bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh Syndrome
Authors: Sánchez-Benito Laura , Compte Joan , Vila Miquel , Sanz Elisenda , Quintana Albert 
Published: October 2024

ABSTRACTDeficits in the mitochondrial energy-generating machinery cause mitochondrial disease (MD), a group of untreatable and usually fatal disorders. Among many severe symptoms, refractory epileptic events are a common neurological presentation of MD. However, the neuronal substrates and circuits for MD-induced epilepsy remain unclear. Here, using mouse models of mitochondrial epilepsy that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrate that mitochondrial dysfunction leads to a reduction in the number of GABAergic neurons in the rostral external globus pallidus (GPe) and identify a specific affectation of pallidalLhx6-expressing inhibitory neurons. Our findings further reveal that viral vector-mediatedNdufs4re-expression in the GPe effectively prevents seizures and improves the survival in the models. Additionally, we highlight the subthalamic nucleus (STN) as a critical structure in the neural circuit involved in mitochondrial epilepsy, as its inhibition effectively reduces epileptic events. Thus, we have identified a novel role for pallido-subthalamic projections in the development of epilepsy in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with MD providing new leads in the quest to identify novel and effective treatments.
Metabolic growth mechanisms and theoretical growth potential of global woody plant communities
Authors: Shu Shumiao , Tang Xiaolu , Kontsevich George , Wang Xiaodan , Zhu Wanze , Zhao Yangyi , Wang Wenzhi , Zhao Xiaoxiang , Hu Zhaoyong 
Published: October 2024

AbstractPredicting the growth and maximum biomass (Mmax) of woody plant communities (WPC) is challenging due to the complexity and variability of tree growth. While Metabolic Scaling Theory (MST) offers a promising concept, its current theoretical framework is still insufficient. Here, we applied MST principles and our previous findings to propose an iterative growth model for forest growth (IGMF). This model and its extension show that WPC growth, net primary productivity and other carbon budgets - such as total primary productivity, autotrophic respiration, organ turnover biomass and non-structural carbohydrates - can be expressed as functions of current biomass, maintenance respiration rate per unit biomass and stand age orMmax. These functions are globally convergent, allowing us to estimate the current (2018-2020) globalMmaxat 1451 ± 26 Pg based on the current state of WPCs alone, with a growth potential of 518 Pg, 83% of which is attributable to shrublands. By the end of the century, climate change is projected to reduce the totalMmaxby 266 Pg, mainly in species-rich evergreen broadleaf forests. Further analysis indicates that species richness increases the climate sensitivity ofMmax, while soil organic and moisture affects the direction of this response. Our findings reveal WPC growth kinetics and show a shift in the main contributor to terrestrial carbon sequestration from forests to shrublands.Significance StatementThis study introduces a new theoretical model for understanding and predicting the growth and carbon budgets of woody plant communities (WPCs), which applies to diverse WPCs globally and reveals their convergent metabolic growth patterns.We predict future changes in the maximum biomass of woody plant communities and find a significant decline in evergreen broadleaf forests, where sensitivity and response to climate change are influenced by current species richness and soil conditions.
Mechanism of DNA entrapment by the MukBEF SMC complex and its inhibition by a viral DNA mimic
Authors: Bürmann Frank , Clifton Bryony , Koekemoer Sophie , Wilkinson Oliver J. , Kimanius Dari , Dillingham Mark S. , Löwe Jan 
Published: October 2024

SummaryRing-like structural maintenance of chromosomes (SMC) complexes are crucial for genome organization and operate through mechanisms of DNA entrapment and loop extrusion. Here, we explore the DNA loading process of the bacterial SMC complex MukBEF. Using electron cryomicroscopy (cryo-EM), we demonstrate that ATP binding opens one of MukBEF’s three potential DNA entry gates, exposing a DNA capture site that positions DNA at the open neck gate. We discover that the gp5.9 protein of bacteriophage T7 blocks this capture site by DNA mimicry, thereby preventing DNA loading and inactivating MukBEF. We propose a comprehensive and unidirectional loading mechanism in which DNA is first captured at the complex’s periphery and then ingested through the DNA entry gate, powered by a single cycle of ATP hydrolysis. These findings illuminate a fundamental aspect of how ubiquitous DNA organizers are primed for genome maintenance and demonstrate how this process can be disrupted by viruses.Graphical abstract
Engineered Whole Lungs for Tissue Biology
Authors: Greaney Allison Marie , Raredon Micha Sam Brickman , Obata Tomohiro , Wang Juan , Adams Taylor , Schupp Jonas , Mizoguchi Satoshi , Edelstein Sophie , Yuan Yifan , Baevova Pavlina , Wang Nuoya , Engler Alex , Leiby Katherine , Tsuchiya Tomoshi , Homer Robert , Kaminski Naftali , Langer Robert , Niklason Laura E. , Medzhitov Ruslan 
Published: October 2024

AbstractEnd-stage lung disease and lung cancer significantly contribute to global mortality, necessitating new research strategies for studying pulmonary biology. Here, we present an engineered whole-lung tissue model used to evaluate the effects of cellular communities on tissue organization and alveolar barrier function. Engineered lungs were grownex vivoon decellularized whole-lung matrices as structurally biomimetic, bioactive scaffolds. Histologic architecture of engineered lungs improved with the addition of alveolar macrophages, coming to resemble neonatal lung. Incorporating alveolar macrophages maximized the differentiation of native-like cellular communities, including alveolar type I-like epithelium, bronchioalveolar stem cells, microvascular endothelium, and pericytes. Cell-cell signaling in engineered lungs showed activation of developmental and inflammatory pathways, including WNT, Notch, and FGF signaling pathways. Engineered lungs containing alveolar macrophages showed a 668% improvement in measured alveolar barrier function. This work demonstrates the potential utility of engineered lung models for studying principles of tissue biology and pulmonary regeneration.
PertEval-scFM: Benchmarking Single-Cell Foundation Models for Perturbation Effect Prediction
Authors: Wenteler A. , Occhetta M. , Branson N. , Huebner M. , Curean V. , Dee W. T. , Connell W. T. , Hawkins-Hooker A. , Chung S. P. , Ektefaie Y. , Gallagher-Syed A. , Córdova C. M. V. 
Published: October 2024

AbstractIn silicomodeling of transcriptional responses to perturbations is crucial for advancing our understanding of cellular processes and disease mechanisms. We present PertEval-scFM, a standardized framework designed to evaluate models for perturbation effect prediction. We apply PertEval-scFM to benchmark zero-shot single-cell foundation model (scFM) embeddings against simpler baseline models to assess whether these contextualized representations enhance perturbation effect prediction. Our results show that scFM embeddings do not provide consistent improvements over baseline models, especially under distribution shift. Additionally, all models struggle with predicting strong or atypical perturbation effects. Overall, this study provides a systematic evaluation of zero-shot scFM embeddings for perturbation effect prediction, highlighting the challenges of this task and revealing the limitations of current-generation scFMs. Our findings underscore the need for specialized models and high-quality datasets that capture a broader range of cellular states. Source code and documentation can be found at:https://github.com/aaronwtr/PertEval.
“Nanoscale biodegradable printing for designed tuneability of vaccine delivery kinetics”
Authors: Peeler David J , Sun Rujie , Kütahya Ceren , Peschke Patrick , Zhou Kun , Brachi Giulia , Yeow Jonathan , Rifaie-Graham Omar , Wojciechowski Jonathan P , Debets Thomas Fernandez , LaLone Vernon , Song Xin , Polra Krunal , Tregoning John S , Shattock Robin J , Stevens Molly M 
Published: October 2024

AbstractTwo photon polymerization (2PP) 3D printing enables top-down biomaterial synthesis with nanoscale spatial resolution forde novodesign of monodisperse injectable drug delivery systems. To address the limitations of current 2PP resins, we developed Spatiotemporal Controlled Release Inks of Biocompatible polyEsters (SCRIBE), a novel poly(lactic-co-glycolic acid)-triacrylate resin family with sub-micron resolution and tuneable hydrolysis. SCRIBE enables direct printing of hollow microparticles with tuneable chemistry and complex geometries inaccessible to molding techniques, which we use to engineer controlled protein releasein vitroandin vivo. We use SCRIBE microparticles to modulate antibody titers and class switching as a function of antigen release rate and extend these findings to enable a single-injection vaccine formulation with extended antibody induction kinetics. Demonstrating how the chemistry and CAD of 2PP-printed microparticles can be used to tune responses to biomacromolecule releasein vivoopens significant opportunities for a new generation of drug delivery vehicles.
Early Intervention with Low-Dose Sclerostin Antibody Therapy can Reduce Osteocyte-mediated Secondary Mineralization after initial bone loss in Ovariectomised Rats
Authors: Naqvi Syeda Masooma , Allison Hollie , O’Sullivan Laoura M. , Holdsworth Gill , Panadero-Perez Juan Alberto , Schiavi-Tritz Jessica , McNamara Laoise M. 
Published: October 2024

AbstractNeutralizing antibodies targeting sclerostin (Scl-Ab) mitigate bone loss and promote bone formation, thereby reducing fracture risk in postmenopausal osteoporosis. Clinical use of Scl-Ab is indicated for postmenopausal women with severe osteoporosis who are at high risk of, or have a history of, fragility fractures, which can occur many years after menopause. However, in early stages of estrogen deficiency there is rapid bone loss, which abates thereafter, whereas in the longer-term changes in bone mineralization occur. This study seeks to investigate whether administering intermittent low-dose monthly sclerostin antibody during early estrogen deficiency could mitigate osteoclastogenesis but also prevent osteocyte-driven secondary mineralization, due to apoptosis, perilacunar remodelling and osteocyte mechanosensitivity. Female Wistar rats that had completed their breeding cycles underwent bilateral ovariectomy as a model of postmenopausal osteoporosis. After 3 weeks of bone loss, one group received monthly low-dose Scl-Ab injections (2 mg/kg/month) and a control group remained untreated. We report that early treatment with intermittent low-dose Scl-Ab mildly increased bone formation, reduced TRAP+ osteoclasts and suppressed catabolic and matrix degradation gene expression (Sost, Ctsk, Mmp9) compared to untreated rats. There was a decrease in the percentage of empty lacunae and MMP14+ osteocytes, along with decreased gene expression associated with osteocyte-mediated mineralization (DMP1, PHEX, OPN, ALP) and mechanotransduction (Vcl, integrins α5, αV, β1, CX43, Axin2, IFT88, Adcy6, Pkd1, and Cav1). Thus, we propose that early intervention with intermittent low-dose Scl-Ab therapy can promote surface bone formation but reduce osteocyte-mediated secondary mineralization after initial bone loss.
Reward processing in children with Affective Dysregulation
Authors: Aggensteiner Pascal-M , Giller Francisca , Holz Nathalie , Kaiser Anna , Igel Christine , Hohmann Sarah , Döpfner Manfred , Roessner Veit , Beste Christian , Banaschewski Tobias , Brandeis Daniel 
Published: October 2024

AbstractIntroductionAffective dysregulation (AD) in children is characterized by irritability, anger, and frequent intense temper outbursts. Considerable evidence implies altered processing of frustration about missed rewards, but few studies investigated the preceding and thus potentially predictive reward anticipation and initial delivery processing in children with AD.MethodsA total of 103 children aged 8 to 12 years (50 with AD and 53 without AD) were examined during a monetary reward anticipation task with event-related potential (ERP) components resolving reward anticipation (cue-CNV [Contingent Negative Variation]) and reward delivery phases (Reward Positivity and Feedback-Related Negativity). All components were analyzed by repeated measures ANOVA. Regression analyses also evaluated the associations between those ERP components and dimensional AD symptoms.ResultsChildren with AD showed attenuated anticipatory reward processing compared to No-ADs. The CNV at fronto-central site (FCz) showed a significant group effect (No-AD>AD, p=0.017). Post-hoc test showed that this group difference was stronger for the cue monetary condition (monetary cue: p=.007, d=0.56, verbal cue: p=.901, d=0.16), and that only the No-AD group showed a significant difference between conditions (p<0.001). No significant effects were obtained for the delivery phase. Regression analysis showed that a reduced anticipatory CNV at FCz significantly explained AD symptoms, and that anger/irritability and anxiety/depressive symptoms predicted a reduced anticipatory CNV at FCz.ConclusionThis neurophysiological characterization of reward anticipation and delivery in children with AD demonstrates altered neural activity in AD during anticipation of reward rather than following the delivery (or omission) of the reward itself. Our results highlight that altered reward anticipation in AD can occur outside frustration-prone tasks or settings, and underline the important role of both anger/irritability and anxiety/depressive symptoms in the pathophysiology of AD for atypical reward anticipation.
Trichomonas vaginalisextracellular vesicles suppress IFNε-mediated protection against host cell cytolysis
Authors: Kochanowsky Joshua A. , Betts Emma L. , Encinas Gabriel , Amoah Johnson , Mukherjee Sandip Kumar , Johnson Patricia J. 
Published: October 2024

AbstractTrichomonas vaginalisis a commonly acquired sexually transmitted infection (STI) often found in symbiosis with the intracellular bacteriumMycoplasma hominis, an opportunistic pathogen of the female reproductive tract associated with bacterial vaginosis. How this symbiosis affects infection outcomes, and the host cell innate immune response is still poorly understood. Here we show thatT. vaginalisextracellular vesicles down-regulate a non-canonical type I interferon, interferon-epsilon, and suppress type I interferon responses. Transcriptomic analysis reveals that infection withT. vaginalisin symbiosis withM. hominisorM. hominisalone upregulates genes involved in the type I IFN response, but infection withT. vaginalisalone does not. Finally, we show that interferon-epsilon stimulation is protective againstT. vaginaliscytoadherence and cytolysis of host cells and increases the ability of neutrophils to kill the parasite. These studies provide insight into the innate immune response induced by a highly prevalent STI and its bacterial symbiont.
Toxoplasma gondiiPROP1 is critical for autophagy and parasite viability during chronic infection
Authors: Thaprawat Pariyamon , Chalasani Shreya , Schultz Tracey L. , Di Cristina Manlio , Carruthers Vern B. 
Published: October 2024

AbstractMacroautophagy is an important cellular process involving lysosomal degradation of cytoplasmic components, facilitated by autophagy-related proteins (ATGs). In the protozoan parasiteToxoplasma gondii, autophagy has been demonstrated to play a key role in adapting to stress and persistence of chronic infection. Despite limited knowledge about the core autophagy machinery inT. gondii, two PROPPIN family proteins (TgPROP1 and TgPROP2) have been identified with homology to Atg18/WIPI. Prior research in acute stage tachyzoites suggests that TgPROP2 is predominantly involved in a non-autophagic function, specifically apicoplast biogenesis, while TgPROP1 may be involved in canonical autophagy. Here, we investigated the distinct roles of TgPROP1 and TgPROP2 in chronic stageT. gondiibradyzoites, revealing a critical role for TgPROP1, but not TgPROP2, in bradyzoite autophagy. Conditional knockdown of TgPROP2 did not impair bradyzoite autophagy. In contrast, TgPROP1 KO parasites had impaired autolysosome formation, reduced cyst burdens in chronically infected mice, and decreased viability. Together, our findings clarify the indispensable role of TgPROP1 toT. gondiiautophagy and chronic infection.ImportanceIt is estimated that up to a third of the human population is chronically infected withToxoplasma gondii; however, little is known about how this parasite persists long term within its hosts. Autophagy is a self-eating pathway that has recently been shown to play a key role in parasite persistence, yet few proteins that carry out this process duringT. gondiichronic infection are known. Here, we provide evidence for a non-redundant role of TgPROP1, a protein important in the early steps of the autophagy pathway. Genetic disruption of TgPROP1 resulted in impaired autophagy and chronic infection of mice. Our results reveal a critical role for TgPROP1 in autophagy and underscore the importance of this pathway in parasite persistence.
Genetic Diversity ofZymoseptoria triticiPopulations in Central and South-eastern Ethiopia
Authors: Tucho Ayantu , Mekonnen Tilahun , Ghadamgahi Farideh , Gosh Samrat , Muleta Diriba , Tesfaye Kassahun , Wang Eu Shang , Alemu Tesfaye , Vetukuri Ramesh Raju 
Published: October 2024

AbstractSeptoria tritici blotch (STB), caused by the hemibiotrophic fungusZymoseptoria tritici, is a serious threat to global wheat production, and a major bottleneck to wheat production in Ethiopia. Accurate identification and analysis of the pathogen’s genetic structure helps inform robust STB management. This study analyzed the molecular identity and genetic structure of 200Z. triticiisolates retrieved from diseased crops in central and south-eastern regions of Ethiopia. Allelic diversity at 12 simple sequence repeat (SSR) loci was examined for all 200 isolates, and 165 isolates were identified by Sanger sequencing of the internal transcribed spacer (ITS) region of nuclear DNA (rDNA) region. The microsatellites were highly polymorphic, with mean number of alleles (Na) = 6.23, effective alleles (Ne) =2.90, Nei’s gene diversity (H) =0.57, and polymorphic information content (PIC) =0.59, and an analysis of molecular variance confirmed the presence of low population differentiation (Fixation Index (FST) = 0.02, Gene Flow (Nm) = 14.7), with 95% of the total genetic variation residing within populations, and only 5% residing between populations. The highest genetic diversity (Number of allele (Na) = 9.33, Effective number of allele (Ne) = 3.41 and Nei’s gene diversity (H) = 0.68) was observed in the Oromia special zone surrounding Finfinnee (OSZ)Z. triticipopulations, followed by Arsi and North Shewa populations, indicating that these areas are ideal for multi-location germplasm resistance screening, and also pathogen genetic and genomic analyses. Cluster analyses did not clearly divide the populations into genetically separate clusters according to their geographic sampling areas, probably because of high gene flow. All individual samples showed genetic admixture, and shared genomic backgrounds from two subgroups (K=2). Overall, the SSR markers proved to be highly informative and effective genetic tools for unlocking the pathogen’s genetic structure. TheZ. triticipopulations of central and southeast Ethiopia exhibit high genetic diversity, indicating the need to deploy durable and diverse disease management strategies. North Shewa, OSZ, Arsi and West Arsi administrative zones represent hotspots for genetic and genomic analyses ofZ. tritici. Moreover, these areas would be excellent locations for host–pathogen interaction studies, and wheat germplasm screening for STB resistance.
Prosocial reward relates to speech reception thresholds and age relates to subjective ratings of speech perception in noise
Authors: Oakeson Ryan J , Herbert Jesca , Roper Simon , Zhang Hongyi , Rosen Stuart , Scott Sophie K 
Published: October 2024

AbstractThis study explores how prosocial motivation and social reward relate to speech perception in noise (SPiN). We investigated SPiN performance and subjective listening experiences across different masker conditions: 1-speaker, 2-speaker, and steady-state noise (SSN). Results indicate that individuals who rated themselves higher in prosocial traits performed better in the condition that yielded the worst threshold out of the three conditions i.e., the 2-speaker condition. Age significantly influenced subjective ratings of listening effort across all conditions where older participants reported greater effort. These findings highlight prosocial motivation as a potential factor influencing SPiN abilities, particularly in complex listening scenarios, alongside the role of age in shaping subjective auditory experiences.
Striatal modulation supports policy-specific reinforcement and not action selection
Authors: Hodge A.T. , Yttri E.A. 
Published: October 2024

AbstractTwo contrasting models dominate our understanding of basal ganglia function: action selection and reinforcement learning. Prolonged, indiscriminate stimulation of direct and indirect pathway striatal neurons produces effects consistent with the action selection; however this approach ignores the transient, movement-specific dynamics that characterize these cells. To determine how striatal subpopulations contribute to mouse behavior, we applied brief closed-loop optogenetic stimulation to modulate ongoing activity in a manner that directly dissociates the contrasting models: upon the detection of locomotor arrest or leftward turns. While action selection models predict that increased direct pathway stimulation should induce locomotion and turning contralaterally to the side of stimulation, selective stimulation biased behavioral policies towards more frequent locomotor arrest and leftward turns, regardless of the side of stimulation. Indirect pathway stimulation had the opposite effect. Behavior followed the policy associated with the change in striatal activity, providing a mechanism to enable the reinforcement a wide range of behavioral features to shape performance.