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Identification of the genetic defect underlying early-onset diabetes is important for determining the specific diabetes subtype, which would then permit appropriate treatment and accurate assessment of recurrence risk in offspring. Given the extensive genetic and clinical heterogeneity of the disease, high-throughput sequencing might provide additional diagnostic potential when Sanger sequencing is ineffective. Our aim was to develop a targeted next-generation assay able to detect mutations in several genes involved in glucose metabolism. All 13 known MODY genes, genes identified from a genome-wide linkage study or genome-wide association studies as increasing the risk of type 2 diabetes and genes causing diabetes in animal models, were included in the custom panel. We selected a total of 102 genes by performing a targeting re-sequencing in 30 patients negative for mutations in the GCK , HNF1 α, HNF4 α, HNF1 β and IPF1 genes at the Sanger sequencing analysis. Previously unidentified variants in the RFX6 gene were found in three patients and in two of them we also detected rare variants in WFS1 and ABCC8 genes. All patients showed a good therapeutic response to dipeptidyl peptidase-4 (DPP4) inhibitors. Our study reveals that next-generation sequencing provides a highly sensitive method for identification of variants in new causative genes of diabetes. This approach may help in understanding the molecular etiology of diabetes and in providing more personalized treatment for each genetic subtype.

Whenever the carbon/nitrogen ratio of a domestic wastewater is too low, full denitrification is difficult to obtain and an additional source of organic carbon has to be provided. Since loading conditions may vary appreciably over the diurnal cycle, depending on the weather and sewage conditions, dosing should be controlled by an adaptive regulator to keep into account the time-varying process dynamics. A fuzzy predictive controller is proposed in this paper and its performance is tested through numerical simulations. The new aspects brought forward are the use of an improved model for denitrification, the use of benchmark (i.e. thoroughly tested and standardised) input files and the conclusion about regulator performance in overall plant performance, in terms of carbon saving and discharge compliance.

Background Genetic polymorphisms in genes involved in pain modulation have been reported to be associated to opioid efficacy and safety in different clinical settings. Methods The association between COMT Val158Met polymorphism (rs4680) and the inter-individual differences in the response to opioid analgesic therapy was investigated in a cohort of 87 Italian paediatric patients receiving opioids for cancer pain (STOP Pain study). Furthermore, a systematic review of the association between opioid response in cancer patients and the COMT polymorphism was performed in accordance with the Cochrane Handbook and the Prisma Statement. Results In the 87 paediatric patients, pain intensity (total time needed to reach the lowest possible level) was significantly higher for G/G than A/G and A/A carriers ( p -value = 0.042). In the 60 patients treated only with morphine, the mean of total dose to reach the same pain intensity was significantly higher for G/G than A/G and A/A carriers (p-value = 0.010). Systematic review identified five studies on adults, reporting that opioid dose (mg after 24 h of treatment from the first pain measurement) was higher for G/G compared to A/G and A/A carriers. Conclusions Present research suggests that the A allele in COMT polymorphism could be a marker of opioid sensitivity in paediatric cancer patients (STOP Pain), as well as in adults (Systematic Review), indicating that the polymorphism impact could be not age-dependent in the cancer pain context. Trial registration Registration number: CRD42017057831 .

Sequence variation of the hypervariable segments (HVS) I/II of mitochondrial DNA (mtDNA) and the haplogroup affiliation were determined in a sample of 271 Italian subjects. This analysis showed that 42% of the individuals could be ascribed to H, the most frequent haplogroup in European Caucasian populations. This fraction was then screened for specific single nucleotide polymorphisms located in the coding region to identify H subclades H1-H15. We set up two multiplex polymerase chain reactions and specific SNaPshot assays to investigate the frequency distribution of these subgroups in our population sample and to examine their usefulness in discriminating among commonly shared HVS I/II sequences. This allowed the assignment of a large portion of the mtDNAs ( approximately 70%) to specific subhaplogroups, with H1 and H5 being the most represented. About two-thirds of the individuals sharing common HVS I/II sequences were subdivided and ascribed to specific H subhaplogroups with a significant reduction of the frequencies of the most common mtDNA haplotypes. Haplogroup H subtyping could thus be extremely useful in forensic identification when many samples have to be analysed and compared, avoiding excessive time-consuming and labor-intensive sequencing analysis.

The unidentified TeV source HESS J1702-420 has recently been proposed as a new hadronic PeVatron candidate, based on the discovery of a small-scale emission sub-region with extremely hard gamma-ray spectrum up to 100 TeV (named HESS J1702-420A). Given the difficulty to discriminate between a hadronic or leptonic origin of the TeV emission, based on the H.E.S.S. measurement alone, we opted for a multi-wavelength approach. A deep X-ray observation was carried out using the XMM-Newton satellite, with the goal of probing a possible association with a hidden leptonic accelerator. No evidence of a clear counterpart for HESS J1702-420A was found in the X-ray data. After excluding an association with all nearby X-ray point sources, we derived strict upper limits on the diffuse X-ray emission and average magnetic field in the HESS J1702-420A region. We additionally report the serendipitous discovery of a new extended X-ray source, whose association with HESS J1702-420A is not obvious but cannot be ruled out either. A set of scripts dedicated to the multi-wavelength modeling of X-ray and gamma-ray data, based on Gammapy, Naima and Xspec, was developed in the context of this work and is made publicly available along with this paper.

Detecting and studying galactic gamma-ray sources emitting very-high energy photons sheds light on the acceleration and propagation of cosmic rays presumably created in these sources. Currently, there are few sources emitting photons with energies exceeding 100 TeV. In this work we revisit the unidentified source MGRO J1908+06, initially detected by Milagro, using an updated H.E.S.S. dataset and analysis pipeline. The vicinity of the source contains a supernova remnant and pulsars as well as molecular clouds. This makes the identification of the primary source(s) of galactic cosmic rays as well as the nature of the gamma-ray emission challenging, especially in light of the recent HAWC and LHAASO detection of the high energy tail of its spectrum. Exploiting the better angular resolution as compared to particle detectors, we investigate the morphology of the source as well as its spectral properties.

Observations with imaging atmospheric Cherenkov telescopes (IACTs) have enhanced our knowledge of nearby supernova (SN) remnants with ages younger than 500 years by establishing Cassiopeia A and the remnant of Tycho's SN as very-high-energy (VHE) gamma-ray sources. The remnant of Kepler's SN, which is the product of the most recent naked-eye supernova in our Galaxy, is comparable in age to the other two, but is significantly more distant. If the gamma-ray luminosities of the remnants of Tycho's and Kepler's SNe are similar, then the latter is expected to be one of the faintest gamma-ray sources within reach of the current generation IACT arrays. Here we report evidence at a statistical level of 4.6 sigma for a VHE signal from the remnant of Kepler's SN based on deep observations by the High Energy Stereoscopic System (H.E.S.S.) with an exposure of 152 hours. The measured integral flux above an energy of 226 GeV is ~0.3% of the flux of the Crab Nebula. The spectral energy distribution (SED) reveals a gamma-ray emitting component connecting the VHE emission observed with H.E.S.S. to the emission observed at GeV energies with Fermi-LAT. The overall SED is similar to that of the remnant of Tycho's SN, possibly indicating the same non-thermal emission processes acting in both these young remnants of thermonuclear SNe.

Context. HESS J1809\\(-\\)193 is an unassociated very-high-energy \\(\\gamma\\)-ray source located on the Galactic plane. While it has been connected to the nebula of the energetic pulsar PSR J1809\\(-\\)1917, supernova remnants and molecular clouds present in the vicinity also constitute possible associations. Recently, the detection of \\(\\gamma\\)-ray emission up to energies of \\(\\sim\\)100 TeV with the HAWC observatory has led to renewed interest in HESS J1809\\(-\\)193. Aims. We aim to understand the origin of the \\(\\gamma\\)-ray emission of HESS J1809\\(-\\)193. Methods. We analysed 93.2 h of data taken on HESS J1809\\(-\\)193 above 0.27 TeV with the High Energy Stereoscopic System (H.E.S.S.), using a multi-component, three-dimensional likelihood analysis. In addition, we provide a new analysis of 12.5 yr of Fermi-LAT data above 1 GeV within the region of HESS J1809\\(-\\)193. The obtained results are interpreted in a time-dependent modelling framework. Results. For the first time, we were able to resolve the emission detected with H.E.S.S. into two components: an extended component that exhibits a spectral cut-off at \\(\\sim\\)13 TeV, and a compact component that is located close to PSR J1809\\(-\\)1917 and shows no clear spectral cut-off. The Fermi-LAT analysis also revealed extended \\(\\gamma\\)-ray emission, on scales similar to that of the extended H.E.S.S. component. Conclusions. Our modelling indicates that based on its spectrum and spatial extent, the extended H.E.S.S. component is likely caused by inverse Compton emission from old electrons that form a halo around the pulsar wind nebula. The compact component could be connected to either the pulsar wind nebula or the supernova remnant and molecular clouds. Due to its comparatively steep spectrum, modelling the Fermi-LAT emission together with the H.E.S.S. components is not straightforward. (abridged)

Allele frequencies for the 13 STRs of the Combined DNA Index System (CODIS) core were obtained from a sample of 188 unrelated individuals living in the area of Florence, Prato and Pistoia (Tuscany, Central Italy).

Direct sequencing of polymerase chain reaction (PCR)-generated templates is a commonly used technique in molecular biology laboratories. We describe an improved method for direct sequencing of PCR fragments longer than 20 kb obtained with a commercial mixture of Taq and Pwo DNA polymerases. The sequencing protocol was optimized for an automated infrared DNA sequencer, consistently yielding long reads (500-600 bases).