The role of CD38 and TRPM2 in adipose tissue and liver during thermogenesis

BACKGROUND: Different strategies to boost cellular NAD+ levels, such as supplementation of NAD+ precursors, or inhibition of NAD+ consumption, are currently under investigation as promising means to promote healthy aging and ameliorate dysfunctional metabolism. CD38 is a NAD+-dependent enzyme that converts NAD+ to different Ca2+-active second messengers, involved in the regulation of different signaling pathways, cell functions and metabolism. TRPM2, is an ion channel that allows Ca2+ influx from the extracellular space toward the cytosol, and is gated by ADPR, one of the molecules produced from the NAD+ degradation. In the context of systemic energy metabolism, brown adipocytes, the parenchymal cells of brown adipose tissue (BAT) as well as beige adipocytes that emerge in white adipose tissue (WAT) depots in response to catabolic conditions, are important to maintain metabolic homeostasis, together with liver. HYPOTHESIS: We aim to understand the functional relevance of CD38 and TRPM2 in the regulation of energy metabolism and NAD(P)(H) levels in BAT, WAT and liver during thermogenesis. METHODS: We used wild type, Cd38-/- and Trpm2-/- mice, exposed to cold temperatures and BAT, WAT and liver were collected. We evaluated mRNA levels by RT-PCR, proteins/enzymes levels by Western blot, FACS analysis and enzymatic activities. NAD(P)(H) levels were determined with cycling assays. Furthermore, we performed a set of in vivo experiments in which O2 consumption, CO2 production and energy expenditure were measured in mice upon thermogenic stimulation. RESULTS: We confirmed that CD38 is a major NAD+-consumer in BAT, WAT and liver: increased NAD+ levels were observed in these tissues from Cd38-/- compared with wild type mice. Interestingly, during cold exposure, a marked downregulation of CD38 expression (as detected at the mRNA, protein and enzymatic level) occurred in BAT, WAT and in liver of wild type mice. As a consequence of CD38 downregulation, an increase in NAD+ levels occurred in BAT. Instead, in WAT, CD38 downregulation was accompanied by a strong increase in NADP(H) levels, likely as a consequence of increased NADK, G6PD and malic enzyme activities. In liver, CD38 downregulation was paralleled by increased NAD(H) levels. NADK activity and NADP+ levels were not significantly modified in liver during cold-exposure. Notably, a marked decrease of NADPH level occurred in liver from both wild type and Cd38-/- mice exposed to a cold temperature, possibly as a consequence of the observed downregulation of the hepatic G6PD activity. Saving G6P from the PPP is in line with the increased activity of the enzyme glucose-6-phosphatase in liver of wild type, but not Cd38-/-, cold-exposed mice, with up-regulated gluconeogenesis. When Cd38-/- mice were kept at 6\ub0C, higher levels of Ucp1 and Pgc-1\uf061 in BAT and WAT were revealed, compared with wild type mice. Conversely, when Trpm2-/- mice were exposed to cold temperature, lower levels of these two browning marker genes were detected, compared with wild type mice. In line with this, mice lacking Trpm2 displayed lower respiration rate and energy expenditure, when thermogenesis was induced by cold exposure and CL316,243 (a specific compound triggering adipose tissue activation). Interestingly, during cold exposure, a marked Trpm2 overexpression was observed in WAT and BAT of wild type mice. In addition, ADPR levels and mono/poly-ADPR hydrolases expression were higher in mice exposed to cold, in comparison with wild type mice. CONCLUSION: Taken together, these results demonstrate that CD38, by modulating cellular NAD(P)+ levels, is involved in the regulation of thermogenic responses in cold-activated BAT and WAT. Indeed, CD38 inhibition is being investigated as a possible strategy to ameliorate dysfunctional metabolism, by boosting NAD+ levels and sirtuins\u2019 activity. In addition, TRPM2 plays a pivotal role in BAT and WAT activation. TRPM2 gating, is likely due to alternative pathways that do not include CD38 activity

Efficient preconditioners for solving dynamical optimal transport via interior point methods

In this paper we address the numerical solution of the quadratic optimal transport problem in its dynamical form, the so-called Benamou-Brenier formulation. When solved using interior point methods, the main computational bottleneck is the solution of large saddle point linear systems arising from the associated Newton-Raphson scheme. The main purpose of this paper is to design efficient preconditioners to solve these linear systems via iterative methods. Among the proposed preconditioners, we introduce one based on the partial commutation of the operators that compose the dual Schur complement of these saddle point linear systems, which we refer as $\boldsymbol{B}\boldsymbol{B}$-preconditioner. A series of numerical tests show that the $\boldsymbol{B}\boldsymbol{B}$-preconditioner is the most efficient among those presented, despite a performance deterioration in the last steps of the interior point method. It is in fact the only one having a CPU-time that scales only slightly worse than linearly with respect to the number of unknowns used to discretize the problem

“Don’t leave me behind!” problematic Internet use and fear of missing out through the lens of epistemic trust in emerging adulthood

the present study investigates the association between fear of missing out (FoMO) and problematic Internet Use (PIU) in a sample of 358 cisgender emerging adults (74.58% females assigned at birth; mage = 25.02, SD = 2.60; age range: 18–29 years), with a specific focus on the roles of various stances of epistemic trust, including trust, mistrust, and credulity. the aim is to explore the complexities of these relationships and their implications for the psychological well-being of this population. we computed a mediation model to examine the relationships among PIU as the dependent variable, FoMO as the predictor, and epistemic trust, mistrust, and credulity as the mediating factors. covariates such as age, gender, and sexual orientation were also considered in the analysis. the results revealed significant indirect effects for both mistrust and credulity. specifically, higher levels of FoMO were associated with increased mistrust and credulity, leading to greater PIU. In contrast, the indirect effect of trust was not significant. also, FoMO had a direct effect on PIU. the results highlight the importance of considering mistrust and credulity as potential risk factors for Internet addiction in emerging adults. these findings have practical implications for clinical practice, psychological assessment, and intervention strategies, emphasizing the need to address FoMO and its associated vulnerabilities within different therapeutic settings. by doing so, mental health professionals can better support the psychological well-being of emerging adults and assist them in navigating the challenges inherent to this crucial developmental stage

Rayleigh–Bénard convection of a model emulsion: anomalous heat-flux fluctuations and finite-size droplet effects

We present mesoscale numerical simulations of Rayleigh-B\'enard (RB) convection in a two-dimensional model emulsion. The systems under study are constituted of finite-size droplets, whose concentration Phi_0 is systematically varied from small (Newtonian emulsions) to large values (non-Newtonian emulsions). We focus on the characterisation of the heat transfer properties close to the transition from conductive to convective states, where it is known that a homogeneous Newtonian system exhibits a steady flow and a time-independent heat flux. In marked contrast, emulsions exhibit a non-steady dynamics with fluctuations in the heat flux. In this paper, we aim at the characterisation of such non-steady dynamics via detailed studies on the time-averaged heat flux and its fluctuations. To understand the time-averaged heat flux, we propose a side-by-side comparison between the emulsion system and a single-phase (SP) system, whose viscosity is constructed from the shear rheology of the emulsion. We show that such local closure works well only when a suitable degree of coarse-graining (at the droplet scale) is introduced in the local viscosity. To delve deeper into the fluctuations in the heat flux, we propose a side-by-side comparison between a Newtonian emulsion and a non-Newtonian emulsion, at fixed time-averaged heat flux. This comparison elucidates that finite-size droplets and the non-Newtonian rheology cooperate to trigger enhanced heat-flux fluctuations at the droplet scales. These enhanced fluctuations are rooted in the emergence of space correlations among distant droplets, which we highlight via direct measurements of the droplets displacement and the characterisation of the associated correlation function. The observed findings offer insights on heat transfer properties for confined systems possessing finite-size constituents.Comment: 15 pages, 22 figures. arXiv admin note: substantial text overlap with arXiv:2010.02139, arXiv:2010.0213

Problematic internet use in emerging adulthood to escape from maternal helicopter parenting: defensive functioning as a mediating mechanism

The increasing use of the Internet has raised concerns about its problematic use, particularly among emerging adults who grew up in a highly digitalized world. Helicopter parenting, characterized by excessive involvement, overcontrol, and developmentally inappropriate behavior, has been identified as a potential factor contributing to problematic Internet use (PIU). Under these circumstances, considering that emerging adults navigate their adult lives and strive to reduce their sense of being in-between, implicit emotion regulation strategies, such as defense mechanisms, may help comprehend PIU. The present questionnaire-based study investigated the associations between maternal and paternal helicopter parenting and PIU through defensive functioning among a community sample of 401 cisgender emerging adults (71.82% females; 82.04% heterosexuals; Mage=24.85, SD=2.52) living in Italy. About one-fourth (25.19%) reported PIU. Greater maternal, B=0.904, SE=0.235, p<.001, but not paternal, B=0.343, SE=0.188, p=.068, helicopter parenting was significantly associated with PIU through a less mature defensive functioning. Conversely, neither maternal, B=1.158, SE=0.722, p=.109, nor paternal, B=0.355, SE=0.731, p=.628, helicopter parenting had a direct association with PIU. The results suggest the importance for psychotherapists to incorporate individuals' defense mechanisms and parent-child relationship history when designing tailored interventions for effective treatment of PIU. This emphasis is crucial because, in the context of a developmentally appropriate parenting style, relying on more mature defenses after psychotherapeutic intervention can lead to healthier adjustment among emerging adults

Different epistemic stances for different traumatic experiences: implications for mentalization

Traumatic experiences may impair reflective functioning (RF), making it difficult for individuals to understand their own and others' mental states. Epistemic trust (ET), which enables evaluating social information as reliable and relevant, may vary in association with RF. In this study, we explored the implications of different ET stances (i.e., trust, mistrust, and credulity) in the relation between different childhood traumatic experiences (i.e., emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect) and different types of RF impairments (uncertainty and certainty about mental states). A non-clinical community sample of 496 cisgender emerging adults (mage = 24.91, standard deviation = 2.66, 71.85% assigned female at birth, 63.63% heterosexual) reported on their childhood traumatic experiences, ET, and RF. We used structural equation models to examine direct and indirect associations. The results showed significant indirect effects between emotional abuse and uncertainty about mental states through credibility. We also observed significant indirect effects between emotional abuse and certainty about mental states through mistrust and credibility. The findings suggest that a lack of discrimination when evaluating knowledge from others (i.e., credulity) might promote increased uncertainty in RF when emerging adults have experienced emotional abuse in their childhood. Conversely, a tendency to view all information sources as unreliable or ill-intentioned (i.e., mistrust) may foster greater certainty in RF as a protective mechanism against an unreliable and potentially harmful world when combined with childhood emotional abuse. The implications for clinical practice and intervention are discussed

The rate of entropy increase at the edge of chaos

Under certain conditions, the rate of increase of the statistical entropy of a simple, fully chaotic, conservative system is known to be given by a single number, characteristic of this system, the Kolmogorov-Sinai entropy rate. This connection is here generalized to a simple dissipative system, the logistic map, and especially to the chaos threshold of the latter, the edge of chaos. It is found that, in the edge-of-chaos case, the usual Boltzmann-Gibbs-Shannon entropy is not appropriate. Instead, the non-extensive entropy $S_q\equiv \frac{1-\sum_{i=1}^W p_i^q}{q-1}$, must be used. The latter contains a parameter q, the entropic index which must be given a special value $q^*\ne 1$ (for q=1 one recovers the usual entropy) characteristic of the edge-of-chaos under consideration. The same q^* enters also in the description of the sensitivity to initial conditions, as well as in that of the multifractal spectrum of the attractor.Comment: 6 pages, Latex, 4 figures included, final version accepted for publication in Physics Letters