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Background: Currently, ERAS for spinal surgery field is still in its beginnings, the major protocol lessons learned from other surgical specialties and lack of ERAS program for elderly patients (>70 years old). Geriatric patients has its own special characteristics resulting in more harmed by surgical stress. The enhanced recovery after surgery (ERAS) are designed to improving recovery after surgery and can result in substantial benefits in both clinical outcomes and cost-effectiveness. In the present study, we aimed to determine whether enhanced recovery after surgery (ERAS) significantly improved satisfaction and outcomes in elderly patients (>70 years old) with long-level lumbar fusion. Methods: A total of 154 patients were included, 72 in the ERAS group and 82 case-matched patients in the non-ERAS group. Data including demographic, comorbidity and surgical information were collected from electronic medical records. ERAS interventions were categorised as preoperative, intraoperative and postoperative. We also evaluated primary outcome, surgical complication and length of stay (LOS).Results: There were no statistically significant intergroup differences in regards to demographics, comorbidities, American Society of Anaesthesiologists (ASA) grade, or the number of fusion levels. There were also no differences between mean surgery time of intraoperative blood loss between the ERAS and non-ERAS groups. In addition, the mean preoperative Visual Analogue Score (VAS) for the back and legs and Oswestry Disability Index (ODI) score were not significantly different between the two groups. Overall, ERAS pathway compliance was 91.5%. There were no significant differences in the readmission and mortality rates at 30-day follow-up between the ERAS and non-ERAS groups. However, we observed a statistically significant decrease in the complications in the ERAS group(8 in the ERAS group versus 23 in the non-ERAS group, p=0.009) and LOS in the ERAS group (17.74±5.56 of ERAS group versus 22.13±12.21 in non-ERAS group, p=0.041). Multivariable linear regression showed that comorbidities (p=0.028) and implementation of ERAS program (p=0.002) were correlated with prolonged LOS. Multivariable logistic regression showed that comorbidities (p=0.029)， implementation of ERAS program (p=0.043) and preoperative VAS Back (p=0.046), were correlated with complications. Conclusions: This report describes the first ERAS protocol used in elderly patients after long-level lumbar fusion surgery. Our ERAS program is safe and could help decreases LOS and complication in elderly patients with long-level lumbar fusion.

Mechanosensitive ion channels (MSCs) are key molecules in the mechano-electrical transduction of arterial baroreceptors. Among them, acid-sensing ion channel 2 (ASIC2) and transient receptor potential vanilloid subfamily member 1 (TRPV1) have been studied extensively and documented to play important roles. In this study, experiments using aortic arch–aortic nerve preparations isolated from rats revealed that both ASIC2 and TRPV1 are functionally necessary, as blocking either abrogated nearly all pressure-dependent neural discharge. However, whether ASIC2 and TRPV1 work in coordination remained unclear. So we carried out cell-attached patch-clamp recordings in HEK293T cells co-expressing ASIC2 and TRPV1 and found that inhibition of ASIC2 completely blocked stretch-activated currents while inhibition of TRPV1 only partially blocked these currents. Immunofluorescence staining of aortic arch–aortic adventitia from rats showed that ASIC2 and TRPV1 are co-localized in the aortic nerve endings, and co-immunoprecipitation assays confirmed that the two proteins form a compact complex in HEK293T cells and in baroreceptors. Moreover, protein modeling analysis, exogenous co-immunoprecipitation assays, and biotin pull-down assays indicated that ASIC2 and TRPV1 interact directly. In summary, our research suggests that ASIC2 and TRPV1 form a compact complex and function synergistically in the mechano-electrical transduction of arterial baroreceptors. The model of synergism between MSCs may have important biological significance beyond ASIC2 and TRPV1. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12264-021-00737-1.

Biotin is an essential micro-nutrient across the three domains of life. The paradigm earlier step of biotin synthesis denotes “BioC-BioH” pathway in Escherichia coli. Here we report that BioZ bypasses the canonical route to begin biotin synthesis. In addition to its origin of Rhizobiales, protein phylogeny infers that BioZ is domesticated to gain an atypical role of β-ketoacyl-ACP synthase III. Genetic and biochemical characterization demonstrates that BioZ catalyzes the condensation of glutaryl-CoA (or ACP) with malonyl-ACP to give 5’-keto-pimeloyl ACP. This intermediate proceeds via type II fatty acid synthesis (FAS II) pathway, to initiate the formation of pimeloyl-ACP, a precursor of biotin synthesis. To further explore molecular basis of BioZ activity, we determine the crystal structure of Agrobacterium tumefaciens BioZ at 1.99 Å, of which the catalytic triad and the substrate-loading tunnel are functionally defined. In particular, we localize that three residues (S84, R147, and S287) at the distant bottom of the tunnel might neutralize the charge of free C-carboxyl group of the primer glutaryl-CoA. Taken together, this study provides molecular insights into the BioZ biotin synthesis pathway., Biotin is an essential enzyme cofactor and two pathways for the generation of the biotin precursor pimeloyl-ACP are known. Here, the authors identify and characterize a third pathway for biotin precursor synthesis involving BioZ and they also present the Agrobacterium tumefaciens BioZ crystal structure.

Background Enhanced recovery after surgery (ERAS) program is an evidence-based improvement over non-ERAS traditional care. The aim of the present study was to analyze the safety, feasibility, and efficacy of an ERAS program in patients over 70 years undergoing lumbar arthrodesis by comparison with non-ERAS traditional care. Methods During January 2018 to December 2018, patients enrolled received non-ERAS traditional care, while the ERAS program was implemented from January to December 2019. Demographic characteristics, comorbidities, surgical data and postoperative recovery parameters were collected from all patients. Postoperative pain scores were evaluated by visual analog scales (VAS). The clinical outcomes were length of stay (LOS), postoperative complications and postoperative pain scores. Compliance results were also collected. Result A total of 127 patients were enrolled, including 67 patients in the non-ERAS traditional care group and 60 patients in the ERAS group. The demographic characteristics and comorbidities of the two groups showed no significant differences. The LOS of patients treated with ERAS program (13.6 ± 4.0 days) was significantly less than that of patients treated with non-ERAS traditional care (15.6 ± 3.9 days) (p = 0.034). Complication rate was 8.3% in the ERAS group versus 20.9% in the non-ERAS traditional care group (p = 0.048). VAS (back) in the ERAS group was significantly lower on postoperative day (POD) 1 and POD2. Postoperative recovery parameters were improved in the ERAS group. The overall compliance with the ERAS program was 94%. Conclusions Based on our results, ERAS program is safer and more effective for elderly patients over 70 undergoing lumbar arthrodesis than non-ERAS traditional care.

Accurate nationwide spatiotemporal distribution of ambient ozone product is critical for environment & health departments and for researches to investigate the influence of ozone for epidemiological studies. Our hybrid method, the novel CAMS (The Copernicus Atmosphere Monitoring Service) ozone improvement (CAO3_I) method, is the first attempt to predict ambient ozone by improving CAMS ozone (CAO3) products. For this novel framework, the SVM (Support Vector Machine) has been adopted for classification through the most significant regional ozone patterns which were extracted through the REOF (Rotated Empirical Orthogonal Function) technique. For each classified region, meteorological data, geographical data, CAMS ozone and ground-sites ozone are fed into random forest for regional regulation training and prediction. The CAO3_I method has shown its great feasibility in daily ozone surface distribution prediction. Based on daily averaged ozone concentrations for each station (STO3), the performance of CAO3 products (R2 = 0.35, RMSE = 25.77 μg/m3, MAPE = 42.06) have significantly improved to CAO3_I (R2 = 0.81, RMSE = 14.10 μg/m3, MAPE = 22.37), which shows above 97.4% R2 and RMSE have been improved. Our model is also capable to predict high level ozone concentrations in summer where the R2 has improved from 0.37 (for CAO3) to 0.81. In comparison with ground monitoring stations, the CAMS ozone improvement results can excellently reflect the distribution of daily ground-level ozone concentration and outperform previous statistical models in predicting ambient O3 concentrations. Therefore, the prediction results and our proposed model can be used for future epidemiological studies and air pollution controlling programs.

Background Degenerative disorders of the lumbar spine decrease the mobility and quality of life of elderly patients. Lumbar fusion surgery is the primary method of treating degenerative lumbar spine disorders; however, the surgical stress response associated with major surgery has been linked to pathophysiological changes in the elderly, resulting in undesirable postoperative morbidity, complications, pain, fatigue, and extended convalescence. In the present study, we aimed to determine whether enhanced recovery after surgery significantly improved satisfaction and outcomes in elderly patients (> 65 years old) with short-level lumbar fusion. Methods The study enrolled lumbar disc herniation or lumbar spinal stenosis patients if they were over the age of 65 years old underwent lumbar fusion at one or two levels. Data including demographic, comorbidity, and surgical information were collected from electronic medical records. Enhanced recovery after surgery interventions was categorized as preoperative, intraoperative, and postoperative. We also evaluated primary outcome, surgical complication, length of stay, postoperative pain scores, and 30-day readmission rates. Results A total of 192 patients were included, 96 in the enhanced recovery after surgery group and 96 case-matched patients in the non- enhanced recovery after surgery group. There were no statistically significant intergroup differences in regards to demographics, comorbidities, American Society of Anaesthesiologists grade, or the number of fusion levels. There were also no differences between mean surgery time of intraoperative blood loss between the enhanced recovery after surgery and non- enhanced recovery after surgery groups. In addition, the mean preoperative Japanese Orthopaedic Association score, visual analog score for the back and legs, and Oswestry Disability Index score were not significantly different between the two groups. Overall, enhanced recovery after surgery pathway compliance was 92.1%. There were no significant differences in the number of complications or the mortality rates between the enhanced recovery after surgery and non-enhanced recovery after surgery groups. Furthermore, the mean postoperative Japanese Orthopaedic Association score, Visual analog score for the back and legs, Oswestry Disability Index score, and readmission rates score revealed no significant differences between the groups at 30-day follow-up point. However, we observed a statistically significant decrease in length of stay in the enhanced recovery after surgery group (12.30 ± 3.03 of enhanced recovery after surgery group versus 15.50 ± 1.88 in non- enhanced recovery after surgery group, p = 0). Multivariable linear regression showed that comorbidities (p = 0.023) and implementation of enhanced recovery after surgery program (p = 0.002) were correlated with prolonged length of stay. Multivariable logistic regression showed that no characteristics were associated with complications. Conclusions This report describes the first enhanced recovery after surgery protocol used in elderly patients after short-level lumbar fusion surgery. Our enhanced recovery after surgery program is safe and could help decrease length of stay in elderly patients with short-level lumbar fusion.

Background and Aim Frailty is an independent predictor of mortality and adverse events (AEs) in patients undergoing surgery. This study aimed to quantify the ability of Modified Frailty Index (mFI) to predict AEs in older patients undergoing elective posterior thoracolumbar fusion surgery. Methods We retrospectively reviewed the results of 426 patients with the following diagnoses and follow-up evaluations of at least 12 months duration: lumbar disc herniation, 125; degenerative spondylolisthesis, 81; lumbar spinal canal stenosis, 187; and adult spinal deformities, 33. The cases were divided into two groups. The long spinal fusion (LSF) group was defined as ≥3 spinal levels with segmental pedicle-screw fixation. Short spinal fusion (SSF) were defined with at most two levels. The mFI used in the present study is an 11-variable assessment. The association of frailty with AEs was determined after adjusting for known and suspected confounders. Results Frailty was presented in 66 patients (15.5%) within the total population (LSF, 21.9% and SSF, 11.8%). Rates of AEs assessed in the study increased stepwise with an increase in the mFI for the two groups. The severity of frailty was an independent predictor of any, major, and minor complications in the LSF group and any, minor complication in the SSF group (P

Baroreceptors are nerve endings located in the adventitia of the carotid sinus and aortic arch. They act as a mechanoelectrical transducer that can sense the tension stimulation exerted on the blood vessel wall by the rise in blood pressure and transduce the mechanical force into discharge of the nerve endings. However, the molecular identity of mechanical signal transduction from the vessel wall to the baroreceptor is not clear. We discovered that exogenous integrin ligands, such as RGD, IKVAV, YIGSR, PHSRN, and KNEED, could restrain pressure-dependent discharge of the aortic nerve in a dose-dependent and reversible manner. Perfusion of RGD at the baroreceptor site in vivo can block the baroreceptor reflex. An immunohistochemistry study showed the binding of exogenous RGD to the nerve endings under the adventitia of the rat aortic arch, which may competitively block the binding of integrins to ligand motifs in extracellular matrix. These findings suggest that connection of integrins with extracellular matrix plays an important role in the mechanical coupling process between vessel walls and arterial baroreceptors.

Background: In order to achieve the proper sagittal alignment, previous studies have developed different assessment systems for degenerative spinal deformity which could help us in making treatment strategies. The purpose of our study is to evaluate whether Roussouly classification or GAP score is more appropriate in the prediction of mechanical complications in the treatment of ADS.Methods: The ADS patients who received long segmental fusion in the treatment during the period from December 2016 to December 2018 were evaluated in this study. The basic information of the patients and all radiologic measurements, which were included in GAP score and Roussouly classification, were collected for analysis. Patients were divided into two groups according to occurrence or absence of mechanical complications for comparison. The correlation between evaluation systems and mechanical complications could be analyzed in logistic regression model via stepwise backward elimination based on the Wald statistics. ROC curve was used to determine the predictability of the evaluation systems in the occurrence of mechanical complications and calculate their cut-off value. A two-tailed P value < 0.05 was statistically significant for all statistical tests.Results: A total of 80 cases were included in this study. The results of logistic regression showed: GAP score (P = 0.008) and GAP categories (P = 0.007) were positively correlated with Mechanical complications; Roussouly score was negatively correlated with mechanical complications (P=0.034); GAP score was positively correlated with PJK (P = 0.021); Roussouly score was negatively correlated with implant-related complications (P = 0.018); GAP categories were correlated with implant loosening (P = 0.023). Results of ROC showed that GAP score was mostly effective in predicting PJK (AUC = 0.863) and PJF (AUC = 0.724); GAP categories (AUC = 0.561) was more effective than GAP score (AUC = 0.555) in predicting implant-related complications.Conclusions: Roussouly-type matching could not accurately predict the risk of mechanical complications. In contrast, GAP score was mostly effective in predicting PJK and PJF. The GAP score was better than Roussouly classification in predicting mechanical complications.

Background To achieve the proper sagittal alignment, previous studies have developed different assessment systems for adult degenerative scoliosis (ADS) which could help the spine surgeon in making treatment strategies. The purpose of our study is to evaluate whether Roussouly classification or global alignment and proportion (GAP) score is more appropriate in the prediction of mechanical complications after surgical treatment of ADS. Methods ADS patients who received long segmental fusion in the treatment during the period from December 2016 to December 2018 were evaluated in this study. Basic information and radiologic measurements were collected for analysis. Patients were divided into two groups according to occurrence or absence of mechanical complications for comparison. Mechanical complications included proximal junctional kyphosis (PJK), proximal junctional failure (PJF). GAP categories divided GAP score into proportioned spinopelvic position, moderately disproportioned position, and severely disproportioned position according to the cut-off values. The correlation between evaluation systems and mechanical complications was analyzed through a logistic regression model via stepwise backward elimination based on the Wald statistics. Receiver operator characteristic (ROC) curve was used to determine the predictability of the evaluation systems in the occurrence of mechanical complications and calculate their cut-off value. Area under the curve (AUC) was used to evaluate the validity of the thresholds. Results A total of 80 patients were included in this study. There were 41 patients in mechanical complication group and 39 patients in no mechanical complication group. GAP score (P = 0.008) and GAP categories (P = 0.007) were positively correlated with mechanical complications; Roussouly score was negatively correlated with mechanical complications (P = 0.034); GAP score was positively correlated with PJK (P = 0.021); Roussouly score was negatively correlated with implant-related complications (P = 0.018); GAP categories were correlated with implant loosening (P = 0.023). Results of ROC showed that GAP score was more effective in predicting PJK (AUC = 0.863) and PJF (AUC = 0.724) than Roussouly score; GAP categories (AUC = 0.561) was more effective than GAP score (AUC = 0.555) in predicting implant-related complications. Conclusions Roussouly classification could only be a rough estimate of optimal spinopelvic alignment. Quantitative parameters in GAP score made it more effective in predicting mechanical complications, PJK and PJF than Roussouly classification.

Summary Biotin is an indispensable cofactor in the three domains of life. The unusual virulence factor BioJ of Francisella catalyzes the formation of pimeloyl-ACP, an intermediate in biotin synthesis. Here, we report the 1.58 Å crystal structure of BioJ, the enzymatic activity of which is determined with the in vitro reconstituted reaction and biotin bioassay in vivo. Unlike the paradigm BioH, BioJ displays an atypical α/β-hydrolase fold. A structurally conserved catalytic triad (S151, D248, and H278) of BioJ is functionally defined. A proposed model for BioJ catalysis involves two basic residues-rich cavities, of which cavity-1, rather than cavity-2, binds to the ACP moiety of its physiological substrate, pimeloyl-ACP methyl ester. In summary, this finding provides molecular insights into the BioJ gatekeeper of biotin synthesis., Graphical Abstract, Highlights • BioJ is a distinct gatekeeper of biotin synthesis • We report structural and functional definition of BioJ • We propose a working model for BioJ-substrate binding in addition to catalytic triad • It furthers our understanding how the substrate is gatekept by BioJ in biotin synthesis, Biological Sciences; Microbiology; Structural Biology

Background: Currently, ERAS for spinal surgery field is still in its beginnings, the major protocol lessons learned from other surgical specialties and lack of ERAS program for elderly patients (>70 years old). Geriatric patients has its own special characteristics resulting in more harmed by surgical stress. The enhanced recovery after surgery (ERAS) are designed to improving recovery after surgery and can result in substantial benefits in both clinical outcomes and cost-effectiveness. In the present study, we aimed to determine whether enhanced recovery after surgery (ERAS) significantly improved satisfaction and outcomes in elderly patients (>70 years old) with long-level lumbar fusion. Methods: A total of 144 patients were included, 62 in the ERAS group and 82 case-matched patients in the non-ERAS group. Data including demographic, comorbidity and surgical information were collected from electronic medical records. ERAS interventions were categorised as preoperative, intraoperative and postoperative. We also evaluated primary outcome, surgical complication and length of stay (LOS).Results: There were no statistically significant intergroup differences in regards to demographics, comorbidities、American Society of Anaesthesiologists (ASA) grade、or the number of fusion levels. There were also no differences between mean surgery time of intraoperative blood loss between the ERAS and non-ERAS groups. In addition, the mean preoperative Visual Analogue Score (VAS) for the back and legs and Oswestry Disability Index (ODI) score were not significantly different between the two groups. Overall, ERAS pathway compliance was 91.5%. There were no significant differences in the mortality rates between the ERAS and non-ERAS groups. However, we observed a statistically significant decrease in the complications in the ERAS group(6 in the ERAS group versus 23 in the non-ERAS group, p=0.006) and LOS in the ERAS group (17.74±5.56 of ERAS group versus 22.13±12.21 in non-ERAS group, p=0.041). Multivariable linear regression showed that comorbidities (p=0.028) and implementation of ERAS program (p=0.002) were correlated with prolonged LOS. Multivariable logistic regression showed that comorbidities (p=0.029)， implementation of ERAS program (p=0.043) and preoperative VAS Back (p=0.046), were correlated with complications. Conclusions: This report describes the first ERAS protocol used in elderly patients after long-level lumbar fusion surgery. Our ERAS program is safe and could help decreases LOS and complication in elderly patients with long-level lumbar fusion.

Zhong-En Li,1– 3 Shi-Bao Lu,1– 3 Chao Kong,1– 3 Wen-Zhi Sun,1– 3 Peng Wang,1– 3 Si-Tao Zhang1,2 1Department of Orthopedics, Xuanwu Hospital Capital Medical University, Beijing, People’s Republic of China; 2National Clinical Research Center for Geriatric Diseases, Beijing, People’s Republic of China; 3Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Shi-Bao Lu Email xuanwuspine@163.comBackground and Aim: The benefits of the enhanced recovery after surgery (ERAS) program to elderly patients have not been evaluated in lumbar fusion surgery. Compliance with the ERAS program is associated with prognosis. There is currently no adequate assessment about the importance of the individual components of ERAS program in lumbar fusion surgery. The aim of the study was to analyze the effect of compliance with our ERAS program and the relative importance of the individual ERAS program components among elderly patients undergoing lumbar fusion surgery.Methods: A retrospective case-review study was conducted from March 2018 to March 2020. The ERAS program for lumbar fusion surgery at our department was implemented. Overall compliance was found to be 92.9%, and this was used as a cutoff for dividing patients into higher compliance and lower compliance groups. Patient characteristics and clinical outcomes were compared between groups.Results: The overall compliance rate was 92.9%, distributing 91 patients into the higher compliance group and 169 patients into the lower compliance group. Patients with higher compliance were younger (p=0.045). The length of stay (LOS) of patients with higher compliance was significantly shorter than that of patients with lower compliance. Patients with higher compliance had significantly fewer complications (p=0.031). A multivariate analysis showed that surgical time (p=0.029), lower compliance (p=0.034), and early oral feeding (p=0.026) were predictors of any postoperative complications. On multivariate analysis, the following items remained correlated with prolonged LOS (LOS≥ 12 days): older age (p=0.010), lower compliance (p< 0.0001), early ambulation (p=0.018), and stick to discharge criteria (p=0.040).Conclusion: Low compliance with ERAS program among elderly patients undergoing lumbar fusion surgery was associated with a higher incidence of complications and prolonged LOS. The failure of early oral feeding was associated with increased complications, and the failure of early ambulation or sticking to discharge criteria was significantly more influential on prolonged LOS.Keywords: compliance, elderly, enhanced recovery after surgery; ERAS, lumbar fusion surgery

Background When talking about backward displacement of the vertebra, it generally refers to the retrolisthesis under low pelvic incidence (PI). It is worth to mention that lumbar retrolisthesis could also occur under a high-grade PI. Little knowledge was known about the radiographic characteristics and developmental mechanism of the retrolisthesis under high PI. This study was designed to describe the radiographic features and to explore the developmental mechanism of this type of backward vertebral displacement. Methods A total of 887 consecutive subjects from our database were retrospectively reviewed. Degenerative lumbar retrolisthesis was found in 78 patients, including 54 patients with a relative low-grade PI (Group L) and 24 patients with a relative high-grade PI (Group H). 60 subjects without lumbar spondylolisthesis were randomly selected as the control group. Clinical and radiologic data were collected and compared between different groups. Results 91.4% of patients in Group H had the type 4 sagittal construction in terms of Roussouly classification, while 92.6% of patients in Group L had the type 1 sagittal construction. The distribution of retrolisthesis was found about two vertebrae higher with larger backward slope in Group H than Group L. Compared with the control, patients with retrolisthesis under high PI had significantly greater thoracolumbar kyphosis (TLK), PI, sacral slope, sagittal vertical axis, T1 pelvic angle and severer disc degeneration and facet arthritis. Logistic regression analysis showed TLK was the independent factor predicting the development of retrolisthesis under a high-grade PI. Conclusions Retrolisthesis under a high-grade PI and type 4 sagittal construction had higher location and larger backward slope than retrolisthesis under a low-grade PI. Retrolisthesis under high PI might be primarily associated with the increased backward sliding forces at the hypertilted vertebra in large TLK segment and lumbar instability caused by disc degeneration and facet arthritis.

The large conductance Ca2+-activated potassium (BKCa) channel is activated by stretch. The stress-regulated exon (STREX) in α-subunits is known to affect the mechanosensitivity of BKCa channels. However, in human colonic smooth muscle cells (HCoSMCs), we found that the α-subunits without STREX (ZERO-BK) and β1-subunits could be detected yet the cells were mechanosensitive. Whether the β1-subunit is involved in the regulation of BKCa mechanosensitivity is unclear. In the present study, ZERO-BK and β1-subunits were individually expressed or coexpressed in HEK293 cells and cell-attached patch-clamp techniques were used to measure BKCa currents defining mechanosensitivity. Single-channel patch-clamp recordings from HEK293 cells cotransfected with ZERO-BK and β1-subunits showed stretch sensitivity, but there was no mechanosensitivity in HEK293 cells transfected only with ZERO-BK. We also showed that expression of the β1-subunit could increase mechanosensitivity of the STREX-type α-subunits (STREX-BK). To identify the domain in β1-subunits responsible for affecting stretch sensitivity, we expressed β1- LoopDel (chimeric β1-subunits without the extracellular loop) or β1- C TermDel (chimeric β1-subunits without COOH terminus) with ZERO-BK in HEK293 cells. The data showed that deletion of the extracellular loop but not the COOH terminus of β1-subunits virtually abolished the mechanosensitivity. These results suggest that the extracellular loop of the β1-subunit is involved in the regulation of BKCa channel mechanosensitivity and that role is independent of STREX.

Demyelination in the central nervous system (CNS) underlies many human diseases, including multiple sclerosis (MS). We report here the findings of our study of the CNS demyelination process using immune-induced [experimental autoimmune encephalomyelitis (EAE)] and chemical-induced [cuprizone (CPZ)] mouse models of demyelination. We found that necroptosis, a receptor-interacting protein 3 (RIP3) kinase and its substrate mixed lineage kinase domain-like protein (MLKL)-dependent cell death program, played no role in the demyelination process, whereas the MLKL-dependent, RIP3-independent function of MLKL in the demyelination process initially discovered in the peripheral nervous system in response to nerve injury, also functions in demyelination in the CNS in these models. Moreover, a receptor-interacting protein 1 (RIP1) kinase inhibitor, RIPA-56, blocked disease progression in the EAE-induced model but showed no effect in the CPZ-induced model. It does so most likely at a step of monocyte elevation downstream of T cell activation and myelin-specific antibody generation, although upstream of breakdown of the blood-brain barrier. RIP1-kinase dead knock-in mice shared a similar result as mice treated with the RIP1 inhibitor. These results indicate that RIP1 kinase inhibitor is a potential therapeutic agent for immune-mediated demyelination diseases that works by prevention of monocyte elevation, a function previously unknown for RIP1 kinase.

Heart sounds play an important role in the initial screening of heart diseases. However, the accurate diagnosis with heart sound signals requires doctors to have many years of clinical experience and relevant professional knowledge. In this study, we proposed an end-to-end lightweight neural network model that does not require heart sound segmentation and has very few parameters. We segmented the original heart sound signal and performed a short-time Fourier transform (STFT) to obtain the frequency domain features. These features were sent to the improved two-dimensional convolutional neural network (CNN) model for features learning and classification. Considering the imbalance of positive and negative samples, we introduced FocalLoss as the loss function, verified our network model with multiple random verifications, and, hence, obtained a better classification result. Our main purpose is to design a lightweight network structure that is easy for hardware implementation. Compared with the results of the latest literature, our model only uses 4.29 K parameters, which is 1/10 of the size of the state-of-the-art work.

The large conductance Ca

Stretch-induced relaxation has not been clearly identified in gastrointestinal tract. The present study is to explore the role of large conductance calcium-activated potassium channels (BKCa) in stretch-induced relaxation of colon. The expression and currents of BKCawere detected and the basal muscle tone and contraction amplitude of colonic smooth muscle strips were measured. The expression of BKCain colon is higher than other GI segments (P< 0.05). The density of BKCacurrents was very high in colonic smooth muscle cells (SMCs). BKCain rat colonic SMCs were sensitive to stretch. The relaxation response of colonic SM strips to stretch was attenuated by charybdotoxin (ChTX), a nonspecific BKCablocker (P< 0.05). After blocking enteric nervous activities by tetrodotoxin (TTX), the stretch-induced relaxation did not change (P> 0.05). Still, ChTX and iberiotoxin (IbTX, a specific BKCablocker) attenuated the relaxation of the colonic muscle strips enduring stretch (P< 0.05). These results suggest stretch-activation of BKCain SMCs was involved in the stretch-induced relaxation of colon. Our study highlights the role of mechanosensitive ion channels in SMCs in colon motility regulation and their physiological and pathophysiological significance is worth further study.

Summary Successful regeneration of severed peripheral nerves requires the breakdown and subsequent clearance of myelin, tightly packed membrane sheaths of Schwann cells that protect nerve fibers and harbor nerve growth-inhibitory proteins. How Schwann cells initiate myelin breakdown in response to injury is still largely unknown. Here we report that, following sciatic nerve injury, MLKL, a pseudokinase known to rupture cell membranes during necroptotic cell death, is induced and targets the myelin sheath membrane of Schwann cells to promote myelin breakdown. The function of MLKL in disrupting myelin sheaths requires injury-induced phosphorylation of serine 441, an activation signal distinct from the necroptosis-inducing phosphorylation by RIP3 kinase. Mice with Mlkl specifically knocked out in Schwann cells showed delayed myelin sheath breakdown. Lack of MLKL reduced nerve regeneration following injury, whereas overexpression of MLKL accelerated myelin breakdown and promoted the regeneration of axons.