bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human primitive mesenchymal stem cell-derived retinal progenitor cells promoted neuroprotection and neurogenesis in rd12 mice
Authors: Brown Christina , Agosta Patrina , McKee Christina , Walker Keegan , Mazzella Matteo , Svinarich David , Chaudhry G. Rasul 
Published: September 2021

AbstractRetinal degenerative diseases (RDD) such as retinitis pigmentosa (RP) have no treatment. Stem cell-based therapies could provide promising opportunities to repair the damaged retina and restore vision. We investigated a novel approach in which human retinal progenitor cells (RPCs) derived from primitive mesenchymal stem cells (pMSCs) were examined to treat retinal degeneration in an rd12 mouse model of RP. Intravitreally transplanted cells improved retinal function and significantly increased retinal thickness. Transplanted cells homed, survived, and integrated to various retinal layers. They also induced anti-inflammatory and neuroprotective responses and upregulated neurogenesis genes. We found that RPCs were more efficacious than pMSCs in improving the retinal structure and function. RNA analyses suggest that RPCs promote neuroprotection and neuronal differentiation by activating JAK/STAT and MAPK, and inhibiting BMP signaling pathways. These promising results provide the basis for clinical studies to treat RDD using RPCs derived from pMSCs.
Lung epithelial CYP1 activity regulates aryl hydrocarbon receptor dependent allergic airway inflammation
Authors: Alessandrini Francesca , de Jong Renske , Wimmer Maria , Maier Ann-Marie , Fernandez Isis , Hils Miriam , Buters Jeroen T. , Biedermann Tilo , Zissler Ulrich , Hoffmann Christian , Esser-von-Bieren Julia , Schmidt-Weber Carsten B. , Ohnmacht Caspar 
Published: September 2021

AbstractThe lung epithelial barrier serves as a guardian towards environmental insults and responds to allergen encounter with a cascade of immune reactions that can possibly lead to inflammation. Whether the environmental sensor aryl hydrocarbon receptor (AhR) together with its downstream targets cytochrome P450 (CYP1) family members contribute to the regulation of allergic airway inflammation remains unexplored. By employing knockout mice for AhR and for single CYP1 family members, we found that AhR-/- and CYP1B1-/- but not CYP1A1-/- or CYP1A2-/- animals display enhanced allergic airway inflammation compared to WT. Expression analysis, immunofluorescence staining of murine and human lung sections and bone marrow chimeras suggest an important role of CYP1B1 in non-hematopoietic lung epithelial cells to prevent exacerbation of allergic airway inflammation. Transcriptional analysis of murine and human lung epithelial cells indicates a functional link of AhR to barrier protection/inflammatory mediator signaling upon allergen challenge. In contrast, CYP1B1 deficiency leads to enhanced expression and activity of CYP1A1 in lung epithelial cells and to an increased availability of the AhR ligand kynurenic acid following allergen challenge. Thus, differential CYP1 family member expression and signaling via the AhR in epithelial cells represents an immunoregulatory layer protecting the lung from exacerbation of allergic airway inflammation.
The anterior paired lateral neuron normalizes odour-evoked activity at the mushroom body calyx
Authors: Prisco Luigi , Deimel Stephan Hubertus , Yeliseyeva Hanna , Fiala André , Tavosanis Gaia 
Published: September 2021

AbstractTo identify and memorize discrete but similar environmental inputs, the brain needs to distinguish between subtle differences of activity patterns in defined neuronal populations. The Kenyon cells of the Drosophila adult mushroom body (MB) respond sparsely to complex olfactory input, a property that is thought to support stimuli discrimination in the MB. To understand how this property emerges, we investigated the role of the inhibitory anterior paired lateral neuron (APL) in the input circuit of the MB, the calyx. Within the calyx, presynaptic boutons of projection neurons (PNs) form large synaptic microglomeruli (MGs) with dendrites of postsynaptic Kenyon cells (KCs). Combining EM data analysis and in vivo calcium imaging, we show that APL, via inhibitory and reciprocal synapses targeting both PN boutons and KC dendrites, normalizes odour-evoked representations in MGs of the calyx. APL response scales with the PN input strength and is regionalized around PN input distribution. Our data indicate that the formation of a sparse code by the Kenyon cells requires APL-driven normalization of their MG postsynaptic responses. This work provides experimental insights on how inhibition shapes sensory information representation in a higher brain centre, thereby supporting stimuli discrimination and allowing for efficient associative memory formation.
DeNovoCNN: A deep learning approach to de novo variant calling in next generation sequencing data
Authors: Khazeeva Gelana , Sablauskas Karolis , van der Sanden Bart , Steyaert Wouter , Kwint Michael , Rots Dmitrijs , Hinne Max , van Gerven Marcel , Yntema Helger , Vissers Lisenka , Gilissen Christian 
Published: September 2021

ABSTRACTDe novo mutations (DNMs) are an important cause of genetic disorders. The accurate identification of DNMs from sequencing data is therefore fundamental to rare disease research and diagnostics. Unfortunately, identifying reliable DNMs remains a major challenge due to sequence errors, uneven coverage, and mapping artifacts. Here, we developed a deep convolutional neural network (CNN) DNM caller (DeNovoCNN), that encodes the alignment of sequence reads for a trio as 160×164 resolution images. DeNovoCNN was trained on DNMs of 5,616 whole exome sequencing (WES) trios achieving total 96.74% recall and 96.55% precision on the test dataset. We find that DeNovoCNN has increased recall/sensitivity and precision compared to existing DNM calling approaches (GATK, DeNovoGear, DeepTrio, Samtools) based on the Genome in a Bottle reference dataset and independent WES and WGS trios. Validations of DNMs based on Sanger and PacBio HiFi sequencing confirm that DeNovoCNN outperforms existing methods. Most importantly, our results suggest that DeNovoCNN is likely robust against different exome sequencing and analyses approaches, thereby allowing the application on other datasets. DeNovoCNN is freely available as a Docker container and can be run on existing alignment (BAM/CRAM) and variant calling (VCF) files from WES and WGS without a need for variant recalling.
Single-cell genetic heterogeneity linked to immune infiltration in glioblastoma
Authors: Walentynowicz Kacper A. , Engelhardt Dalit , Yadav Shreya , Onubogu Ugoma , Salatino Roberto , Vincentelli Cristina , McDonald Thomas O. , Michor Franziska , Janiszewska Michalina 
Published: September 2021

SUMMARYGlioblastoma (GBM) is the most aggressive brain tumor with a median survival of ~15 months. Targeted approaches have not been successful in this tumor type due to the large extent of intratumor heterogeneity. Mosaic amplification of oncogenes suggests that multiple genetically distinct clones are present in each tumor. To uncover the relationships between genetically diverse subpopulations of GBM cells and their native tumor microenvironment, we employed highly multiplexed spatial protein profiling, coupled with single-cell spatial mapping of fluorescence in situ hybridization (FISH) for EGFR, CDK4, and PDGFRA. Single-cell FISH analysis of a total of 35,843 single nuclei (~2,100 per tumor) revealed that tumors in which amplifications of EGFR and CDK4 more frequently co-occur in the same cell exhibit higher infiltration of CD163+ immunosuppressive macrophages. Our results suggest that high throughput assessment of genomic alterations at the single cell level could provide a measure for predicting the immune state of GBM.
Bayesian hierarchical models can infer interpretable predictions of leaf area index from heterogeneous datasets
Authors: Stojanović Olivera , Siegmann Bastian , Jarmer Thomas , Pipa Gordon , Leugering Johannes 
Published: September 2021

AbstractEnvironmental scientists often have to predict a complex phenomenon from a heterogeneous collection of datasets. This is particularly challenging if there are systematic differences between them, as is often the case. Accounting for these differences requires a larger number of parameters and thus increases the risk of overfitting. We investigate how Bayesian hierarchical models can help mitigate this problem by allowing the practitioner to explicitly incorporate information about the dataset structure and general domain knowledge. To this end, we look at a typical application in remote sensing: the estimation of leaf area index (of white winter wheat), an important indicator for agronomical modeling, from measurements of reflectance spectra collected at different locations and growth stages. Since the insights gained from such a model could be used to inform policy or business decisions, the interpretability of the model is a primary concern. We, therefore, focus on models that capture the association between leaf area index and the spectral reflectance at various wavelengths by spline-based kernel functions, which can be visually inspected and analyzed. We compare models with three different levels of hierarchy: a non-hierarchical baseline model, a model with hierarchical bias parameter, and a model in which bias and kernel parameters are hierarchically structured. We analyze them using Markov Chain Monte Carlo sampling diagnostics and an intervention-based measure of feature importance. The improved robustness and interpretability of this approach lead us to recommend Bayesian hierarchical models as a versatile tool for environmental sciences and beyond, particularly in scenarios where the available data sources are heterogeneous.
Characteristics and mechanism of reciprocal ST-segment depression in acute ST segment elevation myocardial infarction
Authors: Gao Qijun , Bie Fangfang , Hu Yinfu , Chen Yafeng , Yang Bo 
Published: September 2021

AbstractBackgroundAt present, the mechanism of reciprocal ST-segment depression(RSTD) is still not clear.MethodsThe electrocardiogram and angiography of 85 STEMI patients were retrospectively analyzed to summarize the characteristics of ST segment changes and explore the mechanism of RSTD.ResultsA total of 85 patients were included, of which 75 were patients with RSTD (10 patients with anterior myocardial infarction had no RSTD), all 45 patients with inferior myocardial infarction had limb leads RSTD, and 37 of them had anterior lead ST segment depression.Thirty patients with anterior myocardial infarction were accompanied by mild ST segment changes in the limb leads. According to the characteristics of RSTD, it is speculated that the mechanism of RSTD is that the action potential of infarct area decreased, which could not offset the action potential in non-infarct area.Conclusionthe mechanism of RSTD in acute myocardial infarction maybe that the negative electrode action potential of the lead was weakened or disappeared, and the positive electrode action potential could not be completely offset, resulting in ST segment depression.
A Purkinje cell to parabrachial nucleus pathway enables broad cerebellar influence over the forebrain
Authors: Chen Christopher H. , Newman Leannah N. , Stark Amanda P. , Bond Katherine E. , Zhang Dawei , Nardone Stefano , Vanderburg Charles R. , Nadaf Naeem M. , Yao Zhiyi , Mutume Kefiloe , Flaquer Isabella , Lowell Bradford B. , Macosko Evan Z. , Regehr Wade G. 
Published: September 2021

AbstractIn addition to its well-known contributions to motor function, the cerebellum is involved in emotional regulation, anxiety, and affect1-4. We found that suppressing the firing of cerebellar Purkinje cells (PCs) rapidly excites forebrain areas that could contribute to such functions (including the amygdala, basal forebrain, and septum), but that the classic cerebellar outputs, the deep cerebellar nuclei (DCN), do not project to these forebrain regions. Here we show that PCs directly inhibit parabrachial nuclei (PBN) neurons that project to and influence numerous forebrain regions in a manner distinct from the DCN pathway. We also found that the PBN and DCN output pathways differentially influence behavior: suppressing the PC to PBN pathway is aversive and does not affect the speed of movement, whereas suppressing the PC to DCN pathway is not aversive and reduces speed. Molecular profiling shows that PCs inhibit numerous types of PBN neurons that control diverse nonmotor behaviors5-9. Therefore, the PBN pathway allows the cerebellum to regulate activity in many forebrain regions and may be an important substrate for nonmotor disorders related to cerebellar dysfunction.
Ion currents through Kir potassium channels are gated by anionic lipids
Authors: Jin Ruitao , He Sitong , Black Katrina A. , Clarke Oliver B. , Wu Di , Bolla Jani R. , Johnson Paul , Periasamy Agalya , Wardak Ahmad , Czabotar Peter , Colman Peter M. , Robinson Carol V. , Laver Derek , Smith Brian J. , Gulbis Jacqueline M. 
Published: September 2021

AbstractIon currents through potassium channels are gated. Constriction of the ion conduction pathway at the inner helix bundle, the textbook ‘gate’ of Kir potassium channels, has been shown to be an ineffective permeation control, creating a rift in our understanding of how these channels are gated. Here we present the first evidence that anionic lipids act as interactive response elements sufficient to gate potassium conduction. We demonstrate the limiting barrier to K+ permeation lies within the ion conduction pathway and show that this ‘gate’ is operated by the fatty acyl tails of lipids that infiltrate the conduction pathway via fenestrations in the walls of the pore. Acyl tails occupying a surface groove extending from the cytosolic interface to the conduction pathway provide a potential means of relaying cellular signals, mediated by anionic lipid head groups bound at the canonical lipid binding site, to the internal gate.
Unidirectional ion transport mechanism of a light-driven chloride pump revealed using X-ray free electron lasers
Authors: Hosaka Toshiaki , Nomura Takashi , Kubo Minoru , Nakane Takanori , Fangjia Luo , Sekine Shun-ichi , Ito Takuhiro , Murayama Kazutaka , Ihara Kentaro , Ehara Haruhiko , Kashiwagi Kazuhiro , Katsura Kazushige , Akasaka Ryogo , Hisano Tamao , Tanaka Tomoyuki , Tanaka Rie , Arima Toshi , Yamashita Ayumi , Sugahara Michihiro , Naitow Hisashi , Matsuura Yoshinori , Yoshizawa Susumu , Tono Kensuke , Owada Shigeki , Nureki Osamu , Kimura-Someya Tomomi , Iwata So , Nango Eriko , Shirouzu Mikako 
Published: September 2021

ABSTRACTLight-driven chloride-pumping rhodopsins actively transport anions, including various halide ions, across cell membranes. Recent studies using time-resolved serial femtosecond crystallography (TR-SFX) have uncovered the structural changes and ion transfer mechanisms in light-driven cation-pumping rhodopsins. However, the mechanism by which the conformational changes pump an anion to achieve unidirectional ion transport, from the extracellular side to the cytoplasmic side, in anion-pumping rhodopsins remains enigmatic. We have collected TR-SFX data ofNonlabens marinusrhodopsin-3 (NM-R3), derived from a marine flavobacterium, at 10 μs and 1 ms time-points after photoexcitation. Our structural analysis reveals the conformational alterations during ion transfer and after ion release. Movements of the retinal chromophore initially displace a conserved tryptophan to the cytoplasmic side of NM-R3, accompanied with a slight shift of the halide ion bound to the retinal. After ion release, the inward movements of helix C and helix G and the lateral displacements of the retinal block access to the extracellular side of NM-R3. Anomalous signal data have also been obtained from NM-R3 crystals containing iodide ions. The anomalous density maps provide insight into the halide binding site for ion transfer in NM-R3.SignificanceLight-driven chloride pumps have been identified in various species, including archaea and marine flavobacteria. The function of ion transportation controllable by light is utilized for optogenetics tools in neuroscience. Chloride pumps differ among species, in terms of amino acid homology and structural similarity. Our time-resolved crystallographic studies using X-ray free electron lasers reveal the molecular mechanism of halide ion transfer in a light-driven chloride pump from a marine flavobacterium. Our data indicate a common mechanism in chloride pumping rhodopsins, as compared to previous low temperature trapping studies of chloride pumps. These findings are significant not only for further improvements of optogenetic tools but also for a general understanding of the ion pumping mechanisms of microbial rhodopsins.
High Enhancer Activity is an Epigenetic Feature of HPV Negative Atypical Head and Neck Squamous Cell Carcinoma
Authors: Callahan S. Carson , Kochat Veena , Liu Zhiyi , Raman Ayush T , Schulz Jonathan , Terranova Christopher , Divenko Margarita , Ghosh Archit , Tang Ming , Pickering Curtis , Myers Jeffrey N. , Rai Kunal 
Published: September 2021

ABSTRACTHead and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with significant morbidity and mortality and frequent recurrence. Pre-NGS efforts to transcriptionally classify HNSCC into groups of varying prognosis have identified four accepted molecular subtypes of disease: Atypical (AT), Basal (BA), Classical (CL), and Mesenchymal (MS). Here, we investigated the active enhancer landscapes of these subtypes using representative HNSCC cell lines and identified samples belonging to the AT subtype as having increased enhancer activity compared to the other 3 HNSCC subtypes. Cell lines belonging to atypical subtype were more resistant to bromodomain inhibitors (BETi). PRO-Seq experiments that both TCGA tumors and AT cell lines showed higher eRNA transcripts for enhancers controlling BETi resistance pathways, such as lipid metabolism and MAPK signaling. Additionally, HiChIP experiments suggested higher enhancer-promoter (E-P) contacts in the AT subtype, including on genes identified in the eRNA analysis. Consistently, known BETi resistance pathways were upregulated upon exposure to these inhibitors. Together, our results identify that the AT subtype of HNSCC is associated with high enhancer activity, resistance to BET inhibition, and signaling pathways that could serve as future targets for sensitizing HNSCC to BET inhibition.
KMT2D Loss Promotes Head and Neck Squamous Carcinoma Through Enhancer Reprogramming and Modulation of Immune Microenvironment
Authors: Callahan S. Carson , Divenko Margarita , Barrodia Praveen , Singh Anand K , Arslan Emre , Liu Zhiyi , Yang Jiah , Anvar Nazanin , Amit Moran , Xie Tongxin , Jiang Shan , Schulz Jonathan , Tang Ming , Myers Jeffrey N , Rai Kunal 
Published: September 2021

ABSTRACTHead and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with 5-year survival of ∼50%. Genomic profiling studies have identified important somatic mutations in this disease which presents an opportunity for precision medicine. We demonstrate that KMT2D, a histone methyltransferase harbors somatic mutations in ∼17% of HNSCC and is associated with 2-year recurrence in TCGA data. Consistent with algorithmic prediction of bring a driver tumor-suppressor event, its loss results in larger oral tumors in immune-proficient orthotopic models. Mechanistically, we find that KMT2D knockdown or KMT2D mutation causes loss of H3K4me1-marked enhancers harboring IRF7/9 binding sites, which is known to regulate interferon signaling. Indeed, KMT2D loss in human and murine cell lines deregulated transcriptional levels of cytokine expression and impacted numerous immune signaling pathways, including interferon signaling. Consistently, Kmt2d knockdown in murine tumors exhibited decrease in IFNγ-producing effector T cells and an increase in T-cells with an exhausted phenotype. Epistasis experiments showed that exogenous treatment with IFNγ abrogated the increased tumor growth in Kmt2d-deficient oral tumors. Together, these results support the role of KMT2D as a tumor suppressor in HNSCC that regulates the tumor microenvironment by modulating H3K4me1-marked enhancers controlling interferon signaling.
Stimulant Use Interventions May Strengthen ‘Getting to Zero’ Initiatives in Illinois: Insights from a Modeling Study
Authors: Lee Francis , Sheeler Daniel , Hotton Anna , Del Vecchio Natascha , Flores Rey , Fujimoto Kayo , Harawa Nina , Schneider John A. , Khanna Aditya S. 
Published: September 2021

AbstractObjective(s)Young Black men who have sex with men (YBMSM) are a key population identified in the Illinois Getting to Zero (GTZ) initiative who have experienced disproportionate HIV incidence. Rising stimulant use has been determined to impede the effectiveness of ART and pre-exposure prophylaxis for suppressing HIV transmission in populations. This modeling study explores the impact of stimulant use on HIV incidence among YBMSM – given the limited development of dedicated or culturally appropriate interventions for this population – and assesses the impact of these interventions on downstream HIV transmission in the context of achieving GTZ goals.MethodsA previously developed agent-based network model (ABNM), calibrated using data for YBMSM in Illinois, was extended to incorporate the impact of stimulant use (methamphetamines, crack/cocaine, and ecstasy) on sexual networks and engagement in HIV treatment and prevention continua. The model simulated the impact of a residential behavioral intervention (BI) for reducing stimulant dependency and an outpatient biomedical intervention (mirtazapine) for treating methamphetamine dependence on improved engagement in the HIV treatment and prevention continua. The downstream impact of these interventions on population-level HIV incidence was the primary intervention outcome.ResultsBaseline simulated annual HIV incidence in the ABNM was 6.9(95% CI: 6.83,7.04) per 100 person years (py) and 453 (95% CI: 445.9,461.2) new infections annually. A residential targeted to 25% of stimulant users yielded a 27.1% decline in the annual number of new infections. Initiating about 50% of methamphetamine users on mirtazapine reduced the overall HIV incidence by about 11%. A 25% increase in antiretroviral treatment (ART) and preexposure prophylaxis (PrEP) uptake in the non-stimulant using YBMSM population combined with a 25% uptake of BI for stimulant users produces an HIV incidence consistent with HIV elimination targets (about 200 infections/year) identified in the GTZ initiative.ConclusionsTargeted behavioral and biomedical interventions to treat stimulant dependency are likely to provide additive benefits to expanding ART and PrEP uptake for everyone in accomplishing GTZ initiatives for HIV elimination.
Lowland ecotype Cyperus rotundus L. affects growth and yield of rice under flooded conditions in the Philippines
Authors: Donayre Dindo King M. , Jimenez Jessica Joyce L. , Latonio Anna Maria Lourdes S. , Martin Edwin C. , Chauhan Bhagirath S. 
Published: September 2021

AbstractLowland ecotype Cyperus rotundus L. has been reported infesting irrigated lowland ricefields in the Philippines. Its effects on growth and yield of rice under flooded conditions are unknown. Two experimental runs were conducted in a screenhouse to determine the growth of lowland ecotype C. rotundus with transplanted rice and wet direct-seeded rice at a sowing density of 0, 22, 44, 66, and 88 tubers m-2; and its effect on growth and yield of rice. Except for height, growth variables of lowland ecotype C. rotundus were increased with the increase in its initial tuber densities. Compared with 22 tubers m-2, its number of off-shoots and tubers, and shoot and root biomass at 44 to 88 tubers m-2 increased by up to 3x. Growth variables of rice were reduced by the weed. Grain yield of transplanted rice was reduced by 14 to 38%; wet direct-seeded rice by 11 to 28%. Results suggest that lowland ecotype C. rotundus can grow well and reduce growth and yield of rice under flooded conditions. It also imply the need of developing a holistic weed control strategy against the weed.