Calpains are a family of Ca 2؉ -dependent intracellular cysteine proteases, including the ubiquitously expressed -and m-calpains. Both -and m-calpains are heterodimers, consisting of a distinct large 80-kDa catalytic subunit, encoded by the genes Capn1 and Capn2, and a common small 28-kDa regulatory subunit (Capn4). The physiological roles and possible functional distinctions of -and m-calpains remain unclear, but suggested functions include participation in cell division and migration, integrin-mediated signal transduction, apoptosis, and regulation of cellular control proteins such as cyclin D1 and p53. Homozygous disruption of murine Capn4 eliminated both -and m-calpain activities, but this did not affect survival and proliferation of cultured embryonic stem cells or embryonic fibroblasts, or the early stages of organogenesis. However, mutant embryos died at midgestation and displayed defects in the cardiovascular system, hemorrhaging, and accumulation of erythroid progenitors.

The ubiquitous Fer protein-tyrosine kinase has been proposed to regulate diverse processes such as cell growth, cell adhesion, and neurite outgrowth. To gain insight into the biological function of Fer, we have targeted the fer locus with a kinase-inactivating missense mutation (fer D743R ). Mice homozygous for this mutation develop normally, have no overt phenotypic differences from wild-type mice, and are fertile. Since these mice lack both Fer and the testis-specific FerT kinase activities, these proteins are clearly not essential for development and survival. No differences were observed in overall cellularity of bone marrow, spleen, or thymus in the absence of Fer activity. While most platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation was unchanged in fer D743R homozygous embryonic fibroblasts, cortactin phosphorylation was reduced. However, Fer kinase activity was not required for PDGF-induced Stat3, p120 ctn , or epidermal growth factor (EGF)-induced ␤-catenin phosphorylation. Also, no defects were observed in changes to the actin cytoskeleton, adherens junctions, or focal adhesions in PDGF-or EGF-stimulated fer D743R homozygous embryonic fibroblasts. Therefore, Fer likely serves a redundant role in regulating cell growth, cell adhesion, retinal development, and spermatogenesis but is required for efficient phosphorylation of cortactin.

TYK2 is a JAK family protein tyrosine kinase activated in response to multiple cytokines, including type I IFNs, IL-6, IL-10, IL-12, and IL-23. Extensive studies of mice that lack TYK2 expression indicate that the IFN-α, IL-12, and IL-23 pathways, but not the IL-6 or IL-10 pathways, are compromised. In contrast, there have been few studies of the role of TYK2 in primary human cells. A genetic mutation at the tyk2 locus that results in a lack of TYK2 protein in a single human patient has been linked to defects in the IFN-α, IL-6, IL-10, IL-12, and IL-23 pathways, suggesting a broad role for TYK2 protein in human cytokine responses. In this article, we have used a panel of novel potent TYK2 small-molecule inhibitors with varying degrees of selectivity against other JAK kinases to address the requirement for TYK2 catalytic activity in cytokine pathways in primary human cells. Our results indicate that the biological processes that require TYK2 catalytic function in humans are restricted to the IL-12 and IL-23 pathways, and suggest that inhibition of TYK2 catalytic activity may be an efficacious approach for the treatment of select autoimmune diseases without broad immunosuppression.

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Although mitogen-activated protein (MAP)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition is predicted to cause cell death by stabilization of the proapoptotic BH3-only protein BIM, the induction of apoptosis is often modest. To determine if addition of a Bcl-2 family inhibitor could increase the efficacy of a MEK inhibitor, we evaluated a panel of 53 non-small cell lung cancer and pancreatic cancer cell lines with the combination of navitoclax (ABT-263), a Bcl-2/Bcl-x L (BCL2/BCL2L1) antagonist, and a novel MAP kinase (MEK) inhibitor, G-963. The combination is synergistic in the majority of lines, with an enrichment of cell lines harboring KRAS mutations in the high synergy group. Cells exposed to G-963 arrest in G 1 and a small fraction undergo apoptosis. The addition of navitoclax to G-963 does not alter the kinetics of cell-cycle arrest, but greatly increases the percentage of cells that undergo apoptosis. The G-963/navitoclax combination was more effective than either single agent in the KRAS mutant H2122 xenograft model; BIM stabilization and PARP cleavage were observed in tumors, consistent with the mechanism of action observed in cell culture.

The self is shared with the eating disorder in AN, and separating the self from AN is crucial to recover from the disorder. Therapeutic interventions for AN need to target the enmeshed relationship between the self and the eating disorder, as opposed to focusing exclusively on weight and shape concerns.

Background: µ-calpain and m-calpain are ubiquitously expressed proteases implicated in cellular migration, cell cycle progression, degenerative processes and cell death. These heterodimeric enzymes are composed of distinct catalytic subunits, encoded by Capn1 (µ-calpain) or Capn2 (mcalpain), and a common regulatory subunit encoded by Capn4. Disruption of the mouse Capn4 gene abolished both µ-calpain and m-calpain activity, and resulted in embryonic lethality, thereby suggesting essential roles for one or both of these enzymes during mammalian embryogenesis. Disruption of the Capn1 gene produced viable, fertile mice implying that either m-calpain could compensate for the loss of µ-calpain, or that the loss of m-calpain was responsible for death of Capn4 -/-mice.

Children diagnosed with Asperger syndrome present a special challenge in the educational milieu. This article provides teachers with descriptions of seven defining characteristics of Asperger syndrome, in addition to suggestions and strategies for addressing these symptoms in the classroom. Behavioral and academic interventions based on the author 1 s teaching experiences with children with Asperger syndrome are offered.Children diagnosed with Asperger syndrome (AS; see Note) present a special challenge in the educational milieu. Typically viewed as eccentric and peculiar by classmates, their inept social skills often cause them to be made victims of scapegoating. Clumsiness and an obsessive interest in obscure subjects add to their "odd" presentation. Children with AS lack understanding of human relationships and the rules of social convention; they are naive and conspicuously lacking in common sense. Their inflexibility and inability to cope with change causes these individuals to be easily stressed and emotionally vulnerable. At the same time, children with AS (the majority of whom are boys) are often of average to above-average intelligence and have superior rote memories. Their single-minded pursuit of their interests can lead to great achievements later in life.Asperger syndrome is considered a disorder at the higher end of the autistic continuum. Comparing individuals within this continuum, Van Krevelen (cited in Wing, 1991) noted that the low-functioning child with autism "lives in a world of his own," whereas the higher functioning child with autism "lives in our world but in his own way" (p. 99).Naturally, not all children with AS are alike. Just as each child with AS has his or her own unique personality, "typical" AS symptoms are manifested in ways specific to each individual. As a result, there is no exact recipe for classroom approaches that can be provided for every youngster with AS, just as no one educational method fits the needs of all children not afflicted with AS.Following are descriptions of seven defining characteristics of Asperger syndrome, followed by suggestions and classroom strategies for addressing these symptoms. (Classroom interventions are illustrated with examples from my own teaching experiences at the University of Michigan Medical Center Child and Adolescent Psychiatric Hospital School.) These suggestions are offered only in the broadest sense and should be tailored to the unique needs of the individual student with AS. Insistence on SamenessChildren with AS are easily overwhelmed by minimal change, are highly sensitive to environmental stressors, and sometimes engage in rituals. They are anxious and tend to worry obsessively when they do not know what to expect; stress, fatigue, and sensory overload easily throw them off balance. Programming Suggestions• Provide a predictable and safe environment; • Minimize transitions; • Offer consistent daily routine: The child with AS must understand each day's routine and know what to expect in order to be able to concentrate on the tas...