bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex-specific resilience of neocortex to food restriction
Authors: Padamsey Zahid , Katsanevaki Danai , Maeso Patricia , Rizzi Manuela , Osterweil Emily , Rochefort Nathalie L. 
Published: October 2023

AbstractMammals have evolved sex-specific adaptations to reduce energy usage in times of food scarcity. These adaptations are well described for peripheral tissue, though much less is known about how the energy-expensive brain adapts to food restriction, and how such adaptations differ across the sexes. Here, we examined how food restriction impacts energy usage and function in the primary visual cortex (V1) of adult male and female mice. Molecular analysis and RNA sequencing in V1 revealed that in males, but not in females, food restriction significantly modulated canonical, energy-regulating pathways, including pathways associated with AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor alpha (PPARα), mammalian target of rapamycin (mTOR), and oxidative phosphorylation. Moreover, we found that in contrast to males, food restriction in females did not significantly affect V1 ATP usage or visual coding precision (assessed by orientation selectivity). Decreased serum leptin is known to be necessary for triggering energy-saving changes in V1 during food restriction. Consistent with this, we found significantly decreased serum leptin in food-restricted males but no significant change in food-restricted females. Collectively, our findings demonstrate that cortical function and energy usage in female mice are more resilient to food restriction than in males. The neocortex, therefore, contributes to sex-specific, energy-saving adaptations in response to metabolic challenge.
LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology spread
Authors: Lubben Noah , Brynildsen Julia K. , Webb Connor M. , Li Howard L. , Leyns Cheryl E. G. , Changolkar Lakshmi , Zhang Bin , Meymand Emily S. , O’Reilly Mia , Madaj Zach , DeWeerd Daniella , Fell Matthew J. , Lee Virginia M.Y. , Bassett Dani S. , Henderson Michael X. 
Published: October 2023

ABSTRACTMutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). These mutations elevate LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic target. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define.LRRK2-PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carrying LRRK2 mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of LRRK2 inhibitors’ efficacy against disease processes. We hypothesized that mutations in LRRK2 may not be directly related to a single disease pathway, but instead may elevate susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of α-synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages. Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wildtype or LRRK2G2019Sknock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3 to 6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 665 brain regions and subsequent linear diffusion modeling of progression. Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2G2019Smice that were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2G2019Smice, but had minimal effect in wildtype mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers, but additional work may be necessary to determine the potential effect in non-carriers. This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development.
A metapopulation framework integrating landscape heterogeneity to model an airborne plant pathogen: the case of brown rot of peach in France
Authors: Radici Andrea , Martinetti Davide , Vanalli Chiara , Cunniffe Nik J. , Bevacqua Daniele 
Published: October 2023

AbstractPlant disease dynamics are driven by the concurrent interplay of host susceptibility, pathogen presence, and environmental conditions. While host susceptibility and local environmental conditions can readily be characterised, the transmission of an airborne pathogen depends on the biotic and abiotic conditions of the surrounding environment.Here, we propose an original metapopulation framework integrating landscape heterogeneity, in terms of climate and host density, where local populations of plant hosts are connected via air-masses which allow pathogen dispersal. We explicitly account for climatic drivers affecting pathogen release and survival while modelling aerial dispersal using Lagrangian simulations, as well as host phenology and infection. We calibrate the model parameters according to the literature and using Approximate Bayesian Computation against observations of brown rot incidence in French peach orchards from 2001-2020 across an area of 50,000km2. We used the model to produce maps of risk, distinguishing site dangerousness (risk of causing secondary infection in other sites) and vulnerability (risk of becoming infected) across the our study area.We find that most dangerous and vulnerable sites are located along the Rhône Valley, due to the concurrence of high density of peach cultivation, a suitable climate and persistent airborne connections. Our work represents a first step to integrate metapopulation theory, epidemiology and air-mass movements to inform plant protection strategies, and could be adapted to optimize crop protection under future climate projections.
N-cadherin mechanosensing in ovarian follicles controls oocyte maturation and ovulation
Authors: Emery Alaknanda , Blaschuk Orest W. , Dinh Thao D. , McPhee Tim , Becker Rouven , Abell Andrew D. , Mrozik Krzysztof M. , Zannettino Andrew C.W. , Robker Rebecca L , Russell Darryl L 
Published: October 2023

ABSTRACTThe cell adhesion molecule N-cadherin (CDH2) is a membrane component of adherens junctions which regulates tissue morphogenesis and architecture. In the follicles of mammalian ovaries, N-cadherin adherens junctions are present between granulosa cells, cumulus cells and at the interface of cumulus cell transzonal projections and the oocyte. We demonstrate a mechanosensory role of N-cadherin integrating tissue structure and hormonal regulation of follicular morphogenic events including expansion of the cumulus oocyte complex (COC) matrix, oocyte maturation and ovulation. Two small molecule N-cadherin antagonists inhibited COC maturationin vitro. Transcriptome profiling revealed that targets of β-catenin and YAP1 pathways were dysregulated by N-cadherin antagonists.In vivo, N-cadherin antagonist significantly reduced ovulation in mice compared to controls (11 vs 26 oocytes/ovary; p=5.8×10-6). Ovarian follicles exhibited structural dysgenesis with granulosa and cumulus cell layers becoming disorganised and the connection between cumulus cells and the oocyte disrupted and the transcriptome again indicated altered mechanical sensing causing dysregulation of the Hippo/YAP and β-catenin pathways and ECM reorganization. Granulosa specific N-cadherin depletion in Cdh2Fl/FL;Amhr2-Cre also showed significantly altered mechanosensitive gene expression and reduced ovulation. Our findings demonstrate a critical role for N-cadherin in ovarian follicular development and ovulation, and the potential to inhibit ovulation through targeting this signalling mechanism.
Deep mutational scanning of CYP2C19 reveals a substrate specificity-abundance tradeoff
Authors: Boyle Gabriel E. , Sitko Katherine , Galloway Jared G. , Haddox Hugh K. , Bianchi Aisha Haley , Dixon Ajeya , Thomson Raine E. S. , Garge Riddhiman K. , Rettie Allan E. , Rubin Alan , Geck Renee C. , Gillam Elizabeth M. J. , DeWitt William S. , Matsen Frederick A. , Fowler Douglas M. 
Published: October 2023

AbstractCytochrome P450s (CYPs) are a family of enzymes responsible for metabolizing nearly 80% of small molecule drugs. Variants in CYPs can substantially alter drug metabolism, which may result in improper dosing and severe adverse drug reactions. CYPs have low sequence conservation, making it difficult to anticipate whether variant effects measured in one CYP may extend to others based on sequence alone. Even closely related CYPs, like CYP2C9 and its closest homolog CYP2C19, have distinct phenotypic properties despite sharing 92% amino acid sequence identity. Thus, we used Variant Abundance by Massively Parallel sequencing (VAMP-seq) to measure the steady-state protein abundance, a proxy for protein stability, of 7,660 missense variants in CYP2C19 expressed in cultured human cells. Our results confirmed positions and structural features critical for CYP function and revealed how variants at positions conserved across all eukaryotic CYPs influence abundance. We jointly analyzed 4,670 variants whose abundance was measured in both CYP2C19 and CYP2C9, finding that the homologs have different variant abundances in substrate recognition sites within the hydrophobic core, and that substitutions in some regions reduced abundance in CYP2C19 but not CYP2C9. We also measured the abundance of all single and some multiple WT amino acid exchanges between CYP2C19 and CYP2C9. While most exchanges had no effect, substitutions in substrate recognition site 4 (SRS4) reduced abundance in CYP2C19. When nearby amino acids were exchanged in double and triple mutants, we found distinct interactions between the sites in CYP2C19 and CYP2C9, revealing a region that is partially responsible for the difference in thermodynamic stability between the two homologs. Since these positions are also important for determining substrate specificity, there may be an evolutionary tradeoff between stability and altered enzymatic function. Finally, we used our data to analyze 368 previously unannotated human variants, finding that 43% had decreased abundance. Thus, by comparing variant effects between two closely related and important human genes, we have uncovered regions underlying their functional differences and paved the way for a more complete understanding of one of the most versatile families of enzymes.
Introducing return of results in the Million Veteran Program: Design and pilot results of the MVP-ROAR Familial Hypercholesterolemia Study
Authors: Vassy Jason L. , Brunette Charles A. , Yi Thomas , Harrison Alicia , Cardellino Mark P. , Assimes Themistocles L. , Christensen Kurt D. , Devineni Poornima , Gaziano J. Michael , Gong Xin , Hui Qin , Knowles Joshua W. , Muralidhar Sumatra , Natarajan Pradeep , Pyarajan Saiju , Sears Mary Gavin , Shi Yunling , Sturm Amy C. , Whitbourne Stacey B. , Sun Yan V. , Danowski Morgan E. ,   the Million Veteran Program
Published: October 2023

ABSTRACTBackgroundAs a mega-biobank linked to a national healthcare system, the Million Veteran Program (MVP) can directly improve the health care and health outcomes of participants. Return of genetic research results at this scale presents challenges and complexities.MethodsTo determine the feasibility and outcomes of returning medically actionable genetic results to MVP participants, the program launched the MVP Return Of Actionable Results (MVP-ROAR) Study, with familial hypercholesterolemia (FH) as the exemplar actionable condition. The MVP-ROAR-FH Study consists of a completed pilot phase and an ongoing randomized clinical trial (RCT), in which MVP participants are recontacted and invited to receive clinical confirmatory gene sequencing testing and a telegenetic counseling intervention. The primary outcome of the RCT is 6-month change in low-density lipoprotein cholesterol (LDL-C) between participants receiving results at baseline and those receiving results after 6 months.ResultsNine MVP participants suspected to have a pathogenic variant inlow-density lipoprotein receptor(LDLR) enrolled in the single-arm pilot phase of the study; one was lost to follow-up prior to confirmatory testing. Clinical sequencing confirmed the pathogenic variant for 5 of the remaining 8 participants. Six-month ΔLDL-C among enrollees after the genetic counseling intervention was −37 mg/dL (95% CI: −12 to −61;p=0.03).ConclusionsWhile underscoring the importance of analytic validity and clinical confirmation of research results, the pilot phase of the MVP-ROAR-FH Study demonstrates the feasibility of a protocol to return genetic results to MVP participants and their providers. The ongoing RCT will contribute to understanding of how such a program might improve patient health care and outcomes.
A model of marmoset monkey vocal turn-taking
Authors: Grijseels Dori M. , Fairbank Daniella A. , Miller Cory T. 
Published: October 2023

SummaryVocal turn-taking has been described in a diversity of species. Yet a model that captures the various processes underlying this social behavior across species has not been developed. To this end, here we recorded a large and diverse dataset of marmoset monkey vocal behavior in social contexts comprising one, two and three callers and developed a model to determine the keystone factors that affect the dynamics of these natural communicative interactions. While a coupled oscillator model failed to account for turn-taking in marmosets, our model alternatively revealed four key factors that encapsulate much of patterns evident in the behavior, ranging from internal processes, such as the state of the individual, to social context driven suppression of calling. In addition, we show that the same key factors apply to the meerkat, a carnivorous species, in a multicaller setting. These findings indicate that vocal turn-taking is affected by a broader suite of mechanisms than previously considered and that our model provides a predictive framework with which to further explicate this natural behavior in marmosets and for direct comparisons with the analogous behavior in other species.
Immunomodulators and risk for breakthrough infection after third COVID-19 mRNA vaccine among patients with rheumatoid arthritis: A cohort study
Authors: Schiff Abigail E. , Wang Xiaosong , Patel Naomi J. , Kawano Yumeko , Kowalski Emily N. , Cook Claire E. , Vanni Kathleen M.M. , Qian Grace , Bade Katarina J. , Saavedra Alene A. , Srivatsan Shruthi , Williams Zachary K. , Venkat Rathnam K. , Wallace Zachary S. , Sparks Jeffrey A. 
Published: October 2023

ABSTRACTObjectivesTo investigate COVID-19 breakthrough infection after third mRNA vaccine dose among patients with RA by immunomodulator drug class, and we hypothesized that CD20 inhibitors (CD20i) would have higher risk for breakthrough COVID-19 vs. TNF inhibitors (TNFi).MethodsWe performed a retrospective cohort study investigating breakthrough COVID-19 among RA patients at Mass General Brigham in Boston, MA, USA. Patients were followed from the date of 3rd vaccine dose until breakthrough COVID-19, death, or end of follow-up (18/Jan/2023). Covariates included demographics, lifestyle, comorbidities, and prior COVID-19. We used Cox proportional hazards models to estimate breakthrough COVID-19 risk by immunomodulator drug class. We used propensity score (PS) overlap-weighting to compare users of CD20i vs. TNFi.ResultsWe analyzed 5781 patients with RA that received 3 mRNA vaccine doses (78.8% female, mean age 64.2 years). During mean follow-up of 12.8 months, 1173 (20.2%) had breakthrough COVID_19. Use of CD20i (adjusted HR 1.74, 95%CI 1.30-2.33) and glucocorticoid monotherapy (adjusted HR 1.47, 95%CI 1.09-1.98) were each associated with breakthrough COVID-19 compared to TNFi use. In the PS overlap-weighted analysis, CD20i users also had higher breakthrough COVID-19 risk than TNFi users (HR 1.62, 95%CI 1.02-2.56). A sensitivity analysis excluding patients with cancer or interstitial lung disease yielded similar findings.ConclusionsWe identified CD20i and glucocorticoid monotherapy as risk factors for breakthrough COVID-19 among patients with RA after a 3rd vaccine dose. This contemporary study highlights the real-world impact of blunted immune responses in these subgroups and the need for effective risk mitigation strategies.What is already known about this topicPatients with RA are at increased risk for COVID-19 breakthrough infection after two vaccine doses so a third dose is recommended to complete the initial series.Some immunomodulator medications, particularly CD20 inhibitors, can impact vaccine immunogenicity and waning.What this study addsCD20 inhibitor use was associated with increased risk of COVID-19 breakthrough infection in people with RA who received 3 vaccine doses compared to TNF inhibitor use.Glucocorticoid monotherapy was also associated with increased risk of COVID-19 breakthrough infection.How this study might affect research, practice or policyPatients with RA who are using CD20 inhibitors or glucocorticoid monotherapy should be prioritized for risk mitigation strategies after the initial vaccine series of 3 mRNA doses.The impact of additional vaccine doses, timing of medication dosing, and other protective measures will need further study.
Pilot study of the FoxP3+ T lymphocyte count and its relationship with the Gensini score in patients with coronary heart disease and type 2 diabetes mellitus from a South American cohort
Authors: Estévez Gómez María Juliana , Acevedo Peña Diego Andrey , Castillo Goyeneche Silvia Fernanda , Arias Anderson Felipe , Dulcey Sarmiento Luis Andres , Gomez Jaime , Hernandez Carlos , Theran Leon Juan Sebastián , Caltagirone Raimondo , Blanco Edgar , Ciliberti María 
Published: October 2023

AbstractINTRODUCTIONOne of the pathogenic links between type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) is low-intensity chronic inflammation, which is limited by FoxP3+ regulatory T cells.MATERIALS AND METHODSA comparative, observational, single-center, single-stage study was carried out. The severity of atherosclerosis was assessed by calculating the Gensini score based on selective coronary angiography. The absolute and relative content of CD4+CD25 high FoxP3+ and CD4+CD25 low FoxP3+ T cells in the blood was evaluated by flow cytometry.RESULTS57 patients with chronic ischemic heart disease were examined. Patients with a combination of CHF and T2DM are characterized by an increase in the relative and absolute content of FoxP3+CD25 lymphocytes in the peripheral blood and an increase in the intranuclear content of FoxP3 in them, which is more pronounced in patients with disease moderate. atherosclerosis (Gensini score 17 to 45 points).CONCLUSIONSThis was the first Latin American study that managed to show the relationship between an increase in the content of low FoxP3+CD25 lymphocytes in the peripheral blood with atherosclerosis in patients with a combination of coronary artery disease and DM2.
Hibernating ribosomes tether to mitochondria as an adaptive response to cellular stress during glucose depletion
Authors: Gemin Olivier , Gluc Maciej , Purdy Michael , Rosa Higor , Niemann Moritz , Peskova Yelena , Mattei Simone , Jomaa Ahmad 
Published: October 2023

AbstractCell survival under nutrient-deprived conditions relies on cells’ ability to adapt their organelles and to rewire their metabolic pathways. In the fission yeastSchizosaccharomyces pombe, nutrient depletion is an unfavorable condition for protein synthesis and triggers a response characterized by mitochondrial fragmentation and the sequestration of cytosolic ribosomes on mitochondria. The molecular mechanism underlying ribosomal sequestration remains elusive. In this study, we performed time-lapsein situcryo-electron tomography and cryo-electron microscopy complemented by biochemical experiments to elucidate the molecular details of this adaptive response. Our analysis indicate that upon glucose depletion protein synthesis is halted, causing ribosomes to enter an inactive state characterized by a conformational change that obstructs the peptidyl transferase center. Ourin situexperiments reveal the presence of oligomeric arrays of hibernating ribosomes tethered to the mitochondrial surface. Surprisingly, ribosomes bind to the outer mitochondrial membraneviathe small ribosomal subunit, an interaction facilitated by the ribosomal protein RACK1-orthologue Cpc2. Our experiments show that ribosome tethering is important for cell survival under glucose depletion conditions. This study broadens our understanding of the cellular adaptations triggered by nutrient scarcity and the underlying molecular mechanisms that regulate cell quiescence.
PAX6 protein in neuromasts of the lateral line system of salamanders (Eurycea)
Authors: Dobbins Brittany A. , Tovar Ruben U. , Oddo Braden J. , Devitt Thomas J. , Hillis David M. , García Dana M. 
Published: October 2023

AbstractPAX6 is well known as a transcription factor that drives eye development in animals as widely divergent as flies and mammals. In addition to its localization in eyes, PAX6 expression has been reported in the central nervous system, the pancreas, testes, Merkel cells, nasal epithelium, and developing cells of the inner ear. Here we show that PAX6 is also found in the mechanosensory neuromasts of the lateral line system in paedomorphic salamanders of the genusEurycea. Using immunohistochemistry and confocal microscopy, we found that PAX6 is extranuclear, and antibody labeling is most intense in the apical appendages of the hair cells of the neuromast. This extranuclear localization raises the possibility of an as yet undescribed function for PAX6 as a cytoskeleton-associated protein.