Alkene Cross-Metathesis with 2,5-Dimethyl-2,4-Hexadiene Enables Isobutylenyl/Prenyl Functionalizations and Rubber Valorization.

2,5-Dimethyl-2,4-hexadiene is a readily available and easily managable compound, whose symmetric and polymethylated dienic structure should be prone to engage in cross-metathesis reactions with other alkenes, but this has not been apparently exploited so far. Here we show that this reactant enables the easy synthesis of tri- and tetra-susbtituted alkenes (i. e. isobutylenyl and prenyl groups) from simple alkenes under mild reaction conditions, not only with the conventional 2nd generation Grubbs catalyst but also with other Grela-type catalyts such as StickyCat,TM AquaMetTM and GreenCatTM. The use of liquid and low volatile 2,5-dimethyl-2,4-hexadiene avoids the use of gaseous alkene reactants and, besides, showcases the reactivity of polyisoprene (rubber), thus allowing to optimize the reaction conditions for rubber upcycling, after metathesis reaction of the pristine or used polymer with simple alkenes. These results bring low volatile isoprene-type compounds as privileged poly-substituted reactants for alkene cross-metathesis reactions.

[Cardiometabolic effects of weight loss]. / Efectos cardiometabólicos de la pérdida de peso.

The prevalence of overweight and obesity, and, consequently, associated comorbidities, is increasing significantly worldwide. The guidelines recommend a percentage of weight loss> 5% to achieve beneficial effects on metabolic comorbidities associated with obesity. Furthermore, greater weight losses (> 10%) produce more significant improvements, and may even produce remission of some of these comorbidities. In this chapter, we review the evidence of the effect of weight loss through different strategies (lifestyle intervention, pharmacological treatment, or bariatric surgery) on the main cardiometabolic pathologies associated with excess adipose tissue (type 2 diabetes, high blood pressure, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, inflammation, cardiovascular diseases, and mortality).

Apolipoprotein J protects cardiomyocytes from lipid-mediated inflammation and cytotoxicity induced by the epicardial adipose tissue of diabetic patients.

Diabetic patients present increased volume and functional alterations in epicardial adipose tissue (EAT). We aimed to analyze EAT from type 2 diabetic patients and the inflammatory and cytotoxic effects induced on cardiomyocytes. Furthermore, we analyzed the cardioprotective role of apolipoprotein J (apoJ). EAT explants were obtained from nondiabetic patients (ND), diabetic patients without coronary disease (DM), and DM patients with coronary disease (DM-C) after heart surgery. Morphological characteristics and gene expression were evaluated. Explants were cultured for 24 h and the content of nonesterified fatty acids (NEFA) and sphingolipid species in secretomes was evaluated by lipidomic analysis. Afterwards, secretomes were added to AC16 human cardiomyocytes for 24 h in the presence or absence of cardioprotective molecules (apoJ and HDL). Cytokine release and apoptosis/necrosis were assessed by ELISA and flow cytometry. The EAT from the diabetic samples showed altered expression of genes related to lipid accumulation, insulin resistance, and inflammation. The secretomes from the DM samples presented an increased ratio of pro/antiatherogenic ceramide (Cer) species, while those from DM-C contained the highest concentration of saturated NEFA. DM and DM-C secretomes promoted inflammation and cytotoxicity on AC16 cardiomyocytes. Exogenous Cer16:0, Cer24:1, and palmitic acid reproduced deleterious effects in AC16 cells. These effects were attenuated by exogenous apoJ. Diabetic secretomes promoted inflammation and cytotoxicity in cardiomyocytes. This effect was exacerbated in the secretomes of the DM-C samples. The increased content of specific NEFA and ceramide species seems to play a key role in inducing such deleterious effects, which are attenuated by apoJ.

Arabidopsis seeds altered in the circadian clock protein TOC1 are characterized by higher level of linolenic acid.

The circadian clock plays a critical role in regulating plant physiology and metabolism. However, the way in which the clock impacts the regulation of lipid biosynthesis in seeds is partially understood. In the present study, we characterized the seed fatty acid (FA) and glycerolipid (GL) compositions of pseudo-response regulator mutants. Among these mutants, toc1 (timing of cab expression 1) exhibited the most significant differences compared to control plants. These included an increase in total FA content, characterized by elevated levels of linolenic acid (18:3) along with a reduction in linoleic acid (18:2). Furthermore, our findings revealed that toc1 developing seeds showed increased expression of genes related to FA metabolism. Our results show a connection between TOC1 and lipid metabolism in Arabidopsis seeds.

Increasing the complexity of lipoprotein characterization for cardiovascular risk in type 2 diabetes.

The burden of cardiovascular disease is particularly high among individuals with diabetes, even when LDL cholesterol is normal or within the therapeutic target. Despite this, cholesterol accumulates in their arteries, in part, due to persistent atherogenic dyslipidaemia characterized by elevated triglycerides, remnant cholesterol, smaller LDL particles and reduced HDL cholesterol. The causal link between dyslipidaemia and atherosclerosis in T2DM is complex, and our contention is that a deeper understanding of lipoprotein composition and functionality, the vehicle that delivers cholesterol to the artery, will provide insight for improving our understanding of the hidden cardiovascular risk of diabetes. This narrative review covers three levels of complexity in lipoprotein characterization: 1-the information provided by routine clinical biochemistry, 2-advanced nuclear magnetic resonance (NMR)-based lipoprotein profiling and 3-the identification of minor components or physical properties of lipoproteins that can help explain arterial accumulation in individuals with normal LDLc levels, which is typically the case in individuals with T2DM. This document highlights the importance of incorporating these three layers of lipoprotein-related information into population-based studies on ASCVD in T2DM. Such an attempt should inevitably run in parallel with biotechnological solutions that allow large-scale determination of these sets of methodologically diverse parameters.

Metabolic and Clinical Outcomes in Type 1 Diabetes in the COVID-19 Pre- and Post-Vaccination Periods in Spain: The COVID-SED1 Study.

Aims: To evaluate the metabolic and clinical outcomes in the Spanish type 1 diabetes mellitus (T1D) population before and after COVID-19 vaccination. Methods: A retrospective observational study was carried out in Spanish public hospitals previously enrolled in the SED1 study. Adults and children with T1D were included and their clinical electronic records were reviewed. Clinical, laboratory, and glucometric parameters from continuous glucose monitoring (CGM) data corresponding to the periods before and after administering the first COVID-19 vaccination were analyzed. Results: A total of 26 centers and 228 patients participated in this new phase of the SED1 study and 187 were finally evaluable (mean age 37.5 ± 15.6 years, 56.7% women). Overall, 94.6% of the sample was vaccinated, and this percentage increased with higher levels of education (p-value = 0.027). In the pre- and post-vaccination periods, respectively, the number of patients with acute hyperglycemic decompensation was 6/161 (3.7%) and 7/161 (4.3%) (p = 1) and with acute hypoglycemic decompensation was 6/161 (3.7%) and 6/161 (3.7%) (p = 1). The HbA1c level was lower in the post-vaccination period(mean ± SD, mg/dL): pre-vaccination 7.4 ± 0.9; post-vaccination 7.2 ± 1.0, (-0.19; p-value = 0.0006). A total of 31.9% of patients (95% CI: 24.7-39.7) in the pre-vaccination period and 45.0% (IC95%: 37.1-53.1) in the post-vaccine period had HbA1c < 7% (p-value < 0.001). Glucometrics from CGM data also showed numerical improvements post-vaccination. Conclusions: The COVID-19 vaccination was highly accepted in the Spanish T1D population, with hesitancy about the COVID-19 vaccine being higher in those with lower educational levels. A mildly better glycemic control was observed in the post-vaccination period.

An Organic Electrochemical Transistor-Based Sensor for IgG Levels Detection of Relevance in SARS-CoV-2 Infections.

Organic electrochemical transistors appear as an alternative for relatively low-cost, easy-to-operate biosensors due to their intrinsic amplification. Herein, we present the fabrication, characterization, and validation of an immuno-detection system based on commercial sensors using gold electrodes where no additional surface treatment is performed on the gate electrode. The steady-state response of these sensors has been studied by analyzing different semiconductor organic channels in order to optimize the biomolecular detection process and its the application to monitoring human IgG levels due to SARS-CoV-2 infections. Detection levels of up to tens of µgmL-1 with sensitivities up to 13.75% [µg/mL]-1, concentration ranges of medical relevance in seroprevalence studies, have been achieved.

Soluble individual metal atoms and ultrasmall clusters catalyze key synthetic steps of a natural product synthesis.

Metal individual atoms and few-atom clusters show extraordinary catalytic properties for a variety of organic reactions, however, their implementation in total synthesis of complex organic molecules is still to be determined. Here we show a 11-step linear synthesis of the natural product (±)-Licarin B, where individual Pd atoms (Pd1) catalyze the direct aerobic oxidation of an alcohol to the carboxylic acid (steps 1 and 6), Cu2-7 clusters catalyze carbon-oxygen cross couplings (steps 3 and 8), Pd3-4 clusters catalyze a Sonogashira coupling (step 4) and Pt3-5 clusters catalyze a Markovnikov hydrosylilation of alkynes (step 5), as key reactions during the synthetic route. In addition, the new synthesis of Licarin B showcases an unexpected selective alkene hydrogenation with metal-free NaBH4 and an acid-catalyzed intermolecular carbonyl-olefin metathesis as the last step, to forge a trans-alkene group. These results, together, open new avenues in the use of metal individual atoms and clusters in organic synthesis, and confirm their exceptional catalytic activity in late stages during complex synthetic programmes.

Effectiveness and safety of adalimumab biosimilar in patients with inflammatory bowel disease.

BACKGROUND: Adalimumab biosimilar MSB11022 (Idacio ®) has been approved for the same indications as its originator (Humira ®), based on findings from clinical trials in plaque psoriasis. Data on its efficacy and safety in inflammatory bowel disease, however, are scarce. METHODS: Retrospective, observational study of 44 patients with inflammatory bowel disease: 30 were treated with originator adalimumab, 5 were directly started on MSB11022, and 9 switched from originator to biosimilar adalimumab. To evaluate the effectiveness of the use of adalimumab in inflammatory bowel disease, both laboratory markers (fecal calprotectin and C-reactive protein) and scales that measure the activity of inflammatory bowel disease using specific scales (Harvey-Bradshaw Index (HBI) have been usEd.) for Crohn's disease and Mayo Score for Ulcerative Colitis. Efficacy was evaluated by recording the adverse effects that could occur with the administration of adalimumab (original or biosimilar). The success of the switch was determined by analyzing meaningful differences in effectiveness and safety criteria. Concomitant therapy and the need for dose intensification were also analyzed. Objective of this study was to assess the effectiveness and safety of biosimilar adalimumab in adalimumab-naïve patients and patients switched from originator adalimumab. RESULTS: No significant differences were observed in clinical disease activity (P=.317) or biochemical parameters [fecal calprotectin (P=.445) and C-reactive protein P=.661)] after the switch from the originator adalimumab to MSB11022. There was not a significant reduction in the concomitant use of corticosteroids and thiopurines (P=.157). No emergency room visits or hospitalizations were observed during the study period and none of the patients experienced serious adverse effects. CONCLUSIONS: Between originator adalimumab and biosimilar-start cohorts, no differences were observed, between originator adalimumab and switch cohorts, no significant differences were found either, and with the pre- and post-switch to biosimilar comparison, 2 of the 9 patients experienced AEs after the switch. The biosimilar showed a favorable safety profile (one patient with a serious adverse effect (rash) with biosimilar discontinued treatment) and no significant changes to clinical or biochemical parameters were observed after the switch.

Weight loss benefits on HDL cholesterol persist even after weight regaining.

BACKGROUND: Obesity-related comorbidities may relapse in patients with weight regain after bariatric surgery. However, HDL cholesterol (HDLc) levels increase after surgery and seem to remain stable despite a gradual increase in BMI. The aim of this study is to analyze the effects of weight regain after bariatric surgery on HDL cholesterol. MATERIALS AND METHODS: This is a retrospective, observational, cohort study in patients who underwent bariatric surgery in the Hospital de la Santa Creu i Sant Pau (Barcelona) between 2007 and 2015. Patients without at least 5 years of follow-up after surgery, under fibrate treatment, and those who required revisional surgery were excluded from the analysis. Data were collected at baseline, 3 and 6 months after surgery, and then annually until 5 years post-surgery. RESULTS: One hundred fifty patients were analyzed. 93.3% of patients reached > 20% of total weight loss after surgery. At 5th year, 37% of patients had regained > 15% of nadir weight, 60% had regained > 10%, and 22% had regained < 5% of nadir weight. No differences were found in HDLc levels between the different groups of weight regain, nor in the % of change in HDLc levels between nadir weight and 5 years, or in the proportion of patients with normal HDLc concentrations either. CONCLUSION: HDLc remains stable regardless of weight regain after bariatric surgery.

New beam-based models for fire-induced buckling analysis of class 4 steel columns.

Steel cross-sections with thin walls are vulnerable to fire-induced buckling instability, which reduces their load-bearing capacity. Eurocode 3 design provisions have been found inadequate, leading to alternative methods such as effective design strategies and advanced structural models built mostly with shell FE, which can be complex. For Class 4 steel beam-columns subjected to fire conditions, beam-type modelling to predict the Flexural-Torsional Buckling (FTB) strength has been proposed as an alternative approach, but it has not yielded satisfactory results for large compressive load eccentricities. This paper presents two new low computational cost modelling strategies based on Timoshenko's beam FE to address this issue: the Single beam-column Model (SbcM) and the Cruciform beam-column Model (CbcM). The first consists of a single line of beam FE, while the second uses a grid of beam FE for more flexibility. Both strategies effectively simulate the FTB behaviour in Class 4 steel beam-column during a fire, offering quicker computations compared to shell models. Still, the single-line model is favoured for its simplicity, making it more efficient in analysing complex fire engineering problems.

An Insertion Within SIRPß1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response.

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPß1, a surface receptor that triggers amyloid-ß(Aß) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPß1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPß1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPß1 protein isoform landscape compromising its ability to bind oligomeric Aß and its affinity for TYROBP. SIRPß1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aß ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPß1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPß1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aß. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPß1 structural variant might be considered as a potential modulator of this causative pathway.

PCSK9 plasma concentration is associated with epicardial adipose tissue volume and metabolic control in patients with type 1 diabetes.

Patients with type 1 diabetes (T1D) have a greater risk of cardiovascular disease. Proconvertase subtilisin-kexin 9 (PCSK9) is involved in the atherosclerosis process. This study aimed to determine the relationship between PCSK9 levels and epicardial adipose tissue (EAT) volume and cardiometabolic variables in patients with T1D. This was an observational cross-sectional study including 73 patients with T1D. Clinical, biochemical and imaging data were collected. We divided the patients into two groups according to their glycemic control and the EAT index (iEAT) percentile. We performed a correlation analysis between the collected variables and PCSK9 levels; subsequently, we performed a multiple regression analysis with the significant parameters. The mean age was 47.6 ± 8.5 years, 58.9% were men, and the BMI was 26.9 ± 4.6 kg/m2. A total of 31.5%, 49.3% and 34.2% of patients had hypertension, dyslipidemia and smoking habit, respectively. The PCSK9 concentration was 0.37 ± 0.12 mg/L, which was greater in patients with worse glycemic control (HbA1c > 7.5%), dyslipidemia and high EAT volume (iEAT > 75th percentile). The PCSK9 concentration was positively correlated with age (r = 0.259; p = 0.027), HbA1c (r = 0.300; p = 0.011), insulin dose (r = 0.275; p = 0.020), VLDL-C level (r = 0.331; p = 0.004), TG level (r = 0.328; p = 0.005), and iEAT (r = 0.438; p < 0.001). Multiple regression analysis revealed that 25% of the PCSK9 variability was explained by iEAT and HbA1c (p < 0.05). The PCSK9 concentration is associated with metabolic syndrome parameters, poor glycemic control and increased EAT volume in patients with T1D.

Role of Leptin in Obesity, Cardiovascular Disease, and Type 2 Diabetes.

Diabetes mellitus (DM) is a highly prevalent disease worldwide, estimated to affect 1 in every 11 adults; among them, 90-95% of cases are type 2 diabetes mellitus. This is partly attributed to the surge in the prevalence of obesity, which has reached epidemic proportions since 2008. In these patients, cardiovascular (CV) risk stands as the primary cause of morbidity and mortality, placing a substantial burden on healthcare systems due to the potential for macrovascular and microvascular complications. In this context, leptin, an adipocyte-derived hormone, plays a fundamental role. This hormone is essential for regulating the cellular metabolism and energy balance, controlling inflammatory responses, and maintaining CV system homeostasis. Thus, leptin resistance not only contributes to weight gain but may also lead to increased cardiac inflammation, greater fibrosis, hypertension, and impairment of the cardiac metabolism. Understanding the relationship between leptin resistance and CV risk in obese individuals with type 2 DM (T2DM) could improve the management and prevention of this complication. Therefore, in this narrative review, we will discuss the evidence linking leptin with the presence, severity, and/or prognosis of obesity and T2DM regarding CV disease, aiming to shed light on the potential implications for better management and preventive strategies.

Covalent bonding of N-hydroxyphthalimide on mesoporous silica for catalytic aerobic oxidation of p-xylene at atmospheric pressure.

The surface of SBA-15 mesoporous silica was modified by N-hydroxyphthalimide (NHPI) moieties acting as immobilized active species for aerobic oxidation of alkylaromatic hydrocarbons. The incorporation was carried out by four original approaches: the grafting-from and grafting-onto techniques, using the presence of surface silanols enabling the formation of particularly stable O-Si-C bonds between the silica support and the organic modifier. The strategies involving the Heck coupling led to the formation of NHPI groups separated from the SiO2 surface by a vinyl linker, while one of the developed modification paths based on the grafting of an appropriate organosilane coupling agent resulted in the active phase devoid of this structural element. The successful course of the synthesis was verified by FTIR and 1 H NMR measurements. Furthermore, the formed materials were examined in terms of their chemical composition (elemental analysis, thermal analysis), structure of surface groups (13 C NMR, XPS), porosity (low-temperature N2 adsorption), and tested as catalysts in the aerobic oxidation of p-xylene at atmospheric pressure. The highest conversion and selectivity to p-toluic acid were achieved using the catalyst with enhanced availability of non-hydrolyzed NHPI groups in the pore system. The catalytic stability of the material was additionally confirmed in several subsequent reaction cycles.

Time-resolved control of nanoparticle integration in titanium-organic frameworks for enhanced catalytic performance.

Among the multiple applications of metal-organic frameworks (MOFs), their use as a porous platform for the support of metallic nanoparticles stands out for the possibility of integrating a good anchorage, that improves the stability of the catalyst, with the presence of a porous network that allows the diffusion of substrates and products. Here we introduce an alternative way to control the injection of Au nanoparticles at variable stages of nucleation of a titanium(iv) MOF crystal (MUV-10). This allows the analysis of the different modes of nanoparticle integration into the porous matrix as a function of the crystal formation stage and their correlation with the catalytic performance of the resulting composite. Our results reveal a direct effect of the stage at which the Au nanoparticles are integrated into MUV-10 crystals not only on their catalytic activity for the cyclotrimerization of propargyl esters and the hydrochlorination of alkynes, but also on the selectivity and recyclability of the final solid catalyst, which are far superior than those reported for the same reactions with TiO2 supports.