Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress

Solid tumors exhibit heterogeneous microenvironments, often characterized by limiting concentrations of oxygen (O₂), glucose, and other nutrients. How oncogenic mutations alter stress response pathways, metabolism, and cell survival in the face of these challenges is incompletely understood. Here we report that constitutive mammalian target of rapamycin complex 1 (mTORC1) activity renders hypoxic cells dependent on exogenous desaturated lipids, as levels of de novo synthesized unsaturated fatty acids are reduced under low O₂. Specifically, we demonstrate that hypoxic Tsc2^−/− (tuberous sclerosis complex 2^−/−) cells deprived of serum lipids exhibit a magnified unfolded protein response (UPR) but fail to appropriately expand their endoplasmic reticulum (ER), leading to inositol-requiring protein-1 (IRE1)-dependent cell death that can be reversed by the addition of unsaturated lipids. UPR activation and apoptosis were also detected in Tsc2-deficient kidney tumors. Importantly, we observed this phenotype in multiple human cancer cell lines and suggest that cells committed to unregulated growth within ischemic tumor microenvironments are unable to balance lipid and protein synthesis due to a critical limitation in desaturated lipids.     

Does the choice of the reference model affect the results of 3D-3D superimposition procedure? A comparison of different protocols for personal identification

International Journal of Legal Medicine - In literature, 3D-3D superimposition has been widely recognized as a valid method for personal identification. However, very little information is...     

Ankle proprioception,range of motion and drop landing ability differentiates competitive and non-competitive surfers

ObjectivesTo determine whether ankle proprioception differs by competitive level and is related to years of surf-specific experience. A secondary objective of this study is to further compare the physical capacities and abilities that may differentiate between the competitive levels of surfing.DesignCross-sectional.MethodsTwelve junior-elite (currently competing at a state level or higher and 12–18 years of age), twelve senior-elite (currently competing at a national level and/or the World Qualifying Series and over 16 years of age), and twelve recreational surfers (minimum of two years surfing experience; actively surfing at least once a week and over 18 years of age) were recruited for this study. All participants completed a pre-exercise medical questionnaire, anthropometric assessment, ankle dorsiflexion range of motion assessment, medial-lateral ankle proprioception assessment, countermovement jump, squat jump, isometric mid-thigh pull and drop-and-stick.ResultsSenior-elite surfers had large and significantly better ankle proprioception and range of motion than junior-elite and recreational surfers. However, the relationship between years of surf-specific experience and ankle proprioception was small and non-significant. Better drop-and-stick performance, indicated by lower relative peak force, was present in the senior-elite compared to the junior-elite and recreational groups.ConclusionsThe results indicate that medial-lateral ankle proprioception is a distinguishing characteristic of senior-elite surfers and therefore, may be a critical ability for competitive success. Greater ankle range of motion and the ability to attenuate energy to reduce landing force may be developed through long-term training commensurate with competitive surfing.     

The Effects of Inattention/Impulsivity and Aggression on the Development of Toddlers with Autism Spectrum Disorder

Autism spectrum disorder (ASD) frequently co-occurs with additional symptoms of psychopathology and challenging behaviors. While aggressive behaviors are often associated with attention deficits and hyperactivity in children with ASD, there is limited research on the impact that inattention/impulsivity and aggressive behaviors have on the developmental functioning of toddlers with ASD. However, identifying comorbidities is necessary for proper intervention. The aim of the current study was to examine the effects of inattention/impulsivity and aggressive behaviors on several domains of developmental functioning in infants and toddlers with ASD as measured by the Battelle Developmental Inventory, Second Edition (BDI-2). This study compared four groups consisting of 29 toddlers each: without inattention/impulsivity or aggressive behaviors (i.e., -I/-A), with inattention/impulsivity but without aggressive behaviors (i.e.,?+?I/-A), without inattention/impulsivity but with aggressive behaviors (i.e., –I/?+?A), and with both inattention/impulsivity and aggressive behaviors (i.e.,?+?I/?+?A). The results of the current study revealed significant group differences in Personal-Social, Communication, Motor, and Cognitive domains of the BDI-2. The significance and implications of the present study are discussed.

     

Higher Glucocorticoid Secretion in the Physiological Range Is Associated With Lower Bone Strength at the Proximal Radius in Healthy Children: Importance of Protein Intake Adjustment

Whether higher production of glucocorticoids (GCs) within the physiological range may already be affecting bone status in healthy children is unknown. Because dietary protein intake affects both bone and GCs, we examined the association of urinary measures of glucocorticoid status and cortical bone in healthy non‐obese children, after particularly controlling for protein intake. Proximal forearm bone parameters were measured by peripheral quantitative computed tomography (pQCT). Subjects studied (n = 175, 87 males, aged 6 to 18 years) had two 24‐hour urine samples collected: the first sample at 1 year before bone measurement, and the second sample at the time of bone measurement. Major urinary GC metabolites were measured by mass spectrometry and summed to assess daily adrenal GC secretion (∑C21). Urinary free cortisol (UFF) and cortisone (UFE) were summed to assess potentially bioactive free GCs (UFF + UFE). After controlling for several covariates and especially urinary nitrogen (the biomarker of protein intake) cortisol secretion ∑C21 was inversely associated with all analyzed pQCT measures of bone quality. ∑C21 also predicted a higher endosteal and lower periosteal circumference, explaining both a smaller cortical area and (together with lower BMD) a lower strength‐strain‐index (SSI). UFF + UFE, UFE itself, and a urinary metabolite‐estimate of 11beta‐hydroxysteroid dehydrogenase type1 (11beta‐HSD1) activity showed corresponding reciprocal associations (p < 0.05) with BMD and bone mineral content, but not with SSI and bone geometry variables. In conclusion, higher GC levels, even within the physiological range, appear to exert negative influences on bone modeling and remodeling already during growth. Our physiological data also suggest a relevant role of cortisone as the direct source for intracrine‐generated cortisol by bone cell 11beta‐HSD1. © 2014 American Society for Bone and Mineral Research.     

One-pot synthesis of enantiopure syn-1,3-diacetates from racemic syn/anti mixtures of 1,3-diols by dynamic kinetic asymmetric transformation

A one-pot synthesis of enantiomerically pure syn-1,3-diacetates starting from readily accessible racemic diastereomeric mixtures of 1,3-diols has been realized by combining (i) enzymatic transesterification, (ii) ruthenium-catalyzed epimerization of a secondary alcohol in a diol or diol monoacetate, and (iii) intramolecular acyl migration in a syn-1,3-diol monoacetate. The in situ coupling of these three processes results in an efficient enantioselective synthesis of acyclic syn-1,3-diacetates via combined deracemization-deepimerization and constitutes a dynamic kinetic asymmetric transformation concept. Several differently substituted unsymmetrical, acyclic syn-1,3-diacetates were obtained in yields up to 73% with excellent enantioselectivities (>99%) and good diastereomeric ratios (>90% syn).     

Cholesterol feeding of mice expressing cholesterol 7alpha-hydroxylase increases bile acid pool size despite decreased enzyme activity

Dietary cholesterol regulation of cholesterol 7alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classical pathway of bile acid synthesis, has been implicated in plasma cholesterol responsiveness. In the current study, the effects of 0.0% and 0.5% cholesterol diets were examined in Cyp7a1 knockout (KO), heterozygous Cyp7a1 KO (Het), and human Cyp7a1 transgenic mice on the mouse Cyp7a1 KO background (Tg+KO). We confirmed previous findings that dietary cholesterol increased mouse Cyp7a1 activity in Het mice but decreased human Cyp7a1 activity in Tg+KO mice. However, in both Het and Tg+KO mice, dietary cholesterol increased bile acid pool size (36% and 72%, respectively) and fecal bile acid excretion (2.2- and 3.6-fold, respectively). The expression of cholesterol 27-hydroxylase (Cyp27), the major enzyme of the alternative pathway of bile acid synthesis, was not significantly different in cholesterol-fed KO, Het, or Tg+KO mice. Furthermore, dietary cholesterol had comparable effects on total plasma cholesterol and non-high-density lipoprotein cholesterol in KO, Het, and Tg+KO mice. Thus, in Tg+KO mice, dietary cholesterol regulates bile acid pool size, fecal bile acid excretion, and plasma cholesterol independently of Cyp7a1 activity. These results challenge the notion that dietary cholesterol regulation of Cyp7a1 is a major determinant of plasma cholesterol responsiveness.