bluuebunny/crossref_metadata_2025 huggingface dataset:
Calestous Juma. 9 June 1953—15 December 2017
Authors: Clark Norman G.
Published: June 2021

Until his untimely death in December 2017 Professor Calestous Juma was an internationally-recognized authority and leader in the application of science, engineering and innovation to sustainable development in developing and developed countries. His continuing original work focused on analysing the co-evolution of technological innovation and institutional change in socio-economic systems. He ran programmes that advanced science, technology and innovation policy research, especially biotechnology, provided high-level science and technology advice and promoted the conservation of biological diversity. Juma was a Kenyan national and US permanent resident.
Temporal trends in primary care-recorded self-harm during and beyond the first year of the COVID-19 pandemic: time series analysis of electronic healthcare records for 2.8 million patients in the Greater Manchester Care Record
Authors: Steeg Sarah , Bojanić Lana , Tilston George , Williams Richard , Jenkins David A. , Carr Matthew J. , Peek Niels , Ashcroft Darren M. , Kapur Nav , Voorhees Jennifer , Webb Roger T.
Published: June 2021

Background

Surveillance of clinically treated self-harm episode frequency is an important component of suicide prevention in the dynamic context of COVID-19. Studies published to date have investigated the initial months following the onset of the pandemic, despite national and regional restrictions persisting to Summer 2021.

Methods

We conducted a descriptive time series analysis utilising data from the Greater Manchester Care Record, which contains de-identified, primary care health records of 2.8 million patients. Counts of incident and all episodes of self-harm recorded between 1st January 2019 and 31st May 2021 were made for all patients, with stratification by sex, age group, ethnicity, and index of multiple deprivation (IMD) quintile and examination of overall differences by national and regional restriction phases.

Findings

Between 1st January 2019 and 31st May 2021, 33,444 episodes of self-harm by 13,148 individuals were recorded. Frequency ratios of incident and all episodes of self-harm were 0.59 (95% CI 0.51 to 0.69) and 0.69 (CI 0.63 to 0.75) respectively in April 2020 compared to February 2020. Between August 2020 and May 2021 frequency ratios were 0.92 (CI 0.88 to 0.96) for incident episodes and 0.86 (CI 0.84 to 0.88) for all episodes compared to the same months in 2019. Reductions were largest among men and people living in the most deprived neighbourhoods. An increase in all-episode self-harm (frequency ratio 1.09, CI 1.03 to 1.16) was observed for adolescents aged 10-17 between August 2020 and May 2021.

Interpretation

The COVID-19 pandemic has had a sustained impact on help seeking for self-harm. Reductions in primary care recorded self-harm have implications for clinicians’ ability to assess the needs and risks of individuals. Some patients may be experiencing prolonged untreated deterioration in their mental health while other groups are presenting in higher numbers. Our findings have important implications for primary care and mental health services in manging ongoing demand.

Funding

UKRI COVID-19 Rapid Response Initiative (grant reference COV0499), University of Manchester Presidential Fellowship (SS), and NIHR Greater Manchester Patient Safety Translational Research Centre.
The Impact of COVID-19 Restrictions on Childhood Vaccination Uptake: A Rapid Review
Authors: Heneghan C , Brassey J , Jefferson T.
Published: June 2021

Background

Vaccines are highly effective for preventing a range of childhood infections. However, there have been concerns about an alarming decline in vaccinations in 2020 due to the COVID-19 pandemic.

Methods

We performed a rapid review for studies that assessed childhood vaccination uptake during restrictive phases of the COVID-19 pandemic.

Results

We found 35 published studies that compared changes in the pattern of childhood vaccinations before and during the pandemic. Thirteen were surveys; two mixed-methods surveys and interviews, three modelling studies and 17 retrospective cohort studies with historical controls. We also included ten reports by national or international agencies that had original data on vaccination uptake. Significant global disruptions to vaccine services were reported in Africa, Asia, America (including Latin America and the Caribbean) and Europe. We also found evidence of significant disruption to vaccine uptake for diphtheria tetanus pertussis, BCG, measles and polio. Countries where vaccination rates were already suboptimal had greater drops in uptake and there was evidence of smaller declines in younger children compared to older children. Children born to women who could not read and write were more likely to be incompletely immunized. Various initiatives were used to drive up vaccination rates post restrictions.

Conclusions

Obstacles to the delivery of vaccination services during the Covid-19 pandemic drove down immunisation rates, especially in disadvantaged people and poorer countries.
A systematic review of persistent symptoms and residual abnormal functioning following acute COVID-19: Ongoing symptomatic phase vs. post-COVID-19 syndrome
Authors: Jennings Glenn , Monaghan Ann , Xue Feng , Mockler David , Romero-Ortuño Román
Published: June 2021

Objective

To compare the two phases of long COVID, namely ongoing symptomatic COVID-19 (OSC; signs and symptoms from 4 to 12 weeks from initial infection) and post-COVID-19 syndrome (PCS; signs and symptoms beyond 12 weeks) with respect to symptomatology, abnormal functioning, psychological burden, and quality of life.

Design

Systematic review.

Data Sources

Electronic search of EMBASE, MEDLINE, ProQuest Coronavirus Research Database, LitCOVID, and Google Scholar between January and April 2021, and manual search for relevant citations from review articles.

Eligibility Criteria

Cross-sectional studies, cohort studies, randomised control trials, and case-control studies with participant data concerning long COVID symptomatology or abnormal functioning.

Data Extraction

Studies were screened and assessed for risk of bias by two independent reviewers, with conflicts resolved with a third reviewer. The AXIS tool was utilised to appraise the quality of the evidence. Data were extracted and collated using a data extraction tool in Microsoft Excel.

Results

Of the 1,145 studies screened, 39 were included, all describing adult cohorts with long COVID and sample sizes ranging from 32 to 1,733. Studies included data pertaining to symptomatology, pulmonary functioning, chest imaging, cognitive functioning, psychological disorder, and/or quality of life. Fatigue presented as the most prevalent symptom during both OSC and PCS at 43% and 44%, respectively. Sleep disorder (36%; 33%), dyspnoea (31%; 40%), and cough (26%; 22%) followed in prevalence. Abnormal spirometry (FEV1 <80% predicted) was observed in 15% and 11%, and abnormal chest imaging observed in 34% and 28%, respectively. Cognitive impairments were also evident (20%; 15%), as well as anxiety (28%; 34%) and depression (25%; 32%). Decreased quality of life was reported by 40% of patients with OSC and 57% by those with PCS.

Conclusions

The prevalences of OSC and PCS were highly variable. Reported symptoms covered a wide range of body systems, with general overlap in frequencies between the two phases. However, abnormalities in lung function and imaging seemed to be more common in OSC, whilst anxiety, depression, and poor quality of life seemed more frequent in PCS. In general, the quality of the evidence was moderate and further research is needed to better understand the complex interplay of somatic versus psychosocial drivers in long COVID.

Systematic Review Registration

Registered with PROSPERO with ID #CRD42021247846.
Biophysical Models of PAR Cluster Transport by Cortical Flow in C. elegans Early Embryogenesis
Authors: Zmurchok Cole , Holmes William R.
Published: June 2021

The clustering of membrane-bound proteins facilitates their transport by cortical actin flow in early Caenorhabditis elegans embryo cell polarity. PAR-3 clustering is critical for this process, yet the bio-physical processes that couple protein clusters to cortical flow remain unknown. We develop a discrete, stochastic agent-based model of protein clustering and test four hypothetical models for how clusters may interact with the flow. Results show that the canonical way to assess transport characteristics from single particle tracking data used thus far in this area, the Péclet number, is insufficient to distinguish these hypotheses and that all models can account for transport characteristics quantified by this measure. However, using this model, we demonstrate that these different cluster-cortex interactions may be distinguished using a different metric, namely, the scalar projection of cluster displacement on to the flow displacement vector. Our results thus provide a testable way to use existing single particle tracking data to test how endogenous protein clusters may interact with the cortical flow to localize during polarity establishment. To facilitate this investigation, we also develop both improved simulation and semi-analytic methodologies to quantify motion summary statistics (e.g., Péclet number and scalar projection) for these stochastic models as a function of biophysical parameters.
HPLC Method to Resolve, Identify and Quantify Guanine Nucleotides Bound to the GTPase Ras
Authors: Hannan Jonathan P. , Hayden Swisher G. , Martyr Justin G. , Cordaro Nicholas J. , Erbse Annette H. , Falke Joseph J.
Published: June 2021

The Ras superfamily of small G proteins play central roles in diverse signaling pathways. Superfamily members act as molecular on-off switches defined by their occupancy with GTP or GDP, respectively. In vitro functional studies require loading with a hydrolysis-resistant GTP analogue to increase the on-state lifetime, as well as knowledge of fractional loading with activating and inactivating nucleotides. The present study describes a method combining elements of previous approaches with new, optimized features to analyze the bound nucleotide composition of a G protein loaded with activating (GMPPNP) or inactivating (GDP) nucleotide. After nucleotide loading, the complex is washed to remove unbound nucleotides then bound nucleotides are heat-extracted and subjected to ion-paired, reverse-phase HPLC-UV to resolve, identify and quantify the individual nucleotide components. These data enable back-calculation to the nucleotide composition and fractional activation of the original, washed G protein population prior to heat extraction. The method is highly reproducible. Application to multiple HRas preparations and mutants confirms its ability to fully extract and analyze bound nucleotides, and to resolve the fractional on- and off-state populations. Furthermore, the findings yield a novel hypothesis for the molecular disease mechanism of Ras mutations at the E63 and Y64 positions.
Complex basis of hybrid female sterility and Haldane’s rule inHeliconiusbutterflies: Z-linkage and epistasis
Authors: Rosser Neil , Edelman Nathaniel B. , Queste Lucie M. , Nelson Michaela , Seixas Fernando , Dasmahapatra Kanchon K. , Mallet James
Published: June 2021

Hybrids between diverging populations are often sterile or inviable. Hybrid unfitness usually evolves first in the heterogametic sex – a pattern known as Haldane’s rule. The genetics of Haldane’s Rule have been extensively studied in species where the male is the heterogametic (XX/XY) sex, but its basis in taxa where the female is heterogametic (ZW/ZZ), such as Lepidoptera and birds, is largely unknown. Here, we analyse a new case of female hybrid sterility between geographic subspecies ofHeliconius pardalinus. The two subspecies mate freely in captivity, but female F1 hybrids in both directions of cross are sterile. Sterility is due to arrested development of oocytes after they become differentiated from nurse cells, but before yolk deposition. We backcrossed fertile male F1 hybrids to parental females, and mapped quantitative trait loci (QTLs) for female sterility. We also identified genes differentially expressed in the ovary, and as a function of oocyte development. The Z chromosome has a major effect, similar to the “large X effect” inDrosophila, with strong epistatic interactions between loci at either end of the Z chromosome, and between the Z chromosome and autosomal loci on chromosomes 8 and 20. Among loci differentially expressed between females with arrested vs. non-arrested ovary development, we identified six candidate genes known also fromDrosophila melanogasterandParage aegeriaoogenesis. This study is the first to characterize hybrid sterility using genome mapping in the Lepidoptera. We demonstrate that sterility is produced by multiple complex epistastic interactions often involving the sex chromosome, as predicted by the dominance theory of Haldane’s Rule.
Strategies ofMycoplasma ovipneumoniaeto evade immune clearance by alveolar macrophages
Authors: Gao Liyang , Zhang Kai , Zhang Ying , Ma Chunji , Zhou Xiaoyu , Li Min
Published: June 2021

Chronic nonprogressive pneumonia is a prevalent disease that infects many young sheep.Mycoplasma ovipneumoniaewas isolated from the lungs of sheep with chronic nonprogressive pneumonia. Evidences showed that it might associate with the development and duration of chronic pneumonia, moreover, sheep infected withM. ovipneumoniaeare easily infected by other organisms, suggesting thatM. ovipneumoniaemay play an immunosuppressive role during infection. However, the mechanism is still poorly understood. The infection occurs in the airway, where resident alveolar macrophages first encounterM. ovipneumoniae. Therefore, primary alveolar macrophages (AMs) were collected from the lungs of healthy adult sheep, and the (iTRAQ) protein assay was used to investigate the immunosuppressive effects ofM. ovipneumoniaeon sheep AMs. The RAW264.7 cells were used to confirm the findings. The results showed thatM. ovipneumoniaepromoted higher expression of anti-apoptotic proteins and lower expression of apoptosis-related proteins in the infected AMs. Moreover, the number of infected AMs increased. However,M. ovipneumoniaereduced ATP levels in AMs and impaired late endosome maturation and phagolysosome fusion. Furthermore,M. ovipneumoniaeinhibited the autophagy pathway via the Akt-mTOR axis in AMs. These findings indicated thatM. ovipneumoniaehad distinctive strategies to evade elimination caused by the AMs. The findings might explain the chronic infection and co-infection in sheep infected byM. ovipneumoniae.
Natural isolate and recombinant SARS-CoV-2 rapidly evolve in vitro to higher infectivity through more efficient binding to heparan sulfate and reduced S1/S2 cleavage
Authors: Shiliaev Nikita , Lukash Tetyana , Palchevska Oksana , Crossman David K. , Green Todd J. , Crowley Michael R. , Frolova Elena I. , Frolov Ilya
Published: June 2021

One of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virulence factors is the ability to interact with high affinity to the ACE2 receptor, which mediates viral entry into cells. The results of our study demonstrate that within a few passages in cell culture, both the natural isolate of SARS-CoV-2 and the recombinant, cDNA-derived variant acquire an additional ability to bind to heparan sulfate (HS). This promotes a primary attachment of viral particles to cells before their further interactions with the ACE2. Interaction with HS is acquired through multiple mechanisms. These include i) accumulation of point mutations in the N-terminal domain (NTD) of the S protein, which increase the positive charge of the surface of this domain, ii) insertions into NTD of heterologous peptides, containing positively charged amino acids, and iii) mutation of the first amino acid downstream of the furin cleavage site. This last mutation affects S protein processing, transforms the unprocessed furin cleavage site into the heparin-binding peptide and makes viruses less capable of syncytia formation. These viral adaptations result in higher affinity of viral particles to heparin sepharose, dramatic increase in plaque sizes, more efficient viral spread, higher infectious titers and two orders of magnitude lower GE:PFU ratios. The detected adaptations also suggest an active role of NTD in virus attachment and entry. As in the case of other RNA+ viruses, evolution to HS binding may result in virus attenuation in vivo.

IMPORTANCE

The spike protein of SARS-CoV-2 is a major determinant of viral pathogenesis. It mediates binding to ACE2 receptor and later, fusion of viral envelope and cellular membranes. The results of our study demonstrate that SARS-CoV-2 rapidly evolves during propagation in cultured cells. Its spike protein acquires mutations in the N-terminal domain (NTD) and in P1‘ position of the furin cleavage site (FCS). The amino acid substitutions or insertions of short peptides in NTD are closely located on the protein surface and increase its positive charge. They strongly increase affinity of the virus to heparan sulfate, make it dramatically more infectious for the cultured cells and decrease GE:PFU ratio by orders of magnitude. The S686G mutation also transforms the FCS into the heparin-binding peptide. Thus, the evolved SARS-CoV-2 variants efficiently use glycosaminoglycans on the cell surface for primary attachment before the high affinity interaction of the spikes with the ACE2 receptor.
Chloride intracellular channel 4 (CLIC4) expression is transcriptionally regulated by crosstalk of the TGF-β, Wnt and Hedgehog signalling pathways
Authors: Wasson Christopher W. , Caballero-Ruiz Begoña , Mankouri Jamel , Canettieri Gianluca , Riobo-Del Galdo Natalia A. , Del Galdo Francesco
Published: June 2021

Chloride intracellular channel 4 (CLIC4) is a recently discovered driver of fibroblast activation in Scleroderma (SSc) and cancer-associated fibroblasts. CLIC4 expression and activity are regulated by TGF-β signalling through the SMAD3 transcription factor. In view of the aberrant activation of canonical Wnt and Hedgehog (Hh) signalling in fibrosis, we investigated their role in CLIC4 upregulation. Here, we show Wnt3a/β-catenin and Smoothened/GLI signalling cooperate with SMAD3 to regulate CLIC4 expression in normal dermal fibroblasts, and that inhibition of SMAD3 expression or activity abolishes Wnt and Hh-dependent CLIC4 induction. We further show that expression of the profibrotic marker α-smooth muscle actin strongly correlates with CLIC4 expression in dermal fibroblasts. Our data highlight novel mechanisms that regulate CLIC4 expression that present targetable pathways to prevent fibroblast activation in SSc and other fibrotic conditions.
Absolute quantitation of individual SARS-CoV-2 RNA molecules: a new paradigm for infection dynamics and variant differences
Authors: Lee Jeffrey Y , Wing Peter AC , Gala Dalia S , Noerenberg Marko , Järvelin Aino I , Titlow Josh , Zhuang Xiaodong , Palmalux Natasha , Iselin Louisa , Thompson Mary Kay , Parton Richard M , Wainman Alan , Agranoff Daniel , James William , Castello Alfredo , McKeating Jane A , Davis Ilan
Published: June 2021

Despite an unprecedented global research effort on SARS-CoV-2, early replication events remain poorly understood. Given the clinical importance of emergent viral variants with increased transmission, there is an urgent need to understand the early stages of viral replication and transcription. We used single molecule fluorescence in situ hybridisation (smFISH) to quantify positive sense RNA genomes with 95% detection efficiency, while simultaneously visualising negative sense genomes, sub-genomic RNAs and viral proteins. Our absolute quantification of viral RNAs and replication factories revealed that SARS-CoV-2 genomic RNA is long-lived after entry, suggesting that it avoids degradation by cellular nucleases. Moreover, we observed that SARS-CoV-2 replication is highly variable between cells, with only a small cell population displaying high burden of viral RNA. Unexpectedly, the B.1.1.7 variant, first identified in the UK, exhibits significantly slower replication kinetics than the Victoria strain, suggesting a novel mechanism contributing to its higher transmissibility with important clinical implications.

Graphical Abstract

In brief

By detecting nearly all individual SARS-CoV-2 RNA molecules, we quantified viral replication and defined cell susceptibility to infection. We discovered that a minority of cells show significantly elevated viral RNA levels and observed slower replication kinetics for the Alpha variant relative to the Victoria strain.

Highlights

Single molecule quantification of SARS-CoV-2 replication uncovers early infection kinetics

There is substantial heterogeneity between cells in rates of SARS-CoV-2 replication

Genomic RNA is stable and persistent during the initial stages of infection

B.1.1.7 variant replicates more slowly than the Victoria strain
Insulin-dependent and -independent dynamics of insulin receptor trafficking in muscle cells
Authors: Cen Haoning Howard , Rogalski Jason , Abraham Libin , Gold Michael R. , Foster Leonard J. , Johnson James D.
Published: June 2021

Insulin resistance contributes to type 2 diabetes and can be driven by hyperinsulinemia. Insulin receptor (INSR) internalization and cell-surface dynamics at rest and during insulin exposure are incompletely understood in muscle cells. Using surfacing labeling and live-cell imaging, we observed robust basal internalization of INSR in C2C12 myoblasts, without a robust effect of added insulin. Mass-spectrometry analysis of INSR-binding proteins identified potential molecular mechanisms associated with internalization. We confirmed known interactors, including IGF1R, but also identified underappreciated INSR-binding factors such as ANXA2. Protein-protein interaction network mapping suggested links between INSR and caveolin-mediated endocytosis. INSR interacted with both caveolin and clathrin heavy chain (CLTC) in mouse skeletal muscle and C2C12 myoblasts. Whole cell 2D super-resolution imaging revealed that high levels of insulin (20 nM) increased INSR colocalization with CAV1 but decreased its colocalization with CLTC. Single particle tracking confirmed the colocalization of cell-surface INSR with both over-expressed CAV1-mRFP and CLTC-mRFP. INSR tracks that colocalized with CAV1 exhibited longer radii and lifetimes, regardless of insulin exposure, compared to non-colocalized tracks, whereas insulin further increased the lifetime of INSR/CLTC colocalized tracks. Overall, these data suggest that muscle cells utilize both CAV1 and CLTC-dependent pathways for INSR dynamics and internalization.
Estimating the conjugative transfer rate of antibiotic resistance genes: Effect of model structural errors
Authors: Mishra Sulagna , Berendonk Thomas U , Kneis David
Published: June 2021

The spread of antibiotic resistance genes (ARG) occurs widely through plasmid transfer majorly facilitated via bacterial conjugation. To assess the spread of these mobile ARG, it is necessary to develop appropriate tools to estimate plasmid transfer rates under different environmental conditions. Process-based models are widely used for the estimation of plasmid transfer rate constants. Empirical studies have repeatedly highlighted the importance of subtle processes like delayed growth, the maturation of transconjugants, the physiological cost of plasmid carriage, and the dependence of conjugation on the culture′s growth stage. However, models used for estimating the transfer rates typically neglect them. We conducted virtual mating experiments to quantify the impact of these four typical structural model deficits on the estimated plasmid transfer rate constants. We found that under all conditions, the plasmid cost and the lag phase in growth must be taken into account to obtain unbiased estimates of plasmid transfer rate constants. We observed a tendency towards the underestimation of plasmid transfer rate constants when structurally deficient models were fitted to virtual mating data. This holds for all the structural deficits and mating conditions tested in our study. Our findings might explain an important component of the negative bias in model predictions known as the plasmid paradox. We also discuss other structural deficits that could lead to an overestimation of plasmid transfer rate constants and we demonstrate the impact of ill-fitted parameters on model predictions.
Lipid-mediated Association of the Slg1 Transmembrane Domains in Yeast Plasma Membranes
Authors: Alavizargar Azadeh , Elting Annegret , Wedlich-Söldner Roland , Heuer Andreas
Published: June 2021

Clustering of transmembrane proteins underlies a multitude of fundamental biological processes at the plasma membrane (PM) such as receptor activation, lateral domain formation and mechanotransduction. The self-association of the respective transmembrane domains (TMD) has also been suggested to be responsible for the micron-scaled patterns seen for integral membrane proteins in the budding yeast plasma membrane. However, the underlying interplay between local lipid composition and TMD identity is still not mechanistically understood. In this work we combined coarse-grained molecular dynamics (MD) simulations of simplified bilayer systems with high resolution live-cell microscopy to analyze the distribution of a representative helical yeast TMD from the PM sensor Slg1 within different lipid environments. In our simulations we specifically evaluated the effects of acyl chain saturation and anionic lipids head groups on the association of two TMDs. We found that weak lipid-protein interactions significantly affect the configuration of TMD dimers and the free energy of association. Increased amounts of unsaturated phospholipids strongly reduced helix-helix interaction, while the presence of anionic phosphatidylserine (PS) hardly affected dimer formation. We could experimentally confirm this surprising lack of effect of PS using the network factor, a mesoscopic measure of PM pattern formation in yeast cells. Simulations also showed that formation of TMD dimers in turn increased the order parameter of the surrounding lipids and induced long-range perturbations in lipid organization. In summary, our results shed new light on the mechanisms for lipid-mediated dimerization of TMDs in complex lipid mixtures.
Generation of liver organoids from human induced pluripotent stem cells as liver fibrosis and steatosis models
Authors: Tsang Hoi Ying , Yi Lo Paulisally Hau , Ho Lee Kenneth Ka
Published: June 2021

Background & Aims

Liver cirrhosis is a major cause of death worldwide, and its prevalence is growing rapidly due to the growth of obesity and diabetes population with non-alcoholic fatty liver disease (NAFLD). Yet, no effective therapeutics have been developed to treat NAFLD or its more advanced stage, non-alcoholic steatohepatitis (NASH). This has raised great concern for a representative liver model to be developed so that novel drugs could be screened, identified and developed. Presently, we aim to develop a liver organoid entirely from human induced pluripotent stem cells (hiPSC) to model liver fibrogenesis and NAFLD.

Methods

Hepatoblasts (HBs), mesenchymal stem cells (MSCs), hepatic stellate cell (HSCs) and endothelial cells (ECs) were derived from hiPSCs, allowed to self-organized and differentiated into liver organoids. Liver functions, transcriptomic and protein expression of liver organoids were characterized and validated. Liver organoids were exposed to thioacetamide (TAA) and free fatty acids (FFA) to be induced into liver disease model.

Results

The liver organoids we fabricated were highly vascularized, exhibited liver-specific functions and hepatic cellular spatial organization. The presence of liver specific ECs, macrophages and cholangiocytes were found within our organoids. TAA induced fibrosis in our liver organoids that exhibited diminished liver functions, elevated pro-inflammatory cytokines and fibrosis-related gene expression, as well as extensive collagen deposit. Organoids treated with FFA developed steatosis, inflammation and fibrosis.

Conclusions

We generated a novel method, that is Matrigel-independent and size-controllable, for making human liver organoids. These organoids can potentially be utilized as tissue-mimetic in vitro model for high throughput screening to identify drugs that can be used to treat liver fibrosis and NAFLD.
The Lon protease temporally restricts polar cell differentiation events during the Caulobacter cell cycle
Authors: Omnus Deike J. , Fink Matthias J. , Szwedo Klaudia , Jonas Kristina
Published: June 2021

The highly conserved protease Lon has important regulatory and protein quality control functions in cells from the three domains of life. Despite many years of research on Lon, only few specific protein substrates are known in most organisms. Here, we used a quantitative proteomics approach to identify novel substrates of Lon in the dimorphic bacterium Caulobacter crescentus. We focused our study on proteins involved in polar cell differentiation and investigated the developmental regulator StaR and the flagella hook length regulator FliK as specific Lon substrates in detail. We show that Lon recognizes these proteins at their C-termini, and that Lon-dependent degradation ensures their temporally restricted accumulation in the cell cycle phase when their function is needed. Disruption of this precise temporal regulation of StaR and FliK levels in a Δlon mutant contributes to defects in stalk biogenesis and motility, respectively, revealing a critical role of Lon in coordinating developmental processes with cell cycle progression. Our work underscores the importance of Lon in the regulation of complex temporally controlled processes by adjusting the concentrations of critical regulatory proteins. Furthermore, this study includes the first characterization of FliK in C. crescentus and uncovers a dual role of the C-terminal amino acids of FliK in protein function and degradation.
Nascent alt-protein chemoproteomics reveals a repressor of ribosome biogenesis
Authors: Cao Xiongwen , Khitun Alexandra , Harold Cecelia M. , Bryant Carson J. , Zheng Shu-Jian , Baserga Susan J. , Slavoff Sarah A.
Published: June 2021

Many unannotated microproteins and alternative proteins (alt-proteins) have recently been found to be co-encoded with canonical proteins, but few of their functions are known. Motivated by the hypothesis that alt-proteins undergoing active or stress-induced synthesis could play important cellular roles, here, we developed a chemoproteomic pipeline to identify nascent alt-proteins in human cells. We identified 22 actively translated unannotated alt-proteins, one of which is upregulated after DNA damage stress. We further defined MINAS-60 (MIcroprotein thatNegatively regulatesASsembly of the pre-60S ribosomal subunit), a nucleolar localized alt-protein co-encoded with human RBM10.Depletion of MINAS-60 increases the amount of the mature 60S ribosomal subunit, consequently upregulating global protein synthesis and cell proliferation by repressing late-stage pre-60S assembly and export of the 60S ribosome subunit to the cytoplasm. Together, these results implicate MINAS-60 as a repressor of ribosome biogenesis, and demonstrate that chemoproteomics can enable generation of functional hypotheses for uncharacterized alt-proteins.
An RNAi screen for genes that affect nuclear morphology in Caenorhabditis elegans reveals the involvement of unexpected processes
Authors: Maheshwari Richa , Rahman Mohammad M. , Joseph-Strauss Daphna , Cohen-Fix Orna
Published: June 2021

Aberration in nuclear morphology is one of the hallmarks of cellular transformation. However, the processes that, when mis-regulated, result aberrant nuclear morphology are poorly understood. In this study we carried out a systematic, high-throughput RNAi screen for genes that affect nuclear morphology in Caenorhabditis elegans embryos. The screen employed over 1700 RNAi constructs against genes required for embryonic viability. Nuclei of early embryos are typically spherical and their NPCs are evenly distributed. The screen was performed on early embryos expressing a fluorescently tagged component of the nuclear pore complex (NPC), allowing visualization of nuclear shape as well as the distribution of NPCs around the nuclear envelope. Our screen uncovered 182 genes whose down-regulation resulted in one or more abnormal nuclear phenotypes, including multiple nuclei, micronuclei, abnormal nuclear shape, anaphase bridges and abnormal NPC distribution. Many of these genes fall into common functional groups, including some that were not previously known to affect nuclear morphology, such as genes involved in mitochondrial function, the vacuolar ATPase and the CCT chaperonin complex. The results of this screen add to our growing knowledge of processes that affect nuclear morphology and that may be altered in cancer cells that exhibit abnormal nuclear shape.
NON-LINEAR SUSCEPTIBILITY TO INTERFERENCES IN DECLARATIVE MEMORY FORMATION
Authors: Moyano Malen D. , Giulia Carbonari , Matías Bonilla , Pedreira María E. , Brusco Luis I. , Laura Kaczer , Cecilia Forcato
Published: June 2021

After encoding, memories go through a labile state followed by a stabilization process known as consolidation. Once consolidated they can enter a new labile state after the presentation of a reminder of the original memory, followed by a period of restabilization (reconsolidation). During these periods of lability the memory traces can be modified. Currently, there are studies that show a rapid stabilization after 30 min, while others show that stabilization occurs after longer periods (e.g. 6 h). Here we investigate the effect of an interference treatment on declarative memory consolidation, comparing distinct time intervals after acquisition. On day 1, participants learned a list of non-syllable pairs (List 1). Immediately after, 30 min, 3 h or 8 h later, they received an interference list (List 2) that acted as an amnesic agent. On day 2 (48 h after training) participants had to recall List 1 first, followed by List 2. We found that the List 1 memory was susceptible to interference when the List 2 was administered immediately or 3 h after learning; however, shortly after acquisition (e.g. 30 min) the List 1 memory becomes transiently protected against interference. We propose the possibility that this rapid memory protection could be induced by a fast and transient neocortical integration (where the memory is transiently protected) becoming partially independent from the hippocampus followed by a hippocampal re-engagement where the memory becomes susceptible to interferences again. Our results open a discussion about the contribution of molecular and systemic aspects to memory consolidation.
Road crack detection and quantification based on segmentation network using architecture of matrix
Authors: Li Gang , Chen Yongqiang , Zhou Jian , Zheng Xuan , Li Xue
Published: June 2021

Purpose

Periodic inspection and maintenance are essential for effective pavement preservation. Cracks not only affect the appearance of the road and reduce the levelness, but also shorten the life of road. However, traditional road crack detection methods based on manual investigations and image processing are costly, inefficiency and unreliable. The research aims to replace the traditional road crack detection method and further improve the detection effect.

Design/methodology/approach

In this paper, a crack detection method based on matrix network fusing corner-based detection and segmentation network is proposed to effectively identify cracks. The method combines ResNet 152 with matrix network as the backbone network to achieve feature reuse of the crack. The crack region is identified by corners, and segmentation network is constructed to extract the crack. Finally, parameters such as the length and width of the cracks were calculated from the geometric characteristics of the cracks and the relative errors with the actual values were 4.23 and 6.98% respectively.

Findings

To improve the accuracy of crack detection, the model was optimized with the Adam algorithm and mixed with two publicly available datasets for model training and testing and compared with various methods. The results show that the detection performance of our method is better than many excellent algorithms, and the anti-interference ability is strong.

Originality/value

This paper proposed a new type of road crack detection method. The detection effect is better than a variety of detection algorithms and has strong anti-interference ability, which can completely replace traditional crack detection methods and meet engineering needs.
What makes better career opportunities for young graduates? Examining acquired employability skills in higher education institutions
Authors: Ng Peggy M.L. , Chan Jason K. Y. , Wut Tai Ming , Lo Man Fung , Szeto Irene
Published: June 2021

Purpose

The purpose of this paper is to develop a conceptual model to examine key employability skills that match workplace requirements and foster employability.

Design/methodology/approach

This research comprises a cross-sectional study from self-financing institutions in Hong Kong. The current study adopted structural equation modeling to examine key employability skills that match workplace requirements and foster employability.

Findings

Based on the empirical findings, the acquired employability skills of young graduates are entrepreneurship, professional development, work with others, self-management, communication and problem solving. Moreover, higher education institutions should work closely with industry stakeholders to get employers engaged with the work-integrating learning (WIL) programs and subsequently equip young graduates for better employability opportunities. In connection with employer engagement, employability skills of communication, problem solving and self-management would be improved. Furthermore, entrepreneurship and problem-solving skills could further be developed for young graduating students working in SME organizations during WIL.

Originality/value

As a notable gap exists in the current literature to examine young graduates' key employability skills in the context and content of Hong Kong self-financing tertiary education, this research explores key employability skills of self-financed young graduates and the relative importance of employability skills across company size using a quantitative approach.
External wine education and certification for restaurant service staff: a mixed-methods evaluation of training effectiveness
Authors: Orlowski Marissa
Published: June 2021

Purpose

The purpose of this mixed-methods explanatory sequential study was to assess the effects of an external wine education and certification program on trainee reactions, learning, transfer and financial results.

Design/methodology/approach

The quantitative phase was a mixed experimental design in which the training intervention was between-subjects and time was within-subjects. The sample comprises 91 employees (NTraining = 43; NControl = 48) from 12 units of a fine dining restaurant group. The qualitative phase, comprised of semi-structured interviews with training group participants (N = 12), was implemented after the experiment.

Findings

Training group participants reported high scores for attitude toward training content, instructional satisfaction and transfer motivation. Financial metrics, tracked up to 60 days post-training, demonstrated the wine education program was effective in increasing wine knowledge but not wine sales. Four themes emerged from the qualitative data: sense of accomplishment, enhanced guest interaction, tips and gratuities and defeat. Integrated findings revealed increased wine knowledge led to personal financial impact (increased tips) rather than organizational impact.

Originality/value

This research builds on existing training literature and human capital theory by examining external training programs. Further, the use of a mixed-methods design and integration of the quantitative and qualitative findings offers a previously unidentified explanation for why wine training, although effective in facilitating positive reactions and learning, fails to result in transfer behaviors which generate increased wine sales.
A missing link: a distributed cognitive perspective on fit
Authors: Herath Gayanga Bandara
Published: June 2021

Purpose

This article presents a cognitive framework to study dynamic/adaptive aspects of a collection of popular fit measures used in organisation research, in an attempt to highlight what there is to be gained.

Design/methodology/approach

This paper uses a distributed e-cognition (DEC) framework to examine the current organisational literature of fit measures.

Findings

This paper highlights that most measures have a rather narrow focus and do not address dynamic/adaptive aspects in complex social systems (e.g. organisations). To both provide a way to integrate fit measures and cover the cognition gap in this literature, this article highlights the need for a more sophisticated measure.

Originality/value

This paper provides a novel approach to examining organisational fit literature through a distributed (e)-cognitive framework.
Impact assessment of innovation tax incentives in Brazil
Authors: Colombo Daniel Gama e , Cruz Helio Nogueira da
Published: June 2021

Purpose

This paper evaluates the effects of tax incentives on business innovation in Brazil that were established by Law 11,196/05 (the “Fiscal Incentives Law”) to test whether they have had a positive impact on beneficiary firms' innovation input and output and on their performance.

Design/methodology/approach

The policy impacts are estimated using microdata on 13,706 firms available in the 2008 and 2011 editions of the Brazilian Innovation Survey (PINTEC) and by applying propensity score matching with difference-in-differences.

Findings

The results suggest a positive and statistically significant impact of the policy on research and development (R&D) expenditures (average of approximately US$ 264,000 in 2011), the number of research staff (average of five researchers) and total employment (approximately 5% of the beneficiary firms' mean size). However, no impact was found on the overall spending on innovative activities, the percentage of sales and exports from new products, net revenue or net revenue per employee.

Practical implications

The findings provide empirical support in favor of tax incentives as a policy tool to boost business innovation in the country. However, the absence of significant effects on innovative activities expenditures and on most indicators of innovation output and firms' performance reveals shortcomings of the policy that need to be addressed.

Originality/value

The study complements and advances the findings of previous studies by assessing policy impact on total innovative activities expenditures and on innovation output and firm performance.
Influence of trust and risk on peer-to-peer investment willingness: a bidirectional perspective
Authors: Zhai Mengfan , Chen Yuan , Wei Mingxia
Published: June 2021

Purpose

The purpose of this paper is to investigate the influence of trust and perceived risk on investment willingness considering the bidirectional relationship between trust and perceived risk in peer-to-peer (P2P) lending.

Design/methodology/approach

Data were collected from a leading Chinese P2P platform, PPDAI.com. In total, 328 valid responses were received and analyzed using structural equation modeling (SEM).

Findings

The results show that the influence of trust on investment willingness is significant, whereas that of perceived risk is insignificant. The results also indicate that platform reputation has a positive effect on trust, and the quality of alternatives is positively associated with perceived risk. In addition, the bidirectional perspective should be preferred to cope with the bidirectional relationship between trust and perceived risk in P2P lending.

Originality/value

This study extends existing research on the influence of trust and perceived risk on investment willingness from a bidirectional perspective, which has not been addressed in the P2P lending context. In addition, this research enriches the current literature about trust and perceived risk by providing more evidence that the relationship between trust and perceived risk is bidirectional and thus the bidirectional model should be preferred. For practice, the study suggests that managers can earn trust and reduce the perceived risk of lenders by continuously providing high-quality products, services and enhancing platform reputation, ultimately improving their investment willingness.
A multidisciplinary response to sexual assault: the case review process for previously unsubmitted sexual assault kits
Authors: Melton Heather C.
Published: June 2021

Purpose

Sexual assault continues to be a major criminal problem. Sexual assault kits (SAK) are one way to preserve evidence to use to pursue justice in sexual assault cases. In recent years, it has become clear that very often these SAKs are never sent to the crime lab to be processed. In an effort to deal with these unsubmitted kits and to research their impact, the Bureau of Justice Assistance funded various grants, known as the Sexual Assault Kit Initiative (SAKI) nationwide to create multidisciplinary teams to both improve the process and response to sexual assault and to provide research on this issue. This paper aims to explore a process created by one of the multidisciplinary teams in one SAKI site – the case review. Ultimately, the goal is to explore how different participants in the case review process perceive and experience the case review and provide implications of these findings.

Design/methodology/approach

Using surveys of case review participants, participant observation and key stakeholder interviews findings indicate that case reviews are beneficial in terms of training, collaboration and overall response to sexual assault.

Findings

Using all methods, the participants of case reviews found them beneficial. Both new information was gleaned from almost every case review and decisions on particular cases were potentially changed, particularly among the key stakeholders with the ability to impact decisions in sexual assault cases – law enforcement and prosecutors. Issues were raised through the case review process that might not have been without this process. Thus, case reviews have the potential to affect policy and practice and improve future reporting, investigations and prosecutions of sexual assault cases.

Practical implications

Multidisciplinary responses to sexual assault cases, specifically the case review process, are beneficial. Issues for training, opportunities for collaboration and general issues for a particular jurisdiction are all potentially raised during a case review. The case reviews need to be organized, preparation work completed and properly facilitated to be effective. Participants in the case review process themselves perceive case reviews to be beneficial.

Originality/value

This paper presents findings from one of the SAKI sites. A specific process, the case review process, that was developed and implemented at this site was explored. The findings on this process have implications for both practice and policy.