Regulation of axon guidance by compartmentalized nonsense-mediated mRNA decay.

Growth cones enable axons to navigate toward their targets by responding to extracellular signaling molecules. Growth-cone responses are mediated in part by the local translation of axonal messenger RNAs (mRNAs). However, the mechanisms that regulate local translation are poorly understood. Here we show that Robo3.2, a receptor for the Slit family of guidance cues, is synthesized locally within axons of commissural neurons. Robo3.2 translation is induced by floor-plate-derived signals as axons cross the spinal cord midline. Robo3.2 is also a predicted target of the nonsense-mediated mRNA decay (NMD) pathway. We find that NMD regulates Robo3.2 synthesis by inducing the degradation of Robo3.2 transcripts in axons that encounter the floor plate. Commissural neurons deficient in NMD proteins exhibit aberrant axonal trajectories after crossing the midline, consistent with misregulation of Robo3.2 expression. These data show that local translation is regulated by mRNA stability and that NMD acts locally to influence axonal pathfinding.

Cbln1 regulates axon growth and guidance in multiple neural regions.

The accurate construction of neural circuits requires the precise control of axon growth and guidance, which is regulated by multiple growth and guidance cues during early nervous system development. It is generally thought that the growth and guidance cues that control the major steps of axon development have been defined. Here, we describe cerebellin-1 (Cbln1) as a novel cue that controls diverse aspects of axon growth and guidance throughout the central nervous system (CNS) by experiments using mouse and chick embryos. Cbln1 has previously been shown to function in late neural development to influence synapse organization. Here, we find that Cbln1 has an essential role in early neural development. Cbln1 is expressed on the axons and growth cones of developing commissural neurons and functions in an autocrine manner to promote axon growth. Cbln1 is also expressed in intermediate target tissues and functions as an attractive guidance cue. We find that these functions of Cbln1 are mediated by neurexin-2 (Nrxn2), which functions as the Cbln1 receptor for axon growth and guidance. In addition to the developing spinal cord, we further show that Cbln1 functions in diverse parts of the CNS with major roles in cerebellar parallel fiber growth and retinal ganglion cell axon guidance. Despite the prevailing role of Cbln1 as a synaptic organizer, our study discovers a new and unexpected function for Cbln1 as a general axon growth and guidance cue throughout the nervous system.

Observed changes in China's methane emissions linked to policy drivers.

China is set to actively reduce its methane emissions in the coming decade. A comprehensive evaluation of the current situation can provide a reference point for tracking the country's future progress. Here, using satellite and surface observations, we quantify China's methane emissions during 2010-2017. Including newly available data from a surface network across China greatly improves our ability to constrain emissions at subnational and sectoral levels. Our results show that recent changes in China's methane emissions are linked to energy, agricultural, and environmental policies. We find contrasting methane emission trends in different regions attributed to coal mining, reflecting region-dependent responses to China's energy policy of closing small coal mines (decreases in Southwest) and consolidating large coal mines (increases in North). Coordinated production of coalbed methane and coal in southern Shanxi effectively decreases methane emissions, despite increased coal production there. We also detect unexpected increases from rice cultivation over East and Central China, which is contributed by enhanced rates of crop-residue application, a factor not accounted for in current inventories. Our work identifies policy drivers of recent changes in China's methane emissions, providing input to formulating methane policy toward its climate goal.

Phase 2 study of pegylated liposomal doxorubicin plus cyclophosphamide, vincristine/vindesine, and prednisone in newly diagnosed PTCL: 8-year results.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is a liposome-encapsulated form of doxorubicin with equivalent efficacy and less cardiotoxicity. This phase 2 study evaluated the efficacy and safety of the PLD-containing CHOP regimen in newly diagnosed patients with aggressive peripheral T-cell lymphomas (PTCL). METHODS: Patients received PLD, cyclophosphamide, vincristine/vindesine, plus prednisone every 3 weeks for up to 6 cycles. The primary endpoint was the objective response rate at the end of treatment (EOT). RESULTS: From September 2015 to January 2017, 40 patients were treated. At the EOT, objective response was achieved by 82.5% of patients, with 62.5% complete response. As of the cutoff date (September 26, 2023), median progression-free survival (mPFS) and overall survival (mOS) were not reached (NR). The 2-year, 5-year, and 8-year PFS rates were 55.1%, 52.0%, and 52.0%. OS rate was 80.0% at 2 years, 62.5% at 5 years, and 54.3% at 8 years. Patients with progression of disease within 24 months (POD24) had worse prognosis than those without POD24, regarding mOS (41.2 months vs NR), 5-year OS (33.3% vs 94.4%), and 8-year OS (13.3% vs 94.4%). Common grade 3-4 adverse events were neutropenia (87.5%), leukopenia (80.0%), anemia (17.5%), and pneumonitis (17.5%). CONCLUSION: This combination had long-term benefits and manageable tolerability, particularly with less cardiotoxicity, for aggressive PTCL, which might provide a favorable benefit-risk balance. CLINICALTRIALS.GOV IDENTIFIER: Chinese Clinical Trial Registry, ChiCTR2100054588; IRB Approved: Ethics committee of Fudan University Shanghai Cancer Center (Date 2015.8.31/No. 1508151-13.

Safety of embryo cryopreservation: insights from mid-term placental transcriptional changes.

BACKGROUND: In recent years, with benefits from the continuous improvement of clinical technology and the advantage of fertility preservation, the application of embryo cryopreservation has been growing rapidly worldwide. However, amidst this growth, concerns about its safety persist. Numerous studies have highlighted the elevated risk of perinatal complications linked to frozen embryo transfer (FET), such as large for gestational age (LGA) and hypertensive disorders during pregnancy. Thus, it is imperative to explore the potential risk of embryo cryopreservation and its related mechanisms. METHODS: Given the strict ethical constraints on clinical samples, we employed mouse models in this study. Three experimental groups were established: the naturally conceived (NC) group, the fresh embryo transfer (Fresh-ET) group, and the FET group. Blastocyst formation rates and implantation rates were calculated post-embryo cryopreservation. The impact of FET on fetal growth was evaluated upon fetal and placental weight. Placental RNA-seq was conducted, encompassing comprehensive analyses of various comparisons (Fresh-ET vs. NC, FET vs. NC, and FET vs. Fresh-ET). RESULTS: Reduced rates of blastocyst formation and implantation were observed post-embryo cryopreservation. Fresh-ET resulted in a significant decrease in fetal weight compared to NC group, whereas FET reversed this decline. RNA-seq analysis indicated that the majority of the expression changes in FET were inherited from Fresh-ET, and alterations solely attributed to embryo cryopreservation were moderate. Unexpectedly, certain genes that showed alterations in Fresh-ET tended to be restored in FET. Further analysis suggested that this regression may underlie the improvement of fetal growth restriction in FET. The expression of imprinted genes was disrupted in both FET and Fresh-ET groups. CONCLUSION: Based on our experimental data on mouse models, the impact of embryo cryopreservation is less pronounced than other in vitro manipulations in Fresh-ET. However, the impairment of the embryonic developmental potential and the gene alterations in placenta still suggested it to be a risky operation.

YTHDF2 in dentate gyrus is the m6A reader mediating m6A modification in hippocampus-dependent learning and memory.

N6-methyladenosine (m6A) has been demonstrated to regulate learning and memory in mice. To investigate the mechanism by which m6A modification exerts its function through its reader proteins in the hippocampus, as well as to unveil the specific subregions of the hippocampus that are crucial for memory formation, we generated dentate gyrus (DG)-, CA3-, and CA1-specific Ythdf1 and Ythdf2 conditional knockout (cKO) mice, respectively. Surprisingly, we found that only the DG-specific Ythdf2 cKO mice displayed impaired memory formation, which is inconsistent with the previous report showing that YTHDF1 was involved in this process. YTHDF2 controls the stability of its target transcripts which encode proteins that regulate the elongation of mossy fibers (MF), the axons of DG granule cells. DG-specific Ythdf2 ablation caused MF overgrowth and impairment of the MF-CA3 excitatory synapse development and transmission in the stratum lucidum. Thus, this study identifies the m6A reader YTHDF2 in dentate gyrus as the only regulator that mediates m6A modification in hippocampus-dependent learning and memory.

Association between frozen embryo transfer and childhood allergy: a retrospective cohort study.

RESEARCH QUESTION: Does frozen embryo transfer (FET) increase the risk of allergic diseases in offspring? DESIGN: This study followed up 653 singleton children: 166 born through FET and 487 born through natural conception. Demographic characteristics, perinatal information and allergic diseases of children and their parents were collected through clinical medical systems and questionnaires. Among these 653 children, allergen-specific immunoglobulin E (IgE) testing was performed using peripheral blood samples collected from 207 children: 145 in the FET group and 62 in the natural conception group. The prevalence of allergic diseases and positive rates of allergen-specific IgE testing were compared between the two groups with adjustments for confounding factors. RESULTS: The prevalence of food allergy was significantly higher in children born through FET compared with children born through natural conception (adjusted OR = 3.154, 95% CI 1.895-5.250; P < 0.001). In addition, positive rates of food allergen sensitization were higher in children in the FET group compared with children in the natural conception group (adjusted OR = 5.769, 95% CI 2.859-11.751, P < 0.001). Children in the FET group had a higher positive sensitization rate to at least one allergen compared with children in the natural conception group (adjusted OR = 3.127, 95% CI 1.640-5.961, P < 0.001). No association was observed between FET and other allergic diseases, including asthma (P = 0.136), atopic dermatitis (P = 0.130) and allergic rhinitis (P = 0.922). Allergen sensitization IgE testing indicated no differences between the two groups in terms of positive sensitization rates of other common allergens, including animal and insect allergens (P = 0.627), inhaled outdoor allergens (P = 0.915) and inhaled outdoor allergens (P = 0.544). CONCLUSION: This study suggests that children born through FET have increased risk of developing food allergy in early childhood.

Mettl14-Mediated m6A Modification Is Essential for Germinal Center B Cell Response.

The germinal center (GC) response is essential for generating memory B and long-lived Ab-secreting plasma cells during the T cell-dependent immune response. In the GC, signals via the BCR and CD40 collaboratively promote the proliferation and positive selection of GC B cells expressing BCRs with high affinities for specific Ags. Although a complex gene transcriptional regulatory network is known to control the GC response, it remains elusive how the positive selection of GC B cells is modulated posttranscriptionally. In this study, we show that methyltransferase like 14 (Mettl14)-mediated methylation of adenosines at the position N 6 of mRNA (N 6-methyladenosine [m6A]) is essential for the GC B cell response in mice. Ablation of Mettl14 in B cells leads to compromised GC B cell proliferation and a defective Ab response. Interestingly, we unravel that Mettl14-mediated m6A regulates the expression of genes critical for positive selection and cell cycle regulation of GC B cells in a Ythdf2-dependent but Myc-independent manner. Furthermore, our study reveals that Mettl14-mediated m6A modification promotes mRNA decay of negative immune regulators, such as Lax1 and Tipe2, to upregulate genes requisite for GC B cell positive selection and proliferation. Thus, our findings suggest that Mettl14-mediated m6A modification plays an essential role in the GC B cell response.

Fecal Signatures of Streptococcus anginosus and Streptococcus constellatus for Noninvasive Screening and Early Warning of Gastric Cancer.

BACKGROUND & AIMS: Most patients with gastric cancer (GCa) are diagnosed at an advanced stage. We aimed to investigate novel fecal signatures for clinical application in early diagnosis of GCa. METHODS: This was an observational study that included 1043 patients from 10 hospitals in China. In the discovery cohort, 16S ribosomal RNA gene analysis was performed in paired samples (tissues and feces) from patients with GCa and chronic gastritis (ChG) to determine differential abundant microbes. Their relative abundances were detected using quantitative real-time polymerase chain reaction to test them as bacterial candidates in the training cohort. Their diagnostic efficacy was validated in the validation cohort. RESULTS: Significant enrichments of Streptococcus anginosus (Sa) and Streptococcus constellatus (Sc) in GCa tumor tissues (P < .05) and feces (P < .0001) were observed in patients with intraepithelial neoplasia, early and advanced GCa. Either the signature parallel test Sa∪Sc or single signature Sa/Sc demonstrated superior sensitivity (Sa: 75.6% vs 72.1%, P < .05; Sc: 84.4% vs 64.0%, P < .001; and Sa∪Sc: 91.1% vs 81.4%, P < .01) in detecting early GCa compared with advanced GCa (specificity: Sa: 84.0% vs 83.9%, Sc: 70.4% vs 82.3%, and Sa∪Sc: 64.0% vs 73.4%). Fecal signature Sa∪Sc outperformed Sa∪CEA/Sc∪CEA in the discrimination of advanced GCa (sensitivity: 81.4% vs 74.2% and 81.4% vs 72.3%, P < .01; specificity: 73.4% vs 81.0 % and 73.4% vs 81.0%). The performance of Sa∪Sc in the diagnosis of both early and advanced GCa was verified in the validation cohort. CONCLUSION: Fecal Sa and Sc are noninvasive, accurate, and sensitive signatures for early warning in GCa. (ClinicalTrials.gov, Number: NCT04638959).

Comparison of haploidentical-allogeneic hematopoietic stem cell transplantation and intensive immunosuppressive therapy for patients with severe aplastic anemia with an absolute neutrophil count of zero: a retrospective study.

A retrospective analysis was conducted based on the clinical data from 60 patients older than 16 years from January 2016 to January 2021. All the patients were newly diagnosed with severe aplastic anemia (SAA) with an absolute neutrophil count (ANC) of zero. We compared the hematological response and survival of haploidentical-allogeneic hematopoietic stem cell transplantation (HID-HSCT) (n = 25) and intensive immunosuppressive therapy (IST) (n = 35) treatments. At six months, the overall response rate and complete response were significantly higher in the HID-HSCT group than those in the IST group (84.0% vs. 40.0%, P = 0.001; 80.0% vs. 17.1%, P = 0.001). With a median follow-up of 18.5 months (4.3~30.8 months), patients in the HID-HSCT group had longer overall survival and event-free survival (80.0% vs. 47.9%, P = 0.0419; 79.2% vs. 33.5%, P = 0.0048). These data suggested that HID-HSCT might be an effective alternative treatment option for adult patients with SAA with an ANC of zero, which requires further validation in an additional prospective study.

Double-negative T cells regulate the progression of liver fibrosis through Th9 cells differentiation.

Our previous study found that double negative T cells (DNTs) could promote the NLRP3 activation through high expression of TNF-α, thereby leading to hepatic fibrosis progression. We focused on investigating the role and mechanism of DNTs in regulating the Th9 cells differentiation in liver fibrosis. In our results, among patients with liver fibrosis, the proportions of peripheral blood DNTs and Th9 cells were up-regulated and positively correlated. While promoting the progression of liver fibrosis in mice, DNTs could elevate the proportion of Th9 cells and activate the TNFR2-STAT5-NF-κB pathway. The use of IL-9 and TNF-α monoclonal antibodies (mAbs) inhibited the effect of DNTs and lowered the proportion of Th9 cells in tissues. In vitro experiments showed that DNTs could promote the Th9 cells differentiation of Naive T cells, while TNF-α mAbs could inhibit such effect of DNTs to lower the proportion of Th9 cells. We found that DNTs can activate TNFR2-STAT5-NF-κB pathway by secreting TNF-α, thereby promoting the Th9 Cells differentiation to facilitate the progression of liver fibrosis. There is interaction between DNTs and Th9 cells.

Endoscopic resection of gastric low-grade dysplasia with high risk factors is associated with decreased advanced neoplasia: a single-center retrospective cohort study.

BACKGROUND: The natural course of gastric low-grade dysplasia (LGD) remains unclear, and there are inconsistent management recommendations among guidelines and consensus. OBJECTIVE: This study aimed to investigate the incidence of advanced neoplasia in patients with gastric LGD and identify the related risk factors. METHODS: Cases of biopsy demonstrated LGD (BD-LGD) at our center from 2010 to 2021 were reviewed retrospectively. Risk factors related to histological progression were identified, and outcomes of patients based on risk stratification were evaluated. RESULTS: Ninety-seven (23.0%) of 421 included BD-LGD lesions were diagnosed as advanced neoplasia. Among 409 superficial BD-LGD lesions, lesion in the upper third of the stomach, H. pylori infection, larger size, and narrow band imaging (NBI)-positive findings were independent risk factors of progression. NBI-positive lesions and NBI-negative lesions with or without other risk factors had 44.7%, 1.7%, and 0.0% risk of advanced neoplasia, respectively. Invisible lesions, visible lesions (VLs) without a clear margin, and VLs with a clear margin and size ≤ 10 mm, or > 10 mm had 4.8%, 7.9%, 16.7%, and 55.7% risk of advanced neoplasia, respectively. In addition, endoscopic resection decreased the risk of cancer (P < 0.001) and advanced neoplasia (P < 0.001) in patients with NBI-positive lesions, but not in NBI-negative patients. Similar results were found in patients with VLs with clear margin and size > 10 mm. Moreover, NBI-positive lesions had higher sensitivity and lower specificity for predicting advanced neoplasia than VLs with a clear margin and size > 10 mm determined by white-light endoscopy (97.6% vs. 62.7%, P < 0.001; and 63.0% vs. 85.6%, P < 0.001, respectively). CONCLUSION: Progression of superficial BD-LGD is associated with NBI-positive lesions, as well as with VLs with a clear margin (size > 10 mm) if NBI is unavailable, and selective resection of those lesions offers benefits for patients by decreasing the risk of advanced neoplasia.

Is VATS suitable for lung diseases with hemoptysis? Experience from a hemoptysis treatment center in China.

BACKGROUND: Surgery is crucial in the treatment of the potentially fatal pulmonary hemoptysis condition. Currently, most patients with hemoptysis are treated by traditional open surgery (OS). To illustrate the effectiveness of video-assisted thoracic surgery (VATS) for hemoptysis, we developed a retrospective study of surgical interventions for lung disease with hemoptysis. METHODS: We collected and then analysed the data, including general information and post-operative outcomes, from 102 patients who underwent surgery for a variety of lung diseases with hemoptysis in our hospital between December 2018 and June 2022. RESULTS: Sixty three cases underwent VATS and 39 cases underwent OS. 76.5% of patients were male (78/102). Comorbidities with diabetes and hypertension were 16.7% (17/102) and 15.7% (16/102) respectively. The diagnoses based on postoperative pathology included aspergilloma in 63 cases (61.8%), tuberculosis in 38 cases (37.4%) and bronchiectasis in 1 case (0.8%). 8 patients underwent wedge resection, 12 patients underwent segmentectomy, 73 patients underwent lobectomy and 9 patients underwent pneumonectomy. There were 23 cases of postoperative complications, of which 7 (30.4%) were in the VATS group, significantly fewer than 16 (69.6%) in the OS group (p = 0.001). The OS procedure was identified as the only independent risk factor for postoperative complications. The median (IQR) of postoperative drainage volume in the first 24 h was 400 (195-665) ml, which was 250 (130-500) ml of the VATS group, significantly less than the 550 (460-820) ml of the OS group (p < 0.05). The median (IQR) of pain scores 24 h after surgery was 5 (4-9). The median (IQR) of postoperative drainage tube removal time was 9.5 (6-17) days for all patients, and it was 7 (5-14) days for the VATS group, which was less than 15 (9-20) days for the OS group. CONCLUSION: VATS for patients with lung disease presenting with hemoptysis is an effective and safe option that may be preferred when the hemoptysis is uncomplicated and the patient's vital signs are stable.

Environmental toxin chlorpyrifos induces liver injury by activating P53-mediated ferroptosis via GSDMD-mtROS.

AIM: We investigate the mechanism whereby chlorpyrifos (CHI), an environmental toxin, causes liver injury by inducing ferroptosis in hepatocytes. METHODS: The toxic dose (LD50 = 50 µM) of CHI for inducing AML12 injury in normal mouse hepatocytes was determined, and the ferroptosis-related indices were measured, including the levels of SOD, MDA and GSH-Px, as well as the cellular content of iron ions. JC-1 and DCFH-DA assays were employed to detect the mtROS levels, the levels of mitochondrial proteins (GSDMD, NT-GSDMD), as well as the cellular levels of ferroptosis-related proteins (P53, GPX4, MDM2, SLC7A11). We knocked out the GSDMD and P53 in AML12 and observed the CHI-induced ferroptosis of ALM12 after applying YGC063, an ROS inhibitor. In animal experiments, we explored the effect of CHI on liver injury by using conditional GSDMD-knockout mice (C57BL/6 N-GSDMDem1(flox)Cya) and ferroptosis inhibitor Fer-1. Small molecule-protein docking and Pull-down assay were employed to verify the association between CHI and GSDMD. RESULTS: We found that CHI could induce ferroptosis of AML12. CHI promoted the cleavage of GSDMD, leading to upregulation of mitochondrial NT-GSDMD expression, as well as ROS levels. P53 activation promoted the ferroptosis. Knock out of GSDMD and P53 could inhibit the CHI-induced ferroptosis, and YGC063 could also inhibit ferroptosis. In mice experiments, GSDMD knockout or Fer-1 intervention could significantly inhibit the CHI-induced liver injury. CHI promoted the cleavage of GSDMD by binding to its SER234 site. CONCLUSION: CHI can bind to GSDMD to promote its cleavage, while NT-GSDMD can open mitochondrial membrane to promote the mtROS release. Cytoplasmic upregulation of ROS levels can facilitate the P53-mediated ferroptosis. GSDMD-mtROS is the primary mechanism whereby CHI induces ferroptosis in hepatocytes.

Aspiration and coagulation to reduce risk of delayed bleeding after gastric endoscopic submucosal dissection (with video).

OBJECTIVES: The purpose of this study was to evaluate the feasibility of a simple method named aspiration and coagulation (AC) for reducing the risk of postoperative bleeding after gastric endoscopic submucosal dissection (ESD). METHODS: Data were retrospectively reviewed and collected from the medical records and endoscopic and pathologic reports about consecutive patients who underwent ESD for early gastric cancer or precancerous lesions or gastric submucosal lesions from January 2016 to December 2021 at the Seventh Medical Center of Chinese PLA General Hospital. Enrolled patients who underwent the AC method during ESD were included in the AC group, and the others were included in the control group. Propensity score (PS) matching (1:1 match) was used to compensate for the differences that might affect post-ESD bleeding. Massive hemorrhage and overall delayed bleeding events after gastric ESD were compared between the two groups. RESULTS: Propensity score matching analysis created 242 matched pairs in the study. Characteristics of the subjects such as age and use of antithrombotic drugs were all similar between the two groups after PS matching. The rate of massive hemorrhage and overall delayed bleeding was both significantly lower in the AC group than in the control (0.4% vs. 3.3% for massive hemorrhage, P = 0.037, and 1.2% vs. 5.0% for overall delayed bleeding, P = 0.032), predominantly in mucosal lesions (0.6% vs. 4.4% for massive hemorrhage, P = 0.032, and 1.2% vs. 5.6% for overall delayed bleeding, P = 0.031). CONCLUSIONS: Our study demonstrated that the AC method effectively decreased delayed bleeding events after ESD.

Chinese Consensus Report on Family-Based Helicobacter pylori Infection Control and Management (2021 Edition).

OBJECTIVE: Helicobacter pylori infection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-based H. pylori infection control and management to reduce the related disease burden. METHODS: Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. RESULTS: Experts discussed and modified the original 23 statements on family-based H. pylori infection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1) H. pylori infection and transmission among family members, (2) prevention and management of H. pylori infection in children and elderly people within households, and (3) strategies for prevention and management of H. pylori infection for family members. In addition to the 'test-and-treat' and 'screen-and-treat' strategies, this consensus also introduced a novel third 'family-based H. pylori infection control and management' strategy to prevent its intrafamilial transmission and development of related diseases. CONCLUSION: H. pylori is transmissible from person to person, and among family members. A family-based H. pylori prevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

Gestational diabetes mellitus suppresses fetal testis development in mice†.

The prevalence of gestational diabetes mellitus (GDM) is increasing rapidly. In addition to the metabolic disease risks, GDM might increase the risks of cryptorchidism in children. However, its mechanism involved in abnormalities of the male reproductive system is still unclear. The purpose of this study was to study the effects of GDM on the development of mouse fetal Leydig cells (FLCs) and Sertoli cells (SCs). Pregnant mice were treated on gestational days 6.5 and 12.5 with streptozotocin (100 mg/kg) or vehicle (sodium citrate buffer). Leydig cell and SC development and functions were evaluated by investigating serum testosterone levels, cell number and distribution, genes, and protein expression. GDM decreased serum testosterone levels, the anogenital distance, and the level of desert hedgehog in SCs of testes of male offspring. FLC number was also decreased in testes of GDM offspring by delaying the commitment of stem Leydig cells into the Leydig cell lineage. RNA-seq showed that FOXL2, RSPO1/ß-catenin signaling was activated and Gsk3ß signaling was inhibited in GDM offspring testis. In conclusion, GDM disrupted reproductive tract and testis development in mouse male offspring via altering genes related to development.

Comparison of fully coated anti-reflux metal stenting and per-oral endoscopic myotomy in patients with achalasia: a propensity score-matched retrospective study.

BACKGROUND: Achalasia is a rare primary esophageal motility disorder disease. It is reported that the long-term effect of fully coated anti-reflux metal stent (FCARMS) implantation is satisfactory. Operated by a skilled and experienced endoscopist, the effect of per-oral endoscopic myotomy (POEM) treatment is equivalent to that of surgical myotomy. So far, there is still few evidence to prove FCARMS implantation or POEM which is better for achalasia. The choice of treatment for achalasia is still controversial. The aim of this study is to find a more suitable therapy for achalasia by comparing the efficacy of FCARMS implantation and POEM. METHODS: A propensity score (PS) matching (1:2) was used in this retrospective cohort study. Data collected from consecutive patients of Achalasia, receiving FCARMS implantation or POEM therapy at the department of gastroenterology, the Seventh Medical Center of the Chinese People's Liberation Army General Hospital from May 2007 to May 2018. According to their previous treatment, they are divided into two groups, FCARMS group and POEM group. Clinical efficacy and complications were compared between the two groups. RESULTS: A total of 166 cases were collected, including 113 cases of FCARMS and 53 cases of POEM. By PS matching, 150 patients were enrolled (100 cases of FCARMS and 50 cases of POEM). By comparison, the FCARMS group has shorter operation time, shorter fasting time and lower hospitalization costs than the POEM group (p < 0.05). Common complications in the FCARMS group are nausea, vomiting, and stent shift. Repetitions of gastroscopy in the FCARMS group was more often, which were 3.8 ± 2.4 (vs 2.1 ± 1.8 of POEM) (p = 0.00 < 0.05) The 6-month remission rates of the FCARMS combination POEM group were 89% and 94%, respectively (p = 0.39), and the 2-year remission rates were 61% and 90%, respectively (p = 0.00). CONCLUSIONS: Stent placement is a cost-effective and safe treatment option for achalasia. The short-term effect (less than 6 months) of FCARMS is similar to that of POEM, the long-term effect (more than 2 years), POEM is better than FCARMS. HRMIIis most suitable for POEM treatment. It indicate that Patients can choose treatment methods according to their own conditions.

Axonal mRNA localization and translation: local events with broad roles.

Messenger RNA (mRNA) can be transported and targeted to different subcellular compartments and locally translated. Local translation is an evolutionally conserved mechanism that in mammals, provides an important tool to exquisitely regulate the subcellular proteome in different cell types, including neurons. Local translation in axons is involved in processes such as neuronal development, function, plasticity, and diseases. Here, we summarize the current progress on axonal mRNA transport and translation. We focus on the regulatory mechanisms governing how mRNAs are transported to axons and how they are locally translated in axons. We discuss the roles of axonally synthesized proteins, which either function locally in axons, or are retrogradely trafficked back to soma to achieve neuron-wide gene regulation. We also examine local translation in neurological diseases. Finally, we give a critical perspective on the remaining questions that could be answered to uncover the fundamental rules governing local translation, and discuss how this could lead to new therapeutic targets for neurological diseases.

Oxidative dehydrogenation of light alkanes to olefins on metal-free catalysts.

Metal-free boron- and carbon-based catalysts have shown both great fundamental and practical value in oxidative dehydrogenation (ODH) of light alkanes. In particular, boron-based catalysts show a superior selectivity toward olefins, excellent stability and atom-economy to valuable carbon-based products by minimizing CO2 emission, which are highly promising in future industrialization. The carbonaceous catalysts also exhibited impressive behavior in the ODH of light alkanes helped along by surface oxygen-containing functional groups. This review surveyed and compared the preparation methods of the boron- and carbon-based catalysts and their characterization, their performance in the ODH of light alkanes, and the mechanistic issues of the ODH including the identification of the possible active sites and the exploration of the underlying mechanisms. We discussed different boron-based materials and established versatile methodologies for the investigation of active sites and reaction mechanisms. We also elaborated on the similarities and differences in catalytic and kinetic behaviors, and reaction mechanisms between boron- and carbon-based metal-free materials. A perspective of the potential issues of metal-free ODH catalytic systems in terms of their rational design and their synergy with reactor engineering was sketched.