A novel model predictive control for a piecewise affine class of hybrid system with repetitive disturbance.

The present investigation addresses an innovative method based on explicit form of the model predictive control (EMPC) for a constrained Piecewise affine (PWA) class of hybrid systems, considering repetitive disturbance. This model of hybrid systems is investigated due to the fact that PWA modeling structure can approximate nonlinear systems via various operating points, and also because the simulation of PWA models are easy. With EMPC, the problem of optimization is solved in an offline way only once. Unlike conventional EMPC, the process information of the past and the data which are predicted are applied in the proposed strategy. This is the first time that in this study, the investigators adopt an approach in which these predicted data are weighted by another optimization problem (OP) and this weighted predicted sequence along with the past information of the process as an updating control input formula. In fact, two separate OPs are solved simultaneously at each step of proposed EMPC. The first one is linked with calculating the control input from the constrained cost function of EMPC algorithm and the second one concerns finding the optimal weighting factors in order to minimize the error signal, i.e. the difference between the reference path and the output signal at each optimization step of EMPC strategy. The precision of the proposed method is extremely dependent on the accuracy of the process model, so iterative learning control (ILC) algorithm is applied to protecting the process model against the periodic disturbances. These mathematical analyses are proven and validated by simulation results.

Isolation of a novel human voltage-dependent anion channel gene.

The voltage-dependent anion channel of the mitochondrial outer membrane (VDAC) is a small, abundant pore-forming protein found in the outer membranes of all eukaryotic mitochondria. The VDAC protein is believed to control the movement of adenine nucleotides through the outer membrane and to be the mitochondrial binding site for hexokinase and glycerol kinase. Two human VDAC cDNAs (HVDAC1 and HVDAC2) have been previously isolated and mapped on chromosome X and 21, respectively. Here, we report the isolation of a novel third human VDAC cDNA, corresponding to the mouse MVDAC3 gene. The expression of this gene in various tissues and its chromosomal localization by polymerase chain reaction (PCR) using a human/rodent somatic cell mapping panel and by fluorescence in situ hybridization is also presented.

Molecular mapping of twenty-four features of Down syndrome on chromosome 21.

To determine which regions of chromosome 21 are involved in the pathogenesis of specific features of Down syndrome, we analysed, phenotypically and molecularly, 10 patients with partial trisomy 21. Six minimal regions for 24 features were defined by genotype-phenotype correlations. Nineteen of these features could be assigned to just 2 regions: short stature, joint hyperlaxity, hypotonia, major contribution to mental retardation and 9 anomalies of the face, hand and foot to the region D21S55, or Down syndrome chromosome region (DCR), located on q22.2 or very proximal q22.3, and spanning 0.4-3 Mb; 6 facial and dermatoglyphic anomalies to the region D21S55-MX1, including the DCR and spanning a maximum of 6 Mb on q22.2 and part of q22.3. Thus, the complex phenotype that constitutes Down syndrome may in large part simply result from the overdosage of only one or a few genes within the DCR and/or region D21S55-MX1.

Overexpression of mSim2 gene in the zona limitans of the diencephalon of segmental trisomy 16 Ts1Cje fetuses, a mouse model for trisomy 21: a novel whole-mount based RNA hybridization study.

Trisomy 21 (Down syndrome) is the most common chromosomal abnormality associated with mental retardation in humans. Sim2, a human homologue of Drosophila sim gene, which acts as a master regulator of the early development of the fly central nervous system midline, is located on chromosome 21, in the Down syndrome critical region, and might therefore be involved in the pathogenesis of some of the morphological features and brain anomalies observed in Down syndrome. We report here the detailed expression pattern of murine mSim2 gene in Ts1Cje mice fetuses, a segmental trisomy 16 mouse model for trisomy 21, and its overexpression in the zona limitans of the diencephalon using a new quantitative method based on the whole-mount RNA hybridization technique.

Mapping of the Down syndrome phenotype on chromosome 21 at the molecular level.

Phenotypic and molecular analysis of individuals with partial trisomy 21 can be used to determine which regions of chromosome 21 are involved in the pathogenesis of specific features of Down's Syndrome. Using dosage analysis of 27 sequences we defined, at the molecular level, the extent of the chromosome 21 duplication in ten individuals with partial trisomy 21. Phenotype-genotype correlations led to the definition of minimal regions, the duplications of which are linked to the expression of 23 clinical features of Down's Syndrome. The D21S55 region or Down's Syndrome Chromosome Region 1 (DCR1) (1/20 of the long arm), on 21q22.2-21q22.3 proximal, is involved in four cardinal features of the disease: mental retardation, growth retardation, muscular hypotonia and joint hyperlaxity, and in eight of the 18 more common morphological anomalies of the face, hands and feet. Overlapping the DCR1, the D21S55-MX1 region or DCR2 (1/10 of the long arm), spanning 21q21.2 down to the 1/4th proximal part of 21q22.3, is involved in the features defined by the DCR1 plus congenital heart defect and five additional morphological anomalies. Thus, our results indicate that duplication of a relatively small region of chromosome 21 plays a critical role in the pathogenesis of the Down's phenotype.

[Survival and prognostic factors of germ cell tumors of the testis in the departments of Bas-Rhin, Isère, and Somme]. / Survie et facteurs pronostiques du cancer des cellules germinales du testicule dans les départements du Bas-Rhin, de l'isère et de la Somme.

The authors report a study of the prognosis of germ cell tumours of the testis in populations of the Bas-Rhin, Isère and Some departments. This study was performed on French Eurocare data (European testicular cancer register study). 247 patients diagnosed between 1987 and 1993 were studied. Estèv's method and model were used to estimate the relative survival and for prognosis analysis with reference to the French age-matched male population. 84.6% of patients were between the ages of 20 and 49 years. The 5-years relative survival was 90.1%; 95 CI% [85.5-94.8]. The 5-year relative survival was lower (63.9%) in advanced forms (stage III). Univariate analysis in 223 patients demonstrated the following significant prognostic factors: stage, metastatic sites, treatment, retroperitoneal lymph node dissection and testicular vascular invasion. Multivariate analysis identified: stage, age, CNS metastases, retroperitoneal lymph node dissection and treatment. This study confirms the generally good prognosis of this cancer. As reported in the literature, factors negatively influencing relative survival are those related to advanced disease. Age, a controversial factor in the literature, was correlated with relative survival in this study.

Hepatitis B virus X protein colocalizes to mitochondria with a human voltage-dependent anion channel, HVDAC3, and alters its transmembrane potential.

Understanding the mechanism(s) of action of the hepatitis B virus (HBV)-encoded protein HBx is fundamental to elucidating the underlying mechanisms of chronic liver disease and hepatocellular carcinoma caused by HBV infection. In our continued attempts to identify cellular targets of HBx, we have previously reported the identification of a novel cellular protein with the aid of a yeast two-hybrid assay. This cellular gene was identified as a third member of the family of human genes that encode the voltage-dependent anion channel (HVDAC3). In the present study, physical interaction between HBx and HVDAC3 was established by standard in vitro and in vivo methods. Confocal laser microscopy of transfected cells with respective expression vectors colocalized HVDAC3 and HBx to mitochondria. This novel, heretofore unreported subcellular distribution of HBx in mitochondria implies a functional role of HBx in functions associated with mitochondria. Using a stable cationic fluorophore dye, CMXRos, we show that HBx expression in cultured human hepatoma cells leads to alteration of mitochondrial transmembrane potential. Such functional roles of HBx in affecting mitochondrial physiology have implications for HBV-induced liver injury and the development of hepatocellular carcinoma.

Expression of the mnb (dyrk) protein in adult and embryonic mouse tissues.

Mnb is a human homologue of the Drosophila minibrain gene which encodes a serine/threonine protein kinase that is required in distinct neuroblast proliferation centers during postembryonic neurogenesis. The high degree of homology of the human gene to the murine gene (dyrk) allowed us to use a human polyclonal anti-mnb antibody to study the expression pattern of the protein in adult and embryonic mouse tissues. Western blot analysis and immunohistochemical methods were used to define the detailed distribution of mnb in adult brain and 17 days mouse embryos. The results show a high expression in the cerebral cortex, the cerebellum, the hippocampus which is in accordance with previous reports of in situ hybridization studies using mRNA probes but also a very strong expression in the epithelial layers of the skin, the retina, the tongue, the intestine and the kidney which has not been described before. Since epithelial cells are highly mitotic cells and since mnb shares sequence similarities with the cdk kinases involved in the regulation of cell division, this result may indicate a important role of mnb in the cell cycle control.

Physical mapping of chromosome 21.

Chromosome 21, the smallest human chromosome, has been the subject of intense study because it is the chromosome which, when present in an extra copy, leads to Down Syndrome. Moreover, there are genes important for several human genetic disorders on this chromosome, and a significant number of individuals with aneuploidies of regions of the chromosome have been identified. A high fidelity, high resolution physical map of chromosome 21 will be of immense value in generating an accurate genotype/phenotype map of the chromosome and in identifying and isolating genes on the chromosome which may be responsible for various human genetic disorders. Here we describe the current status of our attempts to create such a map. This includes attempts to integrate various physical mapping approaches. Progress towards construction of a minimal set of yeast artificial chromosomes (YACs) spanning the chromosome is described.

Down syndrome critical region around D21S55 on proximal 21q22.3.

We have analysed the DNA of 2 patients with many manifestations of Down syndrome and partial duplication of distinct regions of chromosome 21, respectively, q11.205----q22.300 and q22.300----qter (Rahmani et al.: Proceedings of the National Academy of Sciences of the United States of America 86:5958-5962, 1989). Assessment of the copy number of five chromosome 21 sequences (SOD1, D21S17, D21S55, ETS2, and D21S15) has shown that D21S55 was duplicated in both cases. The size of the common duplicated region can be estimated between 400 and 3,000 Kb, after the results of pulsed-field gel analysis and from the knowledge of regional mapping of the probes D21S17, D21S55, and ETS2. This region, located on the proximal part of 21q22.3, is postulated to contain genes the overexpression of which plays a major role in the pathogenesis of Down syndrome.

New chromosome 21 DNA markers isolated by pulsed field gel electrophoresis from an ETS2-containing Down syndrome chromosomal region.

To generate new chromosome 21 markers in a region that is critical for the pathogenesis of Down syndrome (D21S55-MX1), we used pulsed field gel electrophoresis (PFGE) to isolate a 600-kb NruI DNA fragment from the WA17 hybrid cell line, which has retained chromosome 21 as the only human material. This fragment, which contains the oncogene ETS2, was used to construct a partial genomic library. Among the 14 unique sequences that were isolated, 3 were polymorphic markers and contained sequences that are conserved in mammals. Five of these markers mapped on the ETS2-containing NruI fragment and allowed us to define an 800-kb high-resolution PFGE map.

Gene-dosage mapping of 30 DNA markers on chromosome 21.

Using a slot-blot method for the dosage of single-copy sequences, the copy numbers of 30 chromosome 21 markers were assessed in the blood DNA of 11 patients with partial trisomy or monosomy 21 and in the DNA of a patient-derived human-hamster hybrid cell line carrying a microduplication of chromosome 21. The physical order of these markers on chromosome 21 was thereby determined.

Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndrome.

The duplication of a specific region of chromosome 21 could be responsible for the main features of Down syndrome. To define and localize this region, we analyzed at the molecular level the DNA of two patients with partial duplication of chromosome 21. These patients belong to two groups of Down syndrome patients characterized by different partial trisomies 21: (i) duplication of the long arm, proximal to 21q22.2, and (ii) duplication of the end of the chromosome, distal to 21q22.2 We assessed the copy number of five chromosome 21 sequences (SOD1, D21S17, D21S55, ETS2, and D21S15) and found that D21S55 was duplicated in both cases. By means of pulsed-field gel analysis and with the knowledge of regional mapping of the probes D21S17, D21S55 and ETS2, we estimated the size of the common duplicated region to be between 400 and 3000 kilobases. This region, localized on the proximal part of 21q22.3, is suspected to contain genes the overexpression of which is crucial in the pathogenesis of Down syndrome.

Slot blot method for the quantification of DNA sequences and mapping of chromosome rearrangements: application to chromosome 21.

As an alternative to the methods of gene dosage based on either RFLP studies or Southern blots using specific and reference probes, we designed a "slot blot" method for the evaluation of the copy number of unique chromosome 21 sequences. Varying amounts of denatured DNA from a normal control, a trisomy 21 patient, and the subject to be analyzed were loaded on the same membrane. Successive hybridizations with reference probes and chromosome 21 probes were then carried out. Intensities of the signals on autoradiograms were quantified by densitometric scanning. Graphic and statistical analysis of the linear regressions between reference and chromosome 21 probe signals were performed, and the conclusion that the DNA from the studied subject had two or three copies for a given chromosome 21 sequence was assessed by statistical comparison of the slopes. As a test for the validation of this method, 10 coded blood DNAs from five normal controls and from five trisomy 21 patients were analyzed, by using two reference (COL1A1 and COL1A2) and two chromosome 21 (D21S11 and D21S17) probes. Among the 10 DNAs analyzed, it was possible to diagnose, with 100% accuracy, normal controls and trisomic 21 individuals. Application of this methodology to the mapping of partial chromosome 21 rearrangements is presented.

Partial physical map of human chromosome 21 from fibroblast and lymphocyte DNA.

A partial physical map of the human chromosome 21 including 26 genes and anonymous sequences was established by pulsed-field gel electrophoresis analysis of restriction fragments obtained from lymphocyte and fibroblast DNAs. The sizes of the restriction fragments obtained by total digestion with eight different enzymes were compared in these two tissues. Differences resulting from the variations in the methylation state of the restriction sites were frequently observed. These differences and partial digestions were used to estimate the order and the distances between genes and sequences. Six linkage groups were defined: D21S13-D21S16, D21S1-D21S11, D21S65-D21S17, (D21S55,ERG)-ETS2, BCEI-D21S19-D21S42-D21S113-CBS-CRYA1, and COL6A2-S100B. For six intergenic distances the resolution of previous maps was significantly increased.

A frequent ala 4 to val superoxide dismutase-1 mutation is associated with a rapidly progressive familial amyotrophic lateral sclerosis.

Familial amyotrophic lateral sclerosis (FALS), a degenerative disorder of motor neurons, is associated with mutations in the Cu/Zn superoxide dismutase gene SOD1 in some affected families. We confirm a recently reported ala4-->val mutation in exon 1 of the SOD1 gene and report that this mutation is both the most commonly detected of all SOD1 mutations and among the most clinically severe. By comparison with our other FALS families, the exon 1 mutation is associated with reduced survival time after onset: 1.2 years, as compared to 2.5 years for all other FALS patients. We also demonstrate that SOD1 is prominently expressed in normal motor neurons and that neural expression of SOD1 is not prevented by this exon 1 mutation. Assays of SOD1 enzymatic activity in extracts from red blood cells, lymphoblastoid cells, and brain tissues revealed an approximately 50% reduction in activity of cytosolic SOD1 in patients with this mutation compared to normal individuals. By contrast, patients with sporadic ALS had normal levels of SOD1 enzymatic activity. Why this SOD1 mutation causes motor neuron death in FALS remains to be established. While it may be that FALS is a consequence of loss of SOD1 function, it is also possible that motor neuron death in this dominantly inherited disease occurs because the mutations confer an additional, cytotoxic function on the SOD1 protein.