Bax triggers cell apoptosis by permeabilizing the outer mitochondrial membrane, leading to membrane potential loss and cytochrome c release. However, it is unclear if proteasomal degradation of Bax ...is involved in the apoptotic process, especially in heart ischemia‐reperfusion (I/R)‐induced injury. In the present study, KPC1 expression was heightened in left ventricular cardiomyocytes of patients with coronary heart disease (CHD), in I/R‐myocardium in vivo and in hypoxia and reoxygenation (H/R)‐induced cardiomyocytes in vitro. Overexpression of KPC1 reduced infarction size and cell apoptosis in I/R rat hearts. Similarly, the forced expression of KPC1 restored mitochondrial membrane potential (MMP) and cytochrome c release driven by H/R in H9c2 cells, whereas reducing cell apoptosis, and knockdown of KPC1 by short‐hairpin RNA (shRNA) deteriorated cell apoptosis induced by H/R. Mechanistically, forced expression of KPC1 promoted Bax protein degradation, which was abolished by proteasome inhibitor MG132, suggesting that KPC1 promoted proteasomal degradation of Bax. Furthermore, KPC1 prevented basal and apoptotic stress‐induced Bax translocation to mitochondria. Bax can be a novel target for the antiapoptotic effects of KPC1 on I/R‐induced cardiomyocyte apoptosis and render mechanistic penetration into at least a subset of the mitochondrial effects of KPC1.
KPC1 expression was increased in left ventricular cardiomyocytes of patients with coronary heart disease (CHD), in I/R‐myocardium in vivo and in hypoxia and reoxygenation (H/R)‐induced cardiomyocytes in vitro. Overexpression of KPC1 reduced cytochrome c release from mitochondria and prevented Bax translocation to mitochondria. Taken together results, KPC1 exerted protective effects on I/R‐ and H/R‐induced cardiomyocyte apoptosis through accelerating proteasomal degradation of Bax and reducing Bax mitochondria translocation.
Cohort evidence that links long-term exposures to air pollution and mortality comes largely from the United States and European countries. We investigated the relationship between long-term exposures ...to particulate matter <10μm in diameter (PM10), nitrogen dioxide (NO2), and sulfur dioxide (SO2) and mortality of lung cancer in Northern China. A cohort of 39,054 participants were followed during 1998–2009. Annual average concentrations for PM10, NO2, and SO2 were determined based on data collected from central monitoring stations. Lung cancer deaths (n=140) were obtained from death certificates, and hazard ratios (HRs) were estimated using Cox proportional hazards models, adjusting for age, gender, BMI, education, marital status, smoking status, passive smoking, occupation, alcohol consumption, etc. Each 10mg/m3 increase in PM10 concentrations was associated with a 3.4%–6.0% increase in lung cancer mortality in the time-varying exposure model and a 4.0%–13.6% increase in the baseline exposure model. In multi-pollutant models, the magnitude of associations was attenuated, most strongly for PM10. The association was different in men and women, also varying across age categories and different smoking status. Substantial differences exist in the risk estimates for participants based on assignment method for air pollution exposure.
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•The relationship between exposure to air pollution and lung cancer is proposed.•Levels of PM10 and SO2 were associated with lung cancer mortality independently.•The association was different in men and women, and varied across smoking status.
Background and purpose
The NOTCH3 mutation is a common cause of hereditary cerebral small vessel disease (CSVD) and may be a cause of spontaneous intracerebral haemorrhage (ICH). The aim was to ...investigate the clinical/imaging features for identifying the NOTCH3‐mutation‐related ICH.
Methods
The study was based on a cohort of 749 CSVD patients in Taiwan who received next‐generation sequencing of CSVD genes including NOTCH3. Patients with a history of ICH (n = 206) were included for analysis. The CSVD neuroimaging markers were compared between the patients with NOTCH3 and those without known genetic mutations.
Results
After excluding patients with other causes of ICH (structural lesions, systemic/medication related or amyloid angiopathy) and those without neuroimaging, 45 NOTCH3 mutation patients and 109 nongenetic ICH patients were included. The NOTCH3 mutation patients were more likely to have thalamic haemorrhage, a family history of stroke and more severe CSVD neuroimaging markers. A five‐point NOTCH3‐ICH score was constructed and consisted of a history of stroke in siblings, thalamic haemorrhage, any deep nuclei lacunae, any hippocampal cerebral microbleed (CMB) and a thalamic CMB >5 (one point for each). A score ≥2 had a sensitivity of 88.9% and a specificity of 64.2% in identifying the NOTCH3 mutation. The NOTCH3 mutation patients had a higher risk of recurrent stroke (9.1 vs. 4.5 per 100 person‐years, log‐rank p = 0.03) during follow‐up.
Conclusion
The patients with NOTCH3‐mutation‐related ICH had a higher burden of CMBs in the hippocampus/thalamus and a higher recurrent stroke risk. The NOTCH3‐ICH score may assist in identifying genetic causes of ICH.
The NOTCH3‐ICH score consisting of a history of stroke in siblings, thalamic haemorrhage, any deep nuclei lacunae, any hippocampal cerebral microbleed and a thalamic cerebral microbleed >5 (one point for each) can assist in identifying genetic causes of ICH.
Optical clearing with high-refractive-index (high-n) reagents is essential for 3D tissue imaging. However, the current liquid-based clearing condition and dye environment suffer from solvent ...evaporation and photobleaching, causing difficulties in maintaining the tissue optical and fluorescent features. Here, using the Gladstone-Dale equation (n-1)/density=constant as a design concept, we develop a solid (solvent-free) high-n acrylamide-based copolymer to embed mouse and human tissues for clearing and imaging. In the solid state, the fluorescent dye-labeled tissue matrices are filled and packed with the high-n copolymer, minimizing scattering in in-depth imaging and dye fading. This transparent, liquid-free condition provides a friendly tissue and cellular environment to facilitate high/super-resolution 3D imaging, preservation, transfer, and sharing among laboratories to investigate the morphologies of interest in experimental and clinical conditions.
Infectious diseases caused by bacterial pathogens are important public issues. In addition, due to the overuse of antibiotics, many multidrug-resistant bacterial pathogens have been widely ...encountered in clinical settings. Thus, the fast identification of bacteria pathogens and profiling of antibiotic resistance could greatly facilitate the precise treatment strategy of infectious diseases. So far, many conventional and molecular methods, both manual or automatized, have been developed for
in vitro
diagnostics, which have been proven to be accurate, reliable, and time efficient. Although Raman spectroscopy (RS) is an established technique in various fields such as geochemistry and material science, it is still considered as an emerging tool in research and diagnosis of infectious diseases. Based on current studies, it is too early to claim that RS may provide practical guidelines for microbiologists and clinicians because there is still a gap between basic research and clinical implementation. However, due to the promising prospects of label-free detection and noninvasive identification of bacterial infections and antibiotic resistance in several single steps, it is necessary to have an overview of the technique in terms of its strong points and shortcomings. Thus, in this review, we went through recent studies of RS in the field of infectious diseases, highlighting the application potentials of the technique and also current challenges that prevent its real-world applications.
To investigate the static performance of precast segmental hollow piers, two precast segmental hollow pier specimens were designed for static loading tests on the top of piers. The finite element ...model of precast segmental hollow piers was established by the finite element software Abaqus and verified based on the test results. Based on the experimental and finite element models, three optimal design solutions were proposed, and the calculation results of each solution were analyzed. The results show that precast segmental hollow pier mechanical behavior is similar to that of cantilevered bending members. The specimens present brittle damage characteristics after the destruction of the structure at the bottom of the pier pressure edge as the axis of the rigid body rotation. Following the test loading process, the bonding between the segments is good, except for the pier bottom damage surface of the rest of the bonding surface, which has no relative displacement. The calculation results of the finite element model are in good agreement with the test results and can effectively predict the load–displacement response of precast piers. Three optimized design solutions are proposed. The finite element simulation proves all three optimized design solutions show better overall ductility than the original solution and can effectively improve the performance of segmental precast hollow piers.
Microtubules tightly regulate various cellular activities. Our understanding of microtubules is largely based on experiments using microtubule‐targeting agents, which, however, are insufficient to ...dissect the dynamic mechanisms of specific microtubule populations, due to their slow effects on the entire pool of microtubules. To overcome this technological limitation, we have used chemo and optogenetics to disassemble specific microtubule subtypes, including tyrosinated microtubules, primary cilia, mitotic spindles, and intercellular bridges, by rapidly recruiting engineered microtubule‐cleaving enzymes onto target microtubules in a reversible manner. Using this approach, we show that acute microtubule disassembly swiftly halts vesicular trafficking and lysosomal dynamics. It also immediately triggers Golgi and ER reorganization and slows the fusion/fission of mitochondria without affecting mitochondrial membrane potential. In addition, cell rigidity is increased after microtubule disruption owing to increased contractile stress fibers. Microtubule disruption furthermore prevents cell division, but does not cause cell death during interphase. Overall, the reported tools facilitate detailed analysis of how microtubules precisely regulate cellular architecture and functions.
SYNOPSIS
Characterization of microtubules in cells via microtubule‐targeting agents is not ideal for assessing dynamics of specific microtubule populations. Here, a novel approach using an engineered microtubule‐severing enzyme allows spatiotemporal manipulation of microtubule disassembly triggered by either chemicals or illumination.
A triple glutamine mutation in Spastin (dNSpastin3Q) reduces its association with microtubules.
Engineered dNSpastin3Q acts as a microtubule‐severing enzyme in living cells.
Recruitment of dNSpastin3Q to microtubules can be controlled by chemical‐ or light‐induced dimerization.
Induced dimerization of dNSpastin3Q leads to acute disassembly of target microtubule subtypes.
Spatiotemporal manipulation of microtubules by either chemical treatment or light allows assessing their function in cells.
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