Type 3 Deiodinase and Consumptive Hypothyroidism: A Common Mechanism for a Rare Disease

The major product secreted by the thyroid is thyroxine (T4), whereas most of the biologically active triiodothyronine (T3) derives from the peripheral conversion of T4 into T3. The deiodinase enzymes are involved in activation and inactivation of thyroid hormones (THs). Type 1 and type 2 deiodinase (D1 and D2) convert T4 into T3 whereas D3 degrades T4 and T3 into inactive metabolites and is thus the major physiological TH inactivator. The hypothalamic-pituitary-thyroid axis maintains circulating TH levels constant, while the deiodinases tissue-specifically regulate intracellular thyroid status by controlling TH action in a precise spatio-temporal fashion. Here we review the data related to the recent identification of a paraneoplastic syndrome called “consumptive hypothyroidism,” which exemplifies how deiodinases alter substantially the concentration of TH in blood. This syndrome results from the aberrant uncontrolled expression of D3 that can induce a severe form of hypothyroidism by inactivating T4 and T3 in defined tumor tissue. This rare TH insufficiency generally affects patients in the first years of life, and has distinct features in terms of diagnosis, treatment, and prognosis with respect to other forms of hypothyroidism

analysis of crack trapping in 3d printed bio inspired structural interfaces

Abstract Specific features of biological materials, such as microstructure, heterogeneities or hybrid compositions, already inspired the fabrication of several architected materials. More recently, special emphasis has been placed on the development of damage tolerant interfaces by introducing tailored surface heterogeneities. However, thanks to the current developments in the area of additive manufacturing, the mating substrates can be now fashioned into complex shapes to confer the desired joint behavior. By taking inspiration from the base plate of the Balanus Amphitrite, we recently employed 3D printing to fabricate bio-inspired structural interfaces and adhesive bonded Double Cantilever Beam (DCB) fracture specimens. The results of DCB tests have shown a remarkable increase in the total dissipated energy with respect to baseline samples. In this work we supplement our previous study by performing finite element simulations in order to ascertain the variation of the driving force as a function of crack advance. The obtained results, which are analyzed in conjunction with high resolution imaging of the crack propagation process, allow to further elucidate the mechanics of debonding. It is shown that the sub-surface channels can modulate the driving force available for crack growth, introducing a crack trapping ability which depends on the specific geometry of the interfacial region

analysis of debonding in bio inspired interfaces obtained by additive manufacturing

Abstract The present work is focused on the analysis of fracture in adhesive bonded Double Cantilever Beam (DCB) specimens with 3D printed nylon substrates. The substrates were obtained using selective laser sintering of polyamide powder and embed sub-surface channels with circular and square cross-section. The proposed strategy allows to mimic the crack trapping effect already observed in a multitude of biological materials, that is originated by the spatial modulation of the driving force available for crack growth. Mechanical tests have shown that the channels induce load fluctuations in the global load-displacement response. A significant increase in the total dissipated energy was observed with respect to bulk samples, i.e. no channels. The observed fluctuations in the global response were associated to the sequential storage and sudden release of elastic energy. Indeed, the spatial modulation of the stiffness around the interfacial region ultimately affects the crack driving force

COUP-TFI promotes radial migration and proper morphology of callosal projection neurons by repressing Rnd2 expression

During corticogenesis, late-born callosal projection neurons (CPNs) acquire their laminar position through glia-guided radial migration and then undergo final differentiation. However, the mechanisms controlling radial migration and final morphology of CPNs are poorly defined. Here, we show that in COUP-TFI mutant mice CPNs are correctly specified, but are delayed in reaching the cortical plate and have morphological defects during migration. Interestingly, we observed that the rate of neuronal migration to the cortical plate normally follows a low-rostral to high-caudal gradient, similar to that described for COUP-TFI. This gradient is strongly impaired in COUP-TFI–/– brains. Moreover, the expression of the Rho-GTPase Rnd2, a modulator of radial migration, is complementary to both these gradients and strongly increases in the absence of COUP-TFI function. We show that COUP-TFI directly represses Rnd2 expression at the post-mitotic level along the rostrocaudal axis of the neocortex. Restoring correct Rnd2 levels in COUP-TFI–/– brains cell-autonomously rescues neuron radial migration and morphological transitions. We also observed impairments in axonal elongation and dendritic arborization of COUP-TFI-deficient CPNs, which were rescued by lowering Rnd2 expression levels. Thus, our data demonstrate that COUP-TFI modulates late-born neuron migration and favours proper differentiation of CPNs by finely regulating Rnd2 expression levels

Cheese whey recycling in traditional dairy food chain: effects of vinegar from whey in dairy cow nutrition

Selected yeast (Kluyveromyces marxianus Y102 strain) and an acetic acid bacterium (Acetobacter aceti, DSM-G3508 strain) were used as inocula respectively in cheese whey for alcoholic and acetic fermentations. The experimental tests were carried out at both laboratory and pilot plant (20 L and 2000 L) levels. The data from the trials (working period 28 days) show increased ethanol production, increased acetic acid yield, and greater fermentation stability with biomass recycling (18.6 g L–1). Batch and fed-batch fermentation tests resulted in increased and standardized alcoholic fermentation, and allowed acetic acid recovery (average lactose consumption 56%, ethanol 6.7 g L–1 d–1 and acetic acid production 4.35 g L–1 d–1). The effects administration were then investigated on milk yield and composition, nutritional status of dairy cows and physical characteristics of total mixed ration (TMR). Twenty Holstein cows were divided into two groups; group C, receiving the traditional TMR, and group W, receiving the TMR plus 10 L wheynegar. The dietary treatment, lasted 35 days, did not affect milk yield and composition except for the urea content, significantly lowered in group W. The selection of coarse (<19 mm), medium (8-19 mm) and fine (<8 mm) dietary particles was not influenced by the wheynegar administration however a tendential lower selection against coarse particles was noted in W. The results highlight that microbial biotechnologies may significantly contribute to both the valorization of whey and the development of a stable nutrient recycling system as a ingredient in dairy cattle diet

Identification of single nucleotide polymorphisms in Toll-like receptor candidate genes associated with tuberculosis infection in water buffalo (Bubalus bubalis)

Toll-like receptors play a key role in innate immunity by recognizing pathogens and activating appropriate responses. Pathogens express several signal molecules (pathogen-associated molecular patterns, PAMPs) essential for survival and pathogenicity. Recognition of PAMPs triggers an array of anti-microbial immune responses through the induction of various inflammatory cytokines. The objective of this work was to perform a case-control study to characterize the distribution of polymorphisms in three candidate genes (toll-like receptor 2, toll-like receptor 4, toll-like receptor 9) and to test their role as potential risk factors for tuberculosis infection in water buffalo (Bubalus bubalis)

Different ways to manage Indocyanine green fluorescence to different purposes in liver surgery. A systematic review.

Fluorescent properties of indocyanine green (ICG) for hepatic tumor identification and features have been recently studied. The aim is to review the published data on the use of ICG enhanced fluorescence surgery during liver resection. A systematic search of literature was performed using MEDLINE, EMBASE, Cochrane and Web of Science libraries. For all eligible studies, the following data were extracted: study design, number of cases, management of indocyanine green (dose, time and method of administration), type of surgery, outcome variables, false positive and accuracy value, if reported. For statistical analysis, it was considered significant P<0.05, when published. 19 articles were fully analyzed and data were extracted. A total of 718 cases were globally analyzed as study group. No side effects of ICG were reported in any articles. 12 prospective observational, 1 randomized and 2 case-control studies were found. Three case reports and one experimental on animal model were also included. Detection of superficial lesions, segmental staining, biliary anatomy investigation (biliary leakage detection, biliary tree anatomy) were the main clinical application of fluorescence liver guided surgery. The overall quality of the data currently available is limited but the role of fluorescence guided liver surgery seems promising

Analysis of the interaction with the hepatitis C virus mRNA reveals an alternative mode of RNA recognition by the human La protein

Human La protein is an essential factor in the biology of both coding and non-coding RNAs. In the nucleus, La binds primarily to 3′ oligoU containing RNAs, while in the cytoplasm La interacts with an array of different mRNAs lacking a 3′ UUUOH trailer. An example of the latter is the binding of La to the IRES domain IV of the hepatitis C virus (HCV) RNA, which is associated with viral translation stimulation. By systematic biophysical investigations, we have found that La binds to domain IV using an RNA recognition that is quite distinct from its mode of binding to RNAs with a 3′ UUUOH trailer: although the La motif and first RNA recognition motif (RRM1) are sufficient for high-affinity binding to 3′ oligoU, recognition of HCV domain IV requires the La motif and RRM1 to work in concert with the atypical RRM2 which has not previously been shown to have a significant role in RNA binding. This new mode of binding does not appear sequence specific, but recognizes structural features of the RNA, in particular a double-stranded stem flanked by single-stranded extensions. These findings pave the way for a better understanding of the role of La in viral translation initiation

Pharmacological inhibition of CDK4/6 impairs diffuse pleural mesothelioma 3D spheroid growth and reduces viability of cisplatin-resistant cells

IntroductionDiffuse pleural mesothelioma (DPM) of the pleura is a highly aggressive and treatment-resistant cancer linked to asbestos exposure. Despite multimodal treatment, the prognosis for DPM patients remains very poor, with an average survival of 2 years from diagnosis. Cisplatin, a platinum-based chemotherapy drug, is commonly used in the treatment of DPM. However, the development of resistance to cisplatin significantly limits its effectiveness, highlighting the urgent need for alternative therapeutic strategies. New selective inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have shown promise in various malignancies by inhibiting cell cycle progression and suppressing tumor growth. Recent studies have indicated the potential of abemaciclib for DPM therapy, and a phase II clinical trial has shown preliminary encouraging results.MethodsHere, we tested abemaciclib, palbociclib, and ribociclib on a panel of DPM cell lines and non-tumor mesothelial(MET-5A) cells.ResultsSpecifically, we focused on abemaciclib, which was the mosteffective cytotoxic agent on all the DPM cell lines tested. Abemaciclib reduced DPM cell viability, clonogenic potential, and ability to grow as three-dimensional (3D) spheroids. In addition, abemaciclib induced prolonged effects, thereby impairing second-generation sphere formation and inducing G0/G1 arrest and apoptosis/ necrosis. Interestingly, single silencing of RB family members did not impair cell response to abemaciclib, suggesting that they likely complement each other in triggering abemaciclib’s cytostatic effect. Interestingly, abemaciclib reduced the phosphorylation of AKT, which is hyperactive in DPM and synergized with the pharmacological AKT inhibitor (AKTi VIII). Abemaciclib also synergized with cisplatin and reduced the viability of DPM cells with acquired resistance to cisplatin.DiscussionOverall, our results suggest that CDK4/6 inhibitors alone or in combination with standard of care should be further explored for DPM therapy