Abstract
Type 2 diabetes mellitus (T2DM) is a risk factor for heart disease. However, the mechanisms of T2DM involvement in cardiac complications are still unclear. In the present study, we ...investigated mitochondria-related mechanisms underlying the pathogenesis of myocardial disorders in diabetic Goto-Kakizaki (GK) rats. We found that remarkable myocardial mitochondrial deficiency and dysfunction as well as oxidative stress occurred in the heart of GK rats. In addition, our results suggested that the loss of mitochondria was in response to elevated autophagy and upstream FoxO factors in diabetic myocardium. More importantly, (-)-epigallocatechin-3-gallate (EGCG), a polyphenol derived from green tea, successfully improved mitochondrial function and autophagy in the heart of GK rats. Our findings revealed that diabetes-associated myocardial mitochondrial deficiency and dysfunction was associated with enhanced autophagy in myocardium, and EGCG might be a potential agent in preventing and treating myocardial disorders involved in diabetes.
Regional climate modeling addresses our need to understand and simulate climatic processes and phenomena unresolved in global models. This paper highlights examples of current approaches to and ...innovative uses of regional climate modeling that deepen understanding of the climate system. High-resolution models are generally more skillful in simulating extremes, such as heavy precipitation, strong winds, and severe storms. In addition, research has shown that finescale features such as mountains, coastlines, lakes, irrigation, land use, and urban heat islands can substantially influence a region’s climate and its response to changing forcings. Regional climate simulations explicitly simulating convection are now being performed, providing an opportunity to illuminate new physical behavior that previously was represented by parameterizations with large uncertainties. Regional and global models are both advancing toward higher resolution, as computational capacity increases. However, the resolution and ensemble size necessary to produce a sufficient statistical sample of these processes in global models has proven too costly for contemporary supercomputing systems. Regional climate models are thus indispensable tools that complement global models for understanding physical processes governing regional climate variability and change. The deeper understanding of regional climate processes also benefits stakeholders and policymakers who need physically robust, high-resolution climate information to guide societal responses to changing climate. Key scientific questions that will continue to require regional climate models, and opportunities are emerging for addressing those questions.
Key points
Weaning from mechanical ventilation (MV) of long‐term intensive care unit (ICU) patients is delayed by impaired respiratory muscle function; however, the mechanisms that cause the ...impairment are not fully understood.
A novel experimental rat ICU model was used for time‐resolved analyses (6 h to 2 weeks) of the effects of MV on diaphragm muscle fibre structure and function, and on gene and protein expression.
A prompt and progressive decline of diaphragm muscle fibre function, preceding atrophy, occurred with MV, and at the end of 2 weeks residual diaphragm muscle fibre function was <15% of control levels.
Cellular and subcellular analyses indicated that oxidative stress‐triggered protein modifications had significantly diminished diaphragm muscle fibre function.
The novel finding that activation of proteolytic pathways and regulation of contractile protein synthesis were different in diaphragm and limb muscles has direct implications for the design of muscle‐specific intervention strategies.
Controlled mechanical ventilation (CMV) plays a key role in triggering the impaired diaphragm muscle function and the concomitant delayed weaning from the respirator in critically ill intensive care unit (ICU) patients. To date, experimental and clinical studies have primarily focused on early effects on the diaphragm by CMV, or at specific time points. To improve our understanding of the mechanisms underlying the impaired diaphragm muscle function in response to mechanical ventilation, we have performed time‐resolved analyses between 6 h and 14 days using an experimental rat ICU model allowing detailed studies of the diaphragm in response to long‐term CMV. A rapid and early decline in maximum muscle fibre force and preceding muscle fibre atrophy was observed in the diaphragm in response to CMV, resulting in an 85% reduction in residual diaphragm fibre function after 9–14 days of CMV. A modest loss of contractile proteins was observed and linked to an early activation of the ubiquitin proteasome pathway, myosin:actin ratios were not affected and the transcriptional regulation of myosin isoforms did not show any dramatic changes during the observation period. Furthermore, small angle X‐ray diffraction analyses demonstrate that myosin can bind to actin in an ATP‐dependent manner even after 9–14 days of exposure to CMV. Thus, quantitative changes in muscle fibre size and contractile proteins are not the dominating factors underlying the dramatic decline in diaphragm muscle function in response to CMV, in contrast to earlier observations in limb muscles. The observed early loss of subsarcolemmal neuronal nitric oxide synthase activity, onset of oxidative stress, intracellular lipid accumulation and post‐translational protein modifications strongly argue for significant qualitative changes in contractile proteins causing the severely impaired residual function in diaphragm fibres after long‐term mechanical ventilation. For the first time, the present study demonstrates novel changes in the diaphragm structure/function and underlying mechanisms at the gene, protein and cellular levels in response to CMV at a high temporal resolution ranging from 6 h to 14 days.
Changes to nanoparticle surface charge, colloidal stability, and hydrodynamic properties induced by interaction with natural organic matter (NOM) warrant consideration in assessing the potential for ...these materials to adversely impact organisms in the environment. Here, we show that acquisition of a coating, or “corona”, of NOM alters the hydrodynamic and electrokinetic properties of diamond nanoparticles (DNPs) functionalized with the polycation poly(allylamine HCl) in a manner that depends on the NOM-to-DNP concentration ratio. The NOM-induced changes to DNP properties alter subsequent interactions with model biological membranes and the Gram-negative bacterium Shewanella oneidensis MR-1. Suwannee River NOM induces changes to DNP hydrodynamic diameter and apparent ζ-potential in a concentration-dependent manner. At low NOM-to-DNP ratios, DNPs aggregate to a limited extent but retain a positive ζ-potential apparently due to nonuniform adsorption of NOM molecules leading to attractive electrostatic interactions between oppositely charged regions on adjacent DNP surfaces. Diamond nanoparticles at low NOM-to-DNP ratios attach to model membranes to a larger extent than in the absence of NOM (including those incorporating lipopolysaccharide, a major bacterial outer membrane component) and induce a comparable degree of membrane damage and toxicity to S. oneidensis. At higher NOM-to-DNP ratios, DNP charge is reversed, and DNP aggregates remain stable in suspension. This charge reversal eliminates DNP attachment to model membranes containing the highest LPS contents studied due to electrostatic repulsion and abolishes membrane damage to S. oneidensis. Our results demonstrate that the effects of NOM coronas on nanoparticle properties and interactions with biological surfaces can depend on the relative amounts of NOM and nanoparticles.
Owing to its ultra high carrier mobility, graphene transistor shows great application potential as high-frequency electronics. Intrinsic cutoff frequency (fT) of 427GHz has been reported. But the ...maximum oscillation frequency (fmax) remains low, limiting its use in practical radio-frequency (RF) circuits. Here, we report an ultra clean self-aligned graphene transistors fabrication by pre-deposition of gold film on graphene as protection layer. This improved self-aligned fabrication keeps graphene away from any possible contamination, which makes our graphene transistors show good gate coupling and less parasitics, thus good dc and RF performances. The 100nm gate-length graphene transistor exhibits a fmax of 105GHz. Our study shows a pathway to fabrication of high-performance graphene transistors for future application in RF circuits.
Display omitted
•The substructures in rotation-twinned T (Al20Cu2Mn3) particles were investigated.•A flattened hexagonal structural subunit with 20 atomic columns was proposed.•The stacking mode of ...these subunits at APB and TB were revealed.•The transition structures at twin domain junctions were unraveled.
The substructures in rotation-twinned T (Al20Cu2Mn3) particles were investigated by means of high resolution transmission electron microscopy (HRTEM) and high angle annular dark field scanning transmission electron microscopy (HAADF-STEM) in the present work. A flattened hexagonal structural subunit with 20 atomic columns was proposed. The stacking mode of these subunits in non-defective T phase was proved to be tessellation of many flattened hexagonal subunits with the same orientations, while the stacking modes near anti-phase boundary (APB) and twin boundary (TB) were tessellations of two differently oriented flattened hexagonal subunits. The transition region at twin domain junctions has hybrid structure and perfect or imperfect pentagram structure. Centered with the perfect pentagram transition structure, a rotation twin with ten fan-shaped domains and constituted by five twin variants can be deduced.
Varying levels of female sex hormones during the menstrual cycle were found to influence the central nervous system. The goal of the present study was to investigate whether the median (50%) ...effective effect-concentration (EC50) of propofol inducing loss of consciousness (LOC) varies between the luteal and the follicular phases of the menstrual cycle.
Twenty-two patients (follicular phase) and 20 patients (luteal phase) undergoing gynaecological procedures under general anaesthesia were enrolled on the study. Anaesthesia was conducted with a target-controlled infusion (TCI) of propofol. The initial target effect-site propofol concentration (Ceprop) was 3.5 µg ml−1 and was adjusted stepwise by 0.5 µg ml−1 at 4 min intervals by an up–down sequential method to reach LOC. Anaesthesia was maintained with a propofol TCI guided by the bispectral index. The correlation between female sex hormones and predicted Ceprop at the time of LOC was analysed and emergence time from anaesthesia was recorded.
Propofol EC50 to induce LOC was higher in patients in the follicular phase than those in the luteal phase (4.17 vs 3.58 µg ml−1, P<0.05). Progesterone correlated significantly with Ceprop at LOC. Emergence time was also longer in the follicular group than in the luteal group (6.5 vs 5.0 min, P<0.05).
During general anaesthesia, patients in the luteal phase of the menstrual cycle had a lower propofol EC50 for LOC and a shorter emergence time compared with those in the follicular phase. Differences in progesterone levels between menstrual phases may contribute to these anaesthetic effects.
ChiCTR-RCH-12002755.
While positively charged nanomaterials induce cytotoxicity in many organisms, much less is known about how the spatial distribution and presentation of molecular surface charge impact ...nanoparticle-biological interactions. We systematically functionalized diamond nanoparticle surfaces with five different cationic surface molecules having different molecular structures and conformations, including four small ligands and one polymer, and we then probed the molecular-level interaction between these nanoparticles and bacterial cells.
MR-1 was used as a model bacterial cell system to investigate how the molecular length and conformation of cationic surface charges influence their interactions with the Gram-negative bacterial membranes. Nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) demonstrate the covalent modification of the nanoparticle surface with the desired cationic organic monolayers. Surprisingly, bacterial growth-based viability (GBV) and membrane damage assays both show only minimal biological impact by the NPs functionalized with short cationic ligands within the concentration range tested, yet NPs covalently linked to a cationic polymer induce strong cytotoxicity, including reduced cellular viability and significant membrane damage at the same concentration of cationic groups. Transmission electron microscopy (TEM) images of these NP-exposed bacterial cells show that NPs functionalized with cationic polymers induce significant membrane distortion and the production of outer membrane vesicle-like features, while NPs bearing short cationic ligands only exhibit weak membrane association. Our results demonstrate that the spatial distribution of molecular charge plays a key role in controlling the interaction of cationic nanoparticles with bacterial cell membranes and the subsequent biological impact. Nanoparticles functionalized with ligands having different lengths and conformations can have large differences in interactions even while having nearly identical zeta potentials. While the zeta potential is a convenient and commonly used measure of nanoparticle charge, it does not capture essential differences in molecular-level nanoparticle properties that control their biological impact.
Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear ...whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.
PDF
