bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macromolecular tissue volume mapping of lateral geniculate nucleus subdivisions in living human brains
Authors: Oishi Hiroki , Takemura Hiromasa , Amano Kaoru 
Published: December 2020

AbstractThe human lateral geniculate nucleus (LGN) is composed mainly of the magnocellular and parvocellular subdivisions. The non-invasive identification of these subdivisions is, however, difficult due to the small size of the LGN. Here we propose a method to identify these subdivisions by combining two structural MR measures: high-resolution proton-density weighted images and macromolecular tissue volume maps. We collected MRI data from 15 healthy subjects and found that the spatial organization of these subdivisions identified by our method was consistent with post-mortem histological data. Furthermore, the stimulus selectivity in these regions measured by functional MRI was consistent with physiological studies. These results suggest that macromolecular tissue volume mapping is a promising approach to evaluating the tissue properties of LGN subdivisions in living humans. This method potentially will enable neuroscientific and clinical hypotheses about the human LGN to be tested.
The neutralization effect of Montelukast on SARS-CoV-2 is shown by multiscalein silicosimulations and combinedin vitrostudies
Authors: Durdagi Serdar , Avsar Timucin , Orhan Muge Didem , Serhatli Muge , Balcioglu Bertan Koray , Ozturk Hasan Umit , Kayabolen Alisan , Cetin Yuksel , Aydinlik Seyma , Bagci-Onder Tugba , Tekin Saban , Demirci Hasan , Guzel Mustafa , Akdemir Atilla , Calis Seyma , Oktay Lalehan , Tolu Ilayda , Butun Yasar Enes , Erdemoglu Ece , Olkan Alpsu , Tokay Nurettin , Işık Şeyma , Ozcan Aysenur , Acar Elif , Buyukkilic Sehriban , Yumak Yesim 
Published: December 2020

AbstractSmall molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of SARS-CoV-2. In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist Montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of Montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by differentin vitroexperiments including the Fluorescent Resonance Energy Transfer (FRET)-based main protease enzyme inhibition assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T / hACE2, and virus neutralization assay using xCELLigence MP real time cell analyzer. Our integratedin silicoandin vitroresults confirmed the dual potential effect of the Montelukast both on virus entry into the host cell (Spike/ACE2) and on the main protease enzyme inhibition. The virus neutralization assay results showed that while no cytotoxicity of the Montelukast was observed at 12 μM concentration, the cell index time 50 (CIT50) value was delayed for 12 hours. Moreover, it was also shown that Favipiravir, a well-known antiviral used in COVID-19 therapy, should be used by 16-fold higher concentrations than Montelukast in order to have the same effect of Montelukast. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and if its effect is proven in clinical phase studies, it should be used against COVID-19.
The mechanism of SARS-CoV-2 nucleocapsid protein recognition by the human 14-3-3 proteins
Authors: Tugaeva Kristina V. , Hawkins Dorothy E. D. P. , Smith Jake L. R. , Bayfield Oliver W. , Ker De-Sheng , Sysoev Andrey A. , Klychnikov Oleg I. , Antson Alfred A. , Sluchanko Nikolai N. 
Published: December 2020

AbstractThe coronavirus nucleocapsid protein (N) controls viral genome packaging and contains numerous phosphorylation sites located within unstructured regions. Binding of phosphorylated SARS-CoV N to the host 14-3-3 protein in the cytoplasm was reported to regulate nucleocytoplasmic N shuttling. All seven isoforms of the human 14-3-3 are abundantly present in tissues vulnerable to SARS-CoV-2, where N can constitute up to ~1% of expressed proteins during infection. Although the association between 14-3-3 and SARS-CoV-2 N proteins can represent one of the key host-pathogen interactions, its molecular mechanism and the specific critical phosphosites are unknown. Here, we show that phosphorylated SARS-CoV-2 N protein (pN) dimers, reconstituted via bacterial co-expression with protein kinase A, directly associate, in a phosphorylation-dependent manner, with the dimeric 14-3-3 protein, but not with its monomeric mutant. We demonstrate that pN is recognized by all seven human 14-3-3 isoforms with various efficiencies and deduce the apparent KDto selected isoforms, showing that these are in a low micromolar range. Serial truncations pinpointed a critical phosphorylation site to Ser197, which is conserved among related zoonotic coronaviruses and located within the functionally important, SR-rich region of N. The relatively tight 14-3-3/pN association can regulate nucleocytoplasmic shuttling and other functions of N via occlusion of the SR-rich region, while hijacking cellular pathways by 14-3-3 sequestration. As such, the assembly may represent a valuable target for therapeutic intervention.HighlightsSARS-CoV-2 nucleocapsid protein (N) binds to all seven human 14-3-3 isoforms. This association with 14-3-3 strictly depends on phosphorylation of N. The two proteins interact in 2:2 stoichiometry and with the Kd in a μM range. Affinity of interaction depends on the specific 14-3-3 isoform. Conserved Ser197-phosphopeptide of N is critical for the interaction.
The chirality of the mitotic spindle provides a mechanical response to forces and depends on microtubule motors and augmin
Authors: Trupinić Monika , Kokanović Barbara , Ponjavić Ivana , Barišić Ivan , Šegvić Siniša , Ivec Arian , Tolić Iva M. 
Published: December 2020

SUMMARYForces produced by motor proteins and microtubule dynamics within the mitotic spindle are crucial for proper chromosome segregation. In addition to linear forces, rotational forces or torques are present in the spindle, reflected in the left-handed twisted shapes of microtubule bundles that make the spindle chiral. However, the biological role and molecular origins of spindle chirality are unknown. By developing methods for measuring spindle twist, we show that spindles are most chiral near the metaphase-to-anaphase transition. To assess the role of chirality in maintaining spindle robustness under force, we compressed the spindles along their axis. This resulted in stronger left-handed twist, suggesting that the twisted shape allows for a mechanical response to forces. Inhibition or depletion of motor proteins that perform chiral stepping, Eg5/kinesin-5, Kif18A/kinesin-8, MKLP1/kinesin-6, and dynein, decreased the left-handed twist or led to right-handed twist, implying that these motors regulate the twist by rotating microtubules within their antiparallel overlaps or at the spindle pole. Right-handed twist was also observed after the depletion of the microtubule nucleator augmin, indicating its contribution to the twist through the nucleation of antiparallel bridging microtubules. The uncovered switch from left-handed to right-handed twist reveals the existence of competing mechanisms that promote twisting in opposite directions. As round spindles were more twisted than elongated ones, we infer that bending and twisting moments are generated by similar molecular mechanisms and propose a physiological role for spindle chirality in allowing the spindle to absorb mechanical load.
Increased ketohexokinase-A governs fructose-induced podocyte hypertrophy by IL-6/STAT3 signaling activation
Authors: Zhou Jie , Zhang Dong-Mei , Yang Jie , Ding Hong , Li Tu-Shuai , Liu Zhi-Hong , Chen Li , Jiao Rui-Qing , Kong Ling-Dong 
Published: December 2020

AbstractGlomerular hypertrophy is crucial for podocyte damage and proteinuria. Our previous study showed that fructose induced podocyte injury. However, the molecular mechanism underlying podocyte hypertrophy under fructose is unclear. We observed that fructose significantly initiated the hypertrophy in rat glomeruli and cultured differentiated human podocytes (HPCs). Consistently, it induced inflammatory response with the down-regulation of zinc-finger protein tristetraprolin (TTP) and the activation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling in these animal and cell models. Subsequently, high-expression of miR-92a-3p and its target protein cyclin-dependent kinase inhibitor p57 (P57) down-regulation, representing the abnormal proliferation and apoptosis, were observedin vivoandin vitro. Moreover, fructose increased ketohexokinase-A (KHK-A) in rat glomeruli and HPCs. Animal-free recombinant human IL-6, maslinic acid andTTPsiRNA were used to manifest that fructose may decrease TTP to activate IL-6/STAT3 signaling in podocyte overproliferation and apoptosis, causing podocyte hypertrophy.KHK-AsiRNA transfection further demonstrated that the inactivation of IL-6/STAT3 to relieve podocyte hypertrophy mediated by inhibiting KHK-A to increase TTP may be a novel strategy for fructose-associated podocyte injury and proteinuria.Graphic Abstract
Effect of Cholesterol on Membrane Partitioning Dynamics of Hepatitis A Virus-2B peptide
Authors: Sikdar Samapan , Banerjee Manidipa , Vemparala Satyavani 
Published: December 2020

ABSTRACTUnderstanding the viral peptide detection, partitioning and subsequent host membrane composition-based response is required for gaining insights into viral mechanism. Here, we probe the crucial role of presence of membrane lipid packing defects, depending on the membrane composition, in allowing the viral peptide belonging to C-terminal Hepatitis A Virus-2B (HAV-2B) to detect, attach and subsequently partition into the host cell membrane mimics. We conclusively show that the hydrophobic residues in the viral peptide detect the transiently present lipid packing defects, insert themselves into such defects, form anchor points and facilitate the partitioning of the peptide. We also show that the presence of cholesterol significantly alters such lipid packing defects, both in size and in number, thus mitigating the partitioning of the membrane active viral peptide into cholesterol-rich membranes. These results show differential ways in which presence and absence of cholesterol can alter the permeability of the host membranes to the membrane active viral peptide component of HAV-2B virus, via lipid packing defects, and can possibly be a part of general membrane detection mechanism for the viroporin class of viruses.
Precision mapping of the mouse brain metabolome
Authors: Pang Huanhuan , Li Jun-Liszt , Hu Xiao-Ling , Chen Fei , Gao Xiaofei , Zacharias Lauren G. , Cai Feng , DeBerardinis Ralph J. , Sun Wenzhi , Hu Zeping , Ge Woo-ping 
Published: December 2020

AbstractMetabolism is physiologically fundamental to a biological system. Understanding brain metabolism is critical for our comprehensive knowledge of brain function in health and disease. Combining a microarray collection system with targeted metabolomics analysis, here we performed precision mapping of the metabolome in the mouse brain and created maps for 79 metabolites with a resolution of 0.125mm3per pixel (i.e., brain subregion). The metabolome atlas provides researchers with a useful resource to interpret the vulnerability of specific brain regions to various disease-relevant metabolic perturbations.
Priming of Myelin-Specific T Cells in the Absence of Dendritic Cells Results in Accelerated Development of Experimental Autoimmune Encephalomyelitis
Authors: Luu Thaiphi , Cheung Julie F. , Waldner Hanspeter 
Published: December 2020

AbstractExperimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), is predominantly mediated by pro-inflammatory CD4+T cell responses to CNS antigens, including myelin proteolipid protein (PLP). Dendritic cells (DCs) are considered critical for inducing T cell responses against infectious agents, but the importance of DCs in priming self-reactive CD4+ T cells in autoimmune disease such as MS has been unclear.To determine the requirement of DCs in PLP-specific CD4+T cell responses and EAE, we genetically deleted CD11c+DCs in PLP T cell receptor (TCR) transgenic SJL mice constitutively. DC deficiency did not impair the development, selection or the pathogenic function of PLP-specific CD4+T cells in these mice, and resulted in accelerated spontaneous EAE compared to DC sufficient controls. In addition, using a genetic approach to ablate DCs conditionally in SJL mice, we show that CD11c+DCs were dispensable for presenting exogenous or endogenous myelin antigen to PLP-specific T cells and for promoting pro-inflammatory T cell responses and severe EAE. Our findings demonstrate that constitutive or conditional ablation of CD11c+DCs diminished self-tolerance to PLP autoantigen. They further show that in the absence of DCs, non-DCs can efficiently present CNS myelin antigens such as PLP to self-reactive T cells, resulting in accelerated onset of spontaneous or induced EAE.
A computational model for investigating the evolution of colonic crypts during Lynch syndrome carcinogenesis
Authors: Haupt Saskia , Gleim Nils , Ahadova Aysel , Bläker Hendrik , von Knebel Doeberitz Magnus , Kloor Matthias , Heuveline Vincent 
Published: December 2020

Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, increases the cancer risk in affected individuals. LS is caused by pathogenic germline variants in one of the DNA mismatch repair (MMR) genes, complete inactivation of which causes numerous mutations in affected cells. As CRC is believed to originate in colonic crypts, understanding the intra-crypt dynamics caused by mutational processes is essential for a complete picture of LS CRC and may have significant implications for cancer prevention.We propose a computational model describing the evolution of colonic crypts during LS carcinogenesis. Extending existing modeling approaches for the non-Lynch scenario, we incorporated MMR deficiency and implemented recent experimental data demonstrating that somaticCTNNB1mutations are common drivers of LS-associated CRCs, if affecting both alleles of the gene. Further, we simulated the effect of different mutations on the entire crypt, distinguishing non-transforming and transforming mutations.As an example, we analyzed the spread of mutations in the genesAPCandCTNNB1, which are frequently mutated in LS tumors, as well as of MMR deficiency itself. We quantified each mutation’s potential for monoclonal conversion and investigated the influence of the cell location and of stem cell dynamics on mutation spread.Thein silicoexperiments underline the importance of stem cell dynamics for the overall crypt evolution. Further, simulating different mutational processes is essential in LS since mutations without survival advantages (the MMR deficiency-inducing second hit) play a key role. The effect of other mutations can be simulated with the proposed model. Our results provide first mathematical clues towards more effective surveillance protocols for LS carriers.
Come together: bioelectric healing-on-a-chip
Authors: Zajdel Tom J. , Shim Gawoon , Cohen Daniel J. 
Published: December 2020

AbstractThere is a growing interest in bioelectric wound treatment and electrotaxis, the process by which cells detect an electric field and orient their migration along its direction, has emerged as a potential cornerstone of the endogenous wound healing response. Despite recognition of the importance of electrotaxis in wound healing, no experimental system to date demonstrates that the actual closing of a wound can be accelerated solely by the electrotaxis response itself, and in vivo systems are too complex to resolve cell migration from other healing stages such as proliferation and inflammation. This uncertainty has led to a lack of standardization between stimulation methods, model systems, and electrode technology required for device development. In this paper, we present a ‘healing-on-chip’ approach that is a standardized, low-cost, model for investigating electrically accelerated wound healing. Our device provides the first convergent field geometry used in a stimulation device. We validate this device by using electrical stimulation to close a 1.5 mm gap between two large (30 mm2) primary skin keratinocyte layers to double the rate of healing over an unstimulated tissue. This proves that convergent electrotaxis is both possible and can accelerate healing, and offers a new ‘healing-on-a-chip’ platform to explore future bioelectric interfaces.
SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia
Authors: Olajide Olumayokun A , Iwuanyanwu Victoria U , Adegbola Oyinkansola D , Al-Hindawi Alaa A 
Published: December 2020

AbstractIn addition to respiratory complications produced by SARS-CoV-2, accumulating evidence suggests that some neurological symptoms are associated with the disease caused by this coronavirus. In this study, we investigated the effects of the SARS-CoV-2 spike protein S1 stimulation on neuroinflammation in BV-2 microglia. Analyses of culture supernatants revealed an increase in the production of TNFα, IL-6, IL-1β and iNOS/NO. S1 also increased protein levels of phospho-p65 and phospho-IκBα, as well as enhancing DNA binding and transcriptional activity of NF-κB. These effects of the protein were blocked in the presence of BAY11-7082 (1 μM). Exposure of S1 to BV-2 microglia also increased the protein levels of NLRP3 inflammasome and enhanced caspase-1 activity. Increased protein levels of p38 MAPK was observed in BV-2 microglia stimulated with the spike protein S1 (100 ng/mL), an action that was reduced in the presence of SKF 86002 (1 μM). Results of immunofluorescence microscopy showed an increase in TLR4 protein expression in S1-stimulated BV-2 microglia. Furthermore, pharmacological inhibition with TAK 242 (1 μM) and transfection with TLR4 siRNA resulted in significant reduction in TNFα and IL-6 production in S1-stimulated BV-2 microglia. These results have provided the first evidence demonstrating S1-induced neuroinflammation in BV-2 microglia. We propose that induction of neuroinflammation by this protein in the microglia is mediated through activation of NF-κB and p38 MAPK, possibly as a result of TLR4 activation. These results contribute to our understanding of some of the mechanisms involved in CNS pathologies of SARS-CoV-2.
Reduced complexity of brain and behavior due to MeCP2 disruption and excessive inhibition
Authors: Li Jingwen , Kells Patrick A. , Gautam Shree Hari , Shew Woodrow L. 
Published: December 2020

ABSTRACTRett syndrome (RTT) is a devastating neurodevelopmental disorder, caused by disruptions to the MECP2 gene, and resulting in severe cognitive and motor impairment. Previous work strongly suggests that healthy MECP2 function is required to have a normal balance between excitatory and inhibitory neurons. However, the details of how neural circuit dynamics and motor function are disrupted remain unclear. How might imbalanced E/I cause problems for motor function in RTT? We addressed this question in the motor cortex of awake, freely behaving rats, comparing normal rats with a transgenic rat model of RTT. We recorded single-unit spiking activity while simultaneously recording body movement of the rats. We found that RTT rats tend to have excessive synchrony among neurons in the motor cortex and less complex body movements. Importantly, greater synchrony was correlated with greater stereotypy of relationships between neurons and body movements. To further test how our observations were related to an E/I imbalance, we pharmacologically altered inhibitory synaptic interactions. We were able to recapitulate many of the phenomena we found in MECP2-deficient rats by enhancing inhibition in normal rats. Our results suggest that RTT-related E/I imbalance in the motor cortex gives rise to excessive synchrony and, consequently, a stereotyped motor code, which may underlie abnormal motor function in RTT.
Hundreds of motif pairs may facilitate enhancer-promoter interactions
Authors: Wang Saidi , Hu Haiyan , Li Xiaoman 
Published: December 2020

AbstractPrevious studies have shown that pairs of interacting transcription factors (TFs) bind to enhancers and promoters and contribute to their physical interactions. However, to date, we have limited knowledge about these interacting TF pairs. To identify such TF pairs, we systematically studied the co-occurrence of TF-binding motifs in interacting enhancer-promoter (EP) pairs in seven human cell lines. We discovered hundreds of motif pairs that significantly co-occur in enhancers and promoters of interacting EP pairs. We demonstrated that these motif pairs are biologically meaningful and significantly enriched with motif pairs of known interacting TF pairs. We also showed that the identified motif pairs facilitated the discovery of the interacting EP pairs. The predicted motifs and motif pairs are available athttp://www.cs.ucf.edu/~xiaoman/ET/EPmotif/.
IHR-PVS National Bridging Workshops, a tool to operationalize the collaboration between human and animal health while advancing sector-specific goals in countries
Authors: Belot Guillaume , Caya François , Errecaborde Kaylee Myhre , Traore Tieble , Lafia Brice , Skrypnyk Artem , Montabord Djhane , Carron Maud , Corning Susan , Sreedharan Rajesh , Isla Nicolas , Schmidt Tanja , Gongal Gyanendra , Samhouri Dalia , Perez-Gutierrez Enrique , Riviere-Cinnamond Ana , Xing Jun , Chungong Stella , de la Rocque Stephane 
Published: December 2020

AbstractCollaborative, One Health approaches support governments to effectively prevent, detect and respond to emerging health challenges, such as zoonotic diseases, that arise at the human-animal-environmental interfaces. To overcome these challenges, operational and outcome-oriented tools that enable animal health and human health services to work specifically on their collaboration are required. While international capacity and assessment frameworks such as the IHR-MEF (International Health Regulations - Monitoring and Evaluation Framework) and the OIE PVS (Performance of Veterinary Services) Pathway exist, a tool and process that could assess and strengthen the interactions between human and animal health sectors was needed. Through a series of six phased pilots, the IHR-PVS National Bridging Workshop (NBW) method was developed and refined. The NBW process gathers human and animal health stakeholders and follows seven sessions, scheduled across three days. The outputs from each session build towards the next one, following a structured process that goes from gap identification to joint planning of corrective measures. The NBW process allows human and animal health sector representatives to jointly identify actions that support collaboration while advancing evaluation goals identified through the IHR-MEF and the OIE PVS Pathway. By integrating sector-specific and collaborative goals, the NBWs help countries in creating a realistic, concrete and practical joint road map for enhanced compliance to international standards as well as strengthened preparedness and response for health security at the human-animal interface.