Graphene oxide quantum dots-loaded sinomenine hydrochloride nanocomplexes for effective treatment of rheumatoid arthritis via inducing macrophage repolarization and arresting abnormal proliferation of fibroblast-like synoviocytes.

The characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in developing a suitable therapeutic strategy for RA that targets the synovial macrophages and fibroblast-like synoviocytes (FLSs). In this study, we used graphene oxide quantum dots (GOQDs) for loading anti-arthritic sinomenine hydrochloride (SIN). By combining with hyaluronic acid (HA)-inserted hybrid membrane (RFM), we successfully constructed a new nanodrug system named HA@RFM@GP@SIN NPs for target therapy of inflammatory articular lesions. Mechanistic studies showed that this nanomedicine system was effective against RA by facilitating the transition of M1 to M2 macrophages and inhibiting the abnormal proliferation of FLSs in vitro. In vivo therapeutic potential investigation demonstrated its effects on macrophage polarization and synovial hyperplasia, ultimately preventing cartilage destruction and bone erosion in the preclinical models of adjuvant-induced arthritis and collagen-induced arthritis in rats. Metabolomics indicated that the anti-arthritic effects of HA@RFM@GP@SIN NPs were mainly associated with the regulation of steroid hormone biosynthesis, ovarian steroidogenesis, tryptophan metabolism, and tyrosine metabolism. More notably, transcriptomic analyses revealed that HA@RFM@GP@SIN NPs suppressed the cell cycle pathway while inducing the cell apoptosis pathway. Furthermore, protein validation revealed that HA@RFM@GP@SIN NPs disrupted the excessive growth of RAFLS by interfering with the PI3K/Akt/SGK/FoxO signaling cascade, resulting in a decline in cyclin B1 expression and the arrest of the G2 phase. Additionally, considering the favorable biocompatibility and biosafety, these multifunctional nanoparticles offer a promising therapeutic approach for patients with RA.

Feature variability determines specificity and transfer in multiorientation feature detection learning.

Historically, in many perceptual learning experiments, only a single stimulus is practiced, and learning is often specific to the trained feature. Our prior work has demonstrated that multi-stimulus learning (e.g., training-plus-exposure procedure) has the potential to achieve generalization. Here, we investigated two important characteristics of multi-stimulus learning, namely, roving and feature variability, and their impacts on multi-stimulus learning and generalization. We adopted a feature detection task in which an oddly oriented target bar differed by 16° from the background bars. The stimulus onset asynchrony threshold between the target and the mask was measured with a staircase procedure. Observers were trained with four target orientation search stimuli, either with a 5° deviation (30°-35°-40°-45°) or with a 45° deviation (30°-75°-120°-165°), and the four reference stimuli were presented in a roving manner. The transfer of learning to the swapped target-background orientations was evaluated after training. We found that multi-stimulus training with a 5° deviation resulted in significant learning improvement, but learning failed to transfer to the swapped target-background orientations. In contrast, training with a 45° deviation slowed learning but produced a significant generalization to swapped orientations. Furthermore, a modified training-plus-exposure procedure, in which observers were trained with four orientation search stimuli with a 5° deviation and simultaneously passively exposed to orientations with high feature variability (45° deviation), led to significant orientation learning generalization. Learning transfer also occurred when the four orientation search stimuli with a 5° deviation were presented in separate blocks. These results help us to specify the condition under which multistimuli learning produces generalization, which holds potential for real-world applications of perceptual learning, such as vision rehabilitation and expert training.

Early-life infection of the airways with Streptococcus pneumoniae exacerbates HDM-induced asthma in a murine model.

Respiratory tract infection early in life plays a significant role in the pathogenesis of asthma. In the present study we examine, using a murine surrogate, the effects of early life respiratory infection with Streptococcus pneumoniae (SP) on adult asthma induced by sensitisation and exposure to house dust mite (HDM) allergen. Mice (one week old) were infected with SP, then 3 weeks later sensitised to HDM emulsified with Al (OH)3 intraperitoneally and challenged intranasally with same allergen for up to a further 5 weeks to establish the asthma surrogate. Outcome measures were quantified using the FlexiVent apparatus, histology and immunohistology, ELISA and flow cytometry. The murine surrogates of asthma infected with SP early in life exhibited significantly more severe disease compared with the controls of mice without SP infection, as shown by airways responsiveness, inflammatory cellular infiltration of the airways, expression of markers of airways remodelling, serum concentrations of HDM-specific IgE and the concentrations of Th2-type cytokines and the numbers of activated Th2 and ILC2 cells in the lung tissues. These data are compatible with the hypothesis that early-life infection of the airways with SP exacerbates, at least in some individuals, subsequent HDM-induced allergic airways inflammation and associated asthma in adulthood in this murine surrogate.

[Characteristics of supramolecular imprinting template on liver meridian tropism of traditional Chinese medicine based on molecular connectivity index].

The molecular connectivity index was adopted to explore the characteristics of supramolecular imprinting template of herbs distributed to liver meridian, in order to provide scientific basis for traditional Chinese medicines(TCMs) distributed to liver meridian. In this paper, with "12th five-year plan" national planning textbooks Science of Traditional Chinese Medicine and Chemistry of Traditional Chinese Medicine as the blueprint, literatures and TCMSP sub-databases in TCM pharmacology of northwest science and technology university of agriculture and forestry were retrieved to collect and summarize active constituents of TCM distributed to liver meridian, and calculate the molecular connectivity index. The average molecular connectivity index of ingredients distributed to liver meridian was 9.47, which was close to flavonoid glycosides' (9.17±2.11) and terpenes (9.30±3.62). Therefore, it is inferred that template molecule of liver meridian is similar to physicochemical property of flavonoid glycosides and terpenes, which could be best matched with imprinting template of liver meridian.

[Chromosomal microarray analysis of 2000 pediatric cases].

OBJECTIVE: To assess the feasibility of chromosomal microarray analysis(CMA) for studying the correlation between birth defects and chromosomal aberrations. METHODS: A total of 2000 patients with birth defects were recruited for the CMA testing. RESULTS: Five hundred twenty two patients (26.1%) were found to have chromosomal abnormalities. These included 24 cases with numerical abnormalities, 11 with mosaicisms, and 11 with uniparental disomies. The remaining 476 cases were of well-known microdeletion or microduplication syndromes. The advantage of CMA over conventional karyotyping was demonstrated in many cases. CONCLUSION: As a powerful tool for patients with birth defects, CMA can produce a higher diagnostic yield compared with conventional karyotyping.

Inhibition of IL-17 signaling in macrophages underlies the anti-arthritic effects of halofuginone hydrobromide: Network pharmacology, molecular docking, and experimental validation.

BACKGROUND: Rheumatoid arthritis (RA) is a prevalent autoimmune disease marked by chronic synovitis as well as cartilage and bone destruction. Halofuginone hydrobromide (HF), a bioactive compound derived from the Chinese herbal plant Dichroa febrifuga Lour., has demonstrated substantial anti-arthritic effects in RA. Nevertheless, the molecular mechanisms responsible for the anti-RA effects of HF remain unclear. METHODS: This study employed a combination of network pharmacology, molecular docking, and experimental validation to investigate potential targets of HF in RA. RESULTS: Network pharmacology analyses identified 109 differentially expressed genes (DEGs) resulting from HF treatment in RA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses unveiled a robust association between these DEGs and the IL-17 signaling pathway. Subsequently, a protein-protein interaction (PPI) network analysis revealed 10 core DEGs, that is, EGFR, MMP9, TLR4, ESR1, MMP2, PPARG, MAPK1, JAK2, STAT1, and MAPK8. Among them, MMP9 displayed the greatest binding energy for HF. In an in vitro assay, HF significantly inhibited the activity of inflammatory macrophages, and regulated the IL-17 signaling pathway by decreasing the levels of IL-17 C, p-NF-κB, and MMP9. CONCLUSION: In summary, these findings suggest that HF has the potential to inhibit the activation of inflammatory macrophages through its regulation of the IL-17 signaling pathway, underscoring its potential in the suppression of immune-mediated inflammation in RA.

Surgical methods of total thyroidectomy for differentiated thyroid cancer: a systematic review and Bayesian network meta-analysis.

BACKGROUND: Emerging remote-access surgical methods are utilized to treat differentiated thyroid cancer. The study aimed to compare the surgical integrity, safety, efficacy, and postoperative experience of patients among common surgical methods. METHODS: The PubMed, Medline, Cochrane Library, Web of Science, and EMBASE databases were searched from their inception until March 2023. Pairwise meta-analysis and Bayesian network meta-analysis were performed. The surface under the cumulative ranking curve (SUCRA) was used to illuminate the probability that each method would be the best for each outcome. RESULTS: Thirty-two studies comprising 7042 patients were included. Robotic bilateral axillo-breast approach (RBABA) and robotic gasless transaxillary approach (RGAA) retrieved fewer lymph nodes (LNs) than open thyroidectomy (OT). RBABA showed a significantly lower permanent recurrent laryngeal nerve (RLN) palsy rate than OT. According to SUCRA values, endoscopic transoral approach (EOA) ranked the highest in retrieved LNs (0.84), the proportion of stimulated serum thyroglobulin less than 1.0 ng/ml (0.77), and the pain score (0.77). Endoscopic bilateral areola approach (EBAA) ranked the highest in the transient RLN palsy rate (0.72). The endoscopic gasless transaxillary approach (EGAA) ranked the highest in the transient hypoparathyroidism rate (0.78). RBABA ranked the highest in the rate of permanent RLN palsy (0.94) and hypoparathyroidism (0.77). OT ranked the highest in operative time (0.92). CONCLUSIONS: Each surgical method of total thyroidectomy has benefits and limitations. EOA performed the best in maintaining surgical integrality and reducing the pain score, while taking a long operative time. Generally, RBABA showed the best advantage in protecting parathyroid glands and RLN but with the longest operative time. OT had the best advantage in operative time. Therefore, OT and EOA are ideal methods for patients with a higher risk of central LN metastasis. RBABA and EOA may not be suitable for elderly patients or those with high anesthesia risk.

Deep learning-based computer-aided diagnosis system for the automatic detection and classification of lateral cervical lymph nodes on original ultrasound images of papillary thyroid carcinoma: a prospective diagnostic study.

PURPOSE: This study aims to develop a deep learning-based computer-aided diagnosis (CAD) system for the automatic detection and classification of lateral cervical lymph nodes (LNs) on original ultrasound images of papillary thyroid carcinoma (PTC) patients. METHODS: A retrospective data set of 1801 cervical LN ultrasound images from 1675 patients with PTC and a prospective test set including 185 images from 160 patients were collected. Four different deep leaning models were trained and validated in the retrospective data set. The best model was selected for CAD system development and compared with three sonographers in the retrospective and prospective test sets. RESULTS: The Deformable Detection Transformer (DETR) model showed the highest diagnostic efficacy, with a mean average precision score of 86.3% in the retrospective test set, and was therefore used in constructing the CAD system. The detection performance of the CAD system was superior to the junior sonographer and intermediate sonographer with accuracies of 86.3% and 92.4% in the retrospective and prospective test sets, respectively. The classification performance of the CAD system was better than all sonographers with the areas under the curve (AUCs) of 94.4% and 95.2% in the retrospective and prospective test sets, respectively. CONCLUSIONS: This study developed a Deformable DETR model-based CAD system for automatically detecting and classifying lateral cervical LNs on original ultrasound images, which showed excellent diagnostic efficacy and clinical utility. It can be an important tool for assisting sonographers in the diagnosis process.

PGR-KITLG signaling drives a tumor-mast cell regulatory feedback to modulate apoptosis of breast cancer cells.

The immune microenvironment constructed by tumor-infiltrating immune cells and the molecular phenotype defined by hormone receptors (HRs) have been implicated as decisive factors in the regulation of breast cancer (BC) progression. Here, we found that the infiltration of mast cells (MCs) informed impaired prognoses in HR(+) BC but predicted improved prognoses in HR(-) BC. However, molecular features of MCs in different BC remain unclear. We next discovered that HR(-) BC cells were prone to apoptosis under the stimulation of MCs, whereas HR(+) BC cells exerted anti-apoptotic effects. Mechanistically, in HR(+) BC, the KIT ligand (KITLG), a major mast cell growth factor in recruiting and activating MCs, could be transcriptionally upregulated by the progesterone receptor (PGR), and elevate the production of MC-derived granulin (GRN). GRN attenuates TNFα-induced apoptosis in BC cells by competitively binding to TNFR1. Furthermore, disruption of PGR-KITLG signaling by knocking down PGR or using the specific KITLG-cKIT inhibitor iSCK03 potently enhanced the sensitivity of HR(+) BC cells to MC-induced apoptosis and exerted anti-tumor activity. Collectively, these results demonstrate that PGR-KITLG signaling in BC cells preferentially induces GRN expression in MCs to exert anti-apoptotic effects, with potential value in developing precision medicine approaches for diagnosis and treatment.

E2F1 promotes Warburg effect and cancer progression via upregulating ENO2 expression in Ewing sarcoma.

Altered glucose metabolism is an important characteristic of cancer cells, which is referred to as Warburg effect or aerobic glycolysis. Ewing sarcoma (EWS) is a highly malignant tumor that occurs in children and adolescents. However, the functions of aerobic glycolysis in EWS remain to be elucidated. The present study identified a transcription factor, E2F transcription factor 1 (E2F1), as a new regulator of cancer the aerobic glycolysis and progression in EWS. The present study showed that E2F1 modulated aerobic glycolysis in EWS cells by effecting glucose uptake, lactate production and ATP generation. Altered E2F1 expression increased or decreased cell viability and invasion in EWS. Mechanistically, the results demonstrated that E2F1 may promote the Warburg effect and cancer progression in EWS via upregulating enolase 2 expression. Generally, these findings indicated that E2F1 involvement in the progression of EWS and could serve as a clinical therapeutic target in EWS.

BAHD1 serves as a critical regulator of breast cancer cell proliferation and invasion.

Breast cancer patients with lymphatic metastasis suffer from poor prognoses. There is an urgent need for controlling lymph node metastasis, but it has proven challenging so far. Here, we implemented LASSO analysis of The Cancer Genome Atlas database to identify genes related to lymph node metastasis and prognosis, and 15 genes were selected. We constructed a functional protein association network and univariate Cox regression to identify significant genes. The results showed that BAHD1 could be predictive of lymph node metastasis as well as prognosis. In vitro studies demonstrated that BAHD1 exerted appreciable effects on the proliferation, migration, and invasion capacity of breast cancer cells. Furthermore, downregulation of BAHD1 induced cell cycle arrest in G1 phase. Additionally, the mRNA levels of CCND1, CDK1 and YWHAZ were decreased upon BAHD1 silencing. These findings indicate that the expression of BAHD1 is essential in the progression of breast cancer, which may provide novel therapeutic and diagnostic clues and insights into the prevention of lymph node metastasis in breast cancer.

Factors in the occurrence and restoration of hypoparathyroidism after total thyroidectomy for thyroid cancer patients with intraoperative parathyroid autotransplantation.

Introduction: Postoperative hypoparathyroidism (POH) is the most common and important complication for thyroid cancer patients who undergo total thyroidectomy. Intraoperative parathyroid autotransplantation has been demonstrated to be essential in maintaining functional parathyroid tissue, and it has clinical significance in identifying essential factors of serum parathyroid hormone (PTH) levels for patients with parathyroid autotransplantation. This retrospective cohort study aimed to comprehensively investigate influential factors in the occurrence and restoration of POH for patients who underwent total thyroidectomy with intraoperative parathyroid autotransplantation (TTIPA). Method: This study was conducted in a tertiary referral hospital, with a total of 525 patients who underwent TTIPA. The postoperative serum PTH levels were collected after six months, and demographic characteristics, clinical features and associated operative information were analyzed. Results: A total of 66.48% (349/525) of patients who underwent TTIPA were diagnosed with POH. Multivariate logistic regression indicated that Hashimoto's thyroiditis (OR=1.93, 95% CI: 1.09-3.42), P=0.024), the number of transplanted parathyroid glands (OR=2.70, 95% CI: 1.91-3.83, P<0.001) and postoperative blood glucose levels (OR=1.36, 95% CI: 1.06-1.74, P=0.016) were risk factors for POH, and endoscopic surgery (OR=0.39, 95% CI: 0.22-0.68, P=0.001) was a protective factor for POH. Multivariate Cox regression indicated that PTG autotransplantation patients with same-side central lymph node dissection (CLND) (HR=0.50; 95% CI: 0.34-0.73, P<0.001) demonstrated a longer time for increases PTH, and female patients (HR=1.35, 95% CI: 1.00-1.81, P=0.047) were more prone to PTH increases. Additionally, PTG autotransplantation with same-side CLND (HR=0.56, 95% CI: 0.38-0.82, P=0.003) patients had a longer time to PTH restoration, and patients with endoscopic surgery (HR=1.54, 95% CI: 1.04-2.28, P=0.029) were more likely to recover within six months. Conclusion: High postoperative fasting blood glucose levels, a large number of transplanted PTGs, open surgery and Hashimoto's thyroiditis are risk factors for postoperative POH in TTIPA patients. Elevated PTH levels occur earlier in female patients and patients without CLND on the transplant side. PTH returns to normal earlier in patients without CLND and endoscopic surgery on the transplant side.

Trichinella spiralis infection decreases the diversity of the intestinal flora in the infected mouse.

BACKGROUND: Trichinella spiralis is a kind of intestinal nematode that can strongly modulate the host immune system. However, the effects of T. spiralis infection on the intestinal flora are poorly understood. This study aimed to explore the effect of T. spiralis infection on the intestinal flora. METHODS: The intestinal contents of T. spiralis infected mice were examined through high-throughput sequencing (Illumina) of the V3-V4 hypervariable region in bacterial 16S rRNA gene. The sequences were analyzed using the QIIME software package and other bioinformatics methods. RESULTS: Altogether 2,899,062 sequences were generated from the samples collected from different intestinal regions at various infection time points; the 44,843 Operational Taxonomic Unit (OTUs) analysis showed that T. spiralis infection would decrease the diversity of intestinal flora in the infected mice relative to that in the uninfected ones, especially in the large intestine and feces. Further analysis indicated that, the genera Oscillospira from the phylum Firmicutes showed a higher abundance in the helminth-infected small and larger intestines; the genera Bacteroides from the phyla Bacteroides, the genera Lactobacillus from the phyla Firmicutes, the genera Escherichia from the phyla Proteobacteria, and the genera Akkermansia from the phyla Verrucomicrobia displayed increased abundances in the T. spiralis positive fecal samples compared with those in the negative samples. CONCLUSIONS: T. spiralis infection decreases the diversity of the intestinal flora in the infected mouse. However, it remains unclear about the association between the changes in intestinal flora caused by T. spiralis infection and the parasite pathogenesis, which should be further examined.

Metabolic heterogeneity and immunocompetence of infiltrating immune cells in the breast cancer microenvironment (Review).

Breast cancer is one of the most common malignancies in women and is characterized by active immunogenicity. Immune cell infiltration plays an important role in the development of breast cancer. The degree of infiltration influences both the response to and effect of treatment. However, immune infiltration is a complex process. Differences in oxygen partial pressure, blood perfusion and nutrients in the tumor microenvironment (TME) suggest that infiltrating immune cells in different sites experience different microenvironments with corresponding changes in the metabolic mode, that is, immune cell metabolism is heterogenous in the TME. Furthermore, the present review found that lipid metabolism can support the immunosuppressive microenvironment in breast cancer based on a review of published literature. Research in this field is still ongoing; however, it is vital to understand the metabolic patterns and effects of different microenvironments for antitumor therapy. Therefore, this review discusses the metabolic responses of various immune cells to different microenvironments in breast cancer and provides potentially meaningful insights for tumor immunotherapy.

Alteration in Oral Microbiome Among Men Who Have Sex With Men With Acute and Chronic HIV Infection on Antiretroviral Therapy.

Despite the antiretroviral therapy (ART), human immunodeficiency virus (HIV)-related oral disease remains a common problem for people living with HIV (PLWH). Evidence suggests that impairment of immune function in HIV infection might lead to the conversion of commensal bacteria to microorganisms with increased pathogenicity. However, limited information is available about alteration in oral microbiome in PLWH on ART. We performed a longitudinal comparative study on men who have sex with men (MSM) with acute HIV infection (n=15), MSM with chronic HIV infection (n=15), and HIV-uninfected MSM controls (n=15). Throat swabs were collected when these subjects were recruited (W0) and 12 weeks after ART treatment (W12) from the patients. Genomic DNAs were extracted and 16S rRNA gene sequencing was performed. Microbiome diversity was significantly decreased in patients with acute and chronic HIV infections compared with those in controls at the sampling time of W0 and the significant difference remained at W12. An increased abundance of unidentified Prevotellaceae was found in patients with acute and chronic HIV infections. Moreover, increased abundances of Prevotella in subjects with acute HIV infection and Streptococcus in subjects with chronic HIV infection were observed. In contrast, greater abundance in Lactobacillus, Rothia, Lautropia, and Bacteroides was found in controls. After effective ART, Bradyrhizobium was enriched in both acute and chronic HIV infections, whereas in controls, Lactobacillus, Rothia, Clostridia, Actinobacteria, and Ruminococcaceae were enriched. In addition, we found that lower CD4+ T-cell counts (<200 cells/mm3) were associated with lower relative abundances of Haemophilus, Actinomyces, unidentified Ruminococcaceae, and Rothia. This study has shown alteration in oral microbiome resulting from HIV infection and ART. The results obtained warrant further studies in a large number of subjects with different ethnics. It might contribute to improved oral health in HIV-infected individuals.

[Fingerprint analysis of Dipsacus asperoides by HPLC].

OBJECTIVE: To establish the HPLC fingerprints of Dipsacus asperoides for reflecting the internal information, evaluating its internal quality. METHODS: 20 batches of D. asperoides were collected from different place with the HPLC fingerprints method. Chromatographic column: Welchrom-C18 (250 mm x 4. 6 mm, 5 microm), mobile phase: acetonitrile and water (gradient elution), flow rate: 1.0 mL/min, detection wavelength: 212 nm, column temperature: 35 degrees C. RESULTS: The common mode of HPLC fingerprint was established and similar degrees to D. asperoides from different areas were compared. CONCLUSION: The method is stable, reliable, and with full information which can be used for quality evaluation, quality control item and crude drug identification of D. asperoides.

Low Mannose Binding Lectin, but Not L-Ficolin, Is Associated With Spontaneous Clearance of Hepatitis C Virus After Infection.

Some individuals can spontaneously clear the hepatitis C virus (HCV) after infection, whereas others develop a chronic infection. The exact mechanism of this phenomenon is unknown. We aimed to evaluate the association of plasma levels of MBL, L-ficolin, and cytokines with outcome of HCV infections in two groups of patients who cleared HCV spontaneously (CHS), and who developed chronic HCV infections (CHC). Altogether, 86 patients and 183 healthy controls were included. Of 86 patients, 36 had CHS and 50 had CHC. Concentrations of plasma MBL and L-ficolin were measured in patients and controls. Twenty plasma cytokines and adhesion molecules, including GM-CSF, ICAM-1, IFN-γ, IFN-α, IL-1α, IL-1ß, IL-10, IL-12p70, IL-13, IL-17A, IL-4, IL-8, IP-10, MCP-1, IL-6, MIP-1α, MIP-1ß, sE-Selectin, sP-Selectin, and TNF-α, were determined in all patients and randomly selected 45 controls. The level of MBL was significantly lower in subjects with CHS than in healthy controls (median: 293.10 vs. 482.64 ng/ml, p = 0.008), whereas the level of MBL was significantly higher in patients with CHC than in controls (median: 681.32 vs. 482.64 ng/ml, p = 0.001). No such differences in plasma L-ficolin were observed. Plasma levels of all cytokines and adhesion molecules, except ICAM-1, were significantly higher in patients than in controls. Moreover, patients with CHC had significantly higher levels of IFN-γ, IFN-α, IL-1α, IL-10, IL-13, IL-4, IL-6, and TNF-α than those with CHS. These findings implicate that lower levels of plasma MBL, together with lower levels of above mentioned cytokines may play a part in virus clearance of HCV infection.

Effects of TLR7 Polymorphisms on the Susceptibility and Progression of HIV-1 Infection in Chinese MSM Population.

Toll-like receptor (TLR) 7 plays a key role in innate and adaptive immunity for HIV-1 infection. We evaluated the effect of TLR7 polymorphisms on disease susceptibility and progression of HIV-1 infection in Chinese MSM (men who have sex with men). Blood samples were taken from 270 patients with laboratory confirmed HIV infection, 196 male controls were tested, and three TLR7 intronic polymorphisms (rs179010-C > T, X:12884766; rs2074109-T > C, X:12885330; and rs179009-A > G, X:12885361) were analyzed by PCR-based sequencing. The frequency of TLR7 rs179010 T allele was significantly lower in MSM patients than in controls (P = 0.039). The haplotype TTA was associated with a decreased susceptibility to HIV-1 infection (P = 0.013), especially to acute HIV-1 infection (AHI) (P = 0.002), but not to chronic HIV-1 infection (CHI). Furthermore, the haplotype TTA is linked to slow disease progression in AHI patients (P = 0.002) and a lower viral load (P = 0.042). In contrast, TLR7 rs179009 allele A contributed to a higher set point in AHI patients with rapid progression, and the frequency of rs179009 minor allele G was over-presented in CHI patients. This finding supports a role for genetic variations of TLR7 in susceptibility and disease progression of an HIV-1 infection in Chinese Han population and warrants further studies on the effect of TLR7 polymorphisms on HIV-1 infection in different populations.

Antibiotic-Induced Disruption of Gut Microbiota Alters Local Metabolomes and Immune Responses.

Gut microbiome plays an essential role in modulating host immune responses. However, little is known about the interaction of microbiota, their metabolites and relevant inflammatory responses in the gut. By treating the mice with three different antibiotics (enrofloxacin, vancomycin, and polymixin B sulfate), we aimed to investigate the effects of different antibiotics exposure on gut microbiota, microbial metabolism, inflammation responses in the gut, and most importantly, pinpoint the underlying interactions between them. Although the administration of different antibiotics can lead to different effects on mouse models, the treatment did not affect the average body weight of the mice. A heavier caecum was observed in vancomycin treated mice. Treatment by these three antibiotics significantly up-regulated gene expression of various cytokines in the colon. Enrofloxacin treated mice seemed to have an increased Th1 response in the colon. However, such a difference was not found in mice treated by vancomycin or polymixin B sulfate. Vancomycin treatment induced significant changes in bacterial composition at phylum and family level and decreased richness and diversity at species level. Enrofloxacin treatment only induced changes in composition at family presenting as an increase in Prevotellaceae and Rikenellaceae and a decrease in Bacteroidaceae. However, no significant difference was observed after polymixin B sulfate treatment. When compared with the control group, significant metabolic shift was found in the enrofloxacin and vancomycin treated group. The metabolic changes mainly occurred in Valine, leucine, and isoleucine biosynthesis pathway and beta-Alanine metabolism in enrofloxacin treated group. For vancomycin treatment metabolic changes were mainly found in beta-Alanine metabolism and Alanine, aspartate and glutamate metabolism pathway. Moreover, modifications observed in the microbiota compositions were correlated with the metabolite concentrations. For example, concentration of pentadecanoic acid was positively correlated with richness of Rikenellaceae and Prevotellaceae and negatively correlated with Enterobacteriaceae. This study suggests that the antibiotic-induced changes in gut microbiota might contribute to the inflammation responses through the alternation of metabolic status, providing a novel insight regarding a complex network that integrates the different interactions between gut microbiota, metabolic functions, and immune responses in host.