Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient.

We report the 1-year results from one patient as the preliminary analysis of a first-in-human phase I clinical trial (ChiCTR2300072200) assessing the feasibility of autologous transplantation of chemically induced pluripotent stem-cell-derived islets (CiPSC islets) beneath the abdominal anterior rectus sheath for type 1 diabetes treatment. The patient achieved sustained insulin independence starting 75 days post-transplantation. The patient's time-in-target glycemic range increased from a baseline value of 43.18% to 96.21% by month 4 post-transplantation, accompanied by a decrease in glycated hemoglobin, an indicator of long-term systemic glucose levels at a non-diabetic level. Thereafter, the patient presented a state of stable glycemic control, with time-in-target glycemic range at >98% and glycated hemoglobin at around 5%. At 1 year, the clinical data met all study endpoints with no indication of transplant-related abnormalities. Promising results from this patient suggest that further clinical studies assessing CiPSC-islet transplantation in type 1 diabetes are warranted.

Stripe rust effector Pst03724 modulates host immunity by inhibiting NAD kinase activation by a calmodulin.

Puccinia striiformis f. sp. tritici (Pst) secretes effector proteins that enter plant cells to manipulate host immune processes. In this report, we present an important Pst effector, Pst03724, whose mRNA expression level increases during Pst infection of wheat (Triticum aestivum). Silencing of Pst03724 reduced the growth and development of Pst. Pst03724 targeted the wheat calmodulin TaCaM3-2B, a positive regulator of wheat immunity. Subsequent investigations revealed that Pst03724 interferes with the TaCaM3-2B-NAD kinase (NADK) TaNADK2 association and thus inhibits the enzyme activity of TaNADK2 activated by TaCaM3-2B. Knocking down TaNADK2 expression by virus-mediated gene silencing significantly increased fungal growth and development, suggesting a decrease in resistance against Pst infection. In conclusion, our findings indicate that Pst effector Pst03724 inhibits the activity of NADK by interfering with the TaCaM3-2B-TaNADK2 association, thereby facilitating Pst infection.

Glycine-serine-rich effector PstGSRE4 in Puccinia striiformis f. sp. tritici inhibits the activity of copper zinc superoxide dismutase to modulate immunity in wheat.

Puccinia striiformis f. sp. tritici (Pst) secretes an array of specific effector proteins to manipulate host immunity and promote pathogen colonization. In a previous study, we functionally characterized a glycine-serine-rich effector PstGSRE1 with a glycine-serine-rich motif (m9). However, the mechanisms of glycine-serine-rich effectors (GSREs) remain obscure. Here we report a new glycine-serine-rich effector, PstGSRE4, which has no m9-like motif but inhibits the enzyme activity of wheat copper zinc superoxide dismutase TaCZSOD2, which acts as a positive regulator of wheat resistance to Pst. By inhibiting the enzyme activity of TaCZSOD2, PstGSRE4 reduces H2O2 accumulation and HR areas to facilitate Pst infection. These findings provide new insights into the molecular mechanisms of GSREs of rust fungi in regulating plant immunity.

Glycine-serine-rich effector PstGSRE4 in Puccinia striiformis f. sp. tritici targets and stabilizes TaGAPDH2 that promotes stripe rust disease.

Puccinia striiformis f. sp. tritici (Pst) secretes effector proteins that enter plant cells and manipulate host processes. In a previous study, we identified a glycine-serine-rich effector PstGSRE4, which was proven to regulate the reactive oxygen species (ROS) pathway by interacting with TaCZSOD2. In this study, we further demonstrated that PstGSRE4 interacts with wheat glyceraldehyde-3-phosphate dehydrogenase TaGAPDH2, which is related to ROS signalling. In wheat, silencing of TaGAPDH2 by virus-induced gene silencing increased the accumulation of ROS induced by the Pst virulent race CYR31. Overexpression of TaGAPDH2 decreased the accumulation of ROS induced by the avirulent Pst race CYR23. In addition, TaGAPDH2 suppressed Pst candidate elicitor Pst322-triggered cell death by decreasing ROS accumulation in Nicotiana benthamiana. Knocking down TaGAPDH2 expression attenuated Pst infection, whereas overexpression of TaGAPDH2 promoted Pst infection, indicating that TaGAPDH2 is a negative regulator of plant defence. In N. benthamiana, PstGSRE4 stabilized TaGAPDH2 through inhibition of the 26S proteasome-mediated destabilization. Overall, these results suggest that TaGAPDH2 is hijacked by the Pst effector as a negative regulator of plant immunity to promote Pst infection in wheat.

Optical coherence tomography angiography for detection of microvascular changes in early diabetes: A systematic review and meta-analysis.

AIMS: To evaluate the effectiveness of optical coherence tomography angiography (OCTA) in detecting early intraocular microvascular changes in diabetic patients. MATERIALS AND METHODS: A systematic study search was performed on PubMed, Medline, Embase, and the Cochrane Library, ranging from January 2012 to March 2023. Controlled studies compared diabetes mellitus (DM) patients with non-diabetic retinopathy (NDR) or patients with mild non-proliferative diabetic retinopathy (mild NPDR) to healthy people. These studies included parameters of OCTA such as foveal avascular zone (FAZ), vessel density of superficial capillary plexus (VDscp), vessel density of deep capillary plexus (VDdcp), and peripapillary VD. The relevant effect model was used according to the heterogeneity, and the mean difference and 95% confidence intervals were calculated. RESULTS: A total of 18 studies with 2101 eyes were eventually included in this meta-analysis. Our results demonstrated that early alterations of VDscp, VDdcp, and peripapillary VD in NDR patients had a significant difference compared with healthy people by OCTA (VDscp: WMD = -1.34, 95% CI: -1.99 to -0.68, P < 0.0001. VDdcp: WMD = -2.00, 95% CI: -2.95 to -1.04, P < 0.0001. Peripapillary VD: WMD = -1.07, 95% CI: -1.70 to -0.43, P = 0.0010). However, there was no statistically significant difference in total FAZ between them (WMD = -0.00, 95% CI: -0.02-0.01, P = 0.84). In addition, for patients with mild NPDR, OCTA could illustrate prominent changes in VDscp, VDdcp, and total FAZ compared with healthy people (VDscp: WMD = -6.11, 95% CI: -9.90 to -2.32, P = 0.002. VDdcp: WMD = -4.26, 95% CI: -5.95 to -2.57, P < 0.00001. FAZ: WMD = 0.06, 95% CI: 0.01-0.11, P = 0.03). CONCLUSIONS: In diabetic patients with or without retinopathy, the parameters of OCTA such as VDscp, VDdcp, and peripapillary vessel density were demonstrated as potential biomarkers in monitoring the early alterations of retinal microangiopathy, while total FAZ may have no significant changes in diabetic patients without retinopathy.

The role of chemerin in the regulation of cGAS-STING pathway in gestational diabetes mellitus placenta.

Recent studies already confirmed that placenta mitochondrial dysfunction is associated with the progression of gestational diabetes mellitus (GDM). Besides, a possible relationship between adipokine chemerin and disulfide-bond A oxidoreductase-like protein (DsbA-L) had been revealed, whereas the potential interaction remains unclear. In addition, very little is still known about the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and its mechanisms of action in the context of GDM. The present study aims to investigate the underlying mechanism of cGAS-STING pathway and its regulatory relationship with chemerin in GDM. A total of 50 participants, including 25 cases of GDM patients and 25 pregnant women with normal glucose tolerance, were enrolled, and their placenta tissues at term labor were collected. Besides, an insulin resistance cell model was established on the human trophoblastic cell line to explore the molecular mechanism of chemerin on cGAS-STING pathway. Results showed that there were mitochondrial pathological changes in GDM placenta, accompanied by the decreased expression of DsbA-L, increased level of chemerin, and the activation of cGAS-STING pathway. In the insulin resistant cell model, overexpression of chemerin upregulated protein expression of DsbA-L, and recombinant chemerin presented time-dependent inhibition on the cGAS-STING pathway, but this effect was not dependent on DsbA-L. In conclusion, elevated chemerin is probably a protective mechanism, which may be a potential therapeutic strategy for GDM.

Industrialization Mitigates Greenhouse Gas Intensity in China's Dairy Sector yet May Prove Insufficient to Offset Emissions from Future Production Expansion.

China's dairy farming is undergoing a critical transition from extensive to industrial systems. To achieve sustainable milk production within China's dual-carbon goals, understanding the multidimensional impacts of industrialization on greenhouse gas (GHG) emissions is imperative. This study comprehensively analyzed the implications of China's dairy industrialization on GHG emissions and explored future mitigation potential. Results indicated that industrial systems exhibited lower methane but higher carbon dioxide intensities, with net GHG intensity lower than other systems. During 2002-2020, China's milk production increased by 165%, while GHG emissions increased by 105% to 50.27 Tg CO2eq, accompanying an industrialization rate increased from 16% to 75%. The industrialization progress played a mitigating effect on GHG primarily through intensification within individual production systems before 2008 and transformation between systems post-2008. However, the industrialization's effect was relatively modest compared to other socio-economic factors. By 2030, 11.8 Tg CO2eq will be triggered by predicted milk production growth, but only 0.6 Tg can be offset by system transformation. Integrating measures to improve feed, herd, and manure management on industrial farms could decouple GHG emissions from milk production and achieve a carbon peak before 2030. We suggest transforming to improved industrial systems as a necessary step toward sustainable livestock production.

Evaluation and clinical application of a bracketing calibration-based isotope dilution liquid chromatography-tandem mass spectrometry candidate reference measurement procedure for serum theophylline.

A candidate reference measurement procedure (RMP) for serum theophylline via isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. With a single-step precipitation pretreatment and a 6-min gradient elution, the method achieved baseline separation of theophylline and its analogs on a C18-packed column. A bracketing calibration method was used to ensure repeatable signal intensity and high measurement precision. The intra-assay and inter-assay imprecisions were 1.06%, 0.84%, 0.72% and 0.47%, 0.41%, 0.25% at concentrations of 4.22 µg/mL (23.40 µmol/L), 8.45 µg/mL (46.90 µmol/L), and 15.21 µg/mL (84.43 µmol/L), respectively. Recoveries ranged from 99.35 to 102.34%. The limit of detection (LoD) was 2 ng/mL, and the lowest limit of quantification (LLoQ) was 5 ng/mL. The linearity range extended from 0.47 to 60 µg/mL (2.61-333.04 µmol/L). No ion suppression and carry-over (< 0.68%) were observed. The relative bias for this candidate RMP that participated in 2023 External Quality Control for Reference Laboratories (RELA) conducted by the International Federation of Clinical Chemistry (IFCC) was within a range of 0.17 to 0.93%. Furthermore, two clinical immunoassay systems were compared with this candidate RMP, demonstrating good correlations. The results of the Trueness Verification Plan indicate significant differences among routine systems, highlighting the need for standardization efforts. The developed candidate RMP for serum theophylline serves as a precise reference baseline for standardizing clinical systems and assigning values to reference materials.

Proprotein convertase subtilisin/kexin type 9 inhibitor ameliorates cerebral ischemia in mice by inhibiting inflammation.

OBJECTIVES: To investigate the potential protective effects of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, on ischemic stroke and its underlying mechanisms. MATERIALS AND METHODS: We established a mouse model with distal middle cerebral artery occlusion. We evaluated the therapeutic effects through neurological function and infarct size, while the underlying mechanisms were elucidated using western blotting and real-time polymerase chain reaction. RESULTS: Evolocumab improved neurological recovery, reduced the infarct volume, suppressed the activation of Toll-like receptor (TLR) 4 and nuclear factor-kappa B (NF-κB), and attenuated the increased levels of IL-1ß and TNF-α after cerebral ischemia. CONCLUSION: Evolocumab protects against cerebral ischemic injury by inhibiting inflammation. Therefore, the TLR4/NF-кB pathway may represent a major mechanism in ischemic stroke.

A stripe rust fungal effector PstSIE1 targets TaSGT1 to facilitate pathogen infection.

Puccinia striiformis f. sp. tritici (Pst), the causal agent of stripe rust, is a destructive pathogen of Triticum aestivum (wheat), threatening wheat production worldwide. Pst delivers hundreds of effectors to manipulate processes in its hosts during infection. The SGT1 (suppressor of the G2 allele of skp1), RAR1 (required for Mla12 resistance) and HSP90 (heat-shock protein 90) proteins form a chaperone complex that acts as a core modulator in plant immunity. However, little is known about how Pst effectors target this immune component to suppress plant immunity. Here, we identified a Pst effector PstSIE1 that interacts with TaSGT1 in wheat and is upregulated during the early infection stage. Transient expression of PstSIE1 suppressed cell death in Nicotiana benthamiana induced by VmE02 and PcNLP2. Transgenic expression of PstSIE1-RNAi constructs in wheat significantly reduced the virulence of Pst. Overexpression of PstSIE1 in wheat increased the number of rust pustules and reduced the accumulation of reactive oxygen species (ROS), indicating that PstSIE1 functions as an important pathogenicity factor in Pst. PstSIE1 was found to compete with TaRAR1 to bind TaSGT1, thus disrupting the formation of the TaRAR1-TaSGT1 subcomplex. Taken together, PstSIE1 is an important Pst effector targeting the immune component TaSGT1 and involved in suppressing wheat defense.

DHA supplementation and pregnancy complications.

Docosahexaenoic acid (DHA) supplementation is recommended for women during pregnancy because of its neurological, visual, and cognitive effects. Previous studies have suggested that DHA supplementation during pregnancy may prevent and treat certain pregnancy complications. However, there are contradictions in the current related studies, and the specific mechanism by which DHA acts remains unclear. This review summarizes the research on the relationship between DHA intake during pregnancy and preeclampsia, gestational diabetes mellitus, preterm birth, intrauterine growth restriction, and postpartum depression. Furthermore, we explore the impact of DHA intake during pregnancy on the prediction, prevention, and treatment of pregnancy complications as well as its impact on offspring neurodevelopment. Our results suggest that there is limited and controversial evidence for the protective effect of DHA intake on pregnancy complications, with the exception of preterm birth and gestational diabetes mellitus. However, additional DHA supplementation may improve long-term neurodevelopmental outcomes in the offspring of women with pregnancy complications.

Long-term outcomes of offspring from multiple gestations: a two-sample Mendelian randomization study on multi-system diseases using UK Biobank and FinnGen databases.

BACKGROUND: Assisted reproductive technologies (ART) have increased the incidence of multiple births, which can have a negative impact on maternal and offspring health. The study aimed to investigate the association between genetically predicted multiple birth and the risk of 42 common diseases of the nervous, psychiatric, cardiovascular, respiratory, digestive, and endocrine systems. METHODS: The study utilized two-sample Mendelian randomization (MR) analysis to explore the potential causal relationship between genetically predicted multiple birth and the genetically predicted risk of diseases. The study used the FinnGen and UK Biobank datasets for analysis. RESULTS: The study found no significant causal relationship between multiple birth and psychiatric disorders. However, the lower limits of the 95% confidence intervals for bipolar affective disorder and anxiety disorders were not robust, indicating a need for further investigation. The study found that multiple birth may be a strong risk factor for infantile cerebral palsy, and caution is necessary in both natural and ART multiple births. The study revealed a potential causal relationship between multiple birth and coronary heart disease, ischemic heart disease, and deep vein thrombosis, which may be related to abnormal intrauterine environments in multiple pregnancies. Surprisingly, multiple birth appears to have a protective effect against some respiratory diseases, such as chronic obstructive pulmonary disease and asthma. CONCLUSIONS: The study highlights the need for caution regarding the risk of infantile cerebral palsy, cardiovascular diseases, and psychiatric disorders in multiple birth. Our study can lead to the development of preventive strategies and improved clinical management for affected infants.

Modern cities modelled as "super-cells" rather than multicellular organisms: Implications for industry, goods and services.

The structure and "metabolism" (movement and conversion of goods and energy) of urban areas has caused cities to be identified as "super-organisms", placed between ecosystems and the biosphere, in the hierarchy of living systems. Yet most such analogies are weak, and render the super-organism model ineffective for sustainable development of cities. Via a cluster analysis of 15 shared traits of the hierarchical living system, we found that industrialized cities are more similar to eukaryotic cells than to multicellular organisms; enclosed systems, such as factories and greenhouses, paralleling organelles in eukaryotic cells. We further developed a "super-cell" industrialized city model: a "eukarcity" with citynucleus (urban area) as a regulating centre, and organaras (enclosed systems, which provide the majority of goods and services) as the functional components, and cityplasm (natural ecosystems and farmlands) as the matrix. This model may improve the vitality and sustainability of cities through planning and management.

Quantitative Evaluation of the Normal Cervix, Cervical Cancer, and Cervical Precancerous Changes Via Real-Time Shear Wave Elastography.

OBJECTIVES: The present study aims to evaluate the clinical application values of ultrasound real-time shear wave elastography (SWE) in the diagnosis and differential diagnosis of cervical cancer (CC). METHODS: A total of 285 married female patients were screened and divided into three groups according to the results of the pathological examination and the cervical ThinPrep cytologic test: 1) the CC group (n = 94); 2) the cervical intraepithelial neoplasia (CIN) group (n = 91); and 3) the normal control group (n = 100). The maximum Young's modulus (Emax), mean Young's modulus (Emean), minimum Young's modulus (Emin), and Young's modulus stability (Esd) in each group were measured and statistically analyzed. RESULTS: There were no statistically significant differences in Emax, Emean, Emin, and Esd values between the anterior and posterior cervical walls, premenopausal and postmenopausal women, and nonparturient and parturient women in the normal control group. The Emax, Emean, Emin, and Esd values in the CIN group showed no statistically significant differences in different periods when compared with the control group. The differences between the normal control group and the CC group were statistically significant; the CC group showed no statistically significant differences in Emax, Emean, Emin, and Esd values at different clinical stages and in different pathological types. The cutoff value of Emax for CC diagnosis, which was of the highest accuracy (89.7%), was 43.48 kpa. CONCLUSION: Ultrasound real-time SWE can be applied to CC diagnosis.

Mechanism of Salt Tolerance and Plant Growth Promotion in Priestia megaterium ZS-3 Revealed by Cellular Metabolism and Whole-Genome Studies.

Approximately one-third of agricultural land worldwide is affected by salinity, which limits the productivity and sustainability of crop ecosystems. Plant-growth-promoting rhizobacteria (PGPR) are a potential solution to this problem, as PGPR increases crop yield through improving soil fertility and stress resistance. Previous studies have shown that Priestia megaterium ZS-3(ZS-3) can effectively help plants tolerate salinity stress. However, how ZS-3 regulates its metabolic adaptations in saline environments remains unclear. In this study, we monitored the metabolic rearrangement of compatibilisers in ZS-3 and combined the findings with genomic data to reveal how ZS-3 survives in stressful environments, induces plant growth, and tolerates stress. The results showed that ZS-3 tolerated salinity levels up to 9%. In addition, glutamate and trehalose help ZS-3 adapt to osmotic stress under low NaCl stress, whereas proline, K+, and extracellular polysaccharides regulate the osmotic responses of ZS-3 exposed to high salt stress. Potting experiments showed that applying the ZS-3 strain in saline and neutral soils could effectively increase the activities of soil acid phosphatase, urease, and invertase in both soils, thus improving soil fertility and promoting plant growth. In addition, strain ZS-3-GFP colonised the rhizosphere and leaves of Cinnamomum camphora well, as confirmed by confocal microscopy and resistance plate count analysis. Genomic studies and in vitro experiments have shown that ZS-3 exhibits a variety of beneficial traits, including plant-promoting, antagonistic, and other related traits (such as resistance to saline and heavy metal stress/tolerance, amino acid synthesis and transport, volatile compound synthesis, micronutrient utilisation, and phytohormone biosynthesis/regulatory potential). The results support that ZS-3 can induce plant tolerance to abiotic stresses. These data provide important clues to further reveal the interactions between plants and microbiomes, as well as the mechanisms by which micro-organisms control plant health.

[Clinical Significance of Thrombospondin Type 1 Domain-Containing 7A and Neural Epidermal Growth Factor-Like 1 Protein in M-Type Phospholipase A2 Receptor-Negative Membranous Nephropathy].

Objective To investigate the clinical significance of thrombospondin type 1 domain-containing 7A (THSD7A) and neural epidermal growth factor-like 1 protein (NELL1) in phospholipase A2 receptor (PLA2R)-negative membranous nephropathy (MN). Methods A total of 116 PLA2R-negative MN patients treated in Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University from 2014 to 2021 were enrolled in this study.Immunohistochemistry was employed to detect THSD7A and NELL1 in the renal tissue.The pathological characteristics,treatment,and prognosis were compared between positive and negative groups. Results The 116 PLA2R-negative MN patients included 23 THSD7A-positive patients and 9 NELL1-positive patients.One patient was tested positive for both proteins.The THSD7A-positive group showed higher positive rate of IgG4 (P=0.010),more obvious glomerular basement membrane (GBM) thickening (P=0.034),and higher proportion of stage Ⅱ MN and lower proportion of stage I MN (P=0.002) than the THSD7A-negative group.The NELL1-positive group had lower positive rates of C1q and IgG2 (P=0.029,P=0.001),less obvious GBM thickening (P<0.001),more extensive inflammatory cell infiltration (P=0.033),lower proportion of deposits on multi-locations (P=0.001),and lower proportion of atypical MN (P=0.010) than the NELL1-negative group.One patient with THSD7A-positive MN was diagnosed with colon cancer,while none of the NELL1-positive patients had malignancy.Survival analysis suggested that THSD7A-positive MN had worse composite remission (either complete remission or partial remission) of nephrotic syndrome than the negative group (P=0.016),whereas NELL1-positive MN exhibited better composite remission of nephrotic syndrome than the negative group (P=0.015).The MN patients only positive for NELL1 showed better composite remission of nephrotic syndrome than the MN patients only positive for THSD7A (P<0.001). Conclusions THSD7A- and NELL1-positive MN is more likely to be primary MN,and there is no significant malignancy indication.However,it might have a predictive value for the prognosis of MN.

Renal Interstitial Inflammation Predicts Nephropathy Progression in IgA Nephropathy: A Two-Center Cohort Study.

INTRODUCTION: Renal interstitial inflammation often presents in immunoglobulin A nephropathy (IgAN), but its predictive role in kidney disease progression remains controversial. METHODS: This retrospective two-center cohort study included 1,420 adult IgAN patients between January 2003 and May 2018 followed for a median of approximately 7 years at two Chinese hospitals. The predictor was renal interstitial inflammation within the total cortical interstitium (none/mild [0-25%], moderate [26-50%], or severe [>50%]). For the further propensity score matching analyses, the participants with moderate and severe level of interstitial inflammation were pooled to match those with none/mild level of interstitial inflammation. The outcomes included the rate of kidney function decline, and the composite kidney endpoint event defined as a >40% reduction in the estimated glomerular filtration rate, end-stage kidney disease. Linear regression and Cox proportional hazards regression analyses were used to examine the association between interstitial inflammation and the outcomes. The predictive performance of the model also assessed using multivariate logistic regression analyses with the receiver operating characteristic curve analysis. Reclassification was assessed using the continuous net reclassification improvement and integrated discrimination improvement adapted for censoring for the assessment of the model with or without interstitial inflammation. RESULTS: For the check of reproducibility, the kappa statistic was 0.71, and intraclass correlation coefficient was 0.77. After adjustment for relating covariates, a higher level of interstitial inflammation was associated with a faster rate of kidney function decline (eGFR slope [mL/min/1.73 m2] of 1.34 [95% CI: -2.56 to 5.23], 3.50 [95% CI: -0.40 to 7.40], and 7.52 [95% CI: 3.02 to 12.01]) in the patients with none/mild, moderate, and severe interstitial inflammation, respectively, in the multivariable linear regression models and with an increased risk of kidney disease progression (HR for moderate vs. none/mild, 1.85; 95% CI: 1.10-3.13; HR for severe vs. none/mild, 2.95; 95% CI: 1.52-5.73) in the multivariable Cox proportional hazards models. Analyses in the propensity score-matched cohort, subgroups, and the sensitive analyses yielded consistent results. The receiver operating curves indicated a higher area under the curve of 0.83 in the model with interstitial inflammation compared with 0.81 in that without interstitial inflammation. In addition, incorporating interstitial inflammation into the International IgAN Risk Prediction Tool improved the diagnostic power of the algorithm to predict risk of progression. CONCLUSION: Interstitial inflammation is a reproducible pathologic parameter that may be adopted as a predictor for kidney disease progression in patients with IgAN.

Liraglutide Ameliorates Cerebral Ischemia in Mice via Antipyroptotic Pathways.

It was recently shown that pyroptosis, an inflammatory form of programmed cell death, is critically involved in the pathogenesis of ischemic stroke. Liraglutide (Lg) is a novel long-acting analog of glucagon-like peptide-1 that has potential protective effects against stroke. However, the relationship between Lg and pyroptosis in the brain is not well defined. In this study, we found that injection of Lg significantly improved the recovery of motor function, increased cerebral blood flow and ameliorated cerebral damage in a mouse model of focal cerebral cortical ischemia. Our results revealed that Lg treatment significantly reduced the levels of NLRP3, Caspase1, IL-1ß and the pore-forming protein gasdermin D in microglial cells in vitro, suggesting that the neuroprotective effect of Lg may be achieved through the inhibition of pyroptosis. Furthermore, by using a specific inhibitor of NOD-like receptor protein 3 (NLRP3), we confirmed that the antipyroptotic mechanism of Lg may be mediated by NLRP3 in vivo. Our present study unveils a novel neuroprotective mechanism through which Lg alleviates ischemia by exerting NLRP3-dependent antipyroptotic effects.

A prognostic model for oral squamous cell carcinoma using 7 genes related to tumor mutational burden.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a rising problem in global public health. The traditional physical and imageological examinations are invasive and radioactive. There is a need for less harmful new biomarkers. Tumor mutational burden (TMB) is a novel prognostic biomarker for various cancers. We intended to explore the relationship between TMB-related genes and the prognosis of OSCC and to construct a prognostic model. METHODS: TMB-related differential expressed genes (DEGs) were screened by differential analysis and optimized via the univariate Cox and LASSO Cox analyses. Risk Score model was constructed by expression values of screened genes multiplying coefficient of LASSO Cox. RESULTS: Seven TMB-related DEGs (CTSG, COL6A5, GRIA3, CCL21, ZNF662, TDRD5 and GSDMB) were screened. Patients in high-risk group (Risk Score > - 0.684511507) had worse prognosis compared to the low-risk group (Risk Score < - 0.684511507). Survival rates of patients in the high-risk group were lower in the gender, age and degrees of differentiation subgroups compared to the low-risk group. CONCLUSIONS: The Risk Score model constructed by 7 TMB-related genes may be a reliable biomarker for predicting the prognosis of OSCC patients.

[Clinical Significance of IgG4 Level in Predicting the Activity and Outcome of Phospholipase A2 Receptor-associated Membranous Nephropathy].

Objective To investigate the feasibility of IgG4 as a biomarker of the activity and outcome of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (PLA2R-MN). Methods Serum and urine samples were collected from 56 patients with PLA2R-MN,13 patients with secondary membranous nephropathy (SMN),and 10 patients with primary IgA nephropathy (IgAN) when kidney biopsy was performed in the Department of Nephrology,Hangzhou Hospital of Traditional Chinese Medicine from April 2017 to January 2018.Sandwich enzyme-linked immunosorbent assay was employed to measure the serum and urinary IgG4 levels. Results The PLA2R-MN group had higher median serum IgG4/IgG ratio than the SMN group (P=0.009) and the IgAN group (P<0.001) and higher median urinary IgG4/creatinine ratio than the SMN group (P=0.008).In the patients with PLA2R-MN,the median serum IgG4/IgG ratio and urinary IgG4/creatinine ratio were significantly higher in the renal insufficiency group than in the normal renal function group (P=0.049,P=0.015).Moreover,the median serum IgG4/IgG ratio was higher in those with a serum albumin level<30 g/L than in those with a serum albumin level ≥30 g/L (P=0.005).Fifty-three patients with PLA2R-MN were followed up for at least 1 year,and the serum IgG4/IgG ratios of the patients in remission were lower than those of the patients without remission (P=0.005).The median serum IgG4/IgG ratio of 23 patients in remission decreased from 5.82% (4.54%,10.20%)(at initial enrollment) to 2.91% (2.11%,5.37%)(after 1-year follow up) in remission patients (P<0.001).The receiver operating characteristic curve showed that the patients with a serum IgG4/IgG ratio<10.24% had a higher possibility of remission (P=0.005). Conclusion Serum and urinary IgG4 levels may be an indicator of the activity in PLA2R-MN patients and thus may be a predictive biomarker of the outcomes.