bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tests for Segregation Distortion in Tetraploid F1 Populations
Authors: Gerard David , Thakkar Mira , Ferrão Luis Felipe V. 
Published: February 2024

AbstractGenotype data from tetraploid F1 populations are often collected in breeding programs for mapping and genomic selection purposes. A common quality control procedure in these groups is to compare empirical genotype frequencies against those predicted by Mendelian segregation, where SNPs detected to have “segregation distortion” are discarded. However, current tests for segregation distortion are insufficient in that they do not account for double reduction and preferential pairing, two meiotic processes in polyploids that naturally change gamete frequencies, leading these tests to detect segregation distortion too often. Current tests also do not account for genotype uncertainty, again leading these tests to detect segregation distortion too often. Here, we incorporate double reduction, preferential pairing, and genotype uncertainty in likelihood ratio and Bayesian tests for segregation distortion. Our methods are implemented in a user-friendly R package, menbayes. We demonstrate the superiority of our methods to those currently used in the literature on both simulations and real data.
Intrauterine Growth-Restricted Pregnant Rats, from Hypertensive Placental Ischemic Dams Display Preeclamptic-like Symptoms: A New Rodent Model of Preeclampsia
Authors: Smith Jonna , Powell Madison , Cromartie Whitney , Smith Savanna , Jones Kylie , Castillo Angie , Shaw Jordan , Editone Joseph , Howard-Cunningham Ahfiya , Tatum Robert , Smith Alex , Fisher Brandon , Booz George W. , Cunningham Mark 
Published: February 2024

ABSTRACTPreeclampsia (PE) is characterized by de novo hypertension (HTN) and is one of the primary causes of intrauterine growth restriction (IUGR). PE is associated with placental ischemia, decreased nitric oxide (NO) bioavailability, oxidative stress (OS), and organ damage in the kidneys and brain. This study aims to characterize a new model of PE using IUGR rats from hypertensive placental ischemic dams. It is hypothesized that pregnant IUGR rats from hypertensive placental ischemic dams will have elevated blood pressure (BP), OS, and organ damage.MethodsPregnant Sprague Dawley rats are divided into 2 groups: normal pregnant (NP) and reduced uterine perfusion pressure (RUPP) hypertensive placental ischemic dams. Offspring from NP and RUPP dams were mated at 10 weeks of age to generate pregnant IUGR (IUGR Preg; n=3-8) and pregnant CON (CON Preg; n=3-6) rats. BP and other markers of PE were evaluated during late gestation.ResultsPregnant IUGR rats had elevated BP and systemic OS, as demonstrated by higher trending 8-isoprostanes and lower circulating antioxidant capacity. Maternal body weight of pregnant IUGR rats and their pups’ weights were decreased, while the brains were enlarged. Brain OS was elevated, with a rise in hydrogen peroxide (H2O2) and heat shock protein 1 (HSP- 1), along with lower Manganese Superoxide Dismutase (MnSOD) and antioxidant capacity.ConclusionPregnant IUGR rats, born from hypertensive placental ischemic dams, have HTN and increased systemic and brain OS, with larger brain sizes and smaller pups. Pregnant IUGR rats exhibit an preeclamptic-like phenotype, which suggests a new epigenetic model of PE.
Unveiling Circulating Targets in Pancreatic Cancer: Insights from Proteogenomic Evidence and Clinical Cohorts
Authors: Feng Haokang , Chen Zhixue , Li Jianang , Feng Jiale , Yang Fei , Meng Fansheng , Yin Hanlin , Guo Yuquan , Xu Huaxiang , Liu Yuxin , Liu Runjie , Lou Wenhui , Liu Liang , Han Xu , Su Hua , Zhang Lei 
Published: February 2024

AbstractPancreatic cancer (PC), lacking biomarkers and effective therapeutics, remains highly lethal. Data regarding the correlations of PC risk and the individual plasma proteome known for minimally cancer biomarkers, are scarce. Here, we measure 1,345 human plasma proteins via Proteome-Wide Association Studies, presenting 78 proteins are prominently related to PC risk, including 4 proteins (ROR1, FN1, APOA5, ABO) exhibit the strongest causal association identified via Mendelian Randomization and Colocalization. Our two independent cohorts further demonstrate FN1 and ABO are highly expressed in blood or tumors from patients with PC compared to specimens from healthy individuals or para-tumors. Moreover, patients with higher levels of FN1 and ABO in their blood or tumors have worse median survival than those with lower levels. Multiple drugs targeting FN1 are currently available or undergoing clinical testing, making FN1 a promisingly repurposed therapeutic target in addition to severing as a circulating prognostic indicator for PC.
RSV and Rhinovirus asymptomatic upper airway infection increases pneumococcal carriage acquisition rates and density in adults whereas nasal inflammation is associated with bacterial shedding
Authors: Mitsi Elena , Nikolaou Elissavet , Goncalves Andre , Blizard Annie , Hill Helen , Farrar Madlen , Hyder-Wright Angela , Howard Ashleigh , Elterish Filora , Solorzano Carla , Robinson Ryan , Reine Jesus , Collins Andrea M. , Gordon Stephen B. , Weiser Jeffrey N. , Bogaert Debby , Ferreira Daniela M. 
Published: February 2024

ABSTRACTNasopharyngeal pneumococcal colonisation is a necessary step for disease development and the primary reservoir of bacterial spread and transmission. Most epidemiological studies report the impact of co-infection with respiratory viruses upon disease rates and outcome, but their effect on pneumococcal carriage acquisition and bacterial load is scarcely described. Here, we used controlled human infection with pneumococcus to assess whether certain respiratory viruses alter susceptibility to pneumococcal colonisation and bacterial density. A total of 581 healthy adults were screened for presence of upper respiratory tract viral infection before intranasal pneumococcal challenge. We showed that RSV and Rhinovirus asymptomatic infection conferred a substantial increase in carriage rates (88% and 66% of colonised individuals in Rhinovirus and RSV infected groups, respectively, vs 49% in the virus negative group). The risk ratio of pneumococcal colonization in RSV infected group was 5.3 (95% CI: 0.90 – 30.61, p = 0.034) and 2.03 (95% CI: 1.09-3.80, p= 0.035) in rhinovirus infected group. Pneumococcal density was overall greater in virus positive subjects, although RSV infection alone had a major impact on pneumococcal density up to 9 days post challenge, with a substantial 2- log increase at D2 compared to virus negative group (median, SEM: 3.76 ± 0.65 vs 1.79 ± 0.09) (p= 0.02). We also studied rates and kinetics of bacterial shedding through the nose and oral route in a subset of challenged individuals. Nasal bacterial shedding was twice more frequent than cough-induced shedding (64% vs 32%, respectively). High levels of bacterial colonisation density and nasal inflammation was strongly correlated with increased odds of nasal shedding, as opposed to cough-shedding.Healthy adults can act as reservoir of transmission for pneumococcus, particularly when colonised with high density and have local inflammation, two key characteristics of pneumococcal colonisation in paediatrics and/or viral co-infection. Hence, vaccines targeting these respiratory pathogens have the dual potential of reducing transmission and disease burden due to their indirect benefit to off target pathogens.
Restricting CAR T Cell Trafficking Expands Targetable Antigen Space
Authors: Morales Erin A. , Dietze Kenneth A. , Baker Jillian M. , Wang Alexander , Avila Stephanie V. , Iglesias Fiorella , Radhakrishnan Sabarinath V. , Mause Erica Vander , Olson Michael L. , Sun Wenxiang , Rosati Ethan , Chidester Sadie L. , Iraguha Thierry , Fan Xiaoxuan , Atanackovic Djordje , Luetkens Tim 
Published: February 2024

ABSTRACTChimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin ⍺4(A4ko), an adhesion molecule essential for migration across the blood-brain barrier. A4koLINGO1 CAR T cells were efficiently excluded from the CNS but retained efficacy against ES. We show that altering adhesion behavior expands the set of surface antigens targetable by CAR T cells.One sentence summaryAltering integrin-mediated adhesion provides tumor selectivity to CAR T cells by preventing homing to defined normal tissues but retaining tumor trafficking and anti-tumor activity.GRAPHICAL ABSTRACT
Binding Position Dependent Modulation of Smoothened Activity by Cyclopamine
Authors: Kim Kihong , Bansal Prateek D. , Shukla Diwakar 
Published: February 2024

AbstractCyclopamine is a natural alkaloid that is known to act as an agonist when it binds to the Cysteine Rich Domain (CRD) of the Smoothened receptor and as an antagonist when it binds to the Transmembrane Domain (TMD). To study the effect of cyclopamine binding to each binding site experimentally, mutations in the other site are required. Hence, simulations are critical for understanding the WT activity due to binding at different sites. Additionally, there is a possibility that cyclopamine could bind to both sites simultaneously especially at high concentration, the implications of which remain unknown. We performed three independent sets of simulations to observe the receptor activation with cyclopamine bound to each site independently (CRD, TMD) and bound to both sites simultaneously. Using multi-milliseconds long aggregate MD simulations combined with Markov state models and machine learning, we explored the dynamic behavior of cyclopamine’s interactions with different domains of WT SMO. A higher population of the active state at equilibrium, a lower activation free energy barrier of∼2 kcal/mol, and expansion of the hydrophobic tunnel to facilitate cholesterol transport agrees with the cyclopamine’s agonistic behavior when bound to the CRD of SMO. A higher population of the inactive state at equilibrium, a higher free energy barrier of∼4 kcal/mol and restricted the hydrophobic tunnel to impede cholesterol transport showed cyclopamine’s antagonistic behavior when bound to TMD. With cyclopamine bound to both sites, there was a slightly larger inactive population at equilibrium and an increased free energy barrier (∼3.5 kcal/mol). The tunnel was slightly larger than when solely bound to TMD, and showed a balance between agonism and antagonism with respect to residue movements exhibiting an overall weak antagonistic effect.
Molecular attributes of the tropical treeAvicennia schauerianainvolved in the response and tolerance to low temperatures
Authors: de Moura Yohans Alves , Aono Alexandre Hild , Cruz Mariana Vargas , Pereira Alessandro Alves , Vidal João de Deus , de Souza Anete Pereira 
Published: February 2024

ABSTRACTMangroves are coastal ecosystems of great socioenvironmental importance that are highly threatened by human activities. Mangrove trees live under harsh environmental conditions, which makes them sensitive to extreme weather events, particularly freezing events. Such events are unpredictable and have catastrophic consequences for mangrove trees; therefore, understanding and anticipating the impacts of such events are essential for directing future mitigation measures. Freezing cold currently limits the distribution of mangroves to tropical and subtropical latitudes worldwide. Mangrove trees are seriously affected by freezing conditions and suffer severe metabolic fluctuations due to photosystem and cellular structure damage. However, land plants more broadly have developed sophisticated mechanisms of resistance to freezing during their evolution, and the central molecular mechanisms involved in this process are consistent. However, the known information is restricted to models of herbaceous plants, such asArabidopsis thaliana, that are native to temperate habitats, and there is a research gap regarding tropical trees such as mangroves. This work aimed to improve the understanding of the molecular aspects of the response and tolerance to freezing in mangrove trees usingAvicennia schauerianaas a model. This species occurs within the colder range limits of South American mangroves and shows evidence of the existence of two functional groups that are locally adapted to the equatorial (EQ) and subtropical (ST) portions of the Brazilian coast. We investigated the transcriptional profiles of seedlings from both functional groups under freezing shock (−4°C) in a time series. We analyzed transcriptomic data by combining differential expression, coexpression network and protein interaction data. Our results allowed us to describe the profile of the molecular response ofA. schauerianato freezing and the divergence in the behavior of the EQ and ST functional groups. In EQ plants, the response strongly depended on the action of abscisic acid (ABA) and stress signals throughout the experiment. Notably, ABA negatively affects plant growth and promotes the accumulation of carotenoids, anthocyanins and lipids through chlorophyll degradation. On the other hand, in the ST, there were fewer hormones active in the process of primary growth maintenance and metabolic normalization. The accumulation of substances is mainly based on sucrose, anthocyanin and lipid levels, and lipid synthesis is not dependent on chlorophyll degradation. Based on these results, we hypothesize that susceptibility to freezing damage is greater in EQ mangroves than in ST mangroves. Therefore, we recommend that this fact be considered when managing this species, especially at higher latitudes, which are more prone to lower temperatures and extreme freezing events.
Identifying Ferroptosis Inducers, HDAC, and RTK Inhibitor Sensitivity in Melanoma Subtypes through Unbiased Drug Target Prediction
Authors: Pla Indira , Szabolcs Botond L. , Péter Petra Nikolett , Ujfaludi Zsuzsanna , Kim Yonghyo , Horvatovich Peter , Sanchez Aniel , Pawlowski Krzysztof , Wieslander Elisabet , Guedes Jéssica , Pál Dorottya MP , Ascsillán Anna A. , Betancourt Lazaro Hiram , Németh István Balázs , Gil Jeovanis , Almeida Natália Pinto de , Szeitz Beáta , Szadai Leticia , Doma Viktória , Woldmar Nicole , Bartha Áron , Pahi Zoltan , Pankotai Tibor , Győrffy Balázs , Szasz A. Marcell , Domont Gilberto , Nogueira Fábio , Kwon Ho Jeong , Appelqvist Roger , Kárpáti Sarolta , Fenyö David , Malm Johan , Marko-Varga György , Kemény Lajos V. 
Published: February 2024

AbstractThe utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem. Here we mine large scale MM proteogenomic data integrating it with MM cell line dependency screen, and drug sensitivity data to identify druggable targets and forecast treatment efficacy and resistance. Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC and AKT1, across five distinct MM subtypes. These proteins serve as potential drug targets applicable to one or multiple MM subtypes.By analyzing transcriptomic data from 48 publicly accessible melanoma cell lines sourced from Achilles and CRISPR dependency screens, we forecasted 162 potentially targetable genes. We also identified genetic resistance in 260 genes across at least one melanoma subtype. In addition, we employed publicly available compound sensitivity data (Cancer Therapeutics Response Portal, CTRPv2) on the cell lines to assess the correlation of compound effectiveness within each subtype.We have identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype. Remarkably, employing this unbiased approach, we have uncovered compounds targeting ferroptosis, that demonstrate a striking 30x fold difference in sensitivity among different subtypes. This implies that the proteogenomic classification of melanoma has the potential to predict sensitivity to ferroptosis compounds. Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy.Highlights(1)Proteogenomic subtype classification can define the landscape of genetic dependencies in melanoma(2)Nine proteins from molecular subtypes were identified as potential drug targets for specified MM patients(3)20 compounds identified that show potential effectiveness in at least one melanoma subtype(4)Proteogenomics can predict specific ferroptosis inducers, HDAC, and RTK Inhibitor sensitivity in melanoma subtypesGraphical abstract
Therapeutic potential of glabridin and gymnemic acid alleviates eye choroidal thickness and neovascularization in diabetic model rats
Authors: Komolkriengkrai Manaras , Matsathit Udomlak , Khimmaktong Wipapan 
Published: February 2024

AbstractSmall blood vessels in the eyes are more susceptible to injury, which can lead to complications. However, since diabetic retinopathy is often a serious clinical condition, most of this study focuses on the vascular system of the choroid. As part of this study, we looked at how gymnemic acid (fromGymnema sylvestre) and glabridin (fromGlycyrrhiza glabra, or licorice) might help diabetic rats’ choroid thickness and blood vessels. The aim of this study was to explore the effects of glabridin and gymnemic acid on the structural changes of the choroidal layer as well as the expression of VEGF and CD31 in diabetic rats. The animals were separated into five groups: the control group (Control), the diabetic group (DM), the diabetic rats treated with glabridin 40 mg/kg body weight (DM+GB), the diabetic rats treated with gymnemic acid 400 mg/kg body weight (DM+GM), and the diabetic rats treated with glyburide 4 mg/kg body weight (DM+GR). There was an increase in the thickness of both the choroid layer and the wall of the arteries in the diabetic group. A decrease in vascularity and choroidal neovascularization was found in DM rats. After eight weeks of experimentation, the choroidal thickness increased and the walls of choroid arteries, as well as the diameter of the lumen of choroid arteries in the DM+GB, DM+GM, and DM+GR groups, were wider. The expression of VEGF and CD31 was lower compared to the DM group. According to the findings of the current research, glabridin and gymnemic acid can reduce the damage to the choroid, which is a factor that can sometimes result in vision loss.
Comparative analysis of Formyl peptide receptor 1 and Formyl peptide receptor 2 reveals shared and preserved signaling profiles
Authors: Pajonczyk Denise , Sternschulte Merle F. , Soehnlein Oliver , Bermudez Marcel , Raabe Carsten A. , Rescher Ursula 
Published: February 2024

AbstractPattern Recognition Receptors are key in identifying pathogenic or damaged cell-related patterns or molecules. Among these, the closely linked formyl peptide receptors FPR1 and FPR2 are believed to hold pivotal yet differing functions in immune regulation. To address the intriguing question of how these highly related receptors with a shared agonist spectrum play differing roles in modulating inflammation, we analyzed the signaling profile for a panel of FPR agonistsin vivoandex vivosettings. Our analysis uncovered a shared core signature for both FPRs across signaling pathways. Whereas formylated peptides generally acted as potent agonists at FPR1, FPR2 agonists, irrespective of N-terminal formylation, displayed consistently low activity ratios, suggesting an underutilized signaling potential of this receptor. Signaling outcomes were defined by specific agonist-receptor pairings and no receptor-specific signaling texture was identified. Activation of the FPR signaling axis by fMLF in human neutrophils did impact neutrophil survival. Overall, the distinct characteristics underlying inflammatory, anti-inflammatory, or pro-resolving profiles could not be attributed to a specific receptor isoform, signaling pattern, or a particular class of agonists, challenging assumptions about distinct inflammatory profiles linked to specific receptors, signaling patterns, or agonist classes.
NF-κB Signaling is Required for X-Chromosome Inactivation Maintenance Following T cell Activation
Authors: Forsyth Katherine S. , Toothacre Natalie E. , Jiwrajka Nikhil , Driscoll Amanda M. , Shallberg Lindsey A. , Cunningham-Rundles Charlotte , Barmettler Sara , Farmer Joceyln , Verbsky James , Routes John , Beiting Daniel P. , Romberg Neil , May Michael J. , Anguera Montserrat C. 
Published: February 2024

ABSTRACTX Chromosome Inactivation (XCI) is a female-specific process which balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment ofXistRNA and heterochromatic modifications on the inactive X chromosome (Xi), and these modifications become enriched at the Xi after cell stimulation. Here, we examined allele-specific gene expression and the epigenomic profiles of the Xi following T cell stimulation. We found that the Xi in unstimulated T cells is largely dosage compensated and is enriched with the repressive H3K27me3 modification, but not the H2AK119-ubiquitin (Ub) mark, even at promoters of XCI escape genes. Upon CD3/CD28-mediated T cell stimulation, the Xi accumulates H2AK119-Ub and H3K27me3 across the Xi. Next, we examined the T cell signaling pathways responsible for Xist RNA localization to the Xi and found that T cell receptor (TCR) engagement, specifically NF-κB signaling downstream of TCR, is required. Disruption of NF-κB signaling, using inhibitors or genetic deletions, in mice and patients with immunodeficiencies prevents Xist/XIST RNA accumulation at the Xi and alters expression of some X-linked genes. Our findings reveal a novel connection between NF-κB signaling pathways which impact XCI maintenance in female T cells.