bluuebunny/crossref_metadata_2025_split huggingface dataset:
The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation
Authors: Pras Anita , Houben Bert , Aprile Francesco A. , Seinstra Renée , Gallardo Rodrigo , Janssen Leen , Hogewerf Wytse , De Vleeschouwer Matthias , Mata-Cabana Alejandro , Koopman Mandy , Stroo Esther , de Vries Minke , Edwards Samantha Louise , Vendruscolo Michele , Falsone S. Fabio , Rousseau Frederic , Schymkowitz Joost , Nollen Ellen A. A. 
Published: December 2020

AbstractWhile aggregation-prone proteins are known to accelerate ageing and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A and SERF2 have recently been identified as cellular modifiers of such cytotoxicity. Using a peptide array screening approach on human amyloidogenic proteins, we found that SERF2 interacted with specific patterns of negatively charged and hydrophobic, aromatic amino acids. The absence of such patterns, or the neutralization of the positive charge in SERF2, prevented these interactions and abolished the amyloid-promoting activity of SERF2. In a protein aggregation model in the nematodeC. elegans, protein aggregation was suppressed by mutating the endogenous locus of MOAG-4 to neutralize charge. Our data indicate that charge interactions are required for MOAG-4 and SERF2 to promote aggregation. Such charged interactions might accelerate the primary nucleation of amyloid by initiating structural changes and by decreasing colloidal stability. Our finding that negatively charged segments are overrepresented in amyloid-forming proteins suggests that inhibition of charge interactions deserves exploration as a strategy to target age-related protein toxicity.Significance StatementHow aging causes relatively common diseases such as Alzheimer’s and Parkinson’s is still a mystery. Since toxic structural changes in proteins are likely to be responsible, we investigated biological mechanisms that could drive such changes. We made use of a modifying factor called SERF2, which accelerates structural changes and aggregation of several disease-related proteins. Through a peptide-binding screen, we found that SERF2 acts on negatively charged protein regions. The abundance of such regions in the disease-related proteins explains why SERF has its effect. Removing positive charge in SERF was sufficient to suppress protein aggregation in models for disease. We propose that blocking charge-interactions with SERF or other modifiers could serve as a general approach to treat age-related protein toxicity.
Differential expression levels of Sox9 in early neocortical radial glial cells regulate the decision between stem cell maintenance and differentiation
Authors: Fabra-Beser Jaime , de Araujo Jessica Alves Medeiros , Marques-Coelho Diego , Goff Loyal A. , Müller Ulrich , Gil-Sanz Cristina 
Published: December 2020

ABSTRACTRadial glial progenitor cells (RGCs) in the dorsal forebrain directly or indirectly produce excitatory projection neurons and macroglia of the neocortex. Recent evidence shows that the pool of RGCs is more heterogeneous than originally thought and that progenitor subpopulations can generate particular neuronal cell types. Using single cell RNA sequencing, we have studied gene expression patterns of two subtypes of RGCs that differ in their neurogenic behavior. One progenitor type rapidly produces postmitotic neurons, whereas the second progenitor remains relatively quiescence before generating neurons. We have identified candidate genes that are differentially expressed between these RGCs progenitor subtypes, including the transcription factor Sox9. Usingin uteroelectroporation, we demonstrate that elevated Sox9 expression in progenitors prevents RGC division and leads to the generation of upper-layer cortical neurons from these progenitors at later ages. Our data thus reveal molecular differences between cortical progenitors with different neurogenic behavior and indicates that Sox9 is critical for the maintenance of RGCs to regulate the generation of upper layer neurons.SIGNIFICANCE STATEMENTThe existence of heterogeneity in the pool of RGCs and its relationship with the generation of cellular diversity in the cerebral cortex has been an interesting topic of debate for many years. Here we describe the existence of a subpopulation of RGCs with reduced neurogenic behavior at early embryonic ages presenting a particular molecular signature. This molecular signature consists of differential expression of some genes including the transcription factor Sox9, found to be a specific master regulator of this subpopulation of progenitor cells. Functional experiments perturbing Sox9 expression’s levels reveal its instructive role in the regulation of the neurogenic behavior of RGCs and its relationship with the generation of upper layer projection neurons at later ages.
Thermodynamics and free energy landscape of BAR-domain dimerization from molecular simulations
Authors: Jhaveri Adip , Maisuria Dhruw , Varga Matthew , Mohammadyani Dariush , Johnson Margaret E 
Published: December 2020

AbstractNearly all proteins interact specifically with other proteins, often forming reversible bound structures whose stability is critical to function. Proteins with BAR domains function to bind to, bend, and remodel biological membranes, where the dimerization of BAR domains is a key step in this function. Here we characterize the binding thermodynamics of homodimerization between the LSP1 BAR domain proteins in solution, using Molecular Dynamics (MD) simulations. By combining the MARTINI coarse-grained protein models with enhanced sampling through metadynamics, we construct a two-dimensional free energy surface quantifying the bound versus unbound ensembles as a function of two distance variables. Our simulations portray a heterogeneous and extraordinarily stable bound ensemble for these modeled LSP1 proteins. The proper crystal structure dimer has a large hydrophobic interface that is part of a stable minima on the free energy surface, which is enthalpically the minima of all bound structures. However, we also find several other stable nonspecific dimers with comparable free energies to the specific dimer. Through structure-based clustering of these bound structures, we find that some of these ‘nonspecific’ contacts involve extended tail regions that help stabilize the higher-order oligomers formed by BAR-domains, contacts that are separated from the homodimer interface. We find that the known membrane-binding residues of the LSP1 proteins rarely participate in any of the bound interfaces, but that both patches of residues are aligned to interact with the membrane in the specific dimer. Hence, we would expect a strong selection of the specific dimer in binding to the membrane. The effect of a 100mM NaCl buffer reduces the relative stability of nonspecific dimers compared to the specific dimer, indicating that it would help prevent aggregation of the proteins. With these results, we provide the first free energy characterization of interaction pathways in this important class of membrane sculpting domains, revealing a variety of interfacial contacts outside of the specific dimer that may help stabilize its oligomeric assemblies.
Genomic insights on DNase production inStreptococcus agalactiaeST17 and ST19 strains
Authors: Silvestre Inês , Nunes Alexandra , Borges Vítor , Isidro Joana , Silva Catarina , Vieira Luís , Gomes João Paulo , José Borrego Maria 
Published: December 2020

AbstractStreptococcus agalactiaeevasion from the human defense mechanisms has been linked to the production of DNases. These were proposed to contribute to the hypervirulence ofS. agalactiaeST17/capsular-type III strains, mostly associated with neonatal meningitis. We performed a comparative genomic analysis between ST17 and ST19 human strains with different cell tropism and distinct DNase production phenotypes. AllS. agalactiaeST17 strains, with the exception of 2211-04, were found to display DNase activity, while the opposite scenario was observed for ST19, where 1203-05 was the only DNase(+) strain. The analysis of the genetic variability of the seven genes putatively encoding secreted DNases inS. agalactiaerevealed an exclusive amino acid change in the predicted signal peptide of GBS0661 (NucA) of the ST17 DNase(-), and an exclusive amino acid change alteration in GBS0609 of the ST19 DNase(+) strain. Further core-genome analysis identified some specificities (SNVs or indels) differentiating the DNase(-) ST17 2211-04 and the DNase(+) ST19 1203-05 from the remaining strains of each ST. The pan-genomic analysis evidenced an intact phage without homology inS. agalactiaeand a transposon homologous to TnGBS2.3 in ST17 DNase(-) 2211-04; the transposon was also found in one ST17 DNase(+) strain, yet with a different site of insertion. A group of nine accessory genes were identified among all ST17 DNase(+) strains, including the Eco47II family restriction endonuclease and the C-5 cytosine-specific DNA methylase. None of these loci was found in any DNase(-) strain, which may suggest that these proteins might contribute to the lack of DNase activity. In summary, we provide novel insights on the genetic diversity between DNase(+) and DNase(-) strains, and identified genetic traits, namely specific mutations affecting predicted DNases (NucA and GBS0609) and differences in the accessory genome, that need further investigation as they may justify distinct DNase-related virulence phenotypes inS. agalactiae.
Oligodendrocyte progenitor proliferation is disinhibited following traumatic brain injury in LIF heterozygous mice
Authors: Frondelli Michelle J. , Mather Marie. L. , Levison Steven W. 
Published: December 2020

AbstractTraumatic brain injury (TBI) is a significant problem that affects ∼500,000 children each year. As cell proliferation is disturbed by injury and is required for normal brain development, we investigated how a pediatric closed head injury (CHI) would affect the progenitors of the subventricular zone (SVZ). Additionally, we evaluated the contribution of Leukemia Inhibitory Factor (LIF) using LIF-heterozygous mice (LIF Het), as LIF is an injury-induced cytokine, known to influence neurogenesis and gliogenesis. CHI’s were performed on P20 LIF Het and WT mice. Ki-67 staining and stereology revealed that cell proliferation increased ∼250% in injured LIF Het mice compared to the 30% increase observed in injured WT mice at 48 h post CHI. Furthermore, Olig2+ cell proliferation increased in the SVZ and white matter of LIF Het injured mice at 48 h recovery. Using an 8-color flow cytometry panel, the proliferation of three distinct multipotential progenitors were greater in LIF Het injured mice compared to WT injured mice. Early oligodendrocyte progenitor cell (OPC) proliferation was 6-fold higher in LIF Het injured mice compared to WT injured mice. In vitro, addition of LIF decreased overall cell proliferation and OPC proliferation compared to controls. Addition of LIF to OPC cultures induced an increase of phospho-Akt after 20 minutes and an increase of phospho-S6RP at 20 and 40 minutes of exposure, suggesting that LIF stimulates the mammalian target of Rapamycin pathway. Altogether, our data provide new insights into the regulatory role of LIF in suppressing neural progenitor cell proliferation after a mild TBI.Main PointsOPC proliferation is dis-inhibited in LIF haplodeficient mice.LIF directly inhibits glial progenitor cell proliferation.LIF stimulates the mTOR pathway.
A plastid antiporter as a bioindicator ofThalassiosira pseudonanaresilience
Authors: Valenzuela Jacob J. , Ashworth Justin , Cusick Allison , Abbriano Raffaela M. , Armbrust E.Virginia , Hildebrand Mark , Orellana Mónica V. , Baliga Nitin S. 
Published: December 2020

ABSTRACTAcidification of the ocean due to high atmospheric CO2levels may increase the resilience of diatoms causing dramatic shifts in abiotic and biotic cycles with lasting implications on marine ecosystems. Here, we report a potential bioindicator of a shift in the resilience of a coastal and centric model diatomThalassiosira pseudonanaunder elevated CO2. Specifically, we have discovered, through EGFP-tagging, a plastid membrane localized putative Na+(K+)/H+antiporter that is significantly upregulated at > 800 ppm CO2, with a potentially important role in maintaining pH homeostasis. Notably, transcript abundance of this antiporter gene was relatively low and constant over the diel cycle under contemporary CO2conditions. In future acidified oceanic conditions, dramatic oscillations of >10-fold change between nighttime (high) and daytime (low) in transcript abundances of the antiporter gene were associated with increased resilience ofT. pseudonana. By analyzing metatranscriptomic data from the Tara Oceans project, we demonstrate that phylogenetically diverse diatoms express homologs of this antiporter across the globe. We propose that the differential between night- and daytime transcript levels of the antiporter could serve as a bioindicator of a shift in the resilience of diatoms in response to high CO2conditions in marine environments.
Betulonic acid derivatives inhibiting coronavirus replication in cell culture via the nsp15 endoribonuclease
Authors: Krasniqi Besir , Stevaert Annelies , Van Loy Benjamin , Nguyen Tien , Thomas Joice , Vandeput Julie , Jochmans Dirk , Thiel Volker , Dijkman Ronald , Dehaen Wim , Voet Arnout , Naesens Lieve 
Published: December 2020

ABSTRACTThe lack of medication to suppress coronavirus infections is a main reason for the dramatic course of the COVID-19 pandemic. There is an urgent need to identify suitable coronavirus drug targets and corresponding lead molecules. Here we describe the discovery of a class of coronavirus inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. SAR exploration of these 1,2,3-triazolo fused betulonic acid derivatives yielded lead molecule5has a strong inhibitor (antiviral EC50: 0.6 μM) of human coronavirus 229E replication. An nsp15 endoribonuclease active site mutant virus was markedly less sensitive to5h, and selected resistance to the compound mapped to mutations in the N-terminal part of nsp15, at an interface between two nsp15 monomers. The biological findings were substantiated by the nsp15 binding mode for5h, predicted by docking. Hence, besides delivering a distinct class of inhibitors, our study revealed a druggable pocket in the nsp15 hexamer with relevance for anti-coronavirus drug development.
A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilizing immunity against SARS-CoV-2 infection in mice
Authors: Counoupas Claudio , Johansen Matt D. , Stella Alberto O. , Nguyen Duc H. , Ferguson Angela L. , Aggarwal Anupriya , Bhattacharyya Nayan D. , Grey Alice , Patel Karishma , Siddiquee Rezwan , Stewart Erica L. , Feng Carl G. , Hansbro Nicole G. , Palendira Umaimainthan , Steain Megan C. , Saunders Bernadette M. , Low Jason K. K. , Mackay Joel P. , Kelleher Anthony D. , Britton Warwick J. , Turville Stuart G , Hansbro Philip M. , Triccas James A. 
Published: December 2020

ABSTRACTGlobal control of COVID-19 requires broadly accessible vaccines that are effective against SARS-CoV-2 variants. In this report, we exploit the immunostimulatory properties of bacille Calmette-Guérin (BCG), the existing tuberculosis vaccine, to deliver a vaccination regimen with potent SARS-CoV-2-specific protective immunity. Combination of BCG with a stabilized, trimeric form of SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the blood of vaccinated mice, that was further augmented by the addition of alum. This vaccine formulation, BCG:CoVac, induced high-titre SARS-CoV-2 neutralizing antibodies (NAbs) and Th1-biased cytokine release by vaccine-specific T cells, which correlated with the early emergence of T follicular helper cells in local lymph nodes and heightened levels of antigen-specific plasma B cells after vaccination. Vaccination of K18-hACE2 mice with a single dose of BCG:CoVac almost completely abrogated disease after SARS-CoV-2 challenge, with minimal inflammation and no detectable virus in the lungs of infected animals. Boosting BCG:CoVac-primed mice with a heterologous vaccine further increased SARS-CoV-2-specific antibody responses, which effectively neutralized B.1.1.7 and B.1.351 SARS-CoV-2 variants of concern. These findings demonstrate the potential for BCG-based vaccination to protect against major SARS-CoV-2 variants circulating globally.
The combined treatment of Molnupiravir and Favipiravir results in a marked potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model
Authors: Abdelnabi Rana , Foo Caroline S. , Kaptein Suzanne J. F. , Zhang Xin , Langendries Lana , Vangeel Laura , Breuer Judith , Pang Juanita , Williams Rachel , Vergote Valentijn , Heylen Elisabeth , Leyssen Pieter , Dallmeier Kai , Coelmont Lotte , Jochmans Dirk , Chatterjee Arnab K. , De Jonghe Steven , Weynand Birgit , Neyts Johan 
Published: December 2020

AbstractFavipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV2. In recent days preliminary efficacy data have been reported in COVID-19 patients. We here studied the combined antiviral effect of the drugs in the SARS-CoV2 hamster infection model. We first demonstrate that Molnupiravir can reduce infectious virus titers in lungs of infected animals in a dose-dependent manner by up to 3.5 log10which is associated with a marked improvement of virus-induced lung pathology. When animals are treated with a combination of suboptimal doses of Molnupiravir and Favipiravir (that each alone result in respectively a 1.3 log10and 1.1 log10reduction of infectious virus titers in the lungs), a marked combined potency is observed. Infectious virus titers in the lungs of animals treated with the combo are on average reduced by 4.5 log10and infectious virus are no longer detected in the lungs of 60% of treated infected animals. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs. In the combo-treated hamsters an increased frequency of C-to-T and G-to-A mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination. Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir and Favipiravir in the treatment of COVID-19.
Measurement uncertainty and management bias in accounting estimates: the perspective of key audit matters reported by Chinese firms' auditors
Authors: Lau Chee Kwong 
Published: December 2020

PurposeThis study examines (1) the extent of key audit matters (KAMs) reported by auditors is related to accounting estimates, (2) whether measurement uncertainty and management bias affect auditors to do so and (3) whether the use of accounting estimates, given the measurement uncertainty and management bias reported in KAMs adversely affects the decision usefulness of accounting information.Design/methodology/approachData on key audit matters, accounting estimates, measurement uncertainty, management bias, etc. were collected from the auditor's reports of 351 sample Chinese listed firms. It employs regression analyses to assess the hypotheses on issues affecting the report of these key audit matters and the impacts on the decision usefulness of accounting information.FindingsFair value and impairment loss estimations make up of 2.6 and 44.1% of the 606 KAMs identified, respectively. Measurement uncertainty is positively, while management bias is negatively, affecting auditors report KAMs related to accounting estimates. The use of accounting estimates in firms where their auditors reported the KAMs related to accounting estimates does not enhance the value and predictive relevance of reported earnings. The assurance works on, and reporting of, KAMs served as a “red flag” about the accounting estimates.Practical implicationsThe use of accounting estimates does not always lead to enhanced decision-useful accounting information. Auditors, in their stewardship role, shall ensure that the measurement uncertainty issue is appropriately identified, addressed and verified. In addition, they shall provide an effective check-and-balance to the accounting discretion managers have in providing decision-useful information from opportunistic reporting.Originality/valueThis study examines the proposition that while the use of estimates can enhance the decision usefulness of accounting information, it can also induce measurement uncertainty and management bias into financial reporting.
Exploring the effectiveness of unassigned workspaces: a case study analysis of two workplaces
Authors: Patel Tina , Angne Alfaro Sarah M. 
Published: December 2020

PurposeThe purpose of this study is to understand how unassigned workspaces translate into an effective workplace. This is achieved by examining employees and their understanding of how unassigned workspaces impact their engagement, satisfaction and desire to stay with their workplace.Design/methodology/approachTwo workplaces designed on the strategy of 100% unassigned workspaces are analyzed as case studies to understand this phenomenon. Mixed methodology, primarily qualitative method with a survey nested within is used for this study. Grounded theory, one of the strategies of qualitative research methodology is applied as a method for analyzing the data. The study is aimed to reveal the participants' perspectives and interpretations of their actions and physical environment on effectiveness in relation to the unassigned work environment.FindingsThe information afforded the development of an overarching theoretical scheme for integrating spatial categories and describing the employees' experiences of their work environment from the various perspectives. The research reveals that unassigned and flexible spatial attributes contribute positively to employee satisfaction, engagement and retention. However, some of the goals surrounding the culture of trust and autonomy such as privacy, personalization and lack of control are compromised in these environments.Research limitations/implicationsThe insights obtained from this study will provide designers, architects, facility planners and managers a new design tool to aid in making the unassigned workspaces model more effective.Originality/valueThis study bridges the gap while documenting how unassigned workspaces translate into an effective workplace for the employees to be productive, engaged and satisfied.
Leadership styles, justice and whistle-blowing intention: testing a mediation model
Authors: Gupta Smita , Bhal Kanika T. 
Published: December 2020

PurposeThis study aims to focus on justice perceptions as the operating mechanism for leadership to impact whistle-blowing intention (WBI). Consequently, it aimed to test the mediating role of justice perception through which ethical leadership (EL) and servant leadership (SL) lead to WBI.Design/methodology/approachData were gathered from 136 employees of IT companies in India through a questionnaire survey to test the proposed relationships.FindingsThe analysis showed that both EL and SL predict employees’ WBI via justice as the mediating mechanism.Research limitations/implicationsFormal and informal mechanisms by leaders should focus on ensuring that justice is not only done but also perceived by their subordinates in such a way that just being an ethical or servant leader by itself might not result in pro-social behavior like whistle-blowing.Originality/valueMany studies have shown the effect of SL and EL on outcomes like whistle-blowing; however, this study comprises that justice perception might play a critical mediating role through which both leadership styles impact normative/prosocial behavior like whistleblowing. Understanding the role of leadership and justice perception can offer valuable insights into one’s WBI and tendencies, thus increasing the amount of variance in the WBI that researchers can explain.