Self-assembly of collagen bundles and enhanced piezoelectricity induced by chemical crosslinking.

The piezoelectricity of collagen is purported to be linked to many biological processes including bone formation and wound healing. Although the piezoelectricity of tissue-derived collagen has been documented across the length scales, little work has been undertaken to characterise the local electromechanical properties of processed collagen, which is used as a base for tissue-engineering implants. In this work, three chemically distinct treatments used to form structurally and mechanically stable scaffolds-EDC-NHS, genipin and tissue transglutaminase-are investigated for their effect on collagen piezolectricity. Crosslinking with EDC-NHS is noted to produce a distinct self-assembly of the fibres into bundles roughly 300 nm in width regardless of the collagen origin. These fibre bundles also show a localised piezoelectric response, with enhanced vertical piezoelectricity of collagen. Such topographical features are not observed with the other two chemical treatments, although the shear piezoelectric response is significantly enhanced upon crosslinking. These observations are reconciled by a proposed effect of the crosslinking mechanisms on the molecular and nanostructure of collagen. These results highlight the ability to modify the electromechanical properties of collagen using chemical crosslinking methods.ERC, Bill and Melinda Gates Foundation, Geistlich Pharma A

Lipid phenotype and heritage pattern in families with genetic hypercholesterolemia not related to LDLR, APOB, PCSK9, or APOE

Background: A substantial proportion of individuals clinically diagnosed as familial hypercholesterolemia (FH) do not carry pathogenic mutations in candidate genes. Whether in them the high cholesterol trait is transmitted monogenically has not been studied. Objectives: We assessed the inheritance pattern, penetrance, and expression of high low-density lipoprotein (LDL)-cholesterol (LDLc) in families with genetic hypercholesterolemia (GH) without known causative mutations (non-FH-GH). Methods: The study included probands with a clinical diagnosis of FH and their families attending 2 lipid clinics in Spain. Inclusion criteria for probands were LDLc >95th percentile, triglycerides 90th percentile, >5 points in the Dutch Lipid Clinic Network criteria score, and absence of mutations in LDLR, APOB, PCSK9 or APOE. Eleven FH families with a LDLR mutation were also examined for comparison. Results: We analyzed 49 non-FH-GH probands and 277 first-and second-degree relatives. LDLc was >90th percentile in 37.8% of blood relatives, at concentrations similar to those of probands. LDLc had a normal distribution in non-FH-GH families, in contrast with a bimodal distribution in FH families. When a dominant model was tested, family-based association tests gave much lower heritability values for total cholesterol and LDLc in non-FH-GH (0.39 and 0.32, respectively) than in FH (0.78 and 0.61, respectively). Conclusions: Non-FH-GH families have a milder lipid phenotype than genetically defined FH. The heritage pattern of LDLc in non-FH-GH does not fit with a monogenic disorder. Our findings support the concept that most non-FH-GHs are polygenic hypercholesterolemias

Comparative efficacy between atorvastatin and rosuvastatin in the prevention of cardiovascular disease recurrence

Background: There is no randomized clinical trials with recurrence of atherosclerotic cardiovascular disease (ASCVD) as a major outcome with rosuvastatin. In order to analyze potential differences in the clinical response to atorvastatin and rosuvastatin in secondary ASCVD prevention, we have analyzed the clinical evolution of those subjects of the Dyslipemia Registry of the Spanish Society of Arteriosclerosis (SEA) who at the time of inclusion in the Registry had already suffered an ASCVD. Methods: This observational, retrospective, multicenter, national study was designed to determine potential differences between the use of atorvastatin and rosuvastatin in the ASCVD recurrence. Three different follow-up start-times were performed: time of inclusion in the registry; time of first event if this occurred after 2005, and time of first event without date restriction. Results: Baseline characteristics were similar between treatment groups. Among atorvastatin or rosuvastatin users, 89 recurrences of ASCVD were recorded (21.9%), of which 85.4% were coronary. At the inclusion of the subject in the registry, 345 participants had not suffered a recurrence yet. These 345 subjects accumulated 1050 person-years in a mean follow-up of 3 years. Event rates were 2.73 (95% CI: 1.63, 4.25) cases/100 person-years and 2.34 (95% CI: 1.17, 4.10) cases/100 person-years in the atorvastatin and rosuvastatin groups, respectively. There were no statistically significant differences between the two groups independently of the follow-up start-time. Conclusions: This study does not find differences between high doses of rosuvastatin and atorvastatin in the recurrence of ASCVD, and supports their use as clinically equivalent in secondary prevention of ASCVD

Comparative efficacy between atorvastatin and rosuvastatin in the prevention of cardiovascular disease recurrence

Background: There is no randomized clinical trials with recurrence of atherosclerotic cardiovascular disease (ASCVD) as a major outcome with rosuvastatin. In order to analyze potential differences in the clinical response to atorvastatin and rosuvastatin in secondary ASCVD prevention, we have analyzed the clinical evolution of those subjects of the Dyslipemia Registry of the Spanish Society of Arteriosclerosis (SEA) who at the time of inclusion in the Registry had already suffered an ASCVD. Methods: This observational, retrospective, multicenter, national study was designed to determine potential differences between the use of atorvastatin and rosuvastatin in the ASCVD recurrence. Three different follow-up start-times were performed: time of inclusion in the registry; time of first event if this occurred after 2005, and time of first event without date restriction. Results: Baseline characteristics were similar between treatment groups. Among atorvastatin or rosuvastatin users, 89 recurrences of ASCVD were recorded (21.9%), of which 85.4% were coronary. At the inclusion of the subject in the registry, 345 participants had not suffered a recurrence yet. These 345 subjects accumulated 1050 person-years in a mean follow-up of 3 years. Event rates were 2.73 (95% CI: 1.63, 4.25) cases/100 person-years and 2.34 (95% CI: 1.17, 4.10) cases/100 person-years in the atorvastatin and rosuvastatin groups, respectively. There were no statistically significant differences between the two groups independently of the follow-up start-time. Conclusions: This study does not find differences between high doses of rosuvastatin and atorvastatin in the recurrence of ASCVD, and supports their use as clinically equivalent in secondary prevention of ASCVD

Pickering Water‐in‐Oil Emulsions Stabilized Solely by Fat Crystals

Water-in-oil (W/O) emulsions have attracted heightened attention because of the ever-increasing interest in using non-calorific water to replace calorie-dense fat in food. However, designing clean-label and ultra-stable W/O emulsions is a longstanding challenge in colloid science. Herein, a novel, facile approach is introduced to designing cocoa butter (CB)-based crystals to stabilize Pickering W/O emulsions. Results using a combination of small- and wide-angle X-ray scattering and microscopy across length scales reveal that the fat crystals formed in an oleogel of CB with vegetable oil offer high stability to water droplets (up to 60% (v/v)) against coalescence and phase inversion, over storage for 7 months. Such extraordinary stability is attributed to the nanoplatelet-like CB crystals of βV polymorph located at the water–oil interface and to the inter-droplet fat crystal network formation, interlocking the water droplets. The increment in water volume fraction endows gel-like properties with the water droplets acting as “active fillers.” These newly designed Pickering W/O emulsions stabilized solely by fat crystals with unusual rigidity offer great promise for fabricating advanced functional materials in food, pharmaceutics, and cosmetic applications, where long-term stabilization of water droplets using sustainable particles is a necessity

Different protein composition of low-calorie diet differently impacts adipokine profile irrespective of weight loss in overweight and obese women

Background and aims: High-protein (HP) diets have shown benefits in cardiometabolic markers such as insulin or triglycerides but the responsible mechanisms are not known. We aimed to assess the effect of three energy-restricted diets with different protein contents (20%, 27%, and 35%; similar to 80% coming from animal source) on plasma adipokine concentration and its association with changes in cardiometabolic markers. Methods: Seventy-six women (BMI 32.8 +/- 2.93) were randomized to one of three calorie-reduced diets, with protein, 20%, 27%, or 35%; carbohydrates, 50%, 43%, or 35%; and fat, 30%, for 3 months. Plasma adipokine (leptin, resistin, adiponectin, and retinol-binding protein 4; RBP4) levels were assessed. Results: After 3 months, leptin concentration decreased in all groups without differences among them, while resistin levels remained unchanged. Adiponectin concentration heterogeneously changed in all groups (P for trend = 0.165) and resistin concentration did not significantly change. RPB4 significantly decreased by -17.5% (-31.7, -3.22) in 35%-protein diet (P for trend = 0.024 among diets). Triglycerides improved in women following the 35%-protein diet regardless of weight loss; RBP4 variation significantly influenced triglyceride concentration change by 24.9% and 25.9% when comparing 27%- and 35%- with 20%-protein diet, respectively. Conclusions: A 35%-protein diet induced a decrease in RBP4 regardless of weight loss, which was directly associated with triglyceride concentration improvement. These findings suggest that HP diets improve the cardiometabolic profile, at least in part, through changes in adipokine secretion. Whether this beneficial effect of HP diet is due to improvements in hepatic or adipose tissue functionality should be elucidated

Effect of lipid-lowering treatment in cardiovascular disease prevalence in familial hypercholesterolemia

Background and aims: The impact on heterozygous familial hypercholesterolemia (HeFH) health led by high-intensity lipid-lowering therapy (HILLT) is unknown, and the question remains if there is still an unacceptably high residual risk to justify treatment with new lipid-lowering drugs. Methods: This observational, retrospective, multicenter, national study in Spain, whose information was obtained from a national dyslipemia registry, was designed to establish the current prevalence of cardiovascular disease (CVD) in HeFH and to define the impact of HILLT on CVD in this population. Odds were estimated using several logistic regression models with progressive adjustment. Results: 1958 HeFH, mean age 49.3 ± 14.3 years, were included in the analysis. At inclusion in the registry, 295 patients (15.1%) had suffered CVD and 164 (55.6%) had suffered the first event before the onset lipid-lowering treatment. Exposition to treatment associated more than ten times lower odds for CVD than in subjects naïve to treatment (OR 0.085, 95% CI 0.063–0.114, p < 0.001). A first CVD event after a mean treatment period of 9.1 ± 7.2 years occurred in 131 out of 1615 (8.1%) HeFH subjects, and 115 (87.8%) of them were on HILLT. Conclusions: Current prevalence of CVD among HeFH is one third of that reported before the statins era. Early initiation and prolonged lipid-lowering treatment was associated with a reduction in CVD. New cases of CVD, in spite of HILLT, appeared mostly among patients accumulating risk factors and probably they may be considered for further lipid-lowering drugs

Effect of an alcohol-free beer enriched with isomaltulose and a resistant dextrin on insulin resistance in diabetic patients with overweight or obesity

Background & aims: The quality of carbohydrates has an essential role in nutritional management of type 2 diabetes mellitus (T2DM) because of its substantial impact on glucose homeostasis. Alcohol-free beer has beneficial bioactive components but it has a relatively high glycemic-index so its consumption is restricted in diabetic subjects. We aimed to explore the effect of an alcohol-free beer with modified carbohydrate composition almost completely eliminating maltose and adding isomaltulose (16.5 g/day) and a resistant maltodextrin (5.28 g/day) in comparison to a regular alcohol-free beer on glycemic control of diabetic subjects with overweight or obesity. Design: We randomized 41 subjects into two groups: a) consumption of 66 cL/day of; regular alcohol-free beer for the first 10 weeks and 66 cL/day of alcohol-free beer with modified carbohydrate composition for the next 10 weeks; b) the same described intervention in opposite order. There was a washout period for 6–8 weeks between the two interventions. Participants were counseled to adhere to a healthy diet for cardiovascular health and to increase physical activity. Clinical, biochemical, anthropometric, lifestyle and satiety assessments were performed at the beginning and at the end of each period. Results: Subjects showed significantly weight loss after the two ten weeks periods (-1.69 ± 3.21% and -1.77 ± 3.70% after experimental and regular alcohol-free beers, respectively, P = 0.881). Glucose and glycated hemoglobin did not significantly change after any period. Insulin concentrations and HOMA-IR significantly decreased (-11.1 [–21.3-4.64]% and -1.92 ± 32.8% respectively) after the intake of experimental alcohol-free beer but not after regular alcohol-free beer. Reductions remained statistically significant after adjusting for weight loss, energy intake, physical activity and intervention order. Subjects reported higher satiety scores after consuming experimental alcohol-free beer. Conclusions: An alcohol-free beer including the substitution of regular carbohydrates for low doses of isomaltulose and the addition of a resistant maltodextrin within meals led to an improvement in insulin resistance in subjects with T2DM and overweight or obesity. Clinical trial registration: The clinical trial has been registered in ClinicalTrials.gov (Identifier: NCT03337828)

Conjugation inhibitors compete with palmitic acid for binding to the conjugative traffic ATPaseTrwD, providing a mechanism to inhibit bacterial conjugation

Bacterial conjugation is a key mechanism by which bacteria acquire antibiotic resistance. Therefore, conjugation inhibitors (COINs) are promising compounds in the fight against the spread of antibiotic resistance genes among bacteria. Unsaturated fatty acids (uFAs) and alkynoic fatty acid derivatives, such as 2-hexadecanoic acid (2-HDA), have been reported previously as being effective COINs. The traffic ATPase TrwD, a VirB11 homolog in plasmid R388, is the molecular target of these compounds, which likely affect binding of TrwD to bacterial membranes. In this work, we demonstrate that COINs are abundantly incorporated into Escherichia coli membranes, replacing palmitic acid as the major component of the membrane. We also show that TrwD binds palmitic acid, thus facilitating its interaction with the membrane. Our findings also suggest that COINs bind TrwD at a site that is otherwise occupied by palmitic acid. Accordingly, molecular docking predictions with palmitic acid indicated that it shares the same binding site as uFAs and 2-HDA, although it differs in the contacts involved in this interaction. We also identified 2-bromopalmitic acid, a palmitate analog that inhibits many membrane-associated enzymes, as a compound that effectively reduces TrwD ATPase activity and bacterial conjugation. Moreover, we demonstrate that 2-bromopalmitic and palmitic acids both compete for the same binding site in TrwD. Altogether, these detailed findings open up a new avenue in the search for effective synthetic inhibitors of bacterial conjugation, which may be pivotal for combating multidrug-resistant bacteria.This work was supported by Spanish Ministerio de Economia y Competitividad (MINECO) Grants BFU2016-78521-R (to E. C. and I. A.) and BFU2014-55534 (to F. d. l. C.) and by Grant P20GM103475-16 from the National Center for Research Resources and NIGMS, National Institutes of Health (to D. S. R.). The authors declare that they have no conflicts of interest withthe contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

The effects of high-intensity interval training on glucose metabolism, cardiorespiratory fitness and weight control in subjects with diabetes: systematic review a meta-analysis

Aim: The objective of this meta-analysis was to explore the effects of high-intensity interval training (HIIT) compared with control conditions (CON) or moderate intensity continuous training (MICT) on glycemic parameters in diabetes subjects. Methods: Pubmed, Embase and Google Scholar databases were searched for HIIT interventions that were carried out in diabetic subjects and exploring fasting glucose, glycated haemoglobin (HbA1c), fasting insulin and/or HOMA-IR. Results: This systematic review retrieved a total of 1741 studies of which 32 articles fulfilled the eligibility criteria. Nineteen trials were included in the meta-analysis since they compared HIIT intervention with CON or MICT group. There was a significantly reduction of fasting glucose of 13.3 mg/dL (p < 0.001), Hb1Ac -0.34% (p < 0.001), insulin -2.27 UI/L (p = 0.003), HOMA-IR -0.88 (p = 0.005) in the HIIT-group compared with CON-group. Nevertheless, this reduction was not significantly different when comparing HIIT with MICT (p = 0.140, p = 0.315, p = 0.520 and p = 0.389). Besides, there was a significant increase of absolute VO2max of 0.21 L/min (p < 0.001) and relative VO2max of 2.94 ml/kg/min (p < 0.001) in the HIIT-group compared with the CON-group and the MICT-group (0.22 L/min, p = 0.025) and (0.97 ml/kg/min, p = 0.045). Conclusions: These findings revealed that HIIT intervention led to significant improvement in glycemic control and insulin resistance in subjects with diabetes compared with CON-group