A balanced formula of essential amino acids promotes brain mitochondrial biogenesis and protects neurons from ischemic insult

Mitochondrial dysfunction plays a key role in the aging process, and aging is a strong risk factor for neurodegenerative diseases or brain injury characterized by impairment of mitochondrial function. Among these, ischemic stroke is one of the leading causes of death and permanent disability worldwide. Pharmacological approaches for its prevention and therapy are limited. Although non-pharmacological interventions such as physical exercise, which promotes brain mitochondrial biogenesis, have been shown to exert preventive effects against ischemic stroke, regular feasibility is complex in older people, and nutraceutical strategies could be valuable alternatives. We show here that dietary supplementation with a balanced essential amino acid mixture (BCAAem) increased mitochondrial biogenesis and the endogenous antioxidant response in the hippocampus of middle-aged mice to an extent comparable to those elicited by treadmill exercise training, suggesting BCAAem as an effective exercise mimetic on brain mitochondrial health and disease prevention. In vitro BCAAem treatment directly exerted mitochondrial biogenic effects and induced antioxidant enzyme expression in primary mouse cortical neurons. Further, exposure to BCAAem protected cortical neurons from the ischemic damage induced by an in vitro model of cerebral ischemia (oxygen-glucose deprivation, OGD). BCAAem-mediated protection against OGD was abolished in the presence of rapamycin, Torin-1, or L-NAME, indicating the requirement of both mTOR and eNOS signaling pathways in the BCAAem effects. We propose BCAAem supplementation as an alternative to physical exercise to prevent brain mitochondrial derangements leading to neurodegeneration and as a nutraceutical intervention aiding recovery after cerebral ischemia in conjunction with conventional drugs

On coalgebras with internal moves

In the first part of the paper we recall the coalgebraic approach to handling the so-called invisible transitions that appear in different state-based systems semantics. We claim that these transitions are always part of the unit of a certain monad. Hence, coalgebras with internal moves are exactly coalgebras over a monadic type. The rest of the paper is devoted to supporting our claim by studying two important behavioural equivalences for state-based systems with internal moves, namely: weak bisimulation and trace semantics. We continue our research on weak bisimulations for coalgebras over order enriched monads. The key notions used in this paper and proposed by us in our previous work are the notions of an order saturation monad and a saturator. A saturator operator can be intuitively understood as a reflexive, transitive closure operator. There are two approaches towards defining saturators for coalgebras with internal moves. Here, we give necessary conditions for them to yield the same notion of weak bisimulation. Finally, we propose a definition of trace semantics for coalgebras with silent moves via a uniform fixed point operator. We compare strong and weak bisimilation together with trace semantics for coalgebras with internal steps.Comment: Article: 23 pages, Appendix: 3 page

Targeting Multiple Mitochondrial Processes by a Metabolic Modulator Prevents Sarcopenia and Cognitive Decline in SAMP8 Mice

The age-dependent declines of skeletal muscle and cognitive functions often coexist in elderly subjects. The underlying pathophysiological mechanisms share common features of mitochondrial dysfunction, which plays a central role in the development of overt sarcopenia and/or dementia. Dietary supplementation with formulations of essential and branched-chain amino acids (EAA-BCAA) is a promising preventive strategy because it can preserve mitochondrial biogenesis and function. The senescence-accelerated mouse prone 8 (SAMP8) is considered an accurate model of age-related muscular and cognitive alterations. Hence, we aimed to investigate the progression of mitochondrial dysfunctions during muscular and cognitive aging of SAMP8 mice and to study the effects of a novel EAA-BCAA-based metabolic modulator on these changes. We evaluated body condition, motor endurance, and working memory of SAMP8 mice at 5, 9, 12, and 15 months of age. Parallel changes in protein levels of mitochondrial respiratory chain subunits, regulators of mitochondrial biogenesis and dynamics, and the antioxidant response, as well as respiratory complex activities, were measured in the quadriceps femoris and the hippocampus. The same variables were assessed in 12-month-old SAMP8 mice that had received dietary supplementation with the novel EAA-BCAA formulation, containing tricarboxylic acid cycle intermediates and co-factors (PD-0E7, 1.5 mg/kg/body weight/day in drinking water) for 3 months. Contrary to untreated mice, which had a significant molecular and phenotypic impairment, PD-0E7-treated mice showed preserved healthy body condition, muscle weight to body weight ratio, motor endurance, and working memory at 12 months of age. The PD-0E7 mixture increased the protein levels and the enzymatic activities of mitochondrial complex I, II, and IV and the expression of proliferator-activated receptor \u3b3 coactivator-1\u3b1, optic atrophy protein 1, and nuclear factor, erythroid 2 like 2 in muscles and hippocampi. The mitochondrial amyloid-\u3b2-degrading pitrilysin metallopeptidase 1 was upregulated, while amyloid precursor protein was reduced in the hippocampi of PD-0E7 treated mice. In conclusion, we show that a dietary supplement tailored to boost mitochondrial respiration preserves skeletal muscle and hippocampal mitochondrial quality control and health. When administered at the early onset of age-related physical and cognitive decline, this novel metabolic inducer counteracts the deleterious effects of precocious aging in both domains

Ambient Air Pollution, Social Inequalities and Asthma Exacerbation in Greater Strasbourg (France) Metropolitan Area: the PAISA Study

International audienceThe socio-economic status (SES) of populations has an influence on the incidence or mortality rates of numerous health outcomes, among which respiratory diseases (Prescott et al., 2003; Ellison-Loschmann et al., 2007). Considering asthma, the possible contribution of SES to overall prevalence –regardless of asthma severity-, remains controversial in industrialized countries. Several studies indicate that allergic asthma is more prevalent in more well-off populations whereas the non-allergic forms of asthma are more common in the deprived ones (Cesaroni et al., 2003; Blanc et al., 2006). On the other hand, severe asthma whatever its etiology appears to be more frequent in the latter populations, as compared to the more affluent (Basagana et al., 2004). Risk factors for exacerbations (e.g., passive smoking (Wright Subramanian, 2007), psychosocial stress (Gold & Wright, 2005), cockroach allergens (Kitch et al., 2000), and suboptimal compliance with anti-inflammatory medication (Gottlieb et al., 1995)) are generally more common among people with asthma and low SES than their better-off counterparts. These observations support the hypothesis that some factors more present in deprived populations contribute to asthma exacerbation (Mielck et al., 1996)

Non-invasive investigation of adipose tissue by time domain diffuse optical spectroscopy

The human abdominal region is very heterogeneous and stratified with subcutaneous adipose tissue (SAT) being one of the primary layers. Monitoring this tissue is crucial for diagnostic purposes and to estimate the effects of interventions like caloric restriction or bariatric surgery. However, the layered nature of the abdomen poses a major problem in monitoring the SAT in a non-invasive way by diffuse optics. In this work, we examine the possibility of using multi-distance broadband time domain diffuse optical spectroscopy to assess the human abdomen non-invasively. Broadband absorption and reduced scattering spectra from 600 to 1100 nm were acquired at 1, 2 and 3 cm source-detector distances on ten healthy adult male volunteers, and then analyzed using a homogeneous model as an initial step to understand the origin of the detected signal and how tissue should be modeled to derive quantitative information. The results exhibit a clear influence of the layered nature on the estimated optical properties. Clearly, the underlying muscle makes a relevant contribution in the spectra measured at the largest source-detector distance for thinner subjects related to blood and water absorption. More unexpectedly, also the thin superficial skin layer yields a direct contamination, leading to higher water content and steeper reduced scattering spectra at the shortest distance, as confirmed also by simulations. In conclusion, provided that data analysis properly accounts for the complex tissue structure, diffuse optics may offer great potential for the continuous non-invasive monitoring of abdominal fat

Probabilistic Bisimulation: Naturally on Distributions

In contrast to the usual understanding of probabilistic systems as stochastic processes, recently these systems have also been regarded as transformers of probabilities. In this paper, we give a natural definition of strong bisimulation for probabilistic systems corresponding to this view that treats probability distributions as first-class citizens. Our definition applies in the same way to discrete systems as well as to systems with uncountable state and action spaces. Several examples demonstrate that our definition refines the understanding of behavioural equivalences of probabilistic systems. In particular, it solves a long-standing open problem concerning the representation of memoryless continuous time by memory-full continuous time. Finally, we give algorithms for computing this bisimulation not only for finite but also for classes of uncountably infinite systems

NEUROBORRELIOSI DI LYME E MALATTIA DI PARKINSON: STUDIO DI UN CASO POST-MORTEM

n/

Characterising Probabilistic Processes Logically

In this paper we work on (bi)simulation semantics of processes that exhibit both nondeterministic and probabilistic behaviour. We propose a probabilistic extension of the modal mu-calculus and show how to derive characteristic formulae for various simulation-like preorders over finite-state processes without divergence. In addition, we show that even without the fixpoint operators this probabilistic mu-calculus can be used to characterise these behavioural relations in the sense that two states are equivalent if and only if they satisfy the same set of formulae.Comment: 18 page

Efficacy and safety of therapies for COVID-19 in pregnancy: a systematic review and meta-analysis

Background: Clinical evidence suggests that pregnant women are more vulnerable to COVID-19, since they are at increased risk for disease progression and for obstetric complications, such as premature labor, miscarriage, preeclampsia, cesarean delivery, fetal growth restriction and perinatal death. Despite this evidence, pregnant women are often excluded from clinical trials, resulting in limited knowledge on COVID-19 management. The aim of this systematic review and meta-analysis is to provide better evidence on the efficacy and safety of available COVID-19 treatment in pregnant women. Methods: Four authors searched major electronic databases from inception until 1 st November-2022 for controlled trials/observational studies, investigating outcomes after the administration of anti-SARS-CoV-2 treatments in pregnant women affected by COVID-19. The analyses investigated the cumulative incidence of delivery and maternal outcomes in pregnant women, comparing those taking active medication vs standard care. Risk ratios (RRs) with 95% confidence intervals were calculated. Statistical significance was assessed using the random effects model and inverse-variance method. This systematic review and meta-analysis was conducted in accordance with the updated 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol has been registered in Prospero (number registration: CRD42023397445). Results: From initially 937 non duplicate records, we assessed the full texts of 40 articles, finally including ten studies. In six studies, including 1627 patients, the use of casirivimab/imdevimab (CAS/IMD), remdesivir, and IFN-alpha 2b significantly decreased the need of cesarean section ((RR = 0.665; 95%CI: 0.491–0.899; p = 0.008; I 2 = 19.5%;) (Table 1, (Fig. 1). Treatments did not decrease the risk of preterm delivery, admission to neonatal ICU, or stillbirth/perinatal loss (p-values > 0.50 for all these outcomes) and did not prevent the progression of disease towards severe degrees (k = 8; 2,374 pregnant women; RR = 0.778; 95%CI: 0.550–1.099; p = 0.15; I 2 = 0%). Moreover, the use of medications during pregnancy did not modify the incidence of maternal death in two studies (Table 2). Conclusions: To our analysis, CAS/IMD, remdesivir, and IFN alpha 2b reduced the number of cesarean sections but demonstrated no effect on disease progression and other obstetric and COVID-19 related outcomes. The inability to evaluate the influence of viral load on illness development in pregnant women was attributed to lack of data. In our systematic review, no major side effects were reported. Though, it is essential for the medical community to focus more on clinical trials and less on episodic case reports and case series, with standardization of fetal and maternal outcomes