bluuebunny/crossref_metadata_2025_split huggingface dataset:
Substrate Binding and Inhibition of the Anion Exchanger 1 Transporter
Authors: Capper Michael J. , Yang Shifan , Stone Alexander C. , Vatansever Sezen , Zilberg Gregory , Mathiharan Yamuna Kalyani , Habib Raul , Hutchinson Keino , Schlessinger Avner , Mezei Mihaly , Osman Roman , Zhang Bin , Wacker Daniel 
Published: February 2022

AbstractAnion Exchanger 1 (AE1, SLC4A1) is the primary bicarbonate (HCO3-) transporter expressed in erythrocyte membranes where it mediates transport of CO2between lungs and other tissues via import/export of bicarbonate. It is also a key regulator of erythrocyte structure and antigenic recognition. Previous biochemical studies, and a low-resolution crystal structure of the transmembrane domain have provided initial insight into AE1 structure and function. However, key questions remain regarding substrate binding and transport as well as the mechanism of inhibition. The orientation of the intracellular domain as well as the localization of lipid and sterol binding sites also remain enigmatic. We herein present seven novel high resolution cryo-EM structures of the full length human transporter in the apo, bicarbonate-bound, and several inhibitor-bound states combined with uptake- and computational studies. To our knowledge, these studies represent the first full length human, and substrate bound, SLC4 transporter structure. Our results reveal important molecular details about substrate binding and transport, as well as the diverse mechanisms of AE1 inhibition by both research chemicals and prescription drugs. We also provide novel insights into the full-length transporter architecture, identify the conformational space of the Diego blood antigen system and elucidate multiple lipid and sterol binding sites.
TheDrosophilachemokine-like Orion bridges phosphatidylserine and Draper in phagocytosis of neurons
Authors: Ji Hui , Wang Bei , Shen Yifan , Labib David , Lei Joyce , Chen Xinchen , Sapar Maria , Boulanger Ana , Dura Jean-Maurice , Han Chun 
Published: February 2022

ABSTRACTPhagocytic clearance of degenerating neurons is triggered by “eat-me” signals exposed on the neuronal surface. The conserved neuronal eat-me signal phosphatidylserine (PS) and the engulfment receptor Draper (Drpr) mediate phagocytosis of degenerating neurons inDrosophila. However, how PS is recognized by Drpr-expressing phagocytesin vivoremains poorly understood. Using multiple models of dendrite degeneration, we show that theDrosophilachemokine-like protein Orion can bind to PS and is responsible for detecting PS exposure on neurons; it is supplied cell-non-autonomously to coat PS-exposing dendrites and to mediate interactions between PS and Drpr, thus enabling phagocytosis. As a result, the accumulation of Orion on neurons and on phagocytes produces opposite outcomes by potentiating and suppressing phagocytosis, respectively. Moreover, the Orion dosage is a key determinant of the sensitivity of phagocytes to PS exposed on neurons. Lastly, mutagenesis analyses show that the sequence motifs shared between Orion and human immunomodulatory proteins are important for Orion function. Thus, our results uncover a missing link in PS-mediated phagocytosis inDrosophilaand imply conserved mechanisms of phagocytosis of neurons.SIGNIFICANCE STATEMENTPhagocytes efficiently clear sick or damaged neuronal branches by engulfing them, while leaving healthy branches untouched. How phagocytes recognize degenerating neurites remains poorly understood. Here, we identified a key role for the secreted protein Orion in the detection and engulfment of degenerating neurites inDrosophila. Using multiple models of dendrite degeneration, we found that Orion acts as a bridging molecule between the neuronal “eat-me” signal phosphatidylserine and the engulfment receptor Draper on phagocytes, enabling phagocytosis. Our study reveals a missing link in phosphatidylserine-mediated phagocytosisin vivo, sheds light on factors determining the sensitivity of phagocytes, and implies the potential for manipulating the detection of neuronal “eat-me” signals in neurodegenerative diseases.
Kinase Suppressor of Ras 2 promotes self-renewal and clonogenicity of small-cell lung carcinoma
Authors: Huisman Dianna H. , Chatterjee Deepan , Svoboda Robert A. , Vieira Heidi M. , Ireland Abbie S. , Skupa Sydney , Askew James W. , Frodyma Danielle E. , Girard Luc , Fisher Kurt W. , Kareta Michael S. , Minna John D. , Oliver Trudy G. , Lewis Robert E. 
Published: February 2022

AbstractSmall-cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. Here, we show that Kinase Suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells (PNECs) was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony forming ability of tumor propagating cells (TPCs)in vitroand their tumor initiating capacityin vivo.The effect of KSR2 depletion on self-renewal and clonogenicity is dependent on the interaction of KSR2 with ERK. These data indicate that the expression of KSR2 is an essential driver of SCLC-A tumor propagating cell function, and therefore may play a role in SCLC tumor initiation. These findings shed light on a novel effector promoting initiation of ASCL1-subtype SCLC tumors, and a potential subtype-specific therapeutic target.Statement of ImplicationManipulation of the molecular scaffold KSR2 in ASCL1-subtype small-cell lung cancer cells reveals its contribution to self-renewal, clonogenicity, and tumor initiation.
Blockade of ghrelin receptor signaling enhances conditioned passive avoidance and context-associated neural circuit activation in fasted male rats
Authors: Edwards Caitlyn M. , Guerrero Inge Estefania , Dolezel Tyla , Zheng Huiyuan , Rinaman Linda 
Published: February 2022

AbstractInteroceptive feedback to the brain regarding the body’s physiological state plays an important role in guiding motivated behaviors. For example, a state of negative energy balance tends to increase exploratory/food-seeking behaviors while reducing avoidance behaviors. We recently reported that overnight food deprivation reduces conditioned passive avoidance behavior in male (but not female) rats. Since fasting increases circulating levels of ghrelin, we hypothesized that ghrelin signaling contributes to the ability of fasting to reduce conditioned avoidance. To test this,ad libitum-fed male rats were trained in a passive avoidance procedure using mild footshock. Later, following overnight food deprivation, the same rats were pretreated with ghrelin receptor antagonist (GRA) or saline vehicle 30 min before avoidance testing. GRA restored passive avoidance in fasted rats as measured both by latency to enter and time spent in the shock-paired context. In addition, compared to vehicle-injected fasted rats, fasted rats that received GRA before re-exposure to the shock-paired context displayed more activation of prolactin-releasing peptide (PrRP)-positive noradrenergic neurons in the caudal nucleus of the solitary tract, accompanied by more activation of downstream neurons in the bed nucleus of the stria terminalis and paraventricular nucleus of the hypothalamus. These results support the view that ghrelin signaling contributes to the inhibitory effect of fasting on learned passive avoidance behavior, perhaps by suppressing recruitment of PrRP-positive noradrenergic neurons and their downstream hypothalamic and limbic forebrain targets.
In vivo calcium imaging identifies functionally and molecularly distinct subsets of tongue-innervating mechanosensory neurons
Authors: Moayedi Yalda , Xu Shan , Obayashi Sophie K , Hoffman Benjamin U , Gerling Gregory J , Lumpkin Ellen A 
Published: February 2022

AbstractMechanosensory neurons in the mouth provide essential information to guide feeding and speech. How classes of oral mechanoreceptors contribute to oral behaviors is not well understood; in particular, the functional properties of lingual mechanoreceptors remain elusive. Previous work identified putative mechanosensory endings in the tongue with novel morphologies; how these fit into current knowledge of mechanosensory neuron classification is not known. To identify functional classes of lingual mechanosensory neurons, we used in vivo calcium imaging of trigeminal ganglia. We first investigated calcium responses of tongue-innervating trigeminal neurons to thermal and mechanical stimulation (e.g., pressure, fluid flow, temperature changes). We found that around 17% of neurons responded to pressure, and that these pressure responders were significantly larger than neurons that only responded to temperature changes. To further investigate the cadre of functionally distinct mechanosensory neurons, we tested responses to brushing and sustained pressures and found that brush-sensitive neurons comprise the majority of tongue-innervating mechanosensory trigeminal neurons. Qualitatively, mechanosensory neurons responded to pressure with distinct kinetics, suggesting the presence of multiple classes of mechanoreceptors. To determine the number of classes, we developed an unbiased multi-layer hierarchical clustering approach to classify calcium response characteristics to pressure stimulation. This approach revealed that mechanosensory neurons displayed five distinct stimulus-response profiles to pressure. Classes include neuronal populations with sustained, transient, high-threshold, and negative responses to force as well as neurons that responded only to brushing. Analysis of cluster representation in transgenic animals with only subsets of labeled neurons reveals molecular markers of clusters and end organ structures. These studies are amongst the first to determine the functional properties of low-threshold mechanosensory neurons innervating the mouse tongue.
A Self-attention Graph Convolutional Network for Precision Multi-tumour Early Diagnostics with DNA Methylation Data
Authors: Jiang Xue , Li Zhiqi , Mehmood Aamir , Wang Heng , Wang Qiankun , Chu Yanyi , Mao Xueying , Zhao Jing , Jiang Mingming , Zhao Bowen , Lin Guanning , Wang Edwin , Wei Dongqing 
Published: February 2022

AbstractDNA methylation data-based precision tumor early diagnostics is emerging as state of the art technology, which could capture the signals of cancer occurrence 3∼5 years in advance and clinically more homogenous groups. At present, the sensitivity of early detection for many tumors is about 30%, which needs to be significantly improved. Nevertheless, based on the genome wide DNA methylation information, one could comprehensively characterize the entire molecular genetic landscape of the tumors and subtle differences among various tumors. With the accumulation of DNA methylation data, we need to develop high-performance methods that can model and consider more unbiased information. According to the above analysis, we have designed a self-attention graph convolutional network to automatically learn key methylation sites in a data-driven way for precision multi-tumor early diagnostics. Based on the selected methylation sites, we further trained a multi-class classification support vector machine. Large amount experiments have been conducted to investigate the performance of the computational pipeline. Experimental results demonstrated the effectiveness of the selected key methylation sites which are highly relevant for blood diagnosis.
The UCLA ATLAS Community Health Initiative: promoting precision health research in a diverse biobank
Authors: Johnson Ruth , Ding Yi , Bhattacharya Arjun , Chiu Alec , Lajonchere Clara , Geschwind Daniel H. , Pasaniuc Bogdan 
Published: February 2022

AbstractThe UCLA ATLAS Community Health Initiative (ATLAS) has an initial target to recruit 150,000 participants from across the UCLA Health system, with the goal of creating a genomic database to accelerate precision medicine efforts in California. This initiative includes a biobank embedded within the UCLA Health system that comprises de-identified genomic data linked to electronic health records (EHR). The first freeze of data from September 2020 contains 27,987 genotyped samples imputed to 7.9 million SNPs across the genome and is linked with a de-identified EHR extract. This database enables the study of numerous clinically-related phenotypes within the same medical system. Here we describe a centralized repository of the genotype data and provide tools and pipelines to perform genome-wide and phenome-wide association studies across a wide range of EHR-derived phenotypes and genetic ancestry groups. We demonstrate the utility of this resource through the analysis of 7 well-studied traits and recapitulate many previous genetic and phenotypic associations.
Divergence amid recurring gene flow: complex demographic histories for two North American pines (Pinus pungens and P. rigida) fit growing expectations among forest trees
Authors: Bolte Constance E. , Faske Trevor M. , Friedline Christopher J. , Eckert Andrew J. 
Published: February 2022

AbstractLong-lived species of trees, especially conifers, often display weak patterns of reproductive isolation, but clear patterns of local adaptation and phenotypic divergence. Discovering the evolutionary history of these patterns is paramount to a generalized understanding of speciation for long-lived plants. We focus on two closely related yet phenotypically divergent pine species, Pinus pungens and P. rigida, that co-exist along high elevation ridgelines of the southern Appalachian Mountains. In this study, we performed historical species distribution modeling (SDM) to form hypotheses related to population size change and gene flow to be tested in a demographic inference framework. We further sought to identify drivers of divergence by associating climate and geographic variables with genetic structure within and across species boundaries. Population structure within each species was absent based on genome-wide RADseq data. Signals of admixture were present range-wide, however, and species-level genetic differences associated with precipitation seasonality and elevation. When combined with information from contemporary and historical species distribution models, these patterns are consistent with a complex evolutionary history of speciation influenced by Quaternary climate. This was confirmed using inferences based on the multidimensional site- frequency spectrum, where demographic modeling inferred recurring gene flow since divergence (2.74 million years ago) and population size reductions that occurred during the last glacial period (∼35.2 thousand years ago). This suggests that phenotypic and genomic divergence, including the evolution of divergent phenological schedules leading to partial reproductive isolation, as previously documented for these two species, can happen rapidly, even between long-lived species of pines.
Mentalizing in an economic games context is associated with enhanced activation and connectivity in left temporoparietal junction
Authors: Chang Li-Ang , Warns Lotte , Armaos Konstantinos , Ma de Sousa Ava Q. , Paauwe Femke , Scholz Christin , Engelmann Jan B. 
Published: February 2022

AbstractStudies in Social Neuroeconomics have consistently reported activation in social cognition regions during interactive economic games suggesting mentalizing during economic choice. It remains important to test the involvement of neural activity associated with mentalizing in an economic games context within the same sample of participants performing the same task. We designed a novel version of the classic false-belief task in which participants observed interactions between agents in the ultimatum and trust games and were subsequently asked to infer the agents’ beliefs. We compared activation patterns during the economic-games false-belief task to those during the classic false-belief task using conjunction analyses. We find significant overlap in left TPJ, and dmPFC, as well as temporal pole during two task phases: belief formation and belief inference. Moreover, gPPI analyses show that during belief formation right TPJ is a target of both left TPJ and right temporal pole (TP) seed regions, while during belief inferences all seed regions show interconnectivity with each other. These results indicate that across different task types and phases, mentalizing is associated with activation and connectivity across central nodes of the social cognition network. Importantly, this is the case in the context of the novel economic-games and classic false-belief tasks.
Genetic analysis ofC. elegansHaspin-like genes shows thathasp-1plays multiple roles in the germline
Authors: Macaraeg Jommel , Reinhard Isaac , Ward Matthew , Carmeci Danielle , Stanaway Madison , Moore Amy , Hagmann Ethan , Brown Katherine , Wynne David J 
Published: February 2022

AbstractHaspin is a histone kinase that promotes error-free chromosome segregation by recruiting the Chromosomal Passenger Complex (CPC) to mitotic and meiotic chromosomes. Haspin remains less well studied than other M-phase kinases and the models explaining Haspin function have been developed primarily in mitotic cells. Here, we generate new mutations in theC. elegansHaspin homologshasp-1andhasp-2and characterize their phenotypes. We show thathasp-1is responsible for all predicted functions of Haspin and that loss of function ofhasp-1using classical and conditional alleles produces defects in germline stem cell proliferation, spermatogenesis, and confirms its role in oocyte meiosis. Genetic analysis suggestshasp-1acts downstream of the Polo-like kinaseplk-2and shows synthetic interactions betweenhasp-1and two genes expected to promote recruitment of the CPC by a parallel pathway that depends on the kinase Bub1. This work adds to the growing understanding of Haspin function by characterizing a variety of roles in an intact animal.Summary statementWe characterize new mutations in theC. eleganshomologs of the histone kinase Haspin and show roles in spermatogenesis, germline proliferation and genetic interactions during oocyte meiosis.
Shrimp vaccination with insect-adapted yellow head virus (YHV) extends survival upon YHV challenge
Authors: Gangnonngiw Warachin , Kanthong Nipaporn 
Published: February 2022

AbstractThis short paper on yellow head virus Type1 (YHV-1) describes preliminary research worthy of further study. YHV-1 disease outbreaks can cause severe mortality in the cultivated shrimp Penaeus (Penaeus) monodon and Penaeus (Litopenaeus) vannamei. No practical preventative treatment such as vaccination has been reported. However, it has been shown that C6/36 mosquito cell cultures can adapt to YHV-1 and become persistently immunopositive for the virus after 30 split-cell passages or more. Shrimp injection with homogenates from low passages caused yellow head disease (YHD) but from high passages did not, even though injection resulted in immunopositive hemocytes in the injected shrimp. This suggested YHV-1 attenuation during insect cell passaging and the possibility of using cell homogenates as a vaccine to protect shrimp against virulent YHV-1. To test this hypothesis, we injected shrimp with 30th passage homogenates to test for protection against YHD upon subsequent challenge with virulent YHV-1. Results confirmed earlier work that hemocytes of the infected shrimp became both reverse transcriptase PCR positive and immunopositive for YHV-1 but exhibited no mortality. Similarly, there was no mortality in the control group injected with homogenate from YHV-1 negative insect cells. When subsequently challenged with YHV-1, shrimp in the positive control group injected with homogenate from naïve insect cells gave 100 percent mortality within 7 days post challenge while total mortality in the group injected with YHV-1 homogenate did not occur until day 9 post challenge. Kaplan-Meier log-rank survival analysis revealed that survival curves for the two groups were significantly different (p<0.001) and that the mean survival time for the test group (6.5 days) was significantly longer than that in the positive control group (5.4 days). The results confirmed that shrimp injection with YHV-1 immunopositive insect-cell homogenate gave transient resistance to YHV infection and that further research into the possible use of insect cell lines to produce shrimp antiviral vaccines is warranted.
Metagenomes of Red Sea subpopulations challenge the use of morphology and marker genes to assess Trichodesmium diversity
Authors: Koedooder Coco , Landou Etai , Zhang Futing , Wang Siyuan , Basu Subhajit , Berman-Frank Ilana , Shaked Yeala , Rubin-Blum Maxim 
Published: February 2022

AbstractThe bloom forming Trichodesmium are filamentous cyanobacteria of key interest due to their ability to fix carbon and nitrogen within an oligotrophic marine environment. Trichodesmium blooms typically comprise a complex assemblage of subpopulations and colony-morphologies that are predicted to exhibit distinct ecological lifestyles. Here, we assessed the poorly studied diversity of Trichodesmium in the Red Sea, based on metagenome-assembled genomes (MAGs) and hetR gene-based phylotyping.We assembled four non-redundant MAGs from morphologically distinct Trichodesmium colonies (tufts, dense and thin puffs). T. thiebautii (puffs) and T. erythraeum (tufts) were the dominant species within these morphotypes. While subspecies diversity is present for both T. thiebautii and T. erythraeum, a single T. thiebautii genotype comprised both thin and dense puff morphotypes, and we therefore hypothesize that the phenotypic variation between these morphologies is likely attributed to gene regulation. Additionally, we found the rare non-diazotrophic clade IV and V genotypes, related to T. nobis and T. miru respectively, that likely occurred as single filaments. HetR gene phylogeny indicates that the genotype in clade IV could represent the species T. contortum.We further show that hetR phylotyping can overestimate the taxonomic diversity of Trichodesmium, as two copies of the hetR gene were present within T. thiebautii genomes, one of which misidentified this lineage as T. aureum. Taken together, our results highlight the importance of re-assessing Trichodesmium taxonomy while showing the ability of genomics to capture the complex diversity and distribution of Trichodesmium populations.