Transcriptome analysis reveals a reprogramming energy metabolism-related signature to improve prognosis in colon cancer
Although much progress has been made to improve treatment, colon cancer remains a leading cause of cancer death worldwide. Metabolic reprogramming is a significant ability of cancer cells to ensure the necessary energy supply in uncontrolled proliferation. Since reprogramming energy metabolism has emerged as a new hallmark of cancer cells, accumulating evidences have suggested that metabolism-related genes may serve as key regulators of tumorigenesis and potential biomarkers. In this study, we analyzed a set of reprogramming energy metabolism-related genes by transcriptome analysis in colon cancer and revealed a five-gene signature that could significantly predict the overall survival. The reprogramming energy metabolism-related signature could distinguish patients into high-risk and low-risk groups with significantly different survival times (P = 0.0011; HR = 1.92; 95% CI [1.29–2.87]). Its prognostic value was confirmed in another two independent colon cancer cohorts (P = 5.2e–04; HR = 2.09, 95%; CI [1.37–3.2] for GSE17538 and P = 3.8e−04; HR = 2.08, 95% CI [1.37–3.16] for GSE41258). By multivariable analysis, we found that the signature was independent of clinicopathological features. Its power in promoting risk stratification of the current clinical stage was then evaluated by stratified analysis. Moreover, the signature could improve the power of the TNM stage for the prediction of overall survival and could be used in patients who received adjuvant chemotherapy. Overall, our results demonstrated the important role of the reprogramming energy metabolism-related signature in promoting stratification of high-risk patients, which could be diagnostic of adjuvant therapy benefit.
Zhang et al. (2020) Transcriptome analysis reveals a reprogramming energy metabolism-related signature to improve prognosis in colon cancer. PeerJ 8:e9458 https://doi.org/10.7717/peerj.9458
Consolidation chemotherapy may improve pathological complete response for locally advanced rectal cancer after neoadjuvant chemoradiotherapy: a retrospective study
Background Patients with locally advanced rectal cancer (LARC) have an improved prognosis if achieved a pathological complete response (pCR) on account of neoadjuvant chemoradiation therapy (nCRT). However, the proportion of patients achieving pCR is only 8–24%. The purpose of this study was to explore whether the addition of consolidation chemotherapy to nCRT could improve pCR rate in patients with LARC. Materials and Methods The subjects were 144 individuals with clinical stage II (T3–4, N0) or III (any T, N1–2) LARC who had received neoadjuvant CRT followed by total mesorectal excision (TME). Eighty-three patients in the consolidation chemotherapy group received two cycles XELOX between CRT and TME, while 61 patients in the standard treatment group without consolidation chemotherapy. The pCR (ypT0N0), tumor downstaging (ypT0-2N0) after TME and adverse events (AEs) during and post treatment were compared between the treatment groups using multivariable logistic regression analysis. To adjust the unbalanced variables for the primary endpoint, logistic regression analysis and stratified analysis were performed. Results The consolidation chemotherapy group improved pCR rate (19.3% vs 4.9%, p = 0.01) and tumor downstaging rate (45.8% vs 24.6%, p = 0.009) compared to the standard treatment group. After adjustment for clinical tumor stage, clinical nodal stage and time interval to surgery, patients with consolidation chemotherapy were more likely to reach pCR (adjusted odds ratio 4.91, 95% CI [1.01–23.79], p = 0.048). AEs during and post treatment in the two groups were 54.1% vs 49.3% (p = 0.57), respectively. In addition, the incidence of any grade 1–2 AEs in the two groups was 93.4% vs 95.1% (p = 0.93), while the incidence of grade 3 AEs was 1.6% versus 2.4% (p = 0.74), respectively. No grade 4 AEs occurred in two groups. Conclusions The addition of neoadjuvant consolidation chemotherapy after CRT significantly increased the pCR rate and did not increase the AEs during and post treatment and in patients with LARC.
Cui et al. (2020) Consolidation chemotherapy may improve pathological complete response for locally advanced rectal cancer after neoadjuvant chemoradiotherapy: a retrospective study. PeerJ 8:e9513 https://doi.org/10.7717/peerj.9513
Safety evaluation of four faba bean extracts used as dietary supplements in grass carp culture based on hematological indices, hepatopancreatic function and nutritional condition
Faba bean (Vicia faba, FB) is known to improve the texture of fish meat but retards growth possibly by inducing hemolysis, hepatopancreas damage, and metabolic disorder. In this study, we used ultrasonic processing to isolate four FB extracts (water extract, alcohol extract, proteins and residues) and examined their beneficial and detrimental effects. These extracts were separately mixed with commercial feed and fed to grass carp (Ctenopharyngodon idellus) using whole FB and commercial feed as controls. After fish were fed one of the six experimental diets for 50 d and 100 d, we evaluated the growth and hematological parameters, activities of metabolic enzymes, hepatopancreatic histology and oxidative response, and lipid metabolism. Results showed that both whole FB and FB residues caused growth retardation and hepatopancreas damage (P < 0.05), whereas growth performance was improved in the FB water and alcohol extract groups compared to the whole FB group. Although the FB water extract negatively affected the number and morphological parameters of red blood cells (P < 0.05), the hematological damage was less pronounced than that of the whole FB group. Excessive hepatopancreatic fat accumulation was found in the whole FB, FB alcohol extract and FB residues groups. Moreover, serious hepatopancreas damages were observed in the FB residues group. These results suggest that the beneficial and detrimental components of FB were successfully separated in the four extracts, and the FB water extract would be the best choice for grass carp culture in terms of growth performance and health. The safety evaluation of the four FB extracts would facilitate further application of FB in aquatic feed.
Ma et al. (2020) Safety evaluation of four faba bean extracts used as dietary supplements in grass carp culture based on hematological indices, hepatopancreatic function and nutritional condition. PeerJ 8:e9516 https://doi.org/10.7717/peerj.9516
Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide
The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory cytokines, IL-6 and IL-8, as well as TNF-α ultimately culminating in hypercytokinemia (“cytokine storm”). To address this immuno-inflammatory pathogenesis, multiple clinical trials have been proposed to evaluate anti-inflammatory biologic therapies targeting specific cytokines. However, despite the obvious clinical utility of such biologics, their specific applicability to COVID-19 has multiple drawbacks, including they target only one of the multiple cytokines involved in COVID-19’s immunopathy. Therefore, we set out to identify a small molecule with broad-spectrum anti-inflammatory mechanism of action targeting multiple cytokines of innate immunity. In this study, a library of small molecules endogenous to the human body was assembled, subjected to in silico molecular docking simulations and a focused in vitro screen to identify anti-pro-inflammatory activity via interleukin inhibition. This has enabled us to identify the loop diuretic furosemide as a candidate molecule. To pre-clinically evaluate furosemide as a putative COVID-19 therapeutic, we studied its anti-inflammatory activity on RAW264.7, THP-1 and SIM-A9 cell lines stimulated by lipopolysaccharide (LPS). Upon treatment with furosemide, LPS-induced production of pro-inflammatory cytokines was reduced, indicating that furosemide suppresses the M1 polarization, including IL-6 and TNF-α release. In addition, we found that furosemide promotes the production of anti-inflammatory cytokine products (IL-1RA, arginase), indicating M2 polarization. Accordingly, we conclude that furosemide is a reasonably potent inhibitor of IL-6 and TNF-α that is also safe, inexpensive and well-studied. Our pre-clinical data suggest that it may be a candidate for repurposing as an inhaled therapy against COVID-19.
Wang et al. (2020) Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide. PeerJ 8:e9533 https://doi.org/10.7717/peerj.9533
Intermittent theta burst stimulation facilitates functional connectivity from the dorsal premotor cortex to primary motor cortex
Background Motor information in the brain is transmitted from the dorsal premotor cortex (PMd) to the primary motor cortex (M1), where it is further processed and relayed to the spinal cord to eventually generate muscle movement. However, how information from the PMd affects M1 processing and the final output is unclear. Here, we applied intermittent theta burst stimulation (iTBS) to the PMd to alter cortical excitability not only at the application site but also at the PMd projection site of M1. We aimed to determine how PMd iTBS–altered information changed M1 processing and the corticospinal output. Methods In total, 16 young, healthy participants underwent PMd iTBS with 600 pulses (iTBS600) or sham-iTBS600. Corticospinal excitability, short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were measured using transcranial magnetic stimulation before and up to 60 min after stimulation. Results Corticospinal excitability in M1 was significantly greater 15 min after PMd iTBS600 than that after sham-iTBS600 (p = 0.012). Compared with that after sham-iTBS600, at 0 (p = 0.014) and 15 (p = 0.037) min after iTBS600, SICI in M1 was significantly decreased, whereas 15 min after iTBS600, ICF in M1 was significantly increased (p = 0.033). Conclusion Our results suggested that projections from the PMd to M1 facilitated M1 corticospinal output and that this facilitation may be attributable in part to decreased intracortical inhibition and increased intracortical facilitation in M1. Such a facilitatory network may inform future understanding of the allocation of resources to achieve optimal motion output.
Meng et al. (2020) Intermittent theta burst stimulation facilitates functional connectivity from the dorsal premotor cortex to primary motor cortex. PeerJ 8:e9253 https://doi.org/10.7717/peerj.9253
Melatonin improves the germination rate of cotton seeds under drought stress by opening pores in the seed coat
The germination of cotton (Gossypium hirsutum L.) seeds is affected by drought stress; however, little is known about the physiological mechanism affecting germination and the effect of melatonin (MT) on cotton seed germination under drought stress. Therefore, we studied the effects of exogenous MT on the antioxidant capacity and epidermal microstructure of cotton under drought stress. The results demonstrated a retarded water absorption capacity of testa under drought stress, significantly inhibiting germination and growth in cotton seeds. Drought stress led to the accumulation of reactive oxygen species (ROS), malondialdehyde (MDA), and osmoregulatory substances (e.g., proline, soluble protein, and soluble sugars); it also decreased the activity of antioxidant enzymes and α-amylase. Drought stress inhibited gibberellin acid (GA3) synthesis and increased abscisic acid (ABA) content, seriously affecting seed germination. However, seeds pre-soaked with MT (100 µM) showed a positive regulation in the number and opening of stomata in cotton testa. The exogenous application of MT increased the germination rate, germination potential, radical length, and fresh weight, as well as the activities of superoxide dismutase (SOD), peroxidase (POD), and α-amylase. In addition, MT application increased the contents of organic osmotic substances by decreasing the hydrogen peroxide (H2O2), superoxide anion (O2-), and MDA levels under drought stress. Further analysis demonstrated that seeds pre-soaked with MT alleviated drought stress by affecting the ABA and GA3 contents. Our findings show that MT plays a positive role in protecting cotton seeds from drought stress.
Bai et al. (2020) Melatonin improves the germination rate of cotton seeds under drought stress by opening pores in the seed coat. PeerJ 8:e9450 https://doi.org/10.7717/peerj.9450
Rodents’ responses to manipulated plant litter and seed densities: implications for restoration
Rodent populations in arid grasslands do not always track seed production, possibly due to high levels of plant litter. When natural disturbances are suppressed, litter accumulates becoming physically complex, causing rodents to harvest fewer seeds per equivalent time foraging. It also alters security from predation. Restoring natural disturbances may be an important element in conserving rodent communities. The aim of this study was to assess the influence of two levels of plant litter cover and seed densities on nocturnal rodent population characteristics in a semiarid grassland. Specifically, I hypothesized that kangaroo rats, pocket mice, grasshopper mice, and total rodents would be higher in the sparse plant litter treatment than dense litter, whereas deer mice would be lower in sparse plots. I further hypothesized that kangaroo rats and deer mice would be higher in the seed augmented treatment compared to the unseeded treatment. A prescribed fire removed litter in four of eight plots prior to sowing native seeds 1 year postfire into two burned and two unburned plots. Rodents were live-trapped during spring and fall 1 year. Sparse litter treatment had higher total rodent abundance, biomass, and frequency of offspring compared to dense plots indicating use of stored seeds. Banner-tailed kangaroo rats had higher abundance, implying reduced predation risk. Pocket mice body mass was greater in dense plots. After winter, seeded plots had higher kangaroo rat body mass and grasshopper mice abundance than unseeded, reflecting the use of stored seeds. These short term results demonstrate litter’s physical complexity may be equivalent to seed pulses on the responses of nocturnal rodents. Managers might positively influence grassland rodents by providing a mosaic of varying levels of plant litter.
Nicolai (2020) Rodents’ responses to manipulated plant litter and seed densities: implications for restoration. PeerJ 8:e9465 https://doi.org/10.7717/peerj.9465
Predicting the effect of variants on splicing using Convolutional Neural Networks
Mutations that cause an error in the splicing of a messenger RNA (mRNA) can lead to diseases in humans. Various computational models have been developed to recognize the sequence pattern of the splice sites. In recent studies, Convolutional Neural Network (CNN) architectures were shown to outperform other existing models in predicting the splice sites. However, an insufficient effort has been put into extending the CNN model to predict the effect of the genomic variants on the splicing of mRNAs. This study proposes a framework to elaborate on the utility of CNNs to assess the effect of splice variants on the identification of potential disease-causing variants that disrupt the RNA splicing process. Five models, including three CNN-based and two non-CNN machine learning based, were trained and compared using two existing splice site datasets, Genome Wide Human splice sites (GWH) and a dataset provided at the Deep Learning and Artificial Intelligence winter school 2018 (DLAI). The donor sites were also used to test on the HSplice tool to evaluate the predictive models. To improve the effectiveness of predictive models, two datasets were combined. The CNN model with four convolutional layers showed the best splice site prediction performance with an AUPRC of 93.4% and 88.8% for donor and acceptor sites, respectively. The effects of variants on splicing were estimated by applying the best model on variant data from the ClinVar database. Based on the estimation, the framework could effectively differentiate pathogenic variants from the benign variants (p = 5.9 × 10−7). These promising results support that the proposed framework could be applied in future genetic studies to identify disease causing loci involving the splicing mechanism. The datasets and Python scripts used in this study are available on the GitHub repository at https://github.com/smiile8888/rna-splice-sites-recognition.
Thanapattheerakul et al. (2020) Predicting the effect of variants on splicing using Convolutional Neural Networks. PeerJ 8:e9470 https://doi.org/10.7717/peerj.9470
Evaluation of psychological stress in scientific researchers during the 2019–2020 COVID-19 outbreak in China
Background Beginning in December 2019, coronavirus disease 2019 (COVID-19) caused an outbreak of infectious pneumonia. The Chinese government introduced a series of grounding measures to prevent the spread of COVID-19. The living and working patterns of many scientific researchers also underwent significant changes during this period. Methods An opportunity sample (n = 251) was obtained in China using a questionnaire with 42 questions on scientific research progress and psychological stress during the COVID-19 epidemic. Results Of the 251 participants, 76.9% indicated that their research was affected by the COVID-19 outbreak, and participants who were affected by the outbreak had higher stress levels than those who were not affected. Participants who conducted COVID-19 research and indicated concern that they would fail to finish the research on time were more likely to indicate high levels of stress. Respondents indicated that extending deadlines (64.1%), receiving support from superiors for research (51.8%), and increasing benefits for researchers (51.0%) would likely relieve outbreak-related stress. Conclusion The COVID-19 outbreak had a major impact on the experiments of researchers in the life sciences, especially in basic and clinical medicine. It has also caused high levels of psychological stress in these populations. Measures should be taken to relieve psychological pressure on basic medical researchers and students who will soon complete their degrees (e.g., Master’s and PhD candidates in graduation years).
Zhang et al. (2020) Evaluation of psychological stress in scientific researchers during the 2019–2020 COVID-19 outbreak in China. PeerJ 8:e9497 https://doi.org/10.7717/peerj.9497
Novel circulating protein biomarkers for thyroid cancer determined through data-independent acquisition mass spectrometry
Background Distinguishing between different types of thyroid cancers (TC) remains challenging in clinical laboratories. As different tumor types require different clinical interventions, it is necessary to establish new methods for accurate diagnosis of TC. Methods Proteomic analysis of the human serum was performed through data-independent acquisition mass spectrometry for 29 patients with TC (stages I–IV): 13 cases of papillary TC (PTC), 10 cases of medullary TC (MTC), and six cases follicular TC (FTC). In addition, 15 patients with benign thyroid nodules (TNs) and 10 healthy controls (HCs) were included in this study. Subsequently, 17 differentially expressed proteins were identified in 291 patients with TC, including 247 with PTC, 38 with MTC, and six with FTC, and 69 patients with benign TNs and 176 with HC, using enzyme-linked immunosorbent assays. Results In total, 517 proteins were detected in the serum samples using an Orbitrap Q-Exactive-plus mass spectrometer. The amyloid beta A4 protein, apolipoprotein A-IV, gelsolin, contactin-1, gamma-glutamyl hydrolase, and complement factor H-related protein 1 (CFHR1) were selected for further analysis. The median serum CFHR1 levels were significantly higher in the MTC and FTC groups than in the PTC and control groups (P < 0.001). CFHR1 exhibited higher diagnostic performance in distinguishing patients with MTC from those with PTC (P < 0.001), with a sensitivity of 100.0%, specificity of 85.08%, area under the curve of 0.93, and detection cut-off of 0.92 ng/mL. Conclusion CFHR1 may serve as a novel biomarker to distinguish PTC from MTC with high sensitivity and specificity.
Li et al. (2020) Novel circulating protein biomarkers for thyroid cancer determined through data-independent acquisition mass spectrometry. PeerJ 8:e9507 https://doi.org/10.7717/peerj.9507