BAFF activation of the ERK5 MAP kinase pathway regulates B cell survival

B cell activating factor (BAFF) stimulation of the BAFF receptor (BAFF-R) is essential for the homeostatic survival of mature B cells. Earlier in vitro experiments with inhibitors that block MEK 1 and 2 suggested that activation of ERK 1 and 2 MAP kinases is required for BAFF-R to promote B cell survival. However, these inhibitors are now known to also inhibit MEK5, which activates the related MAP kinase ERK5. In the present study, we demonstrated that BAFF-induced B cell survival was actually independent of ERK1/2 activation but required ERK5 activation. Consistent with this, we showed that conditional deletion of ERK5 in B cells led to a pronounced global reduction in mature B2 B cell numbers, which correlated with impaired survival of ERK5-deficient B cells after BAFF stimulation. ERK5 was required for optimal BAFF up-regulation of Mcl1 and Bcl2a1, which are prosurvival members of the Bcl-2 family. However, ERK5 deficiency did not alter BAFF activation of the PI3-kinase-Akt or NF-κB signaling pathways, which are also important for BAFF to promote mature B cell survival. Our study reveals a critical role for the MEK5-ERK5 MAP kinase signaling pathway in BAFF-induced mature B cell survival and homeostatic maintenance of B2 cell numbers

Kansas standard of need and self-sufficiency study, 1999: final report.

Supported by a grant from the Kansas Department of Social and Rehabilitation Services

The Reliability of Parafoveal Cone Density Measurements

Background Adaptive optics scanning light ophthalmoscopy (AOSLO) enables direct visualisation of the cone mosaic, with metrics such as cone density and cell spacing used to assess the integrity or health of the mosaic. Here we examined the interobserver and inter-instrument reliability of cone density measurements. Methods For the interobserver reliability study, 30 subjects with no vision-limiting pathology were imaged. Three image sequences were acquired at a single parafoveal location and aligned to ensure that the three images were from the same retinal location. Ten observers used a semiautomated algorithm to identify the cones in each image, and this was repeated three times for each image. To assess inter-instrument reliability, 20 subjects were imaged at eight parafoveal locations on one AOSLO, followed by the same set of locations on the second AOSLO. A single observer manually aligned the pairs of images and used the semiautomated algorithm to identify the cones in each image. Results Based on a factorial study design model and a variance components model, the interobserver study\u27s largest contribution to variability was the subject (95.72%) while the observer\u27s contribution was only 1.03%. For the inter-instrument study, an average cone density intraclass correlation coefficient (ICC) of between 0.931 and 0.975 was calculated. Conclusions With the AOSLOs used here, reliable cone density measurements can be obtained between observers and between instruments. Additional work is needed to determine how these results vary with differences in image quality

Perimacular Atrophy Following Voretigene Neparvovec-Rzyl Treatment in the Setting of Previous Contralateral Eye Treatment With a Different Viral Vector

PurposeTo report on cases of unilateral perimacular atrophy after treatment with voretigene neparvovec-rzyl, in the setting of previous contralateral eye treatment with a different viral vector.DesignSingle-center, retrospective chart review.MethodsIn this case series, four patients between the ages of six and 11 years old with RPE65-related retinopathy were treated unilaterally with rAAV2-CB-hRPE65 as part of a gene augmentation clinical trial (NCT00749957). Six to 10 years later the contralateral eyes were treated with the Food and Drug Administration-approved drug, voretigene neparvovec-rzyl. Best-corrected visual acuity (BCVA), fundus photos, ocular coherence tomography, two-color dark-adapted perimetry, full field stimulus threshold testing (FST), and location of subretinal bleb and chorioretinal atrophy were evaluated.ResultsThree out of four patients showed unilateral perimacular atrophy after treatment with voretigene, ranging from five to 22 months after treatment. Areas of robust visual field improvement were followed by areas of chorioretinal atrophy. Despite perimacular changes, BCVA, FST, and subjective improvements in vision and nyctalopia were maintained. Perimacular atrophy was not observed in the first eye treated with the previous viral vector.ConclusionsWe observed areas of robust visual field improvement followed by perimacular atrophy in voretigene treated eyes, as compared to the initially treated contralateral eyes.Translational relevanceCaution is advised when using two different viral vectors between eyes in gene therapy. This may become an important issue in the future with increasing gene therapy clinical trials for inherited retinal dystrophies

Radioactive wastes and the social amplification of risk

A significant problem in radioactive waste facility siting is that apparent small risks or minor risks events produce substantial public concern and social impacts. The reasons for this difference in public health and societal impacts is not well understood. This paper explores the issues involved in the social amplification of risk, using the risk associated with site characterization as the example. Noteworthy as sources of amplification are the infomation flow associated with risks and risk events including the large volume of information, the extent of dispute, and misinformation and rumor. Such information passes through the mass media and interpersonal networks. The major mechanisms involved in risk amplifications are discussed and their likely impacts on society described

PROPOSTA METODOLÓGICA PARA DEFINIÇÃO DE ÁREAS PRIORITÁRIAS PARA RECUPERAÇÃO VEGETAL DE ÁREAS DE PRESERVAÇÃO PERMANENTE

O crescimento populacional e a expansão urbana ocasionam fortes pressões nas áreas naturais, resultando na substituição das florestas e degradação ambiental. Assim, o estudo objetivou a proposição de uma metodologia para identificação e definição de áreas prioritárias para recuperação vegetal de Áreas de Preservação Permanente (APP) da Área de Proteção Ambiental (APA) do Ribeirão Engenho d’Água, localizada no município de Porto Feliz, SP. A metodologia consistiu na elaboração de diferentes planos de informação e análise multicritério apoiadas em ambiente de Sistema de Informação Geográfica e Sensoriamento Remoto. Os resultados revelaram que 74,52% das áreas de APP necessitam de recuperação ambiental. Quanto à declividade, 15,32% foi classificada como forte ou média nos extremos norte e sul, e na região central 84,68% variaram de fracas a muito fracas. Os solos apresentaram muito fraca erodibilidade em 72,9% da APA. O uso do solo revelou que 84,53% das áreas que necessitam de recuperação são ocupadas por culturas agrícolas; 7,11% por vegetação arbórea-arbustiva; 3,25% por áreas de várzea e pastagem; e pasto sujo totalizaram 3,94%. Em síntese, as áreas que apresentaram média e alta prioridade de recomposição das APPs compõem 9,34% da área de estudo, possuindo, em grande parte, solo do tipo argissolo vermelho e amarelo classificado com potencial de erosão médio a alto, e valores de declividade médios com elevação entre 12 a 20%. A proposta metodológica, auxiliada por geotecnologia, apresentou resultados bastante satisfatórios, podendo ser aplicada no diagnóstico ambiental de bacias hidrográficas com vistas à proteção dos recursos hídricos.

Venezuelan Equine Encephalitis Virus Capsid Implicated in Infection-Induced Cell Cycle Delay in vitro

Venezuelan equine encephalitis virus (VEEV) is a positive sense, single-stranded RNA virus and member of the New World alphaviruses. It causes a biphasic febrile illness that can be accompanied by central nervous system involvement and moderate morbidity in humans and severe mortality in equines. The virus has a history of weaponization, lacks FDA-approved therapeutics and vaccines in humans, and is considered a select agent. Like other RNA viruses, VEEV replicates in the cytoplasm of infected cells and eventually induces apoptosis. The capsid protein, which contains a nuclear localization and a nuclear export sequence, induces a shutdown of host transcription and nucleocytoplasmic trafficking. Here we show that infection with VEEV causes a dysregulation of cell cycling and a delay in the G0/G1 phase in Vero cells and U87MG astrocytes. Cells infected with VEEV encoding a capsid NLS mutant or treated with the capsid-importin α interaction inhibitor G281-1485 were partially rescued from this cell cycle dysregulation. Pathway analysis of previously published RNA-sequencing data from VEEV infected U87MG astrocytes identified alterations of canonical pathways involving cell cycle, checkpoint regulation, and proliferation. Multiple cyclins including cyclin D1, cyclin A2 and cyclin E2 and other regulators of the cell cycle were downregulated in infected cells in a capsid NLS dependent manner. Loss of Rb phosphorylation, which is a substrate for cyclin/cdk complexes was also observed. These data demonstrate the importance of capsid nuclear localization and/or importin α binding for inducing cell cycle arrest and transcriptional downregulation of key cell cycle regulators

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting