bluuebunny/crossref_metadata_2025_split huggingface dataset:
Machine learning analysis reveals the dynamics of mode transition in dendritic cell migration
Authors: Song Taegeun , Choi Youngjun , Jeon Jae-Hyung , Cho Yoon-Kyoung 
Published: July 2022

AbstractDendritic cells (DCs) patrol the body as immunological sentinels and search for pathogens. Upon stimulation, immature DCs (imDCs) become mature DCs (mDCs), which migrate to the lymph nodes and present antigens to T cells. The migratory behavior is crucial for initiating and controlling immune responses; however, the properties of the highly heterogeneous and dynamic motility phenotype are not fully understood. Here, we established an unsupervised machine learning (ML) strategy to investigate spatiotemporal motility patterns in long-term, two-dimensional cell migration trajectories, and determined the number of motility patterns and how these are related to the maturation status. We identified three distinct migratory modes independent of the cell state: slow-diffusive (SD), slow-persistent (SP), and fast-persistent (FP). We found that maturation-dependent motility changes are emergent properties of the distribution and dynamic transitions of these three modes. Remarkably, imDCs changed their migration modes more frequently, and predominantly followed the SD→FP→SP→SD unicyclic transition, indicating that imDCs rapidly increase their speed during the shift from diffusive to persistent motility; however, persistence progressively declines when switching back to diffusive motility. In contrast, mDCs show no transition directionality. Our ML-promoted motility pattern analysis and history-dependent mode transition investigation may provide new insights into the complex process of biological motility.
Putting the F in FBD analyses: tree constraints or morphological data ?
Authors: Barido-Sottani Joëlle , Pohle Alexander , De Baets Kenneth , Murdock Duncan , Warnock Rachel C. M. 
Published: July 2022

1AbstractThe fossilized birth-death (FBD) process provides an ideal model for inferring phylogenies from both extant and fossil taxa. Using this approach, fossils (with or without character data) are directly considered as part of the tree. This leads to a statistically coherent prior on divergence times, where the variance associated with node ages reflects uncertainty in the placement of fossil taxa in the phylogeny. Since fossils are typically not associated with molecular sequences, additional information is required to place fossils in the tree. Previously, this information has been provided in two different forms: using topological constraints, where the user specifies monophyletic clades based on established taxonomy, or so-called total-evidence analyses, which use a morphological data matrix with data for both fossil and extant specimens in addition to the molecular alignment. In this work, we use simulations to evaluate these different approaches to handling fossil placement in FBD analyses, both in ideal conditions and in datasets including uncertainty or even errors. We also explore how rate variation in fossil recovery or diversification rates impacts these approaches. We find that the extant topology is well recovered under all methods of fossil placement. Divergence times are similarly well recovered across all methods, with the exception of constraints which contain errors. These results are consistent with expectations: in FBD inferences, divergence times are mostly informed by fossil ages, so variations in the position of fossils strongly impact these estimates. On the other hand, the placement of extant taxa in the phylogeny is driven primarily by the molecular alignment. We see similar patterns in datasets which include rate variation, however one notable difference is that relative errors in extant divergence times increase when more variation is included in the dataset, for all approaches using topological constraints, and particularly for constraints with errors. Finally, we show that trees recovered under the FBD model are more accurate than those estimated using non-FBD (i.e., non-time calibrated) inference. This result holds even with the use of erroneous fossil constraints and model misspecification under the FBD. Overall, our results underscore the importance of core taxonomic research, including morphological data collection and species descriptions, irrespective of the approach to handling phylogenetic uncertainty using the FBD process.
Accuracy of a machine learning method based on structural and locational information from AlphaFold2 for predicting the pathogenicity of TARDBP and FUS gene variants in ALS
Authors: Hatano Yuya , Ishihara Tomohiko , Onodera Osamu 
Published: July 2022

AbstractBackgroundIn the sporadic form of amyotrophic lateral sclerosis (ALS), the pathogenicity of rare variants in the causative genes characterizing the familial form remains largely unknown. To predict the pathogenicity of such variants, in silico analysis is commonly used. In some cases of ALS, the gene mutations are concentrated in specific regions, and the resulting alterations in protein structure are thought to significantly affect pathogenicity. However, existing methods have not taken this issue into account. To address this, we have developed a technique termed MOVA (method for evaluating the pathogenicity of missense variants using AlphaFold2), which applies positional information for structural variants predicted by AlphaFold2. Here we examined the utility of MOVA for analysis of several causative genes of ALS.MethodsWe analyzed variants of six ALS-related genes (TARDBP, FUS, SETX, TBK1, OPTN, and SOD1) and classified them as pathogenic or neutral. For each gene, the features of the variants, including their positions in the 3D structure predicted by AlphaFold2, were entered into a random forest algorithm and evaluated by leave-one-out cross-validation. We compared how accurately MOVA was able to classify the pathogenic and neutral mutation variants.ResultsMOVA yielded useful results (AUC ≥0.70 for 3 (TARDBP 0.755, FUS 0.844, and SOD1 0.787) of the 6 genes) and was particularly useful for genes where pathogenic mutations were concentrated at specific sites (TARDBP, FUS).ConclusionsMOVA is useful for predicting the virulence of rare variants of ALS-causing genes in which mutations are concentrated at specific structural sites.
Modulating the proliferative and cytotoxic properties of human TIL by a synthetic immune niche of immobilized CCL21 and ICAM1
Authors: Yunger Sharon , Geiger Benjamin , Friedman Nir , Besser Michal J , Adutler-Lieber Shimrit 
Published: July 2022

AbstractThe major challenge in developing an effective adoptive cancer immunotherapy, is theex-vivogeneration of tumor-reactive cells, in sufficient numbers and with enhanced cytotoxic potential. It was recently demonstrated, that culturing of activated murine CD8+ T-cells on a “Synthetic Immune Niche” (SIN), consisting of immobilized CCL21 and ICAM-1, enhances T-cell expansion, increases cytotoxicity against cultured cancer cells and suppresses tumor growthin vivo[1, 2]. In the study reported here, we have tested the effect of the CCL21+ICAM1 SIN, on the expansion and cytotoxic phenotype of Tumor Infiltrating Lymphocytes (TIL), following activation with immobilized anti-CD3/CD28 stimulation, or commercial activation beads. The majority of TIL tested, displayed higher expansion when cultured on the coated SIN compared to cells incubated on uncoated substrate. Comparable enhancement of TIL proliferation was obtained by the CCL21+ICAM1 SIN, in a clinical setting that includes a 14-day rapid expansion procedure (REP), initiated with feeder cells, anti CD3 and IL-2. Co-incubation of post-REP TIL with matching target cancerous cells, demonstrated increased IFNγ secretion beyond baseline in most of the TILs and a significant increase in granzyme B levels following activation on SIN. The SIN did not significantly alter the relative frequency of CD8/CD4 populations, as well as the expression of CD28, CD25 and several exhaustion markers. These results demonstrate the potential capacity of the CCL21+ICAM1 SIN to reinforce TIL-based immunotherapy.
Antibody-mediated prevention of vaginal HIV transmission is dictated by IgG subclass in humanized mice
Authors: Brady Jacqueline M. , Phelps Meredith , MacDonald Scott W. , Lam Evan C. , Nitido Adam , Parsons Dylan , Boutros Christine L. , Deal Cailin E. , Tanno Serah , Natarajan Harini , Ackerman Margaret E. , Vrbanac Vladimir D. , Balazs Alejandro B. 
Published: July 2022

ABSTRACTHIV broadly neutralizing antibodies (bNAbs) are capable of both blocking viral entry and recruiting innate immunity to HIV-infected cells through their fragment crystallizable (Fc) region. Vaccination or productive infection results in a polyclonal mixture of class-switched IgG antibodies comprised of four subclasses, each encoding distinct Fc regions that differentially engage innate immune functions. Despite evidence that innate immunity contributes to protection, the relative contribution of individual IgG subclasses is unknown. Here we use vectored immunoprophylaxis (VIP) in humanized mice to interrogate the efficacy of individual IgG subclasses during prevention of vaginal HIV transmission by VRC07, a potent CD4-binding site directed bNAb. We find that VRC07-IgG2, which lacks Fc-mediated functionality, exhibits significantly reduced protection in vivo relative to other subclasses. However, even low concentrations of highly functional VRC07-IgG1 yields substantial protection against vaginal challenge, suggesting that interventions capable of eliciting modest titers of functional subclasses may provide meaningful benefit against infection.
Growth of brown trout in the wild predicted by embryo stress reaction in the laboratory
Authors: Bylemans Jonas , Marques da Cunha Lucas , Wilkins Laetitia G. E. , Nusbaumer David , Uppal Anshu , Wedekind Claus 
Published: July 2022

AbstractLaboratory studies on embryos of salmonids, such as the brown trout (Salmo trutta), have been extensively used to study environmental stress and how responses vary within and between natural populations. These studies are based on the implicit assumption that early life-history traits are relevant for stress tolerance in the wild. Here we test this assumption by combining two datasets from studies on the same 60 full-sib families. These families had been experimentally produced from wild breeders to determine, in separate samples, (i) stress tolerances of singly kept embryos in the laboratory and (ii) growth of juveniles during 6 months in the wild. We found that growth in the wild was well predicted by larval size of their full sibs in the laboratory, especially if these siblings had been experimentally exposed to a pathogen. Exposure to the pathogen had not caused elevated mortality among the embryos but induced early hatching. The strength of this stress-induced change of life history was a significant predictor of juvenile growth in the wild: the stronger the response in the laboratory, the slower the growth in the wild. We conclude that embryo performance in controlled environments can be useful predictors of juvenile performance in the wild.
An amino-terminal fragment of apolipoprotein E4 leads to behavioral deficits, increased PHF-1 immunoreactivity, and mortality in zebrafish
Authors: McCarthy Madyson M. , Hardy Makenna J. , Leising Saylor E. , LaFollette Alex , Stewart Erica S. , Cogan Amelia S. , Sanghal Tanya , Matteo Katie , Oxford Julia T.T. , Rohn Troy T. 
Published: July 2022

AbstractAlthough the increased risk of developing sporadic Alzheimer’s disease (AD) associated with the inheritance of the apolipoprotein E4 (APOE4) allele is well characterized, the molecular underpinnings of how ApoE4 imparts risk remains unknown. Enhanced proteolysis of the ApoE4 protein with a toxic-gain of function has been suggested and a 17 kDa amino-terminal ApoE4 fragment (nApoE41-151) has been identified in post-mortem human AD frontal cortex sections. Recently, we demonstrated in vitro, exogenous treatment of nApoE41-151 in BV2 microglial cells leads to uptake, trafficking to the nucleus and increased expression of genes associated with cell toxicity and inflammation. In the present study, we extend these findings to zebrafish (Danio rerio), which is an emerging in vivo model system to study AD. Exogenous treatment of nApoE41-151 to 24-hour post-fertilization for 24 hours resulted in significant mortality. In addition, developmental abnormalities were observed following treatment with nApoE41-151 including improper folding of the hindbrain, delay in ear development, deformed yolk sac, enlarged cardiac cavity, and significantly lower heart rates. Decreased presence of pigmentation was noted for nApoE41-151 treated fish compared with controls. Behaviorally, touch-evoked responses to stimulus were negatively impacted by treatment with nApoE41-151. A similar nApoE31-151 fragment that differs by a single amino acid change (C>R) at position 112 had no effects on these parameters under identical treatment conditions. Additionally, triple-labeling confocal microscopy not only confirmed the nuclear localization of the nApoE41-151 fragment within neuronal populations following exogenous treatment, but also identified the presence of tau pathology, one of the hallmark features of AD. Collectively, these in vivo data demonstrating toxicity as well as sublethal effects on organ and tissue development support a novel pathophysiological function of this AD associated-risk factor.
Genetic diversity in global populations of the Critically Endangered addax (Addax nasomaculatus) and its implications for conservation
Authors: Dicks Kara L , Ball Alex D , Banfield Lisa , Barrios Violeta , Boufaroua Mohamed , Chetoui Abdelkader , Chuven Justin , Craig Mark , Al Faqeer Mohammed Yousef , Mallam Garba Hamissou Halilou , Guedara Hela , Harouna Abdoulaye , Ivy Jamie , Najjar Chawki , Petretto Marie , Pusey Ricardo , Rabeil Thomas , Riordan Philip , Senn Helen V , Taghouti Ezzedine , Wacher Tim , Woodfine Tim , Gilbert Tania 
Published: July 2022

AbstractThreatened species are frequently patchily distributed across small wild populations,ex situpopulations managed with varying levels of intensity, and reintroduced populations. Best practice advocates for integrated management acrossin situandex situpopulations. Wild addax (Addax nasomaculatus) now number fewer than 100 individuals, yet thousands of addax remain inex situpopulations, which can provide addax for reintroductions, as has been the case in Tunisia in the mid-1980s. However, integrated management requires genetic data to ascertain the relationships between wild andex situpopulations that have incomplete knowledge of founder origins, management histories and pedigrees. We undertook a global assessment of genetic diversity across wild,ex situ, and reintroduced populations in Tunisia to assist conservation planning for this Critically Endangered species. We show that the remnant wild populations retain more mitochondrial haplotypes which are more evolutionarily diverse than the entirety of theex situpopulations across Europe, North America and the United Arab Emirates, and the reintroduced Tunisian population. Additionally, 1704 SNPs revealed that whilst population structure within theex situpopulation is minimal, each population carries unique diversity. Finally, we show that careful selection of founders and subsequent genetic management is vital to ensure genetic diversity is provided to, and minimise drift and inbreeding within, reintroductions. Our results highlight a vital need to conserve the last remaining wild addax population, and we provide a genetic foundation for determining integrated conservation strategies to prevent extinction and optimise future reintroductions.
Experimental introgression inDrosophila: asymmetric postzygotic isolation associated with chromosomal inversions and an incompatibility locus on the X chromosome
Authors: Poikela N. , Laetsch D. R. , Kankare M. , Hoikkala A. , Lohse K. 
Published: July 2022

AbstractInterspecific gene flow (introgression) is an important source of new genetic variation, but selection against it can reinforce reproductive barriers between interbreeding species. We used an experimental approach to trace the role of chromosomal inversions and incompatibility genes in preventing introgression between two partly sympatricDrosophila virilisgroup species,D. flavomontanaandD. montana. We backcrossed F1hybrid females from a cross betweenD. flavomontanafemale andD. montanamale with the males of the parental species for two generations and sequenced pools of parental strains and their reciprocal 2ndgeneration backcross (BC2mon and BC2fla) females. Contrasting the observed amount of introgression (mean hybrid index, HI) in BC2female pools along the genome to simulations under different scenarios allowed us to identify chromosomal regions of restricted and increased introgression. We found no deviation from the HI expected under a neutral null model for any chromosome for the BC2mon pool, suggesting no evidence for genetic incompatibilities in backcrosses towardsD. montana. In contrast, the BC2fla pool showed high variation in the observed HI between different chromosomes, and massive reduction of introgression on the X chromosome (large X-effect). This observation is compatible with reduced recombination combined with at least one dominant incompatibility locus residing within the X inversion(s). Overall, our study suggests that genetic incompatibilities arising within chromosomal inversions can play an important role in speciation.
lncRNA H19/Let7b/EZH2 axis regulates somatic cell senescence
Authors: Potnis Manali , Do Justin , Naggar Olivia El , Noguchi Eishi , Sell Christian 
Published: July 2022

AbstractLong non-coding RNAs (lncRNAs) regulate diverse cellular processes and are associated with many age-associated diseases. However, the function of lncRNAs in cellular senescence remains largely unknown. Here we characterize the role of lncRNA H19 in senescence. We show that H19 levels decline as cells undergo senescence, and depletion of H19 results in premature senescence. We find that repression of H19 is triggered by the loss of CTCF and prolonged activation of p53 as part of the senescence pathway. Mechanistically, the loss of H19 drives senescence via increased let7b mediated targeting of EZH2. We further demonstrate that H19 is required for senescence inhibition by the mTOR inhibitor rapamycin, where it maintains lncRNA H19 levels throughout the cellular lifespan and thus prevents the reduction of EZH2 that would otherwise lead to cellular senescence. Therefore, lncRNA H19 is crucial in maintaining the balance between sustained cell growth and the onset of senescence.
Demographic variation and demographic niches of trees species in the Barro Colorado Forest
Authors: Condit Richard , Rüger Nadja 
Published: July 2022

AbstractOne goal for the 50-ha plot on Barro Colorado Island since its inception has been to understand demographic variability across the entire community of tree species. Early papers classified demographic response of many species to canopy gaps, culminating over the last decade with improved statistical methods that could quantify the response of growth, survival, and recruitment rates to increasing light for the entire community. We compile results from recent studies to illustrate the demographic trade-off between fast growth in high light and long life in deep shade. Growth and recruitment in high light are significantly correlated with mortality across species, and this trade-off is the primary demographic differentiation in the community. Here we add a new analysis of expected adult lifespan of 31 dominant canopy species spanning the growth-mortality axis. Using analytical solutions to matrices describing the lifetable, we demonstrate that the trade-off between high growth and long lifespan is not equalizing. The expected adult lifespan of a newly-recruited sapling is shorter in fast-growing pioneers than in long-lived shade-tolerant species: elevated growth rates of pioneers is insufficient to overcome their high death rates. If reproductive output were equal across the demographic axis, pioneer species could not persist. This suggests pioneers out-reproduce shade-tolerant species. The next goal is incorporating seed and seedling production into the demographic analysis to test the trade-off using lifetables having reproductive output included.
Integrating Self-Attention Transformer with Triplet Neural Networks for Protein Gene Ontology Prediction
Authors: Zhu Yi-Heng , Zhang Chengxin , Yu Dong-Jun , Zhang Yang 
Published: July 2022

AbstractAccurate identification of protein function is critical to elucidate life mechanism and design new drugs. We proposed a novel deep-learning method, ATGO, to predict Gene Ontology (GO) attributes of proteins through a triplet neural-network architecture embedded with pre-trained self-attention transformer models. The method was systematically tested on 1068 non-redundant benchmarking proteins and 3328 targets from the third Critical Assessment of Protein Function Annotation (CAFA) challenge. Experimental results showed that ATGO achieved a significant increase of the GO prediction accuracy compared to the state-of-the-art approaches in all aspects of molecular function, biological process, and cellular component. Detailed data analyses showed that the major advantage of ATGO lies in the utilization of attention transformer models which can extract discriminative functional pattern from the feature embeddings. Meanwhile, the proposed triplet network helps enhance the association of functional similarity with feature similarity in the sequence embedding space. In addition, it was found that the combination of the network scores with the complementary homology-based inferences could further improve the accuracy and coverage of the predicted models. These results demonstrated a new avenue for high-accuracy deep-learning function prediction that is applicable to large-scale protein function annotations from sequence alone.AvailabilityThe benchmark dataset, standalone package, and online server for ATGO are available at https://zhanggroup.org/ATGO/.Author SummaryIn the post-genome sequencing era, a major challenge in computational molecular biology is to annotate the biological functions of all gene and gene products, which have been classified, in the context of the widely used Gene Ontology (GO), into three aspects of molecular function, biological process, and cellular component. In this work, we proposed a new open-source deep-learning architecture, ATGO, to deduce GO terms of proteins from the primary amino acid sequence, through the integration of the triplet neural-network with attention transformer models. Large benchmark tests showed that, when powered with a pre-trained self-attention transformer model, ATGO achieved a significantly improved performance than other state-of-the-art approaches in all the GO aspect predictions. Following the rapid progress of self-attention neural network techniques, which have demonstrated remarkable impacts on language processing and multi-sensory data process, and most recently on protein structure prediction, this study showed the significant potential of attention transformer models on protein function annotations.
The inceptionist’s guide to base editing – de novo PAM generation to reach initially inaccessible target-sites
Authors: Pakari Kaisa , Wittbrodt Joachim , Thumberger Thomas 
Published: July 2022

AbstractBase editing by CRISPR crucially depends on the presence of a PAM in proper distance to the editing-site. Here we present and validate an efficient one-shot approach termed “inception”, relaxing these constraints. This is achieved by sequential, combinatorial base editing: de novo generated synonymous, non-synonymous or intronic PAM-sites facilitate subsequent base editing at nucleotide positions inaccessible before, increasing the targeting range of highly precise editing approaches.