An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease

friedreich ataxia (FRDA) is a life-threatening hereditary ataxia; its incidence is 1:50,000 individuals in the caucasian population. a unique therapeutic drug for FRDA, the antioxidant omaveloxolone, has been recently approved by the US food and drug administration (FDA). FRDA is a multi-systemic neurodegenerative disease; in addition to a progressive neurodegeneration, FRDA is characterized by hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. cardiomyopathy is the predominant cause of premature death. the onset of FRDA typically occurs between the ages of 5 and 15. given the complexity and heterogeneity of clinical features and the variability of their onset, the identification of biomarkers capable of assessing disease progression and monitoring the efficacy of treatments is essential to facilitate decision making in clinical practice. we conducted an RNA-seq analysis in peripheral blood mononuclear cells from FRDA patients and healthy donors, identifying a signature of small non-coding RNAs (sncRNAs) capable of distinguishing healthy individuals from the majority of FRDA patients. among the differentially expressed sncRNAs, microRNAs are a class of small non-coding endogenous RNAs that regulate posttranscriptional silencing of target genes. In FRDA plasma samples, hsa-miR-148a-3p resulted significantly upregulated. the analysis of the receiver operating characteristic (ROC) curve, combining the circulating expression levels of hsa-miR-148a-3p and hsa-miR-223-3p (previously identified by our group), revealed an area under the curve (AUC) of 0.86 (95%, confidence Interval 0.77-0.95; p-value < 0.0001). an in silico prediction analysis indicated that the IL6ST gene, an interesting marker of neuroinflammation in FRDA, is a common target gene of both miRNAs. our findings support the evaluation of combined expression levels of different circulating miRNAs as potent epi-biomarkers in FRDA. moreover, we found hsa-miR-148a-3p significantly over-expressed in Intermediate and late-onset friedreich ataxia patients' group (IOG and LOG, respectively) compared to healthy individuals, indicating it as a putative prognostic biomarker in this pathology

Photoconductive properties and electronic structure in 3,5-disubstituted 2-(2′-pyridyl)pyrroles coordinated to a Pd(II) salicylideneiminate synthon

The synthesis and the electrochemical, photophysical, structural, and photoconductive properties of three new heteroleptic Pd(II) complexes with various 3′,5′- disubstituted-2-(2′-pyridil) pyrroles H(N^N) as coordinated ligands are reported. The coordination of the metal center was completed by a functionalized Schiff base H(O^N) used as an ancillary ligand. The [(N^N)Pd(O^N)] complexes showed highly interesting photoconductive properties which have been correlated to their electronic and molecular structures. Theoretical density functional theory (DFT) and time-dependent DFT calculations were performed, and the results were confronted with the organization in crystalline phase, allowing to point out that the photoconductive properties are mainly a consequence of an efficient intramolecular ligand-to-metal charge transfer, combined to the proximity between the central metal and the donor moieties in the solid-state molecular stacks. The reported results confirm that these new Pd(II) complexes form a novel class of organometallic photoconductors with intrinsic characteristics suitable for molecular semiconductors applications.Supported by Ministero dell’Istruzione, dell’Universitàe della Ricerca by the ELIOTROPO.Peer reviewe

Paradoxical Increase in TAG and DAG Content Parallel the Insulin Sensitizing Effect of Unilateral DGAT1 Overexpression in Rat Skeletal Muscle

BACKGROUND: The involvement of muscle triacylglycerol (TAG) storage in the onset of insulin resistance is questioned and the attention has shifted towards inhibition of insulin signalling by the lipid intermediate diacylglycerol (DAG). The enzyme 1,2-acylCoA:diacylglyceroltransferase-1 (DGAT1) esterifies a fatty acyl-CoA on DAG to form TAG. Therefore, the aim of the present study was to investigate if unilateral overexpression of DGAT1 in adult rat Tibialis anterior (TA) muscle will increase conversion of the lipid intermediate DAG into TAG, thereby improving muscle insulin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: The DGAT1 gene construct was injected in the left TA muscle of male rats on chow or high-fat (45% kcal) diet for three weeks, followed by application of one 800 V/cm and four 80 V/cm pulses, using the contralateral leg as sham-electroporated control. Seven days after electroporation, muscle specific insulin sensitivity was assessed with a hyperinsulinemic euglycemic clamp using 2-deoxy-[3H]glucose. Here, we provide evidence that unilateral overexpression of DGAT1 in TA muscle of male rats is associated with an increased rather than decreased DAG content. Strikingly, this increase in DAG content was accompanied by improved muscle insulin sensitivity. Interestingly, markers of muscle lipolysis and mitochondrial function were also increased in DGAT1 overexpressing muscle. CONCLUSIONS/SIGNIFICANCE: We conclude that unilateral DGAT1 overexpression can rescue insulin sensitivity, possibly by increasing DAG and TAG turnover in skeletal muscle. In case of a proper balance between the supply and oxidation of fatty acids in skeletal muscle, the lipid intermediate DAG may not exert harmful effects on insulin signalling

Search for the optical counterpart of the GW170814 gravitational wave event with the VLT Survey Telescope

We report on the search for the optical counterpart of the gravitational event GW170814, which was carried out with the VLT Survey Telescope (VST) by the GRAvitational Wave Inaf TeAm. Observations started 17.5 h after the Laser Interferometer Gravitational-wave Observatory (LIGO) and Virgo alert and we covered an area of 99 deg2 that encloses ∼ 77{{ per cent}} and ∼ 59{{ per cent}} of the initial and refined localization probability regions, respectively. A total of six epochs were secured over nearly two months. The survey reached an average limiting magnitude of 22 AB mag in the r band. After assuming the model described in Perna, Lazzati & Farr, that derives as possible optical counterpart of a BBH (binary black hole) event a transient source declining in about one day, we have computed a survey efficiency of about 5{{ per cent}}. This paper describes the VST observational strategy and the results obtained by our analysis pipelines developed to search for optical transients in multi-epoch images. We report the catalogue of the candidates with possible identifications based on light-curve fitting. We have identified two dozens of SNe, nine AGNs, and one QSO. Nineteen transients characterized by a single detection were not classified. We have restricted our analysis only to the candidates that fall into the refined localization map. None out of 39 left candidates could be positively associated with GW170814. This result implies that the possible emission of optical radiation from a BBH merger had to be fainter than r ∼ 22 (Loptical ∼ 1.4 × 1042 erg s-1) on a time interval ranging from a few hours up to two months after the gravitational wave event

The Large Observatory For X-ray Timing: LOFT

LOFT, the Large Observatory for X-ray Timing, is a new space mission concept devoted to observations of Galactic and extra-Galactic sources in the X-ray domain with the main goals of probing gravity theory in the very strong field environment of black holes and other compact objects, and investigating the state of matter at supra-nuclear densities in neutron stars. The instruments on-board LOFT, the Large area detector and the Wide Field Monitor combine for the first time an unprecedented large effective area (~10 m2 at 8 keV) sensitive to X-ray photons mainly in the 2-30 keV energy range and a spectral resolution approaching that of CCD-based telescopes (down to 200 eV at 6 keV). LOFT is currently competing for a launch of opportunity in 2022 together with the other M3 mission candidates of the ESA Cosmic Vision Progra

The LOFT mission concept: a status update

The Large Observatory For x-ray Timing (LOFT) is a mission concept which was proposed to ESA as M3 and M4 candidate in the framework of the Cosmic Vision 2015-2025 program. Thanks to the unprecedented combination of effective area and spectral resolution of its main instrument and the uniquely large field of view of its wide field monitor, LOFT will be able to study the behaviour of matter in extreme conditions such as the strong gravitational field in the innermost regions close to black holes and neutron stars and the supra-nuclear densities in the interiors of neutron stars. The science payload is based on a Large Area Detector (LAD, >8m2 effective area, 2-30 keV, 240 eV spectral resolution, 1 degree collimated field of view) and a Wide Field Monitor (WFM, 2-50 keV, 4 steradian field of view, 1 arcmin source location accuracy, 300 eV spectral resolution). The WFM is equipped with an on-board system for bright events (e.g., GRB) localization. The trigger time and position of these events are broadcast to the ground within 30 s from discovery. In this paper we present the current technical and programmatic status of the mission

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

GRAWITA: VLT Survey Telescope observations of the gravitational wave sources GW150914 and GW151226

We report the results of deep optical follow-up surveys of the first two gravitational-wave sources, GW150914 and GW151226, done by the GRAvitational Wave Inaf TeAm Collaboration (GRAWITA). The VLT Survey Telescope (VST) responded promptly to the gravitational wave alerts sent by the LIGO and Virgo Collaborations, monitoring a region of 90 and 72 deg2 for GW150914 and GW151226, respectively, and repeated the observations over nearly two months. Both surveys reached an average limiting magnitude of about 21 in the r band. The paper describes the VST observational strategy and two independent procedures developed to search for transient counterpart candidates in multi-epoch VST images. Several transients have been discovered but no candidates are recognized to be related to the gravitational wave events. Interestingly, among many contaminant supernovae, we find a possible correlation between the supernova VSTJ57.77559-59.13990 and GRB 150827A detected by Fermi-GBM. The detection efficiency of VST observations for different types of electromagnetic counterparts of gravitational wave events is evaluated for the present and future follow-up surveys