Reprogramming exosomes for immunity-remodeled photodynamic therapy against non-small cell lung cancer.

Traditional treatments against advanced non-small cell lung cancer (NSCLC) with high morbidity and mortality continue to be dissatisfactory. Given this situation, there is an urgent requirement for alternative modalities that provide lower invasiveness, superior clinical effectiveness, and minimal adverse effects. The combination of photodynamic therapy (PDT) and immunotherapy gradually become a promising approach for high-grade malignant NSCLC. Nevertheless, owing to the absence of precise drug delivery techniques as well as the hypoxic and immunosuppressive characteristics of the tumor microenvironment (TME), the efficacy of this combination therapy approach is less than ideal. In this study, we construct a novel nanoplatform that indocyanine green (ICG), a photosensitizer, loads into hollow manganese dioxide (MnO2) nanospheres (NPs) (ICG@MnO2), and then encapsulated in PD-L1 monoclonal antibodies (anti-PD-L1) reprogrammed exosomes (named ICG@MnO2@Exo-anti-PD-L1), to effectively modulate the TME to oppose NSCLC by the synergy of PDT and immunotherapy modalities. The ICG@MnO2@Exo-anti-PD-L1 NPs are precisely delivered to the tumor sites by targeting specially PD-L1 highly expressed cancer cells to controllably release anti-PD-L1 in the acidic TME, thereby activating T cell response. Subsequently, upon endocytic uptake by cancer cells, MnO2 catalyzes the conversion of H2O2 to O2, thereby alleviating tumor hypoxia. Meanwhile, ICG further utilizes O2 to produce singlet oxygen (1O2) to kill tumor cells under 808 nm near-infrared (NIR) irradiation. Furthermore, a high level of intratumoral H2O2 reduces MnO2 to Mn2+, which remodels the immune microenvironment by polarizing macrophages from M2 to M1, further driving T cells. Taken together, the current study suggests that the ICG@MnO2@Exo-anti-PD-L1 NPs could act as a novel drug delivery platform for achieving multimodal therapy in treating NSCLC.

Blap-6, a Novel Antifungal Peptide from the Chinese Medicinal Beetle Blaps rhynchopetera against Cryptococcus neoformans.

Cryptococcus neoformans (C. neoformans) is a pathogenic fungus that can cause life-threatening meningitis, particularly in individuals with compromised immune systems. The current standard treatment involves the combination of amphotericin B and azole drugs, but this regimen often leads to inevitable toxicity in patients. Therefore, there is an urgent need to develop new antifungal drugs with improved safety profiles. We screened antimicrobial peptides from the hemolymph transcriptome of Blaps rhynchopetera (B. rhynchopetera), a folk Chinese medicine. We found an antimicrobial peptide named blap-6 that exhibited potent activity against bacteria and fungi. Blap-6 is composed of 17 amino acids (KRCRFRIYRWGFPRRRF), and it has excellent antifungal activity against C. neoformans, with a minimum inhibitory concentration (MIC) of 0.81 µM. Blap-6 exhibits strong antifungal kinetic characteristics. Mechanistic studies revealed that blap-6 exerts its antifungal activity by penetrating and disrupting the integrity of the fungal cell membrane. In addition to its direct antifungal effect, blap-6 showed strong biofilm inhibition and scavenging activity. Notably, the peptide exhibited low hemolytic and cytotoxicity to human cells and may be a potential candidate antimicrobial drug for fungal infection caused by C. neoformans.

Oral Chinese Herbal Medicine plus usual care for diabetic kidney disease: study protocol for a randomized, double-blind, placebo-controlled pilot trial.

Background: Diabetic kidney disease (DKD) has become the leading cause of kidney failure, causing a significant socioeconomic burden worldwide. The usual care for DKD fails to achieve satisfactory effects in delaying the persistent loss of renal function. A Chinese herbal medicine, Tangshen Qushi Formula (TQF), showed preliminary clinical benefits with a sound safety profile for people with stage 2-4 DKD. We present the protocol of an ongoing clinical trial investigating the feasibility, efficacy, and safety of TQF compared to placebo in delaying the progressive decline of renal function for people with stage 2-4 DKD. Methods: A mixed methods research design will be used in this study. A randomized, double-blind, placebo-controlled pilot trial will evaluate the feasibility, efficacy, and safety of TQF compared to placebo on kidney function for people with stage 2-4 DKD. An embedded semi-structured interview will explore the acceptability of TQF granules and trial procedures from the participant's perspective. Sixty eligible participants with stage 2-4 DKD will be randomly allocated to the treatment group (TQF plus usual care) or the control group (TQF placebo plus usual care) at a 1:1 ratio for 48-week treatment and 12-week follow-up. Participants will be assessed every 12 weeks. The feasibility will be assessed as the primary outcome. The changes in the estimated glomerular filtration rate, urinary protein/albumin, renal function, glycemic and lipid markers, renal composite endpoint events, and dampness syndrome of Chinese medicine will be assessed as the efficacy outcomes. Safety outcomes such as liver function, serum potassium, and adverse events will also be evaluated. The data and safety monitoring board will be responsible for the participants' benefits, the data's credibility, and the results' validity. The intent-to-treat and per-protocol analysis will be performed as the primary statistical strategy. Discussion: Conducting a rigorously designed pilot trial will be a significant step toward establishing the feasibility and acceptability of TQF and trial design. The study will also provide critical information for future full-scale trial design to further generate new evidence supporting clinical practice for people with stage 2-4 DKD. Trial registration number: https://www.chictr.org.cn/, identifier ChiCTR2200062786.

MTFR2-dependent mitochondrial fission promotes HCC progression.

BACKGROUND: The role of mitochondrial dynamics, encompassing fission, fusion, and mitophagy, in cancer progression has been extensively studied. However, the specific impact of mitochondrial dynamics on hepatocellular carcinoma (HCC) is still under investigation. METHODS: In this study, mitochondrial dynamic genes were obtained from the MitoCarta 3.0 database, and gene expression data were collected from The Cancer Genome Atlas (TCGA) database. Based on the expression of these dynamic genes and differentially expressed genes (DEGs), patients were stratified into two clusters. Subsequently, a prognostic model was constructed using univariate COX regression and the least absolute shrinkage and selection operator (LASSO) regression, and the prognostic signature was evaluated. We analyzed the interaction between these model genes and dynamic genes to identify hub genes and reveal mitochondrial status. Furthermore, we assessed immune infiltration, tumor mutational burden (TMB), tumor stemness indices (TSI), and the response to immune checkpoint block (ICB) therapy using the TIDE algorithm and risk scores. Additionally, transmission electron microscopy (TEM), hematoxylin-eosin (H&E) staining, immunohistochemistry (IHC), western blotting (WB), and immunofluorescence (IF) were conducted to afford detailed visualization of the morphology of the mitochondria and the expression patterns of fission-associated proteins. RESULTS: Patients in Cluster 2 exhibited heightened mitochondrial fission and had a worse prognosis. The up-regulated dynamic genes in Cluster 2 were identified as fission genes. GO/KEGG analyses reconfirmed the connection of Cluster 2 to augmented mitochondrial fission activities. Subsequently, a ten-gene prognostic signature based on the differentially expressed genes between the two clusters was generated, with all ten genes being up-regulated in the high-risk group. Moreover, the potential links between these ten signature genes and mitochondrial dynamics were explored, suggesting their involvement in mediating mitochondrial fission through interaction with MTFR2. Further investigation revealed that the high-risk group had an unfavorable prognosis, with a higher mutation frequency of TP53, increased immune checkpoint expression, a higher TIS score, and a lower TIDE score. The mitochondrial imbalance characterized by increased fission and upregulated MTFR2 and DNM1L expression was substantiated in both HCC specimens and cell lines. CONCLUSIONS: In conclusion, we developed a novel MTFR2-related prognostic signature comprising ten mitochondrial dynamics genes. These genes play crucial roles in mitochondrial fission and have the potential to serve as important predictors and therapeutic targets for HCC.

A compact multi-pixel superconducting nanowire single-photon detector array supporting gigabit space-to-ground communications.

Classical and quantum space-to-ground communications necessitate highly sensitive receivers capable of extracting information from modulated photons to extend the communication distance from near-earth orbits to deep space explorations. To achieve gigabit data rates while mitigating strong background noise photons and beam drift in a highly attenuated free-space channel, a comprehensive design of a multi-functional detector is indispensable. In this study, we present an innovative compact multi-pixel superconducting nanowire single-photon detector array that integrates near-unity detection efficiency (91.6%), high photon counting rate (1.61 Gcps), large dynamic range for resolving different photon numbers (1-24), and four-quadrant position sensing function all within one device. Furthermore, we have constructed a communication testbed to validate the advantages offered by such an architecture. Through 8-PPM (pulse position modulation) format communication experiments, we have achieved an impressive maximum data rate of 1.5 Gbps, demonstrating sensitivities surpassing previous benchmarks at respective speeds. By incorporating photon number information into error correction codes, the receiver can tolerate maximum background noise levels equivalent to 0.8 photons/slot at a data rate of 120 Mbps-showcasing a great potential for daylight operation scenarios. Additionally, preliminary beam tracking tests were conducted through open-loop scanning techniques, which revealed clear quantitative dependence indicating sensitivity variations based on beam location. Based on the device characterizations and communication results, we anticipate that this device architecture, along with its corresponding signal processing and coding techniques, will be applicable in future space-to-ground communication tasks.

Reprogramming Exosomes to Escape from Immune Surveillance for Mitochondrial Protection in Hepatic Ischemia-Reperfusion Injury.

Background: Therapeutic interventions such as synthetic drugs and microRNA (miR) modulators have created opportunities for mitigating hepatic ischemia/reperfusion injury (HIRI) by alleviating mitochondrial dysfunction. However, delivering multi-therapeutic ingredients with low toxicity to hepatocytes still lags behind its development. Methods: In this study, we endowed exosomes with delivery function to concentrate on hepatocytes for multidimensionally halting mitochondria dysfunction during HIRI. Concretely, exosomes were reprogrammed with a transmembrane protein CD47, which acted as a "camouflage cloak" to mimic the "don't eat me" mechanism to escape from immune surveillance. Besides, HuR was engineered bridging to the membrane by fusing with CD47 and located in the cytoplasm for miR loading. Results: This strategy successfully delivered dual payloads to hepatocytes and efficiently protected mitochondria by inhibiting the opening of mitochondrial permeability transition pore (mPTP) and upregulating mitochondrial transcription factor A (TFAM), respectively. Conclusions: The reprogramming of exosomes with CD47 and HuR for targeted delivery of CsA and miR inhibitors represents a promising therapeutic strategy for addressing HIRI. This approach shows potential for safe and effective clinical applications in the treatment of HIRI.

Prevalence and associated factors of frailty in patients with chronic kidney disease: a cross-sectional analysis of PEAKING study.

AIM:  Frailty is common and is reported to be associated with adverse outcomes in patients with chronic diseases in Western countries. However, the prevalence of frailty remains unclear in individuals with chronic kidney disease (CKD) in China. We examined the prevalence of frailty and factors associated with frailty in patients with CKD. METHODS:  This was a cross-sectional analysis of 177 adult patients (mean age 54 ± 15 years, 52% men) with CKD from the open cohort entitled Physical Evaluation and Adverse outcomes for patients with chronic Kidney disease IN Guangdong (PEAKING). Frailty at baseline were assessed by FRAIL scale which included five items: fatigue, resistance, ambulation, illnesses, and loss of weight. Potential risk factors of frailty including age, sex, body mass index, and daily step counts recorded by ActiGraph GT3X + accelerometer were analyzed by multivariate logistic regression analysis. RESULTS: The prevalence of prefrailty and frailty was 50.0% and 11.9% in patients with stages 4-5 CKD, 29.6% and 9.3% in stage 3, and 32.1% and 0 in stages 1-2. In the multivariate logistic regression analysis, an increase of 100 steps per day (OR = 0.95, 95% CI 0.91-0.99, P = 0.01) and an increase of 5 units eGFR (OR = 0.82, 95% CI 0.68-0.99, P = 0.045) were inversely associated with being frail; higher BMI was associated with a higher likelihood of being frail (OR = 1.52, 95% CI 1.11-2.06, P = 0.008) and prefrail (OR = 1.25, 95% CI 1.10-1.42, P = 0.001). CONCLUSION:  Frailty and prefrailty were common in patients with advanced CKD. A lower number of steps per day, lower eGFR, and a higher BMI were associated with frailty in this population.

Cooperation of MLL1 and Jun in controlling H3K4me3 on enhancers in colorectal cancer.

BACKGROUND: Enhancer dysregulation is one of the important features for cancer cells. Enhancers enriched with H3K4me3 have been implicated to play important roles in cancer. However, their detailed features and regulatory mechanisms have not been well characterized. RESULTS: Here, we profile the landscape of H3K4me3-enriched enhancers (m3Es) in 43 pairs of colorectal cancer (CRC) samples. M3Es are widely distributed in CRC and averagely possess around 10% of total active enhancers. We identify 1322 gain variant m3Es and 367 lost variant m3Es in CRC. The target genes of the gain m3Es are enriched in immune response pathways. We experimentally prove that repression of CBX8 and RPS6KA5 m3Es inhibits target gene expression in CRC. Furthermore, we find histone methyltransferase MLL1 is responsible for depositing H3K4me3 on the identified Vm3Es. We demonstrate that the transcription factor AP1/JUN interacts with MLL1 and regulates m3E activity. Application of a small chemical inhibitor for MLL1 activity, OICR-9429, represses target gene expression of the identified Vm3Es, enhances anti-tumor immunity and inhibits CRC growth in an animal model. CONCLUSIONS: Taken together, our study illustrates the genome-wide landscape and the regulatory mechanisms of m3Es in CRC, and reveals potential novel strategies for cancer treatment.

Image distortion by ambiguous multiple-photon detections in a superconducting nanowire single-photon imager and the correction method.

Scaling up superconducting nanowire single-photon detectors (SNSPDs) into a large array for imaging applications is the current pursuit. Although various readout architectures have been proposed, they cannot resolve multiple-photon detections (MPDs) currently, which limits the operation of the SNSPD arrays at high photon flux. In this study, we focused on the readout ambiguity of a superconducting nanowire single-photon imager applying time-of-flight multiplexing readout. The results showed that image distortion depended on both the incident photon flux and the imaging object. By extracting multiple-photon detections on idle pixels, which were virtual because of the incorrect mapping from the ambiguous readout, a correction method was proposed. An improvement factor of 1.3~9.3 at a photon flux of µ = 5 photon/pulse was obtained, which indicated that joint development of the pixel design and restoration algorithm could compensate for the readout ambiguity and increase the dynamic range.

Removal of epigenetic repressive mark on inflammatory genes in fat liver.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. The detailed epigenomic changes during fat accumulation in liver are not clear yet. Here, we performed ChIP-Seq analysis in the liver tissues of high-fat diet and regular chow diet mice and investigated the dynamic landscapes of H3K27ac and H3K9me3 marks on chromatin. We find that the activated typical enhancers marked with H3K27ac are enriched on lipid metabolic pathways in fat liver; however, super enhancers do not change much. The regions covered with H3K9me3 repressive mark seem to undergo great changes, and its peak number and intensity both decrease in fat liver. The enhancers located in lost H3K9me3 regions are enriched in lipid metabolism and inflammatory pathways; and motif analysis shows that they are potential targets for transcription factors involved in metabolic and inflammatory processes. Our study has revealed that H3K9me3 may play an important role during the pathogenesis of NAFLD through regulating the accessibility of enhancers.

Necroptosis-Related Prognostic Model for Pancreatic Carcinoma Reveals Its Invasion and Metastasis Potential through Hybrid EMT and Immune Escape.

Necroptosis, pro-inflammatory programmed necrosis, has been reported to exert momentous roles in pancreatic cancer (PC). Herein, the objective of this study is to construct a necroptosis-related prognostic model for detecting pancreatic cancer. In this study, the intersection between necroptosis-related genes and differentially expressed genes (DEGs) of pancreatic ductal adenocarcinoma (PDAC) was obtained based on GeneCards database, GEO database (GSE28735 and GSE15471), and verified using The Cancer Genome Atlas (TCGA). Next, a prognostic model with Cox and LASSO regression analysis, and divided the patients into high-risk and low-risk groups. Subsequently, the Kaplan-Meier (KM) survival curve and the receiver operating characteristic (ROC) curves were generated to assess the predictive ability of overall survival (OS) of PC patients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the potential biofunction and possible mechanical pathways. The EMTome database and an immune analysis were applied to further explore underlying mechanism. Finally, clinical samples of PDAC patients were utilized to verify the expression of model genes via immunohistochemistry (IHC), and the normal human pancreatic ductal cell line, hTERT-HPNE as well as human pancreatic ductal carcinoma cell lines, PANC-1 and PL45, were used to identify the levels of model genes by Western blot (WB) and immunofluorescence (IF) in vitro. The results showed that 13 necroptosis-related DEGs (NRDEGs) were screened based on GEO database, and finally four of five prognostic genes, including KRT7, KRT19, IGF2BP3, CXCL5, were further identified by TCGA to successfully construct a prognostic model. Univariate and multivariate Cox analysis ultimately confirmed that this prognostic model has independent prognostic significance, KM curve suggested that the OS of low-risk group was longer than high-risk group, and the area under receiver (AUC) of ROC for 1, 3, 5 years was 0.733, 0.749 and 0.667, respectively. A GO analysis illustrated that model genes may participate in cell-cell junction, cadherin binding, cell adhesion molecule binding, and neutrophil migration and chemotaxis, while KEGG showed involvement in PI3K-Akt signaling pathway, ECMreceptor interaction, IL-17 signaling pathway, TNF signaling pathway, etc. Moreover, our results showed KRT7 and KRT19 were closely related to EMT markers, and EMTome database manifested that KRT7 and KRT19 are highly expressed in both primary and metastatic pancreatic cancer, declaring that model genes promoted invasion and metastasis potential through EMT. In addition, four model genes were positively correlated with Th2, which has been reported to take part in promoting immune escape, while model genes except CXCL5 were negatively correlated with TFH cells, indicating that model genes may participate in immunity. Additionally, IHC results showed that model genes were higher expressed in PC tissues than that in adjacent tumor tissues, and WB and IF also suggested that model genes were more highly expressed in PANC-1 and PL45 than in hTERT-HPNE. Tracing of a necroptosis-related prognostic model for pancreatic carcinoma reveals its invasion and metastasis potential through EMT and immunity. The construction of this model and the possible mechanism of necroptosis in PDAC was preliminarily explored to provide reliable new biomarkers for the early diagnosis, treatment, and prognosis for pancreatic cancer patients.

Substantia Nigra Echogenicity Signal Correlated with Clinical Features in Patients with Parkinson's Disease in Xinjiang.

Background: Transcranial sonography (TCS) is a noninvasive test that can reveal structural changes in the substantia nigra (SN) in Parkinson's disease (PD). The purpose of this study was to investigate the relationship between SN signatures and clinical features in PD patients in a multiethnic region of China. Methods: A total of 147 patients with PD were included in the study, and all of whom had underwent a TCS examination. Clinical information was collected from PD patients, and motor and nonmotor symptoms were assessed using assessment scales. Results: There were differences in the substantia nigra hyperechogenicity (SNH) area between age of onset, visual hallucinations (VH), and UPDRS3.0 II scores (P < 0.05), patients with late onset PD had a greater SNH area than early onset (0.326 ± 0.352 vs. 0.171 ± 0.194), and PD patients presenting with VH had a greater SNH area than those without hallucinations (0.508 ± 0.670 vs. 0.278 ± 0.659), and further multifactorial analysis showed that a high SNH area was an independent risk factor for development of VH. The area under the ROC curve for predicting VH from the SNH area in PD patients was 0.609 (95% CI: 0.444-0.774). There was a positive correlation between the SNH area and UPDRS3.0-II scores, but further multifactorial analysis showed that SNH was not an independent predictor of the UPDRS3.0-II score. Conclusion: A high SNH area is an independent risk factor for development of VH, there is a positive correlation between the SNH area and UPDRS3.0 II score, and TCS has guiding significance in predicting clinical VH symptoms and activities of daily living in PD patients.

Blapstin, a Diapause-Specific Peptide-Like Peptide from the Chinese Medicinal Beetle Blaps rhynchopetera, Has Antifungal Function.

Drug resistance against bacteria and fungi has become common in recent years, and it is urgent to discover novel antimicrobial peptides to manage this problem. Many antimicrobial peptides from insects have been reported to have antifungal activity and are candidate molecules in the treatment of human diseases. In the present study, we characterized an antifungal peptide named blapstin that was isolated from the Chinese medicinal beetle Blaps rhynchopetera used in folk medicine. The complete coding sequence was cloned from the cDNA library prepared from the midgut of B. rhynchopetera. It is a 41-amino-acid diapause-specific peptide (DSP)-like peptide stabilized by three disulfide bridges and shows antifungal activity against Candida albicans and Trichophyton rubrum with MICs of 7 µM and 5.3 µM, respectively. The C. albicans and T. rubrum treated with blapstin showed irregular and shrunken cell membranes. In addition, blapstin inhibited the activity of C. albicans biofilm and showed little hemolytic or toxic activity on human cells and it is highly expressed in the fat body, followed by the hemolymph, midgut, muscle, and defensive glands. These results indicate that blapstin may help insects fight against fungi and showed a potential application in the development of antifungal reagents. IMPORTANCE Candida albicans is one of the conditional pathogenic fungi causing severe nosocomial infections. Trichophyton rubrum and other skin fungi are the main pathogens of superficial cutaneous fungal diseases, especially in children and the elderly. At present, antibiotics such as amphotericin B, ketoconazole, and fluconazole are the main drugs for the clinical treatment of C. albicans and T. rubrum infections. However, these drugs have certain acute toxicity. Long-term use can increase kidney damage and other side effects. Therefore, obtaining broad-spectrum antifungal drugs with high efficiency and low toxicity for the treatment of C. albicans and T. rubrum infections is a top priority. Blapstin is an antifungal peptide which shows activity against C. albicans and T. rubrum. The discovery of blapstin provides a novel clue for our understanding of the innate immunity of Blaps rhynchopetera and provides a template for designing antifungal drugs.

Intelligent recognition of CTCs from gallbladder cancer by ultrasensitive electrochemical cytosensor and diagnosis of chemotherapeutic resistance.

Gallbladder carcinoma (GBC) is one of most aggressive and lethal malignancies. Early diagnosis of GBC is crucial for determining appropriate treatment and improving chances of cure. Chemotherapy represents the main therapeutic regimen for unresectable GBC patients to inhibit tumor growth & metastasis. But, chemoresistance is the major cause of GBC recurrence. Thus, there is an urgent need to explore potentially non-invasive and point-of-care approaches to screen GBC and monitor their chemoresistance. Herein, we established an electrochemical cytosensor to specifically detect circulating tumor cells (CTCs) and their chemoresistance. Trilayer of CdSe/ZnS quantum dots (QDs) were cladded upon SiO2 nanoparticles (NPs), forming Tri-QDs/PEI@SiO2 electrochemical probes. Upon conjugation of anti-ENPP1, the electrochemical probes were able to specifically label captured CTCs from GBC. The detection of CTCs and chemoresistance were realized by square wave anodic stripping voltammetric (SWASV) responses to anodic stripping current of Cd 2+ ion when cadmium in electrochemical probes was dissolved and eventually electrodeposited on bismuth film-modified glassy carbon electrode (BFE). Taking use of this cytosensor, one ensured the screening of GBC and limit of detection for CTCs approaches to ～10 cells/mL. Furthermore, by monitoring phenotypic changes of CTCs after drug treatment, the diagnosis of chemoresistance was achieved by our cytosensor.

Effects of Tiaopi Xiezhuo decoction on constipation and gut dysbiosis in patients with peritoneal dialysis.

CONTEXT: A Chinese herbal formula, Tiaopi Xiezhuo decoction (TXD), is developed from a classical Chinese prescription Sanhuang Xiexin decoction. OBJECTIVE: To investigate the regulatory effect of TXD on gut dysbiosis, as a treatment of constipation in patients with peritoneal dialysis (PD). MATERIALS AND METHODS: The chemical content of TXD was assessed by high-performance liquid chromatography. A total of 29 PD patients were enrolled and treated with TXD orally (3 g crude drug/each/twice/day) for 3 months. Blood and faecal samples were collected at the beginning and end, to determine the changes in biochemical characteristics and gut microbial composition. The stool conditions were asked to be scored. Additional 30 healthy individuals were recruited as a control for the analysis of gut microbiota. RESULTS: Although having no significant effects on serum biochemical characteristics, 3-month TXD intervention improved constipation in PD patients: decreased 80% abdominal distention (p < 0.01), increased 2.6-fold sloppy stools (p < 0.05) and eliminated hard stool completely (p < 0.01). The analysis of gut microbiota showed that, compared to the healthy group, the microbial richness was reduced in PD patients. After a 3-month TXD treatment, this reduced richness was raised, and Paraprevotella clara, Lachnospiraceae bacterium 2-146FA, Phascolarctobaterium succinatutens, Lachnospiraceae bacterium 2-1-58FAA, Fusobacterium mortiferum, and Prevotella copri were accumulated in the intestinal flora. Furthermore, the bacterial species enriched by TXD correlated with the improvement of constipation. DISCUSSION AND CONCLUSIONS: TXD treatment may improve constipation by modulating gut dysbiosis in PD patients. These findings provide data to support the further application of TXD in the adjuvant treatment of PD.

Metagenomics-based systematic analysis reveals that gut microbiota Gd-IgA1-associated enzymes may play a key role in IgA nephropathy.

Background: IgA nephropathy (IgAN) is the most common type of glomerulonephritis in Asia. Its pathogenesis involves higher expression of galactose-deficient IgA1 (Gd-IgA1) and dysregulated intestinal mucosal immunity. The objective of this study was to explore whether specific gut microbiota and associated enzymes affect Gd-IgA1 in IgAN. Methods: This study carried out shotgun metagenomic sequencing with Illumina on fecal samples collected from 20 IgAN patients (IgAN group) and 20 healthy controls (HCs group) who were recruited from January 2016 to December 2018 at the Second Clinical College of Guangzhou University of Chinese Medicine. Differences analysis in gut microbiota was performed to determine the overall microbiota composition, the representative enterotypes, and the microbiota abundance. Correlations between gut microbiota and clinical indicators were assessed by Spearman's analysis. Moreover, the functional prediction of microbial communities and the quantitative calculation of enzymes encoded by microbiome were performed using the MetaCyc pathway and the bioBakery three platform, respectively. Results: Bacteroides plebeius and Bacteroides vulgatus levels were higher, while Prevotella copri and Alistipes putredinis levels were lower in the IgAN group compared to HCs group. Enterotype I characterized by Bacteroides was closely related to the IgAN patients. Moreover, Bacteroides fragilis, Flavonifractor plautii and Ruminococcus gnavus were characteristic bacteria enriched in IgAN patients. Spearman's correlation analysis found that Eggerthella lenta and Ruminococcus bromii were positively correlated with urine protein-creatinine ratio, while Ruminococcus gnavus showed a direct association with red blood cells in urine, and Bacteroides vulgatus and Ruminococcus gnavus were positively correlated with eGFR. These results indicated that intestinal dysbacteriosis occurred in IgAN patients and was associated with clinical and biochemical features. In addition, MetaCyc pathway analysis predicted microbiota-related metabolic pathways, including the biosynthesis of amino acids and glycans, were associated with the IgAN group. Microbial enzymes analysis highlighted that Gd-IgA1-associated α-galactosidase and α-N-acetyl-galactosaminidase secreted by Flavonifractor plautii were enriched in IgAN patients. Conclusion: These findings suggested that α-galactosidase and α-N-acetyl-galactosaminidase secreted by Flavonifractor plautii might be related to the production of Gd-IgA1, indicating that enzymes originated from abnormal intestinal microbiota may contribute to the production of Gd-IgA1 and play an important role in the pathogenesis of IgAN.

64-Pixel Mo80Si20 superconducting nanowire single-photon imager with a saturated internal quantum efficiency at 1.5 µm.

A superconducting nanowire single-photon imager (SNSPI) uses a time-multiplexing method to reduce the readout complexity. However, due to the serial connection, the nanowire should be uniform so that a common bias can set all segments of the nanowire to their maximum detection efficiency, which becomes more challenging as the scalability (i.e., the length of the nanowire) increases. Here, we have developed a 64-pixel SNSPI based on amorphous Mo80Si20 film, which yielded a uniform nanowire and slow transmission line. Adjacent detectors were separated by delay lines, giving an imaging field of 270 µm × 240 µm. Benefiting from the high kinetic inductance of Mo80Si20 films, the delay line gave a phase velocity as low as 4.6 µm/ps. The positions of all pixels can be read out with a negligible electrical cross talk of 0.02% by using cryogenic amplifiers. The timing jitter was 100.8 ps. Saturated internal quantum efficiency was observed at a wavelength of 1550 nm. These results demonstrate that amorphous film is a promising material for achieving SNSPIs with large scalability and high efficiency.

NLRP6-Dependent Pyroptosis-Related lncRNAs Predict the Prognosis of Hepatocellular Carcinoma.

Pyroptosis, a novel pro-inflammatory type of programmed cell death, is involved in the tumorigenesis of various cancers. Recent findings have implicated long non-coding RNAs (lncRNAs) in the serial steps of cancer development. However, the expression and prognostic signatures of pyroptosis-related lncRNAs in hepatocellular carcinoma (HCC) remain largely unknown. Therefore, a pyroptosis-related lncRNA prognostic model was constructed for HCC. Thirty-four pyroptosis-related genes were obtained from previous reviews, and gene expression data were collected from The Cancer Genome Atlas (TCGA) database. Spearman's correlation test was used to identify potential pyroptosis-related lncRNAs. Cox and LASSO regression analyses were used to construct a prognostic model. Subsequently, receiver operating characteristic (ROC) curves were constructed to assess the model's predictive ability for the overall survival (OS) of HCC patients. CytoHubba was used to screen out the potential hub gene, whose expression was verified using clinical samples from HCC patients. Finally, nine pyroptosis-related differentially expressed lncRNAs in HCC were identified, and a prognostic model with four pyroptosis-related lncRNAs was constructed with an area under the ROC curve (AUC) of approximately 0.734. Single-sample gene set enrichment analysis and TCGA revealed different immune infiltration and immune checkpoints between the two risk groups. Moreover, these lncRNAs are closely related to the pyroptosis-related gene, NLRP6, which may be considered a hub gene. NLRP6 was lower-expressed in HCC samples, and patients with lower expression of NLRP6 had the longer OS. In conclusion, NLRP6-dependent pyroptosis-related lncRNAs play important roles in tumor immunity and may be potential predictors and therapeutic targets for HCC.

A reinforced suture method for stapled gastrointestinal anastomosis to reduce gastrointestinal hemorrhage during Whipple operation in laparoscopy.

PURPOSE: Laparoscopy is being increasingly accepted for pancreaticoduodenectomy. Stapled anastomosis (SA) is used extensively to facilitate laparoscopic pancreaticoduodenectomy (LPD); however, the incidence of anastomotic bleeding after stapled gastrointestinal anastomosis is still high. METHODS: One hundred and thirty-nine patients who underwent LPD using Whipple method were enrolled in our study. We performed the SA with our reinforced method (n = 68, R method) and without the method (n = 71, NR method). We compared the clinical characteristics and anastomosis methods of patients with or without gastrointestinal-anastomotic hemorrhage (GAH), and operative parameters were also compared between the anastomotic methods. RESULTS: Of the 139 patients undergoing LPD, 15 of them developed GAH. The clinical characteristics of patients with or without GAH were not significantly different except in the anastomotic method (P < 0.001). In the univariate logistic regression analyses, only the anastomotic method was associated with GAH. Furthermore, patients with the NR method had significantly higher incidences of GAH (P < 0.001) and Clavien-Dindo grade ≥ III complications (P < 0.001). CONCLUSION: Our retrospective analysis showed that the SA performed with reinforced method might be a reform of SA without the reinforcement, as indicated by the lower incidence of GAH. However, further research is necessary to evaluate the utility of this reinforced method.

The Role of Gut Microbiota and Microbiota-Related Serum Metabolites in the Progression of Diabetic Kidney Disease.

Objective: Diabetic kidney disease (DKD) has become the major cause of end-stage renal disease (ESRD) associated with the progression of renal fibrosis. As gut microbiota dysbiosis is closely related to renal damage and fibrosis, we investigated the role of gut microbiota and microbiota-related serum metabolites in DKD progression in this study. Methods: Fecal and serum samples obtained from predialysis DKD patients from January 2017 to December 2019 were detected using 16S rRNA gene sequencing and liquid chromatography-mass spectrometry, respectively. Forty-one predialysis patients were divided into two groups according to their estimated glomerular filtration rate (eGFR): the DKD non-ESRD group (eGFR ≥ 15 ml/min/1.73 m2) (n = 22), and the DKD ESRD group (eGFR < 15 ml/min/1.73 m2) (n = 19). The metabolic pathways related to differential serum metabolites were obtained by the KEGG pathway analysis. Differences between the two groups relative to gut microbiota profiles and serum metabolites were investigated, and associations between gut microbiota and metabolite concentrations were assessed. Correlations between clinical indicators and both microbiota-related metabolites and gut microbiota were calculated by Spearman rank correlation coefficient and visualized by heatmap. Results: Eleven different intestinal floras and 239 different serum metabolites were identified between the two groups. Of 239 serum metabolites, 192 related to the 11 different intestinal flora were mainly enriched in six metabolic pathways, among which, phenylalanine and tryptophan metabolic pathways were most associated with DKD progression. Four microbiota-related metabolites in the phenylalanine metabolic pathway [hippuric acid (HA), L-(-)-3-phenylactic acid, trans-3-hydroxy-cinnamate, and dihydro-3-coumaric acid] and indole-3 acetic acid (IAA) in the tryptophan metabolic pathway positively correlated with DKD progression, whereas L-tryptophan in the tryptophan metabolic pathway had a negative correlation. Intestinal flora g_Abiotrophia and g_norank_f_Peptococcaceae were positively correlated with the increase in renal function indicators and serum metabolite HA. G_Lachnospiraceae_NC2004_Group was negatively correlated with the increase in renal function indicators and serum metabolites [L-(-)-3-phenyllactic acid and IAA]. Conclusions: This study highlights the interaction among gut microbiota, serum metabolites, and clinical indicators in predialysis DKD patients, and provides new insights into the role of gut microbiota and microbiota-related serum metabolites that were enriched in the phenylalanine and tryptophan metabolic pathways, which correlated with the progression of DKD.