bluuebunny/crossref_metadata_2025_split huggingface dataset:
Network States in the Basolateral Amygdala Predicts Voluntary Alcohol Consumption
Authors: DiLeo Alyssa , Antonodiou Pantelis , Blandino Katrina , Conlin Eli , Melón Laverne , Maguire Jamie L. 
Published: June 2023

AbstractAlthough most adults in the United States will drink alcohol in their life, only about 6% will go on to develop an alcohol use disorder (AUD). While a great deal of work has furthered our understanding of the cycle of addiction, it remains unclear why certain people transition to disordered drinking. Altered activity in regions implicated in AUDs, like the basolateral amygdala (BLA), has been suggested to play a role in the pathophysiology of AUDs, but how these networks contribute to alcohol misuse remains unclear. Our recent work demonstrated that alcohol can modulate BLA network states and that GABAergic parvalbumin (PV) interneurons are crucial modulators of network activity in the BLA. Further, our lab has demonstrated that δ subunit-containing GABAAreceptors, which are modulated by alcohol, are highly expressed on PV interneurons in the BLA. These receptors on PV interneurons have also been shown to influence alcohol intake in a voluntary binge drinking paradigm and anxiety-like behavior in withdrawal. Therefore, we hypothesized that alcohol may impact BLA network states via δ subunit-containing GABAAreceptors on PV interneurons to impact the extent of alcohol use. To test this hypothesis, we measured the impact of acute alcohol exposure on oscillatory states in the basolateral amygdala and then assessed the relationship to the extent of voluntary ethanol consumption in the Intermittent Access, Drinking-in-the-Dark-Multiple Scheduled Access, and Chronic Intermittent Ethanol exposure paradigms. Remarkably, we demonstrate that the average alcohol intake negatively correlates with δ subunit-containing GABAAreceptor expression on PV interneurons and gamma power in the BLA after the first exposure to alcohol. These data implicate δ subunit-containing GABAAreceptor expression on PV interneurons in the BLA in voluntary alcohol intake and suggest that BLA network states may serve as a useful biomarker for those at risk for alcohol misuse.Significance StatementOscillatory states in the BLA have been demonstrated to drive behavioral states involved in emotional processing, including negative valence processing. Given that negative emotional states/hyperkatifeia contribute to the cycle of AUDs, our previous work demonstrating the ability of alcohol to modulate BLA network states and thereby behavioral states suggests that this mechanism may influence alcohol intake. Here we demonstrate a relationship between the ability of alcohol to modulate oscillations in the BLA and future alcohol intake such that the extent to which alcohol influences BLA network states predict the extent of future voluntary alcohol intake. These findings suggest that individual variability in the sensitivity of the BLA network to alcohol influences voluntary alcohol consumption.
Developmental exposure to the Parkinson’s disease-associated organochlorine pesticide dieldrin alters dopamine neurotransmission in α- synuclein pre-formed fibril (PFF)-injected mice
Authors: Boyd Sierra L. , Kuhn Nathan C. , Patterson Joseph R. , Stoll Anna C. , Zimmerman Sydney A. , Kolanowski Mason R. , Neubecker Joseph J. , Luk Kelvin C. , Ramsson Eric S. , Sortwell Caryl E. , Bernstein Alison I. 
Published: June 2023

AbstractParkinson’s disease (PD) is the most common movement disorder and one of the fastest-growing neurological diseases worldwide. This increase outpaces the rate of aging and is most rapid in recently industrialized areas, suggesting the role of environmental factors. Consistent with this, epidemiological studies show an association between exposure to persistent organic pollutants and an increased risk of PD. When combined with post-mortem analysis and mechanistic studies, a role for specific compounds, including the organochlorine pesticide dieldrin, emerges. In mouse models, developmental dieldrin exposure causes male-specific exacerbation of neuronal susceptibility to MPTP and synucleinopathy. Specifically, our novel two-hit model combining developmental dieldrin exposure with the α-synuclein (α-syn) pre-formed fibril (PFF) model showed a male-specific exacerbation of PFF-induced increases in striatal dopamine (DA) turnover and motor deficits on the challenging beam 6 months post-PFF injection in male offspring developmentally exposed to dieldrin. Here, we hypothesized that alterations in DA handling contribute to the observed changes and assessed vesicular monoamine transporter 2 (VMAT2) function and DA release in this dieldrin/PFF two-hit model. Female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin or vehicle every 3 days, starting at 8 weeks of age by feeding and continuing throughout breeding, gestation, and lactation. Male offspring from independent litters underwent unilateral, intrastriatal injections of α-syn PFFs via stereotaxic surgery at 12 weeks of age and DA handling was assessed 4 months post-PFF injection via vesicular3H-DA uptake assay and fast-scan cyclic voltammetry (FSCV). We observed no dieldrin-associated change in VMAT2 activity, but a dieldrin-induced increase in DA release in striatal slices in PFF-injected animals. These results suggest that developmental dieldrin exposure alters the dopaminergic response to synucleinopathy-triggered toxicity and supports our hypothesis that alterations in DA handling may underly the observed exacerbation of PFF-induced deficits in motor behavior and DA turnover.Graphical Abstract
Soil carbon mineralization and microbial community dynamics in response to PyOM addition
Authors: Zeba Nayela , Berry Timothy D. , Fischer Monika S. , Traxler Matthew F. , Whitman Thea 
Published: June 2023

AbstractWildfires can either negatively impact soil carbon (C) stocks through combustion or increase soil carbon stocks through the production of pyrogenic organic matter (PyOM), which is highly persistent and can affect non-pyrogenic soil organic carbon (SOC) mineralization rates. In this study, we used fine-resolution13CO2flux tracing to investigate PyOM-C mineralization, soil priming effects, and their impacts on soil microbial communities in a Californian mixed conifer forest Xerumbrept soil burned in the 2014 King Fire. We added PyOM produced from pine biomass at 350 °C and 550 °C to the soil and separately traced the mineralization of13C-labeled water-extractable and non-water-extractable PyOM-C fractions in a short-term incubation.Our results indicate that the water-extractable fraction is 10-50x more mineralizable in both 350 °C and 550 °C PyOM treatments than the SOC or non-water-extractable PyOM fraction. 350 °C PyOM addition led to a short-term positive priming effect, likely due to co-metabolism of easily mineralizable PyOM-C and the SOC, whereas 550 °C PyOM addition induced negative priming, potentially due to physical protection of SOC. We observed significant shifts in bacterial community composition in response to both 350 °C and 550 °C PyOM, with positive PyOM responders belonging to the generaNoviherbaspirillum,Pseudonocardia, andGemmatimonas. In contrast, fungal communities were less responsive to PyOM additions. Our findings expand our understanding of the post-fire cycling of PyOM and SOC, providing insights into the microbial mineralization of different PyOM-C fractions and their influence on soil C dynamics in fire-affected ecosystems.
Identification of ERAD-dependent degrons for the endoplasmic reticulum lumen
Authors: Sharninghausen Rachel , Hwang Jiwon , Dennison Devon D. , Baldridge Ryan D. 
Published: June 2023

SummaryDegrons are minimal protein features that are sufficient to target proteins for degradation. In most cases, degrons allow recognition by components of the cytosolic ubiquitin proteasome system. Currently, all of the identified degrons only function within the cytosol. UsingSaccharomyces cerevisiae, we identified the first short linear sequences that function as degrons from the endoplasmic reticulum (ER) lumen. We show that when these degrons are transferred to proteins, they facilitate proteasomal degradation through the ERAD system. These degrons enable degradation of both luminal and integral membrane ER proteins, expanding the types of proteins that can be targeted for degradation in budding yeast and mammalian tissue culture. This discovery provides a framework to target proteins for degradation from the previously unreachable ER lumen and builds toward therapeutic approaches that exploit the highly-conserved ERAD system.
The genetic and dietary landscape of the muscle insulin signalling network
Authors: van Gerwen Julian , Masson Stewart W. C. , Cutler Harry B. , Díaz-Vegas Alexis , Potter Meg , Stöckli Jacqueline , Madsen Søren , Nelson Marin E. , Humphrey Sean J. , James David E. 
Published: June 2023

AbstractMetabolic disease is caused by a combination of genetic and environmental factors, yet few studies have examined how these factors influence signal transduction, a key mediator of metabolism. Using mass spectrometry-based phosphoproteomics, we quantified 23,126 phosphosites in skeletal muscle of five genetically distinct mouse strains in two dietary environments, with and without acutein vivoinsulin stimulation. Almost half of the insulin-regulated phosphoproteome was modified by genetic background on an ordinary diet, and high-fat high-sugar feeding affected insulin signalling in a strain-dependent manner. Our data revealed coregulated subnetworks within the insulin signalling pathway, expanding our understanding of the pathway’s organisation. Furthermore, associating diverse signalling responses with insulin-stimulated glucose uptake uncovered regulators of muscle insulin responsiveness, including the regulatory phosphosite S469 on Pfkfb2, a key activator of glycolysis. Finally, we confirmed the role of glycolysis in modulating insulin action in insulin resistance. Our results underscore the significance of genetics in shaping global signalling responses and their adaptability to environmental changes, emphasizing the utility of studying biological diversity with phosphoproteomics to discover key regulatory mechanisms of complex traits.
Re-investigating the correctness of decoy-based false discovery rate control in proteomics tandem mass spectrometry
Authors: Freestone Jack , Noble William Stafford , Keich Uri 
Published: June 2023

AbstractTraditional database search methods for the analysis of bottom-up proteomics tandem mass spectrometry (MS/MS) data are limited in their ability to detect peptides with post-translational modifications (PTMs). Recently, “open modification” database search strategies, in which the requirement that the mass of the database peptide closely matches the observed precursor mass is relaxed, have become popular as a way to find a wider variety of types of PTMs. Indeed, in one study, Konget al. reported that the open modification search tool MSFragger can achieve higher statistical power to detect peptides than a traditional “narrow window” database search. At the same time, Konget al. reported that their empirical results suggest a problem with false discovery (FDR) control in the narrow window setting. We investigated these claims empirically and, in the process, uncovered a potential problem with FDR control in the machine learning post-processors Percolator and PeptideProphet. However, we also found that, after accounting for chimeric spectra as well as for the inherent difference in the number of candidates in open and narrow searches, the data does not provide sufficient evidence that FDR control in proteomics MS/MS database search is problematic.
Pathway Centric Analysis for single-cell RNA-seq and Spatial Transcriptomics Data with GSDensity
Authors: Liang Qingnan , Huang Yuefan , He Shan , Chen Ken 
Published: June 2023

AbstractAdvances in single-cell technology have enabled molecular cellular dissection of heterogeneous biospecimens at unprecedented scales and resolutions. Although cluster-centric approaches followed by gene-set analysis can reveal distinct cell types and states, they have limited power in dissecting and interpretating highly heterogenous, dynamically evolving data. Here, we present GSDensity, a graph-modeling approach that allows users to obtain pathway-centric interpretation and dissection of single-cell and spatial transcriptomics (ST) data without performing clustering. We show that GSDensity can not only accurately detect biologically distinct gene sets but also reveal novel cell-pathway associations that are ignored by existing methods. This is particularly evident in characterizing cancer cell states that are transcriptomically distinct but are driven by shared tumor-immune interaction mechanisms. Moreover, we show that GSDensity, combined with trajectory analysis can identify pathways that are active at various stages of mouse brain development. Finally, we show that GSDensity can identify spatially relevant pathways in mouse brains including those following a high-order organizational patterns in the ST data. We also created a pan-cancer pathway activity ST map, which revealed pathways spatially relevant and recurrently active across six different tumor types. GSDensity is available as an open-source R package and can be widely applied to single-cell and ST data generated by various technologies.
Nonequilibrium switching of segmental states can influence compaction of chromatin
Authors: Sahoo Soudamini , Kadam Sangram , Padinhateeri Ranjith , Kumar P. B. Sunil 
Published: June 2023

Knowledge about the dynamic nature of chromatin organization is essential to understand the regulation of processes like DNA transcription and repair. While most models assume protein organization and chemical states along chromatin as static, experiments have shown that these are dynamic and lead to the switching of chromatin segments between different physical states. To understand the implications of this inherent nonequilibrium switching, we present a diblock copolymer model of chromatin, with switching of its segmental states between two states, mimicking active/repressed or protein unbound/bound states. We show that competition between switching timescaleTt, polymer relaxation timescaleτp, and segmental relaxation timescaleτscan lead to non-trivial changes in chromatin organization, leading to changes in local compaction and contact probabilities. As a function of the switching timescale, the radius of gyration of chromatin shows a non-monotonic behavior with a prominent minimum whenTt≈τpand a maximum whenTt≈τs. We find that polymers with a small segment length exhibit a more compact structure than those with larger segment lengths. We also find that the switching can lead to higher contact probability and better mixing of far-away segments. Our study also shows that the nature of the distribution of chromatin clusters varies widely as we change the switching rate.Significance statementDifferent cells in multicellular organisms have the same DNA but different functions. The function of any given cell type can be time-dependent. The current understanding is that differences in gene expression arising from local compaction and the probability for far-away regulatory segments to come in contact play an important role in establishing these differences. The necessary structural variations are achieved through a combination of changes in the chemical and physical states of chromatin regions. In this paper, we present a model for chromatin accounting for the dynamic switching of chromatin regions between different chemical and physical states. We demonstrate the implications of such switching in determining the local 3D structure of chromatin.
Stuck on a small tropical island: widein-situdiversification of an urban-dwelling bat
Authors: Aguillon Samantha , Castex Clara , Duchet Avril , Turpin Magali , Minter Gildas Le , Lebarbenchon Camille , Hoarau Axel O. G. , Toty Céline , Joffrin Léa , Tortosa Pablo , Mavingui Patrick , Goodman Steven M. , Dietrich Muriel 
Published: June 2023

AbstractBats are often the only mammals naturally colonizing isolated islands and are thus an excellent model to study evolutionary processes of insular ecosystems. Here, we studied the Reunion free-tailed bat (Mormopterus francoismoutoui), an endemic species to Reunion Island that has adapted to urban settings. At regional scale, we investigated the evolutionary history ofMormopterusspecies, as well as on Reunion Island sex-specific and seasonal patterns of genetic structure. We used an extensive spatio-temporal sampling including 1,136 individuals from 18 roosts and three biological seasons (non-reproductive/winter, pregnancy/summer, and mating), with additional samples fromMormopterusspecies from neighbouring islands (M. jugularisof Madagascar andM. acetabulosusof Mauritius). Complementary information gathered from both microsatellite and mitochondrial markers revealed a high genetic diversity but no signal of spatial genetic structure and weak evidence of female philopatry. Regional analysis suggests a single colonization event forM. francoismoutoui, dated around 175,000 years ago, and followed byin-situdiversification and the evolution of divergent ancestral lineages, which today form a large metapopulation. Population expansion was relatively ancient (55,000 years ago) and thus not linked to human colonization of the island and the availability of new anthropic day-roost sites. Discordant structure between mitochondrial and microsatellite markers suggests the presence of yet-unknown mating sites, or the recent evolution of putative ecological adaptations. Our study illustrates how understanding mechanisms involved in speciation can be challenging and the importance of both mitochondrial and nuclear DNA in resolving the widein-situdiversification of an urban-dwelling bat, endemic to a small island.
Genomic characterization of a nematode tolerance locus in sugar beet
Authors: Sielemann Katharina , Pucker Boas , Orsini Elena , Elashry Abdelnaser , Schulte Lukas , Viehöver Prisca , Müller Andreas E. , Schechert Axel , Weisshaar Bernd , Holtgräwe Daniela 
Published: June 2023

AbstractBackgroundInfection by beet cyst nematodes (BCN,Heterodera schachtii) causes a serious disease of sugar beet, and climatic change is expected to improve the conditions for BCN infection. Yield and yield stability under adverse conditions are among the main breeding objectives. Breeding of BCN tolerant sugar beet cultivars offering high yield in the presence of the pathogen is therefore of high relevance.ResultsTo identify causal genes providing tolerance against BCN infection, we combined several experimental and bioinformatic approaches. Relevant genomic regions were detected through mapping-by-sequencing using a segregating F2 population. DNA sequencing of contrasting F2 pools and analyses of allele frequencies for variant positions identified a single genomic region which confers nematode tolerance. The genomic interval was confirmed and narrowed down by genotyping with newly developed molecular markers. To pinpoint the causal genes within the potential nematode tolerance locus, we generated long read-based genome sequence assemblies of the tolerant parental breeding line Strube U2Bv and the susceptible reference line 2320Bv. We analyzed continuous sequences of the potential locus with regard to functional gene annotation and differential gene expression upon BCN infection. A cluster of genes with similarity to theArabidopsis thalianagene encoding nodule inception protein-like protein 7 (NLP7) was identified. Gene expression analyses confirmed transcriptional activity and revealed clear differences between susceptible and tolerant genotypes.ConclusionsOur findings provide new insights into the genomic basis of plant-nematode interactions that can be used to design and accelerate novel management strategies against BCN.
In-situ spectroscopic detection of large-scale reorientations of transmembrane α-helices during viroporin channel opening
Authors: Paschke Ronja , Mohr Swantje , Lange Sascha , Lange Adam , Kozuch Jacek 
Published: June 2023

AbstractViroporins are small ion channels in membranes of enveloped viruses that play key roles during viral life cycles. To use viroporins as drug targets against viral infection requires in-depth mechanistic understanding and, with that, methods that enable investigations under in-situ conditions. Here, we apply surface-enhanced infrared absorption (SEIRA) spectroscopy to Influenza A M2 reconstituted within a solid-supported membrane, to shed light on the mechanics of its viroporin function. M2 is a paradigm of pH-activated proton channels and controls the proton flux into the viral interior during viral infection. We use SEIRA to track the large-scale reorientation of M2’s transmembrane α-helices in-situ during pH-activated channel opening. We quantify this event as a helical tilt from 26° to 40° by correlating the experimental results with solid-state NMR-informed computational spectroscopy. This mechanical motion is impeded upon addition of the inhibitor rimantadine, giving a direct spectroscopic marker to test antiviral activity. The presented approach provides a spectroscopic tool to quantify large-scale structural changes and to track the function and inhibition of the growing number of viroporins from pathogenic viruses in future studies.
Functional precision oncology for follicular lymphoma with patient-derived xenograft in avian embryos
Authors: Zala Manon , Lipinski Boris , Costechareyre Clélia , Jarrosson Loraine , Teinturier Romain , Julia Edith , Lacourrège Marjorie , Verney Aurélie , Guitton Jérôme , Traverse-Glehen Alexandra , Bachy Emmanuel , Salles Gilles , Huet Sarah , Genestier Laurent , Castellani Valérie , Delloye-Bourgeois Céline , Sujobert Pierre 
Published: June 2023

AbstractBackgroundFollicular lymphoma (FL) is an incurable B-cell malignancy that constitutes a quarter of all lymphomas. Although RCHOP immuno-chemotherapy induces high rates of complete remission, almost all FL patients experience multiple relapses post-treatment. The limited understanding of treatment response heterogeneity is due to the absence ofin vitroorin vivoexperimental models, primarily because tumor cells heavily rely on their microenvironment to survive. In this study, we present an innovative xenograft model of primary FL cells in avian embryos, circumventing these limitations.MethodsWe developed the FL-AVI-PDX model by transplanting 20 biopsy FL samples, including good (n=11) and poor clinical responders (POD24, n=9), into chicken embryos. Each set of embryos was treated with RCHOP or vehicle intravenously. We evaluated the effect of immuno-chemotherapy on tumor volume by light sheet microscopy and on tumor biology by transcriptomic analysis at the single-cell level.ResultsWe successfully engrafted all samples in avian embryos. We found that RCHOP treatmentin ovoled to tumor volume reduction, which predicted progression-free survival in multivariate analysis, demonstrating the model’s capacity to capture clinical heterogeneity at the patient level. The FL-AVI-PDX model also provided a unique opportunity to analyze the transcriptomic impact of RCHOP on FL cells using single-cell RNA sequencing. We identified a signature of 21 genes upregulated after RCHOP exposure, displaying significant intra-tumoral heterogeneity. As a proof of concept, we validated the functional involvement ofBAX, a gene from the RCHOP-induced signature, as a critical effector of immuno- chemotherapyin vitroand in avian embryos.ConclusionsThe FL-AVI-PDX model is a platform for functional precision oncology in primary FL cells that captures both inter- and intra-patient heterogeneity of clinical response to a complex therapeutic regimen. It offers a unique opportunity to better understand FL biology, opening perspectives for the development of new drugs.