Association of a homozygous GCK missense mutation with mild diabetes

Background: Homozygous inactivating GCK mutations have been repeatedly reported to cause severe hyperglycemia, presenting as permanent neonatal diabetes mellitus (PNDM). Conversely, only two cases of GCK homozygous mutations causing mild hyperglycemia have been so far described. We here report a novel GCK mutation (c.1116G>C, p.E372D), in a family with one homozygous member showing mild hyperglycemia. Methods: GCK mutational screening was carried out by Sanger sequencing. Computational analyses to investigate pathogenicity and molecular dynamics (MD) were performed for GCK-E372D and for previously described homozygous mutations associated with mild (n = 2) or severe (n = 1) hyperglycemia, used as references. Results: Of four mildly hyperglycemic family-members, three were heterozygous and one, diagnosed in the adulthood, was homozygous for GCK-E372D. Two nondiabetic family members carried no mutations. Fasting glucose (p = 0.016) and HbA1c (p = 0.035) correlated with the number of mutated alleles (0–2). In-silico predicted pathogenicity was not correlated with the four mutations’ severity. At MD, GCK-E372D conferred protein structure flexibility intermediate between mild and severe GCK mutations. Conclusions: We present the third case of homozygous GCK mutations associated with mild hyperglycemia, rather than PNDM. Our in-silico analyses support previous evidences suggesting that protein stability plays a role in determining clinical severity of GCK mutations

Sensitivity of nonlinear photoionization to resonance substructure in collective excitation

Collective behaviour is a characteristic feature in many-body systems, important for developments in fields such as magnetism, superconductivity, photonics and electronics. Recently, there has been increasing interest in the optically nonlinear response of collective excitations. Here we demonstrate how the nonlinear interaction of a many-body system with intense XUV radiation can be used as an effective probe for characterizing otherwise unresolved features of its collective response. Resonant photoionization of atomic xenon was chosen as a case study. The excellent agreement between experiment and theory strongly supports the prediction that two distinct poles underlie the giant dipole resonance. Our results pave the way towards a deeper understanding of collective behaviour in atoms, molecules and solid-state systems using nonlinear spectroscopic techniques enabled by modern short-wavelength light sources

Contained-Reflected Megaturbidites of the Marnoso-arenacea Formation (Contessa Key Bed) and Helminthoid Flysches (Northern Apennines, Italy) and Hecho Group (South-Western Pyrenees)

Contained-reflected beds deposited by fully-ponded or partially-reflected turbidity currents are important because their correct evaluation can give important indications on the degree of basin confinement and on the type, size and orientation of the morphological obstacle. Through a detailed facies analysis of various significant megabeds in the Marnoso-arenacea Formation, including the Contessa key bed, in the helminthoid flysches in the northern Apennines (Italy) and in the Pyrenees (megaturbidite MT5), this work proposes a depositional model that is well consistent with the recent experimental data available in the literature, discussing their strengths and limits. The Contessa and flysch megabeds fit very well with the experimental conditions because they are deposited in narrow and elongated confined basins characterized by axial flows. Indeed, in the proposed model, it is possible to recognize facies deposited by: 1) a basal underflow directed towards the bounding slope (Facies A), 2) an intermediate part of the flow characterized by lateral deflections (facies B1), 3) an upper well-developed reversing flow (facies B2) and 4) an uppermost residual reversing flow recording the final collapse of the fine-grained suspended load forming a poorly-sorted slurry facies C and a very thick mudstone unit D. Facies A, B1 and B2 are usually separated by very thin fine-grained muddy drapes rich in carbonaceous matter, which can be traced throughout the basin. These drapes - very common in contained and confined beds in these settings - can be related to internal density surfaces, along which decoupling processes, separating underflows from reversing overflows, can easily occur. Conversely, as the MT5 is characterized by a source transversal to an elongated narrow basin, the large flow volume versus basin capacity hinders the generation of reversing flows and rebound layers favoring the formation of fully-ponded pulsating overflows able to deposit alternations of laminated and massive units. This facies type can be observed in the basins that are characterized by axial flows only near the basin margins where the pulsating collapse of the reversing flow can dominate. This study shows that the integration of detailed field studies are essential to validate experimental data from an applicative point of view

Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4+CD25+FoxP3+ regulatory T cells activation

Rationale: Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear. Methods: We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses. Results: Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4+/CD25+/FoxP3+ T cells (Tregs). Conclusions: Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance

Two-electron processes in multiple ionization under strong soft-x-ray radiation

In a combined experimental and theoretical study we have investigated the ionization of atomic argon upon irradiation with intense soft-x-ray pulses of 105 eV photon energy from the free-electron laser FLASH. The measured ion yields show charge states up to Ar7+. The comparison with the theoretical study of the underlying photoionization dynamics highlights the importance of excited states in general and of processes governed by electron correlation in particular, namely, ionization with excitation and shake-off, processes usually inaccessible by measurements of ionic yields only. The Ar7+ yield shows a clear deviation from the predictions of the commonly used model of sequential ionization via single-electron processes and the observed signal can only be explained by taking into account the full multiplet structure of the involved configurations and by inclusion of two-electron processes. The competing process of two-photon ionization from the ground state of Ar6+ is calculated to be orders of magnitude smaller

Sleep Does not Help Relearning Declarative Memories in Older Adults

International audienceHow sleep affects memory in older adults is a critical topic, since age significantly impacts both sleep and memory. For declarative memory, previous research reports contradictory results, with some studies showing sleep-dependent memory consolidation and some other not. We hypothesize that this discrepancy may be due to the use of recall as the memory measure, a demanding task for older adults. The present paper focuses on the effect of sleep on relearning, a measure that proved useful to reveal subtle, implicit memory effects. Previous research in young adults showed that sleeping after learning was more beneficial to relearning the same Swahili-French word pairs 12 hours later, compared with the same interval spent awake. In particular, those words that could not be recalled were relearned faster when participants previously slept. The effect of sleep was also beneficial for retention after a one-week and a 6-month delay. The present study used the same experimental design in older adults aged 71 on average but showed no significant effect of sleep on consolidation, on relearning, or on long-term retention. Thus, even when using relearning speed as the memory measure, the consolidating effect of sleep in older adults was not demonstrated, in alignment with some previous findings

A CFD analysis of the influence of plenum configurations on gas distribution in a fluidized bed

Fluidized beds are widely used in many industries. The fluidization quality of these units is strongly related to the characteristics of the plenum and distributor (grid). In this work, the effect of different plenum geometries, and gas entrance sizes and locations on the velocity profile above the distributor was analyzed by Computational Fluid Dynamics (CFD). The results showed that flow uniformity above the distributor improved with an increase in the gas inlet diameter and the plenum height. Channeling was observed for the bottom central inlet. Addition-ally, simulations for plenum heights predicted by one of the frequently used correlations (Litz correlation) were also carried out and showed, especially for a bot-tom central gas inlet, a poor quality flow distribution. This behavior indicated that Litz correlation tends to underestimate the plenum height for obtaining a uni-form flow downstream the distributor.Fil: Soria, Jose Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas. Universidad Nacional del Comahue. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas; ArgentinaFil: Ausina, T. M.. Universidad Nacional del Comahue; ArgentinaFil: Mazza, German Delfor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas. Universidad Nacional del Comahue. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas; Argentin

Reliability of an integrated ultrasound and stereophotogrammetric system for lower limb anatomical characterisation

Background. Lower extremity analysis for preoperative total knee and hip arthroplasty routines can increase surgery success rate and hence reduce associated costs. Current tools are limited by being invasive, limited to supine analysis, or too expensive. This study aimed to propose and validate a device, OrthoPilot®, based on the combined use of a stereophotogrammetric and ultrasound system which can in vivo and noninvasively measure varus/valgus, flexion/extension, femur and tibia torsion, and femur and tibia lengths. Methods. A phantom was measured by four operators to determine the resolution of the system. Interoperator variability was measured on three operators who measured the above six variables on both legs of three subjects in standing and supine positions. Intraoperator variability was assessed on data from three repeats from 9 subjects (18 legs). Results. All 6 variables were reliably detected on a phantom, with a resolution of 1 mm and 0.5° . Inter- and intraoperator consistency was observed for varus/valgus, flexion/extension, and length measurements on the healthy subjects in standing and supine positions (all ICC > 0.93). For torsion measurements, there was a considerable variation. Conclusion. The proposed system, when used on healthy subjects, allowed reliable measurements of key parameters for preoperative procedures in both supine and standing positions. Accuracy testing and further validation on patient populations will be the next step toward its clinical adoption