bluuebunny/crossref_metadata_2025_split huggingface dataset:
The MS remyelinating drug bexarotene (an RXR agonist) promotes induction of human Tregs and suppresses Th17 differentiationin vitro
Authors: Gaunt Christof , Rainbow Daniel , Mackenzie Ruairi , Jarvis Lorna , Mousa Hani , Cunniffe Nicholas , Georgieva Zoya , Brown J. William , Coles Alasdair , Jones Joanne 
Published: February 2021

AbstractThe retinoid X receptor (RXR) agonist bexarotene has recently been shown to promote remyelination in individuals with multiple sclerosis. Murine studies demonstrated that RXR agonists can have anti-inflammatory effects by enhancing the ability of all-trans-retinoic acid (αtRA), the primary active metabolite of vitamin A, to promote T regulatory cell (Treg) induction and reduce Th17 differentiationin vitro, following stimulation of naïve CD4 cells in the presence of TGF-β.Stimulating naïve human CD4 T cells for 7 days, in the presence of either Treg or Th17 skewing cytokines ± bexarotene (1 μM), ± other RXR agonists (9CisRA and NRX 194204), or ±αtRA (100 nM) shows that RXR agonists, including bexarotene, are capable of tipping the human Treg/Th17 axis in favour of Treg induction. Furthermore, this occurs independently ofαtRA and retinoic acid receptor (RAR) signalling. Tregs induced in the presence of bexarotene express many of the canonical markers of T cell regulation and are functionally suppressivein vitro.These findings support a potential immunomodulatory role for bexarotene and highlight the possible therapeutic application of RXR agonists in autoimmune disease, with bexarotene’s pro-remyelinating effects making multiple sclerosis a particularly attractive disease target.Significance StatementThe pan-retinoid X receptor (RXR) agonist bexarotene has recently been shown to promote remyelination in patients with multiple sclerosis. Here we demonstrate that bexarotene, and other RXR agonists have immunomodulating effects, tipping the Th17/T regulatory cell (Treg) differentiation axis in favour of Treg development.These findings lend support to the idea of developing RXR agonists as treatments of autoimmune diseases, in particular multiple sclerosis.
Ancient Migrations - The first complete genome assembly, annotation and variants of the Zoroastrian-Parsi community of India
Authors: Pasha Naseer , Krishnasamy Kashyap , Nagarajan Naveenkumar , Mutya Seshank , Mam Bhavika , Sonnekhan Kouser , Gopalakrishnan Chellappa , Jain Renuka , Morawala-Patell Villoo 
Published: February 2021

AbstractWith the advent of Next Generation Sequencing, many population specific whole genome sequences published thus far, predominantly represent individuals of European ancestry. While sequencing efforts of underrepresented communities in genomes datasets, like the Yoruba West-African, Han Chinese, Tibetan, South Korean, Egyptian and Japanese have recently added to the public genomic repositories, a comprehensive understanding of human genomic diversity and discovery of trait-associated variants necessitates the need for additional population specific analysis. In this context, the genomics of the population from the Indian sub-continent, given its genetic heterogeneity needs further elucidation.In this context, the endogamous Zoroastrian-Parsi community of India, offer an exceptional insight into a homogenous population that has culturally, socially, and genetically remained intact, for 13 centuries amidst the genomic, social and cultural Indian landscape, consequent to their migration from the ancient Persian plateau.Notwithstanding longevity as a trait, this endangered community is highly susceptible to cancers, rare genetic disorders, and display a documented high incidence of neurodegenerative and autoimmune conditions. The community as a matter of cultural practice abstains from smoking.Here, we describe the assembly and annotation of the genome of an adult female, Zoroastrian-Parsi individual sequenced at a high depth of 173X using a combination of short Illumina reads (160X) and long nanopore reads (13X). Using a combination of hybrid assemblers, we created a new, population-specific human reference genome, The Zoroastrian-Parsi Genome Reference Female, AGENOME-ZPGRF, contains 2,778,216,114 nucleotides as compared to 3,096,649,726 in GRCh38 constituting 93.235% of the total genomic fraction. Annotation identified 20833 genomic features, of which 14996 are almost identical to their counterparts on GRCh38 while 5837 genomic features were covered in partial. AGENOME-ZPGRF contained 5,426,310 variants of which the majority were SNP’s (4,291,601) and 960,867 SNPs were AGENOME-ZPGRF specific personal variants not listed in dbSNP.We present, AGENOME-ZPGRF as a whole reference for any genetic studies involving Zoroastrian-Parsi individuals extending their application to identify disease relevant prognostic biomarkers and variants in global population genomics studies.
Biomolecular recognition of the glycan neoantigen CA19-9 by distinct antibodies
Authors: Borenstein-Katz Aliza , Warszawski Shira , Amon Ron , Tasnima Nova , Yu Hai , Chen Xi , Padler-Karavani Vered , Fleishman Sarel Jacob , Diskin Ron 
Published: February 2021

ABSTRACTGlycans decorate cell surface, secreted glycoproteins and glycolipids. Altered glycans are often found in cancers. Despite their high diagnostic and therapeutic potentials, glycans are polar and flexible molecules that are quite challenging for the development and design of high-affinity binding antibodies. To understand the mechanisms by which glycan neoantigens are specifically recognized by antibodies, we analyze the biomolecular recognition of a single tumor-associated carbohydrate antigen CA19-9 by two distinct antibodies using X-ray crystallography. Despite the plasticity of glycans and the very different antigen-binding surfaces presented by the antibodies, both structures reveal an essentially identical extended CA19-9 conformer, suggesting that this conformer’s stability selects the antibodies. Starting from the bound structure of one of the antibodies, we use the AbLIFT computational method to design a variant with seven core mutations that exhibited tenfold improved affinity for CA19-9. The results reveal strategies used by antibodies to specifically recognize glycan antigens and show how automated antibody-optimization methods may be used to enhance the clinical potential of existing antibodies.
Impaired pattern separation in Tg2576 mice is associated with hyperexcitable dentate gyrus caused by Kv4.1 downregulation
Authors: Kim Kyung-Ran , Kim Yoonsub , Jeong Hyeon-Ju , Kang Jong-Sun , Lee Sang Hun , Kim Yujin , Lee Suk-Ho , Ho Won-Kyung 
Published: February 2021

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that causes memory loss. Most AD researches have focused on neurodegeneration mechanisms. Considering that neurodegenerative changes are not reversible, understanding early functional changes before neurodegeneration is critical to develop new strategies for early detection and treatment of AD. We found that Tg2576 mice exhibited impaired pattern separation at the early preclinical stage. Based on previous studies suggesting a critical role of dentate gyrus (DG) in pattern separation, we investigated functional changes in DG of Tg2576 mice. We found that granule cells in DG (DG-GCs) in Tg2576 mice showed increased action potential firing in response to long depolarizations and reduced 4-AP sensitive K+-currents compared to DG-GCs in wild-type (WT) mice. Among Kv4 family channels, Kv4.1 mRNA expression in DG was significantly lower in Tg2576 mice. We confirmed that Kv4.1 protein expression was reduced in Tg2576, and this reduction was restored by antioxidant treatment. Hyperexcitable DG and impaired pattern separation in Tg2576 mice were also recovered by antioxidant treatment. These results highlight the hyperexcitability of DG-GCs as a pathophysiologic mechanism underlying early cognitive deficits in AD and Kv4.1 as a new target for AD pathogenesis in relation to increased oxidative stress.
Pharmacological inhibition of PAI-1 alleviates cardiopulmonary pathologies induced by exposure to air pollutants PM2.5
Authors: Ghosh Asish K , Soberanes Saul , Lux Elizabeth , Shang Meng , Piseaux-Aillon Raul , Eren Mesut , Budinger G.R. Scott , Miyata Toshio , Vaughan Douglas E 
Published: February 2021

OBJECTIVEExposure to air pollutants leads to the development of pulmonary and cardiovascular diseases, and thus air pollution is one of the major global threats to human health. Air pollutant particulate matter 2.5 (PM2.5)-induced cellular dysfunction impairs tissue homeostasis and causes vascular and cardiopulmonary damage. To test a hypothesis that elevated plasminogen activator inhibitor-1 (PAI-1) levels play a pivotal role in air pollutant-induced cardiopulmonary pathologies, we examined the efficacy of a drug-like novel inhibitor of PAI-1, TM5614, in treating PM2.5-induced vascular and cardiopulmonary pathologies.APPROACH AND RESULTSResults from biochemical, histological, and immunohistochemical studies revealed that PM2.5increases the circulating levels of PAI-1 and thrombin and that TM5614 treatment completely abrogates these effects in plasma. PM2.5significantly augments levels of pro-inflammatory cytokine IL-6 in bronchoalveolar lavage fluid, and this also can be reversed by TM5614, indicating its efficacy in amelioration of PM2.5-induced increases in inflammatory and pro-thrombotic factors. TM5614 reduces PM2.5-induced increased levels of inflammatory markers Mac3 and pSTAT3, adhesion molecule VCAM1, and apoptotic marker cleaved caspase 3. Longer exposure to PM2.5induces pulmonary and cardiac thrombosis, but TM5614 significantly ameliorates PM2.5-induced vascular thrombosis. TM5614 also reduces PM2.5-induced increased blood pressure and heart weight.In vitrocell culture studies revealed that PM2.5induces the levels of PAI-1, type I collagen, fibronectin, and SREBP-1/2, a transcription factor that mediates profibrogenic signaling, in cardiac fibroblasts. TM5614 abrogated that stimulation, indicating that it may block PM2.5-induced PAI-1 and profibrogenic signaling through suppression of SREBP-1. Furthermore, TM5614 blocked PM2.5-mediated suppression of Nrf2, a major antioxidant regulator in cardiac fibroblasts.CONCLUSIONSPharmacological inhibition of PAI-1 with TM5614 is a promising therapeutic approach to control air pollutant PM2.5-induced cardiopulmonary and vascular pathologies.Abstract Figure
High-throughput and high-efficiency sample preparation for single-cell proteomics using a nested nanowell chip
Authors: Woo Jongmin , Williams Sarah M. , Aguilera-Vazquez Victor , Sontag Ryan L. , Moore Ronald J. , Markillie Lye Meng , Mehta Hardeep S. , Cantlon Joshua , Adkins Joshua N. , Smith Richard D. , Clair Geremy C. , Pasa-Tolic Ljiljana , Zhu Ying 
Published: February 2021

AbstractGlobal quantification of protein abundances in single cells would provide more direct information on cellular function phenotypes and complement transcriptomics measurements. However, single-cell proteomics (scProteomics) is still immature and confronts technical challenges, including limited proteome coverage, poor reproducibility, as well as low throughput. Here we describe a nested nanoPOTS (N2) chip to dramatically improve protein recovery, operation robustness, and processing throughput for isobaric-labeling-based scProteomics workflow. The N2 chip allows reducing cell digestion volume to <30 nL and increasing processing capacity to > 240 single cells in one microchip. In the analysis of ∼100 individual cells from three different cell lines, we demonstrate the N2 chip-based scProteomics platform can robustly quantify ∼1500 proteins and reveal functional differences. Our analysis also reveals low protein abundance variations (median CVs < 16.3%), highlighting the utility of such measurements, and also suggesting the single-cell proteome is highly stable for the cells cultured under identical conditions.
Dopamine receptor DOP-1 engages a sleep pathway to modulate swimming inC. elegans
Authors: Xu Ye , Zhang Lin , Liu Yan , Topalidou Irini , Hassinan Cera , Ailion Michael , Zhao Zhenqiang , Wang Tan , Chen Zhibin , Bai Jihong 
Published: February 2021

SummaryAnimals require robust yet flexible programs to support locomotion. While it is clear that a variety of processes must be engaged to ensure rhythmic actions, the exact mechanisms remain largely unknown. Here we report a novel pathway that connects the D1-like dopamine receptor DOP-1 with a sleep mechanism to modulate swimming inC. elegans. We show that DOP-1 plays a negative role in sustaining swimming behavior. By contrast, a pathway through the D2-like dopamine receptor DOP-3 negatively regulates the initiation of swimming, but its impact fades quickly over a few minutes. We find that DOP-1 and the GPCR kinase GRK-2 function in the sleep interneuron RIS, where DOP-1 modulates the secretion of a sleep neuropeptide FLP-11. Our genetic studies further show that DOP-1 and FLP-11 act in the same pathway to modulate swimming. Together, these results delineate a functional connection between a dopamine receptor and a sleep program to regulate swimming inC. elegans. The temporal transition between DOP-3 and DOP-1 pathways highlights the dynamic nature of neuromodulation for rhythmic movements that persist over time.HIGHLIGHTSThe D1-like dopamine receptor DOP-1 regulates swimming at 10 minutesAn integrated function of DOP-1 and DOP-3 is required for the continuity of swimmingDOP-1 and GRK-2 act in the sleep neuron RISFLP-11, a neuropeptide that promotes sleep, negatively regulates swimmingIN BRIEFXu et al. investigated genetic programs that modulate swimming behavior in the nematodeC. elegans. They identified a functional link that couples a D1-like dopamine receptor to a sleep program that modulates the sustained phase rather than the initial phase of swimming.
Immune characterization and profiles of SARS-CoV-2 infected patients reveals potential host therapeutic targets and SARS-CoV-2 oncogenesis mechanism
Authors: Policard Martine , Jain Sidharth , Rego Samantha , Dakshanamurthy Sivanesan 
Published: February 2021

AbstractThe spread of SARS-CoV-2 and the increasing mortality rates of COVID-19 create an urgent need for treatments, which are currently lacking. Although vaccines have been approved by the FDA for emergency use in the U.S., patients will continue to require pharmacologic intervention to reduce morbidity and mortality as vaccine availability remains limited. The rise of new variants makes the development of therapeutic strategies even more crucial to combat the current pandemic and future outbreaks. Evidence from several studies suggests the host immune response to SARS-CoV-2 infection plays a critical role in disease pathogenesis. Consequently, host immune factors are becoming more recognized as potential biomarkers and therapeutic targets for COVID-19. To develop therapeutic strategies to combat current and future coronavirus outbreaks, understanding how the coronavirus hijacks the host immune system during and after the infection is crucial. In this study, we investigated immunological patterns or characteristics of the host immune response to SARS-CoV-2 infection that may contribute to the disease severity of COVID-19 patients. We analyzed large bulk RNASeq and single cell RNAseq data from COVID-19 patient samples to immunoprofile differentially expressed gene sets and analyzed pathways to identify human host protein targets. We observed an immunological profile of severe COVID-19 patients characterized by upregulated cytokines, interferon-induced proteins, and pronounced T cell lymphopenia, supporting findings by previous studies. We identified a number of host immune targets including PERK, PKR, TNF, NF-kB, and other key genes that modulate the significant pathways and genes identified in COVID-19 patients. Finally, we identified genes modulated by COVID-19 infection that are implicated in oncogenesis, including E2F transcription factors and RB1, suggesting a mechanism by which SARS-CoV-2 infection may contribute to oncogenesis. Further clinical investigation of these targets may lead to bonafide therapeutic strategies to treat the current COVID-19 pandemic and protect against future outbreaks and viral escape variants.
Plant responses to multiple antagonists are mediated by order of attack and phytohormone crosstalk
Authors: Basu Saumik , Clark Robert E. , Bera Sayanta , Casteel Clare L. , Crowder David W. 
Published: February 2021

AbstractPlants are often attacked by multiple antagonists, and traits of the attacking organisms, and their order of arrival onto hosts, may affect plant defenses. However, few studies have assessed how multiple antagonists, and varying attack order, affect plant defense or nutrition. To address this, we assessed defensive and nutritional responses ofPisum sativumplants after attack by a vector herbivore (Acrythosiphon pisum), a non-vector herbivore (Sitona lineatus), and a pathogen (Pea enation mosaic virus, PEMV). We show PEMV-infectiousA. pisuminduced several pathogen-specific plant defense signals, but these defenses were inhibited whenS. lineatuswas present in peas infected with PEMV. In contrast, feeding byS. lineatusinduced anti-herbivore defense signals, but these defenses were enhanced by PEMV.Sitona lineatusalso increased abundance of plant amino acids, but only when they attacked after PEMV-infectiousA. pisum. Our results suggest that diverse communities of biotic antagonists alter defense and nutritional traits of plants through complex pathways that depend on the identity of attackers and their order of arrival onto hosts. Moreover, we show interactions among a group of biotic stressors can vary along a spectrum from antagonism to enhancement/synergism based on the identity and order of attackers, and these interactions are mediated by a multitude of phytohormone pathways.
coupleCoC+: an information-theoretic co-clustering-based transfer learning framework for the integrative analysis of single-cell genomic data
Authors: Zeng Pengcheng , Lin Zhixiang 
Published: February 2021

AbstractTechnological advances have enabled us to profile multiple molecular layers at unprecedented single-cell resolution and the available datasets from multiple samples or domains are growing. These datasets, including scRNA-seq data, scATAC-seq data and sc-methylation data, usually have different powers in identifying the unknown cell types through clustering. So, methods that integrate multiple datasets can potentially lead to a better clustering performance. Here we proposecoupleCoC+ for the integrative analysis of single-cell genomic data.coupleCoC+ is a transfer learning method based on the information-theoretic co-clustering framework. IncoupleCoC+, we utilize the information in one dataset, the source data, to facilitate the analysis of another dataset, the target data.coupleCoC+ uses the linked features in the two datasets for effective knowledge transfer, and it also uses the information of the features in the target data that are unlinked with the source data. In addition,coupleCoC+ matches similar cell types across the source data and the target data. By applyingcoupleCoC+ to the integrative clustering of mouse cortex scATAC-seq data and scRNA-seq data, mouse and human scRNA-seq data, mouse cortex sc-methylation and scRNA-seq data, and human blood dendritic cells scRNA-seq data from two batches, we demonstrate thatcoupleCoC+ improves the overall clustering performance and matches the cell subpopulations across multimodal single-cell genomic datasets.coupleCoC+ has fast convergence and it is computationally efficient. The software is available athttps://github.com/cuhklinlab/coupleCoC_plus.
Peak shifts and extinction under sex-specific selection
Authors: De Lisle Stephen P. 
Published: February 2021

AbstractA well-known property of sexual selection combined with a cross sex genetic correlation (rmf), is that it can facilitate a peak shift on the adaptive landscape. How do these diversifying effects of sexual selection +rmfbalance with the constraints imposed by such sexual antagonism, to affect macroevolution of sexual dimorphism? Here, I extend existing quantitative genetic models of evolution on complex adaptive landscapes. Beyond recovering classical predictions for the conditions promoting a peak shift, I show that whenrmfis moderate to strong, relatively weak sexual selection is required to induce a peak shift in males only. Increasing the strength of sexual selection leads to a sexually-concordant peak shift, suggesting that macroevolutionary rates of sexual dimorphism may be largely decoupled from the strength of within-population sexual selection. Accounting explicitly for demography further reveals that sex-specific peak shifts may be more likely to be successful than concordant shifts in the face of extinction, especially when natural selection is strong. An overarching conclusion is that macroevolutionary patterns of sexual dimorphism are unlikely to be readily explained by within-population estimates of selection or constraint alone.
On Compton scattering as a source of background in coherent diffraction imaging experiments
Authors: Bikondoa Oier , Carbone Dina 
Published: February 2021

Compton scattering is generally neglected in diffraction experiments because the incoherent radiation it generates does not give rise to interference effects and therefore is negligible at Bragg peaks. However, as the scattering volume is reduced, the difference between the Rayleigh (coherent) and Compton (incoherent) contributions at Bragg peaks diminishes and the incoherent part may become substantial. The consequences can be significant for coherent diffraction imaging at high scattering angles: the incoherent radiation produces background that smears out the secondary interference fringes, affecting thus the achievable resolution of the technique. Here, a criterion that relates the object shape and the resolution is introduced. The Compton contribution for several object shapes is quantified, and it is shown that the maximum achievable resolution along different directions has a strong dependence on the crystal shape and size.
Pushing the limits of accountability: big data analytics containing and controlling COVID-19 in South Korea
Authors: Ahn Paul D. , Wickramasinghe Danture 
Published: February 2021

PurposeThe purpose of this paper is to illustrate how big data analytics pushed the limits of individuals' accountability as South Korea tried to control and contain coronavirus disease 2019 (COVID-19).Design/methodology/approachThe authors draw upon Deleuzo-Guattarian framework elaborating how a surveillant assemblage was rhizomatically created and operated to monitor a segment of the population holding them accountable. Publicly available secondary data, such as press release from the government and media coverage, were used.FindingsA COVID-19 Smart Management System and a Self-Quarantine Safety Protection App constituted a surveillance assemblage operating in a “state-form”. This comprises the central government departments, local councils, policing systems, providers of telecommunication and financial services, and independent groups of people. This assemblage pushed the limits of accountability as individuals who tested positive or might bear possible future risks of the infection and transmission were held accountable for their locations and health conditions.Practical implicationsPolicymakers may consider constructing this type of state-form for containing and controlling pandemics, such as COVID-19, while dealing with the issue of undermined privacy.Social implicationsThe mass may consider to what extent individuals' personal information should be protected and how to hold the governments accountable for the legitimate use of such information.Originality/valueWhile accountability studies have largely focussed on formal organisations, the authors illustrated how a broader context of a state-form, harnessing big data analytics, pushes the limits of accountability.