Inverse association of circulating SIRT1 and adiposity. A study on underweight, normal weight, and obese patients

Context: Sirtuins (SIRTs) are NAD+-dependent deacetylases, cellular sensors to detect energy availability, and modulate metabolic processes. SIRT1, the most studied family member, influences a number of tissues including adipose tissue. Expression and activity of SIRT1 reduce with weight gain and increase in conditions of starvation. Objective: To focus on SIRT1 plasma concentrations in different conditions of adiposity and to correlate SIRT1 with fat content and distribution, energy homeostasis and inflammation in under-weight, normal-weight, and obese individuals. Materials and Methods: 21 patients with anorexia nervosa, 26 normal-weight and 75 patients with obesity were evaluated. Body fat composition by dual-energy X-ray absorptiometry, ultrasound liver adiposity, echocardiographic epicardial fat thickness (EFT), inflammatory (ESR, CRP, and fibrinogen), and metabolic (FPG, insulin, LDL- and HDL-cholesterol, triglycerides) parameters, calculated basal metabolic rate (BMR) and plasma SIRT1 (ELISA) were measured. Results: SIRT1 was significantly higher in anorexic patients compared to normal-weight and obese patients (3.27 ± 2.98, 2.27 ± 1.13, and 1.36 ± 1.31 ng/ml, respectively). Linear regression models for each predictor variable adjusted for age and sex showed that SIRT1 concentration was inversely and significantly correlated with EFT, fat mass %, liver fat content, BMR, weight, BMI, WC, LDL-cholesterol, insulin, ESR. Stepwise multiple regression analysis revealed that age and EFT were the best independent correlates of SIRT1 (β = -0.026 ± 0.011, p = 0.025, and β = -0.516 ± 0.083, p < 0.001, respectively). Conclusions: Plasma SIRT1 shows a continuous pattern that inversely follows the whole spectrum of adiposity. SIRT1 significantly associates with EFT, a strong index of visceral fat phenotype, better than other indexes of adiposity studied here

How to assess appearance distress and motivation in plastic surgery candidates: Italian validation of Derriford Appearance Scale 59 (DAS 59)

The Derriford Appearance Scale (DAS) 59 was specifically designed to measure psychosocial adjustment in patients with appearance problems. Previous studies using the DAS59 have proven it to be a reliable method of assessing the appearance-related quality of life after plastic surgery procedures. The aim of this study was to develop a valid and reliable Italian version of the DAS59

Disentangling elastic and inelastic scattering pathways in the intersubband electron dynamics of n -type Ge/SiGe quantum fountains

n-type Ge/SiGe quantum wells have been suggested as a promising platform for the realization of a Si-compatible THz laser. Focusing on this material system, we have developed a numerical model to describe the intersubband carrier dynamics which restores the equilibrium after pulsed optical excitation in asymmetric coupled Ge/SiGe quantum wells. We take into account inelastic and elastic scattering processes and investigate different quantum-well geometries, doping densities, and excitation regimes. In this configuration space, we disentangle the effect on the overall dynamics of each scattering channel and provide intersubband relaxation times, finding larger values with respect to III-V based materials, thanks to the weaker electron-phonon coupling with respect to III-V compounds. Finally, the model is used to study and optimize the population inversion between the first- and second-excited subband levels and to assess its dependence on the lattice temperature, providing a sound theoretical framework to guide forthcoming experiments

Transposable element activation promotes neurodegeneration in a Drosophila model of Huntington's disease

Huntington's disease (HD) is an autosomal dominant disorder with progressive motor dysfunction and cognitive decline. The disease is caused by a CAG repeat expansion in the IT15 gene, which elongates a polyglutamine stretch of the HD protein, Huntingtin. No therapeutic treatments are available, and new pharmacological targets are needed. Retrotransposons are transposable elements (TEs) that represent 40% and 30% of the human and Drosophila genomes and replicate through an RNA intermediate. Mounting evidence suggests that mammalian TEs are active during neurogenesis and may be involved in diseases of the nervous system. Here we show that TE expression and mobilization are increased in a Drosophila melanogaster HD model. By inhibiting TE mobilization with Reverse Transcriptase inhibitors, polyQ-dependent eye neurodegeneration and genome instability in larval brains are rescued and fly lifespan is increased. These results suggest that TE activation may be involved in polyQ-induced neurotoxicity and a potential pharmacological target

Wettability of soft PLGA surfaces predicted by experimentally augmented atomistic models

A challenging topic in surface engineering is predicting the wetting properties of soft interfaces with different liquids. However, a robust computational protocol suitable for predicting wettability with molecular precision is still lacking. In this article, we propose a workflow based on molecular dynamics simulations to predict the wettability of polymer surfaces and test it against the experimental contact angle of several polar and nonpolar liquids, namely water, formamide, toluene, and hexane. The specific case study addressed here focuses on a poly(lactic-co-glycolic acid) (PLGA) flat surface, but the proposed experimental-modeling protocol may have broader fields of application. The structural properties of PLGA slabs have been modeled on the surface roughness determined with microscopy measurements, while the computed surface tensions and contact angles were validated against standardized characterization tests, reaching a discrepancy of less than 3% in the case of water. Overall, this work represents the initial step toward an integrated multiscale framework for predicting the wettability of more complex soft interfaces, which will eventually take into account the effect of surface topology at higher scales and synergically be employed with experimental characterization techniques

Atomic-Scale Insights into Semiconductor Heterostructures: From Experimental Three-Dimensional Analysis of the Interface to a Generalized Theory of Interfacial Roughness Scattering

In this manuscript, we develop a generalized theory for the scattering process produced by interface roughness on charge carriers that is suitable for any semiconductor heterostructure. By exploiting our experimental insights into the three-dimensional atomic landscape of Ge/Ge-Si heterointerfaces obtained by atom probe tomography, we are able to define the full set of interface parameters relevant to the scattering potential, including both the in-plane and axial correlation inside real diffuse interfaces. Our experimental findings indicate a partial coherence of the interface roughness along the growth direction within the interfaces. We show that it is necessary to include this feature, previously neglected by theoretical models, when heterointerfaces characterized by finite interface widths are taken into consideration. To show the relevance of our generalized scattering model in the physics of semiconductor devices, we implement it in a nonequilibrium Green's function simulation platform to assess the performance of a Ge/Si-Ge-based terahertz quantum cascade laser

Indirect basal metabolism estimation in tailoring recombinant human TSH administration in patients affected by differentiated thyroid cancer: A hypothesis-generating study

Purpose: Recombinant human TSH (rhTSH) is currently used in follow-up of patients affected by differentiated thyroid cancer (DTC). Age, sex, weight, body mass index, body surface area (BSA) and renal function are known factors affecting serum TSH peak levels, but the proper rhTSH dose to deliver to single patient remains elusive. In this study, the correlations of basal metabolic rates with serum TSH peak following rhTSH administration were investigated.Methods: We evaluated 221 patients affected by thyroid cancer that received a standard dose rhTSH. Blood samples were collected at pre-established time points. Data on body weight, height, and BSA were collected. The Mifflin-St Jeor and Fleisch equations were used to assess basal metabolism.Results: The median value (range) of serum TSH peaks was 142 +/- 53 mu U/ml. Serum TSH peaks were significantly lower in males than in females (p = 0.04). TSH values also increased with age. Data showed a significant decrease of TSH peak levels at day 3 from the administration of rhTSH when basal metabolic rates increased (p = 0.002 and p = 0.009, respectively). Similar findings were observed at day 5 (p = 0.004 and p = 0.04, respectively). A multivariate analysis of several factors revealed that patients' basal metabolism (obtained using the Mifflin-St Jeor but not Fleisch equation) predicts serum TSH level peak at day 3 (p &lt; 0.001). These results were used to generate a new formula based on Mifflin-StJeor equation which reveals as a promising tool in tailoring rhTSH dose.Conclusion: Basal metabolism appears an improving factor in tailoring diagnostic rhTSH dose in patients affected by DTC

A human minisatellite hosts an alternative transcription start site for NPRL3 driving its expression in a repeat number-dependent manner

Minisatellites, also called variable number of tandem repeats (VNTRs), are a class of repetitive elements that may affect gene expression at multiple levels and have been correlated to disease. Their identification and role as expression quantitative trait loci (eQTL) have been limited by their absence in comparative genomic hybridization and single nucleotide polymorphisms arrays. By taking advantage of cap analysis of gene expression (CAGE), we describe a new example of a minisatellite hosting a transcription start site (TSS) which expression is dependent on the repeat number. It is located in the third intron of the gene nitrogen permease regulator like protein 3 (NPRL3). NPRL3 is a component of the GAP activity toward rags 1 protein complex that inhibits mammalian target of rapamycin complex 1 (mTORC1) activity and it is found mutated in familial focal cortical dysplasia and familial focal epilepsy. CAGE tags represent an alternative TSS identifying TAGNPRL3 messenger RNAs (mRNAs). TAGNPRL3 is expressed in red blood cells both at mRNA and protein levels, it interacts with its protein partner NPRL2 and its overexpression inhibits cell proliferation. This study provides an example of a minisatellite that is both a TSS and an eQTL as well as identifies a new VNTR that may modify mTORC1 activity

Changes in gene expression in human skeletal stem cells transduced with constitutively active Gs\u3b1 correlates with hallmark histopathological changes seen in fibrous dysplastic bone

Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the \u3b1 subunit of the G protein-coupled receptor complex (Gs\u3b1). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (Gs\u3b1R201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the Gs\u3b1R201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets