Investigating effect of mutation on structure and function of G6PD enzyme: a comparative molecular dynamics simulation study
Several natural mutants of the human G6PD enzyme exist and have been reported. Because the enzymatic activities of many mutants are different from that of the wildtype, the genetic polymorphism of G6PD plays an important role in the synthesis of nucleic acids via ribulose-5-phosphate and formation of reduced NADP in response to oxidative stress. G6PD mutations leading to its deficiency result in the neonatal jaundice and acute hemolytic anemia in human. Herein, we demonstrate the molecular dynamics simulations of the wildtype G6PD and its three mutants to monitor the effect of mutations on dynamics and stability of the protein. These mutants are Chatham (A335T), Nashville (R393H), Alhambra (V394L), among which R393H and V394L lie closer to binding site of structural NADP+. MD analysis including RMSD, RMSF and protein secondary structure revealed that decrease in the stability of mutants is key factor for loss of their activity. The results demonstrated that mutations in the G6PD sequence resulted in altered structural stability and hence functional changes in enzymes. Also, the binding site, of structural NADP+, which is far away from the catalytic site plays an important role in protein stability and folding. Mutation at this site causes changes in structural stability and hence functional deviations in enzyme structure reflecting the importance of structural NADP+ binding site. The calculation of binding free energy by post processing end state method of Molecular Mechanics Poisson Boltzmann SurfaceArea (MM-PBSA) has inferred that ligand binding in wildtype is favorable as compared to mutants which represent destabilised protein structure due to mutation that in turn may hinder the normal physiological function. Exploring individual components of free energy revealed that the van der Waals energy component representing non-polar/hydrophobic energy contribution act as a dominant factor in case of ligand binding. Our study also provides an insight in identifying the key inhibitory site in G6PD and its mutants which can be exploited to use them as a target for developing new inhibitors in rational drug design.
Rani et al. (2022) Investigating effect of mutation on structure and function of G6PD enzyme: a comparative molecular dynamics simulation study. PeerJ 10:e12984 https://doi.org/10.7717/peerj.12984
Synergistic effects of climate and landscape change on the conservation of Amazonian lizards
The leading causes of the worldwide decline in biodiversity are global warming, allied with natural habitat loss and fragmentation. Here, we propose an analysis of the synergistic effects of these two factors in 63 species of Amazonian lizards. We predicted that the high-climatic suitability areas of species would be significantly impacted by different deforestation scenarios and the resultant landscape structure and considered that forest-dwelling species would be especially susceptible to deforestation scenarios. We also pointed out species threatened by both drivers and suggested critical areas for their future conservation. According to our results, most species will face future reductions in suitable areas for their occurrence according to five different patterns, two of which represent significant risks for 15 species. Some of these species already deal with severe habitat loss and fragmentation of their current distribution ranges, whereas others will suffer a considerable area reduction related to future range shifts. We emphasize the importance of protected areas (PAs), especially indigenous lands, and the need to plan combined strategies involving PAs’ maintenance and possible implementation of ecological corridors. Finally, we highlight eight species of thermoconformer lizards that constitute present and future conservation concerns related to the combined effects of climate change and habitat loss and that should be carefully evaluated in extinction risk assessments.
Teixeira et al. (2022) Synergistic effects of climate and landscape change on the conservation of Amazonian lizards. PeerJ 10:e13028 https://doi.org/10.7717/peerj.13028
Rapid parameter estimation for selective inversion recovery myelin imaging using an open-source Julia toolkit
Background Magnetic resonance imaging (MRI) is used extensively to quantify myelin content, however computational bottlenecks remain challenging for advanced imaging techniques in clinical settings. We present a fast, open-source toolkit for processing quantitative magnetization transfer derived from selective inversion recovery (SIR) acquisitions that allows parameter map estimation, including the myelin-sensitive macromolecular pool size ratio (PSR). Significant progress has been made in reducing SIR acquisition times to improve clinically feasibility. However, parameter map estimation from the resulting data remains computationally expensive. To overcome this computational limitation, we developed a computationally efficient, open-source toolkit implemented in the Julia language. Methods To test the accuracy of this toolkit, we simulated SIR images with varying PSR and spin-lattice relaxation time of the free water pool (R1f) over a physiologically meaningful scale from 5% to 20% and 0.5 to 1.5 s−1, respectively. Rician noise was then added, and the parameter maps were estimated using our Julia toolkit. Probability density histogram plots and Lin’s concordance correlation coefficients (LCCC) were used to assess accuracy and precision of the fits to our known simulation data. To further mimic biological tissue, we generated five cross-linked bovine serum albumin (BSA) phantoms with concentrations that ranged from 1.25% to 20%. The phantoms were imaged at 3T using SIR, and data were fit to estimate PSR and R1f. Similarly, a healthy volunteer was imaged at 3T, and SIR parameter maps were estimated to demonstrate the reduced computational time for a real-world clinical example. Results Estimated SIR parameter maps from our Julia toolkit agreed with simulated values (LCCC > 0.98). This toolkit was further validated using BSA phantoms and a whole brain scan at 3T. In both cases, SIR parameter estimates were consistent with published values using MATLAB. However, compared to earlier work using MATLAB, our Julia toolkit provided an approximate 20-fold reduction in computational time. Conclusions Presented here, we developed a fast, open-source, toolkit for rapid and accurate SIR MRI using Julia. The reduction in computational cost should allow SIR parameters to be accessible in clinical settings.
Sisco et al. (2022) Rapid parameter estimation for selective inversion recovery myelin imaging using an open-source Julia toolkit. PeerJ 10:e13043 https://doi.org/10.7717/peerj.13043
NanoForms: an integrated server for processing, analysis and assembly of raw sequencing data of microbial genomes, from Oxford Nanopore technology
Background Next Generation Sequencing (NGS) techniques dominate today’s landscape of genetics and genomics research. Though Illumina still dominates worldwide sequencing, Oxford Nanopore is one of the leading technologies currently being used by biologists, medics and geneticists across various applications. Oxford Nanopore is automated and relatively simple for conducting experiments, but generates gigabytes of raw data, to be processed by often ambiguous set of alternative bioinformatics command-line tools, and genomics frameworks which require a knowledge of bioinformatics to run. Results We established an inter-collegiate collaboration across experimentalists and bioinformaticians in order to provide a novel bioinformatics tool, free for academics. This tool allows people without extensive bioinformatics knowledge to simply process their raw genome sequencing data. Currently, due to ICT resources’ maintenance reasons, our server is only capable of handling small genomes (up to 15 Mb). In this paper, we introduce our tool, NanoForms: an intuitive and integrated web server for the processing and analysis of raw prokaryotic genome data, coming from Oxford Nanopore. NanoForms is freely available for academics at the following locations: http://nanoforms.tech (webserver) and https://github.com/czmilanna/nanoforms (GitHub source repository).
Czmil et al. (2022) NanoForms: an integrated server for processing, analysis and assembly of raw sequencing data of microbial genomes, from Oxford Nanopore technology. PeerJ 10:e13056 https://doi.org/10.7717/peerj.13056
Subject specific muscle synergies and mechanical output during cycling with arms or legs
Background Upper (UL) and lower limb (LL) cycling is extensively used for several applications, especially for rehabilitation for which neuromuscular interactions between UL and LL have been shown. Nevertheless, the knowledge on the muscular coordination modality for UL is poorly investigated and it is still not known whether those mechanisms are similar or different to those of LL. The aim of this study was thus to put in evidence common coordination mechanism between UL and LL during cycling by investigating the mechanical output and the underlying muscle coordination using synergy analysis. Methods Twenty-five revolutions were analyzed for six non-experts’ participants during sub-maximal cycling with UL or LL. Crank torque and muscle activity of eleven muscles UL or LL were recorded. Muscle synergies were extracted using nonnegative matrix factorization (NNMF) and group- and subject-specific analysis were conducted. Results Four synergies were extracted for both UL and LL. UL muscle coordination was organized around several mechanical functions (pushing, downing, and pulling) with a proportion of propulsive torque almost 80% of the total revolution while LL muscle coordination was organized around a main function (pushing) during the first half of the cycling revolution. LL muscle coordination was robust between participants while UL presented higher interindividual variability. Discussion We showed that a same principle of muscle coordination exists for UL during cycling but with more complex mechanical implications. This study also brings further results suggesting each individual has unique muscle signature.
Cartier et al. (2022) Subject specific muscle synergies and mechanical output during cycling with arms or legs. PeerJ 10:e13155 https://doi.org/10.7717/peerj.13155
Mechanisms and potential immune tradeoffs of accelerated coral growth induced by microfragmentation
Microfragmentation is the act of cutting corals into small pieces (~1 cm2) to accelerate the growth rates of corals relative to growth rates observed when maintaining larger-sized fragments. This rapid tissue and skeletal expansion technique offers great potential for supporting reef restoration, yet the biological processes and tradeoffs involved in microfragmentation-mediated accelerated growth are not well understood. Here we compared growth rates across a range of successively smaller fragment sizes in multiple genets of reef-building corals, Orbicella faveolata and Montastraea cavernosa. Our results confirm prior findings that smaller initial sizes confer accelerated growth after four months of recovery in a raceway. O. faveolata transcript levels associated with growth rate include genes encoding carbonic anhydrase and glutamic acid-rich proteins, which have been previously implicated in coral biomineralization, as well as a number of unannotated transcripts that warrant further characterization. Innate immunity enzyme activity assays and gene expression results suggest a potential tradeoff between growth rate after microfragmentation and immune investment. Microfragmentation-based restoration practices have had great success on Caribbean reefs, despite widespread mortality among wild corals due to infectious diseases. Future studies should continue to examine potential immune tradeoffs throughout the microfragmentation recovery period that may affect growout survival and disease transmission after outplanting.
Schlecker et al. (2022) Mechanisms and potential immune tradeoffs of accelerated coral growth induced by microfragmentation. PeerJ 10:e13158 https://doi.org/10.7717/peerj.13158
In vitro evaluation of probiotic properties of lactic acid bacteria isolated from the vagina of yak (Bos grunniens)
Bovine endometritis is an inflammatory disease of the uterus that occurs after parturition and can result in the destruction of uterine microecology, disruption of hormone secretion, and even infertility. Problems such as antibiotic residues, pathogen resistance, and microbiota dysbiosis caused by conventional antibiotic therapy cannot be ignored. According to the microecological balance theory, probiotics have the potential to prevent or cure endometritis in cattle. Probiotics can positively influence host physiology by regulating microecological imbalance, modulating immunity, and antagonizing pathogens. Since some probiotics contribute to host health only in their specific natural niches, lactic acid bacteria (LAB) from the vagina may have better potential to fight against vaginal and uterine infection. The yak (Bos grunniens) is an ancient and primitive livestock animal that is adapted to high altitude and harsh environments (cold, nutritional deficiencies, and hypoxia). However, to our knowledge, there have been no studies on yak vaginal LAB. Therefore, the purpose of this study was to isolate vaginal LAB from yak, evaluate and compare the probiotic potential and safety of the isolates, and help establish the probiotics library that can be used in the prevention and/or treatment of endometritis. Twenty-five vaginal swabs were collected from healthy yak and cultured in deMan, Rogosa, and Sharpe (MRS) broth. Tentative LAB strains were preliminarily determined through calcium dissolving zone and morphological identification, and the strains were then identified using 16S rRNA gene sequencing. The probiotics of the isolates were detected using cell aggregation, hydrophobicity, resistance to acid and bile salt, adhesion, and antibacterial activities. Additionally, antimicrobial susceptibility, hemolytic activity, and detection of potential virulence factors were determined in order to confirm the safety of these strains. Five isolates were identified: Leuconostoc mesenteroides, Lactobacillus plantarum, Enterococcus hirae, Lacticaseibacillus camelliae, and Lactobacillus mucosae. All isolates had certain growth resistance, aggregation ability, effective antimicrobial potency against Escherichia coli, Staphylococcus aureus, and Salmonella typhimurium, were sensitive to most antibiotics, and could effectively adhere to bovine endometrial epithelial cells (BEECs). None of the isolates showed hemolytic activity or harbored virulence factors. Our results indicated that the five isolates have considerable potential as probiotics that can be used to prevent and/or treat bovine endometritis. We speculate that a mixture of YD6, YD9, and YD25 may yield better results, although this would require extensive experiments to verify.
Zhang et al. (2022) In vitro evaluation of probiotic properties of lactic acid bacteria isolated from the vagina of yak (Bos grunniens). PeerJ 10:e13177 https://doi.org/10.7717/peerj.13177
Using cluster and rest redistribution set structures as alternatives to resistance training prescription method based on velocity loss thresholds
Background The purpose of this study was to compare the effects of cluster (CS), rest redistribution (RR) and traditional (TS) set configurations on acute neuromuscular performance, and to determine the viability of using CS and RR as alternatives to training prescription based on velocity loss (VL). Methods Thirty-one resistance-trained men performed, in a randomised order, three experimental sessions consisting of the squat (SQ) and bench press (BP) exercises performed against the 10-repetition maximum load using CS (three sets of six repetitions; 30 s of intra-set rest every two repetitions; 3 min of inter-set rest), RR (9 sets of two repetitions; 45 s of inter-set rest), and TS (3 sets of 6 repetitions; 3 min of inter-set rest), set configurations. Results Linear mixed-effects model analysis revealed that participants had significantly lower VL (p = 0.0005) during CS and RR than TS. Generalised mixed-effects model analysis yielded significant main effects of set structure (p < 0.0001; RR > CS > TS), exercise (p < 0.0001; SQ > BP), and set number (p = 0.0006; Set 1 > Set 2 > Set 3) for maintaining repetition velocity above a 20% VL threshold. Conclusions These findings suggest that CS and RR are effective at reducing the overall fatigue-included decrease in velocity compared to TS and allow the majority of repetitions to be completed with less than 20% VL. Therefore, both CS and RR can be used to manage fatigue during resistance training, and as alternatives to training prescription method based on 20% VL threshold.
Jukic et al. (2022) Using cluster and rest redistribution set structures as alternatives to resistance training prescription method based on velocity loss thresholds. PeerJ 10:e13195 https://doi.org/10.7717/peerj.13195
Comprehensive analysis of the correlations of S100B with hypoxia response and immune infiltration in hepatocellular carcinoma
S100B has been found to be dysregulated in many cancers including hepatocellular carcinoma (HCC). However, the functions of S100B and its underlying mechanisms in HCC remain poorly understood, especially in the tumor microenvironment. In this study, functions enrichment analysis indicated that S100B expression was correlated with hypoxia and immune responses. We found that hypoxia could induce S100B expression in an HIF-1α-dependent manner in HepG2 cells. Luciferase reporter and ChIP-qRCR assays demonstrated that HIF-1α regulates S100B transcription by directly binding to hypoxia-response elements (HREs) of the S100B promoter. Functionally, knockdown of S100B reduces hypoxia-induced HepG2 cell invasion and migration. Furthermore, GSVA enrichment results displayed that S100B and its co-expressed genes were positively correlated with EMT pathway in HCC. Additionally, GO/KEGG cluster analysis results indicated that co-expressed genes of S100B were involved in biological processes of immune response and multiple tumor immune-related signaling pathways in HCC. S100B expression was positively correlated with multiple immune cells tumor infiltration and associated with chemokines/chemokine receptors and immune checkpoint genes. Moreover, S100B is predominantly expressed in immune cells, especially NK (Natural Killer) cell. In addition, the hub genes of S100B co-expression and hypoxia response in HepG2 cell were also associated with immune cells infiltration in HCC. Taken together, these findings provide a new insight into the complex networks between hypoxia response and immune cells infiltration in tumor microenvironment of liver cancer. S100B maybe serve as a novel target for future HCC therapies.
Yan et al. (2022) Comprehensive analysis of the correlations of S100B with hypoxia response and immune infiltration in hepatocellular carcinoma. PeerJ 10:e13201 https://doi.org/10.7717/peerj.13201
Relation between lymphocyte to monocyte ratio and survival in patients with hypertrophic cardiomyopathy: a retrospective cohort study
Background The lymphocyte-to-monocyte ratio (LMR) has been proposed as a novel prognostic factor in malignancies and cardiovascular diseases. Our study aimed to ascertain whether LMR is a useful biomarker in discriminating the hypertrophic cardiomyopathy (HCM) patients at higher risk of all-cause mortality. Methods This retrospective study consisted of 354 adult HCM patients. Cox’s proportional hazards regression models were used to analyze the association between LMR and all-cause mortality. Smooth curve fitting was conducted to explore the linear relationship between LMR and all-cause mortality. Results During the follow-up, 44 patients reached the study endpoint. The all-cause mortality rate was 7.3 per 100 person-years in the first tertile and decreased across the three tertiles of LMR. With the first tertile as reference, adjusted hazard ratios (HR) for all-cause mortality were 0.43 for the second tertile (95% CI [0.20–0.91], p = 0.027) and 0.39 for the third tertile (95% CI [0.17–0.90], p = 0.028), respectively. Smooth curve fitting exhibited a nonlinear relationship between LMR values and all-cause mortality. For LMR < 6.5, per SD increase resulted in a significantly decreased risk of all-cause mortality by 62% (HR: 0.38, 95% CI [0.21–0.68]). For LMR ≥ 6.5, the all-cause mortality risk did not progressively increase. Stratified and subgroup analyses revealed similar results to the main analyses,andE-value analysis suggested robustness to unmeasured confounding. Conclusions The study demonstrated that LMR was an independent predictor of all-cause mortality in HCM patients, and LMR may be useful for identifying HCM patients at high mortality risk.
Chen et al. (2022) Relation between lymphocyte to monocyte ratio and survival in patients with hypertrophic cardiomyopathy: a retrospective cohort study. PeerJ 10:e13212 https://doi.org/10.7717/peerj.13212