Organic fertilizer substituting 20% chemical N increases wheat productivity and soil fertility but reduces soil nitrate-N residue in drought-prone regions.

Organic fertilizer substitution is an effective measure for increasing both the quantity and quality of wheat grain while reducing chemical fertilizer input. However, the effects of reducing nitrogen (N) fertilizer combined with organic fertilizer substitution on grain yield, grain protein content and protein yield, plant N accumulation and translocation, N use efficiency, soil fertility, N apparent surplus and nitrate-N residue in rain-fed drought-prone areas remains limited. In this study, field experiments were conducted over four consecutive seasons (2019-2023) at two sites with four treatments: zero N application (ZN), farmer N application (FN), reduced 20% N of FN (RN), and organic fertilizer substituting 20% N of RN (OSN). The results showed that compared with the ZN treatment, the FN, RN and OSN treatments increased grain yield and its components, grain protein content and protein yield, aboveground N accumulation at the anthesis and maturity stages, pre-anthesis N translocation, post-anthesis N accumulation, N use efficiency, soil fertility. Compared with RN and FN, OSN increased grain yield by 17.12% and 15.03%, grain protein yield by 3.31% and 17.15%, grain N accumulation by 17.78% and 15.58%, and N harvest index by 2.63% and 4.45% averaged across years and sites, respectively. Moreover, OSN increased the contents of organic matter, total N, available P and available K in both 0-20 and 20-40 cm soil layers, decreased N apparent surplus and nitrate-N residue in 0-100 cm, and pH in both 0-20 and 20-40 cm soil layer. Fundamentally, this study suggests that integrating a 20% reduction N from conventional farmer practices with the utilization of organic fertilizer to replace 20% of the chemical N fertilizer (OSN) represents an effective strategy. This approach shows promise in enhancing wheat grain yield, grain protein yield, and N use efficiency. Additionally, it supports the improvement of soil fertility while simultaneously reducing soil nitrate-N residues and the apparent surplus of N in rain-fed drought-prone regions.

Nrf2 Mitigates RANKL and M-CSF Induced Osteoclast Differentiation via ROS-Dependent Mechanisms.

Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been shown to be a negative regulator of osteoclast differentiation, but the precise mechanisms have not yet been established. We examined the precise roles of Nrf2 in regulating antioxidants and reactive oxygen species (ROS) levels, especially the cytoplasmic and mitochondrial ROS during osteoclastogenesis in vitro. In the current study, we found that the absence of Nrf2 promotes osteoclast differentiation in bone-marrow-derived macrophages (BMMs) and RAW 264.7 cells. The receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) significantly lowered the levels of Nrf2 and its downstream antioxidant enzymes at mRNA and/or protein levels during osteoclast differentiation in the BMMs of mice and RAW 264.7 mouse leukemic monocytes. Compared to the wild-type cells, Nrf2-deficient cells exhibited heightened sensitivity to both transient RANKL-induced cytoplasmic ROS and prolonged RANKL and M-CSF-induced cytoplasmic and mitochondrial ROS accumulation. Furthermore, exogenous antioxidant agents, including N-acetyl-cysteine (NAC), diphenyleneiodonium chloride (DPI), and mitoquinone mesylate (MitoQ), exhibited substantial capability to suppress the elevation of ROS levels during osteoclast differentiation induced by Nrf2 deficiency, and they consequently inhibited osteoclast differentiation augmented by the lack of Nrf2. The activation of phosphorylated c-FOS resulting from elevated ROS promoted osteoclast differentiation. The inhibition of c-FOS blocked osteoclast differentiation, which was elevated by Nrf2-deficiency. Taken together, these data reveal that Nrf2 effectively decreased the accumulation of intracellular ROS and the phosphorylation of c-FOS during osteoclastic differentiation by regulating antioxidant enzymes and subsequently inhibited RANKL-induced osteoclast differentiation.

Efficacy and Safety of Tofacitinib in Patients with Polymyalgia Rheumatica (EAST PMR): An open-label randomized controlled trial.

BACKGROUND: Polymyalgia rheumatica (PMR) is a common inflammatory disease in elderly persons whose mechanism of pathogenesis has not been elucidated. Glucocorticoids are the main first-line treatments but result in numerous side effects. Therefore, there is a need to explore pathogenetic factors and identify possible glucocorticoid-sparing agents. We aimed to study the pathogenetic features of the disease and assess the efficacy and safety of Janus tyrosine kinase (JAK)-inhibitor tofacitinib in patients with PMR. METHODS AND FINDINGS: We recruited treatment-naïve PMR patients from the First Affiliated Hospital, Zhejiang University School of Medicine, between September 2020 and September 2022. In the first cohort, we found that the gene expression patterns of peripheral blood mononuclear cells (PBMCs) in 11 patients (10 female, 1 male, age 68.0 ± 8.3) with newly diagnosed PMR were significantly different from 20 healthy controls (17 female, 3 male, age 63.7 ± 9.8) by RNA sequencing. Inflammatory response and cytokine-cytokine receptor interaction were the most notable pathways affected. We observed marked increases in expression of IL6R, IL1B, IL1R1, JAK2, TLR2, TLR4, TLR8, CCR1, CR1, S100A8, S100A12, and IL17RA, which could trigger JAK signaling. Furthermore, tofacitinib suppressed the IL-6R and JAK2 expression of CD4+T cells from patients with PMR in vitro. In the second cohort, patients with PMR were randomized and treated with tofacitinib or glucocorticoids (1/1) for 24 weeks. All PMR patients underwent clinical and laboratory examinations at 0, 4, 8, 12, 16, 20, and 24 weeks, and PMR activity disease scores (PMR-AS) were calculated. The primary endpoint was the proportion of patients with PMR-AS ≤10 at weeks 12 and 24. Secondary endpoints: PMR-AS score, c-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) at weeks 12 and 24. Thirty-nine patients with newly diagnosed PMR received tofacitinib, and 37 patients received glucocorticoid. Thirty-five patients (29 female, 6 male, age 64.4 ± 8.4) and 32 patients (23 female, 9 male, age 65.3 ± 8.7) patients completed the 24-week intervention, respectively. There were no statistically significant differences in primary or secondary outcomes. At weeks 12 and 24, all patients in both groups had PMR-AS <10. PMR-AS, CRP, and ESR were all significantly decreased in both groups. No severe adverse events were observed in either group. Study limitations included the single-center study design with a short observation period. CONCLUSIONS: We found that JAK signaling was involved in the pathogenesis of PMR. Tofacitinib effectively treated patients with PMR as glucocorticoid does in this randomized, monocenter, open-label, controlled trial (ChiCTR2000038253). TRIAL REGISTRATION: This investigator-initiated clinical trial (IIT) had been registered on the website (http://www.chictr.org.cn/, ChiCTR2000038253).

A novel germline frameshift mutation in the MLH1 gene in a patient with Lynch syndrome.

Lynch syndrome (LS) is an autosomal dominant inherited disorder, characterized by a predisposition to various cancers, mainly colorectal cancer (CRC). LS is caused by germline mutations in DNA mismatch repair genes i.e. mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and post-meiotic segregation increased 2 (PMS2). In this study, we report a novel germline frameshift mutation in the MLH1 gene [NM_000249: exon1: c.99dup p.(Glu34ArgfsTer4)] in a 34-year-old male patient with LS. This MLH1 alteration has never been reported in any database or any publications. The frameshift mutation in MLH1 gene [NM_000249: exon1: c.99dup p.(Glu34ArgfsTer4)] was confirmed by Sanger sequencing conducted on peripheral blood of the proband. Meanwhile, Sanger sequencing results revealed the proband's uncle was the carrier. As multiple downstream germline frameshift mutations of this variation are pathogenic, such as MLH1 M35fs, N38fs, and S44fs, it is predicted that MLH1 p.(Glu34ArgfsTer4) might be also pathogenic. Meanwhile, this MLH1 mutation p.(Glu34ArgfsTer4) is predicted to be disease-causing by the MutationTaster software, as the duplication c.99dupA introduced a premature stop codon early in the translation, resulting in a non-functional protein. This study may contribute to the mutational spectrum of MLH1 leading to LS.

Elderly-onset rheumatoid arthritis vs. polymyalgia rheumatica: Differences in pathogenesis.

Rheumatoid arthritis is a chronic autoimmune disease that mainly affects the facet joints. Elderly-onset rheumatoid arthritis appears to exhibit symptoms similar to those of polymyalgia rheumatica, characterized by morning stiffness and pain in the shoulder and hip joints. Both diseases develop in the elderly, and it is sometimes challenging to distinguish them. Here, we identify the differences in pathogenesis between elderly-onset rheumatoid arthritis and polymyalgia rheumatica to assist with a clear differential diagnosis and effective early intervention.

CNC-bZIP protein NFE2L1 regulates osteoclast differentiation in antioxidant-dependent and independent manners.

Fine-tuning of osteoclast differentiation (OD) and bone remodeling is crucial for bone homeostasis. Dissecting the mechanisms regulating osteoclastogenesis is fundamental to understanding the pathogenesis of various bone disorders including osteoporosis and arthritis. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1), which belongs to the CNC-bZIP family of transcription factors, orchestrates a variety of physiological processes and stress responses. While Nfe2l1 gene may be transcribed into multiple alternatively spliced isoforms, the biological function of the different isoforms of NFE2L1 in bone metabolism, osteoclastogenesis in particular, has not been reported. Here we demonstrate that knockout of all isoforms of Nfe2l1 transcripts specifically in the myeloid lineage in mice [Nfe2l1(M)-KO] results in increased activity of osteoclasts, decreased bone mass and worsening of osteoporosis induced by ovariectomy and aging. In comparison, LysM-Cre-mediated Nfe2l1 deletion has no significant effect on the osteoblast and osteocytes. Mechanistic investigations using bone marrow cells and RAW 264.7 cells revealed that deficiency of Nfe2l1 leads to accelerated and elevated OD, which is attributed, at least in part, to enhanced accumulation of ROS in the early stage of OD and expression of nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1α (Nfatc1/α). In addition, NFE2L1 regulates the transcription of multiple antioxidant genes and Nfatc1/α and OD in an isoform-specific manner. While long isoforms of NFE2L1 function as accelerators of induction of Nfatc1/α and antioxidant genes and OD, the short isoform NFE2L1-453 serves as a brake that keeps the long isoforms' accelerator effects in check. These findings provide a novel insight into the regulatory roles of NFE2L1 in osteoclastogenesis and highlight that NFE2L1 is essential in regulating bone remodeling and thus may be a valuable therapeutic target for bone disorders.

A combination of methylation and protein markers is capable of detecting gastric cancer detection by combined markers.

Aim: This study aimed to validate a combination of mSEPT9, mRNF180 and CA724 for gastric cancer (GC) detection. Patients & methods: The performance of mSEPT9, mRNF180 and CA724 was examined in a prospective cohort study with 518 participants (151 with GC, 56 with atrophic gastritis, 87 with other gastrointestinal diseases and 224 with no evidence of disease). Results:mSEPT9, mRNF180 or CA724 alone detected 48.3, 37.1 and 43.1% of GC, respectively. The combination of mSEPT9 and mRNF180 detected 60.3% of GC, and the combination of all three markers detected 68.6% of GC. The detection sensitivity of mSEPT9 and mRNF180 was significantly higher for gastric body and in elder subjects. mSEPT9 was correlated with poorer GC survival. Conclusion: The combination of mSEPT9, mRNF180 and CA724 was adequately sensitive for GC detection. The blood mSEPT9 was predictive for GC prognosis.

Lay abstract Gastric cancer is the most common cancer type in the digestive system. In this study we developed an effective and convenient blood-based test to detect gastric cancer. This test combined a conventional protein test with a newly invented methylation test. We aimed to validate the test and examine its performance using a prospective cohort study. The study showed that the test has promising potential for noninvasive early detection of gastric cancer. We found that single protein or methylation markers detected a proportion of gastric cancer cases, while a combination of these markers exhibited maximal detection capability. Therefore we concluded that the combined test provided adequate efficacy and should be used as a strategy for future gastric cancer detection.

LncRNA ADAMTS9-AS1 knockdown restricts cell proliferation and EMT in non-small cell lung cancer.

A recent bioinformatics analysis identified long non-coding RNA antisense 1 ADAMTS9-AS1 as an independent prognostic marker in several tumors, including prostate cancer and bladder cancer. Nevertheless, the prognostic value and functional role of ADAMTS9-AS1 in non-small cell lung cancer (NSCLC) remain elusive. Here, we first found that the expression of ADAMTS9-AS1 was significantly upregulated in NSCLC tissues compared with adjacent normal tissues using quantitative real time PCR analysis. Clinically, we observed that ADAMTS9-AS1 expression was associated with TNM stage, lymph node metastasis and poor prognosis in NSCLC patients. By performing loss-of-function assay in A549 and 95D cells, our in vitro experiments further showed that knockdown of ADAMTS9-AS1 remarkedly suppressed cell proliferation, caused cell cycle G0/G1 arrest and apoptosis, and inhibited cell migration and invasion in NSCLC cells using CCK-8, colony formation, flow cytometry and transwell assays. Moreover, we found that ADAMTS9-AS1 knockdown downregulated the expression of CDK4, N-cadherin, Vimentin, but upregulated the expression of Bad and E-cadherin. In summary, our results revealed that ADAMTS9-AS1 may serve as a potential therapeutic target for the treatment of patients with NSCLC.

Digital filtering ghost imaging to remove light disturbances.

Ghost imaging (GI) can reconstruct the image of an object when the light traveling from the object to the detector is scattered or distorted. It is usually used in complicated environments, where the environmental light may heavily impact measurement. However, the traditional GI algorithm will be seriously affected if the environmental light changes during the measurement. In this paper, we analyze the frequency of environmental light and the light source, and introduce a digital filtering method that can improve the image quality of the traditional GI algorithm. Compared to the traditional GI algorithm, the digital filtering method can obtain an image even if the environmental light changes seriously.

Small nucleolar RNA host gene 22 (SNHG22) promotes the progression of esophageal squamous cell carcinoma by miR-429/SESN3 axis.

BACKGROUND: It has been observed that lncRNAs have been taking part in many cancer progressions, including non-small cell lung cancer and gastric cancer. Meanwhile, lncRNA small nucleolar RNA host gene 22 (SNHG22) has been studied, taking part in the progression of ovarian epithelial carcinoma. However, we know little about the function of SNHG22 in esophageal squamous cell carcinoma (ESCC). METHODS: In this study, we will explore the inner mechanism of SNHG22 in ESCC. Quantitative real-time PCR (qRT-PCR) assay was implemented in ESCC cells for detecting the expression of lncRNA, SNHG22, and miR-429. Also, functional experiments, including CCK8 and colony formation assay, were implemented to assess the growth of ESCC cells. Meanwhile, flow cytometry analysis was conducted to test the apoptosis of ESCC cells. The immunofluorescence (IF) assay and western blot were conducted to verify the autophagy of ESCC cells. RESULTS: Inhibition of SNHG22 was found that can inhibit the progression and promotes autophagy and apoptosis of ESCC cells. Meanwhile, as subcellular fraction assay and FISH assay found that SNHG22 mainly in the cytoplasm, miR-429 was found can bind to SNHG22 and SESN3 by RIP assay and luciferase reporter assay. SESN3 was found it can play the oncogene in ESCC cells. CONCLUSIONS: SNHG22 promotes the progression of ESCC by the miR-429/SESN3 axis.

Collapse Mechanism of Single-Layer Cylindrical Latticed Shell under Severe Earthquake.

In this paper, the results of finite element analyses of a single-layer cylindrical latticed shell under severe earthquake are presented. A 3D Finite Element model using fiber beam elements is used to investigate the collapse mechanism of this type of shell. The failure criteria of structural members are simulated based on the theory of damage accumulation. Severe earthquakes with peak ground acceleration (PGA) values of 0.5 g are applied to the shell. The stress and deformation of the shell are studied in detail. A three-stage collapse mechanism "double-diagonal -members-failure-belt" of this type of structure is discovered. Based on the analysis results, measures to mitigate the collapse of this type of structure are recommended.

Effect of miR-19b on the protective effect of Exendin-4 on islet cells in non-obese diabetic mice.

This study analyzed the effect of miR-19b on the protective effect of Exendin-4 on islet cells in non-obese diabetic (NOD) mice. Twenty-four NOD/LT mice were randomized, according to the random number table, into a control group (4 µg/kg•day), a low-dose group (2 µg/kg•day Exendin-4), a medium-dose group (4 µg/kg•day Exendin-4) and a high-dose group (8 µg/kg•day Exendin-4) (n=6), with miR-19b expression interfered (an interference group) except for the control group. RT-qPCR was used to detect interference results and different doses of Exendin-4 were given for 8 weeks of intervention after the interference. CD4+ and CD8+ cell levels were detected by flow cytometry, IL-2 and IL-10 levels in the peripheral blood by enzyme-linked immunosorbent assay, and the apoptosis rate of islet cells in the pancreatic tissue by TUNEL. After 4 and 8 weeks of Exendin-4 intervention, mice in the high-dose group had lower blood glucose level than the medium-dose group (P<0.05). The medium-dose group had lower CD4+ cell level than the high-dose group (P<0.05), while the medium-dose group had higher CD8+ cell level than the high-dose group (P<0.05). After 8 weeks of intervention, compared with the medium-dose group, the high-dose group had lower IL-2 level (P<0.05), but higher IL-10 level (P<0.05). After 8 weeks of intervention, the medium-dose group had a higher apoptosis rate than the high-dose group (P<0.05). In conclusion, the decrease in miR-19b expression can improve the therapeutic effect of Exendin-4 on NOD, control blood glucose effectively and improve inflammatory response and immune function, as well as reduce islet cell injury. The increase in the dose of Exendin-4 can further improve its therapeutic effect on NOD.

Exendin-4 prevented pancreatic beta cells from apoptosis in (Type I) diabetic mouse via keap1-Nrf2 signaling.

IMPACT STATEMENT: Nrf2 is an essential part of the defense mechanism of vertebrates and protects them from surrounding stress via participation in stimulated expression of detoxification as well as antioxidant enzymes. It also exerts a role in defending hosts from different stress in the environment, including reactive oxygen species. Our study investigates the role of exendin-4 on Nrf2 pathway as well as cell death in pancreatic ß-cell and in non-obese diabetic mice. Result of study indicates exendin-4 mediates activation of Keap1-Nrf2-ARE pathway and may serve as a potential agent to treat type I diabetes mellitus. In our research, we observed excessive reactive oxygen species production, low level of cell death, and PKC phosphorylation on exendine-4 treatment. Nrf2 knockdown led to suppression of reactive oxygen species generation as well as increasing apoptosis. Moreover, siRNA-mediated Nrf2 down-regulation attenuated the suppressive effect of exendin-4 in pancreatic ß-cell viability, via modulating apoptosis promoting- and counteracting-proteins, Bax, and Bcl-2.

KEAP1/NRF2 axis regulates H2O2-induced apoptosis of pancreatic ß-cells.

In human pancreatic ß-cells, oxidative stress and cellular injures can be induced by H2O2 treatment. The KEAP1/NRF2 axis is a key antioxidant signaling pathway. The present study attempted to elucidate the mechanism by which the KEAP1/NRF2 axis mediates oxidative stress-induced death in pancreatic ß-cells. Our data showed that H2O2 treatment obviously induced the apoptosis of ß-cells. Further experiments demonstrated that KEAP1 expression was downregulated in H2O2-treated pancreatic ß-cells and this change correlated with increase in the cellular abundance and nuclear translocation of NRF2. The restoration of KEAP1 expression in cells resulted in a recovery of cell proliferation and inhibition of apoptosis. Furthermore, we found that KEAP1 overexpression negatively regulated the abundance of NRF2, subsequently causing decreased antioxidant response element activation. This led to HO-1 protein downregulation in H2O2-treated human pancreatic ß-cells, which was also observed in NRF2-silenced ß-cells. Conversely, the silencing of KEAP1 led to NRF2 upregulation and inhibited ARE and HO-1 signaling in pancreatic ß-cells. The increase in the abundance of NRF2 following treatment with H2O2 drastically elevated the production of BAX, FAS, FAS-L, CASP-3, and CASP-9, and this change was reversed by KEAP1 overexpression or NRF2 silencing. Taken together, H2O2 treatment activated KEAP1/NRF2 signaling to promote the production of pro-apoptotic factors and consequently led to the apoptosis of human pancreatic ß-cells.

Noninvasive evaluation of gastric emptying and gastric wall thickness in SLE patients.

OBJECTIVE: The objective of this study is to evaluate the gastric emptying in patients with systemic lupus erythematosus (SLE) with gastrointestinal involvement using three-dimensional (3D) ultrasonography. METHODS: The gastric emptying times at 25% (T1), 50% (T2), and 75% (T3) of SLE patients with gastrointestinal involvement (n = 40) and healthy controls (n = 80) were evaluated and compared. In addition, the correlations among the gastric wall thickness, SLE disease activity index (SLEDAI), and upper gastrointestinal symptoms were calculated. RESULTS: The gastric wall thickness was correlated with the SLEDAI (r = 0.928, p < 0.001) and the upper gastrointestinal symptom index (r = 0.848, p < 0.001). The emptying times T1, T2, and T3 of the SLE patients were 17.08 ± 2.65 min (mean ± standard deviation), 39.85 ± 6.54 min, and 83.58 ± 7.12 min, respectively. For healthy controls, they were 19.65 ± 5.39 min, 41.08 ± 7.51 min, and 70.34 ± 8.03 min. The T1 of the SLE patients was shorter (p < 0.01), while the T3 was longer (p < 0.001). Moreover, T3 in the SLE group had the best correlation with the upper gastrointestinal symptom index (r = 0.553, p < 0.001). T1 in the SLE group was anti-correlated with early satiety (r = -0.366, p < 0.05). CONCLUSIONS: Combining the emptying times T1 and T3, as well as the gastric wall thickness, the SLEDAI and the upper gastrointestinal symptoms index can provide accurate clinical diagnosis of SLE with gastric involvement.

The influence of exendin-4 intervention on -obese diabetic mouse blood and the pancreatic tissue immune microenvironment.

The aim of the study was to determine the influence of exendin-4 intervention on non-obese diabetic (NOD) mouse blood and the pancreatic tissue immune microenvironment. A total of 40 clean NOD mice were used in the study and randomly divided into 4 groups (n=10/group). The first group was blank control group D with normal saline intervention, and with different doses of exendin, i.e.,-4 2, 4 and 8 µg/kg/day. The three remaining groups were: i) Low-dose group A; ii) medium-dose group B; and iii) high-dose group C. Mice in the four groups went through intervention for 8 weeks. Their mass and blood glucose levels were tested each week. After 8 weeks, the mice were sacrificed, and mouse serum samples were reserved. The ELISA method was used to test peripheral blood (PB), IL-2, IFN-γ and IL-10 levels. Pancreatic samples were created. Immunohistochemistry was used to observe the infiltration degree of mouse pancreatitis and the local expression state of pancreatic IL-10. Mouse pancreatic tissues were suspended in pancreatic cell suspension. Flow cytometry was used to test the state of T-cell subsets CD4 and CD25. Mouse pancreatitis in control group D was mainly at grade 2and 3. Under a light microscope, it was observed that pancreatic cell morphology was in disorder, and the size and quantity of the pancreas was small. Mouse pancreatitis in the exendin-4 low-dose group A, medium-dose group B and high-dose group C was mainly at grade 0 and 1. Under a light microscope, it was observed that pancreatic cell morphology improved, the infiltration degree of lymphocyte was improved and pancreatic islet size was restored somewhat. Additionally, a few brownish granules were identified within the pancreatic sample cells in control group D. There were many brownish granules with deep color within the pancreatic sample cells in exendin-4 low-dose group A, medium-dose group B and high-dose group C. IL-10 immunohistochemistry scores in the low-dose group A, medium-dose group B and high-dose group C were 3.82±0.72, 4.34±0.86 and 4.81±0.94, respectively, and were higher than the score of 2.25±0.63 in control group D. CD4+CD25+T-cell proportions in mouse pancreatic tissues of low-dose group A, medium-dose group B and high-dose group C were 5.31, 5.53 and 5.74%, respectively, which were higher than that of the CD4+CD25+T-cell proportion (1.62% in control group D). The CD4+CD25high T-cell proportion in CD4+T-cells in group A, B and C increased. Compared with control group D, serum IL-10 levels in the exendin-4 low-dose group A, medium-dose group B and high-dose group C increased (P<0.05), while levels of IL-2 and IFN-γ decreased (P<0.05). Additionally, the difference of serum IL-10, IL-2 and IFN-γ levels in the low-dose group A, medium-dose group B and high-dose group C was of statistical significance (P<0.05). Exendin-4 intervention can increase quantities of CD4 and CD8+T cells in NOD mouse pancreases, with PB IL-10 expression and local expression of IL-10 in pancreatic tissues. It also can inhibit the expression of serum IL-2 and IFN-γ, regulate the organism immune microenvironment and prevent diabetes. CD4+CD25high T cells increase in NOD tumor infiltration lymphocytes mediated by exendin-4 intervention, which may be related to the fact that exendin-4 inhibits the lethal effect of CD8+T cells through contact among cells and eventually exerts immunosuppressive effect.

Evaluation of gastric blood supply in diabetic patients with gastroparesis by contrast-enhanced ultrasound.

OBJECTIVE: Improvement in regional blood flow has been shown to ameliorate diabetic gastroparesis. We compared the gastric blood supply in patients with diabetes with gastroparesis with that in healthy subjects, by using contrast-enhanced ultrasound (CEUS). METHODS: 30 healthy subjects and 40 patients with diabetic gastroparesis were enrolled. The CEUS parameters of greater curvatures of the antrum (GCOA) and lesser curvatures of the antrum (LCOA), including peak intensity (PI) and the area under the curve (AUC), were compared between the two groups. RESULTS: Intraclass correlation coefficient (ICC) for PI in healthy subjects measured on CEUS were 0.831-0.857 and 0.803-0.823, respectively. Intra-ICC and inter-ICC values for AUC were 0.805-0.823 and 0.813-0.815, respectively. In both groups, no significant difference was observed in PI and AUC values of GCOA and LCOA (p > 0.05). The PI and AUC of GCOA and LCOA in the diabetes group were less than those in the normal group (p < 0.05). CONCLUSION: CEUS can assess stomach wall vascularity with a high reproducibility. Microcirculation in the antrum of patients with diabetic gastroparesis is poorer than that of normal group, which is consistent with the mechanisms of diabetic neuropathy. CEUS can be used for evaluation of microvascular perfusion in patients with stomach wall disease. Advances in knowledge: This was the first study to use CEUS for assessment of blood supply of the gastric wall and to compare microvascular perfusion between healthy individuals and patients with diabetes with gastroparesis.

Influx-Operated Ca(2+) Entry via PKD2-L1 and PKD1-L3 Channels Facilitates Sensory Responses to Polymodal Transient Stimuli.

The polycystic TRP subfamily member PKD2-L1, in complex with PKD1-L3, is involved in physiological responses to diverse stimuli. A major challenge to understanding whether and how PKD2-L1/PKD1-L3 acts as a bona fide molecular transducer is that recombinant channels usually respond with small or undetectable currents. Here, we discover a type of Ca(2+) influx-operated Ca(2+) entry (ICE) that generates pronounced Ca(2+) spikes. Triggered by rapid onset/offset of Ca(2+), voltage, or acid stimuli, Ca(2+)-dependent activation amplifies a small Ca(2+) influx via the channel. Ca(2+) concurrently drives a self-limiting negative feedback (Ca(2+)-dependent inactivation) that is regulated by the Ca(2+)-binding EF hands of PKD2-L1. Our results suggest a biphasic ICE with opposite Ca(2+) feedback regulation that facilitates sensory responses to multimodal transient stimuli. We suggest that such a mechanism may also occur for other sensory modalities and other Ca(2+) channels.

PKD2L1/PKD1L3 channel complex with an alkali-activated mechanism and calcium-dependent inactivation.

Polycystic kidney disease-like (PKDL) genes that are expressed in sour taste cells have been proposed to be involved in the transduction of sourness by producing off-responses, which shows a large inward current after withdrawing the acid stimuli. However, the underlying mechanisms of off-responses are still unclear. Here, we demonstrate that an alkali-activated mechanism is responsible for eliciting off-responses, as evidenced by both experimental and theoretical analyses. In addition, we showed that the decaying phase of offset responses in PKD2L1/PKD1L3 channels was substantially accelerated by extracellular Ca(2+).

Effect of CXCL10 receptor antagonist on islet cell apoptosis in a type I diabetes rat model.

In recent years, the incidence of type 1 diabetes mellitus (T1DM) has been increasing. The role of CXCL10 and its receptor, CXCR3, in the occurrence of T1DM has drawn lots of research interests, as the disease incidence was correlated with their expression levels. We thus used an antagonist of CXCR3, NBI-74330, to block the specific binding, for further observation of islet cell apoptosis in a T1MD rat model. A total of 80 SD rats were given STZ intraperitoneally for generating T1DM model. Different concentrations of NBI-74330 were then applied, followed by the collection of blood and pancreatic tissue samples. CXCL10 and CXCR3 levels were detected by enzyme linked immunosorbent assay (ELISA), followed by expressional assays in pancreatic tissues by real-time PCR, Western blotting and flow cytometry. Compared to control group, model rats had significantly elevated blood glucose level (>16.7 mmol/L), with depressed CXCL10 and CXCR3 levels compared to model group (P<0.05). After NBI-74330 treatment, mRNA and protein levels of CXCL10 and CXCR3 were significantly lowered, with significantly decreased apoptotic cell ratios compared to model group (P<0.05). CXCL10 receptor antagonist NBI-74330 can inhibit the apoptosis of pancreatic islet cells in T1DM rats.