The murine catecholamine methyltransferase mTOMT is essential for mechanotransduction by cochlear hair cells

Hair cells of the cochlea are mechanosensors for the perception of sound. Mutations in the LRTOMT gene, which encodes a protein with homology to the catecholamine methyltransferase COMT that is linked to schizophrenia, cause deafness. Here, we show that Tomt/Comt2, the murine ortholog of LRTOMT, has an unexpected function in the regulation of mechanotransduction by hair cells. The role of mTOMT in hair cells is independent of mTOMT methyltransferase function and mCOMT cannot substitute for mTOMT function. Instead, mTOMT binds to putative components of the mechanotransduction channel in hair cells and is essential for the transport of some of these components into the mechanically sensitive stereocilia of hair cells. Our studies thus suggest functional diversification between mCOMT and mTOMT, where mTOMT is critical for the assembly of the mechanotransduction machinery of hair cells. Defects in this process are likely mechanistically linked to deafness caused by mutations in LRTOMT/Tomt

Vertical distribution of Fe, P and correlation with organic carbon in coastal sediments of Yellow Sea, Eastern China

The coastal zone is considered as a major carbon pool. Iron minerals and phosphates are vital factors affecting the amounts and occurrence of total organic carbon (TOC) in sediments. However, coupling mechanisms of iron (Fe) and phosphorous (P) in the source-sink transition of TOC in coastal sediments is poorly understood. This study characterized the distribution of Fe, P and TOC contents of three independent 170 cm sediment cores sampled from a coastal aquaculture area in the eastern Jiangsu Province, and quantified the correlations among Fe, P, median grain diameter (Dx(50)), and TOC. The results showed total phosphorus (TP) content ranges in a scope of 337.4-578.0 mg/kg, and many depths recorded moderate P eutrophication. Inorganic phosphorus (DA + IP) and biogenic apatite were the primary components of TP, accounting for 25.19–55.00 and 26.71–49.62%, respectively. The Fe contents varied from 987.9 mg/kg to 2900.7 mg/kg, in which oxidized iron (Feox) accounted for about 62.2–79.4%. In the vertical profile, the TOC was positively correlated with the contents of low-crystallinity Fe-bearing carbonates (Fecarb), high crystallinity pyrite (FePy), iron-bound phosphorus (PCDB), manganeses (Mn), and nitrogen (N), while it was negatively correlated with DA + IP, organic phosphorus (OP), and Dx(50). Based on the the partial least squares (PLS) model, we proposed that the higher FePy, Mn, magnetite (FeMag), Fecarb, PCDB, amorphous exchangeable Fe (Ex-Fe), and authigenic apatite phosphorus (Bio-P) in sediments represent the high capacity for TOC sink, whereas, higher DA + IP, and OP indicate a TOC conversion to the source. The non-siginificat indication of Feox on TOC source-sink is due to its surplus and strong reactivity relative to TOC content. These revealed correlations provide a theoretical reference for understanding and regulating the burial rate and storage of TOC by changing the input of Fe minerals and P components into coastal sediments

TMIE defines pore and gating properties of the mechanotransduction channel of mammalian cochlear hair cells

TMC1 and TMC2 (TMC1/2) have been proposed to form the pore of the mechanotransduction channel of cochlear hair cells. Here, we show that TMC1/2 cannot form mechanotransduction channels in cochlear hair cells without TMIE. TMIE binds to TMC1/2, and a TMIE mutation that perturbs TMC1/2 binding abolishes mechanotransduction. N-terminal TMIE deletions affect the response of the mechanotransduction channel to mechanical force. Similar to mechanically gated TREK channels, the C-terminal cytoplasmic TMIE domain contains charged amino acids that mediate binding to phospholipids, including PIP2. TMIE point mutations in the C terminus that are linked to deafness disrupt phospholipid binding, sensitize the channel to PIP2 depletion from hair cells, and alter the channel's unitary conductance and ion selectivity. We conclude that TMIE is a subunit of the cochlear mechanotransduction channel and that channel function is regulated by a phospholipid-sensing domain in TMIE with similarity to those in other mechanically gated ion channels

淋毒性副睪丸炎ノ療法追加

Abstract We demonstrate the synergistic antitumor effect of oridonin and the PI3K/mTOR inhibitor NVP-BEZ235 on the non-germinal center B cell-like subtype of diffuse large B cell lymphoma (non-GCB DLBCL) both in vitro and in vivo. The underlying mechanism may be multifunctional, involving apoptosis, AKT/mTOR and NF-kB inactivation, and ROS-mediated DNA damage response. Our findings pave the way for a new potential treatment option for non-GCB DLBCL with the combination of oridonin and NVP-BEZ235

HIV-1 Membrane-Proximal External Region Fused to Diphtheria Toxin Domain-A Elicits 4E10-Like Antibodies in Mice.

The production of broadly neutralizing antibodies (bNAbs) is a major goal in the development of an HIV-1 vaccine. The membrane-proximal external region (MPER) of gp41, which plays a critical role in the virus membrane fusion process, is highly conserved and targeted by bNAbs 2F5, 4E10, and 10E8. As such, MPER could be a promising epitope for vaccine design. In this study, diphtheria toxin domain A (CRM197, amino acids 1-191) was used as a scaffold to display the 2F5 and 4E10 epitopes of MPER, named CRM197-A-2F5 and CRM197-A-4E10. Modest neutralizing activities were detected against HIV-1 clade B and D viruses in the sera from mice immunized with CRM197-A-4E10. Monoclonal antibodies raised from CRM197-A-4E10 could neutralize several HIV-1 strains, and epitope-mapping analysis indicated that some antibodies recognized the same amino acids as 4E10. Collectively, we show that 4E10-like antibodies can be induced by displaying MPER epitopes using an appropriate scaffold. These results provide insights for HIV-1 MPER-based immunogens design

Atomic structures of Coxsackievirus A6 and its complex with a neutralizing antibody

手足口病是一种由人肠道病毒引起的全球性传染病，主要发生于5岁以下的婴幼儿，严重危害公众健康。根据获得的手足口病流行病学和病原学调查数据，目前认为CVA6与EV71和CVA16一样应作为优先的手足口病疫苗预防对象，亟需研制有效的预防和治疗方法。然而令人遗憾的是，目前对于CVA6的基础病毒学特别是结构生物学知识均缺乏足够了解，严重制约了相关研究的有效开展。 夏宁邵教授团队研究首次揭示了手足口病重要病原体柯萨奇病毒A组6型（CVA6）的病毒颗粒及其与中和抗体复合物的精确三维结构，为新型疫苗和治疗药物的研制提供了重要的理论基础。这项研究发现并精确描绘了CVA6的病毒颗粒及其与优势中和抗体的结构特征，首次完成了对CVA6的高精度“成像”，为新型疫苗和治疗药物研制提供了关键基础。 该研究工作在厦门大学分子疫苗学和分子诊断学国家重点实验室、国家传染病诊断试剂与疫苗工程技术研究中心科研平台完成。夏宁邵教授、颜晓东博士、程通副教授为该研究论文的共同通讯作者。颜晓东博士来自美国加州大学圣地亚哥分校，同时受聘为我校双聘教授。共同第一作者为徐龙发博士生、郑清炳工程师和李少伟教授。【Abstract】Coxsackievirus A6 (CVA6) has recently emerged as a major cause of hand, foot and mouth disease in children worldwide but no vaccine is available against CVA6 infections. Here, we demonstrate the isolation of two forms of stable CVA6 particles-procapsid and A-particle-with excellent biochemical stability and natural antigenicity to serve as vaccine candidates. Despite the presence (in A-particle) or absence (in procapsid) of capsid-RNA interactions, the two CVA6 particles have essentially identical atomic capsid structures resembling the uncoating intermediates of other enteroviruses. Our near-atomic resolution structure of CVA6 A-particle complexed with a neutralizing antibody maps an immune-dominant neutralizing epitope to the surface loops of VP1. The structure-guided cell-based inhibition studies further demonstrate that these loops could serve as excellent targets for designing anti-CVA6 vaccines.This work was supported by a grant from the National Natural Science Foundation of China (No. 31670933 and 81401669), the National Science and Technology Major Projects for Major New Drugs Innovation and Development (No. 2017ZX09101005-005-003), the National Science and Technology Major Project of Infectious Diseases (No. 2017ZX10304402-002-003) and the Natural Science Foundation of Fujian Province (No. 2015J05073). This work was also supported in part by funding to T.S.B. from the National Institutes of Health (Grant R37-GM33050). 研究工作也得到了国际病毒结构生物学权威专家美国加州大学洛杉矶分校周正洪教授的大力支持和帮助，获得了国家自然科学基金、新药创制国家科技重大专项、传染病防治国家科技重大专项和福建省自然科学基金的资助

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P\u3c0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P\u3c0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P\u3c0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P\u3c0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P\u3c0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials

Redefining cardiac biomarkers in predicting mortality and adverse outcomes of inpatients with COVID-19

The prognostic power of circulating cardiac biomarkers, their utility and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multi-centered retrospective study, we enrolled 3,219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effect Cox model, after adjusting for age, gender and comorbidities, the adjusted hazard ratios of 28-day mortality for high-sensitivity cardiac troponin I (hs-cTnI) was 7.12 (95%CI, 4.60-11.03; P<0.001), NT-proB-type natriuretic peptide (NT-proBNP) was 5.11 (95%CI, 3.50-7.47; P<0.001), CK-MB was 4.86 (95%CI, 3.33-7.09; P<0.001), myoglobin was 4.50 (95%CI, 3.18-6.36; P < 0.001), and CK was 3.56 (95%CI, 2.53-5.02; P < 0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 49% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoffs for of these values might be much lower than the current reference standards. These findings can assist better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19 associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials