Pharmacological targets of SGLT2 inhibitors on IgA nephropathy and membranous nephropathy: a mendelian randomization study.

Introduction: Emerging research suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors may play a pivotal role in the treatment of primary glomerular diseases. This study was aimed to investigate potential pharmacological targets connecting SGLT2 inhibitors with IgA nephropathy (IgAN) and membranous nephropathy (MN). Methods: A univariate Mendelian randomization (MR) analysis was conducted using publicly available genome-wide association studies (GWAS) datasets. Co-localization analysis was used to identify potential connections between target genes and IgAN and MN. Then, Comparative Toxicogenomics Database (CTD) was employed to predict diseases associated with these target genes and SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin). Subsequently, phenotypic scan analyses were applied to explore the causal relationships between the predicted diseases and target genes. Finally, we analyzed the immune signaling pathways involving pharmacological target genes using the Kyoto encyclopedia of genes and genomes (KEGG). Results: The results of MR analysis revealed that eight drug targets were causally linked to the occurrence of IgAN, while 14 drug targets were linked to MN. In the case of IgAN, LCN2 and AGER emerged as co-localized genes related to the pharmacological agent of dapagliflozin and the occurrence of IgAN. LCN2 was identified as a risk factor, while AGER was exhibited a protective role. KEGG analysis revealed that LCN2 is involved in the interleukin (IL)-17 immune signaling pathway, while AGER is associated with the neutrophil extracellular traps (NETs) signaling immune pathway. No positive co-localization results of the target genes were observed between two other SGLT2 inhibitors (canagliflozin and empagliflozin) and the occurrence of IgAN, nor between the three SGLT2 inhibitors and the occurrence of MN. Conclusion: Our study provided evidence supporting a causal relationship between specific SGLT2 inhibitors and IgAN. Furthermore, we found that dapagliflozin may act on IgAN through the genes LCN2 and AGER.

A novel regulatory sex-skewing method that inhibits testicular DPY30 expression to increase female rate of dairy goat offspring.

The demand for goat milk products has increased exponentially with the growth of the global population. The shortage of dairy products will be addressed extraordinarily by manipulating the female rate of goat offspring to expand the goat population and goat milk yield. No studies have reported bioinformatic analyses of X- and Y-bearing sperm of dairy goats, although this will contribute to exploring novel and applied sex-skewing technologies. Regulatory subunit of the histone methyltransferase complex (DPY30) was determined to be the key differentially expressed protein (DEP) among 15 DEPs identified in the present study. The spatiotemporal expression of DPY30 strongly suggested a functional involvement of the protein in spermatogenesis. DPY30 promoted meiosis via upregulating SYCP3, which played a crucial role in mediating sex ratio skewing in goats. Although DPY30 suppressed the self-renewal of spermatogonia stem cells through AKT/PLZF, DPY30 inhibition in the testis did not induce testicular dysgenesis. Based on the biosafety assessment in mice testes, lentivirus-mediated DPY30 knockdown in bucks' testes increased X-bearing sperm proportion and female kids' rate (22.8 percentage points) without affecting sperm quality, pregnancy rate, and kidding rate. This study provides the first evidence of the DEGs in the sexed sperm of dairy goats. DPY30 inhibition in the testes of bucks increased the female kids' rate without influencing reproductive performance. The present study provides evidence for expanding the female dairy goat population to address the concern of dairy product shortage.

Goat milk has high digestibility, high nutritional quality, low allergenicity, and potential nutraceutical properties so the valorization of goat milk into value-added products is becoming increasingly important. However, the goat's milk production was less than 20% of cow's milk. To increase production, we investigated the differentially expressed proteins in the X- and Y-bearing sperm of dairy goat to explore the new sex-skewing method. The results showed that inhibiting the expression of DPY30 in the testes of male goats significantly increased the female kids' rate (22.8 percentage points). As such, no adverse effects on sperm quality, pregnancy rate or kidding rate were observed. The DPY30 silence mediated sex-skewing was achieved by disrupting meiosis via targeting SYCP3. Our results provide new insights into the preliminary mechanisms of sex-skewing in dairy goats, which could also form the basis for the development of novel sex-skewing strategies in livestock.

Targeting ONECUT3 blocks glycolytic metabolism and potentiates anti-PD-1 therapy in pancreatic cancer.

BACKGROUND: Reprogramming glucose metabolism, also known as the Warburg effect (aerobic glycolysis), is a hallmark of cancers. Increased tumor glycolysis not only favors rapid cancer cell proliferation but reprograms the immune microenvironment to enable tumor progression. The transcriptional factor ONECUT3 plays key roles in the development of the liver and pancreas, however, limited is known about its oncogenic roles, particularly metabolic reprogramming. METHODS: Immunohistochemistry and Western blotting are applied to determine the expression pattern of ONECUT3 and its clinical relevance in pancreatic ductal adenocarcinoma (PDAC). Knockdown and overexpression strategies are employed to determine the in vitro and in vivo functions of ONECUT3. Chromatin immunoprecipitation, luciferase reporter assay, and gene set enrichment analysis are used to decipher the molecular mechanisms. RESULTS: The glycolytic metabolism is inversely associated with T-cell infiltration in PDAC. ONECUT3 is identified as a key regulator for PDAC glycolysis and CD8+ T-cell infiltration. Genetic silencing of ONECUT3 inhibits cell proliferation, promotes cell apoptosis, and reduces glycolytic metabolism as evidenced by glucose uptake, lactate production, and extracellular acidification rate. Opposite effects of ONECUT3 are observed in overexpression studies. ONECUT3 enhances aerobic glycolysis via transcriptional regulation of PDK1. Targeting ONECUT3 effectively suppresses tumor growth, increases CD8+ T-cell infiltration, and potentiates anti-PD-1 therapy in PDAC. Pharmacological inhibition of PDK1 also shows a synergistic effect with anti-PD-1 therapy. In clinical setting, ONECUT3 is closely associated with PDK1 expression and T-cell infiltration in PDAC and acts as an independent prognostic factor. CONCLUSIONS: Our study reveals a previous unprecedented regulatory role of ONECUT3 in PDAC glycolysis and provides in vivo evidence that increased glycolysis is linked to an immunosuppressive microenvironment. Moreover, targeting ONECUT3-PDK1 axis may serve as a promising therapeutic approach for the treatment of PDAC.

Enhancement of PPARα-Inhibited Leucine Metabolism-Stimulated ß-Casein Synthesis and Fatty Acid Synthesis in Primary Bovine Mammary Epithelial Cells.

Leucine, a kind of branched-chain amino acid, plays a regulatory role in the milk production of mammalian mammary glands, but its regulatory functions and underlying molecular mechanisms remain unknown. This work showed that a leucine-enriched mixture (LEUem) supplementation increased the levels of milk protein and milk fat synthesis in primary bovine mammary epithelial cells (BMECs). RNA-seq of leucine-treated BMECs indicated alterations in lipid metabolism, translation, ribosomal structure and biogenesis, and inflammatory response signaling pathways. Meanwhile, the supplementation of leucine resulted in mTOR activation and increased the expression of BCKDHA, FASN, ACC, and SCD1. Interestingly, the expression of PPARα was independently correlated with the leucine-supplemented dose. PPARα activated by WY-14643 caused significant suppression of lipogenic genes expression. Furthermore, WY-14643 attenuated leucine-induced ß-casein synthesis and enhanced the level of BCKDHA expression. Moreover, promoter analysis revealed a peroxisome-proliferator-response element (PPRE) site in the bovine BCKDHA promoter, and WY-14643 promoted the recruitment of PPARα onto the BCKDHA promoter. Together, the present data indicate that leucine promotes the synthesis of ß-casein and fatty acid and that PPARα-involved leucine catabolism is the key target.

Single-Dose Rifapentine in Household Contacts of Patients with Leprosy.

BACKGROUND: Previous studies have suggested that a single dose of rifampin has protective effects against leprosy in close contacts of patients with the disease. Rifapentine was shown to have greater bactericidal activity against Mycobacterium leprae than rifampin in murine models of leprosy, but data regarding its effectiveness in preventing leprosy are lacking. METHODS: We conducted a cluster-randomized, controlled trial to investigate whether single-dose rifapentine is effective in preventing leprosy in household contacts of patients with leprosy. The clusters (counties or districts in Southwest China) were assigned to one of three trial groups: single-dose rifapentine, single-dose rifampin, or control (no intervention). The primary outcome was the 4-year cumulative incidence of leprosy among household contacts. RESULTS: A total of 207 clusters comprising 7450 household contacts underwent randomization; 68 clusters (2331 household contacts) were assigned to the rifapentine group, 71 (2760) to the rifampin group, and 68 (2359) to the control group. A total of 24 new cases of leprosy occurred over the 4-year follow-up, for a cumulative incidence of 0.09% (95% confidence interval [CI], 0.02 to 0.34) with rifapentine (2 cases), 0.33% (95% CI, 0.17 to 0.63) with rifampin (9 cases), and 0.55% (95% CI, 0.32 to 0.95) with no intervention (13 cases). In an intention-to-treat analysis, the cumulative incidence in the rifapentine group was 84% lower than that in the control group (cumulative incidence ratio, 0.16; multiplicity-adjusted 95% CI, 0.03 to 0.87; P = 0.02); the cumulative incidence did not differ significantly between the rifampin group and the control group (cumulative incidence ratio, 0.59; multiplicity-adjusted 95% CI, 0.22 to 1.57; P = 0.23). In a per-protocol analysis, the cumulative incidence was 0.05% with rifapentine, 0.19% with rifampin, and 0.63% with no intervention. No severe adverse events were observed. CONCLUSIONS: The incidence of leprosy among household contacts over 4 years was lower with single-dose rifapentine than with no intervention. (Funded by the Ministry of Health of China and the Chinese Academy of Medical Sciences; Chinese Clinical Trial Registry number, ChiCTR-IPR-15007075.).

Probiotic has prophylactic effect on spatial memory deficits by modulating gut microbiota characterized by the inhibitory growth of Escherichia coli.

Background: The aim of this study is to interrogate the prophylactic effect of probiotic on the lead-induced spatial memory impairment, as well as the underlying mechanisms based on gut microbiota. Methods: Rats were exposed postnatally to 100 ppm of lead acetate during lactation (from postnatal day 1 to 21), to establish the memory deficits model. A probiotic bacterium, namely Lacticaseibacillus rhamnosus, was administered by drinking into pregnant rats with a dosage of 109 CFU/rat/day till birth. At postnatal week 8 (PNW8), the rats were subjected to Morris water maze and Y-maze test, with fecal samples collected for 16S rRNA sequencing. Besides, the inhibitory effect of Lb. rhamnosus on Escherichia coli was carried out in bacterial co-culture. Results: Female rats prenatally exposed to probiotic improved their performances in the behavioral test, indicating that probiotic could protect rats from memory deficits caused by postnatal lead exposure. This bioremediation activity varies depending on the intervention paradigm used. As revealed by microbiome analysis, although administered in a distinct period from lead exposure, Lb. rhamnosus further changed the microbial structure disrupted by lead exposure, suggesting an effective transgenerational intervention. Of note, gut microbiota, represented by Bacteroidota, varied greatly depending on the intervention paradigm as well as the developmental stage. The concerted alterations were revealed between some keystone taxa and behavioral abnormality, including lactobacillus and E. coli. To this end, an in vitro co-culture was created to demonstrate that Lb. rhamnosus could inhibit the growth of E. coli with direct contact, which is dependent on the growth condition under study. In addition, in vivo infection of E. coli O157 aggravated memory dysfunction, which could also be rescued by probiotic colonization. Conclusions: Early probiotic intervention could prevent organisms from lead-induced memory decline in later life through reprogramming gut microbiota and inhibiting E. coli, providing a promising approach to ameliorate the cognitive damage with environmental origins.

Prolonged Intermittent Renal Replacement Therapy Combined with Hemoperfusion Can Improve Early Recovery of Moderate and Severe Acute Pancreatitis, Especially in Patients with Acute Kidney Injury.

INTRODUCTION: The aim of this study was to investigate the efficacy of prolonged intermittent renal replacement therapy (PIRRT) plus hemoperfusion (HP) in treating moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP). METHODS: A total of 105 MSAP and SAP patients were enrolled. Sixty of them received routine internal medical therapy (control group), and 45 received PIRRT and HP in addition to routine internal medical therapy (PIRRT + HP group). The vital signs, laboratory results, and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score were compared between the two groups before treatment and on the 3rd and 7th days of treatment. RESULTS: No deaths or treatment-related serious adverse reactions occurred in both groups. After 3 and 7 days of treatment, the APACHE II score decreased more significantly in the PIRRT + HP group than in the control group (3 days: 5.47 [±3.30] vs. 7.53 [±3.89], p = 0.005. 7 days: 4.82 [±3.49] vs. 6.87 [±3.54], p = 0.004). After 3 days of treatment, the inflammatory combination parameters systemic immune-inflammation index (SII) and neutrophil-to-lymphocyte ratio (NLR) in the PIRRT + HP group decreased more significantly than those in the control group (SII: 1,239.00 [737.80-1,769.00] vs. 2,013.00 [1,260.00-3,167.00], p = 0.001. NLR: 8.78 [±4.52] vs. 11.88 [±7.30], p = 0.009). After 7 days of treatment, SII, NLR, and hypersensitive C-reactive protein decreased significantly compared with baseline, but no statistical differences between the two groups were observed. AST in both groups remained stable with treatment. There was no significant difference in baseline creatinine between the two groups of AKI patients, but after 3 and 7 days of treatment, the proportion of acute kidney injury (AKI) patients in the PIRRT + HP group whose creatinine decreased by 50% from baseline or fell to the normal range was significantly higher than that in the control group (p < 0.05). CONCLUSION: PIRRT + HP therapy could not only improve the general conditions, as measured by APACHE II score, but also reduce the inflammatory cascade of patients with acute pancreatitis. For MSAP and SAP patients complicated with AKI, this therapy may accelerate the recovery of renal function.

A 1-µm-Band Injection-Locked Semiconductor Laser with a High Side-Mode Suppression Ratio and Narrow Linewidth.

We demonstrate a narrow-linewidth, high side-mode suppression ratio (SMSR) semiconductor laser based on the external optical feedback injection locking technology of a femtosecond-apodized (Fs-apodized) fiber Bragg grating (FBG). A single frequency output is achieved by coupling and integrating a wide-gain quantum dot (QD) gain chip with a Fs-apodized FBG in a 1-µm band. We propose this low-cost and high-integration scheme for the preparation of a series of single-frequency seed sources in this wavelength range by characterizing the performance of 1030 nm and 1080 nm lasers. The lasers have a maximum SMSR of 66.3 dB and maximum output power of 134.6 mW. Additionally, the lasers have minimum Lorentzian linewidths that are measured to be 260.5 kHz; however, a minimum integral linewidth less than 180.4 kHz is observed by testing and analyzing the power spectra of the frequency noise values of the lasers.

Overexpression of hsa_circ_0006470 inhibits the malignant behavior of gastric cancer cells via regulation of miR-1234/TP53I11 axis.

Gastric cancer (GC) is a subtype of a common malignant tumor found in the digestive system. Hsa_circ_0006470 is known to be closely associated with the development of GC. Nevertheless, the mechanism by which hsa_circ_0006470 regulates the tumorigenesis of GC has not been fully elucidated. To investigate the role of hsa_circ_0006470 in GC, its expression levels were assessed in GES-1, AGS, MKN45, and SNU5 cells by reverse transcription-quantitative PCR. Fluorescence in situ hybridization was used to evaluate the localization of hsa_circ_0006470 in AGS and MKN45 cells. In addition, cell counting kit-8 and 5-ethynyl-2'-deoxyuridine assays were performed to evaluate the viability and proliferation of GC cells, respectively. The dual-luciferase reporter assay was used to explore the interaction among hsa_circ_0006470, microRNA (miR)-1234, and TP53I11. The expression levels of TP53I11, Akt, p-Akt, forkhead box O1, and cyclin dependent kinase 2 in AGS cells were analyzed by Western blotting. The data indicated that hsa_circ_0006470 expression was downregulated in AGS cells. In addition, overexpression (OE) of hsa_circ_0006470 could inhibit the viability and proliferation of GC cells. Moreover, OE of hsa_circ_0006470 inhibited the migration of GC cells and induced G1 cell cycle phase arrest. Moreover, miR-1234 was bound to hsa_circ_0006470 and TP53I11 was targeted by miR-1234. Furthermore, OE of hsa_circ_0006470 inhibited the tumorigenesis of GC via the regulation of the miR-1234/TP53I11 axis. In summary, the present study demonstrated that OE of hsa_circ_0006470 notably inhibited the tumorigenesis of GC by regulating the miR-1234/TP53I11 axis. Therefore, the present study may provide a theoretical basis for exploring novel therapeutic strategies for the treatment of GC.

Characterization of an autonomous pathway complex that promotes flowering in Arabidopsis.

Although previous studies have identified several autonomous pathway components that are required for the promotion of flowering, little is known about how these components cooperate. Here, we identified an autonomous pathway complex (AuPC) containing both known components (FLD, LD and SDG26) and previously unknown components (EFL2, EFL4 and APRF1). Loss-of-function mutations of all of these components result in increased FLC expression and delayed flowering. The delayed-flowering phenotype is independent of photoperiod and can be overcome by vernalization, confirming that the complex specifically functions in the autonomous pathway. Chromatin immunoprecipitation combined with sequencing indicated that, in the AuPC mutants, the histone modifications (H3Ac, H3K4me3 and H3K36me3) associated with transcriptional activation are increased, and the histone modification (H3K27me3) associated with transcriptional repression is reduced, suggesting that the AuPC suppresses FLC expression at least partially by regulating these histone modifications. Moreover, we found that the AuPC component SDG26 associates with FLC chromatin via a previously uncharacterized DNA-binding domain and regulates FLC expression and flowering time independently of its histone methyltransferase activity. Together, these results provide a framework for understanding the molecular mechanism by which the autonomous pathway regulates flowering time.

Simultaneous Determination of Fifteen Polyphenols in Fruit Juice Using Ultrahigh-Performance Liquid Chromatography-Tandem Mass Spectrometry Combining Dispersive Liquid-Liquid Microextraction.

Polyphenols are secondary metabolites of plants and used as effective antioxidants in dietary supplements, whose main sources are fruits, vegetables, and grains. To clarify the content and distribution of polyphenols in different fruit species samples accurately, a rapid and sensitive ultrahigh-pressure liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) method combining dispersive liquid-liquid microextraction (DLLME) was developed for quantitative determination of fifteen polyphenol compounds in fruit juice. In this method, the targets were first extracted from 1 g of fruit juice sample using 10 mL of 80% ethanol solution by ultrasonic-assisted extraction (UAE). Then, 1.0 mL of UAE extracted solution, 60 µL of n-octanol and 2.0 mL of H2O were performed in the following DLLME procedure. A C18 reversed-phase column, ZORBAX SB (100 × 4.6 mm, 3.5 µm), was proposed under gradient elution with 0.1% formic acid aqueous solution and methanol mobile phases for the determination of 15 polyphenols, allowing us to obtain polyphenolic profiles in less than 23.0 min. Under the optimum conditions, the enrichment factors ranged from 162 to 194. The results showed that the 15 polyphenols had linear correlation coefficients (R 2) more than 0.99. The limits of detection (LODs) were between 18.3 and 103.5 ng/g, and the average recoveries were between 96.9 and 116.3% with interday relative standard deviations (RSDs) ranging from 4.4 to 8.2% in all cases. The method was successfully applied to the analysis of real fruit juice samples and presented itself as a simple, rapid, practical, and environment-friendly technique.

Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) overexpression alleviates endoplasmic reticulum stress after acute kidney injury.

BACKGROUND: Mitochondrial biogenesis dysregulation and enhanced endoplasmic reticulum (ER) stress have been implicated in the progression of acute kidney injury (AKI). However, the interaction between these two events remains poorly understood. This study was designed to investigate the role of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression, a key factor in mitochondrial biogenesis, in renal ER stress at 24 h after AKI and the underlying mechanisms. METHODS: Mice were administered recombinant adenovirus encoding murine PGC-1α (100 µl, 1.0 × 109PFU/ml) or vehicle five days before renal ischemia reperfusion (I/R) or sham operation. Twenty-four hours after the operation, kidney and serum samples were collected for evaluation. RESULTS: We first confirmed that PGC-1α transfection elevated the PGC-1α levels and mitochondrial transcripts in the kidney 24 h after AKI. Then, we found PGC-1α overexpression improved renal function. PGC-1α transfection inhibited AKI-induced ER stress through the unfolded protein response (UPR) pathway, resulting in the suppression of apoptosis via both mitochondrial and ER pathways. Further study showed that the expression of mitofusin 2 (Mfn2), an interaction protein between mitochondria and ER, was increased after PGC-1α overexpression. We also found the expression of a novel ER stress regulator, hairy and enhancer of split 1 (Hes1), was decreased after PGC-1α transfection. CONCLUSIONS: Our findings reveal that mitochondrial biogenesis plays an important role in the progression of AKI-induced ER stress and provide useful evidence for research on organelle crosstalk during AKI.

High linear polarization, narrow linewidth hybrid semiconductor laser with an external birefringence waveguide Bragg grating.

We demonstrate a high linear polarization, narrow linewidth hybrid laser composed of a semiconductor gain chip and a high birefringence waveguide Bragg grating (WBG). The laser operates in the C-band, and a maximum output power of 8.07 mW is obtained in the fiber waveguide. With careful temperature tuning, the hybrid laser can operate in a single longitudinal mode state from above the threshold current to 410 mA. The side mode suppression ratio (SMSR) reaches a value of 50.2 dB, and the polarization extinction ratio exceeds 39.6 dB. We numerically analyze the linewidth suppression for the Bragg grating based on adiabatic chirp theory. The hybrid laser shows a narrow linewidth of 4.15 kHz and a low relative intensity noise (RIN) of <-155 dBc/Hz, providing a high-performance light source for coherent light communication.

Long non-coding RNA HOTAIR/microRNA-761 sponge regulates PPME1 and further influences cell biological functions in thyroid carcinoma.

BACKGROUND: Most well-differentiated thyroid carcinomas display good therapeutic outcomes, but there are still some patients who are not sensitive to the general treatments lose their treatment opportunities. Thus, it is important to understand the molecular mechanisms that cause thyroid carcinoma, so as to find effective diagnostic and therapeutic targets. AIM OF THE STUDY: To explore the role of homeobox transcript antisense RNA (HOTAIR) in thyroid carcinoma through protein phosphatase methylesterase 1 (PPME1) by sponging microRNA 761 (miR-761). METHODS: The regulation network amongst HOTAIR, miR-761 and PPME1 was predicted by online sources. RT-PCR was conducted to evaluate the expression of HOTAIR and miR-761 in tumor tissues. Clinical data was collected and analyzed by Chi-square test. Cell apoptosis and proliferation was evaluated using three types of cancer cells (HTh-7, CAL-62, BCPAP) after treated with si-HOTAIR and miR-761inhibitor. The binding site among HOTAIR, miR-761 and PPME1 was verified by dual luciferase reporter assay. PPME1 expression was measured after HOTAIR and miR-761 were suppressed by western blot. Survival time was measured in nude mice using log-rank test. RESULTS: HOTAIR was expressed to a significantly greater extent than miR-761 in thyroid tumor tissues (P < .001). miR-761 and PPME1 were negatively correlated (coef = -1.91, P < .001). HOTAIR competitively binds to miR-761 and miR-761 directly targets PPME1. HOTAIR was highly correlated with TNM (χ 2 = 5.797, P = .016), tumor size (χ 2 = 7.955, P = .005) and lymphatic metastasis (χ 2 = 6.0, P = .014). HOTAIR promoted cell proliferation and inhibited cell apoptosis, whereas miR-761 did not. HOTAIR elevated and miR-761 suppressed PPME1 expression. HOTAIR expression appears to affect the survival time in vivo. CONCLUSION: HOTAIR regulated thyroid cancer cells by binding to miR-761 through PPME1.

Predictive Value of IL-6 Combined with NLR in Inflammation and Cancer.

The strong association between inflammation and cancer is reflected by the high interleukin-6 (IL-6) levels in the tumor microenvironment, where it promotes carcinogenesis by regulating all hallmarks of cancer and multiple signaling pathways. In this study, we investigated the prognostic value of IL-6 and other clinical indexes in inflammatory and cancer patients. All the patients were divided into the inflammation group (n = 400) and the cancer group (n = 672) composed of hematological malignancies group (n = 338) and solid tumors group (n = 334). Continuous variables were measured by one-way ANOVA and t-test, and the independent risk factors for carcinogenesis were determined by multivariate logistic regression analysis. The receiver operating characteristic (ROC) curves subsequently performed the predictive value of significant serological parameters and the Corheatmaps illustrated the correlation of these parameters in every case. Our retrospective study revealed that various serological indexes could reflect carcinogenesis in inflammatory patients, as significant differences existed in many indexes between them. It was notable that indicator composed of IL-6 and neutrophils/lymphocytes ratio (NLR) occupied the superior position of Area Under Curve (AUC) values in cancer cases, especially in patients with solid tumors (AUC = 0.85). The newly-found indicator could also be referred as an independent risk factor, which provided us with novel clues on the investigation of more reliable and affordable clinical indexes in tumor prediction.

Association between Prolonged Intermittent Renal Replacement Therapy and All-Cause Mortality in COVID-19 Patients Undergoing Invasive Mechanical Ventilation: A Retrospective Cohort Study.

BACKGROUND: The mortality rate of critically ill patients with coronavirus disease 2019 (COVID-19) was high. We aimed to assess the association between prolonged intermittent renal replacement therapy (PIRRT) and mortality in patients with COVID-19 undergoing invasive mechanical ventilation. METHODS: This retrospective cohort study included all COVID-19 patients receiving invasive mechanical ventilation between February 12 and March 2, 2020. All patients were followed until death or March 28, and all survivors were followed for at least 30 days. RESULTS: For 36 hospitalized COVID-19 patients receiving invasive mechanical ventilation, the mean age was 69.4 (±10.8) years, and 30 patients (83.3%) were men. Twenty-two (61.1%) patients received PIRRT (PIRRT group), and 14 cases (38.9%) were managed with conventional strategy (non-PIRRT group). There were no differences in age, sex, comorbidities, complications, treatments, and most of the laboratory findings. During the median follow-up period of 9.5 (interquartile range 4.3-33.5) days, 13 of 22 (59.1%) patients in the PIRRT group and 11 of 14 (78.6%) patients in the non-PIRRT group died. Kaplan-Meier analysis demonstrated prolonged survival in patients in the PIRRT group compared with that in the non-PIRRT group (p = 0.042). The association between PIRRT and a reduced risk of mortality remained significant in 3 different models, with adjusted hazard ratios varying from 0.332 to 0.398. Increased IL-2 receptor, TNF-α, procalcitonin, prothrombin time, and NT-proBNP levels were significantly associated with an increased risk of mortality in patients with PIRRT. CONCLUSION: PIRRT may be beneficial for the treatment of COVID-19 patients with invasive mechanical ventilation. Further prospective multicenter studies with larger sample sizes are required.

Aggressive Quarantine Measures Reduce the High Morbidity of COVID-19 in Patients on Maintenance Hemodialysis and Medical Staff of Hemodialysis Facilities in Wuhan, China.

INTRODUCTION: Maintenance hemodialysis (MHD) patients are highly vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Medical staff of dialysis facilities without sufficient biosecurity protection are susceptible once exposed to asymptomatic coronavirus disease 2019 (COVID-19) patients. This study evaluated the epidemiological characteristics of COVID-19 in all MHD patients and medical staff of dialysis facilities in Wuhan, China. METHODS: We collected COVID-19 morbidity and mortality data from MHD patients and medical staff from 52 hemodialysis centers in Wuhan. Then, we analyzed the symptoms and signs of patients and staff in our hospital (Tongji Hospital in Wuhan), and chest CT, SARS-CoV-2 nucleic acid detection and laboratory tests were performed. After aggressive quarantine of the COVID-19 patients, we followed up on the prognosis of them. RESULTS: We analyzed the hemodialysis data from Wuhan and found that 10% of MHD patients and 6.0% of medical staff were suspected of COVID-19. Further detection of SARS-CoV-2 nucleic acid showed that 1.7% of MHD patients and 2.9% of medical staff were confirmed as having COVID-19. In our facility, 18.9% (46/244) of patients and 9.5% (6/63) of medical staff were suspected of COVID-19. Among them, 2.9% (7/244) of MHD patients and 4.8% (3/63) of medical staff tested positive for SARS-CoV-2 were confirmed as having COVID-19. Interestingly, 87.0% of MHD patients suspected of COVID-19 did not have obvious symptoms, but the CT screening showed features of viral pneumonia. There were no significant differences in symptoms, CT findings, comorbidity and laboratory findings of SARS-CoV-2 nucleic-acid-positive and -negative patients. We followed up these patients and found that 57 patients with COVID-19 died (COVID-19 mortality 8.9%). Two patients from our dialysis center with COVID-19 (mortality 4.3%) died. No new infections occurred in our dialysis center after aggressive quarantine was initiated. CONCLUSIONS: The SARS-CoV-2 infection rates in MHD patients and medical staff in dialysis facilities were both high in Wuhan. Frequent chest CT and SARS-CoV-2 nucleic acid detection were needed to screen COVID-19 patients in dialysis facilities. Through the lessons of this experience on the aggressive diagnosis and quarantine measures of COVID-19 patients, we hope medical staff avoid more infections in serious epidemic areas.

DREAM complex suppresses DNA methylation maintenance genes and precludes DNA hypermethylation.

The DNA methyltransferases MET1 and CMT3 are known to be responsible for maintenance of DNA methylation at symmetric CG and CHG sites, respectively, in Arabidopsis thaliana. However, it is unknown how the expression of methyltransferase genes is regulated in different cell states and whether change in expression affects DNA methylation at the whole-genome level. Using a reverse genetic screen, we identified TCX5, a tesmin/TSO1-like CXC domain-containing protein, and demonstrated that it is a transcriptional repressor of genes required for maintenance of DNA methylation, which include MET1, CMT3, DDM1, KYP and VIMs. TCX5 functions redundantly with its paralogue TCX6 in repressing the expression of these genes. In the tcx5 tcx6 double mutant, expression of these genes is markedly increased, thereby leading to markedly increased DNA methylation at CHG sites and, to a lesser extent, at CG sites at the whole-genome level. Furthermore, our whole-genome DNA methylation analysis indicated that the CG and CHG methylation level is lower in differentiated quiescent cells than in dividing cells in the wild type but is comparable in the tcx5/6 mutant, suggesting that TCX5/6 are required for maintenance of the difference in DNA methylation between the two cell types. We identified TCX5/6-containing multi-subunit complexes, which are known as DREAM in other eukaryotes, and demonstrated that the Arabidopsis DREAM components function as a whole to preclude DNA hypermethylation. Given that the DREAM complexes are conserved from plants to animals, the preclusion of DNA hypermethylation by DREAM complexes may represent a conserved mechanism in eukaryotes.

Emerging roles of HOTAIR in human cancer.

Long noncoding RNA HOX antisense intergenic RNA (HOTAIR) is overexpressed in many types of cancers, and substantial evidence has suggested a link between cancers and HOTAIR. In the present study, we reviewed the structure and the corresponding biologic function of HOTAIR to clarify its molecular mechanism in cancer progression. HOTAIR promotes proliferation, invasion, and migration, and inhibits apoptosis in cancer cells. HOTAIR also participates in the pathogenesis and progression of cancer by regulating inflammation and immune signaling. These findings suggested that HOTAIR is a novel biomarker in human cancers.

Improve computational efficiency and estimation accuracy of multi-channel surface EMG decomposition via dimensionality reduction.

Electromyography (EMG) decomposition serves as a powerful tool to provide valuable information regarding motor control strategy and muscle pathology. Various approaches have recently been developed to decompose surface electromyography (sEMG) signals into motor unit action potential (MUAP) trains, but there is still room to improve decomposition accuracy and efficiency. In this article, the singular value decomposition (SVD) method is employed to decompose extended multi-channel sEMG signals based on the linear minimum mean square error (LMMSE) estimation and convolution kernel compensation (CKC). The column dimension of the right unitary matrix obtained via SVD is compressed to reduce the run-time of the decomposition process. As such, an innervation pulse train (IPT) can be extracted only using the compressed right unitary matrix. We studied the effect of reduced dimensionality on the computational efficiency and accuracy of the proposed method. Results from both simulated and experimental data demonstrate that this algorithm can decompose multi-channel sEMG efficiently and accurately. In most cases, 20%-60% of run-time can be reduced. In addition, the number of extracted IPTs can also be increased, especially when the signal-to-noise ratio of the EMG data is low. The method developed in this study has potential applications in clinical diagnosis, rehabilitation engineering and research on human motion control systems.