Transcriptomic insights unveil the crucial roles of cytochromes, NADH, and pili in Ag(I) reduction by Geobacter sulfurreducens.

Silver (Ag) is a pivotal transition metal with applications in multiple industries, necessitating efficient recovery techniques. Despite various proposed methods for silver recovery from wastewaters, challenges persist especially for low concentrations. In this context, bioreduction by bacteria like Geobacter sulfurreducens, offers a promising approach by converting Ag(I) to Ag nanoparticles. To reveal the mechanisms driving microbial Ag(I) reduction, we conducted transcriptional profiling of G. sulfurreducens under Ag(I)-reducing condition. Integrated transcriptomic and protein-protein interaction network analyses identified significant transcriptional shifts, predominantly linked to c-type cytochromes, NADH, and pili. When compared to a pilus-deficient strain, the wild-type strain exhibited distinct cytochrome gene expressions, implying specialized functional roles. Additionally, despite a down-regulation in NADH dehydrogenase genes, we observed up-regulation of specific downstream cytochrome genes, highlighting NADH's potential role as an electron donor in the Ag(I) reduction process. Intriguingly, our findings also highlight the significant influence of pili on the morphology of the resulting Ag nanoparticles. The presence of pili led to the formation of smaller and more crystallized Ag nanoparticles. Overall, our findings underscore the intricate interplay of cytochromes, NADH, and pili in Ag(I) reduction. Such insights suggest potential strategies for further enhancing microbial Ag(I) reduction.

Advancements of Macrophages Involvement in Pathological Progression of Colitis-Associated Colorectal Cancer and Associated Pharmacological Interventions.

Intestinal macrophages play crucial roles in both intestinal inflammation and immune homeostasis. They can adopt two distinct phenotypes, primarily determined by environmental cues. These phenotypes encompass the classically activated pro-inflammatory M1 phenotype, as well as the alternatively activated anti-inflammatory M2 phenotype. In regular conditions, intestinal macrophages serve to shield the gut from inflammatory harm. However, when a combination of genetic and environmental elements influences the polarization of these macrophages, it can result in an M1/M2 macrophage activation imbalance, subsequently leading to a loss of control over intestinal inflammation. This shift transforms normal inflammatory responses into pathological damage within the intestines. In patients with ulcerative colitis-associated colorectal cancer (UC-CRC), disorders related to intestinal inflammation are closely correlated with an imbalance in the polarization of intestinal M1/M2 macrophages. Therefore, reinstating the equilibrium in M1/M2 macrophage polarization could potentially serve as an effective approach to the prevention and treatment of UC-CRC. This paper aims to scrutinize the clinical evidence regarding Chinese medicine (CM) in the treatment of UC-CRC, the pivotal role of macrophage polarization in UC-CRC pathogenesis, and the potential mechanisms through which CM regulates macrophage polarization to address UC-CRC. Our objective is to offer fresh perspectives for clinical application, fundamental research, and pharmaceutical advancement in UC-CRC.

WDR12/RAC1 axis promoted proliferation and anti-apoptosis in colorectal cancer cells.

BACKGROUND: WD repeat domain 12 (WDR12) plays a crucial role in the ribosome biogenesis pathway. However, its biological function in colorectal cancer (CRC) remains poorly understood. Therefore, this study aims to investigate the roles of WDR12 in the occurrence and progression of CRC, as well as its underlying mechanisms. METHODS: The expression of WDR12 was assessed through The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA) database. Functional experiments including Celigo assay, MTT assay, and Caspase-3/7 assay were conducted to validate the role of WDR12 in the malignant progression of CRC. Additionally, mRNA chip-sequencing and ingenuity pathway analysis (IPA) were performed to identify the molecular mechanism. RESULTS: WDR12 expression was significantly upregulated in CRC tissues compared to normal colorectal tissues. Knockdown of WDR12 reduced proliferation and promoted apoptosis of CRC cell lines in vitro and in vivo experiments. Furthermore, WDR12 expression had a significantly inverse association with diseases and functions, including cancer, cell cycle, DNA replication, recombination, cellular growth, proliferation and repair, as revealed by IPA analysis of mRNA chip-sequencing data. Moreover, the activation of cell cycle checkpoint kinases proteins in the cell cycle checkpoint control signaling pathway was enriched in the WDR12 knockdown CRC cell lines. Additionally, downregulation of rac family small GTPase 1 (RAC1) occurred upon WDR12 knockdown, thereby facilitating the proliferation and anti-apoptosis of CRC cells. CONCLUSION: Our study demonstrates that the WDR12/RAC1 axis promotes tumor progression in CRC. Therefore, WDR12 may serve as a novel oncogene and a potential target for individualized therapy in CRC. These findings provide an experimental foundation for the clinical development of drugs targeting the WDR12/RAC1 axis.

Bibliometric analysis of global research trends between gut microbiota and pancreatic cancer: from 2004 to 2023.

Background: Pancreatic cancer (PC) is one of the most lethal malignancies of the digestive system and is expected to be the second leading cause of cancer-related death in the United States by 2030. A growing body of evidence suggests that the gut microbiota (GM) is intimately involved in the clinical diagnosis, oncogenic mechanism and treatment of PC. However, no bibliometric analysis of PC and GM has been reported. Methods: The literature on PC and GM was retrieved from the Web of Science Core Collection (WoSCC) database for the period from January 1, 2004 to April 25, 2023. Microsoft Excel 2021, CiteSpace, VOSviewer, Scimago Graphica, Graphpad Prism, Origin, the R package "bibliometrics" and the bibliometric online analysis program were used to visualize the publishing trends and hot spots in this field. Results: A total of 1,449 articles were included, including 918 articles and 531 reviews. Publishing had grown rapidly since 2017, with the 2023 expected to publish 268 articles. Unsurprisingly, the United States ranked highest in terms of number of literatures, H index and average citations. The University of California System was the most active institution, but Harvard University tended to be cited the most on average. The three most influential researchers were Robert M. Hoffman, Zhao Minglei, and Zhang Yong. Cancers had published the most papers, while Nature was the most cited journal. Keyword analysis and theme analysis indicated that "tumor microenvironment," "gemcitabine-resistance," "ductal adenocarcinoma," "gut microbiota" and "diagnosis" will be the hotspots and frontiers of research in the future. Conclusion: In summary, the field is receiving increasing attention. We found that future hotspots of PC/GM research may focus on the mechanism of oncogenesis, flora combination therapy and the exploitation of new predictive biomarkers, which provides effective suggestions and new insights for scholars.

Activation of PI3K/Akt mediates the protective effect of diallyl trisulfide on doxorubicin induced cardiac apoptosis.

Diallyl trisulfide (DATS), an organosulfide compound derived from garlic, is renowned for its potent antioxidant properties, particularly in countering the generation of reactive oxygen species (ROS). It has also gained recognition as a potential agent for preventing heart-related conditions. Doxorubicin (Dox), a commonly used chemotherapeutic drug, is known to induce severe cardiac complications by promoting ROS production. Therefore, it was imperative to investigate whether DATS possesses cardioprotective capabilities against Dox-induced cardiac apoptosis and elucidate the underlying mechanisms. In this study, we observed that the intracellular ROS levels and cardiac apoptosis were heightened in H9c2 cells exposed to Dox (1 µM). However, treatment with 10 µM DATS effectively mitigated the Dox-induced ROS generation and apoptotic signaling, concurrently activating the PI3K/Akt pathway. Notably, the anti-apoptotic effects of DATS were attenuated when PI3K siRNA and the LY294002 PI3K inhibitor were employed. Furthermore, the TUNEL assay results demonstrated a significant reduction in Dox-induced apoptosis with DATS treatment. In summary, our findings indicate that DATS can activate the PI3K/Akt pathway, reducing ROS production in cardiac cells exposed to Dox, and subsequently rescue cardiac cells from apoptosis.

Impact of Type 1 Versus Type 2 Diabetes on Developing Herpes Zoster and Post-herpetic Neuralgia: A Population-based Cohort Study.

Type 2 diabetes is associated with an increased risk of herpes zoster and postherpetic neuralgia. However, the association of type 1 diabetes with herpes zoster or postherpetic neuralgia remains unclear. This retrospective cohort study using Taiwan's Health Insurance Research Database included 199,566 patients with type 1 diabetes and 1,458,331 with type 2 diabetes, identified during the period 2000 to 2012. Patients with type 1 diabetes had a significantly higher risk of developing herpes zoster than those with type 2 diabetes (p < 0.001). Across all age groups, the impact of diabetes on herpes zoster was greater in type 1 than in type 2 diabetes. Patients with both type 1 and type 2 diabetes had a 1.45-fold higher risk of post-herpetic neuralgia than those without diabetes (hazard ratio 1.45, 95% confidence interval 1.28-1.65; hazard ratio 1.45, 95% confidence interval 1.37-1.52, respectively), and there was no difference between the 2 types of diabetes (hazard ratio 1.06; 95% confidence interval 0.93-1.21). The results recommend consideration of herpes zoster vaccination at an earlier age in patients with type 1 diabetes.

Paeoniflorin found in Paeonia lactiflora root extract inhibits melanogenesis by regulating melanin-related signal transduction in B16F10 cells.

BACKGROUND: Skin pigmentation is modulated by various processes, with melanogenesis playing a key role. Melanin is synthesized by the catalysis of melanogenesis-related enzymes, such as tyrosinase and tyrosine-related proteins TRP-1 and TRP-2. Paeoniflorin is the main bioactive component of Paeonia suffruticosa Andr., Paeonia lactiflora., or Paeonia veitchii Lynch and has been used for centuries for its anti-inflammatory, anti-oxidant, and anti-carcinogenic properties. AIMS & METHODS: In this study, melanin biosynthesis in mouse melanoma (B16F10) cells was induced using α-melanocyte-stimulating hormone (α-MSH), and then cells were co-treated with paeoniflorin to evaluate its potential anti-melanogenic effect. RESULTS: α-MSH stimulation increased melanin content, tyrosinase activity, and melanogenesis-related markers in a dose-dependent manner. However, treatment with paeoniflorin reversed α-MSH-induced upregulation of melanin content and tyrosinase activity. Furthermore, paeoniflorin inhibited cAMP response element-binding protein activation and TRP-1, TRP-2, and microphthalmia-associated transcription factor protein expression in α-MSH-stimulated B16F10 cells. CONCLUSION: Overall, these findings show the potential of paeoniflorin as a depigmenting agent for cosmetic products.

m5C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization.

The significance of 5-methylcytosine (m5C) methylation in human malignancies has become an increasing focus of investigation. Here, we show that m5C regulators including writers, readers and erasers, are predominantly upregulated in urothelial carcinoma of the bladder (UCB) derived from Sun Yat-sen University Cancer Center and The Cancer Genome Atlas cohort. In addition, NOP2/Sun RNA methyltransferase family member 2 (NSUN2) as a methyltransferase and Aly/REF export factor (ALYREF) as a nuclear m5C reader, are frequently coexpressed in UCB. By applying patient-derived organoids model and orthotopic xenograft mice model, we demonstrate that ALYREF enhances proliferation and invasion of UCB cells in an m5C-dependent manner. Integration of tanscriptome-wide RNA bisulphite sequencing (BisSeq), RNA-sequencing (RNA-seq) and RNA Immunoprecipitation (RIP)-seq analysis revealed that ALYREF specifically binds to hypermethylated m5C site in RAB, member RAS oncogene family like 6 (RABL6) and thymidine kinase 1 (TK1) mRNA via its K171 domain. ALYREF controls UCB malignancies through promoting hypermethylated RABL6 and TK1 mRNA for splicing and stabilization. Moreover, ALYREF recognizes hypermethylated m5C site of NSUN2, resulting in NSUN2 upregulation in UCB. Clinically, the patients with high coexpression of ALYREF/RABL6/TK1 axis had the poorest overall survival. Our study unveils an m5C dependent cross-regulation between nuclear reader ALYREF and m5C writer NSUN2 in activation of hypermethylated m5C oncogenic RNA through promoting splicing and maintaining stabilization, consequently leading to tumor progression, which provides profound insights into therapeutic strategy for UCB.

Doxorubicin induced ROS-dependent HIF1α activation mediates blockage of IGF1R survival signaling by IGFBP3 promotes cardiac apoptosis.

Doxorubicin (Dox) causes the generation of intracellular reactive oxygen species (ROS) and inactivates insulin-like growth factor 1 (IGF1) signaling, leading to cardiomyocyte apoptosis. IGF-binding protein 3 (IGFBP3) is the most abundant circulating IGF1 carrier protein with high affinity, which has been reported to mediate ROS-induced apoptosis. Hypoxia-inducible factor 1α (HIF1A), an upstream protein of IGFBP3 is regulated by prolyl hydroxylase domain (PHD) through hydroxylation. In this study, we investigated the role of IGFBP3, HIF1A, and PHD in Dox-induced cardiac apoptosis.Cells challenged with 1 µM Dox for 24 h increased ROS generation, augmented intracellular and secreted IGFBP3 levels, and reduced IGF1 signaling. Further, we showed that Dox enhanced the extracellular association of IGF1 with IGFBP3. Moreover, echocardiography parameters, especially ejection fraction (EF) and fractional shortening (FS) were significantly reduced in ventricle tissue of Dox challenged rats. Notably, siRNA approach against IGFBP3 or an anti-IGFBP3 antibody rescued Dox-induced cardiac apoptosis, mitochondrial ROS, and the decrease in the IGF1 signaling activity. Furthermore, silencing HIF1A either using siRNA or inhibitor downregulated intracellular IGFBP3, rescued apoptosis, mitochondrial generation, and reduction in IGF1 signaling. Finally, western blot data revealed that ROS scavenger reversed Dox-induced cardiac apoptosis, increased levels of HIF1A and secreted IGFBP3, and decreased IGF1 survival signaling and PHD expression.These findings suggest that Dox-induced ROS generation suppressed PHD, which might stabilize nuclear HIF1A protein, leading to increased IGFBP3 expression and secretion. This in turn results in enhanced extracellular association of the latter with IGF1 and blocks IGF1 pro-survival signaling and may result in inducing cardiac apoptosis.

Cachexia is associated with depression, anxiety and quality of life in cancer patients.

OBJECTIVES: This study aimed to compare depression, anxiety and quality of life (QoL) between cachexia and non-cachexia patients, and explore the relationship between cachexia and depression, anxiety and QoL in patients with cancer. METHODS: A total of 528 patients from cancer centres of four hospitals were enrolled in this cross-sectional study. All patients were divided into cachexia and non-cachexia according to international consensus definition of cachexia. Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7) and Quality of Life Questionnaire-Cancer 30 (QLQ-C30) were used to evaluate depression, anxiety and QoL. RESULTS: 285 patients (53.98%) were classified as cachexia. The prevalence of depression, anxiety, severe depression and severe anxiety in cachexia was 30.2%, 18.6%, 6.7% and 8.4%, respectively, which were significantly higher than in non-cachexia (all p<0.01). Patients with cachexia obviously acquired poorer physical function (PF), role function (RF), cognitive function (CF), emotional function (EF), social function (SF) and overall QoL than non-cachexia patients (all p<0.01). Cachexia was positively associated with depression (unstandardised coefficient (B)=2.123, p<0.001) and anxiety (B=1.123, p=0.024), and had a negative relationship with PF, CF, EF, SF and overall QoL (all B<0, all p<0.05). CONCLUSIONS: Cachexia was associated with greater depression and anxiety and poorer QoL in patients with cancer, which emphasised the importance of timely identification and management of cachexia to improve the psychological problems and QoL among patients with cancer.

Integrated analysis of transcriptomic and protein-protein interaction data reveals cadmium stress response in Geobacter sulfurreducens.

Bacteria have evolved several mechanisms to resist Cd toxicity, which are crucial for Cd detoxication and have the potential to be used for bioremediation of Cd. Geobacter species are widely found in anaerobic environments and play important roles in natural biogeochemical cycles. However, the transcriptomic response of Geobacter sulfurreducens under Cd stress have not been fully elucidated. Through integrated analysis of transcriptomic and protein-protein interaction (PPI) data, we uncovered a global view of mRNA changes in Cd-induced cellular processes in this study. We identified 182 differentially expressed genes (|log2(fold change)| > 1, adjusted P < 0.05) in G. sulfurreducens exposed to 0.1 mM CdCl2 using RNA sequencing (RNA-seq). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that CdCl2 significantly affected sulfur compound metabolic processes. In addition, through PPI network analysis, hub genes related to molecular chaperones were identified to play important role in Cd stress response. We also identified a Cd-responsive transcriptional regulator ArsR2 (coded by GSU2149) and verified the function of ArsR2-ParsR2 regulatory circuit in Escherichia coli. This study provides new insight into Cd stress response in G. sulfurreducens, and identified a potential sensor element for Cd detection.

Lower urinary tract symptoms in Parkinson's disease and multiple system atrophy / 中华老年医学杂志

Parkinson's disease(PD)and multiple system atrophy(MSA)are two common Parkinsonian syndromes with overlapping clinical manifestations, and clinical differential diagnosis is difficult.Lower urinary tract symptoms are one of the common non-motor symptoms of the two diseases.The incidence of lower urinary tract symptoms in MSA is higher, the onset is earlier, and the micturition period is more prominent.The urinary dysfunction in patients with PD is mainly caused by the central mechanism, leading to overactive bladder.MSA has more extensive lesions with both central and peripheral involvement, leading to overactive bladder and severe voiding dysfunction.Urodynamics can be used to evaluate bladder and urethral function.MSA has more prominent weak detrusor activity, residual urine volume, and early changes of urethral sphincter.The treatment of lower urinary tract symptoms in patients with PD is mainly based on anticholinergic drugs to improve overactive bladder, while in MSA patients with increased residual urine volume, intermittent catheterization is the main method to improve lower urinary tract symptoms.This article reviewed the epidemiology, pathological mechanism, urodynamics and treatment of lower urinary tract symptoms of the two diseases, so as to assist in their differential diagnosis and treatment.

A comparative study on the clinical characteristics of senile Parkinson's disease with depression and unipolar depression in older adults / 中华老年医学杂志

Objective:To explore the difference of clinical characteristics between senile Parkinson's disease(PD)with depression and unipolar depression.Methods:From March 2019 to March 2020, 53 patients with Parkinson's disease depression and 57 patients with unipolar depression who were admitted to the neurology department of Beijing Hospital were continuously collected.The gender, age and education level of the patients were recorded.The course of disease and other general data of the patients with Parkinson's disease were also recorded.Depression and anxiety of the patients were evaluated by Beck Depression Inventory(BDI)and Generalized Anxiety Disorder Scale(GAD-7). Quality of life of patients with Parkinson's disease was evaluated by 8-item Parkinson's disease questionnaire(PDQ-8). Differences in the assessment results and quality of life scores between the two groups were analyzed.Results:The incidence of depression comorbid with anxiety in elderly PD patients was 52.8%(28/53), lower than that in elderly unipolar depression patients comorbid with anxiety [84.2%(48/57)]( χ2=12.664, P<0.001). The scores of activity inhibition [(1.8±0.8)points]and hyposexuality [(0.4±1.0)points]in elderly PD patients with comorbid depression were higher than that in patients with unipolar depression [(1.1±0.8)points, (0.0±0.0)points]( t=4.399, 2.942, P<0.001, =0.005). Moreover, the incidence of activity inhibition(98.1%)and hyposexuality(15.1%)in PD patients with comorbid depression was higher than that in patients with unipolar depression(78.9%, 0.0%)( χ2=9.680, 9.279, both P=0.002). The scores of self-blame [(1.0±0.8)points]and pain [(1.0±0.8)points]in elderly patients with unipolar depression were higher than those in PD patients with comorbid depression [(0.5±0.7)points, (0.9±0.7)points]( t=-3.902, -2.486, P<0.001, =0.014). Moreover, the incidence of self-blame(66.7%), irritability(78.9%)and image distortion(56.1%)in elderly patients with unipolar depression was higher than that in PD patients(35.8%, 56.6%, 35.8%)( χ2=10.447, 6.320, 4.547, P=0.001, 0.012, 0.033). The scores of PDQ-8 in PD patients with comorbid depression and anxiety [14.8(10.8, 19.0)points]( Z=-3.544, P<0.001)were higher than those in PD patients with depression only [7.0(4.8, 11.0)points]. Conclusions:The focus of depression in elderly PD patients is different from that in elderly unipolar depression patients.Elderly patients with unipolar depression are more likely to be comorbid with anxiety.Depression reduces the quality of life in PD patients, and the comorbidity of anxiety further reduces the overall quality of life in PD patients with depression.

Changes in the proportion of lymphocyte subsets and the expression of surface receptors in peripheral blood of patients with colorectal cancer / 细胞与分子免疫学杂志

Objective To identify the sets of lymphocytes that could systematically evaluate immune function of colorectal cancer patients, based on the expression of colorectal cancer T cells, natural killer (NK) cells, and NKT cell surface protein receptors. Methods Peripheral blood samples from 144 patients with colorectal cancer and 87 healthy controls were collected, and the differences in surface receptors of lymphocyte subsets in peripheral blood of patients and healthy controls were analyzed by means of flow cytometry and cell culture. Results Compared with healthy control group, the percentage of peripheral blood total lymphocytes, CD16brightCD56dimNK cells and NKT cells decreased in patients with colorectal cancer. The percentage of T cells, CD16brightCD56dimNK cells and NKT cell surface inhibitory receptors T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitor motif domains (TIGIT) increased; T cells, NK cells, NKT cell surface chemokine receptor C-C motif chemokine receptor 7 (CCR7) slightly decreased. Conclusion There are differences in the proportion of NK cell subsets and the expression profile of surface receptors in peripheral blood of patients with colorectal cancer.

Reversion of glucocorticoid-induced senescence and collagen synthesis decrease by LY294002 is mediated through p38 in skin.

Glucocorticoids (GCs) are the most common treatment for inflammatory skin disorders; however, they show several adverse side effects, including atrophy and collagen decrease following chronic treatment. In particular, transcription factors and p38 signaling for collagen synthesis have been shown to be suppressed by the active glucocorticoid receptor (GR). LY294002 (LY), a phosphoinositide 3-kinase (PI3K) inhibitor, has been reported to protect keratinocytes in epidermis against GC-induced hypoplasia; however, its protective effect in dermis remains unclear. Furthermore, clobetasol propionate (CP) is the most used commercial synthetic GC, yet studies on how CP causes side effects in dermal fibroblasts are limited. In this study, dermal atrophy was modeled using CP in human dermal fibroblasts (HDFs) and C57BL/6 mice. CP treatment significantly upregulated FK506 binding protein 5 (FKBP51), an atrophy marker (2.4 ± 0.25 and 3.3 ± 0.3 fold in in vitro and in vivo, respectively), phosphorylated GR (1.96 ± 0.08 and 2.29 ± 0.25 fold in in vitro and in vivo, respectively), decreased fibroblast proliferation (82.71 ± 1.95% in in vitro), reduced collagen synthesis (0.36 ± 0.05 and 0.3 ± 0.1 fold in in vitro and in vivo, respectively), and induced aging, all of which were reversed by LY treatment (from 1.43 ± 0.08 to 2.8 ± 0.12 fold) without showing growth inhibition and exerting the anti-inflammation of CP. Interestingly, the protective effect of LY was dose-dependently reversed by treatment with a p38 inhibitor and reached 2.9 ± 0.15 fold at dose 20 µM. Taken together, our results demonstrate that LY reduced CP-induced upregulation of the atrophy marker FKBP51, GR phosphorylation, and GR nuclear translocation via the activation of p38, whilst maintaining the anti-inflammatory effect of glucocorticoids.

Population-based Oral Cancer Service Screening Disrupted by COVID-19 Pandemic: Observational and Simulation Study

BackgroundIt is important for understanding the impact of COVID-19 pandemic on the missing opportunity for the early detection of oral cancer. This study aimed to assess the impact of COVID-19 pandemic on the existing population-based oral cancer (OC) service screening program in Taiwan. MethodsBefore and after COVID-19 pandemic design was used to assess the impact of COVID-19 on the reduction of screening rate, referral rate, and the effectiveness of this OC service screening. Data and analysis after pandemic covered non-VOC period in 2020 and VOC period in 2021 compared to the historical control before pandemic in 2019. ResultsThe screening rate decreased substantially from 26.6% before COVID-19 in 2019 to 16.7% in 2020 and 15.3% in 2021 after pandemic. The reduction of screening rate varied with months, being the most remarkable decline in March (RR=0.61, 95% CI (0.60-0.62)) and June (RR=0.09, 95% CI (0.09-0.10)) in 2021 compared with January. The referral rate was stable at 81.5% in 2020 but it was reduced to 73.1% in 2021. The reduction of screening and referral rate led to the attenuation of effectiveness of advance cancer and mortality attenuated by 4% and 5%, respectively. ConclusionCOVID-19 pandemic disrupted the screening and the referral rate and further led to statistically significant reduction in effectiveness for preventing advanced cancer and death. Appropriate prioritized strategies must be adopted to ameliorate malignant transformation and tumor upstaging due to deference from participation in the screening. FundingThis study was financially supported by Health Promotion Administration of the Ministry of Health and Welfare of Taiwan (A1091116).

Single-cell transcriptomics reveals a low CD8+ T cell infiltrating state mediated by fibroblasts in recurrent renal cell carcinoma.

PURPOSE: Recurrent renal cell carcinoma(reRCC) is associated with poor prognosis and the underlying mechanism is not yet clear. A comprehensive understanding of tumor microenvironment (TME) of reRCC may aid in designing effective anticancer therapies, including immunotherapies. Single-cell transcriptomics holds great promise for investigating the TME, however, this technique has not been used in reRCC. Here, we aimed to explore the difference in the TME and gene expression pattern between primary RCC (pRCC) and reRCC at single-cell level. EXPERIMENTAL DESIGN: We performed single-cell RNA sequencing analyses of 32,073 cells from 2 pRCC, 2 reRCC, and 3 adjacent normal kidney samples. 41 pairs of pRCC and reRCC samples were collected as a validation cohort to assess differences observed in single-cell sequencing. The prognostic significance of related cells and markers were studied in 47 RCC patients underwent immunotherapy. The function of related cells and markers were validated via in vitro and in vivo experiments. RESULTS: reRCC had reduced CD8+ T cells but increased cancer-associated fibroblasts (CAFs) infiltration compared with pRCC. Reduced CD8+ T cells and increased CAFs infiltration were significantly associated with a worse response from immunotherapy. Remarkably, CAFs showed substantial expression of LGALS1 (Gal1). In vitro, CAFs could induce CD8+ T cells apoptosis via Gal1. In vivo, knockdown of Gal1 in CAFs suppressed tumor growth, increased CD8+ T cells infiltration, reduced the proportion of apoptotic CD8+ T cells and enhanced the efficacy of immunotherapy. CONCLUSIONS: We delineated the heterogeneity of reRCC and highlighted an innovative mechanism that CAFs acted as a suppressor of CD8+ T cells via Gal1. Targeting Gal1 combined with anti-PD1 showed promising efficacy in treating RCC.

Gene cloning of a highly active phytase from Lactobacillus plantarum and further improving its catalytic activity and thermostability through protein engineering.

Phytase belongs to orthophosphate monoester hydrolase, which can catalyze the gradual hydrolysis of phytic acid to inositol phosphate. It can be added to animal feed to reduce the anti-nutritional factor of phytic acid in feed. The thermostability and specific activity of phytases are two key factors determining their potential applications. In this study, a highly active 233-aa phytase gene (LpPHY233) from Lactobacillus plantarum was cloned and expressed in Escherichia coli (E. coli), achieving 800 times higher activity than that expressed in L. plantarum. Next, the temperature characteristic and catalytic performance of LpPHY233 was improved by disulfide bond engineering and C-terminal truncation, respectively. Surprisingly, the specific activity of the C-terminal truncated mutant LpPHY200 was about 5.6 times higher than that of LpPHY233, and the optimal temperature for the mutant LpPHY233S58C/K61C introduced disulfide bond was 15 °C higher than that of LpPHY233. Moreover, these phytase mutants displayed excellent pH property and kinetic parameters, and have great application prospect in feed additives field. The molecular basis for its catalytic performance was preliminarily explained by in silico design methods. Our results provided a solid theoretical foundation for further molecular modification and industrial application of phytases.

Grey matter alterations in patients with Parkinson′s disease with different sleep disorders / 中华神经科杂志

Objective:To investigate the grey matter alterations of Parkinson′s disease (PD) patients with and without sleep disorders, and to explore the relationship between different sleep-related problems and clinical variables as well as grey matter volume (GMV) in PD.Methods:Forty-six PD patients and 38 healthy controls (HCs) were recruited from January 2018 to December 2021 in the Department of Neurology, Beijing Hospital. PD patients were divided into PD with sleep disorders (PD-S, n=26) and PD without sleep disorders (PD-nS, n=20) subgroups (cutoff points of 82 for Parkinson′s Disease Sleep Scale or less than 5 for each item was considered as an indicator of substantial sleep disorder). The Mini-Mental State Examination (MMSE), the third part of the Unified Parkinson′s Disease Rating Scale (UPDRS-Ⅲ), Hamilton Rating Scale for Anxiety (HAMA), Hamilton Rating Scale for Depression (HAMD), Non-Motor Symptoms Questionnaire (NMSQ), and Parkinson′s Disease Questionnaire-39 (PDQ-39) were used to evaluate cognitive function, motor symptoms, anxious and depressive symptoms, non-motor symptoms, and the quality of life of the patients. Optimized voxel-based morphometry was applied to the magnetic resonance imaging brain images in all participants,and multiple linear regression analysis was used to test the correlation between GMV and sleep quality in patients with PD. Results:Compared with the HCs, PD-nS patients showed decreased GMV in bilateral limbic lobe, parahippocampal gyrus, amygdala, cingulate gyrus, hippocampus, right cerebellum, bilateral frontotemporal lobe, bilateral occipital lobe and the left parietal lobe. PD-S group exhibited reduced GMV in bilateral limbic lobe, parahippocampal gyrus, amygdala, right cerebellum, bilateral frontotemporal lobe and bilateral parietal-occipital lobe, compared to the HCs. Compared with PD-nS, PD-S patients revealed higher depressive (HAMD score: 12.19±5.59 vs 6.95±3.19, t=-4.01, P<0.001), anxious (HAMA score: 12.04±5.32 vs 7.25±4.68, t=-3.18, P=0.003), and non-motor symptoms scores (NMSQ score: 12.92±5.18 vs 9.90±4.10, t=-2.14, P=0.038), poorer quality of life (PDQ-39 score: 35.31±22.01 vs 22.40±9.00, t=-2.71, P=0.010), and reduced GMV in the left insula, frontal, and parietal lobe ( P<0.001, uncorrected, cluster>100). There was a marked relationship between sleep quality and the reduced GMV of the right medial temporal gyrus (β=0.006, 95% CI 0.002-0.010, P=0.003), left middle frontal gyrus (β=0.006, 95% CI 0.002-0.010, P=0.002), the right cerebellum (β=0.014, 95% CI 0.005-0.023, P=0.003), and the right medial occipital gyrus (β=0.017, 95% CI 0.011-0.024, P<0.001). Significant grey matter changes were associated with nocturnal restlessness, mainly within the left limbic lobe, bilateral occipital lobe, the right cerebellum, and parietal lobe (β=0.008, 95% CI 0.006-0.010, P<0.001). Furthermore, nocturia in PD was related to certain grey matter atrophy, including bilateral limbic lobe, the right inferior parietal gyrus, and bilateral frontal lobe (β=0.010, 95% CI 0.008-0.013, P<0.001). The symptom of daytime dozing was correlated with GMV reduction in the right occipital lobe, the left temporal lobe (β=0.014, 95% CI 0.010-0.019, P<0.001). There were also several compensatory brain regions, including bilateral frontal lobe, the left limbic lobe and cingulate ( P<0.001, uncorrected, cluster>60). Conclusions:Sleep disturbance is common in PD, which is related to the anxious and depressive symptoms, non-motor symptoms, and the quality of life. PD patients with different sleep disorders show grey matter alterations in severeal brain regions, which are associated with sleep quality, nocturnal restlessness, psychosis, and daytime dozing.