bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACNN-6mA Prediction of N6-Methyladenine Loci in Multiple Species Based on Rice Dataset Pre-training Model†
Authors: Bai JianGuo , Yang Hai 
Published: November 2022

ABSTRACTN6-methyladenine is an epigenetic modification that plays a significant role in various cellular processes. Genome-wide monitoring of methylation sites is conducive to understanding the biological function of methylation. Due to the limitations of traditional dry and wet experiments, a series of machine learning and deep learning methods have been developed to detect methylation sites, but their detection species are single or performance is poor. First of all, we conducted sufficient experiments on the widely studied rice datasets, and compared with the previous research, we have greatly improved in various indicators on the two rice datasets. Then we used the models trained on the rice dataset to fine-tune training in half of the other 11 datasets and predict the other half of the independent datasets. Then we used 11 trained models to test 11 species respectively. It was found that ACNN-6mA could obtain higher AUC, ACC and MCC whether cross-species prediction or independent verification set prediction. ACNN-6mA model and code for follow-up researchers is provided as an open-source tool available athttps://github.com/jrebai/ACNN-6mA.
Engineering CAR-NK cells targeting CD33 with concomitant extracellular secretion of anti-CD16 antibody revealed superior antitumor effects toward myeloid leukemia
Authors: Zhang Rui , Liu Qingxi , Zhou Sa , He Hongpeng , Zhao Mingfeng , Ma Wenjian 
Published: November 2022

AbstractAcute myeloid leukemia (AML) is a common form of acute leukemia and current drugs are overall unsatisfactory. In the present study, we report an immune cell therapy strategy by employing genetically-modified bifunctional CAR-NK cells that combines efficient targeting of AML cells via the CD33 molecule with the concomitant stimulation of NK cell cytotoxicity through the expression and extracellular secretion of anti-CD16 antibody (B16) that binds back to the FC receptor of NK cells. Comparing to CAR-NK cells that target CD33 only, the bifunctional CD33/B16 CAR-NK cells showed superior killing efficiency toward AML cells in vitro, which increased about 4 times based on the number of cells needed to achieve 80% killing activity. In vivo study with xenograft model also revealed effective clearance of leukemic cells and much longer survival - no relapse or death for at least 60 days. In addition, the safety of CAR-NK is not changed with additional expression of B16 as determined by the release of cytokines. These data revealed a promising CAR-NK approach to treat AML patients, which may improve CAR-NK based treatment in general and have potential applications to deal with other tumors as well.
Blood Transcriptional Correlates of BCG-Induced Protection Against Tuberculosis in Rhesus Macaques
Authors: Liu Yiran E. , Darrah Patricia A. , Zeppa Joseph J. , Kamath Megha , Laboune Farida , Douek Daniel C. , Maiello Pauline , Roederer Mario , Flynn JoAnne L. , Seder Robert A. , Khatri Purvesh 
Published: November 2022

SUMMARYBlood-based correlates of vaccine-induced protection against tuberculosis (TB) are urgently needed. We analyzed the blood transcriptome of rhesus macaques immunized with varying doses of intravenous (IV) BCG followed byMycobacterium tuberculosis(Mtb) challenge. We used high-dose IV BCG recipients for “discovery” and validated our findings in low-dose recipients and in an independent cohort of macaques receiving BCG via different routes. We identified seven vaccine-induced gene modules, including an innate module (module 1) enriched for type 1 interferon and RIG-I-like receptor signaling pathways. Module 1 on day 2 post-vaccination was highly correlated with lung antigen-responsive CD4 T cells at week 8 and withMtband granuloma burden following challenge. Parsimonious signatures within module 1 at day 2 post-vaccination predicted protection following challenge with AUROCs ≥ 0.91. Together these results indicate that the early innate transcriptional response to IV BCG in peripheral blood may provide a robust correlate of protection against TB.
Context-Aware Transcript Quantification from Long Read RNA-Seq data with Bambu
Authors: Chen Ying , Sim Andre , Wan Yuk Kei , Yeo Keith , Lee Joseph Jing Xian , Ling Min Hao , Love Michael I. , Göke Jonathan 
Published: November 2022

AbstractMost approaches to transcript quantification rely on fixed reference annotations. However, the transcriptome is dynamic, and depending on the context, such static annotations contain inactive isoforms for some genes while they are incomplete for others.To address this, we have developed Bambu, a method that performs machine-learning based transcript discovery to enable quantification specific to the context of interest using long-read RNA-Seq data. To identify novel transcripts, Bambu employs a precision-focused threshold referred to as the novel discovery rate (NDR), which replaces arbitrary per-sample thresholds with a single interpretable parameter. Bambu retains the full-length and unique read counts, enabling accurate quantification in presence of inactive isoforms.Compared to existing methods for transcript discovery, Bambu achieves greater precision without sacrificing sensitivity. We show that context-aware annotations improve abundance estimates for both novel and known transcripts. We apply Bambu to human embryonic stem cells to quantify isoforms from repetitive HERVH-LTR7 retrotransposons, demonstrating the ability to estimate transcript expression specific to the context of interest.
Multiparameter stimulation mapping of signaling states in single pediatric immune cells reveals heightened tonic activation during puberty
Authors: Farmer Rohit , Apps Richard , Quiel Juan , Sellers Brian A. , Cheung Foo , Chen Jinguo , Mukherjee Amrita , McGuire Peter J. , Tsang John S. 
Published: November 2022

AbstractCellular stimulation via factors such as cytokines followed by multiparameter single-cell measurements is a powerful approach to interrogate cellular functions. However, transforming such high-dimensional data into biological insights presents unique challenges, particularly given the extensive response heterogeneity among single cells, such as the presence of bimodal responding versus non-responding subpopulations upon stimulation. Here we present an unsupervisedhigh-dimensional approach for analyzingstimulation responses at the single cell level (HDStIM)and apply it to evaluate how pediatric development may shape peripheral immune cell signaling states and responsiveness to stimulations in 42 subjects (age: 2 - 16). We show that in comparison to the conventional approach of assessing one marker at a time by averaging across single cells, HDStIM can effectively learn, in an unsupervised fashion, the multi-parameter signature of responding versus non-responding cells to accurately quantify responses within cell populations. HDStIM reveals that the extent of pre-stimulation/baseline activation of interferon-related and TCR signaling molecules in myeloid and T cells, respectively, increases during puberty. This suggests that puberty is marked by a heightened “tonic” activation state in these cells, perhaps to strengthen defense against pathogens during this period of human development.
Selecting Chromosomes for Polygenic Traits
Authors: Zuk Or 
Published: November 2022

AbstractWe define and study the problem ofchromosomal selectionfor multiple complex traits. In this problem, it is assumed that one can construct a genome by selecting different genomic parts (e.g. chromosomes) from different cells. The constructed genome is associated with a vector of polygenic scores, obtained by summing the polygenic scores of the different genomic parts, and the goal is to minimize a loss function of this vector. While out of reach today, the problem may become relevant in the future with emerging future technologies, and may yield far greater gains in the loss compared to the present day technology of as embryo selection, provided that technological and ethical barriers are overcome. We suggest and study several natural loss functions relevant for both quantitative traits and disease. We propose two algorithms, a Branch-and-Bound technique, to solve the problem for multiple traits and any monotone loss function, and a convex relaxation algorithm applicable for any differentiable loss. Finally, we use the infinitesimal model for genetic architecture to approximate the potential gain achieved by chromosomal selection for multiple traits.
Genetic architecture of acute hyperthermia resistance in juvenile rainbow trout (Oncorhynchus mykiss) and genetic correlations with production traits
Authors: Lagarde Henri , Lallias Delphine , Patrice Pierre , Prchal Martin , François Yoannah , D’Ambrosio Jonathan , Segret Emilien , Acin-Perez Ana , Cachelou Frederic , Haffray Pierrick , Dehaullon Audrey , Dupont-Nivet Mathilde , Phocas Florence 
Published: November 2022

AbstractBackgroundSelective breeding is a promising solution to reduce fish farms vulnerability to heat peaks which intensity and frequency are predicted to increase due to climate change. However, limited information about the genetic architecture of acute hyperthermia resistance in fish is available.Two batches of sibs from a rainbow trout commercial line were produced. The first batch (N=1,382) was phenotyped for acute hyperthermia resistance at nine months, and the second batch (N=1,506) was phenotyped for main production traits (growth, body length, muscle fat content and carcass yield) at twenty months. Fish were genotyped on a 57K SNP array, and their genotypes were imputed at high-density thanks to their parents being genotyped on a 665K SNP array.ResultsThe heritability estimate of resistance to acute hyperthermia in juveniles was 0.29 ± 0.05, confirming the potential of selective breeding for this trait. Genetic correlations between acute hyperthermia resistance and main production traits at near harvest age were all close to zero. Hence, selecting for acute hyperthermia resistance should not impact the main production traits, and reversely.The genome-wide association study revealed that resistance to acute hyperthermia is highly polygenic; altogether, the six detected QTL explained less than 5% of the genetic variance. Two of these QTL, including the most significant one, might explain acute hyperthermia resistance differences across INRAE isogenic lines of rainbow trout. The phenotypic mean differences between homozygotes at peak SNP were up to 69% of the phenotypic standard deviation, showing promising potential for marker-assisted selection. We identified 89 candidate genes within the six QTL regions, among which the most convincing functional candidate genes werednajc7,hsp70b,nkiras2,cdk12,phb,fkbp10,ddx5,cygb1,enpp7,pdhxandacly.ConclusionsThis study provides valuable insight on the genetic architecture of acute hyperthermia resistance in juvenile rainbow trout. The potential for the selective breeding of this trait was shown to be substantial and should not interfere with selection for main production traits. Identified functional candidate genes give a new insight on physiological mechanisms involved in acute hyperthermia resistance, such as protein chaperoning, oxidative stress response, homeostasis maintenance and cell survival.
Phylogenomic comparative methods: accurate evolutionary inferences in the presence of gene tree discordance
Authors: Hibbins Mark S. , Breithaupt Lara C. , Hahn Matthew W. 
Published: November 2022

AbstractPhylogenetic comparative methods have long been a mainstay of evolutionary biology, allowing for inferences of the tempo and mode of trait evolution across species while accounting for their common ancestry. These analyses typically assume a single, bifurcating phylogenetic tree that describes the shared history among species. However, modern phylogenomic analyses have shown that genomes are often composed of a mosaic of different histories that can disagree both with the species tree and with each other—so-called discordant gene trees. These gene trees describe shared histories that are not captured by the species tree, and therefore that are unaccounted for in classic comparative approaches. The application of standard phylogenetic comparative methods to species histories containing discordance leads to incorrect inferences about the timing, direction, and rate of evolution. Here, we develop two approaches for incorporating gene tree histories into comparative methods: one involves constructing a fuller phylogenetic variance-covariance matrix that includes relationships not found in the species tree, and another that applies Felsenstein’s pruning algorithm over a set of gene trees to calculate trait histories and likelihoods. Both approaches are agnostic to the biological causes of gene tree discordance, which may include incomplete lineage sorting and introgression. Using simulation, we demonstrate that our new approaches generate much more accurate estimates of tree-wide rates of trait evolution than standard methods. We apply our methods to two clades of the wild tomato genusSolanumwith varying rates of discordance, demonstrating the contribution of gene tree discordance to variation in a set of floral traits and the ability of our approaches to provide more accurate inferences. Our new approaches have the potential to be applied to a broad range of classic inference problems in phylogenetics, including ancestral state reconstruction and the inference of lineage-specific rate shifts.
Expression of retrotransposons contributes to aging inDrosophila
Authors: Schneider Blair K. , Sun Shixiang , Lee Moonsook , Li Wenge , Skvir Nicholas , Neretti Nicola , Vijg Jan , Secombe Julie 
Published: November 2022

AbstractRetrotransposons are a class of transposable elements capable of self-replication and insertion into new genomic locations. Across species, the mobilization of retrotransposons in somatic cells has been suggested to contribute to the cell and tissue functional decline that occurs during aging. Retrotransposon expression generally increases with age, andde novoinsertions have been observed to occur during tumorigenesis. However, the extent to which new retrotransposon insertions occur during normal aging and their effect on cellular and animal function remains understudied. Here we use a single nucleus whole genome sequencing approach inDrosophilato directly test whether transposon insertions increase with age in somatic cells. Analyses of nuclei from thoraces and indirect flight muscles using a newly developed pipeline, Retrofind, revealed no significant increase in the number of transposon insertions with age. Despite this, reducing the expression of two different retrotransposons,412andRoo,extends lifespan, without increasing stress resistance. This suggests a key role for transposon expression and not insertion in regulating longevity. Transcriptomic analyses revealed similar changes to gene expression in412andRooknockdown flies and highlighted potential changes to genes involved in proteolysis and immune function as potential contributors to the observed changes in longevity. Combined, our data show a clear link between retrotransposon expression and aging.Author SummaryWith the onset of modern medicine, the average age of the population has significantly increased, leading to more individuals living with chronic health issues. Rather than treat each age-associated disorder individually, one approach to target multiple health concerns simultaneously might to be target aging itself. Genomic instability is a hallmark of aging cells that has been proposed to be a key contributor to age-associated cellular decline. Transposons are mobile genetic elements capable of inserting into new genomic locations, thus having the potential to increase genomic instability. Consistent with this, transposon expression generally increases with age. However, the extent to which transposon insertions accumulate to disrupt the genome of cells within aging individuals has remained an open question. We specifically answer this through single cell whole genome sequencing and find that transposon insertions do not increase with age. Even though insertions did not increase, the expression of transposons is linked to aging, as reducing the expression of individual transposons extended lifespan. Transcriptome studies of these long-lived flies revealed increased expression of genes linked to proteolysis genes and to functioning of the immune system. Our study therefore establishes transposon expression, and not insertion, as a critical contributor to animal aging.
Molecular Analyses Place the GenusKerauneaOutside Convolvulaceae
Authors: Muñoz-Rodríguez Pablo , Wood John R.I. , González Lucía Villaescusa , Davis Charles C. , Goodwin Zoë A. , Scotland Robert W. 
Published: November 2022

ABSTRACTThe genusKerauneawas recently described in the Convolvulaceae Juss. family. Two species are currently recognised, both from Brazil. Molecular sequence data using three commonly applied DNA markers (matK, rbcLand thenuclear ribosomal Internal Transcribed Spacer) show that neither species is correctly placed in Convolvulaceae but indicates that the type,K. brasiliensis, should be placed in Malpighiaceae despite several morphological anomalies. The second species,K. capixaba, should be placed in Ehretiaceae. Given the surprising nature of these results, further studies are recommended before formal reclassification of these two taxa is made.
Evidence for Embracing Normative Modeling
Authors: Rutherford Saige , Barkema Pieter , Tso Ivy F. , Sripada Chandra , Beckmann Christian F. , Ruhe Henricus G. , Marquand Andre F. 
Published: November 2022

AbstractIn this work, we expand the normative model repository introduced inRutherford et al. (2022a) to include normative models charting lifespan trajectories of structural surface area and brain functional connectivity, measured using two unique resting-state network atlases (Yeo-17 and Smith-10), and an updated online platform for transferring these models to new data sources. We showcase the value of these models with a head-to-head comparison between the features output by normative modeling and raw data features in several benchmarking tasks: mass univariate group difference testing (schizophrenia versus control), classification (schizophrenia versus control), and regression (predicting general cognitive ability). Across all benchmarks, we confirm the advantage (i.e., stronger effect sizes, more accurate classification and prediction) of using normative modeling features. We intend for these accessible resources to facilitate wider adoption of normative modeling across the neuroimaging community.
Neuroanatomical substrates in Parkinson’s Disease psychosis and their association with serotonergic receptor gene expression: A coordinate-based meta-regression analysis
Authors: Pisani Sara , Gunasekera Brandon , Lu Yining , Vignando Miriam , ffytche Dominic , Aarsland Dag , Chaudhuri K. Ray , Ballard Clive , Lee Jee-Young , Kim Yu Kyeong , Velayudhan Latha , Bhattacharyya Sagnik 
Published: November 2022

AbstractBackgroundCommon neural underpinning of Parkinson’s Disease (PD) psychosis across different structural magnetic resonance imaging (MRI) studies remains unclear to this day with few studies and even fewer meta-analyses available.ObjectivesOur meta-analysis aimed to identify and summarise studies using MRI approach to identify PD psychosis-specific brain regions and examine the relation between cortical volume loss and dopaminergic and serotonergic receptor density.MethodsPubMed, Web of Science and Embase were searched for MRI studies of PD psychosis (PDP) compared to PD patients without psychosis (PDnP). Seed-baseddMapping with Permutation of Subject Images was applied in the meta-analysis where coordinates were available. Multiple linear regressions to examine the relationship between grey matter volume loss in PDP and receptor gene expression density (extracted from the Allen Human Brain Atlas) were conducted in R.ResultsWe observed lower grey matter volume in parietal-temporo-occipital regions from our meta-analysis (N studies =10, PDP n=211, PDnP, n=298). These results remained significant after adjusting for PD medications and for cognitive scores. Grey matter volume loss in PDP was associated with local expression of 5-HT1a (b=0.109,p=0.012) and 5-HT2a receptors (b=-0.106,p=0.002) also after adjusting for PD medications (5-HT1a,p= 0.005; 5-HT2a,p= 0.001).ConclusionsWidespread cortical volume loss in the parieto-temporo-occipital regions involved in information processing and integration, as well as attention, could result in PD psychosis symptoms. Neurobiological mechanisms implicating serotonergic receptors may also contribute to this condition.
Identification and Characterization of ML321: a Novel and Highly Selective D2Dopamine Receptor Antagonist with Efficacy in Animal Models that Predict Atypical Antipsychotic Activity
Authors: Free R. Benjamin , Nilson Ashley N. , Boldizsar Noelia M. , Doyle Trevor B. , Rodriguiz Ramona M. , Pogorelov Vladimir M. , Machino Mayako , Lee Kuo Hao , Bertz Jeremiah W. , Xu Jinbin , Lim Herman D. , Dulcey Andrés E. , Mach Robert H. , Woods James H. , Lane J Robert , Shi Lei , Marugan Juan J. , Wetsel William C. , Sibley David R. 
Published: November 2022

ABSTRACTWe have developed and characterized a novel D2R antagonist with exceptional GPCR selectivity – ML321. In functional profiling screens of 168 different GPCRs, ML321 showed little activity beyond potent inhibition of the D2R, and to a lesser extent the D3R, demonstrating excellent receptor selectivity. The D2R selectivity of ML321 may be related to the fact that, unlike other monoaminergic ligands, ML321 lacks a positively charged amine group and adopts a unique binding pose within the orthosteric binding site of the D2R. PET imaging studies in non-human primates demonstrated that ML321 penetrates the CNS and occupies the D2R in a dose-dependent manner. Behavioral paradigms in rats demonstrate that ML321 can selectively antagonize a D2R-mediated response (hypothermia) while not affecting a D3R-mediated response (yawning) using the same dose of drug, thus indicating exceptionalin vivoselectivity. We also investigated the effects of ML321 in animal models that are predictive of antipsychotic efficacy in humans. We found that ML321 attenuates both amphetamine- and phencyclidine-induced locomotor activity and restored pre-pulse inhibition (PPI) of acoustic startle in a dose-dependent manner. Surprisingly, using doses that were maximally effective in both the locomotor and PPI studies, ML321 was relatively ineffective in promoting catalepsy. Kinetic studies revealed that ML321 exhibits slow-on and fast-off receptor binding rates, similar to those observed with atypical antipsychotics with reduced extrapyramidal side effects. Taken together, these observations suggest that ML321, or a derivative thereof, may exhibit “atypical” antipsychotic activity in humans with significantly fewer side effects than observed with currently FDA-approved D2R antagonists.