Prolonged myelin deficits contribute to neuron loss and functional impairments after ischaemic stroke.

Ischaemic stroke causes neuron loss and long-term functional deficits. Unfortunately, effective approaches to preserving neurons and promoting functional recovery remain unavailable. Oligodendrocytes, the myelinating cells in the CNS, are susceptible to oxygen and nutrition deprivation and undergo degeneration after ischaemic stroke. Technically, new oligodendrocytes and myelin can be generated by the differentiation of oligodendrocyte precursor cells (OPCs). However, myelin dynamics and their functional significance after ischaemic stroke remain poorly understood. Here, we report numerous denuded axons accompanied by decreased neuron density in sections from ischaemic stroke lesions in human brain, suggesting that neuron loss correlates with myelin deficits in these lesions. To investigate the longitudinal changes in myelin dynamics after stroke, we labelled and traced pre-existing and newly-formed myelin, respectively, using cell-specific genetic approaches. Our results indicated massive oligodendrocyte death and myelin loss 2 weeks after stroke in the transient middle cerebral artery occlusion (tMCAO) mouse model. In contrast, myelin regeneration remained insufficient 4 and 8 weeks post-stroke. Notably, neuronal loss and functional impairments worsened in aged brains, and new myelin generation was diminished. To analyse the causal relationship between remyelination and neuron survival, we manipulated myelinogenesis by conditional deletion of Olig2 (a positive regulator) or muscarinic receptor 1 (M1R, a negative regulator) in OPCs. Deleting Olig2 inhibited remyelination, reducing neuron survival and functional recovery after tMCAO. Conversely, enhancing remyelination by M1R conditional knockout or treatment with the pro-myelination drug clemastine after tMCAO preserved white matter integrity and neuronal survival, accelerating functional recovery. Together, our findings demonstrate that enhancing myelinogenesis is a promising strategy to preserve neurons and promote functional recovery after ischaemic stroke.

Insufficient Oligodendrocyte Turnover in Optic Nerve Contributes to Age-Related Axon Loss and Visual Deficits.

Age-related decline in visual functions is a prevalent health problem among elderly people, and no effective therapies are available up-to-date. Axon degeneration and myelin loss in optic nerves (ONs) are age-dependent and become evident in middle-aged (13-18 months) and old (20-22 months) mice of either sex compared with adult mice (3-8 months), accompanied by functional deficits. Oligodendrocyte (OL) turnover is actively going on in adult ONs. However, the longitudinal change and functional significance of OL turnover in aging ONs remain largely unknown. Here, using cell-lineage labeling and tracing, we reported that oligodendrogenesis displayed an age-dependent decrease in aging ONs. To understand whether active OL turnover is required for maintaining axons and visual function, we conditionally deleted the transcription factor Olig2 in the oligodendrocyte precursor cells of young mice. Genetically dampening OL turnover by Olig2 ablation resulted in accelerated axon loss and retinal degeneration, and subsequently impaired ON signal transmission, suggesting that OL turnover is an important mechanism to sustain axon survival and visual function. To test whether enhancing oligodendrogenesis can prevent age-related visual deficits, 12-month-old mice were treated with clemastine, a pro-myelination drug, or induced deletion of the muscarinic receptor 1 in oligodendrocyte precursor cells. The clemastine treatment or muscarinic receptor 1 deletion significantly increased new OL generation in the aged ONs and consequently preserved visual function and retinal integrity. Together, our data indicate that dynamic OL turnover in ONs is required for axon survival and visual function, and enhancing new OL generation represents a potential approach to reversing age-related declines of visual function.SIGNIFICANCE STATEMENT Oligodendrocyte (OL) turnover has been reported in adult optic nerves (ONs), but the longitudinal change and functional significance of OL turnover during aging remain largely unknown. Using cell-lineage tracing and oligodendroglia-specific manipulation, this study reported that OL generation was active in adult ONs and the efficiency decreased in an age-dependent manner. Genetically dampening OL generation by Olig2 ablation resulted in significant axon loss and retinal degeneration, along with delayed visual signal transmission. Conversely, pro-myelination approaches significantly increased new myelin generation in aging ONs, and consequently preserved retinal integrity and visual function. Our findings indicate that promoting OL generation might be a promising strategy to preserve visual function from age-related decline.

Effects of physical activity on the levels of remnant cholesterol: A population-based study.

Physical activity (PA) has the potential to bring about favourable changes in plasma lipid profile. However, the relationship between PA and remnant cholesterol (RC) remains unclear. We aimed to study the link between PA and RC using the database of the 2007-2020 National Health and Nutrition Examination Survey (NHANES). PA was categorized based on Physical Activity Guidelines for Americans. A multivariate linear regression model was used to determine the correlations between PA and RC. The study involved a total of 18,396 participants and revealed that individuals whose PA met the guidelines by engaging in moderate-intensity PA at least 150 min per week had lower body mass index and showed decreased levels of triglyceride, TC, and haemoglobin A1c compared to those who were physically inactive, exercising <150 min per week. Participants whose intensity of PA meets PA guidelines had a lower level of RC than those who did not met PA guidelines (ß = -1.3, 95% confidence interval [CI]: -1.9 to -0.7, p < 0.001), even after adjusting for confounders. During subgroup analysis, we observed that race (pinteraction = 0.0089) emerged as a significant factor of interaction.

Quantification of CH and NH/π-Stacking Interactions in Cells Using Nuclear Magnetic Resonance Spectroscopy.

π-Stacking, a type of noncovalent interactions involving aromatic residues, plays an important role in protein folding and function. In this work, an attempt has been made to measure CH/π and NH/π stacking interactions in a protein in Escherichia coli cells using a combined double-mutant cycle and nuclear magnetic resonance spectroscopy method. The results show that the CH/π and NH/π stacking interactions are generally weaker in cells than those in the buffer. The transient intermolecular noncovalent interactions between the protein and the complex cellular environment may compete with and thus weaken the stacking interactions in the protein. The weakening of stacking interactions can enhance the local conformational opening of proteins in E. coli cells. This is evident from the faster rates of amide hydrogen/deuterium exchange observed in cells than in the buffer, for residues that undergo local conformational opening. This study highlights the influence of the cellular environment on π-stacking and the conformational dynamics of proteins.

Protein Allostery Study in Cells Using NMR Spectroscopy.

Protein allostery is commonly observed in vitro. But how protein allostery behaves in cells is unknown. In this work, a protein monomer-dimer equilibrium system was built with the allosteric effect on the binding characterized using NMR spectroscopy through mutations away from the dimer interface. A chemical shift linear fitting method was developed that enabled us to accurately determine the dissociation constant. A total of 28 allosteric mutations were prepared and grouped to negative allosteric, nonallosteric, and positive allosteric modulators. ∼ 50% of mutations displayed the allosteric-state changes when moving from a buffered solution into cells. For example, there were no positive allosteric modulators in the buffered solution but eight in cells. The change in protein allostery is correlated with the interactions between the protein and the cellular environment. These interactions presumably drive the surrounding macromolecules in cells to transiently bind to the monomer and dimer mutational sites and change the free energies of the two species differently which generate new allosteric effects. These surrounding macromolecules create a new protein allostery pathway that is only present in cells.

Association between tea, coffee and caffeine consumption and risk of female infertility: a cross-sectional study.

OBJECTIVES: To explore the association between tea, coffee, and caffeine consumption and the risk of female infertility. METHODS: We analyzed data from 2099 females aged 18 to 44 years, participating in the National Health and Nutrition Examination Survey (NHANES) 2013-2018. We used generalized linear models (GLM) and generalized additive model (GAM) to investigate the dose-response relationship between the tea, coffee, and caffeine consumption and infertility, adjusting for potential confounders. RESULTS: A non-linear relationship was detected between tea consumption and infertility and the inflection point was 2 cups/day. On the right side of the inflection point, we did not detect a significant association. However, on the left side, we found a negative relationship between tea consumption and infertility (OR: 0.73; 95% CI: 0.57 to 0.93; P = 0.0122). Meanwhile, our study found no significant association between coffee (0.96, 0.81 to 1.13, P = 0.6189) or caffeine consumption (1.15, 0.93 to 1.42, P = 0.2148) and female infertility. CONCLUSIONS: Tea consumption was non-linearly associated with infertility, whereas no significant associations were found between coffee, caffeine consumption and infertility.

Effects of physical activity on infertility in reproductive females.

OBJECTIVES: To explore the relationship between different types of physical activity and female infertility. METHODS: This study analyzed data from 2,796 female participants aged 18-44 years in the United States, obtained from the National Health and Nutrition Examination Survey (NHANES) database spanning the years 2013 to 2020. Multiple logistic regression analyses and generalized linear models were used to explore the relationship between different types of physical activity and infertility after adjusting for potential confounding factors. RESULTS: We found a non-linear relationship between recreational activities and infertility with an inflection point of 5.83 h/week (moderate intensity), while work activities and traffic-related activities did not. On the left side of the inflection point, there was no significant association between recreational activity time and infertility (OR = 0.93, 95% CI: 0.86 to 1.02, P = 0.1146), but on the right side of the inflection point, there was a positive association between recreational activity time and the risk of infertility (OR = 1.04, 95% CI: 1.02 to 1.06, P = 0.0008). CONCLUSIONS: The relationship between different types of physical activity and female infertility varies. We acknowledge the potential influence of confounding variables on this relationship. However, we have already adjusted for these potential variables in our analysis. Therefore, our findings suggest that appropriate recreational activity programs are essential for promoting reproductive health in women of reproductive age. Nevertheless, it is important to note that the observed association does not imply causality. Given the limitations of cross-sectional studies, further prospective cohort studies are needed to explore the causal relationship while accounting for additional confounding factors.

ANGPTL3 as a target for treating lipid disorders in type 2 diabetes patients.

Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder, and cardiovascular disease (CVD) is a significant cause of mortality and morbidity in diabetic individuals. In addition to hyperglycemia, lipid abnormalities associated with T2DM play a crucial role in the development of CVD complications. Diabetic dyslipidemia is characterized by elevated levels of triglyceride (TG)-rich lipoproteins and small dense low-density lipoprotein (LDL) particles, reduced high-density lipoprotein (HDL) cholesterol, and impaired HDL function. Angiopoietin protein-like 3 (ANGPTL3) is a liver-derived protein that plays a crucial role in regulating plasma lipoprotein metabolism by inhibiting lipoprotein lipase and influencing lipid levels. Inhibiting ANGPTL3 has shown promising effects in promoting HDL-mediated cholesterol reverse transport and reducing the levels of TG-rich lipoproteins and LDL cholesterol. Here, we explore the potential of ANGPTL3 as a therapeutic target for lipid management in T2DM patients.

Unlocking the mysteries of VLDL: exploring its production, intracellular trafficking, and metabolism as therapeutic targets.

Reducing circulating lipid levels is the centerpiece of strategies for preventing and treating atherosclerotic cardiovascular disease (ASCVD). Despite many available lipid-lowering medications, a substantial residual cardiovascular risk remains. Current clinical guidelines focus on plasma levels of low-density lipoprotein (LDL). Recent attention has been given to very low-density lipoprotein (VLDL), the precursor to LDL, and its role in the development of coronary atherosclerosis. Preclinical investigations have revealed that interventions targeting VLDL production or promoting VLDL metabolism, independent of the LDL receptor, can potentially decrease cholesterol levels and provide therapeutic benefits. Currently, methods, such as mipomersen, lomitapide, and ANGPTL3 inhibitors, are used to reduce plasma cholesterol and triglyceride levels by regulating the lipidation, secretion, and metabolism of VLDL. Targeting VLDL represents an avenue for new lipid-lowering strategies. Interventions aimed at reducing VLDL production or enhancing VLDL metabolism, independent of the LDL receptor, hold promise for lowering cholesterol levels and providing therapeutic benefits beyond LDL in the management of ASCVD.

The serum soluble ASGR1 concentration is elevated in patients with coronary artery disease and is associated with inflammatory markers.

BACKGROUND AND AIMS: Current research has suggested that asialoglycoprotein receptor 1 (ASGR1) is involved in cholesterol metabolism and is also related to systemic inflammation. This study aimed to assess the correlation between the serum soluble ASGR1 (sASGR1) concentration and inflammatory marker levels. Moreover, the second objective of the study was to assess the association between sASGR1 levels and the presence of coronary artery disease (CAD). METHODS: The study subjects included 160 patients who underwent coronary angiography. Ninety patients were diagnosed with CAD, while seventy age- and sex-matched non-CAD patients served as controls. We measured the serum sASGR1 levels using an ELISA kit after collecting clinical baseline characteristics. RESULTS: Patients with CAD had higher serum sASGR1 levels than non-CAD patients did (P < 0.0001). sASGR1 was independently correlated with the risk of CAD after adjusting for confounding variables (OR = 1.522, P = 0.012). The receiver operating characteristic (ROC) curve showed that sASGR1 had a larger area under the curve (AUC) than did the conventional biomarkers apolipoprotein B (APO-B) and low-density lipoprotein cholesterol (LDL-C). In addition, multivariate linear regression models revealed that sASGR1 is independently and positively correlated with high-sensitivity C-reactive protein (CRP) (ß = 0.86, P < 0.001) and WBC (ß = 0.13, P = 0.004) counts even after adjusting for lipid parameters. According to our subgroup analysis, this relationship existed only for CAD patients. CONCLUSION: Our research demonstrated the link between CAD and sASGR1 levels, suggesting that sASGR1 may be an independent risk factor for CAD. In addition, this study provides a reference for revealing the potential role of sASGR1 in the inflammation of atherosclerosis.

Ga-hybridization-mediated broadband optical amplification in Bi-activated photonic glass and fiber.

A Ga hybridization strategy is proposed for simultaneously enhancing the near-infrared activity and extending the bandwidth of Bi-activated photonic glass. Systematic studies on the near-infrared optical responses of Ga/Bi and Al/Bi co-doped silica glasses are performed. It is interesting to note that Ga/Bi co-doped glasses have a similar near-infrared emission center to Al/Bi co-doped glass, while the former is more effective in improving near-infrared activity. The different luminescence mechanisms of Ga/Bi and Al/Bi co-doped silica glasses are elucidated, and the corresponding microstructure-optical response relationship is discussed. In addition, the Ga/Bi co-doped silica optical fiber is successfully prepared, and the principal fiber amplifier device is fabricated. Furthermore, amplified spontaneous emission and broadband on-off gain are realized. The results suggest that Ga-hybridized Bi-activated photonic glass is a promising gain material for broadband fiber amplifiers.

Correlation between serum soluble ASGR1 concentration and low-density lipoprotein cholesterol levels: a cross-sectional study.

BACKGROUND: Recent studies have shown that loss-of-function mutations in hepatic asialoglycoprotein receptor 1 (ASGR1) are associated with low levels of circulating cholesterol and a reduced risk of coronary artery disease (CAD). In contrast to ASGR1 on the hepatocyte membrane, serum soluble ASGR1 (sASGR1) is a secreted form that has been detected in circulation. However, the functions of serum sASGR1 are unclear. This study aims to investigate the relationship between human serum sASGR1 concentration and low-density lipoprotein cholesterol (LDL-C) levels. METHODS: In a cohort of 134 participants who underwent coronary angiography examination, basic information was recorded, and blood samples were collected for biochemical testing. The serum sASGR1 concentration was determined by ELISA kits. The relationship between sASGR1 concentration and LDL-C levels was examined using linear regression models and interaction tests. Univariate and multivariate analyses were used to identify clinical variables that affect sASGR1 levels. RESULTS: After adjusting for potential confounders such as age, sex, BMI, and statin use, the serum sASGR1 concentration was positively correlated with LDL-C levels (ß = 0.093, 95% CI: 0.04 to 0.14, P < 0.001). Subgroup analysis and interaction tests showed that the effect of serum sASGR1 concentration on LDL-C levels was significantly influenced by hypertension status (P for interaction = 0.0067). The results of a multivariate linear regression analysis incorporating age, serum TG, LDL-C, nonesterified fatty acid (NEFA), white blood cell counts (WBCC), and fibrinogen revealed that LDL-C (ß = 1.005, 95% CI: 0.35 to 1.66, P = 0.003) and WBCC (ß = 0.787, 95% CI: 0.41 to 1.16, P < 0.0001) were independent influencing factors for serum sASGR1 levels. CONCLUSIONS: The serum sASGR1 concentration was positively correlated with LDL-C levels. In addition, hypertension status significantly affected the effect of serum sASGR1 on LDL-C levels. This study provides some research ideas for clinical doctors and researchers, as well as some references for additional research on serum sASGR1.

Research on Detection of Ultra-Low Concentration Anthrax Protective Antigen Using Graphene Field-Effect Transistor Biosensor.

BACKGROUND: Protective antigen (PA) is an important biomarker for the early diagnosis of anthrax, and the accurate detection of protective antigen under extremely low concentration conditions has always been a hot topic in the biomedical field. To complete the diagnosis of anthrax in a timely manner, it is necessary to detect PA at extremely low concentrations, as the amount of PA produced in the early stage of anthrax invasion is relatively small. Graphene field-effect transistor (Gr-FET) biosensors are a new type of material for preparing biosensors, with the advantages of a short detection time and ultra-low detection limit. METHODS: The effect of different concentrations of diluents on the affinity of PA monoclonal antibodies was determined via an ELISA experiment. Combined with the Debye equation, 0.01 × PBS solution was finally selected as the diluent for the experiment. Then, a PA monoclonal antibody was selected as the bio-recognition element to construct a Gr-FET device based on CVD-grown graphene, which was used to detect the concentration of PA while recording the response time, linear range, detection limit, and other parameters. RESULTS: The experimental results showed that the biosensor could quickly detect PA, with a linear range of 10 fg/mL to 100 pg/mL and a detection limit of 10 fg/mL. In addition, the biosensor showed excellent specificity and repeatability. CONCLUSIONS: By constructing a Gr-FET device based on CVD-grown graphene and selecting a PA monoclonal antibody as the bio-recognition element, a highly sensitive, specific, and repeatable Gr-FET biosensor was successfully prepared for detecting extremely low concentrations of anthrax protective antigen (PA). This biosensor is expected to have a wide range of applications in clinical medicine and biological safety monitoring.

Detecting the Hydrogen Bond Cooperativity in a Protein ß-Sheet by H/D Exchange.

The hydrogen bond (H-bond) cooperativity in the ß-sheet of GB3 is investigated by a NMR hydrogen/deuterium (H/D) exchange method. It is shown that the weakening of one backbone N-H…O=C H-bond between two ß-strands, ß1 and ß2, due to the exchange of NH to ND of the H-bond donor in ß1, perturbs the chemical shift of 13Cα, 13Cß, 1Hα, 1HN, and 15N of the H-bond acceptor and its following residue in ß2. Quantum mechanical calculations suggest that the -H-bond chemical shift isotope effect is caused by the structural reorganization in response to the H-bond weakening. This structural reorganization perturbs four neighboring H-bonds, with three being weaker and one being stronger, indicating that three H-bonds are cooperative and one is anticooperative with the perturbed H-bond. The sign of the cooperativity depends on the relative position of the H-bonds. This H-bond cooperativity, which contributes to ß-sheet stability overall, can be important for conformational coupling across the ß-sheet.

Structural Basis for Selective Oxidation of Phosphorylated Ethylphenols by Cytochrome P450 Monooxygenase CreJ.

Selective oxidation of C-H bonds in alkylphenols holds great significance for not only structural derivatization in pharma- and biomanufacturing but also biological degradation of these toxic chemicals in environmental protection. A unique chemomimetic biocatalytic system using enzymes from a p-cresol biodegradation pathway has recently been developed. As the central biocatalyst, the cytochrome P450 monooxygenase CreJ oxidizes diverse p- and m-alkylphenol phosphates with perfect stereoselectivity at different efficiencies. However, the mechanism of regio- and stereoselectivity of this chemomimetic biocatalytic system remained unclear. Here, using p- and m-ethylphenol substrates, we elucidate the CreJ-catalyzed key steps for selective oxidations. The crystal structure of CreJ in complex with m-ethylphenol phosphate was solved and compared with its complex structure with p-ethylphenol phosphate isomer. The results indicate that the conformational changes of substrate-binding residues are slight, while the substrate promiscuity is achieved mainly by the available space in the catalytic cavity. Moreover, the catalytic preferences of regio- and stereoselective hydroxylation for the two ethylphenol substrates is explored by molecular dynamics simulations. The ethyl groups in the complexes display different flexibilities, and the distances of the active oxygen to H pro-S and H pro-R of methylene agree with the experimental stereoselectivity. The regioselectivity can be explained by the distances and bond dissociation energy. These results provide not only the mechanistic insights into CreJ regio- and stereoselectivity but also the structural basis for further P450 enzyme design and engineering.IMPORTANCE The key cytochrome P450 monooxygenase CreJ showed excellent regio- and stereoselectivity in the oxidation of various alkylphenol substrates. C-H bond functionalization of these toxic alkylphenols holds great significance for both biological degradation of these environmental chemicals and production of value-added structural derivatives in pharmaceutical and biochemical industries. Our results, combined with in vitro enzymatic assays, crystal structure determination of enzyme-substrate complex, and molecular dynamics simulations, provide not only significant mechanism elucidation of the regio- and stereoselective catalyzation mediated by CreJ but also the promising directions for future engineering efforts of this enzyme toward more useful products. It also has great extendable potential to couple this multifunctional P450 enzyme with other biocatalysts (e.g., hydroxyl-based glycosylase) to access more alkylphenol-derived high-value chemicals through environment-friendly biocatalysis and biotransformation.

Decreased 11ß-hydroxysteroid dehydrogenase 1 in lungs of steroid receptor coactivator (Src)-1/-2 double-deficient fetal mice is caused by impaired glucocorticoid and cytokine signaling.

Our previous research revealed that steroid receptor coactivators (Src)-1 and -2 serve a critical cooperative role in production of parturition signals, surfactant protein A and platelet-activating factor, by the developing mouse fetal lung (MFL). To identify the global landscape of genes in MFL affected by Src-1/-2 double-deficiency, we conducted RNA-seq analysis of lungs from 18.5 days post-coitum (dpc) Src-1-/- /-2-/- (dKO) vs. WT fetuses. One of the genes most highly downregulated (~4.8 fold) in Src-1/-2 dKO fetal lungs encodes 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which catalyzes conversion of inactive 11-dehydrocorticosterone to the glucocorticoid receptor (GR) ligand, corticosterone. Glucocorticoids were reported to upregulate 11ß-HSD1 expression in various cell types via induction of C/EBP transcription factors. We observed that C/ebpα and C/ebpß mRNA and protein were markedly reduced in Src-1/-2 double-deficient (Src-1/-2d/d ) fetal lungs, compared to WT. Moreover, glucocorticoid induction of 11ß-hsd1, C/ebpα and C/ebpß in cultured MFL epithelial cells was prevented by the SRC family inhibitor, SI-2. Cytokines also contribute to the induction of 11ß-HSD1. Expression of IL-1ß and TNFα, which dramatically increased toward term in lungs of WT fetuses, was markedly reduced in Src-1/-2d/d fetal lungs. Our collective findings suggest that impaired lung development and surfactant synthesis in Src-1/-2d/d fetuses are likely caused, in part, by decreased GR and cytokine induction of C/EBP and NF-κB transcription factors. This results in reduced 11ß-HSD1 expression and glucocorticoid signaling within the fetal lung, causing a break in the glucocorticoid-induced positive feedforward loop.

Selective oxidation of aliphatic C-H bonds in alkylphenols by a chemomimetic biocatalytic system.

Selective oxidation of aliphatic C-H bonds in alkylphenols serves significant roles not only in generation of functionalized intermediates that can be used to synthesize diverse downstream chemical products, but also in biological degradation of these environmentally hazardous compounds. Chemo-, regio-, and stereoselectivity; controllability; and environmental impact represent the major challenges for chemical oxidation of alkylphenols. Here, we report the development of a unique chemomimetic biocatalytic system originated from the Gram-positive bacterium Corynebacterium glutamicum The system consisting of CreHI (for installation of a phosphate directing/anchoring group), CreJEF/CreG/CreC (for oxidation of alkylphenols), and CreD (for directing/anchoring group offloading) is able to selectively oxidize the aliphatic C-H bonds of p- and m-alkylated phenols in a controllable manner. Moreover, the crystal structures of the central P450 biocatalyst CreJ in complex with two representative substrates provide significant structural insights into its substrate flexibility and reaction selectivity.

Characterization of Residue Specific Protein Folding and Unfolding Dynamics in Cells.

In this work, we measured the millisecond residue specific protein folding and unfolding dynamics in E. coli cells for two protein GB3 mutants using NMR. The results show that the protein folding and unfolding dynamics in cells is different from that in buffer. Through a two-site exchange model, it is shown that both the population and the exchange rate are changed by the E. coli cellular environment. Further investigation suggests that the change is likely due to the quinary interaction with crowded molecules in the cell. Our work underlines the importance of cellular environment to protein folding kinetics and thermodynamics although this environmental effect may not be large enough to change the protein structure.

Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management.

With an increasing global burden of coronary artery disease (CAD), early detection and timely management of risk factors are crucial to reduce morbidity and mortality in such patients. Diabetes mellitus (DM) is considered an independent risk factor for the development of CAD. Metformin, an anti-diabetic drug, has been shown in pre-clinical and clinical studies, to lower the cardiovascular events in the DM patients. Growing evidence suggests that metformin has a protective effect on coronary artery beyond its hypoglycemic effects. Given its global availability, route of administration and cost, metformin provides an alternate/additional therapeutic option for primary and secondary prevention of CAD in DM and non-diabetics alike. Future prospective cohort-based studies and randomized clinical trials are needed to identify 'at-risk' population who may potentially benefit from metformin.