bluuebunny/crossref_metadata_2025 huggingface dataset:
Covid-19: analysis of a modified SEIR model, a comparison of different intervention strategies and projections for India
Authors: Das Arghya , Dhar Abhishek , Goyal Srashti , Kundu Anupam
Published: June 2020

To understand the spread of Covid-19, we analyse an extended Susceptible-Exposed-Infected-Recovered (SEIR) model that accounts for asymptomatic carriers, and explore the effect of different intervention strategies such as social distancing (SD) and testing-quarantining (TQ). The two intervention strategies (SD and TQ) try to reduce the disease reproductive number, R0, to a target value , but in distinct ways, which we implement in our model equations. We find that for the same , TQ is more efficient in controlling the pandemic than SD. However, for TQ to be effective, it has to be based on contact tracing and our study quantifies the required ratio of tests-per-day to the number of new cases-per-day. Our analysis shows that the largest eigenvalue of the linearised dynamics provides a simple understanding of the disease progression, both pre- and post-intervention, and explains observed data for many countries. We propose an accurate way of specifying initial conditions for the numerics (from insufficient data) using the fact that the early time exponential growth is well-described by the dominant eigenvector of the linearized equations. Weak intervention strategies (that reduce R0 but not sufficiently) reduce the peak values of infections and the asymptotic affected population and we provide analytic expressions for these in terms of the disease parameters. We apply them in the Indian context to obtain heuristic projections for the course of the pandemic, noting that the predictions strongly depend on the assumed fraction of asymptomatic carriers.
Applying a Prospective Space-Time Scan Statistic to Examine the Evolution of COVID-19 Clusters in the State of São Paulo, Brazil
Authors: Ferreira R.V. , Martines M.R. , Toppa R.H. , Assunção L.M. , Desjardins M.R. , Delmelle E.M.
Published: June 2020

We present the first geographic study that uses space-time statistics to monitor COVID-19 in Brazil. The first cases of COVID-19 were confirmed in December 2019 in Wuhan, China, caused by the contamination of the SARS-CoV-2 virus, and quickly turned into a pandemic. In Brazil, the first case occurred on January 23rd, 2020 but was officially reported by the Brazilian Ministry of Health on February 25th. Since then, the number of deaths and people infected by COVID-19 in Brazil have been steadily increasing. Despite the underreporting of coronavirus cases by government agencies across the country, the State of São Paulo has the highest rate among all Brazilian States. Thus, it is essential to detect which areas contain the highest concentration of COVID-19 to implement public policies, to mitigate the spread of the epidemic. To identify these critical areas, we utilized daily confirmed case data from the Brasil.IO website between February 25th, 2020 to May 5th, 2020; which were aggregated to the municipality level. A prospective space-time scan statistic was applied to evaluate possible active clusters in three different time periods. The results visualize the space-time evolution and dynamics of COVID-19 clusters in the State of São Paulo. Since the first study period, the results highlight approximately 4.6 times the number of municipalities belonging to a significant cluster with a RR>1 on May 5th. These results can inform health authorities and public management to take the necessary measures to minimize the transmission of COVID-19 and track the evolution of significant space-time clusters.

HIGHLIGHTS

Prospective space-time statistics can improve COVID-19 surveillance in Brazil

All statistically significant clusters are located near São Paulo Municipality

There are municipalities with relative risk highest than one in the countryside

4.6 times the number of municipalities belong to a significant cluster on May 5th
YAP and β-catenin co-operate to drive oncogenesis in basal breast cancer
Authors: Quinn Hazel , Koren Elle , Vogel Regina , Popp Oliver , Mertins Philipp , Messerschmidt Clemens , Marangoni Elisabetta , Fuchs Yaron , Birchmeier Walter
Published: June 2020

Targeting cancer stem cells (CSCs) can serve as an effective approach toward limiting resistance to therapies and the development of metastases in many forms of cancer. While basal breast cancers encompass cells with CSC features, rational therapies remain poorly established. Here, we show that receptor tyrosine kinase Met signalling promotes the activity of the Hippo component YAP in basal breast cancer. Further analysis revealed enhanced YAP activity within the CSC population. Using both genetic and pharmaceutical approaches, we show that interfering with YAP activity delays basal cancer formation, prevents luminal to basal trans-differentiation and reduces CSC survival. Gene expression analysis of YAP knock-out mammary glands revealed a strong decrease in β-catenin target genes in basal breast cancer, suggesting that YAP is required for nuclear β-catenin activity. Mechanistically, we find that nuclear YAP interacts and overlaps with β-catenin and TEAD4 at common gene regulatory elements. Analysis of proteomic data from primary breast cancer patients identified a significant upregulation of the YAP activity signature in basal compared to other breast cancers, suggesting that YAP activity is limited to basal types. Our findings demonstrate that in basal breast cancers, β-catenin activity is dependent on YAP signalling and controls the CSC program. These findings suggest that targeting the YAP/TEAD4/β-catenin complex offers a potential therapeutic strategy for eradicating CSCs in basal (triple-negative) breast cancers.
Transcontrol of cardiac mRNA translation in a protein length-dependent fashion
Authors: Witte Franziska , Ruiz-Orera Jorge , Ciolli Mattioli Camilla , Blachut Susanne , Adami Eleonora , Schulz Jana Felicitas , Schneider-Lunitz Valentin , Hummel Oliver , Patone Giannino , Mücke Michael Benedikt , Šilhavý Jan , Heinig Matthias , Bottolo Leonardo , Sanchis Daniel , Vingron Martin , Chekulaeva Marina , Pravenec Michal , Hubner Norbert , van Heesch Sebastiaan
Published: June 2020

Little is known about the impact of naturally occurring genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate how genetic influences on mRNA translational efficiency are associated with complex disease phenotypes using a panel of rat recombinant inbred lines. We identify a locus for cardiac hypertrophy that is associated with a translatome-wide and protein length-dependent shift in translational efficiency. This master regulator primarily affects the translation of very short and very long protein-coding sequences, altering the physiological stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus points to altered ribosome assembly, characterized by accumulation of polysome half-mers, changed ribosomal configurations and misregulation of the small nucleolar RNASNORA48. We postulate that this locus enhances a pre-existing negative correlation between protein length and translation initiation in diseased hearts. Our work shows that a single genomic locus can trigger a complex, translation-driven molecular mechanism that contributes to phenotypic variability between individuals.

Graphical Abstract

Highlights

Genetic variability impacts protein synthesis rates in a rat model for cardiac hypertrophy

Atranslocus affects stoichiometric translation rates of cardiac sarcomeric proteins

This master regulator locus induces a global, protein length-dependent shift in translation

Dysregulated ribosome assembly induces half-mer formation and affects translation initiation rate
Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box
Authors: Reader Janette , van der Watt Mariёtte E. , Taylor Dale , Le Manach Claire , Mittal Nimisha , Ottilie Sabine , Theron Anjo , Moyo Phanankosi , Erlank Erica , Nardini Luisa , Venter Nelius , Lauterbach Sonja , Bezuidenhout Belinda , Horatscheck Andre , van Heerden Ashleigh , Boyle Grant A. , Calvo David , Mancama Dalu , Coetzer Theresa L. , Winzeler Elizabeth A. , Duffy James , Koekemoer Lizette L. , Basarab Gregory , Chibale Kelly , Birkholtz Lyn-Marié
Published: June 2020

New chemical matter is needed to target the divergent biology associated with the different life cycle stages ofPlasmodium. Here, we report the parallel screening of the Medicines for Malaria Venture Pandemic Response Box to identify multistage-active and stage-specific compounds against various life cycle stages ofPlasmodiumparasites (asexual parasites, stage IV/V gametocytes, gametes, oocysts and liver stages) and for endectocidal activity. Hits displayed unique chemotypes and included two multistage-active compounds, 16 asexual-targeted, six with prophylactic potential and ten gametocyte-targeted compounds. Notably, four structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity were identified: the JmjC inhibitor ML324, two azole antifungals including eberconazole, and the antitubercular clinical candidate SQ109. Besides ML324, none of these have previously attributed antiplasmodial activity, emphasizing the success ofde novoparallel screening against differentPlasmodiumstages to deliver leads with novel modes-of-action. Importantly, the discovery of such transmission-blocking targeted compounds covers a previously unexplored base for delivery of compounds required for malaria elimination strategies.
Robust T-cell signaling triggered on soft polydimethylsiloxane-supported lipid-bilayers
Authors: Lippert Anna H. , Dimov Ivan B. , Winkel Alexander , McColl James , Humphrey Jane , Chen Kevin Y. , Santos Ana Mafalda , Jenkins Edward , Franze Kristian , Davis Simon J. , Klenerman David
Published: June 2020

The T-cell receptor (TCR) is thought to be triggered either by mechano-transduction or local tyrosine phosphatase exclusion at cell-cell contacts. However, the effects of the mechanical properties of activating surfaces have only been tested for late-stage T-cell activation, and phosphatase segregation has mostly been studied on glass-supported lipid bilayers that favor imaging but are orders-of-magnitude stiffer than typical cells. We developed a method for attaching lipid bilayers to polydimethylsiloxane polymer supports, producing ‘soft bilayers’ with physiological levels of mechanical resistance (Young’s modulus of 4 kPa). Comparisons of T-cell behavior on soft and glass-supported bilayers revealed that early calcium signaling is unaffected by substrate rigidity, implying that early steps in TCR triggering are not mechanosensitive. Robust phosphatase exclusion was observed on the soft bilayers, however, suggesting it likely occurs at cell-cell contacts. This work sets the stage for an imaging-based exploration of receptor signaling under conditions closely mimicking physiological cell-cell contact.
Lipid membranes from naked mole-rat brain lipids are cholesterol-rich, highly phase-separated, and sensitive to amyloid-induced damage
Authors: Frankel Daniel , Davies Matthew , Bhushan Bharat , Kulaberoglu Yavuz , Urriola-Munoz Paulina , Bertrand-Michel Justine , Pergande Melissa R. , Smith Andrew A. , Preet Swapan , Park Thomas J. , Vendruscolo Michele , Rankin Kenneth , Cologna Stephanie M. , Kumita Janet R. , Cenac Nicolas , John Smith Ewan St
Published: June 2020

Naked mole-rats are extraordinarily long-lived rodents that do not develop age-related neurodegenerative diseases. Remarkably, they do not accumulate amyloid plaques, even though their brains contain high concentrations of amyloid beta peptide, even from a young age Therefore, these animals offer an opportunity to investigate mechanisms of resistance against the neurotoxicity of amyloid beta aggregation. Working in this direction, here we examine the composition, phase behaviour, and amyloid beta interactions of naked mole-rat brain lipids. Relative to mouse, naked mole-rat brain lipids are rich in cholesterol and contain sphingomyelin in lower amounts and of shorter chain lengths. Proteins associated with metabolism of ceramides, sphingomyelin and ceramide receptor activity were also found to be decreased in naked mole-rat brain lysates. Correspondingly, we find that naked mole-rat brain lipid membranes exhibit a high degree of phase separation, with the liquid ordered phase occupying up to 80% of the supported lipid bilayer. These observations are consistent with the ‘membrane pacemaker’ hypothesis of ageing, according to which long-living species have lipid membranes particularly resistant to oxidative damage. However, we found that exposure to amyloid beta disrupts the naked mole-rat brain lipid membranes while those formed from mouse brain lipids exhibit small, well-defined footprints, whereby the amyloid beta penetrates deeply into the lipid membranes. These results suggest that in naked mole-rats the lipid composition of cell membranes may offer neuroprotection through resistance to oxidative processes rather than through mechanical effects.
Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia
Authors: Morales-Nebreda Luisa , Helmin Kathryn A. , Markov Nikolay S. , Piseaux Raul , Acosta Manuel A. Torres , Abdala-Valencia Hiam , Politanska Yuliya , Singer Benjamin D.
Published: June 2020

Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury following viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell pro-repair function following lung injury remains unknown. Here, we show that aging results in a cell-autonomous impairment of reparative Treg cell function following experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provide insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Novel strategies that restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.
The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure
Authors: Sun Yunpeng , Zhao Kun , Xia Wencheng , Gu Jinge , Ma Yeyang , Gui Xinrui , Zhang Xia , Fang Yanshan , Sun Bo , Liu Cong , Li Dan
Published: June 2020

Human heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) serves as a key regulating protein in RNA metabolism. Malfunction of hnRNPA1 in nucleo-cytoplasmic transport or dynamic phase separation leads to abnormal amyloid aggregation and neurodegeneration. The low complexity (LC) domain of hnRNPA1 drives both dynamic phase separation and amyloid aggregation. Here, we use cryo-electron microscopy to determine the amyloid fibril structure formed by hnRNPA1 LC domain. Remarkably, the structure reveals that the nuclear localization sequence of hnRNPA1 (termed PY-NLS), which is initially known to mediate the nucleo-cytoplamic transport of hnRNPA1 through binding with karyopherin-β2 (Kapβ2), represents the major component of the fibril core. The residues that contribute to the binding of PY-NLS with Kapβ2 also exert key molecular interactions to stabilize the fibril structure. Notably, hnRNPA1 mutations found in familial amyotrophic lateral sclerosis (ALS) and multisystem proteinopathoy (MSP) are all involved in the fibril core and contribute to fibril stability. Our work illuminate structural understandings on the pathological amyloid aggregation of hnRNPA1 and the amyloid disaggregase activity of Kapβ2, and highlights the multiple roles of PY-NLS in hnRNPA1 homeostasis.
SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts
Authors: Moustaqil Mehdi , Ollivier Emma , Chiu Hsin-Ping , Van Tol Sarah , Rudolffi-Soto Paulina , Stevens Christian , Bhumkar Akshay , Hunter Dominic J.B. , Freiberg Alex , Jacques David , Lee Benhur , Sierecki Emma , Gambin Yann
Published: June 2020

The genome of SARS-CoV-2 (SARS2) encodes for two viral proteases (NSP3/ papain-like protease and NSP5/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 and NSP5 of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 NSP3 and NSP5 target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease activity of NSP3 and NSP5 on a library of 71 human innate immune proteins (HIIPs), covering most pathways involved in human innate immunity. By expressing each of these HIIPs with a genetically encoded fluorophore in a cell-free system and titrating in the recombinant protease domain of NSP3 or NSP5, we could readily detect cleavage of cognate HIIPs on SDS-page gels. We identified 3 proteins that were specifically and selectively cleaved by NSP3 or NSP5: IRF-3, and NLRP12 and TAB1, respectively. Direct cleavage of IRF3 by NSP3 could explain the blunted Type- I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of IL-6 and inflammatory response observed in COVID-19 patients. Surprisingly, both NLRP12 and TAB1 have each two distinct cleavage sites. We demonstrate that in mice, the second cleavage site of NLRP12 is absent. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for in-depth studies into the pathophysiology of COVID-19 and should facilitate the search or development of more effective animal models for severe COVID-19. Finally, we discovered that one particular species of bats, David’s Myotis, possesses the five cleavage sites found in humans for NLRP12, TAB1 and IRF3. These bats are endemic from the Hubei province in China and we discuss its potential role as reservoir for the evolution of SARS1 and SASR2.
Pharmacological CDK4/6 inhibition unravels a p53-induced secretory phenotype in senescent cells
Authors: Wang Boshi , Brandenburg Simone , Hernandez-Segura Alejandra , van Vliet Thijmen , Jongbloed Elisabeth M. , Wilting Saskia M , Ohtani Naoko , Jager Agnes , Demaria Marco
Published: June 2020

Cellular senescence is a state of stable growth arrest that acts as a tumor suppressive mechanism. Several anti-cancer interventions function partly by inducing malignant cells into senescence. However, because of systemic administration and lack of specificity, anti-cancer treatments are associated with premature senescence of various non-malignant cells. Therapy-induced non-malignant senescent cells can have profound detrimental pro-tumorigenic and pro-disease functions via activation of a pro-inflammatory and NF-κB-mediated secretory phenotype (SASP). Inhibitors of the cyclin-dependent kinases 4/6 (CDK4/6i) has recently shown to have potent cytostatic effects with reduced toxicities. Here, we show that CDK4/6i lead non-malignant cells to a senescent state that lacks the pro-inflammatory and NF-κB-associated SASP. Interestingly, CDK4/6i-induced senescence overexpressed a number of genes encoding for secreted proteins, which we show being dependent on p53 transcriptional activity. CDK4/6i-induced p16+senescent cells with a p53-associated (PASP), but not NF-κB-associated (NASP), secretory phenotype do not exert detrimental and pro-tumorigenic functions, but still retain the capacity to induce paracrine senescence and undergo clearancein vivo.Our data suggest that that senescent cells with a PASP but without a NASP may be well-tolerated and may represent a less toxic outcome for cancer interventions.
Anesthetics fragment hippocampal network activity, alter spine dynamics and affect memory consolidation
Authors: Yang Wei , Chini Mattia , Pöpplau Jastyn A. , Formozov Andrey , Dieter Alexander , Piechocinski Patrick , Rais Cynthia , Morellini Fabio , Sporns Olaf , Hanganu-Opatz Ileana L. , Wiegert J. Simon
Published: June 2020

General anesthesia is characterized by reversible loss of consciousness accompanied by transient amnesia. Yet, long-term memory impairment is an undesirable side-effect. How different types of general anesthetics (GAs) affect the hippocampus, a brain region central to memory formation and consolidation, is poorly understood. Using extracellular recordings, chronic 2-photon imaging and behavioral analysis, we monitor the effects of isoflurane (Iso), medetomidine/midazolam/fentanyl (MMF), and ketamine/xylazine (Keta/Xyl) on network activity and structural spine dynamics in the hippocampal CA1 area of adult mice. GAs robustly reduced spiking activity, decorrelated cellular ensembles, albeit with distinct activity signatures, and altered spine dynamics. CA1 network activity under all three anesthetics was different to natural sleep. Iso anesthesia most closely resembled unperturbed activity during wakefulness and sleep, and network alterations recovered more readily than with Keta/Xyl and MMF. Correspondingly, memory consolidation was impaired after exposure to Keta/Xyl and MMF, but not Iso. Thus, different anesthetics distinctly alter hippocampal network dynamics, synaptic connectivity, and memory consolidation, with implications for GA strategy appraisal in animal research and clinical settings.
Frequent loss-of-heterozygosity in CRISPR-Cas9-edited early human embryos
Authors: Alanis-Lobato Gregorio , Zohren Jasmin , McCarthy Afshan , Fogarty Norah M.E. , Kubikova Nada , Hardman Emily , Greco Maria , Wells Dagan , Turner James M.A. , Niakan Kathy K.
Published: June 2020

CRISPR-Cas9 genome editing is a promising technique for clinical applications, such as the correction of disease-associated alleles in somatic cells. The use of this approach has also been discussed in the context of heritable editing of the human germline. However, studies assessing gene correction in early human embryos report low efficiency of mutation repair, high rates of mosaicism and the possibility of unintended editing outcomes that may have pathologic consequences. We developed computational pipelines to assess single-cell genomics and transcriptomics datasets from OCT4 (POU5F1) CRISPR-Cas9-targeted and control human preimplantation embryos. This allowed us to evaluate on-target mutations that would be missed by more conventional genotyping techniques. We observed loss-of-heterozygosity in edited cells that spanned regions beyond thePOU5F1on-target locus, as well as segmental loss and gain of chromosome 6, on which thePOU5F1gene is located. Unintended genome editing outcomes were present in approximately 16% of the human embryo cells analysed and spanned 4 to 20kb. Our observations are consistent with recent findings indicating complexity at on-target sites following CRISPR-Cas9 genome editing. Our work underscores the importance of further basic research to assess the safety of genome editing techniques in human embryos, which will inform debates about the potential clinical use of this technology.
SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface
Authors: Bertoglio Federico , Meier Doris , Langreder Nora , Steinke Stephan , Rand Ulfert , Simonelli Luca , Heine Philip Alexander , Ballmann Rico , Schneider Kai-Thomas , Roth Kristian Daniel Ralph , Ruschig Maximilian , Riese Peggy , Eschke Kathrin , Kim Yeonsu , Schäckermann Dorina , Pedotti Mattia , Kuhn Philipp , Zock-Emmenthal Susanne , Wöhrle Johannes , Kilb Normann , Herz Tobias , Becker Marlies , Grasshoff Martina , Wenzel Esther Veronika , Russo Giulio , Kröger Andrea , Brunotte Linda , Ludwig Stephan , Fühner Viola , Krämer Stefan Daniel , Dübel Stefan , Varani Luca , Roth Günter , Čičin-Šain Luka , Schubert Maren , Hust Michael
Published: June 2020

COVID-19 is a severe acute respiratory disease caused by SARS-CoV-2, a novel betacoronavirus discovered in December 2019 and closely related to the SARS coronavirus (CoV). Both viruses use the human ACE2 receptor for cell entry, recognizing it with the Receptor Binding Domain (RBD) of the S1 subunit of the viral spike (S) protein. The S2 domain mediates viral fusion with the host cell membrane. Experience with SARS and MERS coronaviruses has shown that potent monoclonal neutralizing antibodies against the RBD can inhibit the interaction with the virus cellular receptor (ACE2 for SARS) and block the virus cell entry. Assuming that a similar strategy would be successful against SARS-CoV-2, we used phage display to select from the human naïve universal antibody gene libraries HAL9/10 anti-SARS-CoV-2 spike antibodies capable of inhibiting interaction with ACE2. 309 unique fully human antibodies against S1 were identified. 17 showed more than 75% inhibition of spike binding to cells expressing ACE2 in the scFv-Fc format, assessed by flow cytometry and several antibodies showed even an 50% inhibition at a molar ratio of the antibody to spike protein or RBD of 1:1. All 17 scFv-Fc were able to bind the isolated RBD, four of them with sub-nanomolar EC50. Furthermore, these scFv-Fc neutralized active SARS-CoV-2 virus infection of VeroE6 cells. In a final step, the antibodies neutralizing best as scFv-Fc were converted into the IgG format. The antibody STE73-2E9 showed neutralization of active SARS-CoV-2 with an IC50 0.43 nM and is binding to the ACE2-RBD interface. Universal libraries from healthy human donors offer the advantage that antibodies can be generated quickly and independent from the availability of material from recovered patients in a pandemic situation.
Dopaminergic Modulation of Working Memory and Cognitive Flexibility in a Zebrafish Model of Aging-Related Cognitive Decline
Authors: Cleal Madeleine , Fontana Barbara D. , Double Molly , Mezabrovschi Roxana , Parcell Leah , Redhead Edward , Parker Matthew O.
Published: June 2020

Healthy aging is associated with a decline in memory and executive function, which have both been linked with aberrant dopaminergic signalling. We examined the relationship between cognitive performance and dopamine function of young and aging zebrafish (Danio rerio). We revealed age-related decreases in working memory and cognitive flexibility in the Free-Movement Pattern (FMP) Y-maze. An increase indrd5gene expression in aging adults coincided with a decrease in cognitive performance. Treatment with a D1/D5 receptor agonist (SKF-38393, 35 μM) 30 minutes prior to behavioural assessment resulted in improved working memory in aging zebrafish, but no effect in younger adults. However, an ‘overdosing’ effect caused by agonist treatment resulted in downregulation ofdatexpression in 6-month old, treated zebrafish. The translational relevance of these findings was tested in humans by analysing exploratory behaviour in young-adult, 18-35-year olds, and aged adults, 70+ year olds, in a virtual FMP Y-maze. Our findings revealed similar age-related decline in working memory. Thus, strongly supporting zebrafish as a translational model of aging and cognitive decline.
HYPERTRIGLICERIDEMIC WAIST, PHYSICAL ACTIVITY AND CARDIOVASCULAR RISK FACTORS IN SCHOOLCHILDREN
Authors: Guilherme Flávio Ricardo , dos Santos Stevan Ricardo , Fiorillo Rodrigo Garcia , Rinaldi Wilson
Published: June 2020

The present study aimed to analyze the prevalence of the Hypertriglyceridemic Waist (HTW) and its rates with levels of physical activity, nutritional status and lipid profile of students from public schools. A sample consisted of 448 schoolchildren between 10 and 18 years old, who are assessed by body mass, height, BMI (waist circumference), triglycerides, total cholesterol, HDL-C, LDL-C, non-HDL cholesterol, fasting blood glucose and weekly physical activity time. The survey results showed a high prevalence of the HTW phenotype in schoolchildren (n = 125; 27.9%). The group diagnosed with phenotype has higher body mass, BMI, total cholesterol, LDL-C and non-HDL cholesterol and a lower level of HDL-C about the group without a diagnosis of the phenotype. However, for fasting blood glucose measurements and time of physical activity, the groups are no different. An association analysis using logistic regression showed the HTW phenotype associated with sex, nutritional status, and total cholesterol, where boys presented 2.0 (95% CI 1.3 - 3.2); obese 6.2 (95% CI 2.7 - 17.2) and cholesterol levels above 150 mg / dL 3.5 (95% CI 2.1 - 5.7) times more likely to have the phenotype. In this way, the present research showed a high prevalence of HTW in schoolchildren from public schools, with boys, obese and schoolchildren with total cholesterol levels, the individuals most likely to have the phenotype. However, it is worth emphasizing the importance of monitoring these variables throughout the year in all courses, given the period of strong, biological, behavioral and psychological changes, as they can quickly change the values of the analyzed variables.
Sublethal concentrations of clothianidin affect honey bee colony behavior and interact with landscapes to affect colony growth
Authors: Meikle William G. , Adamczyk John J. , Weiss Milagra , Ross Janie , Werle Chris , Beren Eli
Published: June 2020

Honey bee colonies were exposed to sublethal concentrations (5 and 20 ppb) of clothianidin in sugar syrup, while control colonies were fed syrup with no pesticide. In addition to standard colony assessments of adult bees and brood, hive weight and internal temperature were monitored on a continuous basis at all sites. Experiments were conducted twice in Arizona, in successive years at the same site, and once in Mississippi, to examine the concomitant effects of weather and landscape. Adult bee masses at the Arizona site were significantly affected by clothianidin concentration. Newly-emerged bee dry weights, measured only at the Arizona site, were significantly lower for colonies fed 5 ppb clothianidin compared to the other groups. CO2concentration, also only measured at the Arizona site, was higher in colonies fed 20 ppb clothianidin. Neither daily hive weight change nor colony thermoregulation were affected by clothianidin exposure. The Mississippi site had higher rainfall, more diverse land use, and a different temperature regime, and bee colonies there did not show any effects of clothianidin. These results suggest that bee colonies in more stressful environments, such as the Sonoran desert of southern Arizona, are affected more by clothianidin exposure than colonies at sites with higher rainfall and more forage. Clothianidin was also found to be, like imidacloprid, highly stable in honey in the hive environment at least over several months. These results also showed that CO2concentration within the hive is potentially valuable in measuring the effects of stressors on bee health.
No evidence for insecticide resistance in a homogenous population ofAedes albopictusin Mecklenburg County, North Carolina
Authors: Mundis Stephanie J. , Hamerlinck Gabriela , Stone Emily K. , Whiteman Ari , Delmelle Eric , Rapp Tyler , Dulin Michael , Ryan Sadie J.
Published: June 2020

Aedes albopictusis a cosmopolitan mosquito species capable of transmitting arboviral diseases such as dengue, chikungunya, and Zika. To control this and similar species, public and private entities often rely on pyrethroid insecticides. Insecticide resistance status and physiological traits, such as body size, may contribute to local patterns of abundance, which is important for planning vector control. In this study, we genetically screenedAe. albopictuscollected from June to August, 2017, in Mecklenburg County, North Carolina, for mutations conferring pyrethroid resistance, and examined spatiotemporal patterns of specimen size, as measured by wing length. We hypothesized that size variation would be associated with factors found to influence abundance in similar populations ofAe. albopictus, and could therefore serve as a proxy measure. The genetic screening results indicated that known pyrethroid resistance alleles in twokdrregions are not present in this population. We detected no significant associations between wing length and socioeconomic and landscape factors, but mosquitoes collected in June had significantly longer wing length than in July or August. The lack of resistance indicators suggest that this population has not developed insecticide resistance via voltage-gated sodium channel mutations. The greater wing lengths in June are likely driven by meteorological patterns, suggesting that short-term weather cues may modulate morphological characteristics that, in turn, affect local fecundity and virus transmission potential.
Biochemical and structural insights into the activation of PBP1b by the essential domain of FtsN
Authors: Boes Adrien , Kerff Frederic , Herman Raphael , Touze Thierry , Breukink Eefjan , Terrak Mohammed
Published: June 2020

Peptidoglycan (PG) is an essential constituent of the bacterial cell wall. During cell division PG synthesis localizes at mid-cell under the control of a multiprotein complex, the divisome. InEscherichia coli, septal PG synthesis and cell constriction rely on the accumulation of FtsN at the division site. The region L75 to Q93 of FtsN (EFtsN) was shown to be essential and sufficient for its functioningin vivobut the specific target and the molecular mechanism remained unknown. Here, we show thatEFtsN binds specifically to the major PG synthase PBP1b and is sufficient to stimulate its GTase activity. We also report the crystal structure of PBP1b in complex withEFtsN which provides structural insights into the mode of binding ofEFtsN at the junction between the GTase and UB2H domains of PBP1b. Interestingly, the mutations R141A/R397A of PBP1b, within theEFtsN binding pocket, reduce the activation of PBP1b by FtsN. This mutant was unable to rescue ΔponB-ponAtsstrain at nonpermissive temperature and induced a mild cell chaining phenotype and cell lysis. Altogether, the results show that PBP1b is a target ofEFtsN and suggest that binding of FtsN to PBP1b contributes to trigger septal PG synthesis and cell constriction.
Mis-annotated multi nucleotide variants in public cancer genomics datasets can lead to inaccurate mutation calls with significant implications
Authors: Srinivasan Sujaya , Kalinava Natallia , Aldana Rafael , Li Zhipan , van Hagen Sjoerd , Rodenburg Sander Y.A. , Wind-Rotolo Megan , Sasson Ariella S. , Tang Hao , Qian Xiaozhong , Kirov Stefan
Published: June 2020

Background

Next generation sequencing is widely used in cancer to profile tumors and detect variants. Most somatic variant callers used in these pipelines identify variants at the lowest possible granularity – single nucleotide variants (SNVs). As a result, multiple adjacent SNVs are called individually instead of as a multi-nucleotide variant (MNV). The problem with this level of granularity is that the amino acid change from the individual SNVs within a codon could be different from the amino acid change based on the MNV that results from combining the SNVs. Most variant annotation tools do not account for this, leading to incorrect conclusions about the downstream effects of the variants.

Method

Here, we used Variant Call Files (VCFs) from the TCGA Mutect2 caller, and developed a solution to merge SNVs to MNVs. Our custom script takes the phasing information from the SNV VCFs and based on a gene model, determines if SNVs are at the same codon and need to be merged into a MNV prior to variant annotation.

Results

We analyzed 10,383 VCFs from TCGA and found 12,141 MNVs that were incorrectly annotated. Strikingly, the analysis of seven commonly mutated genes from 178 studies from cBioPortal revealed that MNVs were consistently missed in 20 of these studies, while they were correctly annotated in 15 more recent studies. The best and most common example of MNVs was found at the BRAF V600 locus, where several public datasets reported separate BRAF V600E and BRAF V600M variants, instead of a single merged V600K variant.

Conclusion

While some datasets merged MNVs correctly, many public datasets have not been corrected for this problem. As a best practice for variant calling, we recommend that MNVs be accounted for in NGS processing pipelines, thus improving analyses on the impact of somatic variants in cancer genomics.
JNK signalling regulates antioxidant responses in neurons
Authors: Ugbode Chris , Garnham Nathan , Fort-Aznar Laura , Evans Gareth , Chawla Sangeeta , Sweeney Sean T.
Published: June 2020

Reactive oxygen species (ROS) are generated during physiological bouts of synaptic activity and as a consequence of pathological conditions in the central nervous system. How neurons respond to and distinguish between ROS in these different contexts is currently unknown. In Drosophila mutants with enhanced JNK activity, lower levels of ROS are observed and these animals are resistant to both changes in ROS and changes in synapse morphology induced by oxidative stress. In wild type flies, disrupting JNK-AP-1 signalling perturbs redox homeostasis suggesting JNK activity positively regulates neuronal antioxidant defense. We validated this hypothesis in mammalian neurons, finding that JNK activity regulates the expression of the antioxidant geneSrxn-1, in a c-Jun dependent manner. We describe a conserved ‘adaptive’ role for neuronal JNK in the maintenance of redox homeostasis that is relevant to several neurodegenerative diseases.
Acute knockdown of extracellular matrix protein Tinagl1 disrupts heart laterality and pronephric cilia in zebrafish embryonic development
Authors: Neiswender Hannah , LeMosy Ellen K.
Published: June 2020

A highly-conserved extracellular matrix protein, Tinagl1, modulates Wnt, integrin, TGF-β, and EGF-R signalingin vitro,but its significancein vivohas remained in doubt. To bypass possible genetic compensation by an ortholog encoded exclusively in mammalian genomes, we examine Tinagl1 function in zebrafish embryos. In this model,tinagl1mRNA is detected in the developing spinal cord and pronephros. Acute knockdown using either CRISPR/Cas9 somatic mutagenesis or splice-blocking morpholinos reveals left-right (LR) heart looping defects, pronephros dilatations, and ventral body curvature. This constellation of defects characteristically results from the loss of motile cilia function, and we confirm the presence of shortened and fewer cilia in the pronephric duct and in the Kupffer’s vesicle where LR asymmetry is established. A link to known Wnt3a/β-catenin signaling that activates the motile cilia transcriptional program is supported by manipulation of Wnt3a and β-catenin levels intinagl1knockdown embryos. In addition to ciliopathy-like defects, thetinagl1knockdown shows disorganization of longitudinal axon tracts in the spinal cord and defects in motor neuron outgrowth. Together, these results provide evidence that Tinagl1 is important in development, and that zebrafish is an ideal model in which to explore its relationships to cilia and secreted signaling molecules.
Insights on cross-species transmission of SARS-CoV-2 from structural modeling
Authors: Rodrigues João PGLM , Barrera-Vilarmau Susana , Teixeira João MC , Seckel Elizabeth , Kastritis Panagiotis , Levitt Michael
Published: June 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global pandemic that has infected more than 14 million people in more than 180 countries worldwide. Like other coronaviruses, SARS-CoV-2 is thought to have been transmitted to humans from wild animals. Given the scale and widespread geographical distribution of the current pandemic, the question emerges whether human-to-animal transmission is possible and if so, which animal species are most at risk. Here, we investigated the structural properties of several ACE2 orthologs bound to the SARS-CoV-2 spike protein. We found that species known not to be susceptible to SARS-CoV-2 infection have non-conservative mutations in several ACE2 amino acid residues that disrupt key polar and charged contacts with the viral spike protein. Our models also predict affinity-enhancing mutations that could be used to design ACE2 variants for therapeutic purposes. Finally, our study provides a blueprint for modeling viral-host protein interactions and highlights several important considerations when designing these computational studies and analyzing their results.
Global landscape of phenazine biosynthesis and biodegradation reveals species-specific colonization patterns in agricultural soils and crop microbiomes
Authors: Dar Daniel , Thomashow Linda S. , Weller David M. , Newman Dianne K.
Published: June 2020

Phenazines are natural bacterial antibiotics that can protect crops from disease. However, for most crops it is unknown which producers and specific phenazines are ecologically relevant, and whether phenazine biodegradation can counter their effects. To better understand their ecology, we developed and environmentally-validated a quantitative metagenomic approach to mine for phenazine biosynthesis and biodegradation genes, applying it to >800 soil and plant-associated shotgun-metagenomes. We discover novel producer-crop associations and demonstrate that phenazine biosynthesis is prevalent across habitats and preferentially enriched in rhizospheres, whereas biodegrading bacteria are rare. We validate an association between maize andDyella japonica, a putative producer abundant in crop microbiomes.D. japonicaupregulates phenazine biosynthesis during phosphate limitation and robustly colonizes maize seedling roots. This work provides a global picture of phenazines in natural environments and highlights plant-microbe associations of agricultural potential. Our metagenomic approach may be extended to other metabolites and functional traits in diverse ecosystems.
Molecular basis for recognition ofListeriacell wall teichoic acid by the pseudo-symmetric SH3b-like repeats of a bacteriophage endolysin
Authors: Shen Yang , Kalograiaki Ioanna , Prunotto Alessio , Dunne Matthew , Boulos Samy , Taylor Nicholas M.I. , Sumrall Eric , Eugster Marcel R. , Martin Rebecca , Julian-Rodero Alicia , Gerber Benjamin , Leiman Petr G. , Menéndez Margarita , Peraro Matteo Dal , Cañada Francisco Javier , Loessner Martin J.
Published: June 2020

Endolysins are bacteriophage-encoded peptidoglycan hydrolases targeting the cell wall of host bacteria via their cell wall-binding domains (CBDs). The molecular basis for selective recognition of surface carbohydrate ligands by CBDs remains elusive. Here, we describe, in atomic detail, the interaction between theListeriaphage endolysin domain CBD500 and its cell wall teichoic acid (WTA) ligands. We show that 3’O-acetylated GlcNAc residues integrated into the WTA polymer chain are the key epitope recognized by a CBD binding cavity located at the interface of tandem copies ofbeta-barrel, pseudo-symmetric SH3b-like repeats. This cavity consists of multiple aromatic residues making extensive interactions with two GlcNAc acetyl groups via hydrogen bonds and van der Waals contacts, while permitting the docking of the diastereomorphic ligands. The multidisciplinary approach described here delineates a previously unknown recognition mechanism by which a phage endolysin specifically recognizes and targets WTA, suggesting an adaptable model for regulation of endolysin specificity.
Co-creating sustainable corporate brands: a consumer framing approach
Authors: Lahtinen Sonja , Närvänen Elina
Published: June 2020

Purpose

The purpose of this research is to explore how consumers co-create sustainable corporate brands (SCBs) by framing brands with a newly adopted sustainability orientation.

Design/methodology/approach

The qualitative data were generated from four focus groups consisting of altogether 25 Finnish millennial consumers. The data were analysed using thematic analysis, and the resulting themes were classified as different framings.

Findings

The findings indicate three ways of framing SCBs: as signs of corporate hypocrite, as threats that increase societal fragmentation and as signs of corporate enlightenment. These framings are based on two components: the perceived attributes and activities of the corporate brand.

Practical implications

The role of corporate brands is expanding from the business sphere towards actively influencing society. Yet, sustainability activities can be risky if consumers, as primary stakeholders, deem them unacceptable, unethical or untrustworthy. This research supports brand managers to succeed in co-creating SCBs as contributors to societal and environmental well-being, at a time when multiple stakeholders consider this a worthwhile endeavour.

Originality/value

The theoretical contribution is twofold: firstly, the paper extends the sustainable corporate branding literature by demonstrating how SCBs are co-created through an interactive framing process between the corporation and primary stakeholders, and, secondly, it contributes to the constitutive approach to corporate social responsibility communication (CSRC) research by showing how millennial consumers frame corporate brands that communicate corporations' newly adopted sustainability orientation.
Workplace accountabilities: worthy challenge or potential threat?
Authors: Brees Jeremy R. , Sikora David M. , Ferris Gerald R.
Published: June 2020

Purpose

Combining early and untested accountability perspectives with stress research, the authors examined the degree to which employees perceive workplace accountabilities as either worthy challenges to be overcome or potential threats to be avoided.

Design/methodology/approach

The authors utilized structural equation modeling to evaluate our hypotheses and tested them across two data samples, using two different sampling techniques collected four years apart.

Findings

Employees' individual differences of attribution style, negative affectivity and core self-evaluations influenced how subjects approached accountability pressures in their workplace, which in turn, was associated with job satisfaction and turnover intentions.

Originality/value

By examining how employees evaluate accountability pressures, this investigation advances existing research by exploring the different ways in which employees perceive workplace accountabilities.
Leading by bribing: evidence from China
Authors: Li Shaomin
Published: June 2020

Purpose

This study examines a new type of corruption that has not previously been studied but that significantly affects the world. Traditionally, corruption has referred to individuals or organizations that bribe state officials. The author examines a phenomenon in which the briber is actually the government of a country that bribes the rest of the world in order to gain influence and propose a framework to explain it.

Design/methodology/approach

A multi-case qualitative method is used to compile and analyze evidences and develop my arguments. Specifically, the author compiles information on and analyzes the Confucius Institutes, the training of future foreign leaders, influencing the influencers, the Thousand Talents Plan, the Belt and Road Initiative and foreign aid.

Findings

The findings reveal the existence of state-sponsored bribery of the world.

Social implications

State-sponsored bribery is a threat to the world. Recognizing it is the first step to curb it. Reducing the bribery by China's state will benefit the world and China.

Originality/value

State-sponsored bribery is originally defined and documented. A framework about the motivations and capabilities of state-sponsored bribery is proposed, the effects of and responses to such a bribery are reviewed, and policies to curb it are suggested.