Multiple pathways regulate intracellular shuttling of MoKA, a co-activator of transcription factor KLF7

MoKA is a novel F-box containing protein that interacts with and stimulates the activity of transcription factor KLF7, a regulator of neuronal differentiation. MoKA accumulates throughout the cell and predominantly in the cytosol, consistent with the presence of several putative nuclear localization and export signals (NLSs and NESs). The present study was designed to refine the identity and location of the sequences responsible for MoKA intracellular shuttling and transcriptional activity. Forced expression of fusion proteins in mammalian cells demonstrated that only one of three putative NLSs potentially recognized by karyopherin receptors is involved in nuclear localization of MoKA. By contrast, three distinct sequences were found to participate in mediating cytoplasmic accumulation. One of them is structurally and functionally related to the leucine-rich export signal that interacts with the exportin 1 (CRM1) receptor. The other two export signals instead display either a novel leucine-rich sequence or an undefined peptide motif, and both appear to act through CRM1-independent pathways. Finally, transcriptional analyses using the chimeric GAL4 system mapped the major activation domain of MoKA to a highly acidic sequence that resides between the NLS and NES clusters

Early life stress and macaque annygdala hypertrophy: preliminary evidence for a role for the serotonin transporter gene

Background: Children exposed to early life stress (ELS) exhibit enlarged amygdala volume in comparison to controls. the primary goal of this study was to examine amygdala volumes in bonnet macaques subjected to maternal variable foraging demand (VFD) rearing, a well-established model of ELS. Preliminary analyses examined the interaction of ELS and the serotonin transporter gene on amygdala volume. Secondary analyses were conducted to examine the association between amygdala volume and other stress-related variables previously found to distinguish VFD and non-VFD reared animals.Methods: Twelve VFD-reared and nine normally reared monkeys completed MRI scans on a 3T system (mean age = 5.2 years).Results: Left amygdala volume was larger in VFD vs. control macaques. Larger amygdala volume was associated with: high cerebrospinal fluid concentrations of corticotropin releasing-factor (CRF) determined when the animals were in adolescence (mean age = 2.7 years); reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC) during young adulthood (mean age = 5.2 years) and timid anxiety-like responses to an intruder during full adulthood (mean age = 8.4 years). Right amygdala volume varied inversely with left hippocampal neurogenesis assessed in late adulthood (mean age = 8.7 years). Exploratory analyses also showed a gene-by-environment effect, with VFD-reared macaques with a single short allele of the serotonin transporter gene exhibiting larger amygdala volume compared to VFD-reared subjects with only the long allele and normally reared controls.Conclusion: These data suggest that the left amygdala exhibits hypertrophy after ELS, particularly in association with the serotonin transporter gene, and that amygdala volume variation occurs in concert with other key stress-related behavioral and neurobiological parameters observed across the lifecycle. Future research is required to understand the mechanisms underlying these diverse and persistent changes associated with ELS and amygdala volume.National Institute for Mental HealthNIMHNARSAD Mid-investigator AwardSuny Downstate Med Ctr, Dept Psychiat & Behav Sci, Brooklyn, NY 11203 USAUniversidade Federal de São Paulo, Dept Psiquiatria, São Paulo, BrazilMt Sinai Sch Med, Dept Psychiat, New York, NY USAMt Sinai Sch Med, Dept Neurosci, New York, NY USAMt Sinai Sch Med, Dept Radiol, New York, NY USANew York State Psychiat Inst & Hosp, New York, NY 10032 USAMichael E Debakey VA Med Ctr, Mental Hlth Care Line, Houston, TX USABaylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USAYale Univ, Sch Med, Dept Psychiat, New Haven, CT USANatl Ctr PTSD, Clin Neurosci Div, West Haven, CT USANew York State Psychiat Inst & Hosp, Dept Mol Imaging & Neuropathol, New York, NY 10032 USAColumbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USAColumbia Univ, Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY USAComprehensive NeuroSci Corp, Westchester, NY USAUniv Miami Hlth Sytems, Dept Psychiat & Behav Sci, Miami, FL USAEmory Univ, Sch Med, Dept Psychiat & Behav Sci, Emory, GA USAUniversidade Federal de São Paulo, Dept Psiquiatria, São Paulo, BrazilNational Institute for Mental Health: R01MH65519-01National Institute for Mental Health: R01MH098073NIMH: R21MH066748NIMH: R01MH59990AWeb of Scienc

Genetic Determinants of Phosphate Response in Drosophila

Phosphate is required for many important cellular processes and having too little phosphate or too much can cause disease and reduce life span in humans. However, the mechanisms underlying homeostatic control of extracellular phosphate levels and cellular effects of phosphate are poorly understood. Here, we establish Drosophila melanogaster as a model system for the study of phosphate effects. We found that Drosophila larval development depends on the availability of phosphate in the medium. Conversely, life span is reduced when adult flies are cultured on high phosphate medium or when hemolymph phosphate is increased in flies with impaired Malpighian tubules. In addition, RNAi-mediated inhibition of MAPK-signaling by knockdown of Ras85D, phl/D-Raf or Dsor1/MEK affects larval development, adult life span and hemolymph phosphate, suggesting that some in vivo effects involve activation of this signaling pathway by phosphate. To identify novel genetic determinants of phosphate responses, we used Drosophila hemocyte-like cultured cells (S2R+) to perform a genome-wide RNAi screen using MAPK activation as the readout. We identified a number of candidate genes potentially important for the cellular response to phosphate. Evaluation of 51 genes in live flies revealed some that affect larval development, adult life span and hemolymph phosphate levels

Fakturanoggrannhetsanalys kopplad till Distribution och Logistik Kedjan inom ERICSSON AB

Ericsson är ett världsledande telekommunikationsföretag som förhandlar två gånger per år med logistik tjänsteleverantörer, om priser och transportsträckor som är anslutna till logistisk nätverket. Förhandlingar resulterar i avtal och nya priser för den kommande perioden. Tidigare interna undersökningar visar att Ericsson har fakturerats högre, i jämförelse med de överenskomna priserna. Sammanlagt uppgår det till 7 - 8 siffrigt värde årligen. De tidigare interna undersökningarna identifierar överbetalningar, upptäckta med hänsyn till de uppsatta villkoren för accepterad överbetalningsmarginal i systemet. Inom denna studie skall fokus läggas på kostnader under de uppsatta kostnadsvillkoren i systemet. Genom detta redovisa kostnader som inte tas upp av den integrerade filtret i systemet.Uppdraget är att identifiera avvikelser kopplade till fakturaprocessen. Genom att identifiera uppkomna avvikelser, är målet att hitta främsta orsak för respektive avvikelse. Syftet är att finna en lämplig process för att förebygga framtida avvikelser. För att genomföra studien inom den uppsatta tidsramen, har avgränsning bestämts till att undersöka och analysera två stora logistikföretag. Dessa har anknytning till de tre länder som bidrog till flest överbetalningar under 2012. Teorier inom lean utveckling, processutveckling, supply chain management och EDI gentemot manuellt fakturaflöde, har studerats djupgående. Genom att kombinera en kvalitativ och kvantitativ studie, har det empiriska resultatet lett till identifiering av de mest frekventa avvikelser, kopplade till fakturaprocessen.Resultat från den genomförda studien har legat till grund, för att föreslå konkreta förbättringar, kopplade till fakturaprocessen. En uppsättning av sju genomförbara och kostnadseffektiva förbättringar inom informationsflödet, arbetsmetodik samt processflödet presenteras.1. Produktifiering av logistiktjänster2. Integration av prislistor in till SAP One3. Plattform för kommunikation4. Tydliggör aktörers ansvarsområde5. Andon lösning för kvalitetssäkring inom fakturaprocessen6. LSP tilldelas Ericssonsfraktkalkylator7. Informationsutökning till Prime log från LSPSamlingen består av kortsiktiga förslag som kan implementeras omgående, samt långsiktiga förslag i förebyggande syfte. Presenterade förbättringar är anpassade till respektive angelägen aktör. Rekommendation är att implementera föreslagna förbättringar, för att minska/eliminera de redovisade avvikelserna.A world leading telecommunication company, Ericsson negotiates twice a year with the logistics service providers, regarding prices and lanes connected to the logistics network. The negotiations results in agreements and new prices for the upcoming period. Previous internal studies reveal that Ericsson is being invoiced higher, compared to the agreed prices. The study reveals an overpayment value of 7 - 8 digits annually. Hence, revealing the overpayments detected by the set cost condition in the system. The conducted study will focus on the overpayments that are under the set cost condition in the system. By that, identifying the costs that are not been taken in consideration currently.The mission is to identify upcoming discrepancies, connected to the invoice process. By identifying upcoming discrepancies, the goal is to find the main reason for each detected discrepancy. By that, propose suitable processes for preventing future discrepancies.In order to investigate and conduct the required study, delimitation was made to analyse two major logistics providers. The study includes three targeted countries, which contributed to most discrepancies during 2012. Theories in lean development, process development, supply chain management and EDI vs. manual invoice flow have been studied in detail. By combining a qualitative and quantitative scientific approach, the empirical results have revealed the most upcoming discrepancies, connected to the invoice process.The result from the conducted study has been the main foundation, in order to suggest tangible improvements, connected to the invoice process. A set of seven tangible and cost efficient improvements, within the information flow, work methodology and process flow are presented.1. Productify Logistics Services2. Integration of Pricelists into SAP One3. Platform for Communication4. Stakeholder Clarification5. Andon Solution for Invoice Quality Assurance6. Provide LSP with Ericsson Freight Calculator7. Extended Information into Prime log from LSPThe collection consists of short term proposals that can be implemented immediately and long term proposals for preventive purposes. The proposed improvements are adapted to each involved stakeholder. Recommendation is to implement the proposed improvements, in order to reduce/eliminate the detected discrepancies

Early-life stress, corticotropin-releasing factor, and serotonin transporter gene: A pilot study

Recent studies have indicated a gene-by-environment interaction between serotonin transporter gene (5-HTTLPR) polymorphism and childhood abuse on depressive symptoms. In addition, persistent elevation of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations following early-life adversity has been posited to underlie the subsequent development of major depression. This pilot study tested the hypothesis that elevations of juvenile CSF CRF concentrations are, in part, determined by an interaction between polymorphisms of the 5-HTTLPR and early-life stress. Nine juvenile male bonnet macaques ( Macaca radiata) had been raised under variable foraging demand (VFD) conditions, a nonhuman primate model of early-life stress, whereas nine subjects were normatively raised under LFD (low foraging demand) conditions. Genotyping revealed that four (44.4%) of the VFD-reared monkeys possessed at least one “s” allele whereas five VFD monkeys were of the l/l genotype. Of the nine LFD subjects, two (22%) had the s/l genotype and seven had the l/l genotype. A “juvenile” CSF sample was obtained at approximately 3 years of age. CSF CRF concentrations were elevated specifically in the VFD “s/s” and “s/l” allele group in comparison to each of the remaining three groups, indicating a gene-by-environment (G × E) interaction