IBM announced today that Portland Software, one of New Zealand’s fastest growing technology companies, has created a fully integrated employee benefits administration platform on IBM Cloud.

Etude IBM : les directions Marketing doivent adopter la « disruption créative » pour fidéliser leurs clients La nouvelle étude IBM révèle les principaux axes de priorités des directions Marketing pour 2016

IBM (NYSE: IBM) today announced that Bendigo and Adelaide Bank has selected IBM XIV Storage System Gen3 as a key infrastructure component for its ongoing development and delivery of customer-focussed business applications.

IBM (NYSE: IBM) today announced that the Australian Bureau of Statistics (ABS) is adopting IBM social software to support the way thousands of employees connect and interact.

Dopravní podniky i soukromí dopravci obnovují běžné jízdní řády. Přestože stále hromadnou dopravu využívá zlomek lidí než před zahájením karanténních opaření, poklesy o 80 nebo 90 procent proti běžnému stavu už jsou minulostí.

Mezinárodní ratingová agentura Fitch Ratings snížila hodnocení úvěrové spolehlivosti Slovenska o jeden stupeň na úroveň A se stabilním výhledem. Důvodem jsou hlavně dopady koronaviru na slovenskou ekonomiku. Jde o první změnu ratingu země v době pandemie.

Probert was adopted 6 years ago at about 11 months old from a rescue in Columbus, OH called Measle's Animal Haven. He was a scrawny little pup who had been abused, rescued, and then contracted a mild case of parvo (mild due to being an older puppy) and been bitten by another dog in rescue. Now he's a little snugglebutt who still has issues from his past, but over just the past couple of years is really learning to be a DOG. Finally.


Wrigley was adopted 7 years ago at about 5 months old. He was a direct rescue from people who didn't want him. They said they were watching him for someone who went out of town and never returned to pick him up. Wrigley was living life underneath a trailer at the end of a tow chain and had never even been given a name. The people who had him did doxie rescue and had about 9 rescue dogs in their house, but never thought to bring Wrigley indoors because of his breed. To their credit, they did make some effort to rehome him and I was happy to invite him into my pack! Now he is a wiggly goofball. Definitely the most challenging of my dogs due to his guard barking, but he makes up for it by being one of the most genuinely sweet souls I've ever encountered.





So, there it is. Happy Adoptaversaries to all of my babies. My life would simply NOT be the same without you. I love you all so so much.

Three-time Olympic champion Sun Yang has lodged an appeal an appeal to the Swiss federal court in an attempt to overturn his eight-year doping ban.

HELLO! PLEASE DISABLE YOUR ADBLOCKER OR WHITELIST US! THANKS FOR YOUR SUPPORT!!

People are growing increasingly impatient over the coronavirus lockdown, and politicians are now debating whether to loosen measures. From a scientific point of view this is a disaster. Measures should actually be tightened until we know more about the virus.

Shelter in place orders (SIPOs) require residents to remain home for all but essential activities such as purchasing food or medicine, caring for others, exercise, or traveling for employment deemed essential. Between March 19 and April 20, 2020, 40 states and the District of Columbia adopted SIPOs. This study explores the impact of SIPOs on health, with particular attention to heterogeneity in their impacts. First, using daily state-level social distancing data from SafeGraph and a difference-in-differences approach, we document that adoption of a SIPO was associated with a 5 to 10 percent increase in the rate at which state residents remained in their homes full-time. Then, using daily state-level coronavirus case data collected by the Centers for Disease Control and Prevention, we find that approximately three weeks following the adoption of a SIPO, cumulative COVID-19 cases fell by 44 percent. Event-study analyses confirm common COVID-19 case trends in the week prior to SIPO adoption and show that SIPO-induced case reductions grew larger over time. However, this average effect masks important heterogeneity across states — early adopters and high population density states appear to reap larger benefits from their SIPOs. Finally, we find that statewide SIPOs were associated with a reduction in coronavirus-related deaths, but estimated mortality effects were imprecisely estimated.

The Times has updated its guidelines for covering the LGBTQ community.

Indiana businesses operating during the coronavirus should follow certain sanitation measures. Guidelines vary based on a worker's risk of exposure.

The "notorious" Supreme Court justice posed for pictures with the actress, who was attending a performance of "Fiddler on the Roof" in New York.

Last year, when we felt interest in artificial intelligence (AI) was approaching a fever pitch, we created a survey to ask about AI adoption. When we analyzed the results, we determined the AI space was in a state of rapid change, so we eagerly commissioned a follow-up survey to help find out where AI stands […]

Myriam Ferro
May 1, 2003; 2:325-345
Research

Joris J. Benschop
Jul 1, 2007; 6:1198-1214
Research

Heterotrimeric G proteins mediate a variety of signaling processes by coupling G protein–coupled receptors to intracellular effector molecules. In Drosophila, the Gαq gene encodes several Gαq splice variants, with the Gαq1 isoform protein playing a major role in fly phototransduction. However, Gαq1 null mutant flies still exhibit a residual light response, indicating that other Gαq splice variants or additional Gq α subunits are involved in phototransduction. Here, we isolated a mutant fly with no detectable light responses, decreased rhodopsin (Rh) levels, and rapid retinal degeneration. Using electrophysiological and genetic studies, biochemical assays, immunoblotting, real-time RT-PCR, and EM analysis, we found that mutations in the Gαq gene disrupt light responses and demonstrate that the Gαq3 isoform protein is responsible for the residual light response in Gαq1 null mutants. Moreover, we report that Gαq3 mediates rhodopsin synthesis. Depletion of all Gαq splice variants led to rapid light-dependent retinal degeneration, due to the formation stable Rh1-arrestin 2 (Arr2) complexes. Our findings clarify essential roles of several different Gαq splice variants in phototransduction and retinal integrity in Drosophila and reveal that Gαq3 functions in rhodopsin synthesis.

Nica M. Borradaile
Dec 1, 2006; 47:2726-2737
Research Articles

Following its evoked release, dopamine (DA) signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DA transporter (DAT). DAT surface availability is dynamically regulated by endocytic trafficking, and direct protein kinase C (PKC) activation acutely diminishes DAT surface expression by accelerating DAT internalization. Previous cell line studies demonstrated that PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT. However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis in DAergic terminals or whether there are region- and/or sex-dependent differences in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 controls PKC-stimulated DAT endocytosis are unknown. Here, we directly examined these important questions. Ex vivo studies revealed that PKC activation acutely decreased DAT surface expression selectively in ventral, but not dorsal, striatum. AAV-mediated, conditional Rit2 knockdown in DAergic neurons impacted baseline DAT surface:intracellular distribution in DAergic terminals from female ventral, but not dorsal, striatum. Further, Rit2 was required for PKC-stimulated DAT internalization in both male and female ventral striatum. FRET and surface pulldown studies in cell lines revealed that PKC activation drives DAT-Rit2 surface dissociation and that the DAT N terminus is required for both PKC-mediated DAT-Rit2 dissociation and DAT internalization. Finally, we found that Rit2 and Ack1 independently converge on DAT to facilitate PKC-stimulated DAT endocytosis. Together, our data provide greater insight into mechanisms that mediate PKC-regulated DAT internalization and reveal unexpected region-specific differences in PKC-stimulated DAT trafficking in bona fide DAergic terminals.

Heterotrimeric G proteins mediate a variety of signaling processes by coupling G protein–coupled receptors to intracellular effector molecules. In Drosophila, the Gαq gene encodes several Gαq splice variants, with the Gαq1 isoform protein playing a major role in fly phototransduction. However, Gαq1 null mutant flies still exhibit a residual light response, indicating that other Gαq splice variants or additional Gq α subunits are involved in phototransduction. Here, we isolated a mutant fly with no detectable light responses, decreased rhodopsin (Rh) levels, and rapid retinal degeneration. Using electrophysiological and genetic studies, biochemical assays, immunoblotting, real-time RT-PCR, and EM analysis, we found that mutations in the Gαq gene disrupt light responses and demonstrate that the Gαq3 isoform protein is responsible for the residual light response in Gαq1 null mutants. Moreover, we report that Gαq3 mediates rhodopsin synthesis. Depletion of all Gαq splice variants led to rapid light-dependent retinal degeneration, due to the formation stable Rh1-arrestin 2 (Arr2) complexes. Our findings clarify essential roles of several different Gαq splice variants in phototransduction and retinal integrity in Drosophila and reveal that Gαq3 functions in rhodopsin synthesis.

Human leukocyte antigen (HLA) B*51:01 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly genetically associated with Behcet's disease (BD). Previous studies have defined two subgroups of HLA-B*51 peptidome containing proline (Pro) or alanine (Ala) at position 2 (P2). Little is known about the unconventional non-Pro/Ala2 HLA-B*51-bound peptides. We aimed to study the features of this novel subpeptidome, and investigate its regulation by ERAP1. CRISPR-Cas9 was used to generate an HLA-ABC-triple knockout HeLa cell line (HeLa.ABC-KO), which was subsequently transduced to express HLA-B*51:01 (HeLa.ABC-KO.B51). ERAP1 was silenced using lentiviral shRNA. Peptides bound to HLA-B*51:01 were eluted and analyzed by mass spectrometry. The characteristics of non-Pro/Ala2, Pro2, and Ala2 peptides and their alteration by ERAP1 silencing were investigated. Effects of ERAP1 silencing on cell surface expression of HLA-B*51:01 were studied using flow cytometry. More than 20% of peptides eluted from HLA-B*51:01 lacked Pro or Ala at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared with the Pro2 and Ala2 subpeptidomes and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant leucine at position ). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to ~40%, increased the percentage of longer (10-mer and 11-mer) peptides eluted from HLA-B*51:01 complexes, and abrogated the predominance of leucine at P1. Interestingly knockdown of ERAP1 altered the length and N-terminal residue usage of non-Ala2&Pro2 and Ala2 but not the Pro2 peptides. Finally, ERAP1 silencing regulated the expression levels of cell surface HLA-B*51 in a cell-type-dependent manner. In conclusion, we have used a novel methodology to identify an unconventional but surprisingly abundant non-Pro/Ala2 HLA-B*51:01 subpeptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.

euromicron AG, a medium-sized technology group and expert on digital networking of business and production processes, held its Annual General Meeting 2019 in Frankfurt/Main on August 29, 2019. 42 percent of the share capital was represented. At the Annual General Meeting, the Executive Board reported on the operating performance in fiscal year 2018 and in the first half of 2019 and gave an outlook on the current fiscal year. One focus was on the implementation of the measures initiated to focus on and further develop the business model.

Following its evoked release, dopamine (DA) signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DA transporter (DAT). DAT surface availability is dynamically regulated by endocytic trafficking, and direct protein kinase C (PKC) activation acutely diminishes DAT surface expression by accelerating DAT internalization. Previous cell line studies demonstrated that PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT. However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis in DAergic terminals or whether there are region- and/or sex-dependent differences in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 controls PKC-stimulated DAT endocytosis are unknown. Here, we directly examined these important questions. Ex vivo studies revealed that PKC activation acutely decreased DAT surface expression selectively in ventral, but not dorsal, striatum. AAV-mediated, conditional Rit2 knockdown in DAergic neurons impacted baseline DAT surface:intracellular distribution in DAergic terminals from female ventral, but not dorsal, striatum. Further, Rit2 was required for PKC-stimulated DAT internalization in both male and female ventral striatum. FRET and surface pulldown studies in cell lines revealed that PKC activation drives DAT-Rit2 surface dissociation and that the DAT N terminus is required for both PKC-mediated DAT-Rit2 dissociation and DAT internalization. Finally, we found that Rit2 and Ack1 independently converge on DAT to facilitate PKC-stimulated DAT endocytosis. Together, our data provide greater insight into mechanisms that mediate PKC-regulated DAT internalization and reveal unexpected region-specific differences in PKC-stimulated DAT trafficking in bona fide DAergic terminals.

Heterotrimeric G proteins mediate a variety of signaling processes by coupling G protein–coupled receptors to intracellular effector molecules. In Drosophila, the Gαq gene encodes several Gαq splice variants, with the Gαq1 isoform protein playing a major role in fly phototransduction. However, Gαq1 null mutant flies still exhibit a residual light response, indicating that other Gαq splice variants or additional Gq α subunits are involved in phototransduction. Here, we isolated a mutant fly with no detectable light responses, decreased rhodopsin (Rh) levels, and rapid retinal degeneration. Using electrophysiological and genetic studies, biochemical assays, immunoblotting, real-time RT-PCR, and EM analysis, we found that mutations in the Gαq gene disrupt light responses and demonstrate that the Gαq3 isoform protein is responsible for the residual light response in Gαq1 null mutants. Moreover, we report that Gαq3 mediates rhodopsin synthesis. Depletion of all Gαq splice variants led to rapid light-dependent retinal degeneration, due to the formation stable Rh1-arrestin 2 (Arr2) complexes. Our findings clarify essential roles of several different Gαq splice variants in phototransduction and retinal integrity in Drosophila and reveal that Gαq3 functions in rhodopsin synthesis.

Elena Lorente
Apr 7, 2020; 0:RA120.002014v1-mcp.RA120.002014
Research

Liye Chen
May 1, 2020; 19:871-883
Research

⁶⁸Ga-DOTATOC-PET/MRI (⁶⁸Gallium-DOTATOC-positron emission tomography/magnetic resonance imaging) combines the advantages of PET in the acquisition of metabolic-functional information with the high soft tissue contrast of MRI. Standardized uptake values (SUV) in tumors were suggested as a measure of somatostatin receptor expression. A challenge with receptor ligands is, that the distribution volume is confined to tissues with tracer-uptake, potentially limiting SUV quantification. In this study, different functional, three-dimensional (3D) SUV, apparent diffusion coefficient (ADC) parameters and arterial tumor enhancement were tested for the characterization of gastroendopancreatic neuroendocrine tumors (GEP-NET). Methods: For this single-center, cross-sectional study, 22 patients with 24 histologically confirmed GEP-NET lesions (15 men/7 women; median, 61 years, range, 43-81 years), who received hybrid ⁶⁸Ga-DOTA-PET/MRI examinations at 3T between January 2017 and July 2019 met eligibility criteria. SUVs, tumor-to-background ratios (TBR), the total functional tumor volume (TFTV), ADCmean and ADCmin were measured based on volumes of interest (VOI) and examined with receiver operating characteristic analysis to determine cut-off values for differentiation between low and intermediate grade GEP-NET. Spearman’s rank correlation coefficients were used to assess correlations between functional imaging parameters. Results: The ratio of PET-derived SUVmean and diffusion-weighted imaging (DWI)-derived ADCmin was introduced as a combined variable to predict tumor grade, outperforming single predictors. Based on a threshold ratio of 0.03 to be exceeded, tumors could be classified as grade 2 with a sensitivity of 86% and specificity of 100%. SUV and functional ADC values as well as arterial contrast enhancement parameters showed non-significant and mostly negligible correlations. Conclusion: As receptor density and tumor cellularity appear to be independent, potentially complementary phenomena, the combined PET/MRI ratio SUVmean/ADCmin may be used as a novel biomarker, allowing to differentiate between grade 1 and 2 GEP-NET.