The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury.

Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide1-6. Clinical studies have demonstrated that the severity of cardiac injury following myocardial infarction exhibits a circadian pattern, with larger infarct sizes and poorer outcomes in patients experiencing morning onset myocardial infarctions7-14. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL114-20, a core circadian transcription factor, orchestrates diurnal variability in myocardial injury. Unexpectedly, BMAL1 modulates circadian-dependent cardiac injury by forming a transcriptionally active heterodimer with a non-canonical partner, hypoxia-inducible factor 2 alpha (HIF2A)6,21-23, in a diurnal manner. Substantiating this finding, we determined the cryo-EM structure of the BMAL1/HIF2A/DNA complex, revealing a previously unknown capacity for structural rearrangement within BMAL1, which enables the crosstalk between circadian rhythms and hypoxia signaling. Furthermore, we identified amphiregulin (AREG) as a rhythmic transcriptional target of the BMAL1/HIF2A heterodimer, critical for regulating circadian variations of myocardial injury. Finally, pharmacologically targeting the BMAL1/HIF2A-AREG pathway provides effective cardioprotection, with maximum efficacy when aligned with the pathway's circadian trough. Our findings not only uncover a novel mechanism governing the circadian variations of myocardial injury but also pave the way for innovative circadian-based treatment strategies, potentially shifting current treatment paradigms for myocardial infarction.

Association of tet methylcytosine dioxygenase 2 and 5-hydroxymethylcytosine in endometrioid adenocarcinoma and its clinical significance.

BACKGROUND: Aberrant DNA methylation is a vital molecular alteration commonly detected in type I endometrial cancers (EC), and tet methylcytosine dioxygenase 2 (TET2) and 5-hydroxymethylcytosine (5hmC) play significant roles in DNA demethylation. However, little is known about the function and correlation of TET2 and 5hmC co-expressed in EC. This study intended to investigate the clinical significance of TET2 and 5hmC in EC. METHODS: The levels of TET2 and 5hmC were detected in 326 endometrial tissues by immumohistochemistry, and the correlation of their level was detected by Pearson analysis. The association between the levels of TET2 and 5hmC and clinicopathologic characteristics was analyzed. Prognostic value of TET2 and 5hmC was explored by Kaplan-Meier analysis. The Cox proportional hazard regression model was used for univariate and multivariate analyses. RESULTS: Based on the analysis results, TET2 protein level was positively correlated with 5hmC level in EC tissues (r = 0.801, P < 0.001). TET2+5hmC+ (high TET2 and high 5hmC) association was significantly associated with well differentiation, myometrial invasion, negative lymph node metastasis, and tumor stage in EC. Association of TET2 and 5hmC was confirmed as a prognostic factor (HR = 2.843, 95%CI = 1.226-3.605, P = 0.007) for EC patients, and EC patients with TET2-5hmC- level had poor overall survival. CONCLUSIONS: In summary, the association of TET2 and 5hmC was downregulated in EC tissues, and may be a potential poor prognostic indicator for EC patients. Combined detection of TET2 and 5hmC may be valuable for the diagnosis and prognosis of EC.

A comparison of interferential current efficacy in elderly intervertebral disc degeneration patients with or without sarcopenia: a retrospective study.

BACKGROUND: Intervertebral disc degeneration and sarcopenia are both age-related diseases without effective treatments. Their comorbidities may worsen the prognosis, and further studies on interaction and therapy are needed. The purpose of the study was to investigate the prevalence of sarcopenia in intervertebral disc degeneration, and to compare the characteristics of intervertebral disc degeneration with and without sarcopenia and effects of interferential current. METHODS: One hundred twenty disc degeneration patients were included from 2021 to 2022 in a single institute. Medical records, examination results and radiological reports were reviewed. Patients with sarcopenia were screened and grouped according to Asian Working Group for Sarcopenia 2019. VAS, ODI, SARC-F, SMI, gait speed (GS), grip strength, disc Pfirrmann grading, standard cross-sectional area (SCSA), degree of fatty infiltration (DFF), and nerve conduction velocity (NCV) were assessed before and after treatment. RESULTS: The prevalence of sarcopenia in intervertebral disc degeneration was 28.3%. The difference of VAS, ODI, disc Pfirrmann grading, SCSA, DFF and NCV between two groups were significant before intervention (P < 0.05), SCSA and DFF were related to the degree of disc degeneration. The improvement of SMI, GS, grip strength, VAS, SARC-F and ODI in intervertebral disc degeneration with sarcopenia group was significant after intervention, as well as SMI, GS, grip strength, VAS and ODI in those without sarcopenia (P < 0.05). The improvement of grip strength, GS, ODI and SARC-F in intervertebral disc degeneration with sarcopenia group were greater than the one without sarcopenia (P < 0.05), whereas there was no significance in improvement degree of other indicators between the two groups (P > 0.05). CONCLUSION: The prevalence of sarcopenia was high in intervertebral disc degeneration, and paravertebral muscles degeneration correlated with the degree of disc degeneration. Compared to those without sarcopenia, intervertebral disc degeneration patients with sarcopenia have more severe pain, poorer mobility and neurological function. Interferential current is effective in intervertebral disc degeneration patients and sarcopenia patients.

Associations of body mass index trajectory, waist circumference trajectory, or both with type 2 diabetes mellitus risk in Chinese adults: The China-PAR project.

AIMS: To identify the trajectories of body mass index (BMI) and waist circumference (WC), and assess the associations of BMI trajectory, WC trajectory, or the two combined, with type 2 diabetes mellitus (T2DM) risk in Chinese adults. MATERIALS AND METHODS: This study was based on a prospective project-the Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR). A total of 54 434 participants (39.21% men) who were measured on at least two occasions were included. Three slowly increasing trajectory patterns were identified for BMI, and four for WC, by latent mixed modelling. A nine-category variable was derived by combining the WC trajectory (low, moderate, moderate-high/high) and the BMI trajectory (low, moderate, high). Logistic regression models were applied to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The risk of developing T2DM increased with elevated BMI or WC trajectory levels (all ptrend <0.001). The risks were 2.85 (2.59-3.14) for high BMI trajectory and 4.34 (3.78-4.99) for high WC trajectory versus low trajectory groups, respectively. The association was more pronounced among younger individuals (pinteraction <0.001). In the joint analysis, compared to participants with low WC and BMI trajectory, those with moderate-high/high WC combined with high BMI trajectory had the highest risk of T2DM (OR 3.96, 95% CI 3.48-4.50); even those who maintained moderate-high/high WC but low BMI trajectory showed a higher T2DM risk (OR 3.00, 95% CI 2.31-3.91). CONCLUSIONS: This study suggests that simultaneous dynamic and continuous monitoring of BMI and WC may contribute more than single measurements to predicting T2DM risk and determining preventive strategies.

Myth or fact: 3D-printed off-the-shelf prosthesis is superior to titanium mesh cage in anterior cervical corpectomy and fusion?

BACKGROUND: To find out if three-dimensional printing (3DP) off-the-shelf (OTS) prosthesis is superior to titanium mesh cages in anterior cervical corpectomy and fusion (ACCF) when treating single-segment degenerative cervical spondylotic myelopathy (DCSM). METHODS: DCSM patients underwent ACCF from January 2016 to January 2019 in a single center were included. Patients were divided into the 3DP group (28) and the TMC group (23). The hospital stays, operation time, intraoperative blood loss, and the cost of hospitalization were compared. The Japanese Orthopedic Association (JOA) scores and Neck Disability Index (NDI) were recorded pre-operatively, 1 day, 3, 6, 12, and 24 months post-operatively. Radiological data was measured to evaluate fusion, subsidence, and cervical lordosis. Patients were sent with SF-36 to assess their health-related quality of life (HRQoL). RESULTS: The differences in operative time, intraoperative blood loss, and hospital stay were not statistically significant between groups (p > 0.05). Postoperative dysphagia occurred in 2 cases in the 3DP group and 3 cases in the TMC group, which all relieved one week later. The difference in improvement of JOA and NDI between the two groups was not statistically significant (p > 0.05). No hardware failure was found and bony fusion was achieved in all cases except one in the 3DP group. The difference in cervical lordosis (CL), fused segmental angle (FSA), mean vertebral height (MVH), and subsidence rates between groups at each follow-up time point was not statistically significant and the results of the SF-36 were similar (p > 0.05). The total cost was higher in the 3DP group with its higher graft cost (p < 0.05). CONCLUSION: In treating single-segment DCSM with ACCF, both 3DP OTS prosthesis and TMC achieved satisfactory outcomes. However, the more costly 3DP OTS prosthesis was not able to reduce subsidence as it claimed.

Population-Specific Glucose Prediction in Diabetes Care With Transformer-Based Deep Learning on the Edge.

Leveraging continuous glucose monitoring (CGM) systems, real-time blood glucose (BG) forecasting is essential for proactive interventions, playing a crucial role in enhancing the management of type 1 diabetes (T1D) and type 2 diabetes (T2D). However, developing a model generalized to a population and subsequently embedding it within a microchip of a wearable device presents significant technical challenges. Furthermore, the domain of BG prediction in T2D remains under-explored in the literature. In light of this, we propose a population-specific BG prediction model, leveraging the capabilities of the temporal fusion Transformer (TFT) to adjust predictions based on personal demographic data. Then the trained model is embedded within a system-on-chip, integral to our low-power and low-cost customized wearable device. This device seamlessly communicates with CGM systems through Bluetooth and provides timely BG predictions using edge computing. When evaluated on two publicly available clinical datasets with a total of 124 participants with T1D or T2D, the embedded TFT model consistently demonstrated superior performance, achieving the lowest prediction errors when compared with a range of machine learning baseline methods. Executing the TFT model on our wearable device requires minimal memory and power consumption, enabling continuous decision support for more than 51 days on a single Li-Poly battery charge. These findings demonstrate the significant potential of the proposed TFT model and wearable device in enhancing the quality of life for people with diabetes and effectively addressing real-world challenges.

Spinal infection after vertebral augmentation: a covert complication with serious havoc.

INTRODUCTION: Vertebral augmentation, including percutaneous vertebroplasty (PVP) or kyphoplasty (PKP), is the current least invasive surgical option and has been widely used to treat the painful osteoporotic vertebral compression fractures (OVCF). However, the postoperative infections could be life-threatening, even though they rarely occur. Our studies aim to clarify the causation and outcomes of spinal infections following augmentation and meanwhile to identify the risk factors. METHODS: A retrospective study was conducted on patients with OVCF who underwent PVP or PKP, and were subsequently admitted to our institution with postoperative spinal infection between January 2010 and December 2022. A total of 33 patients were finally included. RESULTS: The rate of spinal infection after augmentation in our single institute was 0.05% (2/3893). In addition to these 2 patients, the remaining 31 were referred from other hospitals. All 33 patients exhibited elevated inflammatory parameters, 14 patients presented with fever, and 9 patients experienced neurological deficits. Additionally, 29 patients had comorbidity and risk factors. Pathogens were identified in 26 patients, while only 7 patients were examined as culture negative. 27 patients underwent revision surgery and 6 patients only received conservative therapy. Anterior surgery was performed in 2 patients, while posterior surgery was performed in 20 patients. A combined anterior-posterior surgery was performed in 5 patients. At the final follow-up, 18 patients had unrestricted mobility, 10 patients required assistance from crutches or a walker for ambulation, 4 patients needed a wheelchair, and 1 patients died after revision surgery. CONCLUSIONS: Spinal infection after vertebral augmentation is rare, but it cannot be ignored. Surgeons should make every effort to detect the potential preoperative spondylitis or discitis. Once postoperative spinal infection is confirmed, a prompt intravenous antibiotic therapy is warranted. If medication therapy fails, revision surgery involving debridement and spinal reconstruction should be considered.

Risk factors of instrumentation failure after laminectomy and posterior cervical fusions (PCF).

BACKGROUND: For patients with multilevel degenerative cervical myelopathy, laminectomy and posterior cervical fusions (PCF) with instrumentation are widely accepted techniques for symptom relief. However, hardware failure is not rare and results in neck pain or even permanent neurological lesions. There are no in-depth studies of hardware-related complications following laminectomy and PCF with instrumentation. METHODS: The present study was a retrospective, single centre, observational study. Patients who underwent laminectomy and PCF with instrumentation in a single institution between January 2019 and January 2021 were included. Patients were divided into hardware failure and no hardware failure group according to whether there was a hardware failure. Data, including sex, age, screw density, end vertebra (C7 or T1), cervical sagittal alignment parameters (C2-C7 cervical lordosis, C2-C7 sagittal vertical axis, T1 slope, Cervical lordosis correction), regional Hounsfield units (HU) of the screw trajectory and osteoporosis status, were collected and compared between the two groups. RESULTS: We analysed the clinical data of 56 patients in total. The mean overall follow-up duration was 20.6 months (range, 12-30 months). Patients were divided into the hardware failure group (n = 14) and no hardware failure group (n = 42). There were no significant differences in the general information (age, sex, follow-up period) of patients between the two groups. The differences in fusion rate, fixation levels, and screw density between the two groups were not statistically significant (p > 0.05). The failure rate of fixation ending at T1 was lower than that at C7 (9% vs. 36.3%) (p = 0.019). The regional HU values of the pedicle screw (PS) and lateral mass screw (LMS) in the failure group were lower than those in the no failure group (PS: 267 ± 45 vs. 368 ± 43, p = 0.001; LMS: 308 ± 53 vs. 412 ± 41, p = 0.001). The sagittal alignment parameters did not show significant differences between the two groups before surgery or at the final follow-up (p > 0.05). The hardware failure rate in patients without osteoporosis was lower than that in patients with osteoporosis (14.3% vs. 57.1%) (p = 0.001). CONCLUSIONS: Osteoporosis, fixation ending at C7, and low regional HU value of the screw trajectory were the independent risk factors of hardware failure after laminectomy and PCF. Future studies should illuminate if preventive measures targeting these factors can help reduce hardware failure and identified more risk factors, and perform long-term follow-up.

Relationships between lumbar lordosis correction and the change in global tilt (GT) in adult spinal deformity.

PURPOSE: This study aimed to explore the relationships between lumbar lordosis (LL) correction and improvement of postoperative global sagittal alignment and to establish corresponding linear regressions to predict the change in global tilt (GT) based on the corrected LL following adult spinal deformity (ASD) surgery. METHODS: A total of 240 ASD patients who underwent lumbar correction were enrolled in this multicentre study. The following sagittal parameters were measured pre- and postoperatively: thoracic kyphosis (TK), LL, upper and lower LL (ULL and LLL), pelvic tilt (PT), sagittal vertical axis (SVA) and GT. The correlations among the changes in GT (△GT), SVA (△SVA), PT (△PT), TK (△TK), LL (△LL), ULL (△ULL) and LLL (△LLL) were assessed, and linear regressions were conducted to predict △GT, △SVA, △PT and △TK from △LL, △ULL and △LLL. RESULTS: △LL was statistically correlated with △GT (r = 0.798, P < 0.001), △SVA (r = 0.678, P < 0.001), △PT (r = 0.662, P < 0.001) and △TK (r = - 0.545, P < 0.001), and the outcomes of the linear regressions are: △GT = 3.18 + 0.69 × â–³LL (R2 = 0.636), △SVA = 4.78 + 2.57 × â–³LL (R2 = 0.459), △PT = 2.57 + 0.34 × â–³LL (R2 = 0.439), △TK = 7.06-0.43 × â–³LL (R2 = 0.297). In addition, △LLL had more correlations with △GT, △SVA and △PT, while △ULL had more correlations with △TK. CONCLUSION: Surgical correction of LL could contribute to the restoration of global sagittal morphology following ASD surgery. These models were established to predict the changes in sagittal parameters, in particular △GT, determined by △LL, which has not been previously done and may help to customize a more precise correction plan for ASD patients.

Activated Drp1 Initiates the Formation of Endoplasmic Reticulum-Mitochondrial Contacts via Shrm4-Mediated Actin Bundling.

Excessive mitochondrial fission following ischemia and hypoxia relies on the formation of contacts between the endoplasmic reticulum and mitochondria (ER-Mito); however, the specific mechanisms behind this process remain unclear. Confocal microscopy and time course recording are used to investigate how ischemia and hypoxia affect the activation of dynamin-related protein 1 (Drp1), a protein central to mitochondrial dynamics, ER-Mito interactions, and the consequences of modifying the expression of Drp1, shroom (Shrm) 4, and inverted formin (INF) 2 on ER-Mito contact establishment. Both Drp1 activation and ER-Mito contact initiation cause excessive mitochondrial fission and dysfunction under ischemic-hypoxic conditions. The activated form of Drp1 aids in ER-Mito contact initiation by recruiting Shrm4 and promoting actin bundling between the ER and mitochondria. This process relies on the structural interplay between INF2 and scattered F-actin on the ER. This study uncovers new roles of cytoplasmic Drp1, providing valuable insights for devising strategies to manage mitochondrial imbalances in the context of ischemic-hypoxic injury.

Unveiling the noncanonical activation mechanism of CDKs: insights from recent structural studies.

The Cyclin-dependent kinases (CDKs) play crucial roles in a range of essential cellular processes. While the classical two-step activation mechanism is generally applicable to cell cycle-related CDKs, both CDK7 and CDK8, involved in transcriptional regulation, adopt distinct mechanisms for kinase activation. In both cases, binding to their respective cyclin partners results in only partial activity, while their full activation requires the presence of an additional subunit. Recent structural studies of these two noncanonical kinases have provided unprecedented insights into their activation mechanisms, enabling us to understand how the third subunit coordinates the T-loop stabilization and enhances kinase activity. In this review, we summarize the structure and function of CDK7 and CDK8 within their respective functional complexes, while also describing their noncanonical activation mechanisms. These insights open new avenues for targeted drug discovery and potential therapeutic interventions in various diseases related to CDK7 and CDK8.

Predicting thoracic kyphosis morphology and the thoracolumbar inflection point determined by individual lumbar lordosis in asymptomatic adults.

PURPOSE: The aims of this study were to explore the correlations between thoracic kyphosis (TK) and lumbar lordosis (LL) parameters and to build corresponding linear regressions to predict TK morphology and the thoracolumbar inflection point (IP) determined by individual LL parameters in asymptomatic adults. METHODS: A total of 280 adult healthy volunteers were recruited, and full-spine X-rays were performed for each subject in a standing posture. The following sagittal parameters were measured: cumulative TK, LL, proximal LL (PLL), the apices of TK (TKA) and LL (LLA), the IP and the distance from the plumb line of the thoracic apex (TAPL) and the lumbar apex (LAPL) to the gravity line. The correlations between TK and LL parameters were analyzed, and the corresponding linear regressions were conducted. RESULTS: Extensive variations existed in TK alignment, including angular and morphological parameters. In addition, there were statistical correlations of all cumulative TK angles with LL (r values from - 0.173 to - 0.708) and PLL (r values from - 0.206 to - 0.803), TKA and IP with LLA (rs = 0.359 and 0.582, respectively) and TAPL with LAPL (rs = 0.335). The common predictive formulas employed in ASD surgery could include T10-L1 = - 3.6-0.2*LL (R2 = 0.201), T4-L1 = 3.4-0.5*LL (R2 = 0.457), TKA = - 10.3 + 1.1*LLA (R2 = 0.180) and IP = - 12.7 + 1.6*LLA (R2 = 0.330). CONCLUSION: There were intimate associations between TK and LL parameters in asymptomatic adults. Moreover, predictive models for thoracic alignment, particularly cumulative TK, based on LL parameters were proposed, which could better delineate anatomical relationships, guide thoracic construction during adult spinal deformity surgery and may help preventing proximal junctional failure.

Correlation of heavy metals' exposure with the prevalence of coronary heart disease among US adults: findings of the US NHANES from 2003 to 2018.

We sought to explore the association between heavy metal exposure and coronary heart disease (CHD) based on data from the US National Health and Nutrition Examination Survey (NHANES, 2003-2018). In the analyses, participants were all aged > 20 and had participated in heavy metal sub-tests with valid CHD status. The Mann-Kendall test was employed to assess the trends in heavy metals' exposure and the trends in CHD prevalence over 16 years. Spearman's rank correlation coefficient and a logistics regression (LR) model were used to estimate the association between heavy metals and CHD prevalence. 42,749 participants were included in our analyses, 1802 of whom had a CHD diagnosis. Total arsenic, dimethylarsonic acid, monomethylarsonic acid, barium, cadmium, lead, and antimony in urine, and cadmium, lead, and total mercury in blood all showed a substantial decreasing exposure level tendency over the 16 years (all Pfor trend < 0.05). CHD prevalence varied from 3.53 to 5.23% between 2003 and 2018. The correlation between 15 heavy metals and CHD ranges from - 0.238 to 0.910. There was also a significant positive correlation between total arsenic, monomethylarsonic acid, and thallium in urine and CHD by data release cycles (all P < 0.05). The cesium in urine showed a negative correlation with CHD (P < 0.05). We found that exposure trends of total arsenic, dimethylarsonic acid, monomethylarsonic acid, barium, cadmium, lead, and antimony in urine and blood decreased. CHD prevalence fluctuated, however. Moreover, total arsenic, monomethylarsonic acid, and thallium in urine all showed positive relationships with CHD, while cesium in urine showed a negative relationship with CHD.

MET Inhibits the Proliferation of EC Cells by Increasing MPA Sensitivity.

Context: The high resistance rate and high recurrence rate of progesterone only as a treatment for endometrial cancer (EC) limit its clinical application. Metformin (MET) may have antitumor ability. Combining MET and medroxyprogesterone acetate (MPA) may strengthen their inhibitory effects on proliferation of EC cells, but MET's mechanisms remain unclear. Objective: The study intended to identify the specific molecular mechanism that MET combined with MPA uses against EC progression. Design: The research team performed a controlled animal study. Setting: The study took place at Xuzhou Medical University in Xuzhou, China. Animals: The animals were16 female non-obese diabetic-severe combined immunodeficient (NOD-SCID) nude mice, about 12 to 16 g in weight. Interventions: The research team divided randomly, the mice into four groups and induced EC in all groups, four in each group: (1) The control group which received received normal saline, (2) the MPA group, which received 100 mg/kg of MPA; (3) the MET group, which received metformin at the rate of 200 mg/kg, each gavage volume was 0.1ml; (4) the MET+MPA group, which received 100 mg/kg of MPA and 200 mg/kg of MET. Outcome measures: The research team: (1) used a CCK-8 kit, an EdU assay, and a flow-cytometry assay to measure cancer-cell proliferation, count, and viability; determine the cell cycle; and measure apoptosis; (2) performed a Western blot analysis to determine the expression of the PR, CD133, pAkt, totalAkt, p-mTOR, and totalTOR antibodies; and (3) determined the size and volume of tumors in vivo and used immunohistochemical staining to determine expression of the Ki67 protein. Results: The MET+MPA group had a significantly lower number of cancer cells than the MET or MDA groups (both P < .001). That group also had significantly more stagnated cancer cells in the G0/G1 phase and significantly fewer cancer cells in the S phase or G2/M phase control, MET, or MPA groups (all P < .01). The MET+MPA group's PCNA and Ki-67 protein expression was significantly lower than that of the MET and MPA group. The EDU assay yielded similar results. Additionally, the MET+MPA group had significantly higher PR expression than that of to MET or MPA group (both P < .001). The MET and MPA groups' expression of CD133, p-Akt, and p-mTOR were significantly lower than those of the control group, while the MET+MPA group's levels were significantly lower than those of the MET and MPA groups. In-vivo experiments revealed that the MET and MPA groups did show decreased tumor size and volume. The MET+MPA group had tumor weights that were significantly lower and tumor volumes were significantly smaller than those of the MET and MPA groups (all P < .001). Immunohistochemical analysis revealed that the MET+MPA group's levels of the Ki-67 antigen were significantly lower than those of the MET and MPA groups. Conclusions: MET inhibited the proliferation of EC cells by increasing MPA-sensitivity, which was dependent on the inhibition of the CD133 expression and the Akt/mTOR pathway. In addition, if MET acts as an effective progestin sensitizer, it certainly offers promising therapeutic prospects for patients with early-stage EC or overgrown endometrium who have fertility requirements.

Effects of Tapered-Strut Design on Fatigue Life Enhancement of Peripheral Stents.

Peripheral stent could fracture from cyclic loadings as a result of our blood pressures or daily activities. Fatigue performance has therefore become a key issue for peripheral stent design. A simple yet powerful tapered-strut design concept for fatigue life enhancement was investigated. This concept is to move the stress concentration away from the crown and re-distribute the stresses along the strut by narrowing the strut geometry. Finite element analysis was performed to evaluate the stent fatigue performance under various conditions consistent with the current clinical practice. Thirty stent prototypes were manufactured in-house by laser with a series of post-laser treatments, followed by the validation of bench fatigue tests for proof of concept. FEA simulation results show that the fatigue safety factor of the 40% tapered-strut design increased by 4.2 times that of a standard counterpart, which was validated by bench tests with 6.6-times and 5.9-times fatigue enhancement at room temperature and body temperature, respectively. Bench fatigue test results agreed very well with the increasing trend predicted by FEA simulation. The effects of the tapered-strut design were significant and could be considered as an option for fatigue optimization of future stent designs.

Structural basis of a transcription pre-initiation complex on a divergent promoter.

Most eukaryotic promoter regions are divergently transcribed. As the RNA polymerase II pre-initiation complex (PIC) is intrinsically asymmetric and responsible for transcription in a single direction, it is unknown how divergent transcription arises. Here, the Saccharomyces cerevisiae Mediator complexed with a PIC (Med-PIC) was assembled on a divergent promoter and analyzed by cryoelectron microscopy. The structure reveals two distinct Med-PICs forming a dimer through the Mediator tail module, induced by a homodimeric activator protein localized near the dimerization interface. The tail dimer is associated with ∼80-bp upstream DNA, such that two flanking core promoter regions are positioned and oriented in a suitable form for PIC assembly in opposite directions. Also, cryoelectron tomography visualized the progress of the PIC assembly on the two core promoter regions, providing direct evidence for the role of the Med-PIC dimer in divergent transcription.

SPTLC2 ameliorates chondrocyte dysfunction and extracellular matrix metabolism disturbance in vitro and in vivo in osteoarthritis.

Disturbances in chondrocyte extracellular matrix (ECM) metabolism in osteoarthritis (OA) are a major cause of OA and potentially lead to personal disability, placing a huge burden on society. Chondrocyte apoptosis and ECM catabolism have a major role in the OA process. Firstly, bioinformatics analysis was performed to screen differentially expressed genes (DEGs) in OA, and serine palmitoyltransferase subunit 2 (SPTLC2) was chosen, which had high-level expression in the OA cartilage tissues and OA chondrocytes. Overexpression and knockdown of SPTLC2 were achieved in OA chondrocytes and normal chondrocytes respectively to study the effect of SPTLC2 upon ECM metabolism of chondrocytes. Cell viability and apoptosis were measured using MTT and flow cytometry analyses; SPTLC2 overexpression enhanced the OA chondrocyte viability and decreased apoptotic rate. In addition, Western blot detection of ECM-related factors (Collagen I, Collage II, MMP-1, MMP-3, and MMP-13) revealed that SPTLC2 overexpression promoted the expression of collagens (Collagen I and Collage II) and suppressed matrix metalloproteinase (MMP-1, MMP-3, and MMP-13) level. In contrast, SPTLC2 knockdown in normal chondrocytes showed opposite effects on cell viability, apoptosis, and ECM degeneration. The articular cartilage of OA rats was transfected with lentivirus overexpressing SPTLC2; HE and Safranin-O fast green demonstrated that SPTLC2 overexpression could alleviate chondrocyte injuries and slow down the development of OA. In conclusion, SPTLC2 plays a role in OA and may be a potential target gene for the treatment of OA.

Tumor-Antigen Activated Dendritic Cell Membrane-Coated Biomimetic Nanoparticles with Orchestrating Immune Responses Promote Therapeutic Efficacy against Glioma.

Immunotherapy has had a profound positive effect on certain types of cancer but has not improved the outcomes of glioma because of the blood-brain barrier (BBB) and immunosuppressive tumor microenvironment. In this study, we developed an activated mature dendritic cell membrane (aDCM)-coated nanoplatform, rapamycin (RAPA)-loaded poly(lactic-co-glycolic acid) (PLGA), named aDCM@PLGA/RAPA, which is a simple, efficient, and individualized strategy to cross the BBB and improve the immune microenvironment precisely. In vitro cells uptake and the transwell BBB model revealed that the aDCM@PLGA/RAPA can enhance homotypic-targeting and BBB-crossing efficiently. According to the in vitro and in vivo immune response efficacy of aDCM@PLGA/RAPA, the immature dendritic cells (DCs) could be stimulated into the matured status, which leads to further activation of immune cells, such as tumor-infiltrating T cells and natural killer cells, and can induce the subsequent immune responses through direct and indirect way. The aDCM@PLGA/RAPA treatment can not only inhibit glioma growth significantly but also has favorable potential ability to induce glial differentiation in the orthotopic glioma. Moreover, the aDCM@PLGA could induce a robust CD8+ effector and therefore suppress orthotopic glioma growth in a prophylactic setup, which indicates certain tumor immunity. Overall, our work provides an effective antiglioma drug delivery system which has great potential for tumor combination immunotherapy.

Stress ulcer prophylaxis in critically ill adult patients with sepsis at risk of gastrointestinal bleeding: a retrospective cohort study.

BACKGROUND: The Surviving Sepsis Campaign Guidelines recommend stress ulcer prophylaxis (SUP) for patients with sepsis who have gastrointestinal (GI) bleeding risks; however, the effect of SUP has not been specially studied in these patients. AIMS: To determine the effects of SUP versus no prophylaxis on patient-important outcomes in critically ill adult patients with sepsis who have risk factors for GI bleeding. METHODS: This retrospective cohort study utilised data from the Medical Information Mart for Intensive Care III database. We compared those who received SUP with proton-pump inhibitors or histamine-2 receptor antagonists for ≥3 days with those who received no prophylaxis. Propensity score matching (PSM) was conducted to make comparisons between groups with similar distributions of study variables. The primary outcome was inhospital mortality. RESULTS: A total of 7744 patients were included in the analysis, with 1088 (14.0%) in the non-SUP group and 6656 (86.0%) in the SUP group. A 1:1 PSM created 866 patients in each cohort. No significant differences were noted between the two groups with regard to inhospital mortality (22.3% vs 20.4%; P = 0.379), GI bleeding (4.7% vs 6.4%; P = 0.172), pneumonia (38.9% vs 36.6%; P = 0.346), Clostridium difficile infection (CDI) (6.4% vs 8.9%; P = 0.0.057) or intensive care unit (ICU) length of stay (LOS) (4.2 days vs 4.6 days; P = 0.394). CONCLUSIONS: Among critically ill, septic, adult patients at risk for GI bleeding, SUP showed no effect on hospital mortality, the rate of GI bleeding, pneumonia, CDI and ICU LOS.

Development of an interpretable machine learning model associated with heavy metals' exposure to identify coronary heart disease among US adults via SHAP: Findings of the US NHANES from 2003 to 2018.

Limited information is available on the links between heavy metals' exposure and coronary heart disease (CHD). We aim to establish an efficient and explainable machine learning (ML) model that associates heavy metals' exposure with CHD identification. Our datasets for investigating the associations between heavy metals and CHD were sourced from the US National Health and Nutrition Examination Survey (US NHANES, 2003-2018). Five ML models were established to identify CHD by heavy metals' exposure. Further, 11 discrimination characteristics were used to test the strength of the models. The optimally performing model was selected for identification. Finally, the SHapley Additive exPlanations (SHAP) tool was used for interpreting the features to visualize the selected model's decision-making capacity. In total, 12,554 participants were eligible for this study. The best performing random forest classifier (RF) based on 13 heavy metals to identify CHD was chosen (AUC: 0.827; 95%CI: 0.777-0.877; accuracy: 95.9%). SHAP values indicated that cesium (1.62), thallium (1.17), antimony (1.63), dimethylarsonic acid (0.91), barium (0.76), arsenous acid (0.79), total arsenic (0.01) in urine, and lead (3.58) and cadmium (4.66) in blood positively contributed to the model, while cobalt (-0.15), cadmium (-2.93), and uranium (-0.13) in urine negatively contributed to the model. The RF model was efficient, accurate, and robust in identifying an association between heavy metals' exposure and CHD among US NHANES 2003-2018 participants. Cesium, thallium, antimony, dimethylarsonic acid, barium, arsenous acid, and total arsenic in urine, and lead and cadmium in blood show positive relationships with CHD, while cobalt, cadmium, and uranium in urine show negative relationships with CHD.