Many basic properties of the T-cell receptor (TCR) repertoire require clarification, and the changes occurring in the TCR repertoire during carcinogenesis, especially during precancerous stages, remain unclear. This study used deep sequencing analyses to examine 41 gastric tissue samples at different pathological stages, including low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, early gastric cancer and matched adjacent tissues, to define the characteristics of the infiltrating TCRβ repertoire during gastric carcinogenesis. Moreover, to illustrate the relationship between the local molecular phenotype and TCR repertoire of the microenvironment, whole-genome gene expression microarray analysis of the corresponding gastric precancerous lesions and early gastric cancer tissues was conducted. Our results showed that the degree of variation in the TCR repertoire gradually increased during tumourigenesis. Integrative analysis of microarray data and the TCR repertoire variation index using the network-based Clique Percolation Method identified an 11-gene module related to the inflammatory response that can predict the overall survival of gastric cancer (GC) patients. In conclusion, our results revealed the multistage heterogeneity of tissue-infiltrating TCR repertoire during carcinogenesis. We report a novel way for identifying prognostic biomarkers for GC patients and improves our understanding of immune responses during gastric carcinogenesis.

Irritable bowel syndrome (IBS) related chronic visceral pain affects 20% of people worldwide. The treatment options are very limited. Although the scholarly reviews have appraised the potential effects of the intestinal microbiota on intestinal motility and sensation, the exact mechanism of intestinal microbiota in IBS-like chronic visceral pain remains largely unclear. The purpose of this study is to investigate whether Folic Acid (FA) attenuated visceral pain and its possible mechanisms. Chronic visceral hyperalgesia was induced in rats by neonatal colonic inflammation (NCI). 16S rDNA analysis of fecal samples from human subjects and rats was performed. Patch clamp recording was used to determine synaptic transmission of colonic-related spinal dorsal horn. Alpha diversity of intestinal flora was increased in patients with IBS, as well as the obviously increased abundance of Clostridiales order (a main bacteria producing hydrogen sulfide). The hydrogen sulfide content was positive correlation with visceral pain score in patients with IBS. Consistently, NCI increased Clostridiales frequency and hydrogen sulfide content in feces of adult rats. Notably, the concentration of FA was markedly decreased in peripheral blood of IBS patients compared with non-IBS human subjects. FA supplement alleviated chronic visceral pain and normalized the Clostridiales frequency in NCI rats. In addition, FA supplement significantly reduced the frequency of sEPSCs of neurons in the spinal dorsal horn of NCI rats. Folic Acid treatment attenuated chronic visceral pain of NCI rats through reducing hydrogen sulfide production from Clostridiales in intestine.

The complete mitochondrial genome of Marsh Sandpiper Tringa stagnatilis was sequenced in this study. The circular mitogenome was 16,799 bp in length, which contained 13 protein-coding genes, two ribosomal RNAs (12S rRNA and 16S rRNA), 22 transfer RNA genes, and a D-loop region. The overall nucleotide composition was A: 31.51%, T: 25.45%, C: 29.51%, and G: 13.53%. Twenty-eight genes were encoded on the heavy strand, and the remaining nine genes were encoded on the light strand. The common start codon was ATG, and four stop codons and an incomplete stop codon (T-) were used in PCGs. This study improves our understanding of the mitogenomic characteristics and its phylogenetic relationships within Charadriiformes.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease characterized by abdominal pain. Our recent study has shown that the acid-sensitive ion channel 1 (ASIC1) in dorsal root ganglion (DRG) is involved in stomachache of adult offspring rats subjected with prenatal maternal stress (PMS). MiR-485 is predicted to target the expression of ASIC1. The aim of the present study was designed to determine whether miR-485/ASIC1 signaling participates in enterodynia in the spinal dorsal horn of adult offspring rats with PMS.

Nonthyroidal illness syndrome (NTIS), also known as low triiodothyronine (T3) syndrome, frequently affects patients with systemic lupus erythematosus (SLE) and may affect lipid metabolism. Dyslipidemia is highly prevalent and associated with the long-term prognosis of SLE. The aim of the present study was to explore the clinical significance of NTIS on disease activity and dyslipidemia in patients with SLE.

Chronic pain is highly prevalent and poorly controlled, of which the accurate underlying mechanisms need be further elucidated. Herbal drugs have been widely used for controlling various pain disorders. The systematic integration of pain herbal data resources might be promising to help investigate the molecular mechanisms of pain phenotypes. Here, we integrated large-scale bibliographic literatures and well-established data sources to obtain high-quality pain relevant herbal data (i.e. 426 pain related herbs with their targets). We used machine learning method to identify three distinct herb categories with their specific indications of symptoms, targets and enriched pathways, which were characterized by the efficacy of treatment to the chronic cough related neuropathic pain, the reproduction and autoimmune related pain, and the cancer pain, respectively. We further detected the novel pathophysiological mechanisms of the pain subtypes by network medicine approach to evaluate the interactions between herb targets and the pain disease modules. This work increased the understanding of the underlying molecular mechanisms of pain subtypes that herbal drugs are participating and with the ultimate aim of developing novel personalized drugs for pain disorders.

RSK1, an essential cellular kinase for Kaposi's sarcoma-associated herpesvirus (KSHV) replication, is highly phosphorylated and SUMOylated during KSHV lytic cycle, which determine the substrate phosphorylation and specificity of RSK1, respectively. However, the SUMO E3 ligase responsible for attaching SUMO to RSK1 has not yet been identified. By genome-wide screening, we found that KSHV ORF45 is necessary and sufficient to enhance RSK1 SUMOylation. Mechanistically, KSHV ORF45 binds to SUMOs via two classic SUMO-interacting motifs (SIMs) and functions as a SIM-dependent SUMO E3 ligase for RSK1. Mutations on these ORF45 SIMs resulted in much lower lytic gene expressions, viral DNA replication, and mature progeny virus production. Interestingly, KSHV ORF45 controls RSK1 SUMOylation and phosphorylation via two separated functional regions: SIMs and amino acid 17-90, respectively, which do not affect each other. Similar to KSHV ORF45, ORF45 of Rhesus Macaque Rhadinovirus has only one SIM and also increases RSK1 SUMOylation in a SIM-dependent manner, while other ORF45 homologues do not have this function. Our work characterized ORF45 as a novel virus encoded SUMO E3 ligase, which is required for ORF45-RSK1 axis-mediated KSHV lytic gene expression.

Trichinella spiralis represents an effective treatment for autoimmune and inflammatory diseases. The effects of recombinant T. spiralis (TS) 53-kDa protein (rTsP53) on acute lung injury (ALI) remain unclear. Here, mice were divided randomly into a control group, LPS group, and rTsP53 + LPS group. ALI was induced in BALB/c mice by LPS (10 mg/kg) injected via the tail vein. rTsP53 (200 µl; 0.4 μg/μl) was injected subcutaneously three times at an interval of 5 d before inducing ALI in the rTsP53+LPS group. Lung pathological score, the ratio and markers of classic activated macrophages (M1) and alternatively activated macrophages (M2), cytokine profiles in alveolar lavage fluid, and pyroptosis protein expression in lung tissue were investigated. RTsP53 decreased lung pathological score. Furthermore, rTsP53 suppressed inflammation by increasing IL-4, IL-10, and IL-13. There was an increase in alveolar M2 macrophage numbers, with an increase in CD206 and arginase-1-positive cells and a decrease in alveolar M1 markers such as CD197 and iNOS. In addition, the polarization of M2 macrophages induced by rTsP53 treatment could alleviate ALI by suppressing lung pyroptosis. RTsP53 was identified as a potential agent for treating LPS-induced ALI via alleviating lung pyroptosis by promoting M2 macrophage polarization.

Dendrocalamus liboensis Hsueh & D. Z. Li 1985 is a unique member of the Bambusoideae subfamily found in Guizhou, China. The species has both economic importance and ornamental value. This study represents the first report of the sequencing and assembly of the complete chloroplast genome of D. liboensis. The total length of the genome was 139,483 bp, with a conventional quadripartite framework consisting of a large single-copy (LSC) region (83,001 bp in length), a small single-copy (SSC) region (12,896 bp in length), and two inverted repeats (IR) regions (both 21,793 bp in length). Overall, the D. liboensis chloroplast genome contained 128 functional genes, including 83 protein-coding genes, 37 tRNAs, and 8 rRNAs. Phylogenetic analysis showed that D. liboensis closely resembled D. sapidus, with both found on a strongly supported branch of the phylogenetic tree.

Mitochondrial membrane permeability has received considerable attention recently because of its key role in apoptosis and necrosis induced by physiological events such as hypoxia. The manner in which mitochondria interact with other molecules to regulate mitochondrial permeability and cell destiny remains elusive. Previously we verified that hypoxia-induced phosphorylation of microtubule-associated protein 4 (MAP4) could lead to microtubules (MTs) disruption. In this study, we established the hypoxic (1% O(2)) cell models of rat cardiomyocytes, H9c2 and HeLa cells to further test MAP4 function. We demonstrated that increase in the pool of MAP4 could promote the stabilization of MT networks by increasing the synthesis and polymerization of tubulin in hypoxia. Results showed MAP4 overexpression could enhance cell viability and ATP content under hypoxic conditions. Subsequently we employed a yeast two-hybrid system to tag a protein interacting with mitochondria, dynein light chain Tctex-type 1 (DYNLT1), by hVDAC1 bait. We confirmed that DYNLT1 had protein-protein interactions with voltage-dependent anion channel 1 (VDAC1) using co-immunoprecipitation; and immunofluorescence technique showed that DYNLT1 was closely associated with MTs and VDAC1. Furthermore, DYNLT1 interactions with MAP4 were explored using a knockdown technique. We thus propose two possible mechanisms triggered by MAP4: (1) stabilization of MT networks, (2) DYNLT1 modulation, which is connected with VDAC1, and inhibition of hypoxia-induced mitochondrial permeabilization.

Traditional Chinese Medicine (TCM) involves a broad range of empirical testing and refinement and plays an important role in the health maintenance for people all over the world. However, due to the complexity of Chinese herbs, a full understanding of TCM's action mechanisms is still unavailable despite plenty of successful applications of TCM in the treatment of various diseases, including especially cardiovascular diseases (CVD), one of the leading causes of death. Thus in the present work, by incorporating the chemical predictors, target predictors and network construction approaches, an integrated system of TCM has been constructed to systematically uncover the underlying action mechanisms of TCM. From three representative Chinese herbs, i.e., Ligusticum chuanxiong Hort., Dalbergia odorifera T. Chen and Corydalis yanhusuo WT Wang which have been widely used in CVD treatment, by combinational use of drug absorption, distribution, metabolism and excretion (ADME) screening and network pharmacology techniques, we have generated 64 bioactive ingredients and identified 54 protein targets closely associated with CVD, of which 29 are common targets (52.7%) of the three herbs. The result provides new information on the efficiency of the Chinese herbs for the treatment of CVD and also explains one of the basic theories of TCM, i.e., "multiple herbal drugs can treat one disease". The predicted potential targets were then mapped to target-disease and target-signal pathway connections, which revealed the relationships of the active ingredients with their potential targets, diseases and signal systems. This means that for the first time, the action mechanism of these three important Chinese herbs for the treatment of CVD is uncovered, by generating and identifying both their active ingredients and novel targets specifically related to CVD, which clarifies some of the common conceptions in TCM, and thus provides clues to modernize such specific herbal medicines.

Aspergillus species are emerging causative agents of non-dermatophyte mold onychomycosis. In this study, 48 Aspergillus isolates were obtained from patients with onychomycosis in Mashhad, Iran, during 2015-2018. The aim is to identify the Aspergillus isolates to the species level by using partial calmodulin and beta-tubulin gene sequencing and MALDI-TOF MS, and to evaluate their in vitro susceptibility to ten antifungal drugs: terbinafine, itraconazole, voriconazole, posaconazole, ravuconazole, isavuconazole, caspofungin, micafungin, anidulafungin and amphotericin B according to CLSI M38-A3. Our results indicate that A.flavus (n = 38, 79%) is the most common Aspergillus species causing onychomycosis in Mashhad, Iran. Other detected species were A. terreus (n = 3), A. tubingensis (n = 2), A. niger (n = 1), A. welwitschiae (n = 1), A. minisclerotigenes (n = 1), A. citrinoterreus (n = 1) and A. ochraceus (n = 1). Aspergillus flavus, A. terreus and A. niger isolates were correctly identified at the species level by MALDI-TOF MS, while all cryptic species were misidentified. In conclusion, A. flavus is the predominant Aspergillus species causing onychomycosis due to Aspergillus spp. in Mashhad, Iran. MALDI-TOF MS holds promise as a fast and accurate identification tool, particularly for common Aspergillus species. It is important that the current database of reference spectra, representing different Aspergillus species is expanded to increase the precision of the species-level identification. Terbinafine, posaconazole and echinocandins were in vitro most active against the studies Aspergillus isolates and terbinafine could be the first choice for treatment of onychomycosis due to Aspergillus.

Parkinson's disease (PD) is an incurable progressive disorder resulting from neurodegeneration, and apoptosis is considered a dominant mechanism underlying the process of neurodegeneration. MicroRNAs (miRNAs), which are small and noncoding RNAs involved in many a biological process like apoptosis and regulation of gene expressions, have been found in postmortem brain samples of patients with PD, as well as in vitro and in vivo models of PD. To explore the impact of miR-15b-5p and Akt3 on apoptosis in the progression of PD, the method of quantitative reverse transcription polymerase chain reaction (qRT-PCR) was employed, and the analysis result showed upregulated expression of miR-15b-5p and downregulated expression of Akt3 in the serum of PD patients, MPP+-induced SH-SY5Y cells, and the brain tissues of MPTP-induced mice. Meanwhile, the dual-luciferase reporter assay was used to demonstrate the regulator-target interaction between miR-15b-5p and Akt3; flow cytometry and spectrophotometry revealed that transfection of miR-15b-5p mimic and si-Akt3 increased the rate of apoptosis and caspase-3 activity, whereas transfecting the miR-15b-5p inhibitor and Akt3-overexpression plasmid repressed the rate of apoptosis and caspase-3 activity in the MPP+-induced SH-SY5Y cell model and the MPTP-induced mouse model. Additionally, analysis of western blotting (WB) assays in vivo and in vitro revealed that proapoptosis proteins (Bax, caspase-3, GSK-3β, and β-catenin) showed markedly upregulated expression in the miR-15b-5p inhibitor and si-Akt3-overexpression groups, while the expression of an antiapoptosis gene (i.e., Bcl2) was downregulated. These analysis results indicate that downregulation of miR-15b-5p by targeting the Akt3-mediated GSK-3β/β-catenin signaling pathway would repress cell apoptosis in PD in vivo and in vitro. It is expected that the research findings would help find new therapeutic targets for treatment of PD.

With the aging of society, the incidence of diseases increases. And along with the increase of surgery rate, the number of elderly patients with postoperative cognitive dysfunction (POCD) is also increasing. POCD seriously affects the mental state and quality of life of patients and their families. Clinical studies have shown that POCD is closely related to inflammatory reaction, and Ulinastatin can inhibit the inflammatory reaction and reduce the incidence of POCD in elderly patients under general anesthesia. However. the effect of Ulinastatin on POCD in elderly patients under general anesthesia has not been systematically evaluated.

Rescue chemotherapy is usually the preferred treatment for patients with advanced estrogen receptor-positive (ER+) breast cancer with endocrinotherapy resistance. However, these patients often simultaneously show a poor response to cytotoxic drugs, and thus the detailed mechanism of this resistance needs to be further investigated. Our previous research indicated that the G-protein-coupled estrogen receptor (GPER) is a novel mediator of the development of multidrug resistance, including resistance to both endocrinotherapy and chemotherapy, and ATP binding cassette subfamily G member 2 (ABCG2) has been identified as an engine that confers cancer cells with chemoresistance by expelling xenobiotics and chemotherapeutics. Here, we are the first to show that the expression levels of GPER and ABCG2 are markedly increased in tamoxifen-resistant ER + metastases compared to the corresponding primary tumors. A plasma membrane expression pattern of GPER and ABCG2 was observed in patients with metastases. Furthermore, both ER modulator tamoxifen, GPER-specific agonist G1 and pure ER antagonist ICI 182,780 significantly enhanced ABCG2 expression in tamoxifen-resistant breast cancer cells (MCF-7R) but not in tamoxifen-sensitive cells (MCF-7). The activated downstream GPER/EGFR/ERK and GPER/EGFR/AKT signaling pathways were responsible for regulating the expression and cell membrane localization of ABCG2, respectively, in MCF-7R cells. Interestingly, the above phenomenon could be alleviated by inhibitors of both the indicated signaling pathways and by knockdown of GPER in MCF-7R cells. More importantly, the tamoxifen-induced GPER/ABCG2 signaling axis was shown to play a pivotal role in the development of chemotherapy (doxorubicin) resistance both in vitro and in vivo. The clinical data further revealed that tamoxifen-resistant patients with high GPER/ABCG2 signaling activation had poor progression-free survival (PFS) when given rescue anthracycline chemotherapy. Therefore, our data provide novel insights into GPER-mediated chemoresistance and provide a rationale for the GPER/ABCG2 signaling axis being a promising target for reversing chemoresistance in patients with advanced ER + tamoxifen-resistant breast cancer.

To detect the expression of the Oncostatin M (OSM) gene and encoded protein in the mucosal epithelium of chronic gastritis, intestinal metaplasia (IM), low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), early gastric cancer (EGC), and advanced gastric cancer (AGC) samples and to explore the correlation and clinicopathological significance of OSM expression in the process of gastric carcinogenesis.

Patients with autoimmune diseases often present with olfactory impairment. The aim of the study was to assess the olfactory functions of patients with primary Sjögren's syndrome and to correlate these findings with their disease activity.

This study aimed to evaluate the effects of microbe-derived antioxidant (MA) on high-fat diet (HFD)-induced hepatic lipid disorders in mother rats and offspring.

Parkinson's disease (PD) is the second most common neurodegenerative disease but still lacks a preclinical strategy to identify it. The diagnostic value of intestinal mucosal α-synuclein (αSyn) in PD has not drawn a uniform conclusion. The relationship between the alteration of intestinal mucosal αSyn expression and mucosal microbiota is unclear. Nineteen PD patients and twenty-two healthy controls were enrolled in our study from whom were collected, using gastrointestinal endoscopes, duodenal and sigmoid mucosal samples for biopsy. Multiplex immunohistochemistry was performed to detect total, phosphorylate, and oligomer α-synuclein. Next-generation 16S rRNA amplicon sequencing was applied for taxonomic analysis. The results implied that oligomer α-synuclein (OSyn) in sigmoid mucosa of PD patients was transferred from the intestinal epithelial cell membrane to the cytoplasm, acinar lumen, and stroma. Its distribution feature was significantly different between the two groups, especially the ratio of OSyn/αSyn. The microbiota composition in mucosa also differed. The relative abundances of Kiloniellales, Flavobacteriaceae, and CAG56 were lower, while those of Proteobacteria, Gammaproteobacteria, Burkholderiales, Burkholdriaceae, Oxalobacteraceae, Ralstonia, Massilla, and Lactoccus were higher in duodenal mucosa of PD patients. The relative abundances of Thermoactinomycetales and Thermoactinomycetaceae were lower, while those of Prevotellaceae and Bifidobacterium longum were higher in patients' sigmoid mucosa. Further, the OSyn/αSyn level was positively correlated with the relative abundances of Proteobacteria, Gammaproteobacteria, Burkholderiales, Pseudomonadales, Burkholderiaceae, and Ralstonia in the duodenal mucosa, while it was negatively correlated with the Chao1 index and observed operational taxonomic units of microbiota in sigmoid mucosa. The intestinal mucosal microbiota composition of PD patients altered with the relative abundances of proinflammatory bacteria in the duodenal mucosa increased. The ratio of the OSyn/αSyn level in the sigmoid mucosa indicated a potential diagnostic value for PD, which also correlated with mucosal microbiota diversity and composition. KEY POINTS: • The distribution of OSyn in sigmoid mucosa differed between PD patients and healthy controls. • Significant alterations in the microbiome were found in PD patients' gut mucosa. • OSyn/αSyn level in sigmoid mucosa indicated a potential diagnostic value for PD.

This study aimed to compare higher-order aberrations (HOAs) after small incision lenticule extraction (SMILE) in patients with different angle kappa. This is a retrospective report in which 341 right eyes of 341 patients who were subjected to SMILE, which used coaxially sighted corneal light reflex (CSCLR) as the treatment zone centered, treated by the same experienced surgeon (LHB) for correction of myopia and myopic astigmatism, preoperative and postoperative spherical equivalent (SE), angle kappa, total higher-order aberrations (total HOA), spherical aberration (SA), vertical coma (VC), horizontal coma (HC), oblique trefoil (OT), and horizontal trefoil (HT), were compared. SMILE showed outstanding performance in terms of safety, efficacy, and predictability. In addition, a comparison of preoperative and postoperative HOAs exhibited the difference of total HOA (P < 0.01), SA (P < 0.01), VC (P < 0.01), and HC (P < 0.01), which was statistically significant; however, for OT and HT with the longer follow-up time, the statistical difference gradually decreased. For stratification of angle kappa into groups based on decantation, angle kappa was divided into three major groups: r < 0.1 mm, 0.1 ≤ r < 0.2 mm, and r ≥ 0.2 mm; the changes of SA (F = 4.127, P = 0.021) and OT (F = 3.687, P = 0.031) exhibited significant difference after 1 year of SMILE. We performed a correlation analysis of all preoperative and postoperative parameters, and the results indicated that the preoperative total HOA was negatively correlated with preoperative cylindrical diopter (DC), and postoperative total HOA, SA, and coma were affected by spherical diopter (DS) and SE. Moreover, we also found a significant difference of SA and VC in the early postoperative with preoperative. SA was positively correlated with Y values and r of 1 year after SMILE. All of the analyzed parameters in the three groups, except for the trefoil, gradually increased over time; however, the trefoil could gradually stabilize over time. We also divided angle kappa into four groups by quadrants; the result showed that the effects of higher-order aberrations were markedly different from the various quadrants. Patients with large angle kappa were able to increase VC and SA postoperatively, and higher HOAs were more significant in patients with high myopia. The differences in quadrants exhibited a diversity of HOAs; this could be attributed to the corneal surface reestablishment and the alteration of angle kappa, but the trend was not apparent. Although all patients displayed increased HOAs after SMILE, the potential application of CSCLR as the treatment zone centered still showed excellent safety, efficacy, and predictability.