Susceptibility to LAK-mediated Cytotoxicity of Multidrug-resistant Variants of the Human RAJI Cell Line is Not Related to Expression of Major Cellular Adhesion Molecules

Author Institution: Department of Biology, Oberlin CollegeThe association of multidrug resistance (MDR) with resistance to lysis by natural killer (NK) and lymphokine-activated killer (LAK) cells is controversial. To address this issue further, drug-resistant variants of a human Burkitt lymphoma cell line (RAJI) were developed in vitro by intermittent exposure to Adriamycin® (R/ADR) or to etoposide (R/VP-16). The RAJI cell line was selected because it is a standard LAK-susceptible target. Both MDR lines as well as the parent cell line were found to be resistant to NK-mediated lysis, but highly susceptible to LAK-mediated lysis. Notably, R/ADR cells, which express high levels of P-glycoprotein (P-gp), were nearly eight-times more susceptible to LAK-mediated lysis than parental cells, whereas R/VP-16 cells, which are P-gp-negative, were equally as susceptible as parental cells. Immunofluorescence analyses revealed that expression of cellular adhesion molecules that have been reported to control susceptibility of targets to NK- and LAK-lysis (ICAM-1, LFA-1, LFA-3, and MHC class I) did not differ significantly between the RAJI parent line and drug-resistant variants. This finding suggests that the increased LAK-sensitivity of R/ADR results from alterations which affect postbinding stages of the LAK lytic pathway

The consolidation and effectiveness of matrix support in mental health in Brazil - bottlenecks and challenges

Passados dez anos da implementação do apoio matricial nas redes de saúde por meio dos Núcleos de Apoio à Saúde da Família, ainda sente-se a falta de dados consistentes quanto à consolidação e efetividade desse arranjo. Nesse sentido, este estudo teve como objetivo revisar a bibliografia nacional dos últimos dez anos a fim de identificar os impasses e desafios vivenciados no apoio matricial em saúde mental na Atenção Primária, classificando-os a partir de uma reconstrução teórico-conceitual e fazendo uma articulação destes com os desafios pontuados em congêneres internacionais do apoio matricial. Entre os principais pontos levantados pelo estudo, destacou-se a necessidade de delineamentos claros para prática de matriciamento; investimento maciço em formação e capacitação dos profissionais; e criação de espaços institucionalizados com encontros sistemáticos dos profissionais para discussão dos casos e avaliação conjunta do andamento das atividades23COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESsem informaçãoTen years on from the introduction of matrix support in health networks through the creation of Family Health Support Centers, there is still a lack of consistent data to measure the success of consolidation and effectiveness of this arrangement. With this in mind, we conducted a literature review of national articles produced over the last ten years to identify the bottlenecks and challenges faced by matrix support in mental health in Primary Care. The problems were classified using a theoretical and conceptual reconstruction and drawing on similar experiences with matrix support in other countries. The following key points emerged from the review: the need to provide clear guidelines for matrix support; the need for major investment in training and capacity building; and the need to create institutionalized spaces to foster systematic communication between professionals to discuss cases and promote joint evaluation of the progress of activitie

Atmospheric Muon Flux at Sea Level, Underground, and Underwater

The vertical sea-level muon spectrum at energies above 1 GeV and the underground/underwater muon intensities at depths up to 18 km w.e. are calculated. The results are particularly collated with a great body of the ground-level, underground, and underwater muon data. In the hadron-cascade calculations, the growth with energy of inelastic cross sections and pion, kaon, and nucleon generation in pion-nucleus collisions are taken into account. For evaluating the prompt muon contribution to the muon flux, we apply two phenomenological approaches to the charm production problem: the recombination quark-parton model and the quark-gluon string model. To solve the muon transport equation at large depths of homogeneous medium, a semi-analytical method is used. The simple fitting formulas describing our numerical results are given. Our analysis shows that, at depths up to 6-7 km w. e., essentially all underground data on the muon intensity correlate with each other and with predicted depth-intensity relation for conventional muons to within 10%. However, the high-energy sea-level data as well as the data at large depths are contradictory and cannot be quantitatively decribed by a single nuclear-cascade model.Comment: 47 pages, REVTeX, 15 EPS figures included; recent experimental data and references added, typos correcte

The Association between Mental Health and Violence among a Nationally Representative Sample of College Students from the United States

Objectives Recent violent attacks on college campuses in the United States have sparked discussions regarding the prevalence of psychiatric disorders and the perpetration of violence among college students. While previous studies have examined the potential association between mental health problems and violent behavior, the overall pattern of findings flowing from this literature remain mixed and no previous studies have examined such associations among college students. Methods The current study makes use of a nationally representative sample of 3,929 college students from the National Epidemiologic Study on Alcohol and Related Conditions (NESARC) to examine the prevalence of seven violent behaviors and 19 psychiatric disorder diagnoses tapping mood, anxiety, personality, and substance use disorders. Associations between individual and composite psychiatric disorder diagnoses and violent behaviors were also examined. Additional analyses were adjusted for the comorbidity of multiple psychiatric diagnoses. Results The results revealed that college students were less likely to have engaged in violent behavior relative to the non-student sample, but a substantial portion of college students had engaged in violent behavior. Age- and sex-standardized prevalence rates indicated that more than 21% of college students reported at least one violent act. In addition, more than 36% of college students had at least one diagnosable psychiatric disorder. Finally, the prevalence of one or more psychiatric disorders significantly increased the odds of violent behavior within the college student sample. Conclusions These findings indicate that violence and psychiatric disorders are prevalent on college campuses in the United States, though perhaps less so than in the general population. In addition, college students who have diagnosable psychiatric disorders are significantly more likely to engage in various forms of violent behavior

E-Cadherin Acts as a Regulator of Transcripts Associated with a Wide Range of Cellular Processes in Mouse Embryonic Stem Cells

We have recently shown that expression of the cell adhesion molecule E-cadherin is required for LIF-dependent pluripotency of mouse embryonic stem (ES) cells.In this study, we have assessed global transcript expression in E-cadherin null (Ecad-/-) ES cells cultured in either the presence or absence of LIF and compared these to the parental cell line wtD3.We show that LIF has little effect on the transcript profile of Ecad-/- ES cells, with statistically significant transcript alterations observed only for Sp8 and Stat3. Comparison of Ecad-/- and wtD3 ES cells cultured in LIF demonstrated significant alterations in the transcript profile, with effects not only confined to cell adhesion and motility but also affecting, for example, primary metabolic processes, catabolism and genes associated with apoptosis. Ecad-/- ES cells share similar, although not identical, gene expression profiles to epiblast-derived pluripotent stem cells, suggesting that E-cadherin expression may inhibit inner cell mass to epiblast transition. We further show that Ecad-/- ES cells maintain a functional β-catenin pool that is able to induce β-catenin/TCF-mediated transactivation but, contrary to previous findings, do not display endogenous β-catenin/TCF-mediated transactivation. We conclude that loss of E-cadherin in mouse ES cells leads to significant transcript alterations independently of β-catenin/TCF transactivation

Non-Redundant Selector and Growth-Promoting Functions of Two Sister Genes, buttonhead and Sp1, in Drosophila Leg Development

The radically distinct morphologies of arthropod and tetrapod legs argue that these appendages do not share a common evolutionary origin. Yet, despite dramatic differences in morphology, it has been known for some time that transcription factors encoded by the Distalless (Dll)/Dlx gene family play a critical role in the development of both structures. Here we show that a second transcription factor family encoded by the Sp8 gene family, previously implicated in vertebrate limb development, also plays an early and fundamental role in arthropod leg development. By simultaneously removing the function of two Sp8 orthologs, buttonhead (btd) and Sp1, during Drosophila embryogenesis, we find that adult leg development is completely abolished. Remarkably, in the absence of these factors, transformations from ventral to dorsal appendage identities are observed, suggesting that adult dorsal fates become derepressed when ventral fates are eliminated. Further, we show that Sp1 plays a much more important role in ventral appendage specification than btd and that Sp1 lies genetically upstream of Dll. In addition to these selector-like gene functions, Sp1 and btd are also required during larval stages for the growth of the leg. Vertebrate Sp8 can rescue many of the functions of the Drosophila genes, arguing that these activities have been conserved, despite more than 500 million years of independent evolution. These observations suggest that an ancient Sp8/Dlx gene cassette was used in an early metazoan for primitive limb-like outgrowths and that this cassette was co-opted multiple times for appendage formation in multiple animal phyla

E-Cadherin Acts as a Regulator of Transcripts Associated with a Wide Range of Cellular Processes in Mouse Embryonic Stem Cells

We have recently shown that expression of the cell adhesion molecule E-cadherin is required for LIF-dependent pluripotency of mouse embryonic stem (ES) cells.In this study, we have assessed global transcript expression in E-cadherin null (Ecad-/-) ES cells cultured in either the presence or absence of LIF and compared these to the parental cell line wtD3.We show that LIF has little effect on the transcript profile of Ecad-/- ES cells, with statistically significant transcript alterations observed only for Sp8 and Stat3. Comparison of Ecad-/- and wtD3 ES cells cultured in LIF demonstrated significant alterations in the transcript profile, with effects not only confined to cell adhesion and motility but also affecting, for example, primary metabolic processes, catabolism and genes associated with apoptosis. Ecad-/- ES cells share similar, although not identical, gene expression profiles to epiblast-derived pluripotent stem cells, suggesting that E-cadherin expression may inhibit inner cell mass to epiblast transition. We further show that Ecad-/- ES cells maintain a functional β-catenin pool that is able to induce β-catenin/TCF-mediated transactivation but, contrary to previous findings, do not display endogenous β-catenin/TCF-mediated transactivation. We conclude that loss of E-cadherin in mouse ES cells leads to significant transcript alterations independently of β-catenin/TCF transactivation

Sp6 and Sp8 transcription factors control AER formation and dorsal-ventral patterning in limb development

The formation and maintenance of the apical ectodermal ridge (AER) is critical for the outgrowth and patterning of the vertebrate limb. The induction of the AER is a complex process that relies on integrated interactions among the Fgf, Wnt, and Bmp signaling pathways that operate within the ectoderm and between the ectoderm and the mesoderm of the early limb bud. The transcription factors Sp6 and Sp8 are expressed in the limb ectoderm and AER during limb development. Sp6 mutant mice display a mild syndactyly phenotype while Sp8 mutants exhibit severe limb truncations. Both mutants show defects in AER maturation and in dorsal-ventral patterning. To gain further insights into the role Sp6 and Sp8 play in limb development, we have produced mice lacking both Sp6 and Sp8 activity in the limb ectoderm. Remarkably, the elimination or significant reduction in Sp6;Sp8 gene dosage leads to tetra-amelia; initial budding occurs, but neither Fgf8 nor En1 are activated. Mutants bearing a single functional allele of Sp8 (Sp6-/-;Sp8+/-) exhibit a split-hand/foot malformation phenotype with double dorsal digit tips probably due to an irregular and immature AER that is not maintained in the center of the bud and on the abnormal expansion of Wnt7a expression to the ventral ectoderm. Our data are compatible with Sp6 and Sp8 working together and in a dose-dependent manner as indispensable mediators of Wnt/βcatenin and Bmp signaling in the limb ectoderm. We suggest that the function of these factors links proximal-distal and dorsal-ventral patterning