A MARKOVIAN APPROACH TO DETERMINING PROCESS MEANS WITH DUAL QUALITY CHARACTERISTICS

This paper studies a production system where products are produced continuously and whose specification limits are specified for screening inspection. In this paper, we consider dual quality characteristics and different costs associated with each quality characteristic that falls below a lower specification limit or above an upper specification limit. Due to these different costs, the expected total profit will greatly depend on the process parameters, especially a process mean. This paper develops a Markovian-based model for determining the optimum process means with the consideration of dual quality characteristics in a single-stage system. The proposed model is then illustrated through a numerical example and sensitivity analysis is performed to validate the model. The results showed that the optimum process mean for both quality characteristics have a significant effect on the performance of the system. Since the literature survey shows that dealing with multi-quality characteristics is extremely limited, the proposed model, coupled with the Markovian approach, provides a unique contribution to this field.     

Brown-headed Cowbird parasitism on endangered species: relationships with neighboring avian species

Loss of reproductive productivity in hosts of the Brown-headed Cowbird ( Molothrus ater ), a nest parasite, may limit the success of conservation and recovery efforts that focus on restoring avian habitat. We investigated the relationships between parasitism frequency of 2 vireos—the endangered Black-capped Vireo ( Vireo atricapillus ) and the White-eyed Vireo ( Vireo griseus )—and characteristics of the neighboring avian assemblage. Our objective was to identify assemblage characteristics that are useful for predicting parasitism frequency. We hypothesized that parasitism frequency of the vireos would decrease with increasing alternate host abundance and increase with increasing abundance of cowbirds. All Black-capped Vireo nests ( n = 20) and 81% of White-eyed Vireo nests ( n = 27) were parasitized. Parasitism frequency of White-eyed Vireos was positively correlated with the number of cowbirds detected ( r = 0.84, df = 4, P = 0.018). Parasitism frequency of White-eyed Vireos was negatively correlated with abundance of the Black-and white Warbler ( Mniotilta varia; r = 0.891, df = 4, P = 0.009) but was not correlated with abundance of other cowbird hosts. The relationship between Black-and-white Warbler abundance and parasitism frequency may be due to chance, given the small sample size and narrow range of parasitism frequencies, but the relationship may also reflect an interaction (requiring further investigation) between parasitism and the vegetation characteristics associated with Black-and white Warblers. Our results imply that reducing cowbird abundance will reduce parasitism frequency of Black-capped Vireos. When the number of cowbirds in an area predicts parasitism, land managers would benefit from identifying a target cowbird abundance based on the levels of parasitism the host population can tolerate while still meeting productivity and population objectives for the species. La disminución de productividad debido al parasitismo por el tordo negro ( Molothrus ater ) podría limitar el éxito de los esfuerzos de conservación y recuperación de las aves que se centran en la restauración del hábitat. Investigamos la relación entre la frecuencia de parasitismo en el vireo gorrinegro ( Vireo atricapilla ), que está en peligro de extinción, y en otra especie de vireo, el vireo ojiblanco ( Vireo griseus ), así como su relación con las características de la población circunvecina de aves para identificar las características que sirven para predecir la frecuencia del parasitismo. Planteamos la hipótesis de que la frecuencia de parasitismo en los vireos disminuiría con el aumento de la abundancia de huéspedes alternativos y aumentaría al incrementarse la abundancia de tordos. Todos los nidos del vireo gorrinegro ( n = 20) y el 81% de los nidos del vireo ojiblanco ( n = 27) fueron parasitados. La frecuencia de parasitismo en los vireos ojiblancos estaba correlacionada positivamente con el número de tordos detectados ( r = 0.84, gdl = 4, P = 0.018). Estaba correlacionada negativamente con la abundancia ( r = 0.891, gdl = 4, P = 0.009) del chipe trepador ( Mniotilta varia ), pero no estaba correlacionada con la abundancia de otros huéspedes de los tordos. La relación entre la abundancia de chipe trepador y la frecuencia da parasitismo podría ser aleatoria, dado lo pequeño de la muestra y la poca variación en las frecuencias de parasitismo, pero también podría reflejar una interacción entre el parasitismo y las características de la vegetación asociada con el chipe trepador que requiere más investigación. Nuestros resultados indican que la disminución de la abundancia de tordos reduce la frecuencia de parasitismo en el vireo gorrinegro. Cuando el número de tordos en una área predice el parasitismo, los administradores de recursos naturales podrían beneficiarse de la identificación de una abundancia meta del tordo, basada en los niveles de parasitismo que la población huésped pueda sostener y todavía alcanzar los objetivos de productividad y población de la especie.     

Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy

In pregnancy, trophoblast invasion and uterine spiral artery remodelling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery remodelling has been implicated in pre-eclampsia, a major complication of pregnancy, for a long time but the underlying mechanisms remain unclear. Corin (also known as atrial natriuretic peptide-converting enzyme) is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone that is important in regulating blood pressure. Unexpectedly, corin expression was detected in the pregnant uterus. Here we identify a new function of corin and ANP in promoting trophoblast invasion and spiral artery remodelling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of pre-eclampsia. In these mice, trophoblast invasion and uterine spiral artery remodelling were markedly impaired. Consistent with this, the ANP potently stimulated human trophoblasts in invading Matrigels. In patients with pre-eclampsia, uterine Corin messenger RNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified Corin gene mutations in pre-eclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to pre-eclampsia.     

Genome sequence of the Brown Norway rat yields insights into mammalian evolution

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.     

The genome of the model beetle and pest Tribolium castaneum

Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, some being expressed in the growth zone crucial for axial elongation in short-germ development. Systemic RNA interference in T. castaneum functions differently from that in Caenorhabditis elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.     

Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits β-catenin degradation

Ablation of tetraspanin protein TSPAN12 from human MDA-MB-231 cells significantly decreased primary tumor xenograft growth, while increasing tumor apoptosis. Furthermore, TSPAN12 removal markedly enhanced tumor-endothelial interactions and increased metastasis to mouse lungs. TSPAN12 removal from human MDA-MB-231 cells also caused diminished association between FZD4 (a key canonical Wnt pathway receptor) and its co-receptor LRP5. The result likely explains substantially enhanced proteosomal degradation of β-catenin, a key effecter of canonical Wnt signaling. Consistent with disrupted canonical Wnt signaling, TSPAN12 ablation altered expression of LRP5, Naked 1 and 2, DVL2, DVL3, Axin 1, and GSKβ3 proteins. TSPAN12 ablation also altered expression of several genes regulated by β-catenin (e.g. CCNA1, CCNE2, WISP1, ID4, SFN, ME1) that may help to explain altered tumor growth and metastasis. In conclusion, these results provide the first evidence for TSPAN12 playing a role in supporting primary tumor growth and suppressing metastasis. TSPAN12 appears to function by stabilizing FZD4–LRP5 association, in support of canonical Wnt-pathway signaling, leading to enhanced β-catenin expression and function.     

Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing

Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.     

Strict evolutionary conservation followed rapid gene loss on human and rhesus Y chromosomes

The human X and Y chromosomes evolved from an ordinary pair of autosomes during the past 200-300 million years. The human MSY (male-specific region of Y chromosome) retains only three percent of the ancestral autosomes' genes owing to genetic decay. This evolutionary decay was driven by a series of five 'stratification' events. Each event suppressed X-Y crossing over within a chromosome segment or 'stratum', incorporated that segment into the MSY and subjected its genes to the erosive forces that attend the absence of crossing over. The last of these events occurred 30 million years ago, 5 million years before the human and Old World monkey lineages diverged. Although speculation abounds regarding ongoing decay and looming extinction of the human Y chromosome, remarkably little is known about how many MSY genes were lost in the human lineage in the 25 million years that have followed its separation from the Old World monkey lineage. To investigate this question, we sequenced the MSY of the rhesus macaque, an Old World monkey, and compared it to the human MSY. We discovered that during the last 25 million years MSY gene loss in the human lineage was limited to the youngest stratum (stratum 5), which comprises three percent of the human MSY. In the older strata, which collectively comprise the bulk of the human MSY, gene loss evidently ceased more than 25 million years ago. Likewise, the rhesus MSY has not lost any older genes (from strata 1-4) during the past 25 million years, despite its major structural differences to the human MSY. The rhesus MSY is simpler, with few amplified gene families or palindromes that might enable intrachromosomal recombination and repair. We present an empirical reconstruction of human MSY evolution in which each stratum transitioned from rapid, exponential loss of ancestral genes to strict conservation through purifying selection.     

Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease.

Initially identified in high-grade gliomas, mutations in the PTEN tumor-suppressor are also found in many sporadic cancers and a few related autosomal dominant hamartoma syndromes. PTEN is a 3'-specific phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) phosphatase and functions as a negative regulator of PI3K signaling. We generated a tissue-specific deletion of the mouse homolog Pten to address its role in brain function. Mice homozygous for this deletion (PtenloxP/loxP;Gfap-cre), developed seizures and ataxia by 9 wk and died by 29 wk. Histological analysis showed brain enlargement in PtenloxP/loxP;Gfap-cre mice as a consequence of primary granule-cell dysplasia in the cerebellum and dentate gyrus. Pten mutant cells showed a cell-autonomous increase in soma size and elevated phosphorylation of Akt. These data represent the first evidence for the role of Pten and Akt in cell size regulation in mammals and provide an animal model for a human phakomatosis condition, Lhermitte-Duclos disease (LDD).     

Structural and functional relationships between photoreceptor tetraspanins and other superfamily members

The two primary photoreceptor-specific tetraspanins are retinal degeneration slow (RDS) and rod outer segment membrane protein-1 (ROM-1). These proteins associate together to form different complexes necessary for the proper structure of the photoreceptor outer segment rim region. Mutations in RDS cause blinding retinal degenerative disease in both rods and cones by mechanisms that remain unknown. Tetraspanins are implicated in a variety of cellular processes and exert their function via the formation of tetraspanin-enriched microdomains. This review focuses on correlations between RDS and other members of the tetraspanin superfamily, particularly emphasizing protein structure, complex assembly, and post-translational modifications, with the goal of furthering our understanding of the structural and functional role of RDS and ROM-1 in outer segment morphogenesis and maintenance, and our understanding of the pathogenesis associated with RDS and ROM-1 mutations.