Upgraded and Light-Up Biosensing Platform: Entropy-Driven Catalysis Circuit Manipulates the Configuration Transformation of Novel DNA Silver Nanoclusters on the Graphene Oxide Surface.

To tackle the predicament of the traditional turn-off mechanism, exploring an activated turn-on system remains an intriguing and crucial objective in biosensing fields. Herein, a dark DNA Ag nanocluster (NC) with hairpin-structured DNA containing a six-base cytosine loop (6C loop) as a template is atypically synthesized. Intriguingly, the dark DNA Ag NCs can be lit to display strong red-emission nanoclusters. Building upon these exciting findings, an unprecedented and upgraded turn-on biosensing system [entropy-driven catalysis circuit (EDCC)-Ag NCs/graphene oxide (GO)] has been created, which employs an EDCC to precisely manipulate the conformational transition of DNA Ag NCs on the GO surface from adsorption to desorption. Benefiting from the effective quenching of GO and signal amplification capability of the EDCC, the newly developed EDCC-Ag NCs/GO biosensing system displays a high signal-to-background (S/B) ratio (26-fold) and sensitivity (limit of detection as low as 0.4 pM). Meanwhile, it has good specificity, excellent stability, and reliability in both buffer and biological samples. To the best of our knowledge, it is the first example that adopts an EDCC to precisely modulate the configuration transformation of DNA Ag NCs on the GO surface to obtain a biosensor with low background, strong fluorescence, high contrast, and sensitivity. This exciting finding may provide a new route to fabricate a novel turn-on biosensor based on hairpin-templated DNA Ag NCs in the optical imaging and bioanalytical fields.

Paratesticular metastasis from colorectal adenocarcinoma presenting as hydrocele: a rare case report and literature review.

Colorectal cancer, with the liver being the most common site of distant metastasis, followed by the lungs and bones. Although reports of metastasis to the testis exist, paratesticular metastasis is extremely rare. A 37-year-old male presented with scrotal swelling. Ultrasound revealed hydrocele of the tunica vaginalis. The patient underwent routine surgical treatment, and postoperative pathology of the tunica vaginalis indicated adenocarcinoma of gastrointestinal origin. Colonoscopic biopsy confirmed adenocarcinoma of the sigmoid colon. After six months of systemic therapy, tumor reduction surgery was performed in conjunction with tunica vaginalis excision. Postoperative pathology suggested histological similarity in both sites, with immunohistochemistry results supporting the diagnosis of sigmoid colon adenocarcinoma metastasizing to the tunica vaginalis. We conducted a literature review, summarizing and discussing clinical presentations, metastatic pathways, and diagnostic approaches.

Imputation accuracy across global human populations.

Genotype imputation is now fundamental for genome-wide association studies but lacks fairness due to the underrepresentation of references from non-European ancestries. The state-of-the-art imputation reference panel released by the Trans-Omics for Precision Medicine (TOPMed) initiative improved the imputation of admixed African-ancestry and Hispanic/Latino samples, but imputation for populations primarily residing outside of North America may still fall short in performance due to persisting underrepresentation. To illustrate this point, we imputed the genotypes of over 43,000 individuals across 123 populations around the world and identified numerous populations where imputation accuracy paled in comparison to that of European-ancestry populations. For instance, the mean imputation r-squared (Rsq) for variants with minor allele frequencies between 1% and 5% in Saudi Arabians (n = 1,061), Vietnamese (n = 1,264), Thai (n = 2,435), and Papua New Guineans (n = 776) were 0.79, 0.78, 0.76, and 0.62, respectively, compared to 0.90-0.93 for comparable European populations matched in sample size and SNP array content. Outside of Africa and Latin America, Rsq appeared to decrease as genetic distances to European-ancestry reference increased, as predicted. Using sequencing data as ground truth, we also showed that Rsq may over-estimate imputation accuracy for non-European populations more than European populations, suggesting further disparity in accuracy between populations. Using 1,496 sequenced individuals from Taiwan Biobank as a second reference panel to TOPMed, we also assessed a strategy to improve imputation for non-European populations with meta-imputation, but this design did not improve accuracy across frequency spectra. Taken together, our analyses suggest that we must ultimately strive to increase diversity and size to promote equity within genetics research.

An attomolar-level electrochemical DNA biosensor based on target-triggered and entropy-driven catalytic amplification integrated with AuNPs@ZIF-8 nanocomposites for oral cancer overexpressed 1 detection.

It is of great interest and necessity to develop a nonenzymatic, simple but highly sensitive biosensor for early diagnosis of oral cancer. Present here is an electrochemical DNA biosensor which integrates a target-triggered, entropy-driven, nonenzymatic and isothermal amplification strategy with gold nanoparticles/zeolitic imidazolate frameworks-8 (AuNPs@ZIF-8) nanocomposites for ultra-sensitive detection of oral cancer-related biomarker (ORAOV 1) in saliva. It is worth noting that the nuclease is not involved in the whole reaction process, which is simple and flexible in design only using a series of linear single-stranded DNA, avoiding undesired secondary structure interference. Meanwhile, due to the synergistic effect of AuNPs and ZIF-8, AuNPs@ZIF-8 nanocomposites display high stability, excellent electrical conductivity and exceptional electrocatalytic activity, further enhancing the electrochemical signal and avoiding labeling electrochemical signal probes. Experimental results demonstrate that this electrochemical DNA biosensor has a wide linear range (1 fM ∼1 nM), a low limit of detection (163 aM), excellent specificity, superior reproducibility and stability to ORAOV 1. More importantly, the actual application of the newly developed electrochemical biosensor is exemplified in human saliva with satisfactory recoveries. Therefore, the newly developed electrochemical biosensor has a broad application prospect in the nondestructive and early screening of oral cancer.

The interaction of diet, alcohol, genetic predisposition, and the risk of breast cancer: a cohort study from the UK Biobank.

BACKGROUND: Dietary factors have consistently been associated with breast cancer risk. However, there is limited evidence regarding their associations in women with different genetic susceptibility to breast cancer, and their interaction with alcohol consumption is also not well understood. METHODS: We analyzed data from 261,853 female participants in the UK Biobank. Multivariable adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between dietary factors and breast cancer risk. Additionally, we assessed the interaction of dietary factors with alcohol consumption and polygenic risk score (PRS) for breast cancer. RESULTS: A moderately higher risk of breast cancer was associated with the consumption of processed meat (HR = 1.10, 95% CI 1.03, 1.18, p-trend = 0.016). Higher intake of raw vegetables and fresh fruits, and adherence to a healthy dietary pattern were inversely associated with breast cancer risk [HR (95% CI):0.93 (0.88-0.99), 0.87 (0.81, 0.93) and 0.93 (0.86-1.00), p for trend: 0.025, < 0.001, and 0.041, respectively]. Furthermore, a borderline significant interaction was found between alcohol consumption and the intake of processed meat with regard to breast cancer risk (P for interaction = 0.065). No multiplicative interaction was observed between dietary factors and PRS. CONCLUSION: Processed meat was positively associated with breast cancer risk, and vegetables, fruits, and healthy dietary patterns were negatively associated with breast cancer risk. We found no strong interaction of dietary factors with alcohol consumption and genetic predisposition for risk of breast cancer.

A Lightweight Recognition Method for Rice Growth Period Based on Improved YOLOv5s.

The identification of the growth and development period of rice is of great significance to achieve high-yield and high-quality rice. However, the acquisition of rice growth period information mainly relies on manual observation, which has problems such as low efficiency and strong subjectivity. In order to solve these problems, a lightweight recognition method is proposed to automatically identify the growth period of rice: Small-YOLOv5, which is based on improved YOLOv5s. Firstly, the new backbone feature extraction network MobileNetV3 was used to replace the YOLOv5s backbone network to reduce the model size and the number of model parameters, thus improving the detection speed of the model. Secondly, in the feature fusion stage of YOLOv5s, we introduced a more lightweight convolution method, GsConv, to replace the standard convolution. The computational cost of GsConv is about 60-70% of the standard convolution, but its contribution to the model learning ability is no less than that of the standard convolution. Based on GsConv, we built a lightweight neck network to reduce the complexity of the network model while maintaining accuracy. To verify the performance of Small-YOLOv5s, we tested it on a self-built dataset of rice growth period. The results show that compared with YOLOv5s (5.0) on the self-built dataset, the number of the model parameter was reduced by 82.4%, GFLOPS decreased by 85.9%, and the volume reduced by 86.0%. The mAP (0.5) value of the improved model was 98.7%, only 0.8% lower than that of the original YOLOv5s model. Compared with the mainstream lightweight model YOLOV5s- MobileNetV3-Small, the number of the model parameter was decreased by 10.0%, the volume reduced by 9.6%, and the mAP (0.5:0.95) improved by 5.0%-reaching 94.7%-and the recall rate improved by 1.5%-reaching 98.9%. Based on experimental comparisons, the effectiveness and superiority of the model have been verified.

Imputation Accuracy Across Global Human Populations.

Genotype imputation is now fundamental for genome-wide association studies but lacks fairness due to the underrepresentation of populations with non-European ancestries. The state-of-the-art imputation reference panel released by the Trans-Omics for Precision Medicine (TOPMed) initiative contains a substantial number of admixed African-ancestry and Hispanic/Latino samples to impute these populations with nearly the same accuracy as European-ancestry cohorts. However, imputation for populations primarily residing outside of North America may still fall short in performance due to persisting underrepresentation. To illustrate this point, we curated genome-wide array data from 23 publications published between 2008 to 2021. In total, we imputed over 43k individuals across 123 populations around the world. We identified a number of populations where imputation accuracy paled in comparison to that of European-ancestry populations. For instance, the mean imputation r-squared (Rsq) for 1-5% alleles in Saudi Arabians (N=1061), Vietnamese (N=1264), Thai (N=2435), and Papua New Guineans (N=776) were 0.79, 0.78, 0.76, and 0.62, respectively. In contrast, the mean Rsq ranged from 0.90 to 0.93 for comparable European populations matched in sample size and SNP content. Outside of Africa and Latin America, Rsq appeared to decrease as genetic distances to European reference increased, as predicted. Further analysis using sequencing data as ground truth suggested that imputation software may over-estimate imputation accuracy for non-European populations than European populations, suggesting further disparity between populations. Using 1496 whole genome sequenced individuals from Taiwan Biobank as a reference, we also assessed a strategy to improve imputation for non-European populations with meta-imputation, which can combine results from TOPMed with smaller population-specific reference panels. We found that meta-imputation in this design did not improve Rsq genome-wide. Taken together, our analysis suggests that with the current size of alternative reference panels, meta-imputation alone cannot improve imputation efficacy for underrepresented cohorts and we must ultimately strive to increase diversity and size to promote equity within genetics research.

A robust model for cell type-specific interindividual variation in single-cell RNA sequencing data.

The development of single-cell RNA sequencing (scRNA-seq) offers opportunities to characterize cellular heterogeneity at unprecedented resolution. Although scRNA-seq has been widely used to identify and characterize gene expression variation across cell types and cell states based on their average gene expression profiles, most studies ignore variation across individual donors. Modelling this inter-individual variation could improve statistical power to detect cell type-specific biology and inform the genes and cell types that underlying complex traits. We therefore develop a new model to detect and quantify cell type-specific variation across individuals called CTMM (Cell Type-specific linear Mixed Model). CTMM operates on cell type-specific pseudobulk expression and is fit with efficient methods that scale to hundreds of samples. We use extensive simulations to show that CTMM is powerful and unbiased in realistic settings. We also derive calibrated tests for cell type-specific interindividual variation, which is challenging given the modest sample sizes in scRNA-seq data. We apply CTMM to scRNA-seq data from human induced pluripotent stem cells to characterize the transcriptomic variation across donors as cells differentiate into endoderm. We find that almost 100% of transcriptome-wide variability between donors is differentiation stage-specific. CTMM also identifies individual genes with statistically significant stage-specific variability across samples, including 61 genes that do not have significant stage-specific mean expression. Finally, we extend CTMM to partition interindividual covariance between stages, which recapitulates the overall differentiation trajectory. Overall, CTMM is a powerful tool to characterize a novel dimension of cell type-specific biology in scRNA-seq.

Comparison of Ophiopogon japonicus and Liriope spicata var. prolifera from Different Origins Based on Multi-Component Quantification and Anticancer Activity.

The tuberous root of Ophiopogon japonicus (Thunb.) Ker-Gawl. is a well-known Chinese medicine also called Maidong (MD) in Chinese. It could be divided into "Chuanmaidong" (CMD) and "Zhemaidong" (ZMD), according to the geographic origins. Meanwhile, the root of Liriope spicata (Thunb.) Lour. var. prolifera Y. T. Ma (SMD) is occasionally used as a substitute for MD in the market. In this study, a reliable pressurized liquid extraction and HPLC-DAD-ELSD method was developed for the simultaneous determination of nine chemical components, including four steroidal saponins (ophiopojaponin C, ophiopogonin D, liriopesides B and ophiopogonin D'), four homoisoflavonoids (methylophiopogonone A, methylophiopogonone B, methylophiopogonanone A and methylophiopogonanone B) and one sapogenin (ruscogenin) in CMD, ZMD and SMD. The method was validated in terms of linearity, sensitivity, precision, repeatability and accuracy, and then applied to the real samples from different origins. The results indicated that there were significant differences in the contents of the investigated compounds in CMD, ZMD and SMD. Ruscogenin was not detected in all the samples, and liriopesides B was only found in SMD samples. CMD contained higher ophiopogonin D and ophiopogonin D', while the other compounds were more abundant in ZMD. Moreover, the anticancer effects of the herbal extracts and selected components against A2780 human ovarian cancer cells were also compared. CMD and ZMD showed similar cytotoxic effects, which were stronger than those of SMD. The effects of MD may be due to the significant anticancer potential of ophiopognin D' and homoisoflavonoids. These results suggested that there were great differences in the chemical composition and pharmacological activity among CMD, ZMD and SMD; thus, their origins should be carefully considered in clinical application.

Erratum: Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium.

[This corrects the article DOI: 10.1016/j.xhgg.2022.100099.].

Association of metabolic dysfunction-associated fatty liver disease, type 2 diabetes mellitus, and metabolic goal achievement with risk of chronic kidney disease.

Background: Although type 2 diabetes mellitus (T2DM) plays a significant role in the association between metabolic dysfunction-associated fatty liver disease (MAFLD) and chronic kidney disease (CKD), how T2DM development and glycemic deterioration affect CKD and its renal function indicators, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), remains unknown. We aimed to assess the association between MAFLD, along with T2DM, and risk of CKD, and then evaluate the effect of metabolic goal achievement in MAFLD on the risk of CKD. Methods: In this cross-sectional study, 5,594 participants were included. Multivariate logistic regression and linear regression were used to examine the association between MAFLD with its T2DM status and metabolic goal achievement and risk of CKD, as well as eGFR and UACR. Results: The MAFLD group had a higher prevalence of CKD (16.2 vs. 7.6%, P < 0.001) than the non-MAFLD group. MAFLD was independently associated with an increased risk of CKD (odds ratio [OR]: 1.35, 95% CI: 1.09-1.67) and increased eGFR and UACR. Among the three MAFLD subtypes, only the T2DM subtype exhibited significant associations with increased risk of CKD (OR: 2.85, 95% CI: 2.24-3.63), as well as increased eGFR and UACR. Glycemic deterioration in MAFLD was dose-dependently associated with an increased risk of CKD (P-trend < 0.001). Achieved metabolic goals in MAFLD decreased the risk of CKD, eGFR, and UACR; MAFLD with 2 or 3 achieved metabolic goals was not significantly associated with the risk of CKD (OR: 0.81, 95% CI: 0.59-1.12) and albuminuria. Conclusion: MAFLD was independently associated with an increased risk of CKD, as well as increased eGFR and UACR. This association is strongly driven by T2DM status. Glycemic deterioration in MAFLD was dose-dependently associated with an increased risk of CKD. Achieved metabolic goals in MAFLD decreased the risk of CKD by reducing the risk of albuminuria.

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium.

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

Phaeoisarialaianensis (Pleurotheciales, Pleurotheciaceae), a new species from freshwater habitats in China.

Background: Freshwater fungi play an indispensable role in the ecosystem and have great research value. Based on morphological and phylogenetic analyses of a concatenated dataset of ITS, LSU and SSU sequences, a new species, Phaeoisarialaianensis, was introduced as a freshwater hyphomycete from Anhui Province, China. New information: Phaeoisarialaianensis was morphologically described as erect, rigid, dark brown to black, velvety synnemata which has macronematous, septate, branched, brown to dark brown, parallel adpressed conidiophores with polyblastic, integrated, terminal, hyaline to pale brown, smooth, denticulate, sympodial conidiogenous cells and ellipsoidal to obovoid, rounded at the apex, obtuse and tapering towards base, septate, guttulate conidia. Based on molecular and morphological characteristics, it is confirmed to be a new species. All illustrations and descriptions have been provided.

2,7-Carbazole Derived Organoboron Compounds: Synthesis and Molecular Fluorescence.

Triarylboranes have drawn much attention in OLEDs owing to their remarkable solid-state luminescence properties. Here two new A-D-A type compounds, 2,7-bis(dimesitylboryl)-N-ethyl-carbazole (BCz) using triarylborane as electron acceptor and carbazole as electron donor while 2,7-bis((4-(dimesitylboryl)phenyl)ethynyl)-9-ethyl-carbazole (BPACz) using phenylacetylene as extra conjugated bridge, have been synthesized and their photoluminescence related properties in various states have been investigated both experimentally and theoretically. Both compounds show blue emission with high quantum yields, being potential candidates for blue OLED materials.

The Effectiveness of Influenza Vaccination on Chronic Obstructive Pulmonary Disease with Different Severities of Airflow Obstruction.

This retrospective study included COPD patients who attended our medical center between January and October 2018, and analyzed the outcomes of their influenza vaccination, including medical visits, hospitalization, medical expenses, and the incidence of respiratory failure. Airflow limitation was stratified according to GOLD guidelines. Overall, 543 COPD patients were enrolled, including 197, 113, 126, and 107 mild, moderate, severe, and very severe patients, respectively. Of all the participants, 238 received an influenza vaccination (43.8%), which significantly reduced hospital utilization for moderate (odds ratio [OR] 0.22, 95%CI 0.09-0.51), severe (OR 0.19, 95%CI 0.08-0.44), and very severe patients (OR 0.15, 95%CI 0.05-0.5) compared to mild patients (OR 0.51, 95%CI 0.2-1.26); reduced emergency department utilization for moderate (OR 0.33, 95%CI 0.14-0.77), severe (OR 0.22, 95%CI 0.10-0.52), and very severe patients (OR 0.30, 95%CI 0.10-0.88) compared to mild patients (OR 0.64, 95%CI 0.30-1.37); and reduced the occurrence of respiratory failure for moderate (OR 0.20, 95%CI 0.06-0.68), severe (OR 0.40, 95%CI 0.16-0.98), and very severe patients (OR 0.36, 95%CI 0.15-0.82) compared to mild patients (OR 0% CI 0.14-3.20). Influenza vaccination is more effective in COPD patients with moderate, severe, and very severe airflow obstruction than in those with mild obstruction with respect to hospital utilization, emergency department utilization, and respiratory failure.

High oxygen atmospheric packaging treatment regulates the postharvest changes of Chinese kale (Brassica oleracea var. alboglabra) during storage.

Chinese kale is one of the most popular vegetables in southern China and Asia, but it has a short shelf-life. The effect of high oxygen atmospheric packaging (HOAP) treatment on the respiration rate as well as chlorophyll content and the expression of their metabolism-related genes of the soluble proteins in Chinese kale during storage were assessed. The results showed that Chinese kale subjected to HOAP treatment showed stimulated respiration rate and regulated expression of chlorophyll metabolism-related genes, such as BrChlases, BrPPH (pheophytin pheophorbide hydrolase), BrPAO (pheidea oxygenase gene), BrRCCR (red chlorophyll catabolite reductase), and BrSAG12 (senescence-associated gene), compared to the Chinese kale in the control. The activities of chlorophyll enzymes, that is, Chlase and Mg-dechelatase, were also influenced by HOAP treatment during storage. Furthermore, the total content of soluble proteins was stimulated to accumulate, and the intensity of protein bands, detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiling, increased in HOAP-treated samples. Based on the current results, as well as the results of our previous study regarding HOAP treatment of other vegetables, we speculate that HOAP may function by regulating the respiration rate and the accumulation of functional proteins, especially chlorophyll catabolic and antioxidant enzymes, to maintain the freshness of Chinese kale during storage. PRACTICAL APPLICATION: HOAP treatment could be a potential method for delaying quality changes and extending the shelf-life of Chinese kale after harvest.

Allele frequency differentiation at height-associated SNPs among continental human populations.

Methods to detect polygenic adaptation have recently been shown to be sensitive to uncorrected stratification in GWAS, thereby casting doubts on whether polygenic adaptation is prevalent among humans. Consistent with a signal of adaptation at human height loci, the mean FST among African, East Asian, and European populations was shown to be significantly higher at height-associated SNPs than that at non-associated SNPs. This conclusion was reached, however, using height-associated SNPs ascertained from a GWAS design impacted by residual confounding due to uncorrected stratification. Specifically, we show here that the estimated effect sizes are significantly correlated with population structure across continents, potentially explaining the elevated differentiation previously reported. We alleviated these concerns of confounding by ascertaining height-associated SNPs from two biobank GWAS (UK Biobank, UKB, and Biobank Japan, BBJ), where measures to control for confounding in GWAS are more effective. Consistent with a global signature of polygenic adaptation, we found that compared to non-associated SNPs, frequencies of height-associated SNPs are indeed significantly more differentiated among continental populations from both the 1000 Genomes Project (p = 0.0012 for UKB and p = 0.0265 for BBJ), and the Human Genome Diversity Project (p = 0.0225 for UKB and p = 0.0032 for BBJ). However, we found no significant difference among continental populations in polygenic height scores. Through simulations, we found that polygenic score-based statistics could lose power in detecting polygenic adaptation in presence of independent converging selections, thereby potentially explaining the inconsistent results based on FST and polygenic scores.

Progress in the application of spider silk protein in medicine.

Spider silk protein has attracted much attention on account of its excellent mechanical properties, biodegradability, and biocompatibility. As the main protein component of spider silk, spidroin plays important role in spider spinning under natural circumstances and biomaterial application in medicine as well. Compare to the native spidroin which has a large molecular weight (>300 kDa) with highly repeat glycine and polyalanine regions, the recombinant spidroin was maintained the core amino motifs and much easier to collect. Here, we reviewed the application of recombinant spider silk protein eADF4(C16), major ampullate spidroin (MaSp), minor ampullate spidroin (MiSp), and the derivatives of recombinant spider silk protein in drug delivery system. Moreover, we also reviewed the application of spider silk protein in the field of alternative materials, repairing materials, wound dressing, surgical sutures along with advances in recombinant spider silk protein.

Chronic Adrenergic Stress Contributes to Metabolic Dysfunction and an Exhausted Phenotype in T Cells in the Tumor Microenvironment.

Metabolic dysfunction and exhaustion in tumor-infiltrating T cells have been linked to ineffectual antitumor immunity and the failure of immune checkpoint inhibitor therapy. We report here that chronic stress plays a previously unrecognized role in regulating the state of T cells in the tumor microenvironment (TME). Using two mouse tumor models, we found that blocking chronic adrenergic stress signaling using the pan ß-blocker propranolol or by using mice lacking the ß2-adrenergic receptor (ß2-AR) results in reduced tumor growth rates with significantly fewer tumor-infiltrating T cells that express markers of exhaustion, with a concomitant increase in progenitor exhausted T cells. We also report that blocking ß-AR signaling in mice increases glycolysis and oxidative phosphorylation in tumor-infiltrating lymphocytes (TIL), which associated with increased expression of the costimulatory molecule CD28 and increased antitumor effector functions, including increased cytokine production. Using T cells from Nur77-GFP reporter mice to monitor T-cell activation, we observed that stress-induced ß-AR signaling suppresses T-cell receptor (TCR) signaling. Together, these data suggest that chronic stress-induced adrenergic receptor signaling serves as a "checkpoint" of immune responses and contributes to immunosuppression in the TME by promoting T-cell metabolic dysfunction and exhaustion. These results also support the possibility that chronic stress, which unfortunately is increased in many patients with cancer following their diagnoses, could be exerting a major negative influence on the outcome of therapies that depend upon the status of TILs and support the use of strategies to reduce stress or ß-AR signaling in combination with immunotherapy.