bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibiting CRF Projections from the Central Amygdala to Lateral Hypothalamus and Amygdala Deletion of CRF Alters Binge-Like Ethanol Drinking in a Sex-Dependent Manner
Authors: Bendrath Sophie C. , Méndez Hernán G. , Dankert Anne M. , Lerma-Cabrera Jose Manuel , Carvajal Francisca , Dornellas-Loper Ana Paula , Lee Sophia , Neira Sofia , Haun Harold , Delpire Eric , Navarro Montserrat , Kash Thomas L. , Thiele Todd E. 
Published: April 2024

ABSTRACTBackgroundBinge alcohol drinking is a dangerous pattern of consumption that can contribute to the development of more severe alcohol use disorders (AUDs). Importantly, the rate and severity of AUDs has historically differed between men and women, suggesting that there may be sex differences in the central mechanisms that modulate alcohol (ethanol) consumption. Corticotropin releasing factor (CRF) is a centrally expressed neuropeptide that has been implicated in the modulation of binge-like ethanol intake, and emerging data highlight sex differences in central CRF systems.MethodsIn the present report we characterized CRF+ neurocircuitry arising from the central nucleus of the amygdala (CeA) and innervating the lateral hypothalamus (LH) in the modulation of binge-like ethanol intake in male and female mice.ResultsUsing chemogenetic tools we found that silencing the CRF+ CeA to LH circuit significantly blunted binge-like ethanol intake in male, but not female, mice. Consistently, genetic deletion of CRF from neurons of the CeA blunted ethanol intake exclusively in male mice. Furthermore, pharmacological blockade of the CRF type-1 receptor (CRF1R) in the LH significantly reduced binge-like ethanol intake in male mice only, while CRF2R activation in the LH failed to alter ethanol intake in either sex. Finally, a history of binge-like ethanol drinking blunted CRF mRNA in the CeA regardless of sex.ConclusionsThese observations provide novel evidence that CRF+ CeA to LH neurocircuitry modulates binge-like ethanol intake in male, but not female mice, which may provide insight into the mechanisms that guide known sex differences in binge-like ethanol intake.
All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis
Authors: Rao Aparna , Zhang Xiaoran , Cillo Anthony R. , Sussman Jonathan H. , Sandlesh Poorva , Tarbay Antonio Corral , Mallela Arka N. , Cardello Carly , Krueger Katharine , Xu Jessica , Li Alex , Xu Jason , Patterson Jonathan , Akca Ebrar , Angione Angelo , Jaman Emade , Kim Wi Jin , Allen Jordan , Venketeswaran Abhishek , Zinn Pascal O. , Parise Robert , Beumer Jan , Duensing Anette , Holland Eric C. , Ferris Robert , Bagley Stephen J. , Bruno Tullia C. , Vignali Dario A.A. , Agnihotri Sameer , Amankulor Nduka M. 
Published: April 2024

ABSTRACTDiffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4+T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.
Major Metabolites fromHypericum PerforatumL., Hyperforin and Hypericin, are both active against Human Coronaviruses
Authors: Raczkiewicz I. , Rivière C. , Bouquet P. , Desmarets L. , Tarricone A. , Camuzet C. , François N. , Lefèvre G. , Samaillie J. , Silva Angulo F. , Robil C. , Trottein F. , Sahpaz S. , Dubuisson J. , Belouzard S. , Goffard A. , Séron K. 
Published: April 2024

ABSTRACTCOVID-19 pandemic has highlighted the need of antiviral molecules against coronaviruses. Plants are an endless source of active compounds. In the current study, we investigated the potential antiviral effects ofHypericum perforatumL.. Its extract contained two major metabolites belonging to distinct chemical classes, hypericin (HC) and hyperforin (HF). First, we demonstrated that HC inhibited HCoV-229E at the entry step by directly targeting the viral particle in a light-dependent manner. While antiviral properties have already been described for HC, the study here showed for the first time that HF has pan-coronavirus antiviral capacity. Indeed, HF was highly active against Alphacoronavirus HCoV-229E (IC50value of 1.10 µM), and Betacoronaviruses SARS-CoV-2 (IC50value of of 0.24 to 0.98 µM), SARS-CoV (IC50value of 1.01 µM) and MERS-CoV (IC50value of 2.55 µM). Unlike HC, HF was active at a post-entry step, most likely the replication step. Antiviral activity of HF on HCoV-229E and SARS-CoV-2 was confirmed in primary human respiratory epithelial cells. Furthermore,in vitrocombination assay of HF with remdesivir showed that their association was additive, which was encouraging for a potential therapeutical association. As HF was active on both Alpha- and Betacoronaviruses, a cellular target was hypothesized. Heme oxygenase 1 (HO-1) pathway, a potential target of HF, has been investigated but the results showed that HF antiviral activity against HCoV-229E was not dependent on HO-1. Collectively, HF is a promising antiviral candidate in view of our results and pharmacokinetics studies already published in animal models or in human.
Loss of age-accumulatedcrh-1circRNAs ameliorate amyloid β-induced toxicity in aC. elegansmodel for Alzheimer’s disease
Authors: Alshareef Hussam , Ballinger Thomas , Rojas Everett , van der Linden Alexander M. 
Published: April 2024

ABSTRACTCircular RNAs (circRNAs) are non-coding RNAs mostly derived from exons of protein-coding genes via a back-splicing process. The expression of hundreds of circRNAs accumulates during healthy aging and is associated with Alzheimer’s disease (AD), characterized by the accumulation of amyloid-beta (Aβ) proteins. InC. elegans, many circRNAs were previously found to accumulate during aging, with loss of age-accumulated circRNAs derived from the CREB gene (circ-crh-1) to increase mean lifespan. Here, we usedC. elegansto study the effects of age-accumulated circRNAs on the age-related onset of Aβ-toxicity. We found that circ-crh-1mutations delayed Aβ-induced muscle paralysis and lifespan phenotypes in a transgenicC. elegansstrain expressing a full-length human Aβ-peptide (Aβ1-42) selectively in muscle cells (GMC101). The delayed Aβ phenotypic defects were associated with inhibiting the deposition of Aβ aggregates, and thus, genetic removal of circ-crh-1provides protection against Aβ-induced toxicity. Consistent with a detrimental role for age-accumulated circRNAs in AD, circ-crh-1expression level is elevated after induction of Aβ during aging, whereas linearcrh-1mRNA expression remains unchanged. Finally, we show that a circ-crh-1upregulated collagen gene,col-49, promotes Aβ-induced paralysis. Taken together, our results show that the loss of an age-accumulated circRNA exerts a protective role on Aβ-induced toxicity, demonstrating the utility ofC. elegansfor studying circRNAs in AD and its relationship to aging.
The Effects of Bipolar Disorder Granule Cell Hyperexcitability and Lithium Therapy on Pattern Separation in a Computational Model of the Dentate Gyrus
Authors: Singh Selena , Khayachi Anouar , Stern Shani , Trappenberg Thomas , Alda Martin , Nunes Abraham 
Published: April 2024

ABSTRACTInduced pluripotent stem cell (iPSC) derived hippocampal dentate granule cell-like neurons from individuals with bipolar disorder (BD) are hyperexcitable and more spontaneously active relative to healthy control (HC) neurons. These abnormalities are normalised after the application of lithium in neurons derived from lithium responders (LR) only. How these abnormalities impact hippocampal microcircuit computation is not understood. We aimed to investigate the impacts of BD-associated abnormal granule cell (GC) activity on pattern separation (PS) using a computational model of the dentate gyrus (DG). We used parameter optimization to fit the parameters of biophysically realistic granule cell (GC) models to electrophysiological data from iPSC GCs from patients with BD. These cellular models were incorporated into DG networks to assess impacts on PS using an adapted spatiotemporal task. Relationships between BD, lithium and spontaneous activity were analysed using linear mixed effects modelling. Lithium and BD negatively impacted PS, consistent with clinical reports of cognitive slowing and memory impairment during lithium therapy. By normalising spontaneous activity levels, lithium improved PS performance in LRs only. Improvements in PS after lithium therapy in LRs may therefore be attributable to the normalisation of spontaneous activity levels, rather than reductions in GC intrinsic excitability as we hypothesised. Our results agree with a hypothesised relationship between behavioural mnemonic discrimination and DG PS, as previous research has suggested that mnemonic discrimination improves after lithium therapy in lithium responders only. Our work can be expanded on in the future by simulating the effects of lithium-induced neurogenesis on PS.
Electrophysiological correlates of lucid dreaming: sensor and source level signatures
Authors: Demirel Çağatay , Gott Jarrod , Appel Kristoffer , Lüth Katharina , Fischer Christian , Raffaelli Cecilia , Westner Britta , Wang Xinlin , Zavecz Zsófia , Steiger Axel , Erlacher Daniel , LaBerge Stephen , Mota-Rolim Sérgio , Ribeiro Sidarta , Zeising Marcel , Adelhöfer Nico , Dresler Martin 
Published: April 2024

AbstractLucid dreaming (LD) is a state of conscious awareness of the current dream state, predominantly associated with REM sleep. Research progress in uncovering the neurobiological basis of LD has been hindered by low sample sizes, diverse EEG setups, and specific artifact issues like saccadic eye movements and signal non-stationarity. To address these matters, we developed a multi-stage preprocessing pipeline that integrates standardized early-stage preprocessing, artifact subspace reconstruction, and signal-space projection. This approach enhanced data quality by precisely removing saccadic potential effects even in setups with minimal channels. To robustly identify the electrophysiological correlates of LD, we applied this methodology to LD data collected across laboratories (pooled N = 44) and explored sensor-and source-level markers hypothesized to underlie LD. Compared to non-lucid REM sleep, we observed few robust differences on the EEG sensor level, which is in line with recent findings. In contrast, on the source level, gamma1 power (30-36 Hz) showed increases during LD in left-hemispheric temporal areas, which might reflect verbal insight processes. Gamma1 power also increased around the onset of LD eye signaling in right temporo-occipital regions including the right precuneus, in line with its involvement in self-referential thinking. Reductions in beta power (12-30 Hz) during LD in right central and parietal areas including the temporo-parietal junction are potentially associated with a conscious reassessment of the veridicality of the currently perceived reality. Notably, functional connectivity in alpha band (8-12 Hz) increased during LD, in contrast to the reductions typically seen in psychedelic states, highlighting enhanced self-awareness. Taken together, these findings illuminate the electrophysiological correlates of LD state, and may serve as a basis to uncover neural mechanisms at the time point of lucid dream insight.
Human Cells for Human Proteins: Isotope Labeling in Mammalian Cells for Functional NMR Studies of Disease-Relevant Proteins
Authors: Rößler Philip , Ruckstuhl Marco , Löbbert Arnelle , Stühlinger Timo , Franchini Lucia R. , Tsai Ching-Ju , Lichtenecker Roman , Shrestha Binesh , Rüdisser Simon H. , Konrat Robert , Schertler Gebhard F. X. , Gossert Alvar D. 
Published: April 2024

AbstractIn biological and biomedical research the focus progressively moves towards difficult human proteins, which often can only be expressed in higher eukaryotic cells. Nuclear magnetic resonance (NMR) could contribute significantly to the understanding of important proteins as it is one of the most information-rich methods: it allows studying structure, function and dynamics of biomolecules and, importantly, their interactions with natural ligands or drugs. However, to exploit the full potential of NMR, proteins must be isotope labeled. Although expression protocols in e.g. HEK293 cells are often established, isotope labeling is difficult and very expensive. To resolve this disparity, we have developed a comprehensive suite of protocols for isotope labeling in HEK293 cells. We demonstrate uniform 15N and 13C labeling, as well as specific labeling, with special focus on methyl bearing amino acids, including the popular ILV 13C-methyl labeling pattern. Labeling is achieved with a simple laboratory setup and affordable labeling media. These are based on either labeled amino acids, their precursors or amino extracts from microorganisms, like yeast, algae or bacteria.This enables NMR studies of important, but difficult to produce proteins, like receptors. We therefore expect that these new methods make many highly important proteins accessible to NMR studies and allow exploiting the high information content of this method for accelerating biological and pharmaceutical research.
Rescuing Photoreceptors in RPE Dysfunction-Driven Retinal Degeneration: The Role of Small Extracellular Vesicles Secreted from Retinal Pigment Epithelium
Authors: Pollalis Dimitrios , Georgescu Constantin , Wren Jonathan D. , Tombulyan Grigor , Leung Justin M. , Lo Pein-An , Bloemhof Clarisa Marie , Lee Ryang Hwa , Bae EunHye , Bailey Jeffrey K. , Pennington Britney O. , Khan Amir I. , Kelly Kaitlin R. , Yeh Ashley K. , Sundaram Kartik S. , Humayun Mark , Louie Stain , Clegg Dennis O. , Lee Sun Young 
Published: April 2024

ABSTRACTDysfunction of the retinal pigment epithelium (RPE) is a common shared pathology in major degenerative retinal diseases despite variations in the primary etiologies of each disease. Due to their demanding and indispensable functional roles throughout the lifetime, RPE cells are vulnerable to genetic predisposition, external stress, and aging processes. Building upon recent advancements in stem cell technology for differentiating healthy RPE cells and recognizing the significant roles of small extracellular vesicles (sEV) in cellular paracrine and autocrine actions, we investigated the hypothesis that the RPE-secreted sEV alone can restore essential RPE functions and rescue photoreceptors in RPE dysfunction-driven retinal degeneration. Our findings support the rationale for developing intravitreal treatment of sEV. We demonstrate that intravitreally delivered sEV effectively penetrate the full thickness of the retina. Xenogenic intraocular administration of human-derived EVs did not induce acute immune reactions in rodents. sEV derived from human embryonic stem cell (hESC)-derived fully differentiated RPE cells, but not sEV-depleted conditioned cell culture media (CCM minus sEV), rescued photoreceptors and their function in a Royal College of Surgeons (RCS) rat model. This model is characterized by photoreceptor death and retinal degeneration resulting from a mutation in theMerTKgene in RPE cells. From the bulk RNA sequencing study, we identified 447 differently expressed genes in the retina after hESC-RPE-sEV treatment compared with the untreated control. Furthermore, 394 out of 447 genes (88%) showed a reversal in expression toward the healthy state in Long-Evans (LE) rats after treatment compared to the diseased state. Particularly, detrimental alterations in gene expression in RCS rats, including essential RPE functions such as phototransduction, vitamin A metabolism, and lipid metabolism were partially reversed. Defective photoreceptor outer segment engulfment due to intrinsicMerTKmutation was partially ameliorated. These findings suggest that RPE-secreted sEV may play a functional role similar to that of RPE cells. Our study justifies further exploration to fully unlock future therapeutic interventions with sEV in a broad array of degenerative retinal diseases.
Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model
Authors: Rojas Julie , Hose James , Dutcher H. Auguste , Place Michael , Wolters John F , Hittinger Chris Todd , Gasch Audrey P 
Published: April 2024

AbstractAlthough implicated as deleterious in many organisms, aneuploidy can underlie rapid phenotypic evolution. However, aneuploidy will only be maintained if the benefit outweighs the cost, which remains incompletely understood. To quantify this cost and the molecular determinants behind it, we generated a panel of chromosome duplications inSaccharomyces cerevisiaeand applied comparative modeling and molecular validation to understand aneuploidy toxicity. We show that 74-94% of the variance in aneuploid strains’ growth rates is explained by the additive cost of genes on each chromosome, measured for single-gene duplications using a genomic library, along with the deleterious contribution of snoRNAs and beneficial effects of tRNAs. Machine learning to identify properties of detrimental gene duplicates provided no support for the balance hypothesis of aneuploidy toxicity and instead identified gene length as the best predictor of toxicity. Our results present a generalized framework for the cost of aneuploidy with implications for disease biology and evolution.
Quantitative Models for Distinguishing Punctuated and Continuous-Time Models of Character Evolution and Their Implications for Macroevolutionary Theory
Authors: Wright April M. , Wagner Peter J. 
Published: April 2024

AbstractThe recent proliferation of quantitative models for assessing anatomical character evolution all assume that character change happens continuously through time. However, punctuated equilibrium model posits that character change should be coincide with cladogenetic events, and thus should be tied to origination rates. Rates of cladogenesis are important to quantitative phylogenetics, but typically only for establishing prior probabilities of phylogenetic topologies. Here, we modify existing character likelihood models to use the local cladogenesis rates from Bayesian analyses to generate the amounts of character change over time dependent on origination rates, as expected under the punctuated equilibrium model. In the case of strophomenoid brachiopods strop from the Ordovician, we find that Bayesian analyses strongly favor punctuated models over continuous-time models, with elevated rates of cladogenesis early in the clade’s history inducing frequencies of change despite constant rates of change per speciation event. This corroborates prior work proposing that the early burst in strophomenoid disparity reflects simply elevated speciation rates,which in turnhas implications for seemingly unrelated macroevolutionary theory about whether early bursts reflect shifts in intrinsic constraints or empty ecospace. Future development of punctuated character evolution models should account for the full durations of species, which will provide a test of continuous change rates. Ultimately, continuous change vs. punctuated change should become part of phylogenetic paleobiology in the same way that other tests of character evolution currently are.Non-technical SummaryPunctuated Equilibrium predicts a distribution of anatomical change that is fundamentally different from the models used in studies of relationships among species. We present a model to assess relationships that assumes punctuated change. We apply this model to a dataset of strophomenoid brachiopods to demonstrate that a model of punctuated change fits better than a model of continuous-time (“phyletic gradualism”) change in this group. Notably, because the punctuated model posits elevated speciation rates early in the strophomenoid history, the model also posits elevated rates of change among the early strophomenoids relative to later ones. This corroborates notions for what causes bursts of anatomical evolution rooted in ecological theory rather than evolutionary developmental theory. More basically, it emphasizes that paleontologists should consider both punctuated and continuous-time models when assessing relationships and other aspects of macroevolutionary theory.
Feeding a low-carbohydrate and high-protein diet diminishes working memory in healthy mice: possible involvement of miR-539-3p/Lrp6/Igf1raxis in the hippocampus
Authors: Shima Takeru , Onishi Hayate , Terashima Chiho 
Published: April 2024

AbstractA low-carbohydrate and high-protein (LC-HP) diet demonstrates favorable impacts on metabolic parameters, albeit it leads to a decline in hippocampal function among healthy mice. The reduction in working memory induced by LC-HP diets is attributed to the decreased expression of hippocampal IGF-1 receptor (IGF-1R). However, the precise mechanisms underlying this phenomenon remain unexplored. Here, we investigated that by analyzing alterations in hippocampal miRNA profiles. C57BL/6 mice were divided into the LC-HP diet-fed group (25.1% carbohydrate, 57.2% protein, and 17.7% fat as percentages of calories) and the control diet-fed group (58.9% carbohydrate, 24.0% protein, and 17.1% fat as percentages of calories). After four weeks, all mice underwent the Y-maze test, followed by analyses of mRNA and miRNA expressions in the hippocampus. Our investigation revealed that feeding the LC-HP diet suppressed working memory function and hippocampalIgf1rmRNA levels in mice. Sequencing of miRNA demonstrated 17 upregulated and 27 downregulated miRNAs in the hippocampus of LC-HP diet-fed mice. Notably, upregulation of miR-539-3p, predicted to modulateIgf1rgene expression, was observed. Consequently, we found decreased hippocampal mRNA levels of low-density lipoprotein receptor-related protein 6 (Lrp6), a gene modulated by miR-539-3p, in mice fed the LC-HP diet. Furthermore, a significant positive correlation was observed betweenLrp6andIgf1rmRNA levels in the hippocampus. These findings suggest that LC-HP diets may suppress hippocampal function via the miR-539-3p/Lrp6/Igf1raxis, offering a potential target for nutritional strategies to preserve hippocampal health.