bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osterix-driven LINC complex disruptionin vivodiminishes bone microarchitecture in 8-week male mice but not after 6-week voluntary wheel running
Authors: Birks Scott , Howard Sean , O’Rourke Caroline , Thompson William R , Lau Anthony , Uzer Gunes 
Published: August 2023

AbstractThe Linker of Nucleoskeleton and Cytoskeleton (LINC) complex is a crucial connective component between the nuclear envelope and the cytoskeleton involving various cellular processes including nuclear positioning, nuclear architecture, and mechanotransduction. How LINC complexes regulate bone formationin vivo, however, is not well understood. To start bridging this gap, here we created a LINC disruption murine model using transgenic mice expressing Cre recombinase enzyme under the control of the Osterix (Osx-Cre) which is primarily active in pre-osteoblasts and floxed Tg(CAG-LacZ/EGFP-KASH2) mice. Tg(CAG-LacZ/EGFP-KASH2) mice contain a lox-STOP-lox flanked LacZ gene which is deleted upon cre recombination allowing for the overexpression of an EGFP-KASH2 fusion protein. This overexpressed protein disrupts endogenous Nesprin-Sun binding leading to disruption of LINC complexes. Thus, crossing these two lines results in aOsx-drivenLINCdisruption (ODLD) specific to pre-osteoblasts. In this study, we investigated how this LINC disruption affects exercise induced bone accrual. ODLD cells had decreased osteogenic and adipogenic potentialin vitrocompared to non-disrupted controls and sedentary ODLD mice showed decreased bone quality at 8-weeks. Upon access to a voluntary running wheel ODLD animals showed increased running time and distance; however, our 6-week exercise intervention did not significantly affect bone microarchitecture and bone mechanical properties.
Consequences of daily rhythm disruption on host-parasite malaria infection dynamics
Authors: Holland Jacob G. , Prior Kimberley F. , O’Donnell Aidan J. , Reece Sarah E. 
Published: August 2023

AbstractUndertaking certain activities at the time of day that maximises fitness is assumed to explain the evolution of circadian clocks. Organisms often use daily environmental cues such as light and food availability to set the timing of their clocks. These cues may be the environmental rhythms that ultimately determine fitness, act as proxies for the timing of less tractable ultimate drivers, or are used simply to maintain internal synchrony. While many pathogens/parasites undertake rhythmic activities, both the proximate and ultimate drivers of their rhythms are poorly understood. Explaining the roles of rhythms in infections offers avenues for novel interventions to interfere with parasite fitness and reduce the severity and spread of disease. Here, we perturb several rhythms in the hosts of malaria parasites to investigate why parasites align their rhythmic replication to the host’s feeding-fasting rhythm. We manipulated host rhythms governed by light, food, or both, and assessed the fitness implications for parasites, and the consequences for hosts, to test which host rhythms represent ultimate drivers of the parasite’s rhythm. We found that alignment with the host’s light-driven rhythms did not affect parasite fitness metrics. In contrast, aligning with the timing of feeding-fasting rhythms may be beneficial for the parasite, but only when the host possess a functional canonical circadian clock. Because parasites in clock-disrupted hosts align with the host’s feeding-fasting rhythms and yet derive no apparent benefit, our results suggest cue(s) from host food act as a proxy rather than being a key selective driver of the parasite’s rhythm. Alternatively, parasite rhythmicity may only be beneficial because it promotes synchrony between parasite cells and/or allows parasites to align to the biting rhythms of vectors. Our results also suggest that interventions can disrupt parasite rhythms by targeting the proxies or the selective factors driving them without impacting host health.
Do working forest easements work for conservation?
Authors: Thompson Jonathan R. , Kalinin Alexey , Lee Lucy G. , Pasquarella Valerie J. , Plisinski Joshua , Sims Katharine R. E. 
Published: August 2023

AbstractConservation easements are voluntary legal agreements designed to achieve conservation goals on private land. Extensive public and private funding has been used to establish “working forest” conservation easements (WFCE) that aim to protect conservation values while maintaining commercial timber production. We use variation in the timing and location of easements to estimate the impacts of WFCEs in Maine from a 33-year time-series of forest loss and harvesting. Compared to matched controls, WFCEs reduced forest loss rates by just 0.0004% yr-1, the equivalent of 3ha yr-1, and increased the rate of harvesting by 0.37% yr-1, or 2935ha yr-1within the 839,000 ha enrolled. More recent easements contained stricter restrictions on harvest practices and these easements reduced harvest by 0.62% yr-1. Overall, WFCEs supported continued harvests, but did not appear to provide substantial ecological benefits. Future easements could be more effective if they include additional provisions for harvest restrictions and monitoring.
CAR T-cell therapy - Paving the way for sensitized kidney transplant patients
Authors: Jarmi Tambi , Luo Yan , Attieh Rose Mary , Qie Yaqing , Gadd Martha E. , Hundal Tanya , Mao Shennen , Murthy Hemant S. , Taner Burcin C. , Kharfan-Dabaja Mohamed A. , Qin Hong 
Published: August 2023

ABSTRACTAnti-HLA donor specific antibodies have been extensively documented for their critical role in kidney transplant rejection and resulting adverse outcomes. Several approaches have been employed to desensitize these patients; however, none of these explored therapeutic approaches has exhibited enduring clinical benefits. In this study, we explore a novel strategy of utilizing chimeric antigen receptor T cells (CAR T-cells) to target B cells in sensitized kidney transplant recipients. Specifically, we investigate the potential of our innovative MC10029 CAR T-cells, which are designed to recognize the B cell activating factor receptor (BAFF-R). BAFF-R is predominantly expressed on mature B cells and plays a crucial role in their survival, as well as in the promotion of autoreactive B cell. Our data revealed that sensitized patients’ B cells exhibited high levels of BAFF-R expression. We have successfully generated patient-derived MC10029 CAR T-cells from 6 sensitized patients. All these patient-derived MC10029 CAR T-cells consistently exhibited antigen-specific cytotoxicity against autologous B cells, accompanied by the release of cytotoxic granules. We have recently obtained FDA approval of an Investigational New Drug application for MC10029 CAR T-cell therapy in B-cell hematological diseases. This significant milestone paves the way for the pioneering launch of a human clinical trial, marking the first-ever application of CAR T-cell therapy in sensitized patients waiting for life-saving organ transplants.
Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activatorPOU2AF2
Authors: Rajasekaran V , Harris B. T , Osborn R. T , Smillie C , Donnelly K , Bacou M , Esiri-Bloom E , Ooi L.Y , Allan M , Walker M , Reid S , Meynert A , Grimes G , Blackmur J. P , Vaughan-Shaw P. G , Law P. J , Fernandez-Rozadilla C , Tomlinson I. P , Houlston R , Myant K. B , Din F. V , Dunlop M. G. , Farrington S. M 
Published: August 2023

AbstractCommon genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, and exerts local (cis) expression quantitative trait locus (cis-eQTL) effects onPOU2AF2, COLCA1 and POU2AF3genes. However, complex linkage disequilibrium and correlated expression at the 11q23.1 locus has thus far hindered elucidation of the mechanisms by which genetic variants impart CRC risk. Here, we establish that rs3087967 is the likely causal eQTL at this locus, co-localising with expression ofPOU2AF2and CRC risk. Furthermore, we show trans-eQTL effects on 21 distant target genes, which are highly enriched for Tuft cell markers. Analysis of available scRNAseq, ChIPseq and scATACseq data implicates POU2AF2 as the primary controller of the tuft cell specific trans-genes through POU2F3-correlated genetic regulation. Immunofluorescence demonstrates that the rs3087967 risk genotype (T) is associated with lower tuft cell abundance in human colonic epithelium. CRISPR-mediated deletion of the 11q23.1 risk locus in the mouse germline exacerbated theApcMin/+mouse phenotype upon abrogation ofPou2af2expression specifically. Taken together, we implicate a key protective role of tuft cells in the large bowel and the importance of mis-regulation ofPOU2AF2as the prime tuft cell transcriptional activator at this locus.
Bacillus subtilisderived lipopeptides disrupt quorum sensing and biofilm assembly inStaphylococcus aureus
Authors: Leistikow Kyle R. , May Daniel S. , Suh Won Se , Asensio Gabriel Vargas , Currie Cameron R. , Hristova Krassimira R. 
Published: August 2023

AbstractMultidrug-resistantStaphylococcus aureusis one of the most clinically important pathogens in the world with infections leading to high rates of morbidity and mortality in both humans and animals.S. aureus’ability to form biofilm protects individual cells from antibiotics and promotes the transfer of antibiotic resistance genes. Therefore, new strategies aimed to inhibit biofilm growth and disassemble mature biofilms are urgently needed. Probiotic species, namelyBacillus subtilis,are gaining interest as a potential therapeutic againstS. aureusfor their ability to reduceS. aureuscolonization and virulence. Here, we collected and screened 1123Bacillusstrains obtained from a variety of agricultural environments in search of isolates with strong antibiofilm activity against clinical multi-drug resistantS. aureus.We selected a single strain,B. subtilis6D1, based on its ability to inhibit biofilm growth, disassemble mature biofilm, and improve antibiotic sensitivity ofS. aureusbiofilms through an Agr quorum sensing interference mechanism. Biochemical and molecular networking analysis of an active organic fraction revealed multiple surfactin isoforms and an uncharacterized compound were both driving this antibiofilm activity. Furthermore, when compared against commercial HPLC grade surfactin obtained fromB. subtilis,this active fraction inhibited biofilm formation against all fourS. aureusAgr backgrounds and preventedS. aureus-induced cytotoxicity when applied to HT29 human intestinal cell lines better than the commercial standard. Our results demonstrate the mixture of compounds produced byB. subtilis6D1 can mitigateS. aureusvirulence through multiple mechanisms.Contribution to the FieldThe biofilm formation capability of bacterial pathogens, such asStaphylococcus aureus, increases these microorganisms’ virulence potential and decreases the efficacy of common antibiotic regiments. Probiotics possess a variety of strain-specific strategies to reduce biofilm formation in competing organisms, however, the mechanisms and compounds responsible for these phenomena often go uncharacterized. In this study, we identified a mixture of small probiotic-derived peptides capable of Agr quorum sensing interference as one of the mechanisms driving antibiofilm activity againstS. aureus.This collection of peptides also improved antibiotic killing and protected human gut epithelial cells fromS. aureus-induced toxicity by stimulating an adaptive immune response. We conclude that purposeful strain screening and selection efforts can be used to identify unique probiotic strains that possess specially desired mechanisms of action. This information can be used to further improve our understanding of the ways in which probiotic and probiotic-derived compounds can be applied to prevent bacterial infections in clinical and agricultural settings.
Developmental adaptation of rod photoreceptor number via photoreception in melanopsin (OPN4) retinal ganglion cells
Authors: D’Souza Shane P. , Upton Brian A. , Eldred Kiara C. , Glass Ian , Grover Kassidy , Ahmed Abdulla , Ngyuen Minh-Thanh , Gamlin Paul , Lang Richard A. 
Published: August 2023

AbstractPhotoreception, a form of sensory experience, is essential for normal development of the mammalian visual system. Detecting photons during development is a prerequisite for visual system function - from vision’s first synapse at the cone pedicle and maturation of retinal vascular networks, to transcriptional establishment and maturation of cell types within the visual cortex. Consistent with this theme, we find that the lighting environment regulates developmental rod photoreceptor apoptosis via OPN4-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). Using a combination of genetics, sensory environment manipulations, and computational approaches, we establish a molecular pathway in which light-dependent glutamate release from ipRGCs is detected via a transiently expressed kainate receptor (GRIK3) in immature rods localized to the inner retina. Communication between ipRGCs and nascent inner retinal rods appears to be mediated by unusual hybrid neurites projecting from ipRGCs that sense light before eye-opening. These structures, previously referred to as outer retinal dendrites (ORDs), span the ipRGC-immature rod distance over the first postnatal week and contain the machinery for sensory detection (melanopsin, OPN4) and axonal/anterograde neurotransmitter release (Synaptophysin, and VGLUT2). Histological and computational assessment of human mid-gestation development reveal conservation of several hallmarks of an ipRGC-to-immature rod pathway, including displaced immature rods, transientGRIK3expression in the rod lineage, and the presence of ipRGCs with putative neurites projecting deep into the developing retina. Thus, this analysis defines a retinal retrograde signaling pathway that links the sensory environment to immature rods via ipRGC photoreceptors, allowing the visual system to adapt to distinct lighting environments priory to eye-opening.
An alpha 5-GABAa receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in an animal model for autism
Authors: Souza Adriana Jesus , Sharmin Dishary , Cook James M. , Guimarães Francisco S. , Gomes Felipe V. 
Published: August 2023

ABSTRACTAutism Spectrum Disorders (ASD) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5-containing GABAAreceptors (α5-GABAARs) SH-053-2’F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in a rat model for autism based onin uteroVPA exposure. We also evaluated if animals exposed to VPAin uteropresent changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2’F-R-CH3 could attenuate these changes.In uteroVPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2’F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Male and female adult VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2’F-R-CH3. Despite sex differences, our findings indicate α5-GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms.
Genotypic variation in resource exchange, use, and production traits in the legume-rhizobia mutualism
Authors: Calvert McCall B. , Hoque Maliha , Wood Corlett W. 
Published: August 2023

AbstractMutualisms, reciprocally beneficial interaction between two or more species, are ubiquitous in nature. A common feature of mutualisms is extensive context-dependent variation in fitness outcomes. This context-dependency is hypothesized to stem from the environment’s mediation of the relative costs and benefits associated with mutualisms. However, traits related to the exchange of goods and services in mutualisms have received little attention in comparison to net fitness outcomes. In this study, we quantified the contribution of host and symbiont genotypes to variation in resource exchange, use, and production traits measured in the host using the model mutualism between legumes and nitrogen-fixing rhizobia. We predicted that plant genotype x rhizobia genotype (GxG) effects would be common to resource exchange traits because resource exchange is hypothesized to be governed by both interacting partners through bargaining. On the other hand, we predicted that plant genotype effects would dominate host resource use and production traits because these traits are only indirectly related to the exchange of resources. Consistent with our prediction for resource exchange traits, but not our prediction for resource use and production traits, we found that rhizobia genotype and GxG effects were the most common sources of variation in the traits that we measured. The results of this study complement the commonly observed phenomenon of GxG effects for fitness by showing that numerous mutualism traits also exhibit GxG variation. Furthermore, our results highlight the possibility that the exchange of resources as well as how partners use and produce traded resources can influence the evolution of mutualistic interactions. Our study lays the groundwork for future work to explore the relationship between resource exchange, use and production traits and fitness (i.e. selection) to test the competing hypotheses proposed to explain the maintenance of fitness variation in mutualisms.
The characteristics of inducible defenses influence predator-prey dynamics
Authors: Cortez Michael H. , Mila Emily , Hammill Edward 
Published: August 2023

ABSTRACTEmpirical and theoretical studies suggest inducible and evolving defenses have different effects on predator-prey dynamics. However, theory for inducible defenses does not account for differences in response stimuli, reversibility, and within-generation versus transgenerational responses. We use predator-prey models to explore how these characteristics influence the effects of inducible defenses on stability and predator-prey oscillations. We find that while inducible defenses are typically stabilizing, defenses responding to any stimuli (predator density, conspecific and predator densities, predation rates, or the fitness gradient) can be destabilizing. Also, while induced defenses typically shorten predator-prey phase lags, defenses that respond to prey densities or the fitness gradient can increase the lags. Our theory helps explain why inducible defenses are less likely to be destabilizing and increase phase lags than evolving defenses: inducible defenses typically have negative feedbacks of the trait on its own dynamics whereas evolving defenses under disruptive selection can have positive feedbacks.
WITHDRAWN: Dynamic Regulation of MAVS Protein Function via Reversible Oxidation at Cys79in Response to Oxidant Stimuli
Authors: Zamorano Cuervo Natalia , Fortin Audray , Vallejo Arroyo Alejandro , Dehbidi Layla , Grandvaux Nathalie 
Published: August 2023

Withdrawal statement“The authors have withdrawn their manuscript owing to changes in the work. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.”
Both phenotypic and genotypic sex influence sex chromosome dosage compensation in a sex reversing lizard
Authors: Hanrahan Benjamin J. , Chang J King , Lister Nicholas C. , Dissanayake Duminda S.B. , Hammond Jillian M. , Reis Andre L.M. , Deveson Ira W. , Ruiz-Herrera Aurora , Patel Hardip R. , Marshall Graves Jennifer A. , Georges Arthur , Waters Paul D. 
Published: August 2023

AbstractStudies of sex chromosome dosage compensation have historically focussed on therian mammals which have a conserved XY sex determination system. In contrast, lizards have sex determination systems that can differ between even closely related species that include XY and ZW systems and thermolabile systems where genetic and temperature interact to various degrees to determine sex. The eastern three-lined skink (Bassiana duperreyi) has a differentiated XY sex determination system, in which low temperature incubation during development can cause female to male sex reversal, producing XX males. This provides a unique opportunity to investigate how genotype and phenotype affect dosage compensation. We generated transcriptomes from brain and heart tissue of normal adult males and females, along with brain tissue of sex-reversed XX males. We observed partial dosage compensation between XX females and XY males in both brain and heart, with median gene expression from the X in normal males being 0.7 times that of normal females. Surprisingly, in brain of sex reversed XX males the median X chromosome output did not match that of either normal males or females, but instead was 0.89 times that of the normal XX female level. This suggests that not just genotype, but also sexual phenotype, influences gene dosage of the X chromosome. This has profound implications for our understanding of the evolution of dosage compensation.