Search

Tetrabromobisphenol A (TBBPA) and tetrabromobisphenol S (TBBPS) are widely distributed brominated flame retardants. While TBBPA has been demonstrated to stimulate adipogenesis, TBBPS is also under suspicion for potentially inducing comparable effects. In this study, we conducted a non-targeted metabolomics to examine the metabolic changes in 3T3-L1 cells exposed to an environmentally relevant dose of TBBPA or TBBPS. Our findings revealed that 0.1 µM of both TBBPA and TBBPS promoted the adipogenesis of 3T3-L1 preadipocytes. Multivariate analysis showed significant increases in glycerophospholipids, sphingolipids, and steroids relative levels in 3T3-L1 cells exposed to TBBPA or TBBPS at the final stage of preadipocyte differentiation. Metabolites set composed of glycerophospholipids was found to be highly effective predictors of adipogenesis in 3T3-L1 cells exposed to TBBPA or TBBPS (revealed from the receiver operating characteristic curve with an area under curve > 0.90). The results from metabolite set enrichment analysis suggested both TBBPA and TBBPS exposures significantly perturbed steroid biosynthesis in adipocytes. Moreover, TBBPS additionally disrupted the sphingolipid metabolism in the adipocytes. Our study presents new insights into the obesogenic effects of TBBPS and provides valuable information about the metabolites associated with adipogenesis induced by TBBPA or TBBPS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To examine the correlation between Atherogenic Index of Plasma (AIP) levels and the progression of non-target lesion vascular disease following the deployment of Drug-eluting Stents (DES)., Methods: We retrospectively enrolled patients who had undergone successful treatment for CAD with DES and subsequently underwent a coronary angiography follow-up at the Cardiology Department of Tianjin Third Central Hospital from January 2017 to July 2022. The annual change in Gensini Score (GS) was calculated according to two angiographic evaluations in order to assess the progression of non-target lesion vascular disease; a change greater than 1 indicated progression, while a change of 1 or less indicated stability. AIP was calculated according to serum lipid parameters. Multivariate Logistic regression model was used to evaluate the relationship between AIP level and progression of non-target coronary artery lesions. The ROC curve analysis was performed to evaluate the diagnostic value of AIP for coronary artery non-target lesion vascular disease progression., Results: Out of the 344 patients who were monitored over a median duration of 1.2 years, 113 exhibited progression of non-target lesion vascular disease. Initially, baseline AIP levels were notably higher in the progression group compared to the non-progression group (0.30 [0.14, 0.43] vs. 0.11 [-0.06, 0.31]), and this difference remained significant during the follow-up period (0.19 [0.06, 0.34] vs. 0.11 [-0.06, 0.22]). Multivariate logistic regression revealed that AIP is an independent predictor for the progression of non-target lesion vascular disease following DES treatment. Individuals in the highest tertile of AIP faced a considerably elevated risk compared to those in the lowest tertile (OR = 4.88, 95% CI: 2.12-11.21, P < 0.001). Moreover, utilizing receiver operating characteristic curve analysis, a 0.15 AIP level cut-off was determined for diagnosing disease progression, with a sensitivity of 73.5% and specificity of 56.7%, and an area under the curve of 0.672 (95% CI: 0.613-0.731, P < 0.01)., Conclusion: AIP significantly correlates with the progression of non-target lesion vascular disease among patients with coronary artery disease who have undergone DES treatment, establishing itself as an independent risk factor in addition to conventional predictors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Hypochloremia and red blood cell distribution width (RDW) play important roles in congestive heart failure (CHF) pathophysiology, and they were associated with the prognosis of CHF. However, the prognostic value of chloride combined with RDW in patients with CHF remains unknown., Methods: We retrospectively analyzed critically ill patients with CHF. The database was derived from the Medical Information Mart for Intensive Care IV v2.0 (MIMIC-IV-v2.0) database., Results: In the final analysis, 5376 critically ill patients with CHF were included, and 2428 patients (45.2 %) experienced 5-year mortality. The restricted cubic spline model revealed a positive correlation between RDW and 5-year mortality, whereas chloride showed a U-shaped correlation with 5-year mortality. The median values of RDW and chloride were used to classify patients into four groups: high chloride/low RDW, low chloride/low RDW, high chloride/high RDW, and low chloride/high RDW. We observed the prognostic value of RDW combined with chloride in the Cox proportional hazard model, in predicting 5-year mortality, in-hospital mortality and 1-year mortality. Furthermore, we discovered that patients with chronic kidney disease (CKD) had a higher 5-year mortality risk than patients without CKD., Conclusion: We found the translational potential role of chloride combined with RDW in prioritizing patients at high risk for short- and long-term mortality in a cohort of critically ill patients with CHF. Prospective multicenter investigations are warranted to validate our results., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Renal dysfunction is associated with increased mortality and length of hospital stay in critically ill patients. However, it remains unclear whether the early administration of an angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) for intensive care unit patients with renal dysfunction is associated with reduced in-hospital mortality. We conducted a retrospective analysis of critically ill patients who received early administration of an ACEI/ARB within 72 hours after being hospitalized. Patients were selected from the Medical Information Mart for Intensive Care IV database. We included 18,986 critically ill patients in our analysis. After propensity score matching, our final study cohort of 4974 patients consisted of patients who received early administration of an ACEI/ARB (n = 2487) and nonusers (n = 2487). Results of logistic regression showed that early administration of an ACEI/ARB was associated with reduced risk of in-hospital mortality (odds ratio, 0.64; 95% confidence interval, 0.53-0.77; P < .001) and intensive care unit death (odds ratio, 0.56; 95% confidence interval, 0.45-0.70; P < .001) when compared to nonusers. There was no meaningful interaction for early administration of an ACEI/ARB versus nonusers across estimated glomerular filtration rate in outcomes. Sensitivity analysis showed there was no difference in the outcomes between early administration of ACEI and that of ARB. In this study, we found that early administration of an ACEI/ARB was associated with a reduced risk of in-hospital adverse outcomes based on renal function among critically ill patients. There was no interaction between early administration of an ACEI/ARB and in-hospital adverse outcomes across estimated glomerular filtration rate., (© 2023, The American College of Clinical Pharmacology.)

Background: Myofascial pain syndrome (MPS) is a common cause of neck pain, which is a global public health problem. Because MPS does not present morphological changes within lesioned muscles, there are no imaging diagnostic criteria for this condition. In this study, we evaluate elasticity changes in upper trapezius muscles most frequently involved in cervical MPS using real-time ultrasound shear-wave elastography, and we examine their potential diagnostic value., Methods: We consecutively enrolled 109 right posterior neck pain patients for this prospective study. Of these, 51 were diagnosed with MPS and 58 with non-MPS in the right side of their neck. Among MPS patients, 19 fell into the 1-3 range (mild pain) for pain scores on the visual analog scale (VAS), 25 fell into the 4-6 range (moderate pain), and 7 into the 7-10 range (severe pain). MPS was diagnosed by two independent clinicians using the diagnostic criteria proposed by Simons et al. Using real-time ultrasound shear-wave elastography, we measured right trapezius mean shear-wave velocity (SWV mean ). The midpoint of the line between the foramen magnum and the end of the right acromion served as measuring point. Regions of interest were scaled to span 0-8.0 m/s., Results: Trapezius SWV mean was significantly higher in MPS patients compared with non-MPS patients (P<0.001). Stratified analysis of MPS patients according to pain severity revealed similar trapezius SWV mean between mild pain and non-MPS patients (P=0.324), however SWV mean was higher in moderate and severe pain MPS patients compared with non-MPS patients (P<0.001). The area under the curve (AUC) value for upper trapezius SWV mean in MPS patients was 0.791 (95% CI: 0.703-0.863). Corresponding sensitivity and specificity values were 86.27% (95% CI: 73.7-94.3%) and 62.07% (95% CI: 48.4-74.5%). Stratified analysis of MPS patients by pain severity produced the following AUC values for trapezius SWV mean in MPS patients with mild, moderate, and severe pain: 0.578 (95% CI: 0.460-0.690), 0.899 (95% CI: 0.814-0.955), and 0.983 (95% CI: 0.914-0.999), respectively., Conclusions: Elasticity changes and increased stiffness in the trapezius occur in cervical MPS patients with moderate and severe pain. The SWV mean parameter reflecting trapezius muscle elasticity may be valuable for successful screening of cervical MPS, especially in patients with moderate and severe pain., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-797/coif). QX is a staff member at the Business Division of Hologic (Shanghai) Medical Supplies Co., Ltd. and assisted with the scientific research for data processing. The other authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Obesity is prevalent in rural areas of China, and there are inconsistent findings regarding the association between metal(loid) exposure and the risk of obesity. Abdominal obesity (AOB), which reflects visceral fat abnormity, is a crucial factor in studying obesity-related diseases. We conducted a study measuring 20 urinary metal(loid)s, 13 health indicators, and the waist circumference (WC) in 1849 participants from 10 rural areas of China to investigate their relationships. In the single exposure models, we found that urinary chromium (Cr) was significantly associated with the odds of having AOB [adjusted odds ratio (OR) = 1.81 (95% confidence interval (CI): 1.24, 2.60)]. In the mixture exposure models, urinary Cr consistently emerged as the top contributor to AOB, while the overall effect of mixed metal(loid)s was positive toward the odds of having AOB [adjusted OR: 1.33 (95% CI: 1.00, 1.77)], as revealed from the quantile g-computation model. After adjusting for the effects of other metal(loid)s, we found that the elevation of apolipoprotein B and systolic blood pressure significantly mediated the association between urinary Cr and the odds of having AOB by 9.7 and 19.4%, respectively. Our results suggest that exposure to metal(loid)s is a key factor contributing to the prevalence of AOB and WC gain in rural areas of China.

Objective: To investigate the differences in the viscoelastic properties between normal trapezius muscles and those in patients with trapezius myofascial pain syndrome (MPS) using real-time shear-wave elastography (SWE)., Materials and Methods: This study included 31 patients with trapezius MPS and 31 volunteers. Sixty-one trapezius muscles (41 and 20 on the affected and non-affected side, respectively) of patients with MPS and 62 normal trapezius muscles in volunteers were assessed. Conventional ultrasonic parameters, including skeletal muscle thickness, resistance index (RI), and mean shear wave velocity (SWV mean ) of trapezius muscles, were obtained in the seated position with the shoulders and neck relaxed. The daily neck leaning time (unit:hours) of all participants was obtained using a questionnaire., Results: Ultrasound showed no statistically significant differences in thickness or RI of the trapezius muscles of the affected and non-affected sides in MPS patients versus normal trapezius muscles ( p  = 0.976 and 0.106, respectively). In contrast, the SWV mean of trapezius muscles in patients with MPS was significantly higher than that of normal trapezius muscles in both the affected and non-affected sides (4.41 ± 1.02 m/s vs. 3.35 ± 0.79 m/s, p  < 0.001; 4.05 ± 0.63 m/s vs. 3.35 ± 0.79 m/s, p  = 0.002). There was no significant difference between the SWV mean of the trapezius muscles on the affected and non-affected sides in patients with MPS (4.41 ± 1.02 m/s vs. 4.05 ± 0.63 m/s, p  = 0.225). Correlation analysis showed that daily neck forward time was positively correlated with the SWV mean of the trapezius muscles on the affected and non-affected sides in patients with MPS ( r  = 0.635, p  < 0.001; r  = 0.576, p  = 0.008)., Conclusion: SWE can quantitatively evaluate stiffness of trapezius muscles in patients with trapezius MPS. The stiffness of both affected and non-affected trapezius muscles increased in patients with trapezius MPS, and the degree of increase positively correlated with the time of cervical forward leaning.

PURPOSE We aimed to examine the usefulness of utilizing a specific contrast-enhanced computed tomog raphy (CT) region of interest (ROI) to differentiate renal oncocytoma (RO) from small clear cell renal cell carcinoma (ccRCC) and chromophobe renal cell carcinoma (chRCC). METHODS A retrospective analysis of pre-contrast phase (PCP), corticomedullary phase (CMP), and nephro graphic phase (NP) contrast-enhanced CT images of the histopathologically confirmed initial cohort (27 ROs, 74 ccRCCs, and 36 chRCCs) was conducted. Small, medium, large, and whole ROIs (S-ROI, M-ROI, L-ROI, and W-ROI, respectively) were utilized for CT attenuation value of tumor (AVT), lesion-to-cortex attenuation (L/C), and heterogeneous degree of tumor (HDT) calcula tions. Differences in these parameters were then compared between RO and ccRCC/chRCC, with receiver operating characteristic (ROC) curves being utilized to gauge the diagnostic utility of the statistically significant parameters. Logistic regression analyses were employed to identify key factors capable of differentiating RO and ccRCC/chRCC, with predictive models further being established. A validation cohort (6 ROs, 30 ccRCCs, and 12 chRCCs) was then employed to vali date the performance of the predictive models. RESULTS Of the parameters evaluated using different ROIs, L/C-CMP (S-ROI) (0.88 ± 0.15 vs. 1.13 ± 0.25, P < .001) and HDT-CMP (W-ROI) (23.02 (12.00-51.21) vs. 37.81 (16.09-89.45), P < .001) were best suited to differentiating RO and ccRCC, yielding respective area under the curve (AUC) values of 0.803 and 0.834. AVT-NP (S-ROI) (122.85 ± 18.87 vs. 86.50 ± 18.65, P < .001) and AVT-NP (M-ROI) (119 (86-167) vs. 81.5 (53-142), P < .001) were better able to differentiate RO and chRCC, yielding respective AUC values of 0.918 and 0.906. Logistic regression analyses revealed that L/C-CMP (S-ROI) and HDT-PCP, as well as AVT-NP (S-ROI) and HDT-CMP, were the primary factors capable of differentiating RO from ccRCC and chRCC, respectively. The predictive model developed to dif ferentiate between RO and ccRCC exhibited a sensitivity of 66.67% and 55.14% in the initial and validation cohorts, respectively, with corresponding specificity of 94.59% and 93.55%, accuracy of 87.13% and 86.84%, and AUC of 0.908 and 0.876. The predictive model developed to differ entiate between RO and chRCC exhibited a sensitivity of 85.19% and 100.00% in the initial and validation cohorts, respectively, with corresponding specificity of 94.59% and 92.86%, accuracy of 87.30% and 95.24%, and AUC of 0.944 and 0.959. CONCLUSION These data demonstrate that a combination of quantitative parameters measured with particu lar ROIs can enable the efficient and reliable differentiation of RO from ccRCC and chRCC for use in routine patient differential diagnosis.

Hermansky-Pudlak syndrome (HPS) is characterized by defects of multiple tissue-specific lysosome-related organelles (LROs), typically manifesting with oculocutaneous albinism or ocular albinism, bleeding tendency, and in some cases with pulmonary fibrosis, inflammatory bowel disease or immunodeficiency, neuropsychological disorders. Eleven HPS subtypes in humans and at least 15 subtypes in mice have been molecularly identified. Current understanding of the underlying mechanisms of HPS is focusing on the defective biogenesis of LROs. Compelling evidences have shown that HPS protein-associated complexes (HPACs) function in cargo transport, cargo recycling, and cargo removal to maintain LRO homeostasis. Further investigation on the molecular and cellular mechanism of LRO biogenesis and secretion will be helpful for better understanding of its pathogenesis and for the precise intervention of HPS., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Rev-erbα represents a powerful transcriptional repressor involved in immunity. However, the regulation, function, and clinical relevance of Rev-erbα in Helicobacter pylori infection are presently unknown., Methods: Rev-erbα was examined in gastric samples from H pylori-infected patients and mice. Gastric epithelial cells (GECs) were isolated and infected with H pylori for Rev-erbα regulation assays. Gastric tissues from Rev-erbα -/- and wild-type (littermate control) mice or these mice adoptively transferred with CD4 + T cells from IFN-γ -/- and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erbα were examined for bacteria colonization. GECs, CD45 + CD11c - Ly6G - CD11b + CD68 - myeloid cells and CD4 + T cells were isolated, stimulated and/or cultured for Rev-erbα function assays., Results: Rev-erbα was increased in gastric mucosa of H pylori-infected patients and mice. H pylori induced GECs to express Rev-erbα via the phosphorylated cagA that activated ERK signaling pathway to mediate NF-κB directly binding to Rev-erbα promoter, which resulted in increased bacteria colonization within gastric mucosa. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and β-defensin-1 expression, which resulted in impaired bactericidal effects against H pylori of these antibacterial proteins in vitro and in vivo; but also directly inhibited chemokine CCL21 expression, which led to decreased gastric influx of CD45 + CD11c - Ly6G - CD11b + CD68 - myeloid cells by CCL21-CCR7-dependent migration and, as a direct consequence, reduced bacterial clearing capacity of H pylori-specific Th1 cell response., Conclusions: Overall, this study identifies a model involving Rev-erbα, which collectively ensures gastric bacterial persistence by suppressing host gene expression required for local innate and adaptive defense against H pylori., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the correlation between breast cancer magnetic resonance imaging features and immune molecular subtypes., Patients and Methods: A total of 129 breast cancer patients were selected as the research object. All the patients were diagnosed by histopathology. All of them had breast magnetic resonance imaging and examination data of immunohistochemical (IHC) ER, PR, HER-2, and Ki-67. The correlation of breast cancer magnetic resonance imaging features with different immune molecular subtypes was retrospectively analyzed., Results: Breast cancer is divided into different molecular subtypes. There were 72 cases with Luminal A type (55.81%), 20 cases with Luminal B type (15.50%), 14 cases with HER-2+ type (HER-2 type for over-expression) (10.85%), 23 cases with TNBC type (ER, PR and HER-2 were negative) (17.84%). The magnetic resonance imaging features of breast cancer were included, the post-enhanced morphology, margins, internal enhancement features, time-signal intensity curve (TIC) and molecular subtype expression of lesions were significantly correlated with the immune molecular subtypes (C=0.602, 0.439, 0.350 and 0.407, p=0.000, 0.000, 0.006 and 0.000). Lesion morphology: Luminal A type was mainly oval, accounting for 76.39% (55/76). Luminal B type and HER-2+ type was mainly irregular, accounting for 75.00% (15/20) and 64.29% (9/14) respectively. TNBC type was mainly shown as lobulation, accounting for 60.87% (14/23). Margin of the lesion: Luminal A type was mainly smooth margin, accounting for 73.61% (53/72). Luminal B type and TNBC type were mainly irregular margin, accounting for 70.00% (14/20) and 56.52% (13/23) respectively. The margin of HER-2+ type was mainly spiculation, accounting for 64.29% (9/14). The internal enhancement features: Luminal A type was mainly even enhancement, accounting for 62.50% (45/72). Luminal B type and HER-2+ type were mainly heterogeneous enhancement, accounting for 65.00% (13/20) and 64.29% (9/14) respectively. TNBC type was mainly annular enhancement, accounting for 73.91% (17/23). TIC type: Luminal A type was mainly Type II, accounting for 66.67% (48/72). Luminal B, HER-2+ type and TNBC type was mainly Type III, accounting for 70.00% (14/20), 64.29% (9/14) and 60.87% (14/23) respectively. The clinical signs include painless breast lumps, bloody breast discharge, and orange peel-like skin changes, nipple retraction and nipple elevation. There is no significant correlation between the above signs and the expression of molecular subtypes (C=0.014, 0.129, 0.154, 0.097 and 0.057, p=0.999, 0.533, 0.447, 0.747 and 0.935 respectively), the difference is not statistically significant (p>0.05)., Conclusions: The characteristics of breast cancer magnetic resonance imaging was certainly correlated with the expression of immune molecular subtypes. The breast cancer molecular subtypes can be predicted by the imaging signs, which can provide valuable information for preoperative neoadjuvant treatment of breast cancer.

Diethylhexyl phthalate (DEHP) is known as a persistent environmental pollutant. However, the possible effects of DEHP on human neural tube defects (NTDs) remain elusive. We set out to investigate the exposure of DEHP in human and explore the association of DEHP and NTDs. The level of DEHP in maternal urine was measured and analyzed by GC-MS. To further validate the results in human NTDs, chick embryos were used as animal models. Viability, reactive oxygen species (ROS) level, oxidative stress indicators and apoptosis were detected in DEHP-treated chick embryos. Our research revealed that the detection ratio of positive DEHP and its metabolites in maternal urine were observed dramatically higher in NTDs population than that in normal controls ( P <  0.01, P <  0.05, respectively). Moreover, DEHP treatment (10 -6  M) led to developmental toxicity in chick embryos via accelerating oxidative stress response and cell apoptosis, and changing the level of oxidative stress-related indicators. Moreover, high dose choline (100 μg/μl) could partially restrain the toxicity effects induced by DEHP. Our data collectively imply that the incidence of NTDs may closely associate with DEHP exposure, which disturbs the development of neural tubes by enhancing oxidative stress., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Arrestin domain containing 3 (ARRDC3) represents a newly discovered α-arrestin involved in obesity, inflammation, and cancer. Here, we demonstrate a proinflammation role of ARRDC3 in Helicobacter pylori-associated gastritis. Increased ARRDC3 was detected in gastric mucosa of patients and mice infected with H. pylori. ARRDC3 in gastric epithelial cells (GECs) was induced by H. pylori, regulated by ERK and PI3K-AKT pathways in a cagA-dependent manner. Human gastric ARRDC3 correlated with the severity of gastritis, and mouse ARRDC3 from non-BM-derived cells promoted gastric inflammation. This inflammation was characterized by the CXCR2-dependent influx of CD45+CD11b+Ly6C-Ly6G+ neutrophils, whose migration was induced via the ARRDC3-dependent production of CXCL2 by GECs. Importantly, gastric inflammation was attenuated in Arrdc3-/- mice but increased in protease-activated receptor 1-/- (Par1-/-) mice. Mechanistically, ARRDC3 in GECs directly interacted with PAR1 and negatively regulated PAR1 via ARRDC3-mediated lysosomal degradation, which abrogated the suppression of CXCL2 production and following neutrophil chemotaxis by PAR1, thereby contributing to the development of H. pylori-associated gastritis. This study identifies a regulatory network involving H. pylori, GECs, ARRDC3, PAR1, and neutrophils, which collectively exert a proinflammatory effect within the gastric microenvironment. Efforts to inhibit this ARRDC3-dependent pathway may provide valuable strategies in treating of H. pylori-associated gastritis.

Benzyl butyl phthalate (BBP) is a persistent environmental pollutant. BBP exposure and the possible effects on human neural tube defects (NTDs) remain elusive. In this study, we found that the detection ratio of positive BBP and its metabolites in maternal urine was obviously higher in NTDs' population than that in normal controls by GC-MS ( P <  0.01, P <  0.05, respectively). Animal experiments showed that BBP treatment induced developmental toxicity in chick embryo by enhancing the levels of oxidative stress and cell apoptosis ( P <  0.01). More interestingly, the supplement of high-dose choline (CHO, 10 5  μg/mL) could partially restore the teratogenic effects of BBP by inhibiting the occurrence of oxidative stress. Our data collectively suggest that BBP exposure may disturb neural tube development by strengthening oxidative stress. CHO can partially restore the toxicity effects of BBP. This study may provide new insight for NTD prevention., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

BHLHE40, a member of the basic helix-loop-helix transcription factor family, has been reported to play an important role in inflammatory diseases. However, the regulation and function of BHLHE40 in Helicobacter pylori (H pylori)-associated gastritis is unknown. We observed that gastric BHLHE40 was significantly elevated in patients and mice with H pylori infection. Then, we demonstrate that H pylori-infected GECs express BHLHE40 via cagA-ERK pathway. BHLHE40 translocates to cell nucleus, and then binds to cagA protein-activated p-STAT3 (Tyr705). The complex increases chemotactic factor CXCL12 expression (production). Release of CXCL12 from GECs fosters CD4 + T cell infiltration in the gastric mucosa. Our results identify the cagA-BHLHE40-CXCL12 axis that contributes to inflammatory response in gastric mucosa during H pylori infection., (© 2019 Federation of American Societies for Experimental Biology.)

Background: Majeed syndrome is a rare, autosomal recessive autoinflammatory disorder first described in 1989. The syndrome starts during infancy with recurrent relapses of osteomyelitis typically associated with fever, congenital dyserythropoietic anemia (CDA), and often neutrophilic dermatosis. Mutations in the LPIN2 gene located on the short arm of chromosome 18 have been identified as being responsible for Majeed syndrome., Case Presentation: We report an 8-month-old boy, who presented with recurrent fever, mild to moderate anemia, and severe neutropenia. Erythrocyte sedimentation rate and C-reactive protein were elevated. Molecular testing identified a paternal splicing donor site variant c.2327 + 1G > C and a maternal frameshift variant c.1691&#95;1694delGAGA (Arg564Lysfs*3) in LPIN2., Conclusions: Only a few cases with LPIN2 mutation have been reported, mainly in the Middle East with homozygous variants. Our patient exhibited a mild clinical phenotype and severe neutropenia, different from previous reports.

The interaction between gastric epithelium and immune response plays key roles in H. pylori -associated pathology. We demonstrated a procolonization and proinflammation role of MMP-10 in H. pylori infection. MMP-10 is elevated in gastric mucosa and is produced by gastric epithelial cells synergistically induced by H. pylori and IL-22 via the ERK pathway. Human gastric MMP-10 was correlated with H. pylori colonization and the severity of gastritis, and mouse MMP-10 from non-BM-derived cells promoted bacteria colonization and inflammation. H. pylori colonization and inflammation were attenuated in IL-22 -/- , MMP-10 -/- , and IL-22 -/- MMP-10 -/- mice. MMP-10-associated inflammation is characterized by the influx of CD8 + T cells, whose migration is induced via MMP-10-CXCL16 axis by gastric epithelial cells. Under the influence of MMP-10, Reg3a, E-cadherin, and zonula occludens-1 proteins decrease, resulting in impaired host defense and increased H. pylori colonization. Our results suggest that MMP-10 facilitates H. pylori persistence and promotes gastritis.

Cathepsin C (CtsC) functions as a central coordinator for activation of many serine proteases in immune cells. However, CtsC expression in gastric epithelial cells and its role in Helicobacter pylori infection remain unclear. Real-time PCR, Western blot, and immunohistochemistry analyses identified that CtsC was decreased in gastric mucosa of H. pylori-infected patients and mice. Isolated gastric epithelial cells and cell lines were stimulated with H. pylori and/or TGF-β1 showed that down-regulation of CtsC in gastric epithelial cells largely depended on H. pylori cagA via Src/ERK and Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways, and the effect could be synergistically augmented by TGF-β1 in an autocrine manner. In human gastric mucosa, CtsC expression was negatively correlated with bacteria colonization; accordingly, provision of exogenous active CtsC overwhelmed H. pylori persistence in gastric mucosa of mice. In the presence of active CtsC, isolated human neutrophils activated via NF-κB pathway with augmented bactericidal capacity in vitro. We also found that neutrophils activated and cleared bacteria in active CtsC-injected mice and that there was no bactericidal capacity in mice that were simultaneously neutrophil-depleted by Ly6G antibody. Our findings identified a mechanism that H. pylori abrogate CtsC to impair neutrophil activation and to ensure persistence in gastric mucosa. Efforts to enable and boost this neutrophil activation pathway by active CtsC may therefore become valuable strategies in treating H. pylori infection.-Liu, Y. G., Teng, Y. S., Cheng, P., Kong, H., Lv, Y. P., Mao, F. Y., Wu, X. L., Hao, C. J., Chen, W., Yang, S. M., Zhang, J. Y., Peng, L. S., Wang, T. T., Han, B., Ma, Q., Zou, Q. M., Zhuang, Y. Abrogation of cathepsin C by Helicobacter pylori impairs neutrophil activation to promote gastric infection.

Interleukin-17 receptor B (IL-17RB), a member of the IL-17 receptor family activated by IL-17B/IL-17E, has been shown to be involved in inflammatory diseases. However, the regulation and function of IL-17RB in Helicobacter pylori (H. pylori) infection, especially in the early-phase is still unknown. Here, we found that gastric IL-17RB mRNA and protein were decreased in gastric mucosa of both patients and mice infected with H. pylori. In vitro experiments show that IL-17RB expression was down regulated via PI3K/AKT pathway on gastric epithelial cells (GECs) stimulated with H. pylori in a cagA-involved manner, while in vivo studies showed that the effect was partially dependent on cagA expression. IL-17E was also decreased during the early-phase of H. pylori infection, and provision of exogenous IL-17E resulted in increased CD11b + CD11c - myeloid cells accumulation and decreased bacteria colonization within the gastric mucosa. In the early-phase of H. pylori infection, IL-17E-IL-17RB promoted gastric epithelial cell-derived CXCL1/2/5/6 to attract CD11b + CD11c - myeloid cells, and also contributed to host defense by promoting the production of antibacterial protein Reg3a. This study defines a negative regulatory network involving IL-17E, GECs, IL-17RB, CD11b + CD11c - myeloid cells, and Reg3a in the early-phase of H. pylori infection, which results in an impaired host defense within the gastric microenvironment, suggesting IL-17RB as a potential early intervening target in H. pylori infection.

Mast cells are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, their precise mechanism of communication in gastric cancer remains largely unclear. Here, we found that patients with GC showed a significantly higher mast cell infiltration in tumors. Mast cell levels increased with tumor progression and independently predicted reduced overall survival. Tumor-derived adrenomedullin (ADM) induced mast cell degranulation via PI3K-AKT signaling pathway, which effectively promoted the proliferation and inhibited the apoptosis of GC cells in vitro and contributed to the growth and progression of GC tumors in vivo, and the effect could be reversed by blocking interleukin (IL)-17A production from these mast cells. Our results illuminate a novel protumorigenic role and associated mechanism of mast cells in GC, and also provide functional evidence for these mast cells to prevent, and to treat this immunopathogenesis feature of GC.

Myeloid-derived suppressor cells (MDSCs) are a prominent component of the pro-tumoral response. The phenotype of and mechanisms used by MDSCs is heterogeneous and requires more precise characterization in gastric cancer (GC) patients. Here, we have identified a novel subset of CD45 + CD33 low CD11b dim MDSCs in the peripheral blood of GC patients compared to healthy individuals. CD45 + CD33 low CD11b dim MDSCs morphologically resembled neutrophils and expressed high levels of the neutrophil marker CD66b. Circulating CD45 + CD33 low CD11b dim MDSCs effectively suppressed CD8 + T cells activity through the inhibition of CD8 + T cell proliferation and interferon-γ (IFN-γ) and granzyme B (GrB) production. The proportion of CD45 + CD33 low CD11b dim MDSCs also negatively correlated with the proportion of IFN-γ + CD8 + T cell in the peripheral blood of GC patients. GC patient serum-derived IL-6 and IL-8 activated and induced CD45 + CD33 low CD11b dim MDSCs to express arginase I via the PI3K-AKT signaling pathway. This pathway contributed to CD8 + T cell suppression as it was partially rescued by the blockade of the IL-6/IL-8-arginase I axis. Peripheral blood CD45 + CD33 low CD11b dim MDSCs, as well as IL-6, IL-8, and arginase I serum levels, positively correlated with GC progression and negatively correlated with overall patient survival. Altogether, our results highlight that a subset of neutrophilic CD45 + CD33 low CD11b dim MDSCs is functionally immunosuppressive and activated via the IL-6/IL-8-arginase I axis in GC patients.

Interleukin (IL)-induced inflammatory responses are critical for the pathogenesis of Helicobacter pylori (H. pylori)-induced gastritis. IL-33 represents a recently discovered proinflammatory cytokine involved in inflammatory diseases, but its relevance to H. pylori-induced gastritis is unknown. Here, we found that gastric IL-33 mRNA and protein expression were elevated in gastric mucosa of both patients and mice infected with H. pylori, which is positively correlated with bacterial load and the degree of gastritis. IL-33 production was promoted via extracellular regulated protein kinases (ERK) signaling pathway activation by gastric epithelial cells in a cagA-dependent manner during H. pylori infection, and resulted in increased inflammation and bacteria burden within the gastric mucosa. Gastric epithelial cell-derived IL-33 promoted TNF-α production from mast cells in vitro, and IL-33 increased TNF-α production in vivo. Increased TNF-α inhibited gastric epithelial cell proliferation, conducing to the progress of H. pylori-associated gastritis and bacteria colonization. This study defined a patent regulatory networks involving H. pylori, gastric epithelial cell, IL-33, mast cell, and TNF-α, which jointly play a pathological effect within the gastric circumstances. It may be a valuable strategy to restrain this IL-33-dependent pathway in the treatment of H. pylori-associated gastritis.

Regulatory T cells (Tregs) are major components of tumor-infiltrating immune cells with potent immunosuppressive properties in gastric cancer (GC) microenvironment. However, different subsets of the Tregs and their relevance to GC are unknown. Here, we found that patients with GC showed a significantly higher Tregs infiltration in tumors, and CD45RA - CCR7 - Treg subset constituted most tumor-infiltrating Tregs. Tumor-infiltrating CD45RA - CCR7 - Treg subset with an effector/memory phenotype accumulated in tumors and expressed low level of HLA-DR. Gastric tumor-derived TNF-α induced CD45RA - CCR7 - Treg subset with similar phenotype to their status in tumors and inhibited their HLA-DR expression via activating STAT3 phosphorylation. These tumor-associated CD45RA - CCR7 - Treg subset exerted superior immunosuppressive properties to effectively suppress CD8 + T cells' anti-tumor function including CD8 + T-cell IFN-γ and granzyme B (GrB) production as well as CD8 + T-cell proliferation in vitro, and also contributed to the growth and progression of human gastric tumors in vivo, via IL-10 secretion and cell-cell contact mechanisms. Moreover, increased tumor-infiltrating CD45RA - CCR7 - Treg subset as well as higher intratumoral CD45RA - CCR7 - Treg/CD8 + T-cell ratio was associated with advanced disease progression and reduced GC patient survival. This study therefore identifies a novel immunosuppressive pathway involving CD45RA - CCR7 - Treg subset development within the GC microenvironment. Efforts to inhibit this pathway may therefore prove a valuable strategy to prevent, and to treat this immune suppressive of GC.

Searching for new regulators of autophagy involved in selective dopaminergic (DA) neuron loss is a hallmark in the pathogenesis of Parkinson disease (PD). We here report that an endoplasmic reticulum (ER)-associated transmembrane protein SLC35D3 is selectively expressed in subsets of midbrain DA neurons in about 10% TH (tyrosine hydroxylase)-positive neurons in the substantia nigra pars compacta (SNc) and in about 22% TH-positive neurons in the ventral tegmental area (VTA). Loss of SLC35D3 in ros (roswell mutant) mice showed a reduction of 11.9% DA neurons in the SNc and 15.5% DA neuron loss in the VTA with impaired autophagy. We determined that SLC35D3 enhanced the formation of the BECN1-ATG14-PIK3C3 complex to induce autophagy. These results suggest that SLC35D3 is a new regulator of tissue-specific autophagy and plays an important role in the increased autophagic activity required for the survival of subsets of DA neurons.

The balance between type 1 and type 2 T helper cells (the Th1-Th2 balance) is closely correlated with cancer, but the correlation in ovarian cancer remains unconfirmed. We investigated the Th1-Th2 balance for the diagnosis, treatment, and prognostic evaluation of ovarian cancer. Fifty healthy subjects and 50 ovarian cancer patients were recruited. The levels of various cytokines were determined in sera and ovarian cancer tissues using a Th1-Th2 human cytokine array. The usefulness of TNFα, IFNγ, TNFα/IL-4, and IFNγ/IL-4 for ovarian cancer diagnosis was assessed based on receiver operating characteristic (ROC) curves. The relationship between the TNFα/IL-4 level and survival time was investigated based on a survival curve. In the ovarian cancer patients, the levels of Th1 factors (IL-2, IFNγ, TNFα, and IL-13) increased significantly in the sera, and IFNγ and TNFα increased significantly in the ovarian cancer tissues. The levels of Th2 factors (IL-5 and IL-6) increased in the sera, but the level of IL-6 decreased significantly in the ovarian cancer tissues. Serum TNFα/IL-4 and IFNγ/IL-4 levels increased significantly in the peripheral blood of the ovarian cancer patients. ROC curve analysis revealed that TNFα, IFNγ, TNFα/IL-4, and IFNγ/IL-4 levels are useful for ovarian cancer diagnosis, with area under the curve values of 0.831, 0.753, 0.846, and 0.803, respectively. The TNFα/IL-4 level in the ovarian cancer patients was positively correlated with survival time, and the Th1-Th2 balance shifted toward Th1 in the ovarian cancer patients. The TNFα/IL-4 ratio might be useful for the diagnosis and prognosis of ovarian cancer.

Obesity is one of the largest health problems facing the world today. Although twin and family studies suggest about two-thirds of obesity is caused by genetic factors, only a small fraction of this variance has been unraveled. There are still large numbers of genes to be identified that cause variations in body fatness and the associated diseases encompassed in the metabolic syndrome (MetS). A locus near a sequence tagged site (STS) marker D6S1009 has been linked to obesity or body mass index (BMI). However, its genetic entity is unknown. D6S1009 is located in the intergenic region between SLC35D3 and NHEG1. Here we report that the ros mutant mice harboring a recessive mutation in the Slc35d3 gene show obesity and MetS and reduced membrane dopamine receptor D1 (D1R) with impaired dopamine signaling in striatal neurons. SLC35D3 is localized to both endoplasmic reticulum (ER) and early endosomes and interacts with D1R. In ros striatal D1 neurons, lack of SLC35D3 causes the accumulation of D1R on the ER to impair its ER exit. The MetS phenotype is reversible by the administration of D1R agonist to the ros mutant. In addition, we identified two mutations in the SLC35D3 gene in patients with MetS, which alter the subcellular localization of SLC35D3. Our results suggest that the SLC35D3 gene, close to the D6S1009 locus, is a candidate gene for MetS, which is involved in metabolic control in the central nervous system by regulating dopamine signaling.

Mono (2-ethylhexyl) phthalate (MEHP), an environmental contaminant, is known to cause many serious diseases, especially in reproductive system. However, little is known about the effect of MEHP on preimplantation embryo development. In this study, we found that the development of mouse 2-cell embryo was blocked by 10(-3)  M MEHP. A significant increase in the level of reactive oxygen species (ROS) was observed in arrested 2-cell embryo following 10(-3)  M MEHP treatment for 24 h. However, antioxidants, catalase (CAT), and superoxide dismutase (SOD), reduced intracellular ROS and protected MEHP-exposed embryos from death but failed to return the arrested embryos. Further experiments demonstrated that the level of apoptosis was not altered in live arrested 2-cell embryo and increased in dead arrested 2-cell embryo after MEHP treatment, which implied that ROS and apoptosis were not related with 2-cell block. During analysis of the indicators of embryonic genome activation (EGA) initiation (Hsc70, MuERV-L, Hsp70.1, eIF-1A, and Zscan4) and maternal-effect genes (OCT4 and SOX2), we found that MEHP treatment could significantly decline Hsc70, MuERV-L mRNA level and SOX2 protein level, and markedly enhance Hsp70.1, eIF-1A, Zscan4 mRNA level, and OCT4 protein level at 2-cell to 4-cell stage. Supplementation of CAT and SOD did not reverse the expression tendency of EGA related genes. Collectively, this study demonstrates for the first time that MEHP-induced 2-cell block is mediated by the failure of EGA onset and maternal-effect genes, not oxidative stress and apoptosis., (Copyright © 2012 Wiley Periodicals, Inc.)

A large-mode-area polymer photonic crystal fiber made of polymethyl methacrylate with the cladding having only one layer of air holes near the edge of the fiber is designed and proposed to be used in surface plasmon resonance sensors. In such sensor, a nanoscale metal film and analyte can be deposited on the outer side of the fiber instead of coating or filling in the holes of the conventional PCF, which make the real time detection with high sensitivity easily to realize. Moreover, it is relatively stable to changes of the amount and the diameter of air holes, which is very beneficial for sensor fabrication and sensing applications. Numerical simulation results show that under the conditions of the similar spectral and intensity sensitivity of 8.3 × 10(-5)-9.4 × 10(-5) RIU, the confinement loss can be increased dramatically.

Dibutyl phthalate (DBP), a widely used phthalate, is known to cause many serious diseases, especially in the reproductive system. However, little is known about the effects of its metabolite, mono-n-butyl phthalate (MBP), on preimplantation embryo development. In the present study, we found that treatment of embryos with 10⁻³ M MBP impaired developmental competency, whereas exposure to 10⁻⁴ M MBP delayed the progression of preimplantation embryos to the blastocyst stage. Furthermore, reactive oxygen species (ROS) levels in embryos were significantly increased following treatment with 10⁻³ M MBP. In addition, 10⁻³ M MBP increased apoptosis via the release of cytochrome c, whereas immunofluorescent analysis revealed that exposure of preimplantation embryos to MBP concentration-dependently (10⁻⁵, 10⁻⁴ and 10⁻³ M) decreased DNA methylation. Together, the results indicate a possible relationship between MBP exposure and developmental failure in preimplantation embryos.

Epidemiology studies indicate that exposure to endocrine disruptors during developmental "window" contributes to adipogenesis and the development of obesity. Implication of endocrine disruptor such as diethylstilbestrol (DES) on adipose tissue development has been poorly investigated. Here we evaluated the effects of DES on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action. DES induced 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and activated the expression of estrogen receptor (ER) and peroxisome proliferator-acivated receptor (PPAR) γ as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPARγ activity. Moreover, DES perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to low dose of DES significantly increased body weight, liver weight and fat mass in female offspring at postnatal day (PND) 60. In addition, serum triglyceride and glucose levels were also significantly elevated. These results suggest that perinatal exposure to DES may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders., (Copyright © 2012 Elsevier Inc. All rights reserved.)

By a series of experiments, we identified a new member of the locoweed family, Oxytropis serioopetala, that produces swainsonine, a phytotoxin harmful to livestock. In order to evaluate the toxicity of Oxytropis serioopetala, its extract was administered to ten rabbits by gavage at a dose of 1.5 mg/kg body weight as swainsonine once daily. After the 20th day, the rabbits appeared depressive and anorexic. In addition, intention tremors were apparent upon movement. Their eyes were dull. The rear limbs were severely weak and even progressed to partial paresis. The activities of serum aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (AKP) and urea nitrogen (BUN) levels in the poisoned rabbits increased significantly. Serum α-mannosidase (AMA) activity decreased markedly. Pathomorphological lesions in the locoweed-poisoned rabbits developed severe microvacuolation of visceral and neurological tissue. Extensive vacuolation was observed in the liver, kidney and brain. These clinical and pathological features are similar to the symptoms of locoism.

In the title complex, [Pr(2)(C(2)O(4))(3)(H(2)O)(4)](n), the two independent Pr(III) ions are both nine-coordinated in a distorted monocapped square-anti-prismatic geometry by seven O atoms from four oxalate ligands and two water mol-ecules. The Pr(III) ions are bridged by the oxalate ligands, forming a layer parallel to (001). O-H⋯O hydrogen bonds connect the layers.

A kind of surface plasmon resonance sensor based on grapefruit photonic crystal fiber (PCF) filled with different numbers of silver nanowires has been studied in this paper. The surface plasmon resonance modes and the sensing properties are investigated comprehensively using the finite element method (FEM). The simulation results show that the intensity sensitivity is related to nanowire numbers and the distance between two nanowires. The optimum value obtained is 2,400 nm/RIU, corresponding to a resolution of 4.51 × 10(-5) RIU with a maximum distance of 2 μm. To a certain extent, the PCF filled with more nanowires is better than with just one. Furthermore, the air holes of grapefruit PCF are large enough to operate in practice. Moreover, the irregularity of the filled nanowires has no effect on sensitivity, which will be very convenient for the implementation of experiments.

Background/aim: The environmental obesogen hypothesis proposes that exposure to endocrine disruptors during developmental "window" contributes to adipogenesis and the development of obesity. Implication of environmental endocrine disruptor such as 4Nonylphenol (4-NP) on adipose tissue development has been poorly investigated., Methods: 3T3-L1 preadipocytes were incubated with different doses of 4-NP. Six-week-old C57BL/6J male mice received an intraperitoneal injection of vehicle, troglitazone or 4-NP (0.5 mg/kg). Gene expression of adipogenic regulators was analyzed. Pregnant mice were dosed by gavage with vehicle or 4-NP (0.05, 0.25 or 0.5 mg/kg) from day 12 of gestation until day 7 of lactation. The body weight, liver weight, fat mass, and serum lipids and glucose levels were measured in offspring at postnatal day 60., Results: Low concentration of 4-NP induced adipocyte differentiation, glycerol-3-phosphate dehydrogenase activity, and expression of peroxisome proliferator-acivated receptor γ as well as its target genes required for adipogenesis. 4-NP perturbed key regulators of adipogenesis and lipogenic pathway in vivo. Perinatal exposure to 4-NP increased body weight, fat mass, and serum total cholesterol and glucose levels in offspring., Conclusions: 4-NP may be expected to increase the incidence of obesity and can act as a potential chemical stressor for obesity and obesity-related disorders., (Copyright © 2012 S. Karger AG, Basel.)

MiR-206 was involved in a series of cellular activities, such as the growth and development of skeletal muscle and the tumorigenesis. MiR-206 was characterized previously as a differentially expressed gene in sodium arsenite (SA)-induced neural tube defects (NTDs) in chick embryos via miRNA microarray analysis. However, the role of miR-206 in the pathological process of nerve cells remained elusive. In this study we found differential expression of miR-206 in SA-treated chick embryos by Northern blot analysis. Ectopic expression of miR-206 inhibited cell proliferation, and promoted cell apoptosis in U343 and SK-N-SH cell by using MTT, Edu Apollo assay and Flow cytometry analysis. Further investigation revealed that miR-206 can interact with 3'-untranslated region (UTR) of Otx2. MiR-206 mimics down-regulated the endogeneous Otx2 expression, whereas the miR-206 inhibitor obviously up-regulated the expression of Otx2. These findings indicate that overexpression of miR-206 promotes cell apoptosis and low expression of miR-206 inhibits cell apoptosis. Otx2 may play an important role in the process of miR-206-mediated cell apoptosis., (Copyright © 2012 S. Karger AG, Basel.)

Background: MicroRNA-101 (miR-101) expression is negatively associated with tumor growth and blood vessel formation in several solid epithelial cancers. However, the role of miR-101 in human breast cancer remains elusive., Results: MiR-101 was significantly decreased in different subtypes of human breast cancer tissues compared with that in adjacent normal breast tissues (P<0.01). Up-regulation of miR-101 inhibited cell proliferation, migration and invasion, and promoted cell apoptosis in ER alpha-positive and ER alpha-negative breast cancer cells and normal breast cells. Down-regulation of miR-101 displayed opposite effects on cell growth and metastasis. Further investigation revealed a significant inverse correlation between the expression of miR-101 and Stathmin1 (Stmn1), and miR-101 could bind to the 3'-untranslated region (UTR) of Stmn1 to inhibit Stmn1 translation. The inhibition of cell growth and metastasis induced by up-regulation of miR-101 was partially restored by overexpression of Stmn1. Knockdown of Stmn1 attenuates the down-regulation of miR-101-mediated enhancement of cell growth and metastasis. More importantly, in vivo analysis found that Stmn1 mRNA and protein level in different subtypes of human breast cancer tissues, contrary to the down-regulation of miR-101, were significantly elevated., Conclusions: This study demonstrates that down-regulation of miR-101 in different subtypes of human breast cancer tissues is linked to the increase of cellular proliferation and invasiveness via targeting Stmn1, which highlights novel regulatory mechanism in breast cancer and may provide valuable clues for the future clinical diagnosis of breast cancer.

Although there are plenty of evidence that single-nucleotide polymorphisms (SNPs) that fall within coding sequences of genes are involved in recurrent pregnancy loss (RPL), it is still unknown whether the polymorphisms in microRNAs (miRNAs) are related with RPL. In this study, we established this kind of association by confirming significant differences in genotype distribution of rs41275794 (P= 0.0005) and rs12976445 (P= 0.001) within the pri-miR-125a in 217 Han Chinese patients of RPL compared with 431 controls. Based on this observation, two-locus haplotypes were constructed and the A-T haplotype was found to be associated with an increased risk of RPL (OR=2.84, 95%C.I. 1.98-4.07, P=0.0000000057). Further analysis showed that the levels of pre- and mature- miR-125a were down-regulated in the cells transfected with the A-T haplotype, which was consistent with in vivo detection that the level of mature miR-125a was lower in 30 pregnant women with A-T haplotype than that with G-C haplotype. During in vitro RNA processing assays, we found a similar decrease in the amount of pre-miR-125a and decline in binding capacity of nuclear factors to pri-miR-125a with A-T haplotype. More importantly, the reduction in miR-125a, as a consequence of A-T haplotype, further led to less efficient inhibition of target genes, LIFR and ERBB2, which play important roles in the embryo implantation and decidualization. Thus, our data collectively suggest that two common polymorphisms in pre-miR-125a might contribute to the genetic predisposition to RPL by disrupting the production of miR-125a, which consequently interfered in the expression and function of target genes of miR-125a.

In the title compound, [Zn(C(7)H(7)N(2)O(4))(2)(H(2)O)(2)]·2C(3)H(7)NO, the Zn(II) ion, which lies on a center of inversion, is coordinated by two O atoms and two N atoms from two 4-carboxy-2-ethyl-1H-imid-azole-5-carboxyl-ato anions and two water O atoms in an octa-hedral environment, Each 4-carboxy-2-ethyl-1H-imid-azole-5-carboxyl-ato ligand adopts a bidentate chelating mode to the Zn(II) ion, forming two five-membered metalla rings. In the crystal, a two-dimensional framework parallel to (010) is formed by N-H⋯O and O-H⋯O hydrogen bonds.

The title compound, C(12)H(8)N(2)O(4), crystallizes as a zwitterion in which the pyridyl N atom is protonated. The dihedral angle between the benzene and pyridinium rings is 27.9 (2)°. In the crystal, N-H⋯O hydrogen bonds link adjacent zwitterions into a three-dimensional structure.

The title compound, [Zn(H(2)O)(6)](C(16)H(12)O(6))·H(2)O, consists of one 4,4'-(1,2-dihy-droxy-ethane-1,2-di-yl)dibenzoate anion lying on an inversion centre, one [Zn(H(2)O)(6)](2+) dication lying on a mirror plane and one solvent water mol-ecule located on a mirror plane. The octahedral [Zn(H(2)O)(6)](2+) cations, solvent water mol-ecules and anions inter-act via O-H⋯O hydrogen bonds, forming a three-dimensional network.

In the crystal structure of the title compound, [Zn(C(8)H(9)N(2)O(4))(2)(H(2)O)(2)]·2C(3)H(7)NO, the Zn(II) atom is coordinated by two N,O-bidentate 2-propyl-1H-imidazole-4,5-dicarboxyl-ate anions and two water mol-ecules in a distorted octa-hedral environment. The asymmetric unit consists of one Zn(II) atom located on a center of inversion as well as one anion, one water mol-ecule and one additional dimethyl-formamide mol-ecule that occupy general positions. Between the carboxyl and the carboxyl-ate group an intra-molecular hydrogen bond is found in which the hydroxy H atom is disordered. Disorder is also found for the H atoms of one of the three methyl groups. In the crystal structure, additional inter-molecular N-H⋯O and O-H⋯O hydrogen bonding is found.

In the title compound, [Mn(H(2)O)(6)](C(16)H(12)O(6))·H(2)O, the [Mn(H(2)O)(6)](2+) complex cation lies on a mirror plane, the 4,4'-(1,2-dihy-droxy-ethane-1,2-di-yl)dibenzoate anion is located on an inversion center and the solvent water mol-ecule also lies on a mirror plane. Extensive O-H⋯O hydrogen-bonding inter-actions between the cations, anions and water mol-ecules stabilize the three-dimensional network.

The asymmetric unit of the title compound, C(22)H(42)N(6)·2CH(4)O, comprises one half of a 14-membered tetra-azacyclo-tetra-decane macrocycle with cyano-ethyl substituents on one of the N atoms and a methanol solvent mol-ecule. The macrocycle lies about an inversion centre. The cyano-ethyl substituents are oriented so that the cyano groups lie over opposite faces of the central cavity of the macrocycle. The methanol solvate mol-ecules lie away from the cavity of the macrocycle and are linked to the macrocycles via O-H⋯N hydrogen bonds.

Schizophrenia (SCZ) is a complex trait with a high heritability. The DTNBP1 gene (encoding dysbindin) is one of the leading susceptible genes of SCZ. This risk gene has been reported to be associated with clinical symptoms such as negative symptoms and cognitive deficits. Although reduction of dysbindin expression in schizophrenic brain tissue has been reported, how this contributes to its symptomatology remains uncertain. The sandy (sdy) mouse, which harbors a spontaneously occurring deletion in the Dtnbp1 gene and expresses no dysbindin protein, provides a unique tool to study the role of dysbindin in SCZ. Our recent findings reveal that the sdy mice exhibit specific defects of neurosecretion and synaptic morphology in hippocampal neurons. We here further described that sdy manifested schizophrenia-like behaviors such as social withdrawal and cognitive deficits. In sdy hippocampus, the steady-state level of snapin (a SNAP25-binding protein and a synaptic priming regulator) was reduced due to loss of dysbindin. We further characterized that a 30-residue peptide in dysbindin (90-119 amino acids) mediated the interaction with snapin. Our results suggest that the destabilization of snapin in sdy mice may lead to abnormal neurotransmission and therefore abnormal behaviors. This further defines the sdy mutant as a potential model in schizophrenia research.

In the title compound, [Cu(C(11)H(11)NO(3))(C(11)H(16)N(4))]·H(2)O, the Cu(II) atom is five-coordinate in a distorted square-pyramidal geometry. The basal positions are occupied by three donor atoms from the tridentate Schiff base ligand and by one N atom from a bis-(3,5-dimethyl-prazol-l-yl)methane ligand. The apical position is occupied by the N atom of the other ligand of this type. There are only van der Waals contacts in the crystal structure.

The mol-ecule of the title compound, C(14)H(10)BrClN(2)O(3), is planar [dihedral angle between the aromatic rings = 3.0 (2)°] and shows a trans configuration with respect to the C=N double bond. The crystal structure is stabilized by inter-molecular N-H⋯O hydrogen bonds and an intramolecular O-H⋯N interaction also occurs.

System X(c)(-) is an anionic amino acid transport system highly specific for cystine and glutamate. The underlying mechanism of cell death of cultured cells from the subtle gray (sut) mouse which contains an xCT null mutation remains elucidated. Our results show that the death of sut cells is likely caused by apoptosis mediated by c-Jun N-terminal kinase (JNK). The JNK activation triggers both a caspase-dependent (caspases-9 and -3) and an ER stress-mediated (eIF2 and CHOP) pathway to induce apoptosis. These findings suggest the possible pathways involved in the cell death of xCT-deficient cells.