FUS mutant human motoneurons display altered transcriptome and microRNA pathways with implications for ALS pathogenesis

The FUS gene has been linked to amyotrophic lateral sclerosis (ALS). FUS is a ubiquitous RNA-binding protein, and the mechanisms leading to selective motoneuron loss downstream of ALS-linked mutations are largely unknown. We report the transcriptome analysis of human purified motoneurons, obtained from FUS wild-type or mutant isogenic induced pluripotent stem cells (iPSCs). Gene ontology analysis of differentially expressed genes identified significant enrichment of pathways previously associated to sporadic ALS and other neurological diseases. Several microRNAs (miRNAs) were also deregulated in FUS mutant motoneurons, including miR-375, involved in motoneuron survival. We report that relevant targets of miR-375, including the neural RNA-binding protein ELAVL4 and apoptotic factors, are aberrantly increased in FUS mutant motoneurons. Characterization of transcriptome changes in the cell type primarily affected by the disease contributes to the definition of the pathogenic mechanisms of FUS-linked ALS

Vincenzo Cardarelli e Sibilla Aleramo: l’epistolario della disillusione

Vincenzo Cardarelli (all’anagrafe Nazareno Caldarelli) ha trentotto anni. Sa bene che, quando la vita volge vorticosamente verso il quarto decennio, è il tempo dei bilanci. Passa in rassegna ciò che è accaduto, ciò che non è accaduto e ciò che sarebbe potuto accadere. Posiziona sui piatti della bilancia i momenti di felicità e i momenti di sconforto. E valuta il valore da assegnare alla speranza, quella che per il credente è la virtù teologica per la quale ci si aspetta da Dio il soccorso in questa vita e la felicità eterna nell’altra. Nel silenzio assordante del vuoto del mattino, si abbandona alla propria memoria. La speranza è ormai perduta. Forse, mai neanche posseduta realmente. La sua prima vita, quella vissuta, è una vita fragile, solo sfiorata, come l’acqua dai gabbiani. La sua seconda vita, quella desiderata, è una vita in burrasca. È tra questi due poli che si muove, costantemente, la voce di Vincenzo Cardarelli

Role of Scaffold Protein Proline-, Glutamic Acid-, and Leucine-Rich Protein 1 (PELP1) in the Modulation of Adrenocortical Cancer Cell Growth

PELP1 acts as an estrogen receptor (ER) coactivator that exerts an essential role in the ER's functions. ER coregulators have a critical role in the progression and response to hormonal treatment of estrogen-dependent tumors. We previously demonstrated that, in adrenocortical carcinoma (ACC), ER\u3b1 is upregulated and that estradiol activates the IGF-II/IGF1R signaling pathways defining the role of this functional cross-talk in H295R ACC cell proliferation. The aim of this study was to determine if PELP1 is expressed in ACC and may play a role in promoting the interaction between ER\u3b1 and IGF1R allowing the activation of pathways important for ACC cell growth. The expression of PELP1 was detected by Western blot analysis in ACC tissues and in H295R cells. H295R cell proliferation decrease was assessed by A3-(4,5-Dimethylthiaoly)-2,5-diphenyltetrazolium bromide (MTT) assay and [3H] thymidine incorporation. PELP1 is expressed in ACC tissues and in H295R cells. Moreover, treatment of H295R with E2 or IGF-II induced a multiprotein complex formation consisting of PELP1, IGF1R, ER\u3b1, and Src that is involved in ERK1/2 rapid activation. PELP1/ER/IGF1R/c-Src complex identification as part of E2- and IGF-II-dependent signaling in ACC suggests PELP1 is a novel and more efficient potential target to reduce ACC growth

Identifying conformational changes with site-directed spin labeling reveals that the GTPase domain of HydF is a molecular switch

[FeFe]-hydrogenases catalyse the reduction of protons to hydrogen at a complex 2Fe[4Fe4S] center called H-cluster. The assembly of this active site is a multistep process involving three proteins, HydE, HydF and HydG. According to the current models, HydF has the key double role of scaffold, upon which the final H-cluster precursor is assembled, and carrier to transfer it to the target hydrogenase. The X-ray structure of HydF indicates that the protein is a homodimer with both monomers carrying two functional domains: a C-terminal FeS cluster-binding domain, where the precursor is assembled, and a N-terminal GTPase domain, whose exact contribution to cluster biogenesis and hydrogenase activation is still elusive. We previously obtained several hints suggesting that the binding of GTP to HydF could be involved in the interactions of this scaffold protein with the other maturases and with the hydrogenase itself. In this work, by means of site directed spin labeling coupled to EPR/PELDOR spectroscopy, we explored the conformational changes induced in a recombinant HydF protein by GTP binding, and provide the first clue that the HydF GTPase domain could be involved in the H-cluster assembly working as a molecular switch similarly to other known small GTPases

Implementation of a cogeneration plant for a food processing facility. A case study

The present work presents an investigation regarding the feasibility analysis of a cogeneration plant for a food processing facility with the aim to decrease the cost of energy supply. The monthly electricity and heat consumption profiles are analyzed, in order to understand the consumption profiles, as well as the costs of the current furniture of electricity and gas. Then, a detailed thermodynamic model of the cogeneration cycle is implemented and the investment costs are linked to the thermodynamic variables by means of cost functions. The optimal electricity power of the co-generator is determined with reference to various investment indexes. The analysis highlights that the optimal dimension varies according to the chosen indicator, therefore it is not possible to establish it univocally, but it depends on the financial/economic strategy of the company through the considered investment index

Cervical spine sagittal alignment variations following posterior spinal fusion and instrumentation for adolescent idiopathic scoliosis

The aim of this study is to quantify the changes in the sagittal alignment of the cervical spine in patients with adolescent idiopathic scoliosis following posterior spinal fusion. Patients eligible for study inclusion included those with a diagnosis of mainly thoracic adolescent idiopathic scoliosis treated by means of posterior multisegmented hook and screw instrumentation. Pre and post-operative anterior-posterior and lateral radiographs of the entire spine were reviewed to assess the changes of cervical sagittal alignment. Thirty-two patients (3 boys, 29 girls) met the inclusion criteria for the study. The average pre-operative cervical sagittal alignment (CSA) was 4.0°±12.3° (range −30° to 40°) of lordosis. Postoperatively, the average CSA was 1.7°±11.4° (range −24° to 30°). After surgery, it was less than 20° in 27 patients (84.4%) and between 20° and 40° in 5 patients (15.6%). The results of the present study suggest that even if rod precontouring is performed and postoperative thoracic sagittal alignment is restored, improved or remains unchanged after significant correction of the deformity on the frontal plane, the inherent rigidity of the cervical spine limits changes in the CSA as the cervical spine becomes rigid over tim

Rudolf Virchow: 200th birth anniversary

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Diffusion-weighted imaging findings in Perthes disease with dynamic gadolinium-enhanced subtracted (DGS) MR correlation: a preliminary study

Background: Legg-Calvé-Perthes disease (LCP) is necrosis of the proximal femoral epiphysis of vascular origin. Clinical course and outcome in LCP disease varies considerably between different patients. Earlier prognostic criteria than those offered by conventional radiography are necessary to identify children who require prompt surgical treatment. Objective: To assess the significance of signal alteration on diffusion-weighted MR imaging (DWI MR) in LCP. Materials and methods: Twelve boys with unilateral LCP disease (Catterall grade 2 and 3), at the initial sclerotic stage and early fragmentation phase, underwent dynamic gadolinium-enhanced subtracted (DGS) and DWI MR. For DGS MR, the lateral pillar enhancement was recorded. For DWI imaging, we measured ADC values in the diseased and the unaffected epiphyses and metaphyses. Receiver operating characteristic curves were performed to analyze the performance of DWI in establishing agreement with the results of DGS MR, which is the gold standard for prognosis. Results: Femoral epiphysis increased diffusivity was observed in the affected hip in all cases. Increased metaphysis diffusivity in the affected side was observed in all cases with absent lateral pillar enhancement at DGS MR. Conclusion: DWI seems to be a noninvasive means of distinguishing between Perthes disease with favourable and unfavourable prognosi

Suggestive evidence of a multi-cytokine resistin pathway in humans and its role on cardiovascular events in high-risk individuals

In cells and tissues resistin affects IL-1β, IL-6, IL-8, IL-12 and TNF-α expression, thus suggesting the existence of a multi-cytokine "resistin pathway". We investigated whether such pathway does exist in humans and, if so, if it is associated with cardiovascular risk factors and with major adverse cardiovascular events (MACE). Serum cytokines were measured in 280 healthy subjects from the Gargano Study 2 (GS2) whose BMI, waist circumference, HOMA IR, triglycerides, HDL-cholesterol, systolic and diastolic blood pressure data were available and in 353 patients with type 2 diabetes and coronary artery disease from the Gargano Heart Study (GHS)-prospective design (follow-up 5.4 ± 2.5 years; 71 MACE). In GS2, cytokines mRNA levels in white blood cells were also measured. In GS2, resistin mRNA was correlated with all cytokines expression (all p < 0.001), but IL-12B. Consistently, serum resistin was correlated with all serum cytokines (all p < 0.001), but IL-12. Expression (eRPS) and serum (sRPS) resistin pathway scores (excluding IL-12) were each other correlated (p < 0.001) and both associated with cardiovascular risk factors (all p < 0.01). In GHS, sRPS was independently associated with MACE (HR = 1.44, 95% CI = 1.10-1.90). Our data indicate the existence of a resistin pathway, which is associated with cardiovascular risk factors and which strongly and independently predicts MACE