bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small-molecule antibiotic inhibitors of post-translational protein secretion
Authors: Hamed Mohamed Belal , Burchacka Ewa , Angus Liselotte , Marchand Arnaud , De Geyter Jozefien , Loos Maria S. , Anné Jozef , Klaassen Hugo , Chaltin Patrick , Karamanou Spyridoula , Economou Anastassios 
Published: November 2020

AbstractThe increasing problem of bacterial resistance to antibiotics underscores the urgent need for new antibacterials. The Sec preprotein export pathway is an attractive potential alternative target. It is essential for bacterial viability and includes components that are absent from eukaryotes. Here we used a new high throughputin vivoscreen based on the secretion and activity of alkaline phosphatase (PhoA), a Sec-dependent secreted enzyme that becomes active in the periplasm. The assay was optimized for a luminescence-based substrate and was used to screen a ~240K small molecule compound library. After hit confirmation and analoging, fourteen HTS secretion inhibitors (HSI), belonging to 8 structural classes, were identified (IC50<60 μM). The inhibitors were also evaluated as antibacterials against 19 Gram−and Gram+bacterial species (including those from the WHO top pathogens list). Seven of them, HSI#6, 9; HSI#1, 5, 10 and HSI#12, 14 representing three structural families were microbicidals. HSI#6 was the most potent (IC50of 0.4-8.7 μM), against 13 species of both Gram−and Gram+bacteria. HSI#1, 5, 9 and 10 inhibited viability of Gram+bacteria with IC50~6.9-77.8 μM. HSI#9, 12 and 14 inhibited viability ofE. colistrains with IC50<65 μM. Moreover, HSI#1, 5 and 10 inhibited viability of anE. colistrain missing TolC to improve permeability with IC504-14 μM, indicating their inability to penetrate the outer membrane.In vitroassays revealed that antimicrobial activity was not related to inhibition of the SecA component of the translocase and hence HSI molecules may target new unknown components that affect secretion. The results provide proof of principle for our approach, and new starting compounds for optimization.
Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice
Authors: Cohen Alexander A. , Gnanapragasam Priyanthi N.P. , Lee Yu E. , Hoffman Pauline R. , Ou Susan , Kakutani Leesa M. , Keeffe Jennifer R. , Wu Hung-Jen , Howarth Mark , West Anthony P. , Barnes Christopher O. , Nussenzweig Michel C. , Bjorkman Pamela J. 
Published: November 2020

AbstractProtection against SARS-CoV-2 and SARS-related emergent zoonotic coronaviruses is urgently needed. We made homotypic nanoparticles displaying the receptor-binding domain (RBD) of SARS-CoV-2 or co-displaying SARS-CoV-2 RBD along with RBDs from animal betacoronaviruses that represent threats to humans (mosaic nanoparticles; 4-8 distinct RBDs). Mice immunized with RBD-nanoparticles, but not soluble antigen, elicited cross-reactive binding and neutralization responses. Mosaic-RBD-nanoparticles elicited antibodies with superior cross-reactive recognition of heterologous RBDs compared to sera from immunizations with homotypic SARS-CoV-2–RBD-nanoparticles or COVID-19 convalescent human plasmas. Moreover, sera from mosaic-RBD–immunized mice neutralized heterologous pseudotyped coronaviruses equivalently or better after priming than sera from homotypic SARS-CoV-2–RBD-nanoparticle immunizations, demonstrating no immunogenicity loss against particular RBDs resulting from co-display. A single immunization with mosaic-RBD-nanoparticles provides a potential strategy to simultaneously protect against SARS-CoV-2 and emerging zoonotic coronaviruses.One sentence summaryNanoparticle strategy for pan-sarbecovirus vaccine125-character summary for online ToCImmunizing with nanoparticles displaying diverse coronavirus RBDs elicits cross-reactive and neutralizing antibody responses.
Functional modulation of T follicular cellsin vivoenhances antigen-specific humoral immunity
Authors: Pagan Jose D. , Vlamakis Hera , Gaca Anthony , Xavier Ramnik , Anthony Robert M. 
Published: November 2020

AbstractGeneration of high-affinity IgG is essential for defense against infections and cancer, is the intended consequence of many vaccines, but can cause autoimmune and inflammatory diseases when inappropriately directed against self (Wang et al., 2018, Ludwig et al., 2017, Chinen et al., 2010). The interplay and balance of T follicular helper cells (TFH) and T follicular regulatory cells (TFR) is critical for production of high-affinity IgG (Wing et al., 2018). Here, we empowered TFHcells and improve antigen-specific IgG responses with two interventions intended to transiently diminish TFRinfluence. First, adult mice were administered an antibiotic cocktail (ABX) for an extended period to deplete the immunoregulatory intestinal microbiota (Belkaid and Harrison, 2017, Thaiss et al., 2016, Rooks and Garrett, 2016, Honda and Littman, 2016, Perruzza et al., 2017, Teng et al., 2016, Block et al., 2016, Proietti et al., 2014, Slack et al., 2014). This treatment skewed T follicular cell ratios, with increased TFHand reduced TFRnumbers. TNP-KLH immunization resulted in higher affinity TNP-specific IgG in ABX mice compared to controls. In a model of IgG-driven inflammatory nephritis, ABX mice had significantly worse nephritis accompanied by higher affinity antigen-specific IgG, and enriched TFHcells compared to controls. Second, we sought to functionally manipulate TFHand TFHcells, which both express the checkpoint inhibitory molecule, PD-1 (Sage et al., 2013), by administration of α-PD-1 during immunization. This intervention enhanced the affinity of antigen-specific IgG and increased in TFHfollowing TNP-KLH immunization and nephritis induction. These results suggest that altering TFHand TFRratio during immunization is an appealing strategy to qualitatively improve IgG responses.
Structural interpretation of the effects of threo-nucleotides on nonenzymatic template-directed polymerization
Authors: Zhang Wen , Kim Seohyun Chris , Tam Chun Pong , Lelyveld Victor S. , Bala Saikat , Chaput John C. , Szostak Jack W. 
Published: November 2020

ABSTRACTThe prebiotic synthesis of ribonucleotides is likely to have been accompanied by the synthesis of noncanonical nucleotides including the threo-nucleotide building blocks of TNA. Here we examine the ability of activated threo-nucleotides to participate in nonenzymatic template-directed polymerization. We find that primer extension by multiple sequential threo-nucleotide monomers is strongly disfavored relative to ribo-nucleotides. Kinetic, NMR and crystallographic studies suggest that this is due in part to the slow formation of the imidazolium-bridged TNA dinucleotide intermediate in primer extension, and in part because of the greater distance between the attacking RNA primer 3’-hydroxyl and the phosphate of the incoming threo-nucleotide intermediate. Even a single activated threo-nucleotide in the presence of an activated downstream RNA oligonucleotide is added to the primer ten-fold more slowly than an activated ribonucleotide. In contrast, a single activated threo-nucleotide at the end of an RNA primer or in an RNA template results in only a modest decrease in the rate of primer extension, consistent with the minor and local structural distortions revealed by crystal structures. Our results are consistent with a model in which heterogeneous primordial oligonucleotides would, through cycles of replication, have given rise to increasingly homogeneous RNA strands.
Structure of the mycobacterial ESX-5 Type VII Secretion System hexameric pore complex
Authors: Beckham Kathrine S. H. , Ritter Christina , Chojnowski Grzegorz , Mullapudi Edukondalu , Rettel Mandy , Savitski Mikhail M. , Mortensen Simon A. , Kosinski Jan , Wilmanns Matthias 
Published: November 2020

AbstractTo establish an infection, pathogenic mycobacteria use the Type VII secretion or ESX system to secrete virulence proteins across their cell envelope. The five ESX systems (ESX-1 to ESX-5) have evolved diverse functions in the cell, with the ESX-5 found almost exclusively in pathogens. Here we present a high-resolution cryo-electron microscopy structure of the hexameric ESX-5 Type VII secretion system. This 2.1 MDa membrane protein complex is built by a total of 30 subunits from six protomeric units, which are composed of the core components EccB5, EccC5, two copies of EccD5, and EccE5. The hexameric assembly of the overall ESX-5 complex is defined by specific inter-protomer interactions mediated by EccB5and EccC5. The central transmembrane pore is formed by six pairs of EccC5transmembrane helices that adopt a closed conformation in the absence of substrate in our structure. On the periplasmic face of the ESX-5 complex, we observe an extended arrangement of the six EccB5subunits around a central cleft. Our structural findings provide molecular details of ESX-5 assembly and observations of the central secretion pore, which reveal insights into possible gating mechanisms used to regulate the transport of substrates.
High Spatial-Resolution Imaging of the Dynamics of Cuticular Lipid Deposition During Arabidopsis Flower Development
Authors: Alexander Liza Esther , Gilbertson Jena S. , Xie Bo , Song Zhihong , Nikolau Basil J. 
Published: November 2020

ABSTRACTThe extensive collection ofglossy(gl) andeceriferum(cer) mutants of maize and Arabidopsis have proven invaluable in dissecting the branched metabolic pathways that support cuticular lipid deposition. This branched pathway integrates the fatty acid elongation-decarbonylative branch and the fatty acid elongation-reductive branch that has the capacity to generate hundreds of cuticular lipid metabolites. In this study a combined transgenic and biochemical strategy was implemented to explore and compare the physiological function of three homologous genes,Gl2, Gl2-likeandCER2in the context of this branched pathway. These biochemical characterizations integrated new extraction-chromatographic procedures with high-spatial resolution mass spectrometric imaging methods to profile the cuticular lipids on developing floral tissues transgenically expressing these transgenes in wild-type orcer2mutant lines of Arabidopsis. Collectively, these datasets establish that both the maizeGl2andGl2-likegenes are functional homologs of the ArabidopsisCER2gene. In addition, the dynamic distribution of cuticular lipid deposition follows distinct floral organ localization patterns indicating that the fatty acid elongation-decarbonylative branch of the pathway is differentially localized from the fatty acid elongation-reductive branch of the pathway.
Reproductive compensation and selection among viable embryos drive the evolution of polyembryony
Authors: Brandvain Yaniv J , Harkness Alexander J , Pyhäjärvi Tanja 
Published: November 2020

AbstractSimple polyembryony – where one gametophyte produces multiple embryos with different sires but the same maternal haplotype – is common among vascular plants. We show that together polyembryony’s two benefits – “reproductive compensation” achieved by providing a backup for inviable embryos, and the opportunity to favor the fitter of surviving embryos, can favor the evolution of polyembryony. To do so, we develop an infinite-site, forward population genetics model to test how these factors can favor the evolution of polyembryony, and how these underlying benefits of polyembryony shape the genetic load under a range of biological parameters. While these two benefits are difficult to disentangle in nature, we construct variant models of polyembryony that either only include or only exclude the opportunity for reproductive compensation. We find that reproductive compensation strongly favors the evolution of polyembryony, and that polyembryony is favored much more weekly in its absence, suggesting that the benefit of a backup embryo is the force favoring polyembryony. Remarkably we find nearly identical results in cases in which mutations impact either embryo or post-embryonic fitness (no pleiotropy), and in cases in which mutations have identical fitness effects embryo or post-embryonic fitness (extreme pleiotropy). Finally, we find that the consequences of polyembryony depends on its function – polyembryony results in a decrease in mean embryonic fitness when acting as a mechanism of embryo compensation, and ultimately increases mean embryonic fitness when we exclude this potential benefit.Nature is, above all, profligate. Don’t believe them when they tell you how economical and thrifty nature is.– Annie Dillard 1974.
Robustness of phylogenetic inference to model misspecification caused by pairwise epistasis
Authors: Magee Andrew F. , Hilton Sarah K. , DeWitt William S. 
Published: November 2020

AbstractLikelihood-based phylogenetic inference posits a probabilistic model of character state change along branches of a phylogenetic tree. These models typically assume statistical independence of sites in the sequence alignment. This is a restrictive assumption that facilitates computational tractability, but ignores how epistasis, the effect of genetic background on mutational effects, influences the evolution of functional sequences. We consider the effect of using a misspecified site-independent model on the accuracy of Bayesian phylogenetic inference in the setting of pairwise-site epistasis. Previous work has shown that as alignment length increases, tree reconstruction accuracy also increases. Here, we present a simulation study demonstrating that accuracy increases with alignment size even if the additional sites are epistatically coupled. We introduce an alignment-based test statistic that is a diagnostic for pair-wise epistasis and can be used in posterior predictive checks.
14-3-3 mitigates alpha-synuclein aggregation and toxicity in thein vivopreformed fibril model
Authors: Underwood Rachel , Gannon Mary , Pathak Aneesh , Kapa Navya , Chandra Sidhanth , Klop Alyssa , Yacoubian Talene A. 
Published: November 2020

AbstractAlpha-synuclein (αsyn) is the key component of proteinaceous aggregates termed Lewy Bodies (LBs) that pathologically define a group of disorders known as synucleinopathies, including Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB). αSyn is hypothesized to misfold and spread throughout the brain in a prion-like fashion. Transmission of αsyn necessitates the release of misfolded αsyn from one cell and the uptake of that αsyn by another, in which it can template the misfolding of endogenous αsyn upon cell internalization. 14-3-3 proteins are a family of highly expressed brain proteins that are neuroprotective in multiple PD models. We have previously shown that 14-3-3θ acts as a chaperone to reduce αsyn aggregation, cell-to-cell transmission, and neurotoxicity in thein vitropre-formed fibril (PFF) model. In this study, we expanded our studies to test the impact of 14-3-3s on αsyn toxicity in thein vivoαsyn PFF model. We used both transgenic expression models and adenovirus associated virus (AAV)-mediated expression to examine whether 14-3-3 manipulation impacts behavioral deficits, αsyn aggregation, and neuronal loss in the PFF model. 14-3-3θ transgene overexpression in cortical and amygdala regions rescued social dominance deficits induced by PFFs at 6 months post injection, whereas 14-3-3 inhibition by transgene expression of the competitive 14-3-3 peptide inhibitor difopein in the cortex and amygdala accelerated social dominance deficits. The behavioral rescue by 14-3-3θ overexpression was associated with delayed αsyn aggregation induced by PFFs in these brain regions. Conversely, 14-3-3 inhibition by difopein in the cortex and amygdala accelerated αsyn aggregation and cortical pyramidal neuron loss induced by PFFs. 14-3-3θ overexpression by AAV in the substantia nigra (SN) also delayed αsyn aggregation in the SN and partially rescued PFF-induced dopaminergic cell loss in the SN. 14-3-3 inhibition in the SN accelerated nigral αsyn aggregation and increased PFF-induced dopaminergic cell loss. These data indicate a neuroprotective role for 14-3-3θ against αsyn toxicityin vivo.
Transient genomic instability drives tumorigenesis through accelerated clonal evolution
Authors: Shoshani Ofer , Bakker Bjorn , Wang Yin , Kim Dong Hyun , Maldonado Marcus , Demarest Matthew A. , Artates Jon , Zhengyu Ouyang , Mark Adam , Wardenaar Rene , Sasik Roman , Spierings Diana C.J. , Vitre Benjamin , Fisch Kathleen , Foijer Floris , Cleveland Don W. 
Published: November 2020

AbstractAbnormal numerical and structural chromosome content is frequently found in human cancer. To test the role of aneuploidy in tumor initiation and progression, we compared tumor development in mice with chronic chromosome instability (CIN) induced by inactivation of the spindle assembly checkpoint (produced by Mad2 deficiency) and mice with transient CIN through transiently increased expression of polo-like kinase 4 (PLK4), a master regulator of centrosome number. Tumors forming under chronic CIN gradually trended toward chromosomal gains producing a specific karyotype profile that could only be partially maintained in end-stage tumors, as determined by single-cell whole genome DNA sequencing. Short term CIN from transient PLK4 induction generated significant centrosome amplification and aneuploidy resulting in formation of aggressive T cell lymphomas in mice with heterozygous inactivation of one p53 allele or accelerated tumor development in the absence of p53. Transient CIN increased the frequency of lymphomainitiating cells (as revealed by T cell receptor sequencing) with a specific karyotype profile containing triploid chromosomes 4, 5, 14, and 15 occurring early in tumorigenesis. Overall, our evidence demonstrates that distinct CIN mechanisms drive cancers presenting specific, complex chromosomal alterations with transient CIN rapidly enhancing tumor formation by accelerating the generation of such events.
Metformin prevented high glucose-induced endothelial reactive oxygen species via OGG1 in an AMPKα-Lin-28 dependent pathway
Authors: Tao Liangliang , Fan Xiucai , Sun Jing , zhang Zhu 
Published: November 2020

AbstractMetformin improved vascular function in obese type 2 diabetic patients. 8-oxoguanine glycosylase (OGG1), a main DNA glycosylase, was involved in vascular complications in diverse diseases. However, whether metformin suppressed endothelial ROS via OGG1 pathway was unclear. Human umbilical vein endothelial cells (HUVECs) were exposed to HG (high glucose) or HG with metformin. OGG1 and AMPfα levels were measured after metformin treatment while HG-caused ROS was measured by DHE prober. Diabetic mice were induced by daily intraperitoneal injections of streptozotocin (STZ). Metformin reduced Endothelial ROS caused by HG via upregulating OGG1. Additionally, OGG1 protein expression was dependent on its mRNA stability, which was reversed by genetic inhibition of AMPKα and Lin-28. The role of OGG1 on ROS stimulated by HG was partially dependent on NFKB/NOX4 pathway in HUVECs. These results suggested that metformin contacted HG-induced endothelial ROS via AMPKα/Lin-28/OGG1 pathway.
Determinants of knowledge-sharing behaviour among students at higher educational institutions in Oman: a planned behaviour theoretical perspective of knowledge sharing
Authors: Abdel Fattah Fadi Abdel Muniem , Mohamed Abdul Hakim H.M , Bashir Mohamed Izzeldin A. , Al Alawi Abrar Mohammed Mubarak 
Published: November 2020

Purpose
This paper aims to investigate how students’ attitude (SA), students’ subjective norms (SN), students’ knowledge sharing intentions (KSI) can contribute to the enhancement of knowledge sharing behaviour (KSB) among students at higher education institutes (HEI) in Oman.

Design/methodology/approach
This study follows the quantitative methodology and the deductive causal research approach. The data were conveniently collected through a Web-based questionnaire (Google forms) from 285 active students who are affiliated to Omani universities. SPSS was used to statistically analyse the collected data, including partial least square-structural equation modelling (PLS-SEM V3.3) to draw the results.

Findings
The study concluded that SA has both direct and indirect positive impact on SN, KSI and KSB. Moreover, the result revealed that there is a mediation effect between SA and KSB through KSI, SA and KSI when SN is playing as a mediation role.

Research limitations/implications
Although this study contributes to the existing body of knowledge, this study is limited by the scarcity of the related literature in the Omani context. It is recommended that these shortfalls be addressed together while improving the knowledge-sharing behaviour among students and administrative staff. Furthermore, the potential variation between academic staff and students in terms of factors affecting their intentions to share knowledge within HEIs should be explored.

Practical implications
This research provides policymakers in academic fields with the appropriate approaches to leverage the knowledge-sharing behaviour amongst Omani students with the understanding of the main factors affecting individuals’ knowledge-sharing behaviours.

Social implications
This will help in improving the means of employing and practising knowledge-sharing strategies within HEIs, which can generate competitive advantages amongst students and institutions while benefiting knowledge management strategies and its members.

Originality/value
The importance of the study stems from its context being conducted in Oman as a developing country. In addition, this study is one of the initial attempts to investigate KSB by considering SA, SN and KSI and its applicability on HEI in Oman. The findings of the study can serve as inputs to HEI in developing best practices across KSB dimensions and expanding the knowledge-sharing culture amongst HEI’s students in Oman. One of the developed strategies is the spreading of the knowledge-sharing culture among students by positively directing their attitude towards the practices of knowledge exchange.
Identifying sustainability drivers in higher education through fuzzy AHP
Authors: Arora Anchal , Jain Jinesh , Gupta Sanjay , Sharma Ajay 
Published: November 2020

PurposeIn today's competitive environment, sustainability is talked out in every sphere of life. Sustainability is a key to stability and for that roots are being focused by incorporating sustainability in higher education. The basic purpose of this paper is to prioritize the sustainability drivers in the higher education system. This research will provide fruitful insight into the sustainability drivers in the higher education system to the education industry and policymakers.Design/methodology/approachThe present research is conducted on the 400 students studying in four major universities in the state of Punjab. Fuzzy analytical hierarchy process was applied to prioritize the sustainability drivers in the higher education system. The primary factors considered for the present study include social-people (social responsibility), environmental-planet (sustainable environmental practices) and financial-profit (economic value created).FindingsThe most influential criteria were environmental-planet (sustainable environmental practices) and social-people (social responsibility). The five most influential subcriteria were “Student engagement in eco co-curricular activities (C21)”, Energy efficiency measures (C23)”, “The HEI as a job driver in the city (C11)”, “Total direct energy consumption (C31)” and “Support from the HEI for local initiatives and help in growing the sustainability of the community or region (C12)”.Research limitations/implicationsAlthough the sample survey conducted in this study was focused on a small sample selected from the state of Punjab which genuinely represented the total population, it is still considered as a limitation for the present study.Practical implicationsThe outcome of this research provides policymakers with a better understanding of the sustainability drivers in higher education. This will further help them toward achieving the aim of sustainability.Originality/valueThe present research is based on the available literature on sustainability and the results of the study would add value to the existing knowledge base.