Repetitive temporal interference stimulation improves jump performance but not the postural stability in young healthy males: a randomized controlled trial.

BACKGROUND: Temporal interference (TI) stimulation, an innovative non-invasive brain stimulation technique, has the potential to activate neurons in deep brain regions. The objective of this study was to evaluate the effects of repetitive TI stimulation targeting the lower limb motor control area (i.e., the M1 leg area) on lower limb motor function in healthy individuals, which could provide evidence for further translational application of non-invasive deep brain stimulation. METHODS: In this randomized, double-blinded, parallel-controlled trial, 46 healthy male adults were randomly divided into the TI or sham group. The TI group received 2 mA (peak-to-peak) TI stimulation targeting the M1 leg area with a 20 Hz frequency difference (2 kHz and 2.02 kHz). Stimulation parameters of the sham group were consistent with those of the TI group but the current input lasted only 1 min (30 s ramp-up and ramp-down). Both groups received stimulation twice daily for five consecutive days. The vertical jump test (countermovement jump [CMJ], squat jump [SJ], and continuous jump [CJ]) and Y-balance test were performed before and after the total intervention session. Two-way repeated measures ANOVA (group × time) was performed to evaluate the effects of TI stimulation on lower limb motor function. RESULTS: Forty participants completed all scheduled study visits. Two-way repeated measures ANOVA showed significant group × time interaction effects for CMJ height (F = 8.858, p = 0.005) and SJ height (F = 6.523, p = 0.015). The interaction effect of the average CJ height of the first 15 s was marginally significant (F = 3.550, p = 0.067). However, there was no significant interaction effect on the Y balance (p > 0.05). Further within-group comparisons showed a significant post-intervention increase in the height of the CMJ (p = 0.004), SJ (p = 0.010) and the average CJ height of the first 15 s (p = 0.004) in the TI group. CONCLUSION: Repetitive TI stimulation targeting the lower limb motor control area effectively increased vertical jump height in healthy adult males but had no significant effect on dynamic postural stability.

Risk factors for cervical lymph node metastasis in the central or lateral cervical region in medullary thyroid carcinoma: a systematic review and meta-analysis.

PURPOSE: Compared with other types of thyroid carcinoma, patients with medullary thyroid carcinoma (MTC) are more likely to develop cervical lymph node metastasis. This study was conducted to clarify the risk factors for cervical lymph node metastasis (central lymph node metastasis or lateral cervical lymph node metastasis) in MTC by meta-analysis, and to provide evidence-based basis for the treatment and prognosis of MTC. METHODS: The literatures related to cervical lymph node metastasis in medullary thyroid carcinoma were searched in PubMed, Embase, Web of Science, Cochrane, CNKI and Wanfang databases, and statistical analysis was performed using Revman 5.3 and Stata 14.0 software. RESULTS: A total of 28 papers were included in this paper, and meta-analysis showed that the occurrence of central lymph node metastasis (CLNM) in MTC patients was significantly associated with tumor size (OR = 3.07, 95%CI: 2.04-4.63, P < 0.00001), multifocality (OR = 0.29, 95%CI: 0.19-0.44, P < 0.00001), bilaterality (OR = 3.75, 95% CI: 1.95-7.14, P < 0.0001), capsular invasion (OR = 9.88, 95% CI: 5.93-16.45, P < 0.00001) and extrathyroidal extension (OR = 5.48, 95% CI: 2.61-11.51, P < 0.00001). While the occurrence of lateral cervical lymph node metastasis (LLNM) in MTC patients was strongly correlated with gender (OR = 2.97, 95%CI: 2.46-3.58, P < 0.00001), tumor size (OR = 3.88, 95%CI: 1.90-7.92, P = 0.0002 < 0.05), multifocality (OR = 0.43, 95%CI: 0.35-0.51, P < 0.00001), bilaterality (OR = 2.93, 95% CI: 1.72-4.98, P < 0.0001), capsular invasion (OR = 8.44, 95% CI: 6.11-11.64, P < 0.00001), extrathyroidal extension (OR = 7.04, 95% CI: 5.54-8.94, P < 0.00001), margin of the tumor (OR = 4.47, 95% CI: 2.37-8.44, P < 0.00001), shape of the tumor (OR = 6.81, 95% CI: 3.64-12.73, P < 0.00001), preoperative calcitonin level (SMD = 1.39, 95% CI: 0.98-1.80, P < 0.00001), preoperative carcinoembryonic antigen level (SMD = 0.97, 95% CI: 0.74-1.20, P < 0.00001) and CLNM (OR = 19.70, 95% CI: 14.16-27.43, P < 0.00001). CONCLUSION: Tumor size, multifocality, bilaterality, capsular invasion and extrathyroidal extension are the main risk factors for developing CLNM in MTC patients; And risk factors for developing LLNM in MTC patients include: gender, tumor size, multifocality, bilaterality, capsular invasion, extrathyroidal extension, margin of the tumor, shape of the tumor, preoperative calcitonin level, preoperative carcinoembryonic antigen level and central lymph node metastasis. These risk factors can guide the individualized treatment plan and improve the prognosis of MTC patients.

Comparative Transcriptome Analysis of Defense Response of Potato to Phthorimaea operculella Infestation.

The potato tuber moth (PTM), Phthorimaea operculella Zeller (Lepidoptera: Gelechiidae), is one of the most destructive pests of potato crops worldwide. Although it has been reported how potatoes integrate the early responses to various PTM herbivory stimuli by accumulatively adding the components, the broad-scale defense signaling network of potato to single stimuli at multiple time points are unclear. Therefore, we compared three potato transcriptional profiles of undamaged plants, mechanically damaged plants and PTM-feeding plants at 3 h, 48 h, and 96 h, and further analyzed the gene expression patterns of a multitude of insect resistance-related signaling pathways, including phytohormones, reactive oxygen species, secondary metabolites, transcription factors, MAPK cascades, plant-pathogen interactions, protease inhibitors, chitinase, and lectins, etc. in the potato under mechanical damage and PTM infestation. Our results suggested that the potato transcriptome showed significant responses to mechanical damage and potato tuber moth infestation, respectively. The potato transcriptome responses modulated over time and were higher at 96 than at 48 h, so transcriptional changes in later stages of PTM infestation may underlie the potato recovery response. Although the transcriptional profiles of mechanically damaged and PTM-infested plants overlap extensively in multiple signaling pathways, some genes are uniquely induced or repressed. True herbivore feeding induced more and stronger gene expression compared to mechanical damage. In addition, we identified 2976, 1499, and 117 genes that only appeared in M-vs-P comparison groups by comparing the transcriptomes of PTM-damaged and mechanically damaged potatoes at 3 h, 48 h, and 96 h, respectively, and these genes deserve further study in the future. This transcriptomic dataset further enhances the understanding of the interactions between potato and potato tuber moth, enriches the molecular resources in this research area and paves the way for breeding insect-resistant potatoes.

Exosomal microRNAs as novel diagnostic biomarkers in breast cancer: A systematic evaluation and meta-analysis.

Circulating tumor-derived exosomal microRNAs (miRNAs) play a key role in the development of cancer. We aimed to assess the diagnostic value of circulating exosomal miRNAs in breast cancer (BC). A computer search was conducted for clinical studies on exosomal miRNA diagnosis of breast cancer published in Wanfang, CNKI, China Biology Medicine disc, VIP, Web of Science, Cochrane Library, PubMed, and Embase built up to August 16, 2022. True/false positive (TP/FP) and true/false negative (TN/FN) rates were extracted from each eligible study to obtain pooled sensitivities, specificities, positive/negative likelihood ratios (PLR/NLR), diagnostic odds ratio (DOR), and their 95% confidence intervals (95% CI). The meta-analysis included 7 articles including 348 Asian patients and 260 controls. All miRNAs were quantified using qRT-PCR assays. The sensitivity and specificity of the combination were 0.67 (95% CI = 0.64-0.71) and 0.81 (95% CI = 0.77-0.86), respectively. The combined DOR was 10.2 (95% CI = 6.00-16.74). The combined AUC(area under the subject operating characteristic curve) was 0.83 (0.91-0.96). In conclusion, exosomal-derived miRNA can be a good indicator to improve the diagnosis of breast cancer.

The predictive value of circular RNAs in the diagnosis, prognosis and clinicopathological features of thyroid cancer: A systematic review and meta-analysis.

OBJECTIVE: An increasing number of studies have reported circular RNAs (circRNAs) as new potential diagnostic and prognostic biomarkers for thyroid cancer. However, the overall predictive value of circRNAs for thyroid cancer remains unclear. Therefore, we performed a comprehensive meta-analysis to investigate the predictive value of circRNAs in the diagnosis, prognosis and clinicopathological features of thyroid cancer (TC). METHODS: PubMed, Embase, Cochrane library and Web of science were searched systematically. The search time limit was from the establishment of the database to October 2021. We used the subject words combined with free words for the search. Furthermore, we used Review Manager 5.3 and Meta-Disc1.4 for relevant data analysis, and Stata 13.1 for sensitivity analysis and publication bias test. The combined sensitivity and specificity were used to evaluate the diagnostic value of circRNAs. The hazard ratio (HR) and its 95% confidence interval (95%CI) were used for statistical analysis of the prognosis of TC. The clinical characteristics were analyzed with Odds Ratio (OR) and its 95% CI. P = 0.05 for all analysis, Q test and I2 analysis were used for heterogeneity evaluation, I2 ≤ 50% and Q test P > 0.1, indicated the lack of heterogeneity. RESULTS: A total of 26 eligible studies including 18 on clinicopathological studies, 7 on prognostic and 6 diagnostic studies were enrolled in our meta-analysis. A total of 1911 patients with TC were included. For the clinicopathological and prognostic value, the results showed that a high expression of circRNAs was correlated with poor clinical parameters, such as the tumor size [OR = 2.79, 95%CI (1.88, 4.13)], extra-glandular metastasis (ETE) [OR = 0.74, 95%CI (0.45, 1.53),P = 0.24], TNM staging [OR = 3.82, 95%CI (2.86, 5.10)], lymph node metastasis (LNM) [OR = 3.88, 95% (2.90, 5.19)], tumor focality [OR = 31.87, 95%CI (1.05, 3.31)] and poor overall survival (OS)[ HR = 1.97, 95%CI (1.37, 2.83)]. For the diagnostic value, the sensitivity, specificity and Area Under Curve (AUC) of the combined group were 0.83 [95%CI (0.77-0.87)], 0.77 [95%CI (0.71-0.82)] and 0.91 respectively. CONCLUSIONS：: CircRNAs have a potential diagnostic value for TC. Meanwhile, an elevated expression of circRNAs has been linked to a poor OS in TC patients, and it also associates with poor prognosis of thyroid cancer patients. The expression of circRNAs is also correlated with certain clinical characteristics, suggesting that it may have important clinical significance.

Roles and peer status of campus bullying bystanders among middle school students / 中国学校卫生

Objective@#Refine and understand the characteristics of different types of bystanders, in order to maximize the exploitation and utilization of bystanders as potential resources for anti bullying, so as to provide more targeted guidance for the formulation of intervention programs.@*Methods@#In this study, 1 279 students from two middle schools in Beijing and Anhui Province and two high schools in Guangdong Province and Guangxi Zhuang Autonomous Region were administered with Participation Role Questionnaire (PRQ) and Peer Nomination Questionnaire.@*Results@#There was a significant difference between male and female in the role of onlooker( χ 2=96.92, P <0.01). Female students were more likely to play the role of defender and outsider, while male students were more likely to play the role of reinforcer( χ 2=31.87, P =0.01). And there were significant differences in the distribution of bystander roles in different grades. The chi square test results were( χ 2=456.26, P <0.01).@*Conclusion@#The bystander plays an important role in the occurrence of bullying incidents. It is an important direction of school bullying intervention programs to promote the positive transformation from passive bystander to active bystander.

Transcriptome analysis reveals that high temperatures alter modes of lipid metabolism in juvenile turbot (Scophthalmus maximus) liver.

With the increase in farming density and the continuously high summer temperatures against the background of global warming, high temperature stress has become a major challenge in fish farming. In this study, we simulated the high temperature environments (20 °C, 24 °C, and 28 °C) that may occur during turbot culture. High-throughput sequencing was used to investigate the lipid metabolism response patterns in juvenile turbot liver under high temperature stress. A total of 2067 differentially expressed genes (DEGs) were identified. KEGG analysis revealed that the DEGs were mainly associated with glycerophospholipid metabolism, steroid biosynthesis, glycerolipid metabolism, fatty acid metabolic pathways, and the PPAR signaling pathway. A regulatory network was constructed to further elucidate the transcriptional regulation of lipid metabolism. We speculated that high temperature activates PPAR signaling pathway through interaction with ligands such as fatty acids. On the one hand, the HMGCS1 gene in this pathway can inhibit sterol synthesis by down-regulating the expression of key genes in steroid biosynthesis pathway (SQLE, EBP, and DHCR24). On the other hand, the expression of ACSL1 in this pathway is significantly increased under high temperature, which may play an important role in regulating fatty acid metabolism. Moreover, we collected blood and detected changes in serum lipid parameters; the variation patterns were also consistent with our results. These findings reveal that lipid metabolism has an important regulatory role in stress resistance when turbot is exposed to high temperatures.

Consistency evaluation of Chaihuang granules based on pharmacokinetics and metabolomics.

Consistency evaluation of Traditional Chinese Medicinal preparations (TCMPs) with complex chemical composition is challenging. Chaihuang granules (CHG), as a well-known TCMP, consists of Chaihu (Bupleuri Radix) and Huangqin (Scutellariae Radix) extract. In this work, we used pharmacokinetics and metabolomics to evaluate consistency of CHG products from two different manufacturers. In the pharmacokinetic study, a liquid chromatography tandem mass spectrometry (LC-MS/MS) method was applied to determine the plasma concentration-time profiles of baicalin in rat plasma. Pharmacokinetic parameters, including the maximum concentration in blood (Cmax), area under the curve (AUC), the time to reach Cmax (Tmax), and half-life (T1/2), were calculated to assess the consistency preliminarily. And there was no significant difference in these pharmacokinetic parameters between the two CHG. In LC-MS-based metabolomics, the metabolic response profiles changes based on relative distance values (RDV) to different CHG products were compared. Meanwhile, the kinetic process of 31 differential endogenous metabolites that altered by CHG were determined. Metabolomics data showed the similar metabolic regulation effects to rats of the two formulations. Both pharmacokinetic and metabolomics results indicated there was no significant difference between CHG products. Furthermore, metabolic pathways significantly altered by CHG were elucidated, including phenylalanine, tyrosine and tryptophan biosynthesis, valine, leucine and isoleucine biosynthesis, phenylalanine metabolism, and sphingolipid metabolism. Pharmacokinetics combined with metabolomics could provide a comprehensive perspective for consistency evaluation of CHG.

Heat stress-induced HSP90 expression is dependent on ERK and HSF1 activation in turbot (Scophthalmus maximus) kidney cells.

Mitogen-activated protein kinases (MAPKs) and heat shock proteins (HSPs) are ubiquitous proteins that are functional mediators in both normal and stressed states of the cell. In this study, we performed heat stress (37 °C) experiments on turbot kidney (TK) cells. Heat stress expression patterns of HSP90, as well as the expression and phosphorylation levels of extracellular-regulated signal kinases (ERKs) and the transcription factor HSF1 and c-Fos, were examined. The results show that heat stress activates ERK1/2 and HSF1, and induces HSP90 gene expression in TK cells. Inhibition of ERK activation attenuates heat stress-induced HSP90 gene expression. The double luciferase reporter gene experiment showed that HSF1 is an important transcription factor for heat-induced HSP90 gene expression. Likewise, c-Fos does not directly regulate the heat-induced expression of HSP90 in turbot kidney cells. To our knowledge, this is the first study to report a signaling pathway that regulates the heat shock response in turbot cells. Our results may facilitate an understanding of the underlying molecular mechanisms of the cellular stress response in marine fish.

Molecular characterization, expression analysis of 14-3-3 beta/alpha and the effect of RNA interference on ion transporter protein Na+-K+-ATPase, Na+-H+-exchanger and CFTR in turbot (Scophthalmus maximus).

To understand the role of 14-3-3 beta/alpha in hypoosmotic regulation of turbot (Scophthalmus maximus), we characterized the 14-3-3 beta/alpha gene and analyzed the tissue distribution and its gene transcriptional patterns in the main expressed tissues under low salt stress. The 14-3-3 beta/alpha cDNA is 892 bp in length, incorporating an ORF of 774 bp with a putative primary structure of 257 residues. The deduced amino acid sequences shared highly conserved structures with other eukaryotes. Quantitative real-time PCR results showed that the 14-3-3 beta/alpha transcripts were widely expressed in various tissues of turbot, with most abundant in the gill (P < .05), to a lesser extent in the kidney, intestine, brain and spleen, and at low levels in the pituitary and other tissues examined. And the expression of turbot 14-3-3 beta/alpha exhibited a trend of increasing first and then decreasing with the time of stress under low salt stress, and the highest value appeared in 12 h (P < .05). After injecting different concentrations of dsRNA, the mRNA expression of 14-3-3 gene decreased significantly during the monitoring period, and the best interference effect was achieved 12 h after injecting 4 µg/g dsRNA. For the first time, the gene was silenced in fish by intramuscular injection of dsRNA. It also provides a new and effective way to study gene function at the individual level. Moreover, the mRNA interference of 14-3-3 beta/alpha would cause changes in the expression of several ion channel proteins, for example, the decrease of Na+-K+-ATPase and Na+-H+-exchanger and the increase of CFTR. As a result, 14-3-3 beta/alpha appears to be an important molecular regulator for osmosensory signal transduction in gill of turbot.

Metabolic responses in Scophthalmus maximus kidney subjected to thermal stress.

Turbot (Scophthalmus maximus) is an economically important marine fish cultured in China. In this study, fish in the experimental group were exposed to four temperatures: 15, 20, 25 and 28 °C. Metabolomics analysis and quantitative real-time PCR were used to assess changes in metabolic profiling and gene expression associated with thermal stress. The results showed the levels of heat shock protein 70 (HSP70), heat shock protein 90 (HSP90), blood creatinine and cortisol in S. maximus were all significantly upregulated (P < 0.05), indicating a stress response at 25 °C or higher. Challenge with thermal stress significantly increased expression levels of succinate dehydrogenase (SDH), fructose-1, 6-bisphosphatase (FBPase), malate dehydrogenase (MDH), cytosolic phosphoenolpyruvate carboxykinase (cPEPCK), glucose-6-phosphatase (G6Pase) and aspartate aminotransferase (AST) (P < 0.05). However, there was no effect on the expression levels of lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and mitochondrial phosphoenolpyruvate carboxykinase (mPEPCK). Moreover, high temperature decreased levels of glycogenic amino acids, including histidine, threonine, glutamine, phenylalanine, arginine, serine, tyrosine, methionine and isoleucine. These findings suggest a significant correlation between gene expression and regulation of carbohydrate and amino acid metabolism in heat-stressed S. maximus kidney. In addition, the maintenance of aerobic metabolism and activation of gluconeogenesis appeared to be a critical metabolic strategy in combating heat stress in turbot kidney.

Vi Capsular Polysaccharide Produced by Recombinant Salmonella enterica Serovar Paratyphi A Confers Immunoprotection against Infection by Salmonella enterica Serovar Typhi.

Enteric fever is predominantly caused by Salmonella enterica serovar Typhi and Salmonella enterica serovar Paratyphi A, and accounts for an annual global incidence of 26.9 millions. In recent years, the rate of S. Paratyphi A infection has progressively increased. Currently licensed vaccines for typhoid fever, live Ty21a vaccine, Vi subunit vaccine, and Vi-conjugate vaccine, confer inadequate cross immunoprotection against enteric fever caused by S. Paratyphi A. Therefore, development of bivalent vaccines against enteric fever is urgently required. The immunogenic Vi capsular polysaccharide is characteristically produced in S. Typhi, but it is absent in S. Paratyphi A. We propose that engineering synthesis of Vi in S. Paratyphi A live-attenuated vaccine may expand its protection range to cover S. Typhi. In this study, we cloned the viaB locus, which contains 10 genes responsible for Vi biosynthesis, and integrated into the chromosome of S. Paratyphi A CMCC 50093. Two virulence loci, htrA and phoPQ, were subsequently deleted to achieve a Vi-producing attenuated vaccine candidate. Our data showed that, despite more than 200 passages, the viaB locus was stably maintained in the chromosome of S. Paratyphi A and produced the Vi polysaccharide. Nasal immunization of the vaccine candidate stimulated high levels of Vi-specific and S. Paratyphi A-specific antibodies in mice sera as well as total sIgA in intestinal contents, and showed significant protection against wild-type challenge of S. Paratyphi A or S. Typhi. Our study show that the Vi-producing attenuated S. Paratyphi A is a promising bivalent vaccine candidate for the prevention of enteric fever.

Safety and immunogenicity of an attenuated Salmonella enterica serovar Paratyphi A vaccine candidate.

Enteric fever caused by Salmonella enterica serovar Paratyphi A has progressively increased in recent years and became a global health issue. Currently licensed typhoid vaccines do not confer adequate cross-immunoprotection against S. Paratyphi A infection. Therefore, vaccines specifically against enteric fever caused by S. Paratyphi A are urgently needed. In the present study, an attenuated vaccine strain was constructed from S. Paratyphi A CMCC50093 by the deletions of aroC and yncD. The obtained strain SPADD01 showed reduced survival within THP-1 cells and less bacterial burden in spleens and livers of infected mice compared with the wild-type strain. The 50% lethal doses of SPADD01 and the wild-type strain were assessed using a murine infection model. The virulence of SPADD01 is approximately 40,000-fold less than that of the wild-type strain. In addition, SPADD01 showed an excellent immunogenicity in mouse model. Single intranasal inoculation elicited striking humoral and mucosal immune responses in mice and yielded effective protection against lethal challenge of the wild-type strain. A high level of cross-reactive humoral immune response against LPS of Salmonella enterica serovar Typhi was also detected in immunized mice. However, SPADD01 vaccination only conferred a low level of cross-protection against S. Typhi. Our data suggest that SPADD01 is a promising vaccine candidate against S. Paratyphi A infection and deserves further evaluation in clinical trial. To date, no study has demonstrated a good cross-protection between serovars of S. Typhi and S. Paratyphi A, suggesting that the dominant protective antigens of both serovars are likely different and need to be defined in future study.

Construction of an attenuated Salmonella enterica serovar Paratyphi A vaccine strain harboring defined mutations in htrA and yncD.

The global epidemic features of enteric fever have changed greatly in recent years. The incidence of enteric fever caused by Salmonella enterica serovar Paratyphi A has progressively increased. In some areas of Asia, infections with S. Paratyphi A have exceeded those with S. Typhi, resulting in S. Paratyphi A becoming the main causative agent of enteric fever. However, two currently licensed typhoid vaccines do not confer adequate cross-protection against S. Paratyphi A infection. Therefore, development of specific vaccines against enteric fever caused by S. Paratyphi A is urgently needed. In the present study, an attenuated strain was constructed by double deletion of the htrA and yncD genes in a wild-type strain of S. Paratyphi A and its safety and immunogenicity assessed. In a mouse model, the 50% lethal dose of the double deletion mutant and the wild-type strain were 3.0 × 10(8) CFU and 1.9 × 10(3) CFU, respectively, suggesting that the double deletion resulted in remarkably decreased bacterial virulence. Bacterial colonization of the double deletion mutant in the livers and spleens of infected mice was strikingly less than that of the wild-type strain. A single nasal administration of the attenuated vaccine candidate elicited high concentrations of anti-LPS and anti-flagellin IgG in a mouse model and protected immunized mice against lethal challenge with the wild-type strain. Thus, our findings suggest that the attenuated vaccine strain is a promising candidate worthy of further evaluation both as a human enteric fever vaccine and as a vaccine delivery vector for heterologous antigens.