bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ancestry-Specific Predisposing Germline Variants in Cancer
Authors: Oak Ninad , Cherniack Andrew D. , Mashl R. Jay ,   TCGA Analysis Network, Hirsch Fred R. , Ding Li , Beroukhim Rameen , Gümüş Zeynep H. , Plon Sharon E. , Huang Kuan-lin 
Published: April 2020

AbstractBackgroundCancer risk differs across ancestries and these differences may result from differing prevalence of inherited genetic predisposition. Yet, most germline genomic studies performed to date have focused on individuals of European ancestry. Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis for each ancestral group. Here, we investigate potentially germline pathogenic variants in cancer predisposition genes (CPG) and their somatic effects in patients across diverse ancestral backgrounds.MethodsWe performed a retrospective analysis of germline genomic data of 9,899 patients from 33 cancer types generated by The Cancer Genome Atlas (TCGA) project along with matching somatic genomic and transcriptomic data. By collapsing pathogenic and likely pathogenic variants to the gene level, we analyzed the association between variants in CPGs and cancer types within each ancestry. We also identified ancestry- specific predisposing variants and their associated somatic two-hit events and gene expression levels.ResultsRecent genetic ancestry analysis classified the cohort of 9,899 cancer cases into individuals of primarily European, (N = 8,184, 82.7%), African (N = 966, 9.8%), East Asian (N = 649, 6.6%), South Asian (N=48, 0.5%), Native/Latin American (N=41, 0.4%), and admixed (N=11, 0.1%) ancestries. In the African ancestry, we discovered a potentially novel association ofBRCA2in lung squamous cell carcinoma (OR = 41.4 [95% CI, 6.1-275.6]; FDR = 0.002) along with the previously identified association ofBRCA2in ovarian serous cystadenocarcinoma (OR=8.5 [95% CI, 1.5-47.4]; FDR=0.045). Similarly, in the East Asian ancestry, we discovered one previously known association ofBRIP1in stomach adenocarcinoma (OR=12.8 [95% CI, 1.8-90.84]; FDR=0.038). Rare variant burden analysis further identified 7 suggestive associations for cancer-gene pairs in African ancestry individuals previously well described in European ancestry includingSDHBin pheochromocytoma and paraganglioma,ATMin prostate adenocarcinoma,VHLin kidney renal clear cell carcinoma,FHin kidney renal papillary cell carcinoma, andPTENin uterine corpus endometrial carcinoma. Loss of heterozygosity was identified for 7 out of the 15 African ancestry carriers of predisposing variants. Further, tumors from theSDHBorBRCA2carriers showed simultaneous allelic specific expression and low gene expression of their respective affected genes; andFHsplice-site variant carriers showed mis-splicing ofFH.ConclusionWhile several predisposing genes are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects. Analysis of larger diverse ancestries genomic cohorts are required to pinpoint ancestry- specific genetic predisposition to inform personalized diagnosis and screening strategies.
Multidrug treatment with nelfinavir and cepharanthine against COVID-19
Authors: Ohashi Hirofumi , Watashi Koichi , Saso Wakana , Shionoya Kaho , Iwanami Shoya , Hirokawa Takatsugu , Shirai Tsuyoshi , Kanaya Shigehiko , Ito Yusuke , Kim Kwang Su , Nishioka Kazane , Ando Shuji , Ejima Keisuke , Koizumi Yoshiki , Tanaka Tomohiro , Aoki Shin , Kuramochi Kouji , Suzuki Tadaki , Maenaka Katsumi , Matano Tetsuro , Muramatsu Masamichi , Saijo Masayuki , Aihara Kazuyuki , Iwami Shingo , Takeda Makoto , McKeating Jane A. , Wakita Takaji 
Published: April 2020

SummaryAntiviral treatments targeting the emerging coronavirus disease 2019 (COVID-19) are urgently required. We screened a panel of already-approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new antiviral agents: the HIV protease inhibitor Nelfinavir and the anti-inflammatory drug Cepharanthine.In silicomodeling shows Nelfinavir binds the SARS-CoV-2 main protease consistent with its inhibition of viral replication, whilst Cepharanthine inhibits viral attachment and entry into cells. Consistent with their different modes of action,in vitroassays highlight a synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation. Mathematical modeling in vitro antiviral activity coupled with the known pharmacokinetics for these drugs predicts that Nelfinavir will facilitate viral clearance. Combining Nelfinavir/Cepharanthine enhanced their predicted efficacy to control viral proliferation, to ameliorate both the progression of disease and risk of transmission. In summary, this study identifies a new multidrug combination treatment for COVID-19.
The relative densities of cell cytoplasm, nucleoplasm, and nucleoli are robustly conserved during cell cycle and drug perturbations
Authors: Kim Kyoohyun , Guck Jochen 
Published: April 2020

AbstractThe cell nucleus is a compartment in which essential processes such as gene transcription and DNA replication occur. While the large amount of chromatin confined in the finite nuclear space could install the picture of a particularly dense organelle surrounded by less dense cytoplasm, recent studies have begun to report the opposite. However, the generality of this newly emerging, opposite picture has so far not been tested. Here, we used combined optical diffraction tomography (ODT) and epi-fluorescence microscopy to systematically quantify the mass densities of cytoplasm, nucleoplasm, and nucleoli of human cell lines, challenged by various perturbations. We found that the nucleoplasm maintains a lower mass density than cytoplasm during cell cycle progression by scaling its volume to match the increase of dry mass during cell growth. At the same time, nucleoli exhibited a significantly higher mass density than the cytoplasm. Moreover, actin and microtubule depolymerization and changing chromatin condensation altered volume, shape, and dry mass of those compartments, while the relative distribution of mass densities was generally unchanged. Our findings suggest that the relative mass densities across membrane-bound and membraneless compartments are robustly conserved, likely by different as of yet unknown mechanisms, which hints at an underlying functional relevance. This surprising robustness of mass densities contributes to an increasing recognition of the importance of physico-chemical properties in determining cellular characteristics and compartments.
Sleep Induction by Mechanosensory Stimulation inDrosophila
Authors: Öztürk-Çolak Arzu , McClanahan Patrick D. , Buchler Joseph R. , Inami Sho , Cruz Andri , Fang-Yen Christopher , Koh Kyunghee 
Published: April 2020

SummaryPeople tend to fall asleep when gently rocked or vibrated. Experimental studies have shown rocking promotes sleep in humans and mice. The prevailing “synchronization” model proposes synchronization of brain activity to mechanosensory stimuli mediates the phenomenon. The alternative “habituation” model proposes habituation, a form of non-associative learning, mediates sleep induction by monotonous stimulation. Here we show that gentle vibration promotes sleep inDrosophilain part through habituation. Vibration-induced sleep (VIS) leads to the accrual of homeostatic sleep credit, is associated with reduced arousability, and can be suppressed by heightened arousal. Sleep induction improves over successive blocks of vibration and exhibits stimulus specificity, supporting the habituation model. Multiple mechanosensory organs mediate VIS, and the magnitude of sleep gain depends on the vibration frequency and genetic background. Our findings suggest habituation is a major contributor to VIS, but synchronization of brain activity may play a role under certain stimulus conditions.
The capacity of the ovarian cancer tumor microenvironment to integrate inflammation signaling conveys a shorter disease-free interval
Authors: Jordan Kimberly R. , Sikora Matthew J. , Slansky Jill E. , Minic Angela , Richer Jennifer K , Moroney Marisa R. , Costello James C. , Clauset Aaron , Behbakht Kian , Kumar T. Rajendra , Bitler Benjamin G. 
Published: April 2020

ABSTRACTOvarian cancer has one of the highest deaths to incidence ratios across all cancers. Initial chemotherapy is typically effective, but most patients will develop chemo-resistant disease. Mechanisms driving clinical chemo-response and -resistance in ovarian cancer are not well understood. However, achieving optimal surgical cytoreduction improves survival, and cytoreduction is improved by neoadjuvant platinum/taxane-based chemotherapy (NACT). NACT offers a window to profile pre-versus post-therapy tumor specimens, which we used to identify chemotherapy-induced changes to the tumor microenvironment. We hypothesized changes in the immune microenvironment correlate with tumor chemo-response and disease progression. We obtained matched pre- and post-NACT archival tumor tissues from patients with high-grade serous ovarian cancer (patient n=6). We measured mRNA levels of 770 genes (NanoString), and performed reverse phase protein array (RPPA) on a subset of matched tumors. We examined cytokine levels in additional pre-NACT ascites samples (n=39) by multiplex ELISA. A tissue microarray with 128 annotated ovarian tumors expanded the transcriptional, RPPA, and cytokine data by multi-spectral immunohistochemistry. In NanoString analyses, transcriptional profiles segregated based on pre- and post-NACT status. The most upregulated gene post-NACT wasIL6(17.1-fold, adjusted p = 0.045). RPPA data were highly concordant with mRNA, consistent with elevated immune infiltration. Elevated IL-6 in pre-NACT ascites specimens correlated with a shorter time to recurrence. Integrating NanoString, RPPA, and cytokine studies identified an activated inflammatory signaling network and inducedIL6andIER3(Immediate Early Response 3) post-NACT, associated with poor chemo-response and decreased time to recurrence. Taken together, multi-omic profiling of ovarian tumor samples before and after NACT provides unique insight into chemo-induced changes to the tumor and microenvironment. We integrated transcriptional, proteomic, and cytokine data and identified a novel IL-6/IER3 signaling axis through increased inflammatory signaling which may drive ovarian cancer chemo-resistance.
Molecular recognition and dynamics of linear poly-ubiquitins: integrating coarse-grain simulations and experiments
Authors: Jussupow Alexander , Messias Ana C. , Stehle Ralf , Geerlof Arie , Solbak Sara M. Ø. , Bach Anders , Sattler Michael , Camilloni Carlo 
Published: April 2020

AbstractPoly-ubiquitin chains are flexible multidomain proteins, whose conformational dynamics enable their molecular recognition by a large number of partners in multiple biological pathways. By using alternative linkage, it is possible to obtain poly-ubiquitin molecules with different dynamical properties. This flexibility is further increased by the possibility to tune the length of poly-ubiquitin chains. Characterizing the dynamics of poly-ubiquitins as a function of their length is thus relevant to understand their biology. Structural characterization of poly-ubiquitin conformational dynamics is challenging both experimentally and computationally due to increasing system size and conformational variability. Here, by developing highly efficient and accurate small-angle X-ray scattering driven Martini coarse-grain simulations, we characterize the dynamics of linear M1-linked di-, tri- and tetra-ubiquitin chains. Our data show that the behavior of the di-ubiquitin subunits is independent of the presence of additional ubiquitin modules. We propose that the conformational space sampled by linear poly-ubiquitins, in general, may follow a simple self-avoiding polymer model. These results, combined with experimental data from small angle X-ray scattering, biophysical techniques and additional simulations show that binding of NEMO, a central regulator in the NF-κB pathway, to linear poly-ubiquitin obeys a 2:1 (NEMO:poly-ubiquitin) stoichiometry in solution, even in the context of four ubiquitin units. Eventually, we show how the conformational properties of long poly-ubiquitins may modulate the binding with their partners in a length-dependent manner.SignificanceProtein conformational dynamics plays an essential role in molecular recognition mechanisms. The characterization of conformational dynamics is hampered by the conformational averaging of observable in experimental structural biology techniques and by the limitations in the accuracy of computational methods. By developing an efficient and accurate approach to combine small-angle X-ray scattering solution experiments and coarse-grain Martini simulations, we show that the conformational dynamics of linear poly-ubiquitins can be efficiently determined and to rationalize the role of poly-ubiquitin dynamic in the molecular recognition of the UBAN domain upon binding to the signaling regulator NEMO. The analysis of the conformational ensembles allows us to propose a general model of the dynamics of linear poly-ubiquitin chains where they can be described as a self-avoiding polymer with a characteristic length associated with their specific linkage.
Genetic Variability of Human Angiotensin-Converting Enzyme 2 (hACE2) Among Various Ethnic Populations
Authors: Li Quan , Cao Zanxia , Rahman Proton 
Published: April 2020

AbstractThere appears to be large regional variations for susceptibility, severity and mortality for Covid-19 infections. We set out to examine genetic differences in the human angiotensin-converting enzyme 2 (hACE2) gene, as its receptor serves as a cellular entry for SARS- CoV-2. By comparing 56,885 Non-Finnish European and 9,197 East Asians (including 1,909 Koreans) four missense mutations were noted in the hACE2 gene. Molecular dynamic demonstrated that two of these variants (K26R and I468V) may affect binding characteristics between S protein of the virus and hACE2 receptor. We also examined hACE2 gene expression in eight global populations from the HapMap3 and noted marginal differences in expression for some populations as compared to the Chinese population. However, for both of our studies, the magnitude of the difference was small and the significance is not clear in the absence of further in vitro and functional studies.
Genome based Evolutionary study of SARS-CoV-2 towards the Prediction of Epitope Based Chimeric Vaccine
Authors: Nazneen Akhand Mst Rubaiat , Azim Kazi Faizul , Hoque Syeda Farjana , Moli Mahmuda Akther , Joy Bijit Das , Akter Hafsa , Afif Ibrahim Khalil , Ahmed Nadim , Hasan Mahmudul 
Published: April 2020

AbstractSARS-CoV-2 is known to infect the neurological, respiratory, enteric, and hepatic systems of human and has already become an unprecedented threat to global healthcare system. COVID-19, the most serious public condition caused by SARS-CoV-2 leads the world to an uncertainty alongside thousands of regular death scenes. Unavailability of specific therapeutics or approved vaccine has made the recovery of COVI-19 more troublesome and challenging. The presentin silicostudy aimed to predict a novel chimeric vaccines by simultaneously targeting four major structural proteins via the establishment of ancestral relationship among different strains of coronaviruses. Conserved regions from the homologous protein sets of spike glycoprotein (S), membrane protein (M), envelope protein and nucleocapsid protein (N) were identified through multiple sequence alignment. The phylogeny analyses of whole genome stated that four proteins (S, E, M and N) reflected the close ancestral relation of SARS-CoV-2 to SARS-COV-1 and bat coronavirus. Numerous immunogenic epitopes (both T cell and B cell) were generated from the common fragments which were further ranked on the basis of antigenicity, transmembrane topology, conservancy level, toxicity and allergenicity pattern and population coverage analysis. Top putative epitopes were combined with appropriate adjuvants and linkers to construct a novel multiepitope subunit vaccine against COVID-19. The designed constructs were characterized based on physicochemical properties, allergenicity, antigenicity and solubility which revealed the superiority of construct V3 in terms safety and efficacy. Essential molecular dynamics and Normal Mode analysis confirmed minimal deformability of the refined model at molecular level. In addition, disulfide engineering was investigated to accelerate the stability of the protein. Molecular docking study ensured high binding affinity between construct V3 and HLA cells, as well as with different host receptors. Microbial expression and translational efficacy of the constructs were checked using pET28a(+) vector ofE. colistrain K12. The development of preventive measures to combat COVID-19 infections might be aided the present study. However, thein vivoandin vitrovalidation might be ensured with wet lab trials using model animals for the implementation of the presented data.
TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets
Authors: Bestle Dorothea , Heindl Miriam Ruth , Limburg Hannah , van Thuy Van Lam , Pilgram Oliver , Moulton Hong , Stein David A. , Hardes Kornelia , Eickmann Markus , Dolnik Olga , Rohde Cornelius , Becker Stephan , Klenk Hans-Dieter , Garten Wolfgang , Steinmetzer Torsten , Böttcher-Friebertshäuser Eva 
Published: April 2020

AbstractIn December 2019, a novel coronavirus named SARS-CoV-2 first reported in Wuhan, China, emerged and rapidly spread to numerous other countries globally, causing the current pandemic. SARS-CoV-2 causes acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. Currently, there is no approved antiviral drug for treating COVID-19 patients and there is an urgent need for specific antiviral therapies and vaccines.In order for SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study we investigated which host cell proteases activate the SARS-CoV-2 S protein in Calu-3 human airway epithelial cells. We show that S can be cleaved by both the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2’ site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 cells through antisense-mediated knockdown of TMPRSS2 expression. Further, we show that SARS-CoV-2 replication can be efficiently inhibited by two synthetic inhibitors of TMPRSS2 and also by the broad range serine protease inhibitor aprotinin. Additionally, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851. Combining various TMPRSS2 inhibitors with MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication.Our data demonstrate that both TMPRSS2 and furin are essential for SARS-CoV-2 activation in human airway cells and are promising drug targets for the treatment of COVID-19 either by targeting one of these proteases alone or by a combination of furin and TMPRSS2 inhibitors. Therefore, this approach has a high therapeutic potential for treatment of COVID-19.
Automated docking refinement and virtual compound screening with absolute binding free energy calculations
Authors: Heinzelmann Germano , Gilson Michael K. 
Published: April 2020

AbstractAbsolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we introduce the software BAT.py, a Python tool that invokes the AMBER simulation package to fully automate the calculation of binding free energies for a protein with a series of ligands. We report encouraging initial test applications of this software both to re-rank docked poses and to estimate overall binding free energies. We also show that it is practical to carry out these calculations cheaply by using graphical processing units in common machines that can be built for this purpose. The combination of automation and low cost allows this procedure to be applied in a relatively high-throughput mode, and thus enables new applications in early-stage drug discovery.
Autonomous performance maximization of research-based hybrid unmanned aerial vehicle
Authors: Çoban Sezer 
Published: April 2020

Purpose
This paper aims to investigate the autonomous performance optimization of a research-based hybrid unmanned aerial vehicle (i.e. HUAV) manufactured at Iskenderun Technical University.

Design/methodology/approach
To maximize the autonomous performance of this HUAV, longitudinal and lateral dynamics were initially obtained. Then, the optimum magnitudes of the autopilot system parameters were estimated by considering the vehicle’s dynamic model and autopilot parameters.

Findings
After determining the optimum values of the longitudinal and lateral autopilots, an improved design for the autonomously controlled (AC) HUAV was achieved in terms of real-time flight.

Practical implications
Simultaneous improvement of the longitudinal and lateral can be used for better HUAV operations.

Originality/value
In this paper, the autopilot systems (i.e. longitudinal and lateral) of an HUAV are for the first time simultaneously designed in the literature. This helps the simultaneous improvement of the longitudinal and lateral flight trajectory tracking performances.
Discussion of Troubled Asset Relief Program and earnings informativeness
Authors: Zhou Nan 
Published: April 2020

PurposeVega et al. (2020) find that incentives in executive compensation result in higher earnings informativeness. The discussion focuses on two areas for improvement. First, the authors could look into additional measures of earnings quality. This further analysis could help us understand whether the enhanced earning informativeness stems from capital market effects or real effects. Second, the authors could consider replacing their main earnings response coefficient (ERC) model with one of the alternative ERC models in the literature. Three different ERC models are discussed.Design/methodology/approachThis paper discusses capital market effects versus real effects and illustrates different ERC models.FindingsThe discussed paper could differentiate between capital market effects and real effects and use an alternative ERC model.Originality/valueAn accounting audience could be interested in the discussion on capital market effects versus real effects and the illustration on various ERC models.