The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability

In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. We found that increased neutral essential amino acid (NEAA) uptake was a critical component of erythropoiesis. As red blood cells matured, expression of the amino acid transporter gene Lat3 increased, which increased NEAA import. Inadequate NEAA uptake by pharmacologic inhibition or RNAi-mediated knockdown of LAT3 triggered a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells through the mTORC1 (mammalian target of rapamycin complex 1)/4E-BP (eukaryotic translation initiation factor 4E–binding protein) pathway. CRISPR-mediated deletion of members of the 4E-BP family in murine erythroid cells rendered them resistant to mTORC1 and LAT3 inhibition and restored hemoglobin production. These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine.National Institutes of Health (U.S.) (P01 HL032262

Determinanti di salute nei migranti irregolari con patologie croniche: analisi degli accessi all’ambulatorio di una organizzazione non governativa [Health determinants in irregular migrants with chronic diseases: analysis of the accesses to the clinic of a non-governmental organization]

Introduction. Of the 112 thousand irregular migrants in Lombardy, 49 thousand reside in the area of Milan. Data on their health conditions and needs are scarce and fragmented, especially about their socio-demographic and clinical determinants. Aim. To describe the main socio-demographic and clinical characteristics of irregular migrants with chronic diseases who access the clinic of a non-governmental organization that provides primary care and their association with the number of accesses. Method. Retrospective observational study of a dataset containing information on irregular migrants with chronic diseases (N = 411) carried out at the Naga Onlus clinic in 2017. Results. The males come essentially from Africa and are often affected by back pain or low back pain (BP-LBP); females, mostly from East Europe or Central-South America, are frequently hypertensive. Up to 24 years of age, anxiety or depression prevails; at 25-44 years BP-LBP, at 45-64 years diabetes and in advanced age, hypertension. The knowledge of a EU language and the diagnosis of BP-LBP are respectively positively and negatively associated to the number of accesses. Discussion. Following the progressive aging with the increasing prevalence of chronic conditions, marginalization and stigma, the "healthy migrant" effect once characterizing irregular migrants is being replaced by the "exhausted migrant" effect and the assimilation of a state of health similar to that of native counterparts

Vegetable residues from garden-produce markets as recyclable biomass for high-quality compost production

A managed composting system based on static pile aeration with temperature feedback control by forced-pressure ventilation was used in order to verify the possibility to achieve the biological stabilisation of vegetable waste separately collected in a metropolitan garden-produce market. Performances of the composting technique adopted in processing these very wet fermentable residues are discussed here. Physico-chemical and biological analyses of the vegetable waste treated and characterisation of the humified organic fertilizer obtained are also reported with a mention to some phytopathogenic aspects associated with this compost production

Multiple determinants within iron-responsive elements dictate iron regulatory protein binding and regulatory hierarchy

Iron regulatory proteins (IRPs) are iron-regulated RNA binding proteins that, along with iron-responsive elements (IREs), control the translation of a diverse set of mRNA with 5′ IRE. Dysregulation of IRP action causes disease with etiology that may reflect differential control of IRE-containing mRNA. IREs are defined by a conserved stem–loop structure including a midstem bulge at C8 and a terminal CAGUGH sequence that forms an AGU pseudo-triloop and N19 bulge. C8 and the pseudo-triloop nucleotides make the majority of the 22 identified bonds with IRP1. We show that IRP1 binds 5′ IREs in a hierarchy extending over a ninefold range of affinities that encompasses changes in IRE binding affinity observed with human L-ferritin IRE mutants. The limits of this IRE binding hierarchy are predicted to arise due to small differences in binding energy (e.g., equivalent to one H-bond). We demonstrate that multiple regions of the IRE stem not predicted to contact IRP1 help establish the binding hierarchy with the sequence and structure of the C8 region displaying a major role. In contrast, base-pairing and stacking in the upper stem region proximal to the terminal loop had a minor role. Unexpectedly, an N20 bulge compensated for the lack of an N19 bulge, suggesting the existence of novel IREs. Taken together, we suggest that a regulatory binding hierarchy is established through the impact of the IRE stem on the strength, not the number, of bonds between C8 or pseudo-triloop nucleotides and IRP1 or through their impact on an induced fit mechanism of binding

Alexithymia partly predicts pain, poor health and social difficulties in patients with temporomandibular disorders

Temporomandibular disorders (TMD) are functional diseases of the masticatory system; their symptoms are clicking, difficulty opening the mouth wide, ear pain, facial pain and headaches. The relationships among distress, emotional factors and TMD are well known. It was shown that patients with TMD have little awareness of their inner states and emotions, and it was found that those reporting oro-facial pain presented higher alexithymia than did asymptomatic people. Other authors confirmed that alexithymia was higher in the painful TMD group than controls. This study was aimed to evaluate whether alexithymia and its components can be considered as predisposing factors for pain severity, poor health and greater social difficulties in patients with TMD. One hundred thirty-three patients received a diagnosis of TMD and completed the 20-item Toronto Alexithymia Scale. Multiple stepwise regressions showed that alexithymia and age explained 10% of the pain and 31% of poor health and also that alexithymia explained 7% of social difficulty. A direct comparison of patients with TMD based on alexithymia revealed a higher presence of pain in alexithymic patients with TMD than in those characterised by moderate or no alexithymia. In conclusion, alexithymia partly predicts pain, poor health and social difficulties in patients with TMD. Furthermore, alexithymic patients have more pain than those with moderate or low alexithymia

Effects of Bovine Somatotropin and Revalor-S® on Growth Performance and Carcass Leanness in Beef Cattle

Twenty crossbred steers were used to evaluate bovine somatotropin (bST) and an anabolic steroid implant, Revalor-S® (REV), to improve growth and increase carcass leanness. During the first 70 days on feed, bST-treated steers tended to improve live weight gains, consume more feed, and numerically improve feed utilization for growth. The implanted steers grew faster and utilized feed better than steers not implanted with REV. The improvement in gain and feed utilization for growth was maintained throughout the feeding period for REV-implanted steers. At slaughter, REV steers had heavier carcasses which resulted in more pounds of muscle, bone, and fat. When adjusted for hot carcass weight, bST increased leanness of the carcass as evident by the increased weight of the semitendinosus muscle, more pounds of dissected lean, and fewer pounds of dissected fat. Thus, REV and bST can be used to improve growth performance and increase carcass leanness

Selective Inhibition of Collagen Prolyl 4‑Hydroxylase in Human Cells

Collagen is the most abundant protein in animals. Its overproduction is associated with fibrosis and cancer metastasis. The stability of collagen relies on post-translational modifications, the most prevalent being the hydroxylation of collagen strands by collagen prolyl 4-hydroxylases (CP4Hs). Catalysis by CP4Hs enlists an iron cofactor to convert proline residues to 4-hydroxyproline residues, which are essential for the conformational stability of mature collagen. Ethyl 3,4-dihydroxybenzoate (EDHB) is commonly used as a “P4H” inhibitor in cells, but suffers from low potency, poor selectivity, and off-target effects that cause iron deficiency. Dicarboxylates of 2,2′-bipyridine are among the most potent known CP4H inhibitors but suffer from a high affinity for free iron. A screen of biheteroaryl compounds revealed that replacing one pyridyl group with a thiazole moiety retains potency and enhances selectivity. A diester of 2-(5-carboxythiazol-2-yl)­pyridine-5-carboxylic acid is bioavailable to human cells and inhibits collagen biosynthesis at concentrations that neither cause general toxicity nor disrupt iron homeostasis. These data anoint a potent and selective probe for CP4H and a potential lead for the development of a new class of antifibrotic and antimetastatic agents