title: PeerJ description: Articles published in PeerJ link: https://peerj.com/articles/index.rss3?journal=peerj&page=589 creator: info@peerj.com PeerJ errorsTo: info@peerj.com PeerJ language: en title: Flexor hallucis brevis motor unit behavior in response to moderate increases in rate of force development link: https://peerj.com/articles/14341 last-modified: 2023-01-10 description: BackgroundStudies on motor unit behaviour with varying rates of force development have focussed predominantly on comparisons between slow and ballistic (i.e., very fast) contractions. It remains unclear how motor units respond to less extreme changes in rates of force development. Here, we studied a small intrinsic foot muscle, flexor hallucis brevis (FHB) where the aim was to compare motor unit discharge rates and recruitment thresholds at two rates of force development. We specifically chose to investigate relatively slow to moderate rates of force development, not ballistic, as the chosen rates are more akin to those that presumably occur during daily activity.MethodsWe decomposed electromyographic signals to identify motor unit action potentials obtained from indwelling fine-wire electrodes in FHB, from ten male participants. Participants performed isometric ramp-and-hold contractions from relaxed to 50% of a maximal voluntary contraction. This was done for two rates of force development; one with the ramp performed over 5 s (slow condition) and one over 2.5 s (fast condition). Recruitment thresholds and discharge rates were calculated over the ascending limb of the ramp and compared between the two ramp conditions for matched motor units. A repeated measures nested linear mixed model was used to compare these parameters statistically. A linear repeated measures correlation was used to assess any relationship between changes in recruitment threshold and mean discharge rate between the two conditions.ResultsA significant increase in the initial discharge rate (i.e., at recruitment) in the fast (mean: 8.6 ±  2.4 Hz) compared to the slow (mean: 7.8 ± 2.3 Hz) condition (P = 0.027), with no changes in recruitment threshold (P = 0.588), mean discharge rate (P = 0.549) or final discharge rate (P = 0.763) was observed. However, we found substantial variability in motor unit responses within and between conditions. A small but significant negative correlation (R2 = 0.33, P = 0.003) was found between the difference in recruitment threshold and the difference in mean discharge rate between the two conditions.ConclusionThese findings suggest that as force increases for contractions with slower force development, increasing the initial discharge rate of recruited motor units produces the increase in rate of force development, without a change in their recruitment thresholds, mean or final discharge rate. However, an important finding was that for only moderate changes in rate of force development, as studied here, not all units respond similarly. This is different from what has been described in the literature for ballistic contractions in other muscle groups, where all motor units respond similarly to the increase in neural drive. Changing the discharge behaviour of a small group of motor units may be sufficient in developing force at the required rate rather than having the discharge behaviour of the entire motor unit pool change equally. creator: Jeroen Aeles creator: Luke A. Kelly creator: Andrew G. Cresswell uri: https://doi.org/10.7717/peerj.14341 license: https://creativecommons.org/licenses/by/4.0/ rights: ©2023 Aeles et al. title: The bony cap and its distinction from the distal phalanx in humans, cats, and horses link: https://peerj.com/articles/14352 last-modified: 2023-01-10 description: It has been recognized as early as the Victorian era that the apex of the distal phalanx has a distinct embryological development from the main shaft of the distal phalanx. Recent studies in regenerative medicine have placed an emphasis on the role of the apex of the distal phalanx in bone regrowth. Despite knowledge about the unique aspects of the distal phalanx, all phalanges are often treated as equivalent. Our morphological study reiterates and highlights the special anatomical and embryological properties of the apex of the distal phalanx, and names the apex “the bony cap” to distinguish it. We posit that the distal phalanx shaft is endochondral, while the bony cap is intramembranous and derived from the ectodermal wall. During development, the bony cap may be a separate structure that will fuse to the endochondral distal phalanx in the adult, as it ossifies well before the distal phalanges across taxa. Our study describes and revives the identity of the bony cap, and we identify it in three mammalian species: humans, cats, and horses (Homo sapiens, Felis catus domestica, and Equus caballus). During the embryonic period, we show the bony cap has a thimble-like shape that surrounds the proximal endochondral distal phalanx. The bony cap may thus play an inductive role in the differentiation of the corresponding nail, claw, or hoof (keratin structures) of the digit. When it is not present or develops erroneously, the corresponding keratin structures are affected, and regeneration is inhibited. By terming the bony cap, we hope to inspire more attention to its distinct identity and role in regeneration. creator: Shannon Smith creator: Laurel R. Yohe creator: Nikos Solounias uri: https://doi.org/10.7717/peerj.14352 license: https://creativecommons.org/licenses/by/4.0/ rights: © 2023 Smith et al. title: Yield-based drought tolerance index evaluates the drought tolerance of cotton germplasm lines in the interaction of genotype-by-environment link: https://peerj.com/articles/14367 last-modified: 2023-01-10 description: BackgroundCotton is an economically important crop in China, and drought has seriously affected cotton production. Understanding genetic variation, genotype ×environment interactions, and the associations between these traits is critical for developing improved cotton varieties with high drought tolerance.MethodsTo screen ideal drought-resistant cotton germplasm lines and excellent genotypes, the yield traits of 103 cotton germplasm lines were analyzed. Cotton resource material was planted under normal watering and water deficit conditions for three consecutive years. The yield traits under normal irrigation and water stress conditions were measured, and then five screening indicators were calculated based on the cotton yield per plant under the two water treatments to determine the ideal genotype and most accurate identification indicators.ResultsThe results of correlation analysis and principal component analysis showed that the geometric mean productivity (GMP), mean productivity (MP), and stress tolerance index (STI) were significantly positively correlated with yield under water stress and could be used to distinguish genotypes with high drought tolerance. Among the experimental germplasm lines, some had higher STI and GMP values, indicating their higher drought tolerance. This result indicates that best linear unbiased prediction (BLUP) analysis of the STI and GMP under drought stress can effectively improve screening for drought tolerance in cotton germplasm lines. The results from the screening index, three-dimensional map, and genotype ×environment (GGE) biplots were consistent with the above results. We determined that CQJ-5, Xin lu zao 45, Bellsno, Zhong R 2016 and ND 359-5 are drought-tolerant genotypes that can be used to breed drought-tolerant germplasm lines that produce high and stable yields. creator: Fenglei Sun creator: Quanjia Chen creator: Qin Chen creator: Menghui Jiang creator: Yanying Qu uri: https://doi.org/10.7717/peerj.14367 license: https://creativecommons.org/licenses/by/4.0/ rights: ©2023 Sun et al. title: Diagnostic value and mechanism of plasma S100A1 protein in acute ischemic stroke: a prospective and observational study link: https://peerj.com/articles/14440 last-modified: 2023-01-10 description: BackgroundPlasma S100A1 protein is a novel inflammatory biomarker associated with acute myocardial infarction and neurodegenerative disease’s pathophysiological mechanisms. This study aimed to determine the levels of this protein in patients with acute ischemic stroke early in the disease progression and to investigate its role in the pathogenesis of acute ischemic stroke.MethodsA total of 192 participants from hospital stroke centers were collected for the study. Clinically pertinent data were recorded. The volume of the cerebral infarction was calculated according to the Pullicino formula. Multivariate logistic regression analysis was used to select independent influences. ROC curve was used to analyze the diagnostic value of AIS and TIA. The correlation between S100A1, NF-κB p65, and IL-6 levels and cerebral infarction volume was detected by Pearson correlation analysis.ResultsThere were statistically significant differences in S100A1, NF-κB p65, and IL-6 among the AIS,TIA, and PE groups (S100A1, [230.96 ± 39.37] vs [185.85 ± 43.24] vs [181.47 ± 27.39], P < 0.001; NF-κB p65, [3.99 ± 0.65] vs [3.58 ± 0.74] vs [3.51 ± 0.99], P = 0.001; IL-6, [13.32 ± 1.57] vs [11.61 ± 1.67] vs [11.42 ± 2.34], P < 0.001). Multivariate logistic regression analysis showed that S100A1 might be an independent predictive factor for the diagnosis of disease (P < 0.001). The AUC of S100A1 for diagnosis of AIS was 0.818 (P < 0.001, 95% CI [0.749–0.887], cut off 181.03, Jmax 0.578, Se 95.0%, Sp 62.7%). The AUC of S100A1 for diagnosis of TIA was 0.720 (P = 0.001, 95% CI [0.592–0.848], cut off 150.14, Jmax 0.442, Se 50.0%, Sp 94.2%). There were statistically significant differences in S100A1, NF-κB p65, and IL-6 among the SCI,MCI, and LCI groups (S100A1, [223.98 ± 40.21] vs [225.42 ± 30.92] vs [254.25 ± 37.07], P = 0.001; NF-κB p65, [3.88 ± 0.66] vs [3.85 ± 0.64] vs [4.41 ± 0.45], P < 0.001; IL-6, [13.27 ± 1.65] vs [12.77 ± 1.31] vs [14.00 ± 1.40], P = 0.007). Plasma S100A1, NF-κB p65, and IL-6 were significantly different from cerebral infarction volume (S100A1, r = 0.259, P = 0.002; NF-κB p65, r = 0.316, P < 0.001; IL-6, r = 0.177, P = 0.036). There was a positive correlation between plasma S100A1 and IL-6 with statistical significance (R = 0.353, P < 0.001). There was no significant positive correlation between plasma S100A1 and NF-κB p65 (R < 0.3), but there was statistical significance (R = 0.290, P < 0.001). There was a positive correlation between IL-6 and NF-κB p65 with statistical significance (R = 0.313, P < 0.001).ConclusionS100A1 might have a better diagnostic efficacy for AIS and TIA. S100A1 was associated with infarct volume in AIS, and its level reflected the severity of acute cerebral infarction to a certain extent. There was a correlation between S100A1 and IL-6 and NF-κB p65, and it was reasonable to speculate that this protein might mediate the inflammatory response through the NF-κB pathway during the pathophysiology of AIS. creator: Guo Hong creator: Tingting Li creator: Haina Zhao creator: Zhaohao Zeng creator: Jinglei Zhai creator: Xiaobo Li creator: Xiaoguang Luo uri: https://doi.org/10.7717/peerj.14440 license: https://creativecommons.org/licenses/by/4.0/ rights: ©2023 Guo et al. title: UHPLC-ESI-QE-Orbitrap-MS based metabolomics reveals the antioxidant mechanism of icaritin on mice with cerebral ischemic reperfusion link: https://peerj.com/articles/14483 last-modified: 2023-01-10 description: BackgroundIcaritin (ICT) has been previously demonstrated to display protective effects against cerebral ischemic reperfusion (I/R) by inhibiting oxidative stress, but the mechanism remains unclear. This study aimed to explore the mechanism from the perspective of metabolomics.MethodsA mice cerebral artery occlusion/reperfusion (MCAO/R) model was explored to mimic cerebral ischemic reperfusion and protective effect of ICT was assessed by neurologic deficit scoring, infarct volume and brain water content. Ultra-high-performance liquid chromatography electrospray ionization orbitrap tandem mass spectrometry (UHPLC-ESI-QE-Orbitrap-MS) based metabolomic was performed to explore potential biomarkers. Brain tissue metabolic profiles were analyzed and metabolic biomarkers were identified through multivariate data analysis. The protein levels of Nrf2, HO-1 and HQO1 were assayed by western blot. The release of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were detected using corresponding assay kits.ResultsThe results showed that after ICT treatment, the neurological deficit, cerebral infarction area, brain edema and the level of MDA in brain tissue of MCAO/R mice were significantly reduced. Meanwhile, ICT enhanced the activity of SOD, CAT and GSH-Px. Western blot results confirmed that ICT up-regulated the protein levels of antioxidant-related protein including Nrf2, HO-1 and NQO1. According to the metabolomic profiling of brain tissues, clear separations were observed among the Sham, Model and ICT groups. A total of 44 biomarkers were identified, and the identified biomarkers were mainly related to linoleic acid metabolism, arachidonic acid metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, arginine and proline metabolism, D-glutamine and D-glutamate metabolism, taurine and hypotaurine metabolism and purine metabolism, respectively. At the same time, the inhibitory effect of ICT on arachidonic acid and linoleic acid in brain tissue, as well as the promoting effect on taurine, GABA, NAAG, may be the key factors for the anti-neurooxidative function of mice after MCAO/R injury.ConclusionOur results demonstrate that ICT has benefits for MCAO/R injury, which are partially related to the suppression of oxidative stress via stimulating the Nrf2 signaling and regulating the production of arachidonic acid, linoleic acid, taurine, GABA, NAAG in brain tissue. creator: Yunfeng Tang creator: Lixin Sun creator: Yun Zhao creator: Jingchun Yao creator: Zhong Feng creator: Zhong Liu creator: Guimin Zhang creator: Chenghong Sun uri: https://doi.org/10.7717/peerj.14483 license: https://creativecommons.org/licenses/by/4.0/ rights: ©2023 Tang et al. title: A data integration framework for spatial interpolation of temperature observations using climate model data link: https://peerj.com/articles/14519 last-modified: 2023-01-10 description: Meteorological station measurements are an important source of information for understanding the weather and its association with risk, and are vital in quantifying climate change. However, such data tend to lack spatial coverage and are often plagued with flaws such as erroneous outliers and missing values. Alternative meteorological data exist in the form of climate model output that have better spatial coverage, at the expense of bias. We propose a probabilistic framework to integrate temperature measurements with climate model (reanalysis) data, in a way that allows for biases and erroneous outliers, while enabling prediction at any spatial resolution. The approach is Bayesian which facilitates uncertainty quantification and simulation based inference, as illustrated by application to two countries from the Middle East and North Africa region, an important climate change hotspot. We demonstrate the use of the model in: identifying outliers, imputing missing values, non-linear bias correction, downscaling and aggregation to any given spatial configuration. creator: Theo Economou creator: Georgia Lazoglou creator: Anna Tzyrkalli creator: Katiana Constantinidou creator: Jos Lelieveld uri: https://doi.org/10.7717/peerj.14519 license: https://creativecommons.org/licenses/by/4.0/ rights: ©2023 Economou et al. title: Computed tomography-based radiomics machine learning models for prediction of histological invasiveness with sub-centimeter subsolid pulmonary nodules: a retrospective study link: https://peerj.com/articles/14559 last-modified: 2023-01-10 description: To improve the accuracy of preoperative diagnoses and avoid over- or undertreatment, we aimed to develop and compare computed tomography-based radiomics machine learning models for the prediction of histological invasiveness using sub-centimeter subsolid pulmonary nodules. Three predictive models based on radiomics were built using three machine learning classifiers to discriminate the invasiveness of the sub-centimeter subsolid pulmonary nodules. A total of 203 sub-centimeter nodules from 177 patients were collected and assigned randomly to the training set (n = 143) or test set (n = 60). The areas under the curve of the predictive models were 0.743 (95% confidence interval CI [0.661–0.824]) for the logistic regression, 0.828 (95% CI [0.76–0.896]) for the support vector machine, and 0.917 (95% CI [0.869–0.965]) for the XGBoost classifier models in the training set, and 0.803 (95% CI [0.694–0.913]), 0.726 (95% CI [0.598–0.854]), and 0.874 (95% CI [0.776–0.972]) in the test set, respectively. In addition, the decision curve showed that the XGBoost model added more net benefit within the range of 0.06 to 0.93. creator: Haochuan Zhang creator: Shixiong Wang creator: Zhenkai Deng creator: Yangli Li creator: Yingying Yang creator: He Huang uri: https://doi.org/10.7717/peerj.14559 license: https://creativecommons.org/licenses/by/4.0/ rights: ©2022 Zhang et al. title: Isopsoralen suppresses receptor activator of nuclear factor kappa-β ligand-induced osteoclastogenesis by inhibiting the NF-κB signaling link: https://peerj.com/articles/14560 last-modified: 2023-01-10 description: Osteoporosis is a serious systemic metabolic bone system disease.This study aimed to identify the target genes of isopsoralen and the signaling pathways involved in the differential expression of the genes involved in osteoclast differentiation. We hypothesized that isopsoralen may inhibit osteoclast differentiation by blocking the nuclear factor kappa-B (NF-κB) signaling pathway and verified our hypothesis through basic experiments. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to detect the effect of isopsoralen on the proliferation and viability of primary mouse bone marrow monocytes (BMMCs). The effect of isopsoralen on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation was determined by using tartrate-resistant acid phosphatase (TRAP) staining. Quantitative real-time PCR (qRT-PCR) and Western blot were used to detect the expression of the related genes and proteins. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of isopsoralen target genes were obtained through comprehensive analysis using the STITCH database, Cytoscape 3.8.2, and R-Studio software. Differentially expressed genes (DEGs) were found in osteoclasts induced by RANKL before and after 3 days using R-Studio, following which KEGG analysis was performed. Next, enrichment analysis was performed on the KEGG pathway shared by the target genes of isopsoralen and the differentially expressed genes during osteoclast differentiation to predict the signaling pathway underlying the inhibition of osteoclast differentiation by isopsoralen. Finally, Western blot was used to detect the effect of isopsoralen on the activation of signaling pathways to verify the results of our bioinformatics analysis. Based on the enrichment analysis of isopsoralen target genes and differentially expressed genes during osteoclastogenesis, we believe that isopsoralen can inhibit RANKL-induced osteoclastogenesis by inhibiting the NF-κB signaling pathway. creator: Wanda Zhan creator: Binjia Ruan creator: Hui Dong creator: Chaoyong Wang creator: Shuangshi Wu creator: Hang Yu creator: Xiaohang Xu creator: Hao Sun creator: Jun Cai uri: https://doi.org/10.7717/peerj.14560 license: https://creativecommons.org/licenses/by/4.0/ rights: ©2022 Zhan et al. title: No detectable changes in reproductive behaviour of Caenorhabditis elegans males after 97 generations under obligatory outcrossing link: https://peerj.com/articles/14572 last-modified: 2023-01-10 description: In Caenorhabditis elegans, a species reproducing mostly via self-fertilization, numerous signatures of selfing syndrome are observed, including differences in reproductive behaviour compared to related obligatory outcrossing species. In this study we investigated the effect of nearly 100 generations of obligatory outcrossing on several characteristics of male reproductive behaviour. A genetically uniform ancestral population carrying a mutation changing the reproductive system to obligatory outcrossing was split into four independent populations. We predicted that the transition from the natural reproductive system, where males were extremely rare, to obligatory outcrossing, where males comprise 50% of the population and are necessary for reproduction, will increase the selection pressure on higher effectiveness of mating behaviour. Several characteristics of male mating behaviour during a 15 min interaction as well as copulation success were compared between the ancestral and evolved populations. No significant differences in male mating behaviour or fertilization success were detected between generations 1 and 97 of obligatory outcrossing populations. We found, however, that longer contact with females increased chances of successful copulation, although this effect did not differ between populations. We conclude that either selection acting on male mating behaviour has not been strong enough, or mutational input of new adaptive variants has not been sufficient to cause noticeable behavioural differences after 97 generations of evolution starting from genetically uniform population. creator: Weronika Antoł creator: Jagoda Byszko creator: Alicja Dyba creator: Joanna Palka creator: Wiesław Babik creator: Zofia Prokop uri: https://doi.org/10.7717/peerj.14572 license: https://creativecommons.org/licenses/by/4.0/ rights: © 2023 Antoł et al. title: Pemafibrate prevents choroidal neovascularization in a mouse model of neovascular age-related macular degeneration link: https://peerj.com/articles/14611 last-modified: 2023-01-10 description: BackgroundPathological choroidal neovascularization (CNV) is one of the major causes of visual impairment in neovascular age-related macular degeneration (AMD). CNV has been suppressed by using anti-vascular endothelial growth factor (VEGF) antibodies. However, some clinical cases have demonstrated the failure of anti-VEGF therapies. Furthermore, anti-VEGF agents might induce the development of ocular atrophy. Recently, peroxisome proliferator-activated receptor alpha (PPARα) activation using pemafibrate treatment was suggested as one of the promising therapeutic targets in the prevention of ocular ischemia. However, the preventive role of pemafibrate remains unclear in CNV. We aimed to examine the preventive role of pemafibrate on laser-induced pathological CNV.MethodsAdult male C57BL/6 mice were orally supplied pemafibrate (0.5 mg/kg) for four days, followed by laser irradiation. Then, pemafibrate was consecutively given to mice with the same condition. CNV was visualized with isolectin-IB4. The eye (retina and/or retinal pigment epithelium [RPE]-choroid), liver, and serum were used for biomolecular analyses.ResultsWe found that pemafibrate administration suppressed CNV volumes. Pemafibrate administration activated PPARα downstream genes in the liver and eye (especially, RPE-choroid). Furthermore, pemafibrate administration elevated serum fibroblast growth factor 21 levels and reduced serum levels of triglycerides.ConclusionsOur data suggest a promising pemafibrate therapy for suppressing CNV in AMD. creator: Deokho Lee creator: Ayaka Nakai creator: Yukihiro Miwa creator: Kazuno Negishi creator: Yohei Tomita creator: Toshihide Kurihara uri: https://doi.org/10.7717/peerj.14611 license: https://creativecommons.org/licenses/by/4.0/ rights: ©2023 Lee et al.