•The question of whether monocarboxylic acids can fuel Drosophila motoneuron neurotransmitter release (NTR) was challenged.•Monocarboxylates trigger a transient enlargement of excitatory postsynaptic ...currents (EPSC) at the motoneuron synapses.•Monocarboxylates fail to support NTR under long synaptic demand, driving the synapses into synaptic depression state.•Glycolysis activation restores the motoneuron NTR ability of monocarboxylate-depressed synapses.•The synaptic monocarboxylate-induced enhancement is reached under extreme glycolysis reduction.
Current evidence suggests that glial cells provide C3 carbon sources to fuel neuronal activity; however, this notion has become challenged by biosensor studies carried out in acute brain slices or in vivo, showing that neuronal activity does not rely on the import of astrocyte-produced L-lactate. Rather, stimulated neurons become net lactate exporters, as it was also shown in Drosophila neurons, in which astrocyte-provided lactate returns as lipid droplets to be stored in glial cells. In this view, we investigate whether exogenously supplied monocarboxylates can support Drosophila motoneuron neurotransmitter release (NTR). By assessing the excitatory post-synaptic current (EPSC) amplitude under voltage-clamp as NTR indicative, we found that both pyruvate and L-lactate, as the only carbon sources in the synapses bathing-solution, cause a large transient NTR enhancement, which declines to reach a synaptic depression state, from which the synapses do not recover. The FM1-43 pre-synaptic loading ability, however, is maintained under monocarboxylate, suggesting that SV cycling should not contribute to the synaptic depression state. The NTR recovery was reached by supplementing the monocarboxylate medium with sucrose. However, monocarboxylate addition to sucrose medium does not enhance NTR, but it does when the disaccharide concentration becomes too reduced. Thus, when pyruvate concentrations become too reduced, exogenously supplied L-lactate could be converted to pyruvate and metabolized by the neural mitochondria, triggering the NTR enhancement.
The question of whether monocarboxylic acids can fuel the Drosophila motoneuron NTR was challenged. Our findings show that exogenously supplied monocarboxylates trigger a large transient synaptic enhancement just under extreme glycolysis reduction but fail to maintain NTR under sustained synaptic demand, still at low frequency stimulation, driven to the synapses to a synaptic depression state. Glycolysis activation, by adding sucrose to the monocarboxylate bath solution, restores the motoneuron NTR ability, giving place to a hexoses role in SV recruitment. Moreover these results suggest exogenously supplied C3 carbon sources could have an additional role beyond providing energetic support for neural activity.
The intercellular transport of lactate is crucial for the astrocyte-to-neuron lactate shuttle (ANLS), a model of brain energetics according to which neurons are fueled by astrocytic lactate. In this ...study we show that the Drosophila chaski gene encodes a monocarboxylate transporter protein (MCT/SLC16A) which functions as a lactate/pyruvate transporter, as demonstrated by heterologous expression in mammalian cell culture using a genetically encoded FRET nanosensor. chaski expression is prominent in the Drosophila central nervous system and it is particularly enriched in glia over neurons. chaski mutants exhibit defects in a high energy demanding process such as synaptic transmission, as well as in locomotion and survival under nutritional stress. Remarkably, locomotion and survival under nutritional stress defects are restored by chaski expression in glia cells. Our findings are consistent with a major role for intercellular lactate shuttling in the brain metabolism of Drosophila.
A compilation of articles with a strong teaching element published since 2018 is presented alongside an overview of the articles in the special issue on this topic.
Trans-fatty acids (TFAs) are generated by the food industry and also occur naturally in trace amounts in dairy products. For the latter, beneficial health effects have been claimed, while there are ...numerous reports about TFA of industrial origin being hazardous to human health. Therefore, we aimed to investigate the association of TFA with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.
The fatty acid composition of erythrocyte membranes was analysed using the HS-Omega-3 Index(®) methodology in 3259 participants of the LURIC study at baseline. During a median of 10.0 years of follow-up, a total of 975 (29.9%) study participants died, 614 (18.8%) from cardiovascular causes including 254 (7.8%) sudden cardiac deaths (SCDs). Association of TFA with clinical outcome was investigated with Cox proportional hazards regression. Total TFAs were inversely associated with mortality due to cardiovascular causes or SCD. This was mainly driven by the naturally occurring TFA C16:1n-7t (trans-palmitoleic acid). The reduced risk of SCD associated with C16:1n-7t persisted after multivariate adjustment with a hazard ratio of 0.63 (0.46-0.86) for the third tertile compared with the first tertile. There was no association of any TFA subgroup with an increased risk of adverse outcomes.
In contrast to previous findings, the low concentrations of total TFAs found in LURIC were inversely associated with adverse cardiac outcomes. While the naturally occurring TFA C16:1n-7t was associated with reduced risk, no increased risk was found for industrially produced TFAs.
The international-normalized-ratio (INR) is typically used to monitor patients on warfarin or related oral anticoagulant therapy. The aim of our study was to investigate the association of the INR ...with mortality in coronary artery disease (CAD) patients not on oral anticoagulant therapy.
Between 1997 to 2000 the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study enrolled 3316 patients of German ancestry that had been referred for coronary angiography. We excluded patients on coumarin therapy (n = 222) and patients with an INR more than 5 standard deviations (SD) away from the mean (n = 30). During a median follow-up of 9.9 years, 884 patients died, 547 patients from cardiovascular causes. After adjustment for cardiovascular risk factors the INR was associated with all-cause mortality in all patients and the CAD positive group with HRs (95% CI) of 1.14(1.07-1.21) and 1.16(1.09-1.23) per 1-SD increase, respectively. Adjustment for NT-proBNP rendered the association insignificant.
In LURIC, the INR was positively associated with mortality in patients with prevalent CAD not on oral anticoagulant therapy as well as in patients without CAD. Adjustment for NT-proBNP abolished the association suggesting clinical or subclinical heart failure strongly contributing to increased INR and higher mortality.
The mucoprotein uromodulin is the most abundant protein in mammalian urine and has important roles in ion transport, maintenance of water and electrolyte balance, and clearance of bacteria from the ...urinary tract. Low urinary uromodulin concentrations have been associated with increased mortality risk. However, measuring uromodulin in urine has several preanalytic drawbacks, and sensitive assays for the detection of uromodulin in blood have become available. In this study, we investigated the association of serum uromodulin concentration with cardiovascular biomarkers and mortality risk in a large cohort of patients referred for coronary angiography. Uromodulin concentrations were available in 3057 of 3316 participants of the Ludwigshafen Risk and Cardiovascular Health Study. Higher serum uromodulin concentration associated with a favorable metabolic profile, lower prevalence rates of comorbidities (arterial hypertension, diabetes mellitus, and heart failure), and a lower risk for 10-year mortality, with hazard ratios (95% confidence intervals) of 0.65 (0.54 to 0.78), 0.71 (0.58 to 0.88), and 0.57 (0.45 to 0.73) in the second, third, and fourth quartiles, respectively, compared with the first quartile. The association with reduced mortality was independent of other cardiovascular risk factors, including eGFR, and stronger after adjustment for the genotype of the rs12917707 polymorphism at the
locus. Adding serum uromodulin concentration to established cardiovascular risk prediction scores improved risk prediction. Uromodulin may, therefore, be a useful marker for cardiovascular and renal health.
Abstract Background and aims There is an ongoing debate whether omega-3-fatty acids protect from cardiovascular disease mortality. We examined the associations of erythrocyte omega-3 fatty acids with ...mortality in patients referred for coronary angiography. Methods Erythrocyte omega-3 fatty acid proportions were measured at baseline in 3259 participants of the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) using the HS-Omega-3 Index method. Associations of omega-3 fatty acid proportions with mortality were investigated using Cox proportional hazards regression. Results During a median follow-up of 9.9 years, 975 patients (29.9%) died, 614 patients (18.8%) from cardiovascular causes. Proportions of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were inversely associated with all-cause and cardiovascular mortality in models adjusted for conventional cardiovascular risk factors. The strongest association was observed for EPA with a hazard ratio (HR) of 0.89 (0.83–0.96) per increase of one standard deviation. Furthermore, we obtained evidence for a non-linear relation between EPA and mortality. Conclusions EPA and DHA were associated with reduced mortality in LURIC, independent of other risk factors, with the association of EPA with mortality being non-linear.
To determine whether Bacille Calmette-Guerin (BCG) vaccination is linked to the risk of acute lower respiratory infection (ALRI) among children <5 years of age.
Data from Macro International ...Demographic and Health Surveys and United Nations Children's Fund Multiple Indicator Cluster Surveys were used to identify a primary cohort of 58,021 children in 19 countries (2005-2010) and a secondary cohort of 93,301 children in 18 countries (2000-2007). Information was collected by trained interviewers during home visits using standardized questionnaires, review of vaccination health cards, and measurement of health indicators.
BCG vaccination was associated with a 17% to 37% risk reduction for suspected ALRI in both cohorts. The only vaccine or vitamin supplement to modify the effect of BCG was diphtheria-tetanus-pertussis (DTP; P < .001). The order in which the vaccines were first received was central to this phenomena (BCG before DTP, adjusted/propensity score-weighted relative risk apRR: 0.79, 95% confidence interval CI: 0.70-0.89; BCG with DTP, apRR: 0.82, 95% CI: 0.71-0.94; and BCG after DTP, apRR: 1.00, 95% CI: 0.87-1.13) but not number of DTP doses received. Other modifiers included vaccine strain used in immunization programs, chlorinating drinking water, using wood-burning fuel cook stoves, and owning livestock.
Children vaccinated with BCG had a significantly lower risk of suspected ALRI. Clarification is needed as to whether this is due to reductions in the underlying risk of tuberculosis or ALRI per se.
LDL receptor traffic: in the fast lane Kleber, Marcus E; Delgado, Graciela E; März, Winfried
European heart journal,
03/2020, Volume:
41, Issue:
9
Journal Article
Short telomeres have been associated with adverse lifestyle factors, cardiovascular risk factors and age-related diseases, including cardiovascular disease (CVD), myocardial infarction, ...atherosclerosis, hypertension, diabetes, and also with mortality. However, previous studies report conflicting results.
The aim of the present study has been to investigate the involvement of telomere length in all-cause and CVD mortality in subjects hospitalized for diagnostic coronary angiography of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.
Relative telomere length (RTL) was measured with a Q-PCR based method in 3,316 participants of the LURIC study. Age-corrected RTL was calculated as the ratio between RTL and age. Median follow-up was 9.9 years. Cox regression and Kaplan-Maier analyses were performed to evaluate the role of RTL for all-cause and cardiovascular mortality.
RTL correlated negatively with age (r = -0.09; p<0.001). In surviving patients the correlation between age and RTL was statistically significant (r = -0.088; p<0.001), but not in patients who died during follow-up (r = -0.043; p = 0.20). Patients in quartiles 2-4 of RTL had a lower hazard ratio for all-cause mortality (HR:0.822; 95%CI 0.712-0.915; p = 0.008) and CVD-mortality (HR:0.836; 95%CI 0.722-0.969; p = 0.017) when compared to those in the 1st quartile. Adjustment for major cardiovascular risk factors did not change this result, however additional adjustment for age attenuated this effect. Patients in the 4th quartile of age-corrected RTL compared to those in the 1st quartile had a lower hazard ratio for all-cause mortality, even with adjustment for major cardiovascular risk factors.
The present study supports the hypothesis that short telomere length increases the risk of all-cause and CVD mortality. Age appears to be an important co-variate that explains a substantial fraction of this effect. It remains unclear whether short telomeres contribute directly to the increase in mortality or if they are simply a surrogate marker for other adverse processes of aging.
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