bluuebunny/crossref_metadata_2025 huggingface dataset:
RNase R, a new virulence determinant ofStreptococcus pneumoniae
Authors: Bárria Cátia , Mil-Homens Dalila , Fialho Arsénio M. , Arraiano Cecília Maria , Domingues Susana
Published: February 2021

Pneumococcal infections have increasingly high mortality rates despite the availability of vaccines and antibiotics. The increase of bacterial resistance to antibiotics urges the discovery of new alternative therapeutics. Therefore, the identification of new virulence determinants, and the understanding of the molecular mechanisms behind pathogenesis and pneumococcal-host interactions has become of paramount importance in the search of new targets for drug development. The exoribonuclease RNase R has been involved in virulence in a growing number of pathogens. In this work, we have usedGalleria mellonellaas an infection model to demonstrate that the presence of ribonuclease R increases the pneumococcus virulence. Although the absence of RNase R does not affect exponential growth, the ability of the RNase R deleted strain to replicate in the hemolymph is compromised. Larvae infected with the RNase R mutant strain show an increased expression level of antimicrobial peptides, and have a lower bacterial load in the haemolymph in the later stages of infection, leading to a higher survival rate. Interestingly RNase R carrying pneumococci suffer a sudden drop in bacterial numbers immediately after infection, resembling the eclipse phase observed after intravenous inoculation in mice. Together our results suggest that RNase R might be involved in the ability of pneumococci to evade the host immune response, probably by interfering with internalisation and/or replication inside the larval hemocytes.
Downregulation of Extraembryonic Tension Controls Body Axis Formation in Avian Embryos
Authors: Kunz Daniele , Wang Anfu , Chan Chon U , Pritchard Robyn H. , Wang Wenyu , Gallo Filomena , Bradshaw Charles R. , Terenzani Elisa , Müller Karin H. , Huang Yan Yan Shery , Xiong Fengzhu
Published: February 2021

Embryonic tissues undergoing shape change draw mechanical input from extraembryonic substrates. In avian eggs, the early blastoderm disk is under the tension of the vitelline membrane (VM). Here we report that the chicken VM characteristically downregulates tension and stiffness to facilitate stage-specific embryo morphogenesis. Experimental relaxation of the VM early in development impairs blastoderm expansion, while maintaining VM tension in later stages resists the convergence of the posterior body causing stalled elongation, failure of neural tube closure, and axis rupture. Biochemical and structural analysis shows that VM weakening is associated with the reduction of outer-layer glycoprotein fibers, which is caused by an increasing albumen pH due to CO2release from the egg. Our results identify a previously unrecognized potential cause of body axis defects through mis-regulation of extraembryonic tissue tension.
Metabolic characteristics of taste differences under the soil and hydroponic cultures of sweet potato leaves by using non-targeted metabolomics
Authors: Lin Zhaomiao , Li Guoliang , Zhang Hong , Ji Rongchang , Xu Yongqing , Xu Guochun , Li Huawei , Liu Zhonghua , Luo Wenbin , Qiu Yongxiang , Qiu Sixin , Tang Hao
Published: February 2021

Sweet potato leaves are consumed as green leafy vegetables in most of the world due to their nutritional and functional values, and the taste characteristics determine their commodity value and consumer acceptance. However, the metabolic composition and formation mechanism of taste quality in its leaves are not clear. In this study, we found that sweet potato leaves under different growing patterns, soil culture and hydroponic culture, which result in different taste quality. In particular, the taste quality in leafy sweet potato was effectively improved under hydroponic culture. Meanwhile, we further profiled metabolites in leaves of sweet potatoes under different growing patterns by using GC–QToF–MS. A total of 200 metabolites were identified, covering most of the metabolic pathways in plants. A comparison of the good taste and poor taste of sweet potato leaves resulted in 71 metabolites related to taste quality formation. In addition, the leaves with poor taste had lower levels of metabolites regarding amino acids metabolism, whereas was accompanied by high levels of metabolites in carbohydrates and secondary metabolism. This study provides new insights into the improvement of taste quality in leafy sweet potato.
Free Energy Landscape of RNA Binding Dynamics in Start Codon Recognition by Eukaryotic Ribosomal Pre-Initiation Complex
Authors: Kameda Takeru , Asano Katsura , Togashi Yuichi
Published: February 2021

Specific interaction between the start codon, 5’-AUG-3’, and the anticodon, 5’-CAU-3’, ensures accurate initiation of translation. Recent studies show that several near-cognate start codons (e.g. GUG and CUG) can play a role in initiating translation in eukaryotes. However, the mechanism allowing initiation through mismatched base-pairs at the ribosomal decoding site is still unclear at an atomic level. In this work, we propose an extended simulation-based method to evaluate free energy profiles, through computing the distance between each base-pair of the triplet interactions (d1,d2andd3) involved in recognition of start codons in eukaryotic translation pre-initiation complex. Our method provides not only the free energy penalty (ΔΔG) for mismatched start codons relative to the AUG start codon, but also the preferred pathways of transitions between bound and unbound states, which has not been described by previous studies. To verify the method, the binding dynamics of cognate (AUG) and near-cognate start codons (CUG and GUG) were simulated. Evaluated free energy profiles agree with experimentally observed changes in initiation frequencies from respective codons. This work proposes for the first time how a G:U mismatch at the first position of codon (GUG)-anticodon base-pairs destabilizes the accommodation in the initiating eukaryotic ribosome and how initiation at a CUG codon is nearly as strong as, or sometimes stronger than, that at a GUG codon. Our method is expected to be applied to study the affinity changes for various mismatched base-pairs.
Chitosan-olive oil microparticles for phenylethyl isothiocyanate delivery: optimal formulation
Authors: Coscueta Ezequiel R. , Sousa Ana Sofia , Reis Celso A. , Pintado Manuela
Published: February 2021

Phenylethyl isothiocyanate (PEITC), a chemopreventive compound, is highly reactive due to its considerably electrophilic nature. Furthermore, it is hydrophobic and has low stability, bioavailability and bioaccessibility, restricting its use in biomedical and nutraceutical or food applications. Thus, the encapsulation of this agent has the function of overcoming these limitations, promoting its solubility in water, and stabilizing it, preserving its bioactivity. So, polymeric microparticles were developed using chitosan-olive oil-PEITC systems. For this, an optimisation process (factors: olive oil: chitosan ratio and PEITC: chitosan ratio) were implemented through a central composite design. The responses were: the particle size, zeta-potential, polydisperse index, and entrapment efficiency. The optimal formulation was further characterized by FTIR and biocompatibility in Caco-2 cells. Optimal conditions were olive oil: chitosan and PEITC: chitosan ratios of 1.46 and 0.25, respectively. These microparticles had a size of 629 nm, a zeta-potential of 32.3 mV, a polydispersity index of 0.329, and an entrapment efficiency of 98.49%. We found that the inclusion process affected the optical behaviour of the PEITC, as well as the microparticles themselves and their interaction with the medium. Furthermore, the microparticles did not show cytotoxicity within the therapeutic values of PEITC. Thus, PEITC was microencapsulated with characteristics suitable for potential biomedical, nutraceutical and food applications.
A missense variant effect prediction and annotation resource for SARS-CoV-2
Authors: Dunham Alistair , Jang Gwendolyn M , Muralidharan Monita , Swaney Danielle , Beltrao Pedro
Published: February 2021

The COVID19 pandemic is a global crisis severely impacting many people across the world. An important part of the response is monitoring viral variants and determining the impact they have on viral properties, such as infectivity, disease severity and interactions with drugs and vaccines. In this work we generate and make available computational variant effect predictions for all possible single amino-acid substitutions to SARS-CoV-2 in order to complement and facilitate experiments and expert analysis. The resulting dataset contains predictions from evolutionary conservation and protein and complex structural models, combined with viral phosphosites, experimental results and variant frequencies. We demonstrate predictions’ effectiveness by comparing them with expectations from variant frequency and prior experiments. We then identify higher frequency variants with significant predicted effects as well as finding variants measured to impact antibody binding that are least likely to impact other viral functions. A web portal is available atsars.mutfunc.com, where the dataset can be searched and downloaded.
Population monitoring of snow leopards using camera trapping in Naryn State Reserve, Kyrgyzstan, between 2016 and 2019
Authors: Rode Julie , Lambert Claire , Marescot Lucile , Chaix Bastien , Beesau Julie , Bastian Suzanne , Kyrbashev Joldoshbek , Cabanat Anne-Lise
Published: February 2021

Four field seasons of snow leopard (Panthera uncia) camera trapping inside Naryn State Reserve, performed thanks to citizen science expeditions, allowed detecting a minimal population of five adults, caught every year with an equilibrated sex ratio (1.5:1), and reproduction: five cubs or subadults have been identified from three litters of two different females. Crossings were observed one to three times a year, in front of most camera traps, and several times a month in front of one of them. Overlap of adults’ territories was observed in front of several camera traps regardless of their sex. Significant snow leopard presence was detected in the buffer area and at Ulan, situated at the reserve border. To avoid poaching on this umbrella species and its preys, extending the more stringent protection measures of the core zone to both the Southern buffer area and land adjacent to Ulan is necessary.
Disruption of the mitochondrial geneorf352partially restores pollen development in cytoplasmic male sterile rice
Authors: Omukai Shiho , Arimura Shin-ich , Toriyama Kinya , Kazama Tomohiko
Published: February 2021

Plant mitochondrial genomes sometimes carry cytoplasmic male sterility (CMS)-associated genes. These genes have been harnessed in agriculture to produce high-yielding F1hybrid seeds in various crops. The geneorf352was reported to be an RT102-type CMS gene in rice (Oryza sativa), although a causal demonstration of its role in CMS is lacking. Here, we employed mitochondrion-targeted transcription activator-like effector nucleases (mitoTALENs), to knock outorf352from the mitochondrial genome in the cytoplasmic male sterile rice RT102A. We isolated 18 independent transformation events in RT102A that resulted in genome editing oforf352, including its complete removal from the mitochondrial genome in several plants. Sequence analysis around the mitoTALEN target sites revealed the repair of their induced double-strand breaks via homologous recombination. Near the 5ʹ target site, repair involved sequences identical toorf284, while repair of the 3ʹ target site yielded various new sequences that generated new chimeric genes consistingorf352fragments. Plants with a new mitochondrial gene encoding amino acids 179 to 352 of ORF352 exhibited the same shrunken pollen grain phenotype as RT102A, whereas plants either lackingorf352or harboring a new gene encoding amino acids 211 to 352 of ORF352 showed partial rescue of pollen viability and germination, although they failed to set seed. These results demonstrated that disruption oforf352partially restored pollen development, indicating that amino acids 179 to 210 from ORF352 may contribute to the establishment of pollen abortion.
Intra-helical salt bridge contribution to membrane protein insertion
Authors: Duart Gerard , Lamb John , Ortiz-Mateu Juan , Elofsson Arne , Mingarro Ismael
Published: February 2021

Salt bridges between negatively (D, E) and positively charged (K, R, H) amino acids play an important role in protein stabilization. This has a more prevalent effect in membrane proteins where polar amino acids are exposed to a very hydrophobic environment. In transmembrane (TM) helices the presence of charged residues can hinder the insertion of the helices into the membrane. This can sometimes be avoided by TM region rearrangements after insertion, but it is also possible that the formation of salt bridges could decrease the cost of membrane integration. However, the presence of intra-helical salt bridges in TM domains and their effect on insertion has not been properly studied yet. In this work, we use an analytical pipeline to study the prevalence of charged pairs of amino acid residues in TM α-helices, which shows that potentially salt-bridge forming pairs are statistically over-represented. We then selected some candidates to experimentally determine the contribution of these electrostatic interactions to the translocon-assisted membrane insertion process. Using bothin vitroandin vivosystems, we confirm the presence of intra-helical salt bridges in TM segments during biogenesis and determined that they contribute between 0.5-0.7 kcal/mol to the apparent free energy of membrane insertion (ΔGapp). Our observations suggest that salt bridge interactions can be stabilized during translocon-mediated insertion and thus could be relevant to consider for the future development of membrane protein prediction software.
Transport Dynamics of MtrD: an RND Multidrug Efflux Pump fromNeisseria gonorrhoeae
Authors: Ammerman Lauren , Mertz Sarah B. , Park Chanyang , Wise John G.
Published: February 2021

The MtrCDE system confers multidrug resistance toNeisseria gonorrhoeae, the causative agent of gonorrhea. Using free and directed Molecular Dynamics (MD) simulations, we analyzed the interactions between MtrD and Azithromycin, a transport substrate of MtrD and a last-resort clinical treatment for multidrug resistant gonorrhea. We then simulated the interactions between MtrD and Streptomycin, an apparent non-substrate of MtrD. Using known conformations of MtrD homologues, we simulated a potential dynamic transport cycle of MtrD using Targeted MD techniques (TMD), and we note that forces were not applied to ligands of interest. In these TMD simulations, we observed the transport of Azithromycin and the rejection of Streptomycin. In an unbiased, long-timescale simulation of AZY-bound MtrD, we observed the spontaneous diffusion of Azithromycin through the periplasmic cleft. Our simulations show how the peristaltic motions of the periplasmic cleft facilitate the transport of substrates by MtrD. Our data also suggest that multiple transport pathways for macrolides may exist within the periplasmic cleft of MtrD.
Identical Sequences, Different Behaviors: Protein Diversity Captured at the Single-Molecule Level
Authors: Tapia-Rojo Rafael , Alonso-Caballero Alvaro , Badilla Carmen L. , Fernandez Julio M.
Published: February 2021

The classical “one sequence, one structure, one function” paradigm has shaped much of our intuition of how proteins work inside the cell. Partially due to the insight provided by bulk biochemical assays, individual biomolecules are assumed to behave as identical entities, and their characterization relies on ensemble averages that flatten any conformational diversity into a unique phenotype. While the emergence of single-molecule techniques opened the gates to interrogating individual molecules, technical shortcomings typically limit the duration of these measurements to a few minutes, which prevents to completely characterize a protein individual and, hence, to capture the heterogeneity among molecular populations. Here, we introduce a magnetic tweezers design, which showcases enhanced stability and resolution that allows us to measure the folding dynamics of a single protein during several uninterrupted days with a high temporal and spatial resolution. Thanks to this instrumental development, we do a complete characterization of two proteins with a very different force-response: the talin R3IVVIdomain and protein L. Days-long recordings on the same single molecule accumulate several thousands of folding transitions sampled with sub-ms resolution, which allows us to reconstruct their free energy landscapes and describe how they evolve with force. By mapping the nanomechanical identity of many different protein individuals, we directly capture their molecular diversity as a quantifiable dispersion on their force response and folding kinetics. Our instrumental development offers a new tool for profiling individual molecules, opening the gates to the characterization of biomolecular heterogeneity.
Implications of central carbon metabolism in SARS-CoV-2 replication and disease severity
Authors: Krishnan Shuba , Nordqvist Hampus , Ambikan Anoop T. , Gupta Soham , Sperk Maike , Svensson-Akusjärvi Sara , Mikaeloff Flora , Benfeitas Rui , Saccon Elisa , Ponnan Sivasankaran Munusamy , Rodriguez Jimmy Esneider , Nikouyan Negin , Odeh Amani , Ahlén Gustaf , Asghar Muhammad , Sällberg Matti , Vesterbacka Jan , Nowak Piotr , Végvári Ákos , Sönnerborg Anders , Treutiger Carl Johan , Neogi Ujjwal
Published: February 2021

Viruses hijack host metabolic pathways for their replicative advantage. Several observational trans-omics analyses associated carbon and amino acid metabolism in coronavirus disease 2019 (COVID-19) severity in patients but lacked mechanistic insights. In this study, using patient- derived multi-omics data andin vitroinfection assays, we aimed to understand i) role of key metabolic pathways in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and ii) its association with disease severity. Our data suggests that monocytes are key to the altered immune response during COVID-19. COVID-19 infection was associated with increased plasma glutamate levels, while glucose and mannose levels were determinants of the disease severity. Monocytes showed altered expression pattern of carbohydrate and amino acid transporters, GLUT1 and xCT respectively in severe COVID-19. Furthermore, lung epithelial cells (Calu-3) showed a strong acute metabolic adaptation following infectionin vitroby modulating central carbon metabolism. We found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, our study highlights that the virus utilizes and re-wires pathways governing central carbon metabolism leading to metabolic toxicity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.
Postembryonic development of the two-spotted field cricket (Gryllus bimaculatus): a staging system
Authors: Neiro Jakke
Published: February 2021

The two-spotted field cricketGryllus bimaculatushas emerged as a central model for studies on insect development, regeneration, and physiology.G. bimaculatushas the most sophisticated functional genetic toolkit of any hemimetabolous insect, making it a foremost model to understand the evolutionary developmental biology and comparative physiology of insects. However, the morphology and stages of postembryonic development have never been comprehensively reported. Here, 8 morphologically defined stages are described. Size, coloration, and the morphology of wing buds, hind tibial spines, and the ovipositor are the best landmarks for staging. The stages correspond to the 8-12 moult-based instars present in the literature. The staging system aims to standardise studies on the postembryonic development ofG. bimaculatusand serve as a point of reference for delineating interspecific postembryonic homologies within Orthoptera.
DYRK1A role in microtubule-based axonal transport regulates the retrograde dynamics of APP vesicles in human neurons
Authors: Bessone Iván Fernandez , Karmirian Karina , Goto-Silva Livia , Holubiec Mariana , Navarro Jordi L. , Martínez Emanuel , Saez Trinidad M.M. , Rehen Stevens , Falzone Tomás L.
Published: February 2021

In Alzheimer’s Disease (AD) the abnormal intracellular distribution of the amyloid precursor protein (APP) affects its processing and, consequently, the generation of Aβ. Axonal transport plays key roles in the neuronal distribution of APP. The dual-specificity-tyrosine phosphorylation-regulated-kinase-1A (DYRK1A) has been associated with AD onset since its overexpression was found in Down syndrome and sporadic AD patients. Experimental evidence confirmed that APP and tau phosphorylations are mediated by DYRK1A. Moreover, DYRK1A can regulate the cytoskeletal architecture by phosphorylation of both tubulin subunits and microtubule-associated proteins. Therefore, we tested whether DYRK1A has a role in APP axonal transport regulation.

We developed highly-polarized human-derived neurons in 2D cultures. At day 14 after terminal plating we inhibited DYRK1A for 48hs with harmine (7.5 μM). DYRK1A overexpression was induced to perform live-cell imaging of APP-loaded vesicles in axons and analyzed transport dynamics. A custom-made MATLAB routine was developed to track and analyze single particle dynamics.

Short-term harmine treatment reduced axonal APP vesicles density, due to a reduction in retrograde particles. Contrarily, DYRK1A overexpression enhanced axonal APP density, due to an increase in the retrograde and stationary component. Moreover, both harmine-mediated DYRK1A inhibition and DYRK1A overexpression revealed opposite phenotypes on single particle dynamics, affecting primarily dynein processivity. These results revealed an increased retrieval of distal APP vesicles in axons when DYRK1A is overexpressed and reinforce the suggestion that DYRK1A enhance APP endocytosis‥

Taken together our results suggest that DYRK1A has a relevant role in the regulation of axonal transport and sub-cellular positioning of APP vesicles. Therefore, our work shed light on the role of DYRK1A in axonal transport regulation, and the putative use of harmine to restore axonal transport impairments.
Characterising ontogeny of quantity discrimination in zebrafish
Authors: Sheardown Eva , Torres-Perez Jose Vicente , Anagianni Sofia , Fraser Scott E. , Vallortigara Giorgio , Butterworth Brian , Miletto-Petrazzini Maria Elena , Brennan Caroline H.
Published: February 2021

A sense of non-symbolic numerical magnitudes is widespread in the animal kingdom and has been documented in adult zebrafish. Here we investigated the ontogeny of this ability using a group size preference task in juvenile zebrafish. Fish showed group size preference from 21 days post fertilization (dpf) and reliably chose the larger group when presented with discriminations of between 1 vs. 3, 2 vs. 5 and 2 vs. 3 conspecifics but not 2 vs. 4 conspecifics. When the ratio between the number of conspecifics in each group was maintained at 1:2, fish could discriminate between 1 vs. 2 individuals and 3 vs. 6, but again, not when given a choice between 2 vs. 4 individuals. These findings are in agreement with studies in other species suggesting the systems involved in quantity representation do not operate separately from other cognitive mechanisms. Rather they suggest quantity processing in fish may be the result of an interplay between attentional, cognitive and memory-related mechanisms as in humans and other animals. Our results emphasise the potential of the use of zebrafish to explore the genetic and neural processes underlying the ontogeny and function of number cognition.
RHAMMB-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment
Authors: Chen Xiang , Lee Seung Koo , Song Mei , Zhang Tiantian , Han Myung Shin , Chen Yao-Tseng , Chen Zhengming , Ma Xiaojing , Tung Ching-Hsuan , Du Yi-Chieh Nancy
Published: March 2021

The incidence of pancreatic neuroendocrine tumor (PNET) has continued to rise. Due to their indolent feature, PNET patients often present with incurable, metastatic diseases. Novel therapies are urgently needed. We have previously shown that Receptor for Hyaluronic Acid-Mediated Motility isoform B (RHAMMB) and Bcl-xL are upregulated in PNETs and both of them promote PNET metastasis. Because RHAMM protein is undetectable in most adult tissues, we hypothesized that RHAMMBcould be a gateway for nanomedicine delivery into PNETs. To test this, we developed RHAMMB-targeting nanoparticle. Inside this nanoparticle, we assembled siRNA against Bcl-xL (siBcl-xL) and mitochondria-fusing peptide KLA. We demonstratsed that RHAMMB-positive PNETs picked up the RHAMMB-targeting nanoparticles. siBcl-xL or KLA alone only killed 30% of PNET cells. In contrast, a synergistic killing effect was achieved with the co-delivery of siBcl-xL and KLA peptidein vitro. Unexpectedly, siBcl-xL induced cell death before reducing Bcl-xL protein levels. The systemically-injected RHAMMB-targeting nanoparticles carrying siBcl-xL and KLA peptide significantly reduced tumor burden in mice bearing RHAMMB-positive PNETs. Together, these findings indicate that the RHAMMB-targeting nanotherapy serves as a promising drug delivery system for PNET and possibly other malignancies upregulating RHAMMB. The combination of siBcl-xL and KLA peptide can be a therapy for PNET treatment.
The gene expression profile of the song control nucleus HVC shows sex specificity, hormone responsiveness, and species specificity among songbirds
Authors: Ko Meng-Ching , Frankl-Vilches Carolina , Bakker Antje , Gahr Manfred
Published: March 2021

Singing occurs in songbirds of both sexes, but some species show typical degrees of sex-specific performance. We studied the transcriptional sex differences in the HVC, a brain nucleus critical for song pattern generation, of the forest weaver (Ploceus bicolor), the blue-capped cordon-bleu (Uraeginthus cyanocephalus), and the canary (Serinus canaria), which are species that show low, medium, and high levels of sex-specific singing, respectively. We observed persistent sex differences in gene expression levels regardless of the species-specific sexual singing phenotypes. We further studied the HVC transcriptomes of defined phenotypes of canary, known for its testosterone-sensitive seasonal singing. By studying both sexes of canaries during both breeding and nonbreeding seasons, nonbreeding canaries treated with testosterone, and spontaneously singing females, we found that the circulating androgen levels and sex were the predominant variables associated with the variations in the HVC transcriptomes. The comparison of natural singing with testosterone-induced singing in canaries of the same sex revealed considerable differences in the HVC transcriptomes. Strong transcriptional changes in the HVC were detected during the transition from nonsinging to singing in canaries of both sexes. Although the sex-specific genes of singing females shared little resemblance with those of males, our analysis showed potential functional convergences. Thus, male and female songbirds achieve comparable singing behaviours with sex-specific transcriptomes.
MEDICC2: whole-genome doubling aware copy-number phylogenies for cancer evolution
Authors: Kaufmann Tom L , Petkovic Marina , Watkins Thomas BK , Colliver Emma C , Laskina Sofya , Thapa Nisha , Minussi Darlan C , Navin Nicholas , Swanton Charles , Van Loo Peter , Haase Kerstin , Tarabichi Maxime , Schwarz Roland F
Published: March 2021

Chromosomal instability (CIN) and somatic copy-number alterations (SCNA) play a key role in the evolutionary process that shapes cancer genomes. SC-NAs comprise many classes of clinically relevant events, such as localised amplifications, gains, losses, loss-of-heterozygosity (LOH) events, and recently discovered parallel evolutionary events revealed by multi-sample phasing. These events frequently appear jointly with whole genome doubling (WGD), a transformative event in tumour evolution involving tetraploidization of genomes preceded or followed by individual chromosomal copy-number changes and associated with an overall increase in structural CIN.

While SCNAs have been leveraged for phylogeny reconstruction in the past, existing methods do not take WGD events into account and cannot model parallel evolution. They frequently make use of the infinite sites assumption, do not model horizontal dependencies between adjacent genomic loci and can not infer ancestral genomes. Here we present MEDICC2, a new phylogeny inference algorithm for allele-specific SCNA data that addresses these shortcomings. MEDICC2 dispenses with the infinite sites assumption, models parallel evolution and accurately identifies clonal and subclonal WGD events. It times SCNAs relative to each other, quantifies SCNA burden in single-sample studies and infers phylogenetic trees and ancestral genomes in multi-sample or single-cell sequencing scenarios with thousands of cells.

We demonstrate MEDICC2’s ability on simulated data, real-world data of 2,778 single sample tumours from the Pan-cancer analysis of whole genomes (PCAWG), 10 bulk multi-region prostate cancer patients and two recent single-cell datasets of triple-negative breast cancer comprising several thousands of single cells.
Gibberellins target shoot-root growth, morpho-physiological and molecular pathways to induce cadmium tolerance in mung bean
Authors: Hakla Haroon Rashid , Sharma Shubham , Urfan Mohammad , Yadav Narendra Singh , Kotwal Dinesh , Pal Sikander
Published: March 2021

Cadmium (Cd) inhibits plant growth, perturb nutrient uptake and affect chloroplast ultra structure. Cd soil pollution is mainly contributed by excessive use of phosphate fertilizers, nickel Cd batteries, plating and sewage sludge. Research investigations deciphering role of Cd in affecting overall performance of mung bean is least understood. Likewise ameliorative effects of gibberellins (GAs) in Cd induced toxicity in mung bean are lesser known. In this context, effects of Cd stress (CdCl2, IC50−500 µM L−1) with or without GA3 application on mung bean (Vigna radiataL. Var. SML-668) plants were comprehensively investigated under controlled conditions. In brief, a total of 80 mung bean plants (15 days old of uniform height) were divided into four groups, with each group (n=20) subjected to four different treatments (Control, CdCl2,GA3, CdCl2+GA3), twice during the entire life cycle of mung bean plants (until harvest 85-90 days). Results revealed negative impacts of Cd stress on shoot morphometry (plant height, leaf surface area, stem diameter, shoot fresh weight, number of leaves, number of pods, length and diameter of pods), root morphometry (root length, root surface area, root dry weight, nodule number and nodule diameter), photosynthetic pigments and agronomic traits. GA3 ameliorated Cd stress by modulating shoot and root growth rates, improving overall plant metabolism, photosynthetic pigments, and shoot and root morphometry and transcript abundance ofVgPCS1,VgPCS2,VgCdRandVgIRT1. Current study proposes GA3 application for the effective management of Cd induced phytotoxicity in mung bean plants.
Are adaptive chemotherapy schedules robust? A three-strategy stochastic evolutionary game theory model
Authors: Dua R. , Ma Y. , Newton P.K.
Published: March 2021

We investigate the robustness of adaptive chemotherapy schedules over repeated cycles and a wide range of tumor sizes. We introduce a non-stationary stochastic three-component fitness-dependent Moran process to quantify the variance of the response to treatment associated with multidrug adaptive schedules that are designed to mitigate chemotherapeutic resistance in an idealized (well-mixed) setting. The finite cell (Ntumor cells) stochastic process consists of populations of chemosensitive cells, chemoresistant cells to drug 1, and chemoresistant cells to drug 2, and the drug interactions can be synergistic, additive, or antagonistic. First, the adaptive chemoschedule is determined by using theN→ ∞ limit of the finite-cell process (i.e. the adjusted replicator equations) which is constructed by finding closed treatment response loops (which we call evolutionary cycles) in the three component phase-space. The schedules that give rise to these cycles are designed to manage chemoresistance by avoiding competitive release of the resistant cell populations. To address the question of how these cycles are likely to perform in practice over large patient populations with tumors across a range of sizes, we then consider the statistical variances associated with the approximate stochastic cycles for finiteN, repeating the idealized adaptive schedule over multiple periods. For finite cell populations, the error distributions remain approximately multi-Gaussian in the principal component coordinates through the first three cycles, with variances increasing exponentially with each cycle. As the number of cycles increases, the multi-Gaussian nature of the distribution breaks down due to the fact that one of the three subpopulations typically saturates the tumor (competitive release) resulting in treatment failure. This suggests that to design an effective and repeatable adaptive chemoschedule in practice will require a highly accurate tumor model and accurate measurements of the subpopulation frequencies or the errors will quickly (exponentially) degrade its effectiveness, particularly when the drug interactions are synergistic. Possible ways to extend the efficacy of the stochastic cycles in light of the computational simulations are discussed.

Prepared for Special Issue

Understanding the Evolutionary Dynamics and Ecology of Cancer Treatment Resistance, Ed. D. Basanta, Cancers (2021)
Multiple evolutionary origins reflect the importance of sialic acid transporters in the colonisation potential of bacterial pathogens and commensals
Authors: Severi Emmanuele , Rudden Michelle , Bell Andrew , Palmer Tracy , Juge Nathalie , Thomas Gavin H
Published: March 2021

Located at the tip of cell surface glycoconjugates, sialic acids are at the forefront of host-microbe interactions and, being easily liberated by sialidase enzymes, are used as metabolites by numerous bacteria, particularly by pathogens and commensals living on or near diverse mucosal surfaces. These bacteria rely on specific transporters for the acquisition of host-derived sialic acids. Here, we present the first comprehensive genomic and phylogenetic analysis of bacterial sialic acid transporters, leading to the identification of multiple new families and subfamilies. Our phylogenetic analysis suggests that sialic acid-specific transport has evolved independently at least 8 times during the evolution of bacteria, from within 4 of the major families/superfamilies of bacterial transporters, and we propose a robust classification scheme to bring together a myriad of different nomenclatures that exist to date. The new transporters discovered occur in diverse bacteria including Spirochaetes, Bacteroidetes, Planctomycetes, and Verrucomicrobia, many of which are species that have not been previously recognised to have sialometabolic capacities. Two subfamilies of transporters stand out in being fused to the sialic acid mutarotase enzyme, NanM, and these transporter fusions are enriched in bacteria present in gut microbial communities. We also provide evidence for a possible function of a sialic acid transporter component in chemotaxis that is independent of transport. Our analysis supports the increasing experimental evidence that competition for host-derived sialic acid is a key phenotype for successful colonisation of complex mucosal microbiomes, such that a strong evolutionary selection has occurred for the emergence of sialic acid specificity within existing transporter architectures.
Intrinsic variability of fluorescence calibrators impacts the assignment of MESF or ERF values to nanoparticles and extracellular vesicles by flow cytometry
Authors: Lozano-Andrés Estefanía , Van Den Broeck Tina , Wang Lili , Mehrpouyan Majid , Tian Ye , Yan Xiaomei , Wauben Marca H.M. , Arkesteijn Ger. J.A.
Published: March 2021

Flow cytometry is commonly used to characterize nanoparticles (NPs) and extracellular vesicles (EVs) but results are often expressed in arbitrary units to indicate fluorescence intensity. This hampers interlaboratory and inter-platform comparisons. We investigated the use of molecules of equivalent soluble fluorophores (MESF)-beads for assignment of fluorescence values to NPs and EVs by comparing two FITC-MESF bead sets as calibrators on different flow cytometry platforms (BD Influx™, CytoFLEX LX™and SORP BD FACSCelesta™). Next, fluorescence signals of NPs and EVs were calibrated using different sets of FITC and PE-MESF beads. Fluorescence calibration using beads designed for cellular flow cytometry allowed inter-platform comparison. However, the intrinsic uncertainty in the fluorescence assignment to these MESF beads impacts the reliable assignment of MESF values to NPs and EVs based on extrapolation into the dim fluorescence range. Our findings demonstrate that the use of the same set of calibration materials (vendor and lot number) and the same number of calibration points, greatly improves robust interlaboratory and inter-platform comparison of fluorescent submicron sized particles.
Synthesis and characterization of enantiopure planar–chiral phosphorus-linked diferrocenes
Authors: Honegger Philipp , Roller Alexander , Widhalm Michael
Published: February 2021

In the course of an ongoing synthetic project on cyclic diferrocenylphosphines, we obtained a group of planar–chiral diferrocenyl compounds useful as precursors for subsequent cyclization. Here we report the crystal structures of two symmetric compounds [(FcA)2(Ph)P], one of which contains four stereogenic centres (two C chiral and two planar chiral centres),i.e.1,1′-(phenylphosphanediyl)bis{(2Sp)-2-[(1R)-1-(acetyloxy)ethyl]ferrocene}, [Fe2(C5H5)2(C24H25O4P)], and the other phosphine sulfide is a purely planar–chiral compound (two planar chiral centres),i.e.bis[(2Sp)--2-ethenylferrocen-1-yl]phenylphosphane sulfide, [Fe2(C5H5)2(C20H17PS)]. Owing to the stereocentres present, reactions performed on [(FcA)2(Ph)P]-type compounds strongly favour one ferrocene unit over the other due to diastereoselectivity. Furthermore, we present four related structures where the ferrocene units are not identical [(FcA)(FcB)(Ph)P]. These are {(2Sp)-2-[(1R)-1-(acetyloxy)ethyl]ferrocen-1-yl}[(2Sp)-2-ethenylferrocen-1-yl]phenyl-(S)-phosphine sulfide, [Fe2(C5H5)2(C22H21O2PS)], [(2Sp)-2-ethenylferrocen-1-yl]{(2Sp)-2-[(1R)-1-hydroxyethyl]ferrocen-1-yl}phenyl-(S)-phosphine sulfide, [Fe2(C5H5)2(C20H19OPS)], {(2Sp)-2-[(1R)-1-(acetyloxy)ethyl]ferrocen-1-yl}{(2Sp)-2-[(1R)-1-hydroxyethyl]ferrocen-1-yl}phenyl-(R)-phosphine sulfide, [Fe2(C5H5)2(C22H23O3PS)], and {(2Sp)-2-[(1R)-1-benzylamino)ethyl]ferrocen-1-yl}[(2Sp)-2-ethenylferrocen-1-yl]phenyl-(S)-phosphine sulfide, [Fe2(C5H5)2(C27H26NPS)]. All of the structures are accessible in one step from known precursors.
Capturing the dynamics of interorganizational governance implementation: a process and cybernetic based conceptualization
Authors: Zhang Tao
Published: February 2021

Purpose

The effectiveness of interorganizational governance is one of the most significant concerns of firms involved in supply chain management. Previous studies have extensively examined various interorganizational governance strategies. However, the dynamic and implementation details of interorganizational governance receive little attention, which leads to the defects of interorganizational governance literature. This study tries to explore this issue.

Design/methodology/approach

Based on the process and cybernetic view, this study conceptualized four interorganizational governance processes and their respective critical activities to capture the dynamic and implementation details of interorganizational governance. Furthermore, this study investigated the mapping of governance strategies into different critical activities, which unveil the various manifestations of governance strategies across these critical activities.

Findings

Four interorganizational governance processes and their respective critical activities would overarch the dynamic and implementation details of governance strategies. Furthermore, various governance strategies also would have different manifestations across the critical activities of the four processes.

Originality/value

This paper fills the gaps in interorganizational governance literature in which the dynamic details of governance strategies are unclear. The new conceptualization provides a new paradigm for researchers to zoom in on the subtle dynamics of interorganizational governance. The new conceptualization indicates a few promising future research directions.
Nurses quality of work life: scale development and validation
Authors: TS Nanjundeswaraswamy
Published: February 2021

Purpose

This is a systematically conducted study to design, develop and validate a measuring instrument to assess the nurses quality of work life (QWL) and determine the vital components of nurses' QWL.

Design/methodology/approach

In this methodical study, vital dimensions of nurses QWL are identified using Pareto analysis; data and information were collected from 474 nurses through the structured questionnaire. By conducting exploratory factor analysis (EFA), the number of dimensions and items was reduced. Through the confirmatory factor analysis (CFA) using SPSS 21 software, nine predominant dimensions were confirmed, they are work environment, working condition, work–life balance, compensation, relationship and cooperation, stress at work, job satisfaction, career development and organization culture. Additional structural equation modeling (SEM) was done to determine the interrelationships between extracted nine components using AMOS. By performing different statistical tests like reliability test, content validity, construct validity, convergent, divergent validity and multicollinearity, the proposed nine-component nurses QWL instrument was validated.

Findings

The proposed measurement model explained 73.18% of total variance; reliability of the instrument Cronbach's alpha value is 0.902. Model fit indices like chi-square df (CMIN) = 685, df = 523, CMIN/DF = 1.310, goodness-of-fit index (GFI) = 0.965, adjusted goodness-of-fit index (AGFI) = 0.937, parsimony goodness-of-fit index (PGFI) = 0.918, incremental fir index (IFI) = 0.933, Tucker–Lewis index (TLI) = 0.921, comparative fit index (CFI) = 0.931 and root mean square error of approximation (RMSEA) = 0.036 fulfill the acceptable criteria. The nine factors nurses QWL measuring instrument is reliable and statistically valid.

Research limitations/implications

Data were collected from 474 nurses, poor responses and time constraints.

Practical implications

Hospitals are trying to improve the quality of patient caring by enhancing the nurses' skill sets, knowledge and attitude to meet global challenges. In this unstable business environment, hospitals face challenges like the high attrition rate and skilled nurses shortage. In this scenario, this study provides a valid instrument to measure the QWL of nurses to know the status of QWL, which will help to build a strategic plan to improve retention rate and to attract the talented workforce to the hospitals.

Originality/value

As a result, the scale developed in this study contributes to the body of the literature on nurses QWL. It seems to be more advantageous for carrying out further research in this field.
Corporate governance, ownership structure and firms’ financial performance: insights from Muscat securities market (MSM30)
Authors: Queiri Abdelbaset , Madbouly Araby , Reyad Sameh , Dwaikat Nizar
Published: February 2021

Purpose

The purpose of this study is to investigate the relationship between selected board characteristics and ownership elements and the performance of firms listed in the Muscat Securities Market (MSM30). The examination focused on how the firm financial performance was affected by the board size, the number of board meetings and the ratio of the independent board of directors along to the ownership concentration types (i.e. institutional, state and concentrated individual ownership).

Design/methodology/approach

Data were extracted from the annual reports available online on the MSM30 website over a period of seven years (2009–2015). The sample consisted of 14 firms belonging to the non-financial sector. The data were of a balanced type and there were 98 observations. The analysis was conducted using the ordinary least square in STATA with the use of the robustness technique of standard error.

Findings

The findings of this study provide evidence that the selected elements for board characteristics and ownership influence firm performance. Nevertheless, such influence has its interpretation that differs to some extent from other securities markets in the developing countries. For instance, the ratio of the independent board of directors, the number of board director’s meetings, state ownership and concentrated individual ownership were inversely affecting the firm performance. However, institutional ownership and board size were found to have a positive effect on firm performance.

Originality/value

Studies on the influence of corporate governance and ownership structures in the context of Oman are still scarce. MSM30 received little attention, even though such an index encompasses the most liquid and the most profitable firms. MSM30 is an important index for investors in Oman looking for capital gains. Accordingly, this present study contributes to the knowledge body by providing new findings related to Oman and compares it with the other markets within Gulf Council Countries (GCC) and around the world. This will provide more understanding of the Omani context. Moreover, the authors anticipate that the outcomes of this research, which so far is the most comprehensive study in the Omani context in terms of the impact of corporate governance and ownership structure on firm financial performance can significantly shape corporate governance discourse, practices and policies in Oman, in particular, and in other GCC countries in general, to improve financial performance and corporate sustainability.
Understanding the Processes Underlying Inter‐firm Collaboration: Mutual Forbearance and the Principle of Congruity
Authors: Buckley Peter J. , De Mattos Claudio
Published: February 2021

This paper makes a theoretical innovation by integrating two key principles – mutual forbearance and the principle of congruity – into one general process model. It examines the micro‐mechanisms underlying the formation of a mutual‐forbearance agreement and explicates the role of time and of individual actions. We further understanding of the process of cooperation building by drawing a parallel between early stages of the formation process of mutual forbearance and cooperation, and argue that mutual forbearance may, under certain conditions, lead to long‐term cooperation or, if mismanaged, completely smother any chances of it. A prospective agreement may be put at risk when potential contributions are evaluated differently by each party and no action to mitigate the consequences is taken; even more so in a mutual‐forbearance context when the parties can only observe their counterparts’ actions through the market. Our model takes into account the micro‐mechanisms associated with the time between the actions of one entity/individual (e.g. the top manager) and the reaction of another entity/individual, the boundary conditions of the background to those actions and the alternative actions available during this time. Propositions for further exploration and implications are drawn.