Calcium-sensing receptor and calcium kidney stones

Calcium nephrolithiasis may be considered as a complex disease having multiple pathogenetic mechanisms and characterized by various clinical manifestations. Both genetic and environmental factors may increase susceptibility to calcium stones; therefore, it is crucial to characterize the patient phenotype to distinguish homogeneous groups of stone formers. Family and twin studies have shown that the stone transmission pattern is not mendelian, but complex and polygenic. In these studies, heritability of calcium stones was calculated around 50

Interaction of glycine, lysine, proline and histidine with dipalmitoylphosphatidylcholine lipid bilayers: a theoretical and experimental study

The interaction of unblocked glycine, lysine, proline, and histidine (in their three forms, namely two tautomers and the protonated form) with a dipalmitoylphosphatidylcholine (DPPC) bilayer was assessed using extensive atomistic molecular dynamics simulations. Free energy profiles for the insertion of each amino acid into the lipid bilayer were computed along an appropriated reaction coordinate. The simulation results for glycine in the presence of DPPC were compared with experimental data obtained by Fourier transform infrared spectroscopy. Experimental results predict, in good agreement with simulations, the existence of intermolecular interactions between the DPPC head groups and glycine. Atomistic simulations were further extended to investigate the free energy profiles for lysine, proline and histidine, leading to the following conclusions: (i) lysine free energy profiles computed using a united atom force-field and an analog molecule, where the side-chain is truncated at the β-carbon atom, differ significantly from each other; (ii) the free energy profiles for the three forms of histidine are all very similar, although the charged form interacts mostly with the carbonyl groups of DPPC, while the tautomers interact with the phosphate groups; and (iii) proline does not show a minimum in the free energy profile, pointing to the absence of binding to the membrane lipids. Overall, this work contributes to our general understanding of the various factors affecting the interactions between amino acids and a model cell membrane, and may spur progress in the effort to develop new molecular models to study larger biological systems.Fil: Porasso, Rodolfo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Matemática Aplicada de San Luis; ArgentinaFil: Ale, Norma Mercedes. Universidad Nacional de Tucuman. Facultad de Bioquimica, Quimica y Farmacia. Instituto de Quimica Fisica; ArgentinaFil: Ciocco Aloia, Facundo. Universidad Nacional de Cuyo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Masone, Diego Fernando. Universidad Nacional de Cuyo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: del Popolo, Mario Gabriel. Universidad Nacional de Cuyo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ben Altabef, Aida. Universidad Nacional de Tucuman. Facultad de Bioquimica, Quimica y Farmacia. Instituto de Quimica Fisica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto de Quimica del Noroeste; ArgentinaFil: Gomez Zavaglia, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Investigaciones en Criotecnología de Alimentos (i); ArgentinaFil: Díaz, Sonia Beatriz. Universidad Nacional de Tucuman. Facultad de Bioquimica, Quimica y Farmacia. Instituto de Quimica Fisica; ArgentinaFil: Vila, Jorge Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Matemática Aplicada de San Luis; Argentina. Cornell University; Estados Unido

Common variants in the regulative regions of GRIA1 and GRIA3 receptor genes are associated with migraine susceptibility

<p>Abstract</p> <p>Background</p> <p>Glutamate is the principal excitatory neurotransmitter in the central nervous system which acts by the activation of either ionotropic (AMPA, NMDA and kainate receptors) or G-protein coupled metabotropic receptors. Glutamate is widely accepted to play a major role in the path physiology of migraine as implicated by data from animal and human studies. Genes involved in synthesis, metabolism and regulation of both glutamate and its receptors could be, therefore, considered as potential candidates for causing/predisposing to migraine when mutated.</p> <p>Methods</p> <p>The association of polymorphic variants of <it>GRIA1</it>-<it>GRIA4 </it>genes which encode for the four subunits (GluR1-GluR4) of the alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor for glutamate was tested in migraineurs with and without aura (MA and MO) and healthy controls.</p> <p>Results</p> <p>Two variants in the regulative regions of <it>GRIA1 </it>(rs2195450) and <it>GRIA3 </it>(rs3761555) genes resulted strongly associated with MA (P = 0.00002 and P = 0.0001, respectively), but not associated with MO, suggesting their role in cortical spreading depression. Whereas the rs548294 variant in <it>GRIA1 </it>gene showed association primarily with MO phenotype, supporting the hypothesis that MA and MO phenotypes could be genetically related. These variants modify binding sites for transcription factors altering the expression of <it>GRIA1 </it>and <it>GRIA3 </it>genes in different conditions.</p> <p>Conclusions</p> <p>This study represents the first genetic evidence of a link between glutamate receptors and migraine.</p

Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration.

Following severe or chronic liver injury, adult ductal cells (cholangiocytes) contribute to regeneration by restoring both hepatocytes and cholangiocytes. We recently showed that ductal cells clonally expand as self-renewing liver organoids that retain their differentiation capacity into both hepatocytes and ductal cells. However, the molecular mechanisms by which adult ductal-committed cells acquire cellular plasticity, initiate organoids and regenerate the damaged tissue remain largely unknown. Here, we describe that ductal cells undergo a transient, genome-wide, remodelling of their transcriptome and epigenome during organoid initiation and in vivo following tissue damage. TET1-mediated hydroxymethylation licences differentiated ductal cells to initiate organoids and activate the regenerative programme through the transcriptional regulation of stem-cell genes and regenerative pathways including the YAP-Hippo signalling. Our results argue in favour of the remodelling of genomic methylome/hydroxymethylome landscapes as a general mechanism by which differentiated cells exit a committed state in response to tissue damage.RCUK Cancer Research UK ERC H2020 Wellcome Trus

Active and poised promoter states drive folding of the extended HoxB locus in mouse embryonic stem cells

Gene expression states influence the three-dimensional conformation of the genome through poorly understood mechanisms. Here, we investigate the conformation of the murine HoxB locus, a gene-dense genomic region containing closely spaced genes with distinct activation states in mouse embryonic stem (ES) cells. To predict possible folding scenarios, we performed computer simulations of polymer models informed with different chromatin occupancy features, which define promoter activation states or CTCF binding sites. Single cell imaging of the locus folding was performed to test model predictions. While CTCF occupancy alone fails to predict the in vivo folding at genomic length scale of 10 kb, we found that homotypic interactions between active and Polycomb-repressed promoters co-occurring in the same DNA fibre fully explain the HoxB folding patterns imaged in single cells. We identify state-dependent promoter interactions as major drivers of chromatin folding in gene-dense regions

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6&nbsp;years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P &lt; 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100&nbsp;years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

ARX-based EEG data balancing for error potential BCI

Objective. Deep learning algorithms employed in brain computer interfaces (BCIs) need large electroencephalographic (EEG) datasets to be trained. These datasets are usually unbalanced, particularly when error potential (ErrP) experiment are considered, being ErrP's epochs much rarer than non-ErrP ones. To face the issue of unbalance of rare epochs, this paper presents a novel, data balancing methods based on ARX-modelling. Approach. AutoRegressive with eXogenous input (ARX)-models are identified on the EEG data of the 'Monitoring error-related potentials' dataset of the BNCI Horizon 2020 and then employed to generate new synthetic data of the minority class of ErrP epochs. The balanced dataset is used to train a classifier of non-ErrP vs. ErrP epochs based on EEGNet. Main results. Compared to classical techniques (e.g. class weights, CW) for data balancing, the new method outperforms the others in terms of resulting accuracy (i.e. ARX 91.5% 88.3

Selective Palladium(II)‐Catalyzed Dimerization of Styrenes and Acrylates in Molten Tetrabutylammonium Acetate as an Ionic Liquid

A method for the selective dimerization of styrenes and acrylates has been developed. The reaction is catalyzed by a very low amount of palladium acetate in molten tetrabutylammonium acetate without the need for any additional ligand. The use of this method enabled the coupling of substituted vinyl arenes in reasonable yields to give exclusively the (E,E)-1,4-diarylbutadiene motif within 7-10 h. Acrylates, on the other hand, exhibit higher reactivity, and the use of dibutyl acrylate resulted in the quantitative synthesis of dibutyl 2-methyleneglutarate in less than 2 h. This selectivity is unprecedented in the literature. The role of the ionic liquid and the different catalytic pathways involved in the two processes were also elucidated.The selective dimerization of styrenes and acrylates was possible with a very low amount of palladium acetate in molten tetrabutylammonium acetate. The coupling of substituted vinyl arenes gave exclusively the (E,E)-1,4-diarylbutadiene motif within 7-10 h, whereas butyl acrylate was converted into dibutyl 2-methyleneglutarate in less than 2 h. The catalytic pathways involved in the two processes were elucidated along with the role of the ionic liquid. imag

Effects of Light Orientation and Mechanical Damage to Leaves on Isoflavone Accumulation in Soybean Seeds

Soybean is largely cultivated worldwide providing high amounts of proteins and oil for food and feed, and isoflavones for nutraceutical uses. The increasing interest in agroforestry practices for improving carbon sequestration and mitigating climate changes suggests the need to assess soybean response to variations of light availability and direction. A two-year pot trial was carried out at Legnaro (NE Italy) in order to mimic the response of the soybean var. Sponsor to contrasting light orientation (east or west) by artificial shading, associated or not with mechanical leaf damage, in terms of protein accumulation, total cotyledon isoflavone concentration (TCIC) and isoflavone profile. Here, we demonstrate that a different intensity of the isoflavone metabolism exists in response to lighting conditions, with higher TCIC and slightly increased seed crude proteins in plants lighted from the east (morning time) and after mechanical leaf damage. The isoflavone profile was not changed, but low temperatures and high rainfall during seed filling (1st year) were associated with increased accumulation of medium-high molecular weight (MW) forms (i.e., glycosyls and malonyls), while high temperatures and low rainfall (2nd year) with increased accumulation of medium-low MW forms (i.e., glycosyls and aglycones). It is concluded that within agroforestry systems, there is possibly a large scope for maximizing isoflavone accumulation by selecting the harvesting area in the neighboring of the east side of the tree alleys, with further improvements if a mild shoot stripping is applied before flowering