bluuebunny/crossref_metadata_2025 huggingface dataset:
A Logistic Formula in Biology and Its Application to Deaths by the Third Wave of COVID-19 in Japan
Authors: Kokado Akira , Saito Takesi
Published: February 2021

A logistic formulation in biology is applied to analyze deaths by the third wave of COVID-19 in Japan.
Clinical Prediction Models for Primary Prevention of Cardiovascular Disease: Validity in Independent Cohorts
Authors: Gulati Gaurav , Brazil Riley J , Nelson Jason , Klaveren David van , Lundquist Christine M. , Park Jinny G. , McGinnes Hannah , Steyerberg Ewout W. , Calster Ben Van , Wessler Benjamin S. , Kent David M.
Published: February 2021

Background

Clinical prediction models (CPMs) are used to inform treatment decisions for the primary prevention of cardiovascular disease. We aimed to assess the performance of such CPMs in fully independent cohorts.

Methods and Results

63 models predicting outcomes for patients at risk of cardiovascular disease from the Tufts PACE CPM Registry were selected for external validation on publicly available data from up to 4 broadly inclusive primary prevention clinical trials. For each CPM-trial pair, we assessed model discrimination, calibration, and net benefit. Results were stratified based on the relatedness of derivation and validation cohorts, and net benefit was reassessed after updating model intercept, slope, or complete re-estimation. The median c statistic of the CPMs decreased from 0.77 (IQR 0.72-0.78) in the derivation cohorts to 0.63 (IQR 0.58-0.66) when externally validated. The validation c-statistic was higher when derivation and validation cohorts were considered related than when they were distantly related (0.67 vs 0.60, p < 0.001). The calibration slope was also higher in related cohorts than distantly related cohorts (0.69 vs 0.58, p < 0.001). Net benefit analysis suggested substantial likelihood of harm when models were externally applied, but this likelihood decreased after model updating.

Conclusions

Discrimination and calibration decrease significantly when CPMs for primary prevention of cardiovascular disease are tested in external populations, particularly when the population is only distantly related to the derivation population. Poorly calibrated predictions lead to poor decision making. Model updating can reduce the likelihood of harmful decision making, and is needed to realize the full potential of risk-based decision making in new settings.
Forskolin-induced swelling of intestinal organoids predicts long-term cystic fibrosis disease progression
Authors: Muilwijk D. , de Poel E. , van Mourik P. , Suen S.W.F. , Vonk A.M. , Brunsveld J.E. , Kruisselbrink E. , Oppelaar H. , Hagemeijer M.C. , Berkers G. , de Winter-de Groot K.M. , Heida-Michel S. , Jans S.R. , van Panhuis H. , van der Eerden M.M. , van der Meer R. , Roukema J. , Dompeling E. , Weersink E.J.M. , Koppelman G.H. , Vries R. , Zomer-van Ommen D.D. , Eijkemans M.J.C. , van der Ent C.K. , Beekman J.M.
Published: February 2021

Patient-derived organoids hold great potential as predictive biomarker for disease expression or therapeutic response. Here, we used intestinal organoids to estimate individual cystic fibrosis transmembrane conductance regulator (CFTR) function of people with cystic fibrosis, a monogenic life-shortening disease associated with more than 2000 CFTR mutations and highly variable disease progression. In vitro CFTR function in CF intestinal organoids of 176 individuals with diverse CFTR mutations was quantified by forskolin induced swelling and was strongly associated with longitudinal changes of lung function and development of pancreatic insufficiency, CF-related liver disease and diabetes. This association was not observed when the commonly used biomarker of CFTR function sweat chloride concentration was used. The data strongly exemplifies the value of an organoid-based biomarker in a clinical disease setting and supports the prognostic value of forskolin induced swelling of intestinal organoids, especially for people with CF who have rare CFTR genotypes with unclear clinical consequences.
Differential expression of Angiotensin-Converting Enzyme 2 in Nasal Tissue of Patients with Chronic Rhinosinusitis with Nasal Polyps
Authors: Fowler Philippa C. , Naluai Åsa Torinsson , Oscarsson Martin , Torkzadeh Sara , Bohman Anton , Bende Mats , Harandi Ali M.
Published: February 2021

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a pandemic and a global health emergency. The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed in nasal epithelial cells and plays a major role in cellular entry leading to infection. High expression of ACE2 has been suggested to be a potential risk factor for virus infection and disease severity. However the profile of ACE2 gene expression in diseases of the upper airways remains poorly understood. We herein investigated ACE2 gene expression in the nasal tissues of a cohort of Swedish patients with chronic rhinosinusitis with nasal polyps (CRSwNPs) using RT-qPCR. ACE2 mRNA expression was significantly reduced in the nasal mucosa of CRSwNP patients compared to that of controls. Moreover, we observed a sex-dependant difference in nasal ACE2 expression, where significantly lower levels of the ACE2 transcript were detected in the nasal mucosa of only female CRSwNP patients. These findings indicate that CRSwNP patients with a decrease in ACE2 gene expression may thereby be less prone to be infected by SARS-CoV-2. These results enhance our understanding on the profile of ACE2 expression in the nasal mucosa of patients with upper airway diseases, and their susceptibility to infection with SARS-CoV-2.
Discovery of 17 conserved structural RNAs in fungi
Authors: Gao William , Jones Thomas A. , Rivas Elena
Published: February 2021

Many non-coding RNAs with known functions are structurally conserved: their intramolecular secondary and tertiary interactions are maintained across evolutionary time. Consequently, the presence of conserved structure in multiple sequence alignments can be used to identify candidate functional non-coding RNAs. Here, we present a bioinformatics method that couples iterative homology search with covariation analysis to assess whether a genomic region has evidence of conserved RNA structure. We used this method to examine all unannotated regions of five well-studied fungal genomes(Saccharomyces cerevisiae, Candida albicans, Neurospora crassa, Aspergillus fumigatus,andSchizosaccharomyces pombe). We identified 17 novel structurally conserved non-coding RNA candidates, which include 4 H/ACA box small nucleolar RNAs, 4 intergenic RNAs, and 9 RNA structures located within the introns and untranslated regions (UTRs) of mRNAs. For the two structures in the 3′ UTRs of the metabolic genesGLY1andMET13, we performed experiments that provide evidence against them being eukaryotic riboswitches.
Machine Learning Differentiates Enzymatic and Non-Enzymatic Metals in Proteins
Authors: Feehan Ryan , Franklin Meghan W. , Slusky Joanna S.G.
Published: February 2021

Metalloenzymes are 40% of all enzymes and can perform all seven classes of enzyme reactions. Because of the physicochemical similarities between the active sites of metalloenzymes and inactive metal binding sites, it is challenging to differentiate between them. Yet distinguishing these two classes is critical for the identification of both native and designed enzymes. Because of similarities between these two types of metal binding sites, finding physicochemical features that distinguish active and inactive metal sites can indicate aspects that are critical to enzyme function. In this work, we develop the largest structural dataset of enzymatic and non-enzymatic metalloprotein sites to date. We then use a decision-tree ensemble machine learning model to classify metals bound to proteins as enzymatic or non-enzymatic with 92.2% precision and 90.1% recall. Our model scores electrostatic and pocket lining features as more important than pocket volume, despite the fact that volume is the most quantitatively different feature between enzyme and non-enzymatic sites. Finally, we find our model has overall better performance in a side-to-side comparison against other methods that differentiate enzymatic from non-enzymatic sequences. We anticipate that our model’s ability to correctly identify which metal sites are responsible for enzymatic activity could enable identification of new enzymatic mechanisms andde novoenzyme design.
Potential Early Rabies Infection Detected in Two Raccoon Cases by LN34 pan-lyssavirus real-time RT-PCR Assay in Pennsylvania
Authors: Dettinger Lisa , Gigante Crystal M. , Strohecker Maria , Seiders Melanie , Patel Puja , Orciari Lillian A. , Yager Pamela , Lute James , Regec Annette , Li Yu , Xia Dongxiang
Published: February 2021

During 2017 – 2019, the Pennsylvania Department of Health Bureau of Laboratories (PABOL) tested 6,855 animal samples for rabies using both the gold standard direct fluorescent antibody (DFA) test and LN34 pan-lyssavirus reverse transcriptase quantitative PCR (RT-qPCR). Two samples (0.03 %) were identified as LN34 RT-qPCR positive after failure to detect rabies virus antigen during initial DFA testing: an adult raccoon collected in 2017 and a juvenile raccoon collected in 2019. After the positive PCR result, additional tissues were collected and re-tested by DFA, where very sparse, disperse antigen was observed. Tissues from both animals were submitted to the Centers for Disease Control and Prevention (CDC) for confirmatory testing, and were confirmed positive. At both PABOL and CDC, rabies virus antigen and RNA levels were much lower than for a typical rabies case. In addition, rabies virus antigen and RNA levels were higher in brain stem and rostral spinal cord than cerebellum, hippocampus and cortex. Cross-contamination was ruled out in the case of the 2019 juvenile raccoon by sequencing, as nucleoprotein and glycoprotein gene sequences displayed >1% nucleotide differences to sequences from all positive samples processed at PABOL within two weeks of the juvenile raccoon. Taken together, the low level of rabies virus in the central nervous system combined with presence in more caudal brain structures suggest the possibility of an early infection in both cases. These two cases highlight the increased sensitivity and ease of interpretation of LN34 RT-qPCR in rabies diagnostics for the identification of low positive cases.
HeterozygousKCNH2variant phenotyping using Flp-In HEK293 and high-throughput automated patch clamp electrophysiology
Authors: Ng Chai-Ann , Farr Jessica , Young Paul , Windley Monique J. , Perry Matthew D. , Hill Adam P , Vandenberg Jamie I
Published: February 2021

KCNH2is one of the 59 medically actionable genes recommended by the American College of Medical Genetics for reporting of incidental findings from clinical genomic sequencing. However, half of the reportedKCNH2variants in the ClinVar database are classified as variants of uncertain significance. In the absence of strong clinical phenotypes, there is a need for functional phenotyping to help decipher the significance of variants identified incidentally. Here, we report detailed methods for assessing the molecular phenotype of anyKCNH2missense variant. The key components of the assay include quick and cost-effective generation of a bicistronic vector to co-express WT and anyKCNH2variant allele, generation of stable Flp-In HEK293 cell lines and high-throughput automated patch-clamp electrophysiology analysis of channel function. Stable cell lines take 3-4 weeks to produce and can be generated in bulk, which will then allow up to 30 variants to be phenotyped per week after 48 hours of channel expression. This high throughput functional genomics assay will enable a much more rapid assessment of the extent of loss of function of anyKCNH2variant.
Synergistic Therapy of Doxorubicin with Cationic Anticancer Peptide L-K6 Reverses Multidrug Resistance in Cancer Cells in vitro via P-glycoprotein Inhibition
Authors: Wang Che , Huang Lili , Li Ruojin , Wang Ying , Wu Xiaoxue , Shang Dejing
Published: February 2021

Multidrug resistance (MDR) is one of the major obstacles to efficient chemotherapy against cancers, resulting from the overexpression of drug efflux transporters such as P-glycoprotein (P-gP). In the present study, we aimed to evaluate the MDR reversal activity and synergistic therapeutic potential of cationic anticancer peptide L-K6 with doxorubicin (DOX) on P-gP-overexpressing and DOX-resistant MCF-7/Adr human breast cancer cells. Flow cytometry and confocal laser scanning microscopy were used to determine the intracellular accumulation of DOX and another P-gP substrate, Rho123. P-gP-Glo assay, Western blot and Biacore analysis were further performed to evaluate the P-gP function and expression. The cytotoxicity in MCF-7 or MCF-7/Adr cells was measured by MTT assay. Flow cytometry assay and confocal laser scanning microscopy observation clearly revealed an increased intracellular accumulation of DOX and Rho123 in MCF-7/Adr cells treated with L-K6, suggesting a P-gP inhibiting potential. Biacore analysis, P-gP-Glo assay and Western blot further confirmed that L-K6 could directly interact with P-gP, inhibit P-gP function and decrease P-gP expression in MCF-7/Adr cells. In addition, as expected, the data from MTT assay indicated that L-K6 restored the sensitivity of MCF-7/Adr cells to DOX, indicating a MDR reversal potential and a promising synergistic anticancer activity. All these findings may provide experimental evidence to support the promising applications and synergistic therapeutic potential of peptidic P-gP inhibitors against MDR cancer.
Functionalized extracellular matrix scaffolds loaded with endothelial progenitor cells promote neovascularization and diabetic wound healing
Authors: He Siqi , Walimbe Tanaya , Chen Hongyuan , Gao Kewa , Kumar Priyadarsini , Wei Yifan , Hao Dake , Liu Ruiwu , Farmer Diana L , S.Lam Kit , Zhou Jianda , Panitch Alyssa , Wang Aijun
Published: February 2021

Diabetic ischemic wound treatment remains a critical clinical challenge. Strategies that enhance angiogenesis and improve ischemic pathology may promote the healing of poor wounds, particularly diabetic wounds in highly ischemic condition. We previously identified a cyclic peptide LXW7 that specifically binds to integrin αvβ3 on endothelial progenitor cells (EPCs) and endothelial cells (ECs), activates VEGF receptors, and promotes EC growth and maturation. In this study, we designed and synthesized a pro-angiogenic molecule LXW7-DS-SILY by conjugating LXW7 to a collagen-binding proteoglycan mimetic DS-SILY and further employed this novel bifunctional ligand to functionalize extracellular matrix (ECM) scaffolds, promote neovascularization and accelerate ischemic wound healing. We established a Zucker Diabetic Fatty (ZDF) rat ischemic skin flap model and found the wounds treated by LXW7-DS-SILY-functionalized ECM scaffolds, with or without EPCs, significantly improved wound healing, enhanced neovascularization and modulated collagen fibrillogenesis. These functionalized ECM scaffolds also significantly promoted EPC attachment, growth and survival in the ischemic environment. Altogether, this study provides a promising novel treatment to accelerate diabetic ischemic wound healing, thereby reducing limb amputation and mortality of diabetic patients.
Computational insights into differential interaction of mamalian ACE2 with the SARS-CoV-2 spike receptor binding domain
Authors: Lupala Cecylia S. , Kumar Vikash , Su Xiao-dong , Wu Chun , Liu Haiguang
Published: February 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causing agent of the COVID-19 pandemic, has spread globally. Angiotensin-converting enzyme 2 (ACE2) has been identified as the host cell receptor that binds to receptor-binding domain (RBD) of the SARS-COV-2 spike protein and mediates cell entry. Because the ACE2 proteins are widely available in mammals, it is important to investigate the interactions between the RBD and the ACE2 of other mammals. Here we analyzed the sequences of ACE2 proteins from 16 mammals and predicted the structures of ACE2-RBD complexes. Analyses on sequence, structure, and dynamics synergistically provide valuable insights into the interactions between ACE2 and RBD. The comparison results suggest that the ACE2 of bovine, cat and panda form strong binding with RBD, while in the cases of rat, least horseshoe bat, horse, pig, mouse and civet, the ACE2 proteins interact weakly with RBD.
A Bayesian method to cluster single-cell RNA sequencing data using Copy Number Alterations
Authors: Milite Salvatore , Bergamin Riccardo , Patruno Lucrezia , Calonaci Nicola , Caravagna Giulio
Published: February 2021

Motivation

Cancers are composed by several heterogeneous subpopulations, each one harbouring different genetic and epigenetic somatic alterations that contribute to disease onset and therapy response. In recent years, copy number alterations leading to tumour aneuploidy have been identified as potential key drivers of such populations, but the definition of the precise makeup of cancer subclones from sequencing assays remains challenging. In the end, little is known about the mapping between complex copy number alterations and their effect on cancer phenotypes.

Results

We introduce CONGAS, a Bayesian probabilistic method to phase bulk DNA and single-cell RNA measurements from independent assays. CONGAS jointly identifies clusters of single cells with subclonal copy number alterations, and differences in RNA expression. The model builds statistical priors leveraging bulk DNA sequencing data, does not require a normal reference and scales fast thanks to a GPU backend and variational inference. We test CONGAS on both simulated and real data, and find that it can determine the tumour subclonal composition at the single-cell level together with clone-specific RNA phenotypes in tumour data generated from both 10x and Smart-Seq assays.

Availability

CONGAS is available as 2 packages: CONGAS (https://github.com/caravagnalab/congas), which implements the model in Python, and RCONGAS (https://caravagnalab.github.io/rcongas/), which provides R functions to process inputs, outputs, and run CONGAS fits. The analysis of real data and scripts to generate figures of this paper are available via RCONGAS; code associated to simulations is available at https://github.com/caravagnalab/rcongas_test.

Contact

gcaravagna@units.it

Supplementary information

Supplementary data are available at Bioinformatics online.
RNA-Sequencing of Long-Term Label-Retaining Colon Cancer Stem Cells Identifies Novel Regulators of Quiescence
Authors: Regan Joseph L. , Schumacher Dirk , Staudte Stephanie , Steffen Andreas , Lesche Ralf , Toedling Joern , Jourdan Thibaud , Haybaeck Johannes , Mumberg Dominik , Henderson David , Győrffy Balázs , Regenbrecht Christian R.A. , Keilholz Ulrich , Schäfer Reinhold , Lange Martin
Published: February 2021

Recent data suggests that colon tumors contain a subpopulation of therapy resistant quiescent cancer stem cells (qCSCs) that are the source of relapse following treatment. Here, using colon cancer patient-derived organoids (PDOs) and xenograft (PDX) models, we identify a rare population of long-term label-retaining (PKH26Positive) qCSCs that can re-enter the cell cycle to generate new tumors. RNA-sequencing analyses demonstrated that these cells are enriched for stem cell associated gene sets such as Wnt and hedgehog signaling, epithelial-to-mesenchymal transition (EMT), embryonic development, tissue development and p53 pathway but have downregulated expression of genes associated with cell cycle, transcription, biosynthesis and metabolism. Furthermore, qCSCs are enriched for p53 interacting negative regulators of cell cycle, includingAKAP12, CD82, CDKN1A, FHL2, GPX3, KIAA0247, LCN2, TFF2, UNC5BandZMAT3, that we show are indicators of poor prognosis and may be targeted for qCSC abolition. Interestingly, CD82, KIAA0247 and UNC5B proteins localize to the cell surface and may therefore be potential markers for the prospective isolation of qCSCs. These data support the temporal inhibition of p53 signaling for the elimination of qCSCs and prevention of relapse in colorectal cancer.
Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry
Authors: van Maldegem Febe , Valand Karishma , Cole Megan , Patel Harshil , Angelova Mihaela , Rana Sareena , Colliver Emma , Enfield Katey , Bah Nourdine , Kelly Gavin , Tsang Victoria Siu Kwan , Mugarza Edurne , Moore Christopher , Hobson Philip , Levi Dina , Molina-Arcas Miriam , Swanton Charles , Downward Julian
Published: February 2021

Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour microenvironment (TME), multiplexed imaging methods can provide a rich source of information. However, the application of such technologies in mouse tissues is still in its infancy. Here we present a workflow for studying the TME using imaging mass cytometry with a panel of 27 antibodies on frozen mouse tissues. We optimise and validate image segmentation strategies and automate the process in a Nextflow-based pipeline (imcyto) that is scalable and portable, allowing for parallelised segmentation of large multi-image datasets. With these methods we interrogate the remodelling of the TME induced by a KRAS G12C inhibitor in an immune competent mouse orthotopic lung cancer model, highlighting the infiltration and activation of antigen presenting cells and effector cells.
Accurate and robust inference of microbial growth dynamics from metagenomic sequencing
Authors: Joseph Tyler A. , Chlenski Philippe , Korem Tal , Pe’er Itsik
Published: February 2021

Patterns of sequencing coverage along a bacterial genome—summarized by a peak-to-trough ratio (PTR)—have been shown to accurately reflect microbial growth rates, revealing a new facet of microbial dynamics and host-microbe interactions. Here, we introduce CoPTR (Compute PTR): a tool for computing PTRs from complete reference genomes and assemblies. We show that CoPTR is more accurate than the current state-of-the-art, while also providing more PTR estimates overall. We further develop theory formalizing a biological interpretation for PTRs. Using a reference database of 2935 species, we applied CoPTR to a case-control study of 1304 metagenomic samples from 106 individuals with irritable bowel disease. We show that PTRs have high inter-individual variation, are only loosely correlated with relative abundances, and are associated with disease status. We conclude by demonstrating how PTRs can be combined with relative abundances and metabolomics to investigate their effect on the microbiome.

Availability

CoPTR is available fromhttps://github.com/tyjo/coptr, with documentation onhttps://coptr.readthedocs.io.
Increased energy expenditure and protection from diet-induced obesity in mice lacking the cGMP-specific phosphodiesterase, PDE9
Authors: Ceddia Ryan P. , Liu Dianxin , Shi Fubiao , Mishra Sumita , Kass David A. , Collins Sheila
Published: February 2021

Obesity is a central component to cardiometabolic diseases, predisposing patients to both heart failure and diabetes. As therapeutics targeting caloric intake have limited long-term efficacy, greater interest has been on increasing thermogenic energy expenditure. Cyclic nucleotides, cAMP and cGMP, are important second messengers that are critical for the regulation of adaptive thermogenesis. These are regulated not only by their synthesis but also by their degradation. Pharmacological inhibitors of the cGMP-specific phosphodiesterase 9 (PDE9) increased PKG signaling and UCP1 expression in adipocytes. To elucidate the role of PDE9 on energy balance and glucose homeostasisin vivo, mice carrying a targeted disruption of the PDE9 gene,Pde9a, were fed a nutrient matched high-fat diet (HFD) or low-fat diet (LFD).Pde9a-/-mice were resistant to obesity induced by a HFD.Pde9a-/-mice exhibited a global increase in energy expenditure while the brown adipose tissue had elevated expression ofUcp1and other thermogenic genes. The reduced adiposity of HFD-fedPde9a-/-mice was associated with improvements in glucose handling and hepatic steatosis. These findings support the conclusion that PDE9 is a critical regulator of energy metabolism and suggest that inhibiting this enzyme may be an important avenue to explore for combating metabolic disease.
Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia
Authors: Garcia-Bermudez Javier , Prasad Sheela , Baudrier Lou , Badgley Michael A. , Liu Yuyang , La Konnor , Soula Mariluz , Williams Robert T. , Yamaguchi Norihiro , Hwang Rosa F. , Taylor Laura J. , Stanchina Elisa De , Rostandy Bety , Alwaseem Hanan , Molina Henrik , Bar-Sagi Dafna , Birsoy Kıvanç
Published: February 2021

Stress-adaptive mechanisms enable tumor cells to overcome metabolic constraints in nutrient and oxygen poor tumors. Aspartate is an endogenous metabolic limitation under hypoxic conditions, but the nature of the adaptive mechanisms that contribute to aspartate availability and hypoxic tumor growth are poorly understood. Here, using a combination of metabolomics and CRISPR-based genetic screens, we identify GOT2-catalyzed mitochondrial aspartate synthesis as an essential metabolic dependency for the proliferation of pancreatic tumor cells under hypoxic culture conditions. In contrast, GOT2-catalyzed aspartate synthesis is dispensable for pancreatic tumor formationin vivo. The dependence of pancreatic tumor cells on aspartate synthesis is bypassed in part by a hypoxia-induced potentiation of extracellular protein scavenging via macropinocytosis. This effect is mutant KRas-dependent, and is mediated by hypoxia inducible factor 1 (HIF1A) and its canonical target carbonic anhydrase-9 (CA9) through the cooption of the bicarbonate-macropinocytosis signaling axis. Our findings reveal high plasticity of aspartate metabolism and define an adaptive regulatory role for macropinocytosis by which mutant KRas tumors can overcome nutrient deprivation under hypoxic conditions.
Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling
Authors: Carbonell Abigail U. , Freire-Cobo Carmen , Deyneko Ilana V. , Erdjument-Bromage Hediye , Clipperton-Allen Amy E. , Rasmusson Randall L. , Page Damon T. , Neubert Thomas A. , Jordan Bryen A.
Published: February 2021

Impaired synaptic function is a common phenotype in animal models for autism spectrum disorder (ASD), and ASD risk genes are enriched for synaptic function. Here we leverage the availability of multiple ASD mouse models exhibiting synaptic deficits and behavioral correlates of ASD and use quantitative mass spectrometry with isobaric tandem mass tagging (TMT) to compare the hippocampal synaptic proteomes from 7 mouse models. We identified common altered cellular and molecular pathways at the synapse, including changes in Rho family small GTPase signaling, suggesting that it may be a point of convergence in ASD. Comparative analyses also revealed clusters of synaptic profiles, with similarities observed among models for Fragile X syndrome (Fmr1knockout), PTEN hamartoma tumor syndrome (Ptenhaploinsufficiency), and the BTBR+ model of idiopathic ASD. Opposing changes were found in models for cortical dysplasia focal epilepsy syndrome (Cntnap2knockout), Phelan McDermid syndrome (Shank3InsG3680), Timothy syndrome (Cacna1cG406R), and ANKS1B syndrome (Anks1bhaploinsufficiency), which were similar to each other. We propose that these clusters of synaptic profiles form the basis for molecular subtypes that explain genetic heterogeneity in ASD despite a common clinical diagnosis. Drawn from an internally controlled survey of the synaptic proteome across animal models, our findings support the notion that synaptic dysfunction in the hippocampus is a shared mechanism of disease in ASD, and that Rho GTPase signaling may be an important pathway leading to disease phenotypes in autism.
Assessment of immunogenicity and protective efficacy of ZyCoV-D DNA vaccine candidates in Rhesus macaques against SARS-CoV-2 infection
Authors: Yadav Pragya D , Kumar Sanjay , Agarwal Kshitij , Jain Mukul , Patil Dilip R , Maithal Kapil , Mathapati Basavaraj , Giri Suresh , Mohandas Sreelekshmy , Shete Anita , Sapkal Gajanan , Patil Deepak Y , Dey Ayan , Chandra Harish , Deshpande Gururaj , Gupta Nivedita , Nyayanit Dimpal , Kaushal Himanshu , Sahay Rima , Tripathy Anuradha , Jain Rajlaxmi , Kumar Abhimanyu , Sarkale Prasad , Baradkar Shreekant , Rajanathan Chozhavel , Raju Hari Prasad , Patel Satish , Shah Niraj , Dwivedi Pankaj , Singh Dharmendra , Abraham Priya
Published: February 2021

Vaccines remain the key protective measure to achieve herd immunity to control the disease burden and stop COVID-19 pandemic. We have developed and assessed the immunogenicity and protective efficacy of two formulations (1mg and 2mg) of ZyCoV-D (a plasmid DNA based vaccine candidates) administered through Needle Free Injection System (NFIS) and syringe-needle (intradermal) in rhesus macaques with three dose vaccine regimens. The vaccine candidate 2mg dose administered using Needle Free Injection System (NFIS) elicited a significant immune response with development of SARS-CoV-2 S1 spike region specific IgG and neutralizing antibody (NAb) titers during the immunization phase and significant enhancement in the levels after the virus challenge. In 2 mg NFIS group the IgG and NAb titers were maintained and showed gradual rise during the immunization period (15 weeks) and till 2 weeks after the virus challenge. It also conferred better protection to macaques evident by the viral clearance from nasal swab, throat swab and bronchoalveolar lavage fluid specimens in comparison with macaques from other immunized groups. In contrast, the animals from placebo group developed high levels of viremia and lung disease following the virus challenge. Besides this, the vaccine candidate also induced increase lymphocyte proliferation and cytokines response (IL-6, IL-5).The administration of the vaccine candidate with NFIS generated a better immunogenicity response in comparison to syringe-needle (intradermal route). The study demonstrated immunogenicity and protective efficacy of the vaccine candidate, ZyCoV-D in rhesus macaques.
Diffusion of the disordered E-cadherin tail on β-catenin
Authors: Wiggers Felix , Wohl Samuel , Dubovetskyi Artem , Rosenblum Gabriel , Zheng Wenwei , Hofmann Hagen
Published: February 2021

Specific protein interactions typically require well-shaped binding interfaces. Here, we report a cunning exception. The disordered tail of the cell-adhesion protein E-cadherin dynamically samples a large surface area of the proto-oncogene β-catenin. Single-molecule experiments and molecular simulations resolve these motions with high resolution in space and time. Contacts break and form within hundreds of microseconds without dissociation of the complex. A few persistent interactions provide specificity whereas unspecific contacts boost affinity. The energy landscape of this complex is rugged with many small barriers (3 – 4kBT) and reconciles specificity, high affinity, and extreme disorder. Given the roles of β-catenin in cell-adhesion, signalling, and cancer, this Velcro-like design has the potential to tune the stability of the complex without requiring dissociation.
Revision of commonly accepted Warburg mechanism of cancer development. Redox-sensitive mitochondrial cytochromes in breast and brain cancers by Raman imaging
Authors: Abramczyk Halina , Surmacki Jakub Maciej , Brozek-Pluska Beata , Kopeć Monika
Published: February 2021

Background

We studied oncogenic processes that characterize human breast cancer (infiltrating ductal carcinoma (IDC)) and human brain tumors: glioma, astrocytoma and medulloblastoma based on the quantification of cytochrome redox status by exploiting the resonance-enhancement effect of Raman scattering.

Methods

We used Raman imaging to monitor changes in the redox state of the mitochondrial cytochromes in ex vivo human brain and breast tissues surgically resected specimens of human tissues and in vitro human brain cells of normal astrocytes (NHA), astrocytoma (CRL-1718), glioblastoma (U87-MG) and medulloblastoma (Daoy), and human breast cells of normal cells (MCF 10A), slightly malignant cells (MCF7) and highly aggressive cells (MDA-MB-231) by means of Raman microspectroscopy at 532 nm.

Results

We visualized localization of cytochromes by Raman imaging in the major organelles in cancer cells. We demonstrated that the “redox state Raman marker” of the ferric low spin heme in cytochrome c at 1584 cm−1can serve as a sensitive indicator of cancer aggressiveness. We compared concentration of reduced cytochrome c and the grade of cancer aggressiveness in cancer tissues and single cells and specific organelles in cells: nucleous, mitochondrium, lipid droplets, cytoplasm, and membrane.

Conclusions

We found that the concentration of reduced cytochrome c becomes abnormally high in human brain tumors and breast cancers in human tissues. Our results suggest that the mechanisms controlling the electron transport chain are spectacularly deregulated in cancers and indicate that electron transport, organized in terms ofelectronegativity, is inhibited between complex III and cytochrome c for isolated cells in vitro and between cytochrome c and complex IV in brain and breast tissues. The results provide evidence that the extracellular matrix and interactions with cell microenvironment play an important role in the mechanisms controlling the electron transport chain by cytochrome c. Our results reveal the universality of Raman vibrational characteristics of mitochondrial cytochromes in metabolic regulation in cancers that arise from epithelial breast cells and brain glial cells.
Optimization of pre-oxidation time for corrosion resistance of cobalt based coating alloy in mixed sulphates
Authors: Rehman Abdul , Bidabadi Mohammad Hassan Shirani , Yang Liang , Yu Zheng , Hao Chen , Zhang Chi , Yang Zhigang
Published: February 2021

Purpose

This study aims to optimise the effect of pre-oxidation on hot corrosion behaviour of Tribaloy T-900 at 900 °C in mixed Na2SO4 and K2SO4.

Design/methodology/approach

Prior to hot corrosion experiment, pre-oxidation treatments were carried in ambient air at 900 °C for 1, 5 and 10 h, respectively. The hot corrosion experiments were performed in a box type furnace at 900 °C. Both surfaces of specimens were brushed with saturated salt solution of 75 wt.% Na2SO4 + 25 wt.% K2SO4. After brushing, the salt-coated specimens were placed in electric stove to ensure drying of salt. After drying, presence of 3 mg/cm2 salt on specimen’s surface was ensured through weighting.

Findings

The 1-h pre-oxidation treatment prior to hot corrosion showed superior hot corrosion resistance against molten salt attack. An optimum pre-oxidation time of 1 h helped timely formation of protective Cr2O3 layer and inhibited the formation of less stable and porous surface oxides of Ni and Mo during hot corrosion.

Originality/value

Pre-oxidation effect on hot corrosion behaviour of refractory metal (such as Mo in investigated alloy) containing alloy has never been reported previously. Refractory metals oxide (e.g. MoO3) could transform the corrosion phenomena to catastrophic failure through acidic fluxing.
Road infrastructure development under PPP model in India: a credit rating perspective
Authors: Koul Puneet , Verma Piyush , Arora Lalit
Published: February 2021

Purpose

The study analyzes significant parameters defining the credit worthiness, economic viability and managerial efficiency of special purpose vehicles (SPVs) of infrastructure development firms engaged in the execution of road projects under PPP model in India.

Design/methodology/approach

The study is based on a comprehensive review of credit rating reports of major rating agencies. In particular, 18 special purpose vehicles (13 BOT-toll–based and 5 BOT-annuity–based road projects) during the period 2010–2019 were considered to conduct a comparative analysis of their rating progression. Considering both financial as well as nonfinancial parameters, their segregation was done on the basis of strengths, constraints and key rating sensitivities influencing the ratings of SPVs involved in road projects under PPP model.

Findings

Promoters' credibility emerged as an important factor affecting PPP credit ratings. Other prominent factors included nature of stretch and regulatory terms and conditions and the project's potential to generate cash flows. Inability of PPP projects to generate the projected levels of toll collections was a major constraint and hampered ratings over time. Growth in traffic was a key sensitive area in a toll-based project. Interestingly, despite the fixed nature of revenues, BOT (annuity) projects were impacted by rating changes.

Research limitations/implications

Fewer sample projects (for which the data were available) was a constraint. Future research could consider larger data sets to provide deeper insights. An examination of credit rating parameters using rating reports of projects in other developing nations could provide meaningful implications. The findings of this research however cannot be undermined as the study bridges a gap in existing literature pertaining to the examination of PPP model from a credit rating perspective.

Practical implications

This study would guide project developers, government agencies and awarding agencies of PPP road projects to anticipate the challenges and take adequate steps to mitigate them.

Originality/value

Research in the area of PPP projects is skewed toward risk assessment with respect to financial parameters. The present study emphasizes the rating framework of SPVs. Comprehensive examination of factors affecting project ratings in the form of projects' strengths, constraints and sensitivities would provide inputs to academics and researchers.
Big data empowered agility for dynamic, volatile, and time-sensitive service industries: the case of tourism sector
Authors: Stylos Nikolaos , Zwiegelaar Jeremy , Buhalis Dimitrios
Published: February 2021

Purpose

Dynamic, volatile, and time-sensitive industries, such as tourism, travel and hospitality require agility and market intelligence to create value and achieve competitive advantage. The aim of the current study is to examine the influence of big data (BD) on the performance of service organizations and to probe for a deeper understanding of implementing BD, based on available technologies.

Design/methodology/approach

An ethnographic study was conducted following an abductive approach. A primary qualitative research scheme was used with 35 information technology and database professionals participating in five online focus groups of seven participants each. Analytical themes were developed simultaneously with the literature being revisited throughout the study to ultimately create sets of common themes and dimensions.

Findings

BD can help organizations build agility, especially within dynamic industries, to better predict customer behavioral patterns and make tailor-made propositions from the BD. An integrated BD-specific framework is proposed to address value according to the dimensions of need, value, time and utility.

Research limitations/implications

Little research exists on the key drivers of BD use for dynamic, real-time and agile businesses. This research adds to the developing literature on BD applications to support organizational decision-making and business performance in the tourism industry.

Originality/value

This study responds to scholars’ recent calls for more empirical research with contextual understanding of the use of BD to add value in marketing intelligence within business ecosystems. It delineates factors contributing to BD value creation and explores the impacts on the respective service encounters.
An emotional intelligence model of entrepreneurial coping strategies
Authors: Pathak Saurav , Goltz Sonia
Published: February 2021

Purpose

The purpose of this article is to recognize emotional intelligence (EI) as a specific emotional competency possessed by entrepreneurs that facilitates their coping with stressors that arise in their day-to-day work. Highlighting the problem-focused and emotion-focused coping strategies employed by entrepreneurs, the paper establishes that EI in entrepreneurs enables the onset of acceptance of the existence of a stressful situation and that of optimism that a stressful situation can be solved.

Design/methodology/approach

The paper reviews literature on the topics related to links between EI, entrepreneurial behaviors and entrepreneurial coping. Subsequently, acceptance-avoidance motivation theory is used to posit that entrepreneurs' EI serves as an antecedent that (1) guides the selection of their coping strategies through onset of optimism and acceptance of stressful situation, (2) assists in perceiving those situations as either controllable or uncontrollable and (3) shapes the actual process through which entrepreneurs cope.

Findings

The proposed conceptual model asserts that entrepreneurs' EI as reflected in their abilities to perceive, use, understand and regulate emotions is key to their coping. EI in entrepreneurs assists them in being optimistic about solving a stressful situation and accepting of such situations as well. Thereafter, selection of a problem-focused or emotion-focused coping strategy or both ensues.

Originality/value

The current work offers a conceptual model that highlights the role of entrepreneurs' EI in coping, integrates both the cognitive and affective components of coping and suggests a variety of avenues for future research. This model extends models of coping that categorize coping types to specify the process thought to be involved. Understanding the role of emotional intelligence in coping with stress by entrepreneurs has theoretical and practical implications which are discussed as well.
Interpersonal forgiveness and employee life satisfaction: the role of affect at work
Authors: Dahiya Rinki
Published: February 2021

Purpose

Amidst the new realities of the modern world, a happy and satisfied workforce has become a necessary requirement for organizations to maintain their competitive edge. While most of the available literature revolves around positive organizational behaviour, there is dearth of research on the influence of interpersonal forgiveness on affect and life satisfaction in employees. Keeping this precept in mind, this study aims at bridging this gap in research by developing and testing a mediation model to examine the link between interpersonal forgiveness to affect and life satisfaction.

Design/methodology/approach

The sample consists of 378 employees working in different Indian manufacturing organizations. To test the hypotheses, structural equation modelling was applied.

Findings

The results reveal that interpersonal forgiveness significantly influences life satisfaction and affect partially mediates this relationship in employees.

Practical implications

The study recommends that organizational development practitioners and human resource professionals focus on forgiveness among co-workers to foster a balanced affect and enhanced life satisfaction by developing and implementing positive psychological interventions and practices. This can help organizations in regulating interpersonal transgressions and conflicts at an early stage and also make the employees happy and satisfied.

Originality/value

This study offers concrete insights into the complicated interplay of affect in the link between interpersonal forgiveness and life satisfaction in the yet underexplored context of Indian organizations.
Aligning individual and organizational R&D goals for self-sustainability: investigating preferences of researchers in selected CSIR laboratories, India
Authors: Kumari Beena , Sahney Sangeeta , Madhukar Anuradha
Published: February 2021

Purpose

This paper intends to explore the measure for aligning the goals of researchers toward achieving organizational R&D targets. The paper also explores the significance and ordering of R&D outputs and the factors that influence generation of R&D outputs, from the perspective of researchers working in the Indian public sector organizations.

Design/methodology/approach

Data were collected in five Indian R&D laboratories, and weighted average method Spearman correlation coefficient and rank regression were utilized for the analysis.

Findings

The findings indicated that various groups of researchers prefer to target different R&D outputs and not all the factors are considered as equally significant in influencing the generation of R&D outputs. Further, the R&D organization should include preferred real factors while policy making for achieving collaborative efforts toward fulfilling organizational objectives. The set of selected R&D outputs and influencing factors were also ordered according to the average rankings given by the researchers.

Practical implications

The findings can help R&D managers to identify the expectations of the researchers and include their preferences in R&D Planning. The study could be extended to a larger dataset of researchers working in other government as well as private R&D organizations.

Originality/value

Hardly any studies were found that explored the preferences of researchers with respect to R&D outputs and influencing factors with respect to the Indian public sector R&D laboratories.
Drivers of sustainable entrepreneurial intentions among university students: an integrated model from a developing world context
Authors: Agu Agu Godswill , Kalu Okwuagwu Okuu , Esi-Ubani Chidadi Obinna , Agu Paul Chinedu
Published: February 2021

Purpose

The purpose of this study is to integrate and extend two models of entrepreneurial intention to investigate the drivers of sustainable entrepreneurial intention among intermediate undergraduate university students in Nigeria. Specifically, this paper aims to introduce education for sustainable entrepreneurship into the integrated model, thereby fitting the model into the context of sustainable entrepreneurship.

Design/methodology/approach

Data was gathered with the help of a structured questionnaire from 435 students of a university in Nigeria. The students passed through a special entrepreneurship training in which they were educated on the concept and practice of sustainable entrepreneurship. SmartPLS was used to test the proposed structural model.

Findings

The findings revealed that education for sustainable entrepreneurship significantly influences all variables of the integrated model, but has nonsignificant direct influence on sustainable entrepreneurial intention. Sustainable entrepreneurial intention is significantly driven by attitude and propensity to act. Therefore, the inclusion of education for sustainable entrepreneurship into the regression equation adds to its explanatory power.

Originality/value

This study contributes toward understanding of sustainable entrepreneurial intention of intermediate university students in a developing world context – Nigeria. Above all, it is among the few studies that shed light on the strength of education for sustainable entrepreneurship in the formation of sustainable entrepreneurial intention among students. This study proposes integration and extension (by adding education for sustainable entrepreneurship) of the theory of planned behavior and entrepreneurial event model in learning about students’ intentions to engage in sustainable entrepreneurship.