On global location-domination in graphs

A dominating set $S$ of a graph $G$ is called locating-dominating, LD-set for short, if every vertex $v$ not in $S$ is uniquely determined by the set of neighbors of $v$ belonging to $S$. Locating-dominating sets of minimum cardinality are called $LD$-codes and the cardinality of an LD-code is the location-domination number $\lambda(G)$. An LD-set $S$ of a graph $G$ is global if it is an LD-set of both $G$ and its complement $\overline{G}$. The global location-domination number $\lambda_g(G)$ is the minimum cardinality of a global LD-set of $G$. In this work, we give some relations between locating-dominating sets and the location-domination number in a graph and its complement.Comment: 15 pages: 2 tables; 8 figures; 20 reference

Extremal Graph Theory for Metric Dimension and Diameter

A set of vertices $S$ \emph{resolves} a connected graph $G$ if every vertex is uniquely determined by its vector of distances to the vertices in $S$. The \emph{metric dimension} of $G$ is the minimum cardinality of a resolving set of $G$. Let $\mathcal{G}_{\beta,D}$ be the set of graphs with metric dimension $\beta$ and diameter $D$. It is well-known that the minimum order of a graph in $\mathcal{G}_{\beta,D}$ is exactly $\beta+D$. The first contribution of this paper is to characterise the graphs in $\mathcal{G}_{\beta,D}$ with order $\beta+D$ for all values of $\beta$ and $D$. Such a characterisation was previously only known for $D\leq2$ or $\beta\leq1$. The second contribution is to determine the maximum order of a graph in $\mathcal{G}_{\beta,D}$ for all values of $D$ and $\beta$. Only a weak upper bound was previously known

Nordhaus-Gaddum bounds for locating domination

A dominating set S of graph G is called metric-locating-dominating if it is also locating, that is, if every vertex v is uniquely determined by its vector of distances to the vertices in S. If moreover, every vertex v not in S is also uniquely determined by the set of neighbors of v belonging to S, then it is said to be locating-dominating. Locating, metric-locating-dominating and locating-dominating sets of minimum cardinality are called b-codes, e-codes and l-codes, respectively. A Nordhaus-Gaddum bound is a tight lower or upper bound on the sum or product of a parameter of a graph G and its complement G. In this paper, we present some Nordhaus-Gaddum bounds for the location number b, the metric-location-number e and the location-domination number l. Moreover, in each case, the graph family attaining the corresponding bound is characterized.Comment: 7 pages, 2 figure

A common mechanism of defective channel trafficking underlying DFNA2 hearing loss result in different cell surface expression levels of KCNQ4 mutants

KCNQ4 mutations underlie DFNA2, a subtype of autosomal dominant hearing loss. We had previously identified the pore-region p.G296S mutation that impaired channel activity in two manners: it greatly reduced surface expression and abolished channel function. Moreover, G296S mutant exerted a strong dominant-negative effect on potassium currents by reducing the channel expression at the cell surface representing the first study to identify a trafficking-dependent dominant mechanism for the loss of KCNQ4 channel function in DFNA2. Here, we have investigated the pathogenic mechanism associated with all the described KCNQ4 mutations (F182L, W242X, E260K, D262V, L274H, W276S, L281S, G285C, G285S and G321S) that are located in different domains of the channel protein. F182L mutant showed a wild type-like cell-surface distribution in transiently transfected NIH3T3 fibroblasts and the recorded currents in Xenopus oocytes resembled those of the wild-type. The remaining KCNQ4 mutants abolished potassium currents, but displayed distinct levels of defective cell-surface expression in NIH3T3 as quantified by flow citometry. Co-localization studies revealed these mutants were retained in the ER, unless W242X, which showed a clear co-localization with Golgi apparatus. Interestingly, this mutation results in a truncated KCNQ4 protein at the S5 transmembrane domain, before the pore region, that escapes the protein quality control in the ER but does not reach the cell surface at normal levels. Currently we are investigating the trafficking behaviour and electrophysiological properties of several KCNQ4 truncated proteins artificially generated in order to identify specific motifs involved in channel retention/exportation. Altogether, our results indicate that a defect in KCNQ4 trafficking is the common mechanism underlying DFNA

Performance of Glass Resistive Plate Chambers for a high granularity semi-digital calorimeter

A new design of highly granular hadronic calorimeter using Glass Resistive Plate Chambers (GRPCs) with embedded electronics has been proposed for the future International Linear Collider (ILC) experiments. It features a 2-bit threshold semi-digital read-out. Several GRPC prototypes with their electronics have been successfully built and tested in pion beams. The design of these detectors is presented along with the test results on efficiency, pad multiplicity, stability and reproducibility.Comment: 16 pages, 15 figure

Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations : Overlap of TWNK-related recessive disorders

Altres ajuts: This research was supported with cofounding from the European Regional Development Fund (ERDF), "A way to make Europe") (to IdC); S2017/BMD‑3721‑RAREGENOMICS‑CM from the Consejería de Educación e Investigación de la Comunidad de Madrid (to MAMP).Background: Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype-phenotype correlations. Methods: Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene. Results: Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29∗), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern. Conclusions: Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype-phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype-phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome

Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data

2 deoxy-D-glucose augments the mitochondrial respiratory chain in heart

2-Deoxy-D-glucose (2DG) has recently received emergency approval for the treatment of COVID-19 in India, after a successful clinical trial. SARS-CoV-2 infection of cultured cells is accompanied by elevated glycolysis and decreased mitochondrial function, whereas 2DG represses glycolysis and stimulates respiration, and restricts viral replication. While 2DG has pleiotropic effects on cell metabolism in cultured cells it is not known which of these manifests in vivo. On the other hand, it is known that 2DG given continuously can have severe detrimental effects on the rodent heart. Here, we show that the principal effect of an extended, intermittent 2DG treatment on mice is to augment the mitochondrial respiratory chain proteome in the heart; importantly, this occurs without vacuolization, hypertrophy or fibrosis. The increase in the heart respiratory chain proteome suggests an increase in mitochondrial oxidative capacity, which could compensate for the energy deficit caused by the inhibition of glycolysis. Thus, 2DG in the murine heart appears to induce a metabolic configuration that is the opposite of SARS-CoV-2 infected cells, which could explain the compound's ability to restrict the propagation of the virus to the benefit of patients with COVID-19 disease

Construction and commissioning of a technological prototype of a high-granularity semi-digital hadronic calorimeter

A large prototype of 1.3m3 was designed and built as a demonstrator of the semi-digital hadronic calorimeter (SDHCAL) concept proposed for the future ILC experiments. The prototype is a sampling hadronic calorimeter of 48 units. Each unit is built of an active layer made of 1m2 Glass Resistive Plate Chamber(GRPC) detector placed inside a cassette whose walls are made of stainless steel. The cassette contains also the electronics used to read out the GRPC detector. The lateral granularity of the active layer is provided by the electronics pick-up pads of 1cm2 each. The cassettes are inserted into a self-supporting mechanical structure built also of stainless steel plates which, with the cassettes walls, play the role of the absorber. The prototype was designed to be very compact and important efforts were made to minimize the number of services cables to optimize the efficiency of the Particle Flow Algorithm techniques to be used in the future ILC experiments. The different components of the SDHCAL prototype were studied individually and strict criteria were applied for the final selection of these components. Basic calibration procedures were performed after the prototype assembling. The prototype is the first of a series of new-generation detectors equipped with a power-pulsing mode intended to reduce the power consumption of this highly granular detector. A dedicated acquisition system was developed to deal with the output of more than 440000 electronics channels in both trigger and triggerless modes. After its completion in 2011, the prototype was commissioned using cosmic rays and particles beams at CERN.Comment: 49 pages, 41 figure