Specific TLR-mediated HSP70 activation plays a potential role in host defense against the intestinal parasite Giardia duodenalis

Giardia duodenalis, an important flagellated noninvasive protozoan parasite, infects the upper small intestine and causes a disease termed giardiasis globally. Few members of the heat shock protein (HSP) family have been shown to function as potential defenders against microbial pathogens, while such information is lacking for Giardia. Here we initially screened and indicated that in vitro Giardia challenge induced a marked early upregulation of HSP70 in intestinal epithelial cells (IECs). As noted previously, apoptotic resistance, nitric oxide (NO)-dependent cytostatic effect and parasite clearance, and epithelial barrier integrity represent effective anti-Giardia host defense mechanisms. We then explored the function of HSP70 in modulating apoptosis, NO release, and tight junction (TJ) protein levels in Giardia-IEC interactions. HSP70 inhibition by quercetin promoted Giardia-induced IEC apoptosis, viability decrease, NO release reduction, and ZO-1 and occludin downregulation, while the agonist celastrol could reverse these Giardia-evoked effects. The results demonstrated that HSP70 played a previously unrecognized and important role in regulating anti-Giardia host defense via attenuating apoptosis, promoting cell survival, and maintaining NO and TJ levels. Owing to the significance of apoptotic resistance among those defense-related factors mentioned earlier, we then elucidated the anti-apoptotic mechanism of HSP70. It was evident that HSP70 could negatively regulate apoptosis in an intrinsic way via direct inhibition of Apaf-1 or ROS-Bax/Bcl-2-Apaf-1 axis, and in an extrinsic way via cIAP2-mediated inhibition of RIP1 activity. Most importantly, it was confirmed that HSP70 exerted its host defense function by downregulating apoptosis via Toll-like receptor 4 (TLR4) activation, upregulating NO release via TLR4/TLR2 activation, and upregulating TJ protein expression via TLR2 activation. HSP70 represented a checkpoint regulator providing the crucial link between specific TLR activation and anti-Giardia host defense responses. Strikingly, independent of the checkpoint role of HSP70, TLR4 activation was proven to downregulate TJ protein expression, and TLR2 activation to accelerate apoptosis. Altogether, this study identified HSP70 as a potentially vital defender against Giardia, and revealed its correlation with specific TLR activation. The clinical importance of HSP70 has been extensively demonstrated, while its role as an effective therapeutic target in human giardiasis remains elusive and thus needs to be further clarified

Radiomics signature as a new biomarker for preoperative prediction of neoadjuvant chemoradiotherapy response in locally advanced rectal cancer

PURPOSEWhether radiomics methods are useful in prediction of therapeutic response to neoadjuvant chemoradiotherapy (nCRT) is unclear. This study aimed to investigate multiple magnetic resonance imaging (MRI) sequence-based radiomics methods in evaluating therapeutic response to nCRT in patients with locally advanced rectal cancer (LARC).METHODSThis retrospective study enrolled patients with LARC (06/2014-08/2017) and divided them into nCRT-sensitive and nCRT-resistant groups according to postoperative tumor regression grading results. Radiomics features from preoperative MRI were extracted, followed by dimension reduction using the minimum redundancy maximum relevance filter. Three machine-learning classifiers and an ensemble classifier were used for therapeutic response prediction. Radiomics nomogram incorporating clinical parameters were constructed using logistic regression. The receiver operating characteristic (ROC), decision curves analysis (DCA) and calibration curves were also plotted to evaluate the prediction performance.RESULTSThe machine learning classifiers showed good prediction performance for therapeutic responses in LARC patients (n=189). The ROC curve showed satisfying performance (area under the curve [AUC], 0.830; specificity, 0.794; sensitivity, 0.815) in the validation group. The radiomics signature included 30 imaging features derived from axial T1-weighted imaging with contrast and sagittal T2-weighted imaging and exhibited good predictive power for nCRT. A radiomics nomogram integrating carcinoembryonic antigen levels and tumor diameter showed excellent performance with an AUC of 0.949 (95% confidence interval, 0.892–0.997; specificity, 0.909; sensitivity, 0.879) in the validation group. DCA confirmed the clinical usefulness of the nomogram model.CONCLUSIONThe radiomics method using multiple MRI sequences can be used to achieve individualized prediction of nCRT in patients with LARC before treatment

Mapping of Cu and Pb Contaminations in Soil Using Combined Geochemistry, Topography, and Remote Sensing: A Case Study in the Le’an River Floodplain, China

Heavy metal pollution in soil is becoming a widely concerning environmental problem in China. The aim of this study is to integrate multiple sources of data, namely total Cu and Pb contents, digital elevation model (DEM) data, remote sensing image and interpreted land-use data, for mapping the spatial distribution of total Cu and Pb contamination in top soil along the Le’an River and its branches. Combined with geographical analyses and watershed delineation, the source and transportation route of pollutants are identified. Regions at high risk of Cu or Pb pollution are suggested. Results reveal that topography is the major factor that controls the spatial distribution of Cu and Pb. Watershed delineation shows evidence that the streamflow resulting from rainfall is the major carrier of metal pollutants

Occupational exposure in swine farm defines human skin and nasal microbiota

Anthropogenic environments take an active part in shaping the human microbiome. Herein, we studied skin and nasal microbiota dynamics in response to the exposure in confined and controlled swine farms to decipher the impact of occupational exposure on microbiome formation. The microbiota of volunteers was longitudinally profiled in a 9-months survey, in which the volunteers underwent occupational exposure during 3-month internships in swine farms. By high-throughput sequencing, we showed that occupational exposure compositionally and functionally reshaped the volunteers’ skin and nasal microbiota. The exposure in farm A reduced the microbial diversity of skin and nasal microbiota, whereas the microbiota of skin and nose increased after exposure in farm B. The exposure in different farms resulted in compositionally different microbial patterns, as the abundance of Actinobacteria sharply increased at expense of Firmicutes after exposure in farm A, yet Proteobacteria became the most predominant in the volunteers in farm B. The remodeled microbiota composition due to exposure in farm A appeared to stall and persist, whereas the microbiota of volunteers in farm B showed better resilience to revert to the pre-exposure state within 9 months after the exposure. Several metabolic pathways, for example, the styrene, aminobenzoate, and N-glycan biosynthesis, were significantly altered through our PICRUSt analysis, and notably, the function of beta-lactam resistance was predicted to enrich after exposure in farm A yet decrease in farm B. We proposed that the differently modified microbiota patterns might be coordinated by microbial and non-microbial factors in different swine farms, which were always environment-specific. This study highlights the active role of occupational exposure in defining the skin and nasal microbiota and sheds light on the dynamics of microbial patterns in response to environmental conversion

Predictive value of the domain specific PLA2R antibodies for clinical remission in patients with primary membranous nephropathy: A retrospective study.

BackgroundM-type phospholipase A2 receptor (PLA2R) is a major auto-antigen of primary membranous nephropathy(PMN). Anti-PLA2R antibody levels are closely associated with disease severity and therapeutic effectiveness. Analysis of PLA2R antigen epitope reactivity may have a greater predictive value for remission compared with total PLA2R-antibody level. This study aims to elucidate the relationship between domain-specific antibody levels and clinical outcomes of PMN.MethodsThis retrospective analysis included 87 patients with PLA2R-associated PMN. Among them, 40 and 47 were treated with rituximab (RTX) and cyclophosphamide (CTX) regimen, respectively. The quantitative detection of -immunoglobulin G (IgG)/-IgG4 targeting PLA2R and its epitope levels in the serum of patients with PMN were obtained through time-resolved fluorescence immunoassays and served as biomarkers in evaluating the treatment effectiveness. A predictive PMN remission possibility nomogram was developed using multivariate logistic regression analysis. Discrimination in the prediction model was assessed using the area under the receiver operating characteristic curve (AUC-ROC).Bootstrap ROC was used to evaluate the performance of the prediction model.ResultsAfter a 6-month treatment period, the remission rates of proteinuria, including complete remission and partial remission in the RTX and CTX groups, were 70% and 70.21% (P = 0.983), respectively. However, there was a significant difference in immunological remission in the PLA2R-IgG4 between the RTX and CTX groups (21.43% vs. 61.90%, P = 0.019). Furthermore, we found differences in PLA2R-CysR-IgG4(P = 0.030), PLA2R-CTLD1-IgG4(P = 0.005), PLA2R-CTLD678-IgG4(P = 0.003), and epitope spreading (P = 0.023) between responders and non-responders in the CTX group. Multivariate logistic analysis showed that higher levels of urinary protein (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.26-0.95; P = 0.035) and higher levels of PLA2R-CTLD1-IgG4 (OR, 0.79; 95%CI,0.62-0.99; P = 0.041) were independent risk factors for early remission. A multivariate model for estimating the possibility of early remission in patients with PMN is presented as a nomogram. The AUC-ROC of our model was 0.721 (95%CI, 0.601-0.840), in consistency with the results obtained with internal validation, for which the AUC-ROC was 0.711 (95%CI, 0.587-0.824), thus, demonstrating robustness.ConclusionsCyclophosphamide can induce immunological remission earlier than rituximab at the span of 6 months. The PLA2R-CTLD1-IgG4 has a better predict value than total PLA2R-IgG for remission of proteinuria at the 6th month