bluuebunny/crossref_metadata_2025_split huggingface dataset:
Powerful mapping ofcis-genetic effects on gene expression across diverse populations reveals novel disease-critical genes
Authors: Akamatsu Kai , Golzari Stephen , Amariuta Tiffany 
Published: September 2024

AbstractWhile disease-associated variants identified by genome-wide association studies (GWAS) most likely regulate gene expression levels, linking variants to target genes is critical to determining the functional mechanisms of these variants. Genetic effects on gene expression have been extensively characterized by expression quantitative trait loci (eQTL) studies, yet data from non-European populations is limited. This restricts our understanding of disease to genes whose regulatory variants are common in European populations. While previous work has leveraged data from multiple populations to improve GWAS power and polygenic risk score (PRS) accuracy, multi-ancestry data has not yet been used to better estimatecis-genetic effects on gene expression. Here, we present a new method, Multi-Ancestry Gene Expression Prediction Regularized Optimization (MAGEPRO), which constructs robust genetic models of gene expression in understudied populations or cell types by fitting a regularized linear combination of eQTL summary data across diverse cohorts. In simulations, our tool generates more accurate models of gene expression than widely-used LASSO and the state-of-the-art multi-ancestry PRS method, PRS-CSx, adapted to gene expression prediction. We attribute this improvement to MAGEPRO’s ability to more accurately estimate causal eQTL effect sizes (p< 3.98 × 10-4, two-sided paired t-test). With real data, we applied MAGEPRO to 8 eQTL cohorts representing 3 ancestries (averagen= 355) and consistently outperformed each of 6 competing methods in gene expression prediction tasks. Integration with GWAS summary statistics across 66 complex traits (representing 22 phenotypes and 3 ancestries) resulted in 2,331 new gene-trait associations, many of which replicate across multiple ancestries, includingPHTF1linked to white blood cell count, a gene which is overexpressed in leukemia patients. MAGEPRO also identified biologically plausible novel findings, such asPIGB, an essential component of GPI biosynthesis, associated with heart failure, which has been previously evidenced by clinical outcome data. Overall, MAGEPRO is a powerful tool to enhance inference of gene regulatory effects in underpowered datasets and has improved our understanding of population-specific and shared genetic effects on complex traits.
Challenges and advances for huntingtin detection in cerebrospinal fluid: in support of relative quantification
Authors: Harding Rachel J. , Xie Yuanyun , Caron Nicholas S. , Findlay-Black Hailey , Lyu Caroline , Potluri Nalini , Chandrasekaran Renu , Hayden Michael R. , Leavitt Blair R. , Langbehn Douglas R. , Southwell Amber L. 
Published: September 2024

AbstractHuntington disease (HD) is a progressive and devastating neurodegenerative disease caused by expansion of a glutamine-coding CAG tract in the huntingtin (HTT) gene above a critical threshold of ∼35 repeats resulting in expression of mutant HTT (mHTT). A promising treatment approach being tested in clinical trials is HTT lowering, which aims to reduce levels of the mHTT protein. Target engagement of these therapies in the brain are inferred using antibody-based assays to measure mHTT levels in the cerebrospinal fluid (CSF), which is frequently reported as absolute mHTT concentration based on a monomeric protein standard used to generate a standard curve. However, patient biofluids are a complex milieu of different mHTT protein species, suggesting that absolute quantitation is challenging, and a single, recombinant protein standard may not be sufficient to interpret assay signal as molar mHTT concentration. In this study, we used immunoprecipitation and flow cytometry (IP-FCM) to investigate different factors that influence mHTT detection assay signal. Our results show that HTT protein fragmentation, protein-protein interactions, affinity tag positioning, oligomerization and polyglutamine tract length affect assay signal intensity, indicating that absolute HTT quantitation in heterogeneous biological samples is not possible with current technologies using a single standard protein. We also explore the binding specificity of the MW1 anti-polyglutamine antibody, commonly used in these assays as a mHTT-selective reagent and demonstrate that mHTT binding is preferred but not specific. Furthermore, we find that MW1 depletion is not only incomplete, leaving residual mHTT, but also non-specific, resulting in pull down of some wildtype HTT protein. Based on these observations, we recommend that mHTT detection assays report only relative mHTT quantitation using normalized arbitrary units of assay signal intensity, rather than molar concentrations, in the assessment of central nervous system HTT lowering in ongoing clinical and preclinical studies, and that MW1-depletion not be used a method for quantifying wildtype HTT protein.
Innovative platelet-derived extracellular vesicle drug delivery system for the treatment of corneal neovascularization
Authors: Liu Guei-Sheung , Chen Huai-An , Chang Che-Yi , Chen Yin-Ju , Wu Yu-Yi , Widhibrata Ariel , Yang Ya-Han , Hsieh Erh-Hsuan , Delila Liling , Lin I-Chan , Burnouf Thierry , Tseng Ching-Li 
Published: September 2024

AbstractPlatelet-derived extracellular vesicles (PEVs) have drawn attention due to their multifunctionality, ease of procurement, and abundant supply from clinical-grade platelet concentrates. PEVs can be easily endocytosed owing to their lipid bilayer membrane and nanosized structure, thereby increasing the bioavailability and functionality of their therapeutic effects. PEVs also possess multiple trophic factors that make them effective therapeutic agents. Since nanomedicine offers advantages over traditional therapies for eye diseases by overcoming physical ocular barriers, PEVs combined with an anti-angiogenic agent, kaempferol (KM), were evaluated for their ability to inhibit abnormal vessel formation in the cornea. Characterization of the nanoparticles indicated successful preparation of KM- loaded PEVs (PEV-KM) with a mean diameter of ∼160 nm and an encapsulation efficiency of ∼61%. PEV-KM was efficiently internalized into human vascular endothelial cells, resulting in inhibited function, evidenced by lower wound closure rates, reduced tube formation capacity, and downregulation of angiogenesis-related gene expression. Moreover, prolonged ocular retention was observed followed by topical application of PEV and PEV-KM in mouse eyes. In an alkali-burned corneal neovascularization (CoNV) mouse model, PEV (1%) was found to reduce vessel formation in the injured cornea. PEV with KM (1% PEV with KM 6 µg/mL) showed an even stronger effect in suppressing CoNV and reducing the expression of proangiogenic and inflammatory cytokines. Together, our data suggests that topical administration of PEVs or in combination with KM (PEV-KM) is a promising therapeutic for managing CoNV.
The mitochondrialorf125affects male fertility ofSolanum tuberosum(+)S. commersoniisomatic hybrids and participates in the onset of “Tuberosum”-Type CMS and evolution of common potato
Authors: Tamburino Rachele , D’Agostino Nunzio , Aufiero Gaetano , Nicolia Alessandro , Facchiano Angelo , Giordano Deborah , Sannino Lorenza , Paparo Rosa , Arimura Shin-Ichi , Scotti Nunzia , Cardi Teodoro 
Published: September 2024

AbstractCytoplasmic male sterility (CMS) is an agronomically significant trait and a powerful tool to study interactions between nuclear and cytoplasmic genomes. In this study, the chondriomes of two isonuclear male-fertile and sterile somatic hybrids (SH9A and SH9B, respectively) between the common potato (Solanum tuberosumGroupTuberosum,tbr) and the wild speciesS. commersonii(cmm), were sequenced and compared to those of parental species to identify mitochondrial genes involved in the expression of male sterility. A putative novel gene (orf125) was found only intbrand in male-sterile hybrids. Two approaches, a physical or functional deletion oforf125by mtDNA editing in SH9B and its allotopic expression in SH9A, clearly demonstrate thatorf125affects male fertility. To trace the origin oforf125and hypothesize its role in the evolution of common potato, we searched it intbrvarieties, tuber-bearing potato relatives and other Solanaceae. The organization of the mitochondrial genome region implicated in CMS remained consistent across all common potato accessions in GenBank. An identicaltbrcopy oforf125was also detected in all six accessions belonging to theS. berthaultiicomplex (ber) analyzed. Such findings corroborate the hypothesis thatberaccessions with T/β cytoplasm crossed as female with Andean potato (S. tuberosumGroupAndigenum,adg), giving rise to the differentiation of the Chilean potato (S. tuberosumGroupChilotanum), and highlights the origin of mitochondrial factors contributing to genic-cytoplasmic male sterility intbrxadg(or some wild species) hybrids.
Genetic and phenotypic characterization of globalLupinus albusgenetic resources for the development of a CORE collection
Authors: Tanwar Umesh Kumar , Tomaszewska Magdalena , Czepiel Katarzyna , Neji Mohamed , Jamil Humaira , Rocchetti Lorenzo , Pieri Alice , Bitocchi Elena , Bellucci Elisa , Pipan Barbara , Meglič Vladimir , Kroc Magdalena , Papa Roberto , Susek Karolina 
Published: September 2024

ABSTRACTLupinus albusis a food grain legume recognized for its high levels of seed protein (30–40%) and oil (6–13%), and its adaptability to different climatic and soil conditions. To develop the next generation ofL. albuscultivars, we need access to well-characterized, genetically and phenotypically diverse germplasm. Here we evaluated more than 2000L. albusaccessions with passport data based on 35 agro-morphological traits to develop Intelligent CORE Collections. The reference CORE (R-CORE), representing global diversity, exemplified the genotypic variation of cultivars, breeding/research materials, landraces and wild relatives. A subset of 300 R-CORE accessions was selected as a training CORE (T-CORE), representing the diversity in the entire collection. We divided theL. albusR-CORE into four phenotypic groups (A1, A2, A3 and B) based on principal component analysis, with groups A3 and B distinguished by pod shattering and seed ornamentation, respectively. The coefficient of additive genetic variation differed across morphological traits, phenotypic groups, geographic regions, and according to biological status. These CORE collections will facilitate agricultural research by identifying the genes responsible for desirable traits in crop improvement programs, and by shedding light on the use of orphan genetic resources for origin and domestication studies inL. albus. Understanding the variation in these genetic resources will allow us to develop sustainable tools and technologies that address global challenges such as providing healthy and sustainable diets for all, and contrasting the current climate change crisis.
In SilicoEngineering of Stable siRNA Lipid Nanoparticles: Exploring the Impact of Ionizable Lipid Concentrations for Enhanced Formulation Stability
Authors: Biswal Malay Ranjan , Roy Sudip , Singh Jayant K 
Published: September 2024

AbstractLipid nanoparticles (LNPs) are crucial in advancing the delivery of RNA-based therapeutics within the domain of gene therapy. A comprehensive understanding of their formation and stability is critical for optimizing the clinical efficacy of LNPs. This study systematically investigates the influence of concentration variations of positive and neutral ionizable lipids - specifically, 2-[2,2-bis[(9Z,12Z)-octadeca-9,12-dienyl]-1,3-dioxolan-4-yl]-N,N-dimethylethanamine (DLinKC2-DMA) and 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) - along with cholesterol and polyethylene glycol, on the formation of LNPs and encapsulation of small interfering RNA (siRNA). Utilizing coarse-grained classical molecular dynamics (MD) simulations with a system size matching experimental range (approximately 0.6 million beads), we conduct a comparative analysis and offer mechanistic insights into siRNA formulation within LNPs containing positive and neutral DLinKC2-DMA. We found that the LNPs with positive ionizable lipids encapsulate more than twice the siRNA compared to the LNPs with neutral ionizable lipids. In addition to the formation of LNPs, our study extends to the forces governing siRNA escape from LNPs, employing steered molecular dynamics simulations. The force experienced by siRNA to cross the LNP lipid layer containing positive ionizable lipids was 400kJ/mol/nm more than that of neutral ionizable lipids, suggesting the encapsulation is more favorable with positive ionisable lipids.
Differential responses and recovery dynamics of HSPC populations followingPlasmodium chabaudiinfection
Authors: Bruno Federica , Georgiou Christiana , Cunningham Deirdre , Atkinson Samantha , Bett Lucy , Secchi Marine , Gonzalez Anton Sara , Birch Flora , Langhorne Jean , Celso Cristina Lo 
Published: September 2024

ABSTRACTSevere infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug-resistance. It is therefore paramount that we better understand how the host’s organism responds to severe infection. Hematopoiesis is particularly of interest in this context because hematopoietic stem and progenitor cells (HSPCs) maintain the turnover of all blood cells, including all immune cells. Severe infections have been widely acknowledged to affecting HSPCs, however this disruption has been mainly studied during the acute phase, and the process and level of HSPC recovery remains understudied. Using a self-resolving model of natural rodent malaria, infection byPlasmodium chabaudi, here we systematically assess HSPCs’ acute response and recovery upon pathogen clearance. We demonstrate that during the acute phase of infection the most quiescent and functional stem cells are depleted, multipotent progenitor compartments are drastically enlarged, and oligopotent progenitors virtually disappear, underpinned by dramatic, population-specific and sometimes unexpected changes in proliferation rates. HSPC populations return to homeostatic size and proliferation rate again through specific patterns of recovery. Overall, our data demonstrate that HSPC populations adopt different responses to cope with severe infection and suggest that the ability to adjust proliferative capacity becomes more restricted as differentiation progresses.
Heterogeneous Appetite Patterns in Depression: Computational Modeling of Nutritional Interoception, Reward Processing, and Decision-Making
Authors: Uchida Yuuki , Hikida Takatoshi , Honda Manabu , Yamashita Yuichi 
Published: September 2024

AbstractAccurate interoceptive processing in decision-making is essential to maintain homeostasis and overall health. Disruptions in this process have been associated with various psychiatric conditions, including depression. Recent studies have focused on nutrient homeostatic dysregulation in depression for effective subtype classification and treatment. Neurophysiological studies have associated changes in appetite in depression with altered activation of the mesolimbic dopamine system and interoceptive regions, such as the insular cortex, suggesting that disruptions in reward processing and interoception drive changes in nutrient homeostasis and appetite. This study aimed to explore the potential of computational psychiatry in addressing these issues. Using a homeostatic reinforcement learning model formalizing the link between internal states and behavioral control, we investigated the mechanisms by which altered interoception affects homeostatic behavior and reward system activity via simulation experiments. Simulations of altered interoception demonstrated behaviors similar to those of depression subtypes, such as appetite dysregulation. Specifically, reduced interoception led to decreased reward system activity and increased punishment, mirroring the neuroimaging study findings of decreased appetite in depression. Conversely, increased interoception was associated with heightened reward activity and impaired goal-directed behavior, reflecting an increased appetite. Furthermore, effects of interoception manipulation were compared with traditional reinforcement learning parameters (e.g., inverse temperatureβand delay discountγ), which represent cognitive-behavioral features of depression. The results suggest that disruptions in these parameters contribute to depressive symptoms by affecting the underlying homeostatic regulation. Overall, this study findings emphasize the importance of integrating interoception and homeostasis into decision-making frameworks to enhance subtype classification and facilitate the development of effective therapeutic strategies.
Disarming emotional memories using Targeted Memory Reactivation during Rapid Eye Movement sleep
Authors: Greco Viviana , Foldes Tamas A. , Harrison Neil A. , Murphy Kevin , Wawrzuta Marta , Abdellahi Mahmoud E. A. , Lewis Penelope A. 
Published: September 2024

SummaryEmotional responses are dampened across sleep, and this is thought to be mediated by neural reactivation during Rapid Eye Movement (REM) Sleep. Such reactivation can be triggered by targeted memory reactivation (TMR), a technique in which a tone previously associated with a memory during wake is re-presented during subsequent sleep. Prior work has shown that TMR in REM reduces arousal responses to negative stimuli. The present study builds on this by measuring autonomic responses and brain activity as well as behaviour. Participants rated the arousal of 48 affective images, paired with semantically matching sounds. Half of these sounds were cued during REM in the subsequent overnight sleep cycle. Participants rated the images in a Magnetic Resonance Imaging (MRI) scanner with pulse oximetry 48 hours after encoding, and again after two weeks. Results showed that TMR during REM was also associated with reduced brain activity in the two primary nodes of the Salience Network (SN): the Anterior Insula and dorsal Anterior Cingulate Cortex (dACC), as well as the orbitofrontal cortex, subgenual cingulate, and left amygdala, all of which are known to be important for emotional processing. TMR markedly reduced the emotional heart rate deceleration (HRD) response, and also reduced subjective arousal ratings for highly arousing images, while increasing ratings for less arousing images. We conclude that REM TMR can facilitate a decrease in physiological and neurological responses to arousal. These findings have potential implications for the use of TMR in treatment of depression and anxiety disorders.HighlightsTMR in REM sleep reduces Salience Network responses to emotional pictures.TMR in REM sleep reduces heart rate deceleration to emotional pictures.TMR in REM sleep reduces subjective arousal ratings of highly arousing images.TMR in REM sleep provides a promising potential avenue for treatment of PTSD.
The immune landscape of tumor-associated macrophage reprogramming
Authors: Duval Florent , Lourenco Joao , Hicham Mehdi , Boivin Gaël , Guichard Alan , Wyser-Rmili Celine , Fournier Nadine , De Palma Michele , Mansouri Nahal 
Published: September 2024

SummaryTumor-associated macrophages (TAMs) generally acquire immunosuppressive and tumor-promoting phenotypes, which may contribute to tumor resistance to immunotherapy. We previously showed that suppression of microRNA activity through geneticDicer1inactivation rewires TAM’s transcriptomes and prompts their immunostimulatory activation. This phenotypic switch enhanced recruitment and activation of CD8+cytotoxic T cells (CTLs) and improved the efficacy of immunotherapy in mouse cancer models. Here, we performed single-cell RNA sequencing of whole tumors grown in either wild-type mice or mice with macrophage-specificDicer1deletion. The analysis of multiple cell populations, including several discrete monocyte and macrophage subsets, indicated broad and convergent immunostimulatory programming of the tumor microenvironment, which was dependent on CTL-derived interferon-gamma (IFNγ), in mice with DICER-deficient macrophages. Intriguingly, dynamic inferences on monocyte/macrophage ontogeny and differentiation by pseudotime analysis revealed trajectories associated with progression into cell cycle, monocyte-to-macrophage differentiation, and transition from an immunostimulatory to an immunosuppressive phenotype in tumors with DICER-proficient macrophages.Dicer1deficiency interfered with this trajectory and stalled TAMs at an intermediate state between immature monocytes and macrophages with T cell-stimulatory capacity, thereby impeding immunosuppressive TAM development. This translated into enhanced response to antiangiogenic immunotherapy in an immunotherapy-resistant model of non-small cell lung cancer. Cycling/M2-like macrophages were conserved in human melanoma and hepatocellular carcinoma and should represent a more promising therapeutic target than the bulk of TAMs.
Morning Engagement of Hepatic Insulin Receptors Improves Afternoon Hepatic Glucose Disposal and Storage
Authors: Waterman Hannah L. , Moore Mary Courtney , Smith Marta S. , Farmer Ben , Yankey Kalisha , Scott Melanie , Edgerton Dale S. , Cherrington Alan D. 
Published: September 2024

AbstractGlucose tolerance improves significantly upon consuming a second, identical meal later in the day (second meal phenomenon). We previously established that morning hyperinsulinemia primes the liver for increased afternoon hepatic glucose uptake (HGU). Although the route of insulin delivery is an important determinant of the mechanisms by which insulin regulates liver glucose metabolism (direct hepatic vs indirect insulin action), it is not known if insulin’s delivery route affects the second meal response. To determine whether morning peripheral insulin delivery (as occurs clinically (subcutaneous)) can enhance afternoon HGU, conscious dogs were treated in the morning with insulin delivered via the portal vein, or peripherally (leg vein), while glucose was infused to maintain euglycemia. Consequently, arterial insulin levels increased similarly in both groups, but relative hepatic insulin deficiency occurred when insulin was delivered peripherally. In the afternoon, all animals were challenged with the same hyperinsulinemic-hyperglycemic clamp to simulate identical postprandial-like conditions. The substantial enhancement of HGU in the afternoon caused by morning portal vein insulin delivery was lost when insulin was delivered peripherally. This indicates that morning insulin does not cause the second meal phenomenon via its indirect actions on the liver, but rather through direct activation of hepatic insulin signaling.Article HighlightsMorning insulin delivery primes the liver for increased hepatic glucose uptake (HGU) later in the day, but the mechanism (direct hepatic and/or indirect insulin action) remains unclear.This study compared insulin infusion via physiologic (hepatic portal vein) and clinical (peripheral) routes to assess their impact on afternoon hepatic glucose disposal.Morning peripheral insulin delivery failed to induce a significant enhancing effect on afternoon HGU and glycogen storage, unlike morning hepatic portal vein insulin delivery, which did.These findings highlight the importance of achieving appropriate hepatic insulin exposure in the morning to effectively prime the liver for efficient glucose disposal.