodie Lauren N. , Melink Lily C. , Midha Mohit , de Araújo Alan M. , Geisler Caroline E. , Alberto Ahren J. , Krusen Brianna M. , Zundell Delaine M. , de Lartigue Guillaume , Hayes Matthew R. , Lazar Mitchell A. 
Published: December 2023

AbstractCircadian desynchrony induced by shiftwork or jetlag is detrimental to metabolic health, but how synchronous/desynchronous signals are transmitted among tissues is unknown. Here we report that liver molecular clock dysfunction is signaled to the brain via the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a previously unrecognized homeostatic feedback signal that relies on synchrony between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a therapeutic target for obesity in the setting of chrono-disruption.One Sentence SummaryThe hepatic vagal afferent nerve signals internal circadian desynchrony between the brain and liver to induce maladaptive food intake patterns.
Sensitivity analysis of a mechanistic model of rumen fermentation and methane production by rumen microbiota in the presence ofAsparagopsis taxiformis
Authors: Merk Katarina , Link Kathryn G. , Guy Robert D. , Hess Matthias 
Published: December 2023

AbstractRuminant animals rely on microbes for the conversion of complex plant material into host accessible metabolites. During this anaerobic conversion of plant biomass, termed enteric fermentation, methanogenic archaea convert hydrogen into the potent greenhouse gas methane (CH4). The search for methane mitigation strategies to combat climate change has identified the red seaweedAsparagopsis taxiformisas a promising feed additive that, when added to a regular cattle diet, reduced enteric CH4by over 80%. A more complete understanding of microbial interactions during enteric fermentation is needed for ongoing improvement to mitigation methods. Mathematical models that permitin silicosimulation of enteric fermentation allow for the identification of key parameters that drive rumen methane production. Here we built upon an existing rumen fermentation model and calibrated it using a preliminary classification of functional microbial groups and gas emission data from a previously publishedin vitrorumen fermentation experiment, but many microbes remained functionally unclassified. The model was then used to conduct anin silicoexperiment to explore how the partition of functionally unclassified microbes into functional groups affects methane output. Thesein silicoexperiments identified that model methane production is more sensitive to microbial variation in the presence ofA. taxiformisversus without. The use of local and global sensitivity analysis approaches revealed other rumen parameters to also be drivers of enteric methane production. In the presence ofA. taxiformis, parameters modulating methane production include bromoform concentration, methanogen abundance, total microbial concentration, a parameter effecting the inhibition of methanogen growth rate by the action of bromoform, and the maximum specific utilization rate of hydrogen. WithoutA. taxiformis, feed composition parameters, the hydrolysis rate constant of cell wall carbohydrates, and a parameter affecting the yield factors during sugar utilization were found to be most significant. For possible methane reduction withoutA. taxiformis, we propose an adjustment in feed composition parameters that reduces predicted methane by 25.6%.