Basecamp’s newest product HEY has lived on Kubernetes since development first began. While our applications are majestic monoliths, a product like HEY has numerous supporting services that run along-side the main app like our mail pipeline (Postfix and friends), Resque (and Resque Scheduler), and nginx, making Kubernetes a great orchestration option for us. As you… keep reading

Heterotrimeric G proteins are the core upstream elements that transduce and amplify the cellular signals from G protein–coupled receptors (GPCRs) to intracellular effectors. GPCRs are the largest family of membrane proteins encoded in the human genome and are the targets of about one-third of prescription medicines. However, to date, no single therapeutic agent exerts its effects via perturbing heterotrimeric G protein function, despite a plethora of evidence linking G protein malfunction to human disease. Several recent studies have brought to light that the Gq family–specific inhibitor FR900359 (FR) is unexpectedly efficacious in silencing the signaling of Gq oncoproteins, mutant Gq variants that mostly exist in the active state. These data not only raise the hope that researchers working in drug discovery may be able to potentially strike Gq oncoproteins from the list of undruggable targets, but also raise questions as to how FR achieves its therapeutic effect. Here, we place emphasis on these recent studies and explain why they expand our pharmacological armamentarium for targeting Gq protein oncogenes as well as broaden our mechanistic understanding of Gq protein oncogene function. We also highlight how this novel insight impacts the significance and utility of using G(q) proteins as targets in drug discovery efforts.

Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies.

Type IV filaments (T4F), which are helical assemblies of type IV pilins, constitute a superfamily of filamentous nanomachines virtually ubiquitous in prokaryotes that mediate a wide variety of functions. The competence (Com) pilus is a widespread T4F, mediating DNA uptake (the first step in natural transformation) in bacteria with one membrane (monoderms), an important mechanism of horizontal gene transfer. Here, we report the results of genomic, phylogenetic, and structural analyses of ComGC, the major pilin subunit of Com pili. By performing a global comparative analysis, we show that Com pili genes are virtually ubiquitous in Bacilli, a major monoderm class of Firmicutes. This also revealed that ComGC displays extensive sequence conservation, defining a monophyletic group among type IV pilins. We further report ComGC solution structures from two naturally competent human pathogens, Streptococcus sanguinis (ComGCSS) and Streptococcus pneumoniae (ComGCSP), revealing that this pilin displays extensive structural conservation. Strikingly, ComGCSS and ComGCSP exhibit a novel type IV pilin fold that is purely helical. Results from homology modeling analyses suggest that the unusual structure of ComGC is compatible with helical filament assembly. Because ComGC displays such a widespread distribution, these results have implications for hundreds of monoderm species.

Amelia C. Peterson
Nov 1, 2012; 11:1475-1488
Technological Innovation and Resources

Hasmik Keshishian
Dec 1, 2007; 6:2212-2229
Research

Ludovic C. Gillet
Jun 1, 2012; 11:O111.016717-O111.016717
Research

Jesper V. Olsen
Dec 1, 2005; 4:2010-2021
Technology

Heterotrimeric G proteins are the core upstream elements that transduce and amplify the cellular signals from G protein–coupled receptors (GPCRs) to intracellular effectors. GPCRs are the largest family of membrane proteins encoded in the human genome and are the targets of about one-third of prescription medicines. However, to date, no single therapeutic agent exerts its effects via perturbing heterotrimeric G protein function, despite a plethora of evidence linking G protein malfunction to human disease. Several recent studies have brought to light that the Gq family–specific inhibitor FR900359 (FR) is unexpectedly efficacious in silencing the signaling of Gq oncoproteins, mutant Gq variants that mostly exist in the active state. These data not only raise the hope that researchers working in drug discovery may be able to potentially strike Gq oncoproteins from the list of undruggable targets, but also raise questions as to how FR achieves its therapeutic effect. Here, we place emphasis on these recent studies and explain why they expand our pharmacological armamentarium for targeting Gq protein oncogenes as well as broaden our mechanistic understanding of Gq protein oncogene function. We also highlight how this novel insight impacts the significance and utility of using G(q) proteins as targets in drug discovery efforts.

20 April 2020

Nuclear deterrence theory, with its roots in the Cold War era, may not account for all eventualities in the 21st century. Researchers at Chatham House have worked with eight experts to produce this collection of essays examining four contested themes in contemporary policymaking on deterrence.

Jennifer L. Macdonald
May 1, 2005; 46:1061-1067
Methods

W Gamble
Nov 1, 1978; 19:1068-1070
Articles

Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies.

Exame poderá detectar a doença na fase inicial. Pesquisadores da Faculdade de Medicina Osteopática da Universidade de Rowan, nos Estados Unidos, afirmam que estão perto de desenvolver um exame de sangue para detectar Alzheimer com precisão, o que dar...

The post Teste de sangue para detectar Alzheimer está próximo da realidade appeared first on Saúde Próspera.

euromicron AG, a medium-sized technology group and specialist for the digital support of business processes through secure infrastructures, is pooling its digital expertise at KORAMIS GmbH, the group subsidiary that specializes in cyber security and automation. With focus on digital platforms and services KORAMIS’ portfolio will also cover the areas Smart IoT, Smart Building as well as Data Management in the future. For this step the management of KORAMIS GmbH was extended by Andreas Schmidt.

euromicron AG, a medium-sized technology group and expert on the digital networking of business and production processes, has now fully placed the capital increase it resolved on July 10, 2019.

Nivedita Bhaskhar and Bastian Haase
Trans. Amer. Math. Soc. 373 (2020), 3709-3732.
Abstract, references and article information

Albert Chau and Man-Chun Lee
Trans. Amer. Math. Soc. 373 (2020), 3627-3647.
Abstract, references and article information

wheehamx posted a photo:

Stay at home pinhole camera, f285, 8seconds exposure, xray film

A. V. Ivanov and I. K. Matsak
Theor. Probability and Math. Statist. 99 (2020), 91-99.
Abstract, references and article information

Alyson Bittner
Proc. Amer. Math. Soc. 148 (2020), 2683-2693.
Abstract, references and article information

Alberto Arenas, Óscar Ciaurri and Edgar Labarga
Proc. Amer. Math. Soc. 148 (2020), 2539-2550.
Abstract, references and article information

N. Arcozzi, K. Domelevo and S. Petermichl
Proc. Amer. Math. Soc. 148 (2020), 2433-2446.
Abstract, references and article information

Joseph Reid
Proc. Amer. Math. Soc. 148 (2020), 2331-2343.
Abstract, references and article information

Caryl Ann O'Reilly
Jul 1, 2005; 18:162-166
Articles

Beatrice K. Gandara
Nov 1, 2011; 24:199-205
From Research to Practice

Sarah S. Farabi
Feb 1, 2016; 29:10-13
From Research to Practice

Jimmy Doumit
Feb 1, 2016; 29:14-19
From Research to Practice

Erika Leung
Aug 1, 2018; 31:245-253
From Research to Practice

John R. White
May 1, 2014; 27:82-86
From Research to Practice