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Problem Notes for SAS®9 - 66401: Using SAS Model Manager to publish a model to SAS Metadata Repository fails and generates an error

When you publish a model to SAS Metadata Repository by using SAS Model Manager, the publishing process fails and the following error is generated: "The model model-name has a function of ';Transformation';, which is not supported for




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Problem Notes for SAS®9 - 66496: Titles and footnotes do not span the full width of a page when you use the COLUMNS= option with the TAGSETS.RTF_SAMPLE tagset

Titles and footnotes do not span the entire width of the page when you use the COLUMNS= option with a value that is greater than 1 with the TAGSETS.RTF_SAMPLE tagset. When a value that is greater than 1 is specified for th




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Multi-modal Functional Imaging of Brown Adipose Tissue [Images in Lipid Research]




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Apolipoprotein C3 and apolipoprotein B colocalize in proximity to macrophages in atherosclerotic lesions in diabetes [Images in Lipid Research]




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Chronic insomnia: diagnosis and non-pharmacological management




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ANGPTL4 inactivates lipoprotein lipase by catalyzing the irreversible unfolding of LPLs hydrolase domain [Images In Lipid Research]




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Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice [Research Articles]

Cognitive decline with age is a harmful process that can reduce quality of life. Multiple factors have been established to contribute to cognitive decline, but the overall etiology remains unknown. Here, we hypothesized that cognitive dysfunction is mediated, in part, by increased levels of inflammatory cytokines that alter allopregnanolone (AlloP) levels, an important neurosteroid in the brain. We assessed the levels and regulation of AlloP and the effects of AlloP supplementation on cognitive function in 4-month-old and 24-month-old male C57BL/6 mice. With age, the expression of enzymes involved in the AlloP synthetic pathway was decreased and corticosterone (CORT) synthesis increased. Supplementation of AlloP improved cognitive function. Interestingly, interleukin 6 (IL-6) infusion in young animals significantly reduced the production of AlloP compared with controls. It is notable that inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein 130, significantly improved spatial memory in aged mice. These findings were supported by in vitro experiments in primary murine astrocyte cultures, indicating that IL-6 decreases production of AlloP and increases CORT levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in AlloP levels and an increase in CORT. Furthermore, our results indicate that AlloP is a critical link between inflammatory cytokines and the age-related decline in cognitive function.




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Accessibility of cholesterol at cell surfaces [Images In Lipid Research]




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Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer [Research Articles]

Nonsmall cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. While mutations in Kras and overexpression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc combined with surface analysis lipid profiling of lung tumors and transcriptomics to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that the activation of Myc leads to the accumulation of cholesteryl esters (CEs) stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumors in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux, and accumulation of CE-rich lipid droplets in lung tumors. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC.




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Novel contact sites between lipid droplets, early endosomes, and the endoplasmic reticulum [Images in Lipid Research]




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Lipid sensing tips the balance for a key cholesterol synthesis enzyme [Images in Lipid Research]




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Accessible cholesterol is localized in bacterial plasma membrane protrusions [Images In Lipid Research]




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Spatial profiling of gangliosides in mouse brain by mass spectrometry imaging [Images In Lipid Research]




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Data, Reagents, Assays and Merits of Proteomics for SARS-CoV-2 Research and Testing [Research]

As the COVID-19 pandemic continues to spread, thousands of scientists around the globe have changed research direction to understand better how the virus works and to find out how it may be tackled. The number of manuscripts on preprint servers is soaring and peer-reviewed publications using MS-based proteomics are beginning to emerge. To facilitate proteomic research on SARS-CoV-2, the virus that causes COVID-19, this report presents deep-scale proteomes (10,000 proteins; >130,000 peptides) of common cell line models, notably Vero E6, Calu-3, Caco-2, and ACE2-A549 that characterize their protein expression profiles including viral entry factors such as ACE2 or TMPRSS2. Using the 9 kDa protein SRP9 and the breast cancer oncogene BRCA1 as examples, we show how the proteome expression data can be used to refine the annotation of protein-coding regions of the African green monkey and the Vero cell line genomes. Monitoring changes of the proteome on viral infection revealed widespread expression changes including transcriptional regulators, protease inhibitors, and proteins involved in innate immunity. Based on a library of 98 stable-isotope labeled synthetic peptides representing 11 SARS-CoV-2 proteins, we developed PRM (parallel reaction monitoring) assays for nano-flow and micro-flow LC–MS/MS. We assessed the merits of these PRM assays using supernatants of virus-infected Vero E6 cells and challenged the assays by analyzing two diagnostic cohorts of 24 (+30) SARS-CoV-2 positive and 28 (+9) negative cases. In light of the results obtained and including recent publications or manuscripts on preprint servers, we critically discuss the merits of MS-based proteomics for SARS-CoV-2 research and testing.




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Molecular Dynamics Simulation-assisted Ionic Liquid Screening for Deep Coverage Proteome Analysis [Technological Innovation and Resources]

In-depth coverage of proteomic analysis could enhance our understanding to the mechanism of the protein functions. Unfortunately, many highly hydrophobic proteins and low-abundance proteins, which play critical roles in signaling networks, are easily lost during sample preparation, mainly attributed to the fact that very few extractants can simultaneously satisfy the requirements on strong solubilizing ability to membrane proteins and good enzyme compatibility. Thus, it is urgent to screen out ideal extractant from the huge compound libraries in a fast and effective way. Herein, by investigating the interior mechanism of extractants on the membrane proteins solubilization and trypsin compatibility, a molecular dynamics simulation system was established as complement to the experimental procedure to narrow down the scope of candidates for proteomics analysis. The simulation data shows that the van der Waals interaction between cation group of ionic liquid and membrane protein is the dominant factor in determining protein solubilization. In combination with the experimental data, 1-dodecyl-3-methylimidazolium chloride (C12Im-Cl) is on the shortlist for the suitable candidates from comprehensive aspects. Inspired by the advantages of C12Im-Cl, an ionic liquid-based filter-aided sample preparation (i-FASP) method was developed. Using this strategy, over 3,300 proteins were confidently identified from 103 HeLa cells (~100 ng proteins) in a single run, an improvement of 53% over the conventional FASP method. Then the i-FASP method was further successfully applied to the label-free relative quantitation of human liver cancer and para-carcinoma tissues with obviously improved accuracy, reproducibility and coverage than the commonly used urea-based FASP method. The above results demonstrated that the i-FASP method could be performed as a versatile tool for the in-depth coverage proteomic analysis of biological samples.




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Serum Protein Profiling Reveals a Landscape of Inflammation and Immune Signaling in Early-stage COVID-19 Infection [Report]

Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.




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A Comprehensive Gender-related Secretome of Plasmodium berghei Sexual Stages [Research]

Plasmodium, the malaria parasite, undergoes a complex life cycle alternating between a vertebrate host and a mosquito vector of the genus Anopheles. In red blood cells of the vertebrate host, Plasmodium multiplies asexually or differentiates into gamete precursors, the male and female gametocytes, responsible for parasite transmission. Sexual stage maturation occurs in the midgut of the mosquito vector, where male and female gametes egress from the host erythrocytes to fuse and form a zygote. Gamete egress entails the successive rupture of two membranes surrounding the parasite, the parasitophorous vacuole membrane and the erythrocyte plasma membrane. In this study, we used the rodent model parasite Plasmodium berghei to design a label-free quantitative proteomic approach aimed at identifying gender-related proteins differentially released/secreted by purified mature gametocytes when activated to form gametes. We compared the abundance of molecules secreted by wild type gametocytes of both genders with that of a transgenic line defective in male gamete maturation and egress. This enabled us to provide a comprehensive data set of egress-related molecules and their gender specificity. Using specific antibodies, we validated eleven candidate molecules, predicted as either gender-specific or common to both male and female gametocytes. All of them localize to punctuate, vesicle-like structures that relocate to cell periphery upon activation, but only three of them localize to the gametocyte-specific secretory vesicles named osmiophilic bodies. Our results confirm that the egress process involves a tightly coordinated secretory apparatus that includes different types of vesicles and may put the basis for functional studies aimed at designing novel transmission-blocking molecules.




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Douleurs côté droit sous les côtes : comment les soulager naturellement

En fonction de leurs causes, les douleurs du côté droit peuvent se manifester de différentes manières. Les symptômes de ces douleurs peuvent également varier d’une personne à une autre. Certaines personnes décrivent les douleurs du côté comme des sensations de crampes, de brûlures ou de piqûres. D’autres en revanche parlent de douleurs sourdes ou lancinantes qui irradient […]

L’article Douleurs côté droit sous les côtes : comment les soulager naturellement est apparu en premier sur Ortho Doc France.




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Quelques remèdes de grand-mère pour soulager les symptômes de la fibromyalgie

En France, environ 2 à 4 % de la population, souvent des femmes, est touchée par la fibromyalgie. Mais en réalité, qu’est-ce que la fibromyalgie ? Quelles sont les astuces naturelles permettant de soulager les patients qui présentent des symptômes de cette maladie ? Quels sont les symptômes de la fibromyalgie ? La fibromyalgie, ou syndrome fibromyalgique, […]

L’article Quelques remèdes de grand-mère pour soulager les symptômes de la fibromyalgie est apparu en premier sur Ortho Doc France.




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Croq’Kilos : programme minceur, rééquilibrage alimentaire

Pour de nombreuses personnes, perte de poids rime obligatoirement avec privations. Et si vous appreniez aujourd’hui que vous pouvez perdre efficacement vos kilos en trop sans pour autant vous priver excessivement ? De nombreux programmes minceur et de rééquilibrage, notamment Croq’kilos offrent ce genre d’alternative. Mais de quoi s’agit-il réellement ? C’est quoi Croq’Kilos ? Croq’Kilos […]

L’article Croq’Kilos : programme minceur, rééquilibrage alimentaire est apparu en premier sur Ortho Doc France.




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Systematic Proteome and Lysine Succinylome Analysis Reveals the Enhanced Cell Migration by Hyposuccinylation in Esophageal Squamous Cell Cancer [Research]

Esophageal squamous cell cancer (ESCC) is an aggressive malignancy with poor therapeutic outcomes. However, the alterations in proteins and post-translational modifications (PTMs) leading to the pathogenesis of ESCC remains unclear. Here, we provide the comprehensive characterization of the proteome, phosphorylome, lysine acetylome and succinylome for ESCC and matched control cells using quantitative proteomic approach. We identify abnormal protein and post-translational modification (PTM) pathways, including significantly downregulated lysine succinylation sites in cancer cells. Focusing on hyposuccinylation, we reveal that this altered PTM was enriched on enzymes of metabolic pathways inextricably linked with cancer metabolism. Importantly, ESCC malignant behaviors such as cell migration are inhibited once the level of succinylation was restored in vitro or in vivo. This effect was further verified by mutations to disrupt succinylation sites in candidate proteins. Meanwhile, we found that succinylation has a negative regulatory effect on histone methylation to promote cancer migration. Finally, hyposuccinylation is confirmed in primary ESCC specimens. Our findings together demonstrate that lysine succinylation may alter ESCC metabolism and migration, providing new insights into the functional significance of PTM in cancer biology.




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N-glycomic signature of stage II colorectal cancer and its association with the tumor microenvironment [Research]

The choice for adjuvant chemotherapy in stage II colorectal cancer (CRC) is controversial as many patients are cured by surgery alone and it is difficult to identify patients with high-risk of recurrence of the disease. There is a need for better stratification of this group of patients. Mass spectrometry imaging could identify patients at risk. We report here the N-glycosylation signatures of the different cell populations in a group of stage II CRC tissue samples. The cancer cells, compared to normal epithelial cells, have increased levels of sialylation and high-mannose glycans, as well as decreased levels of fucosylation and highly branched N-glycans. When looking at the interface between cancer and its microenvironment, it seems that the cancer N-glycosylation signature spreads into the surrounding stroma at the invasive front of the tumor. This finding was more outspoken in patients with a worse outcome within this sample group.




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Transcriptome and secretome analysis of intra-mammalian life-stages of the emerging helminth pathogen, Calicophoron daubneyi reveals adaptation to a unique host environment. [Research]

Paramphistomosis, caused by the rumen fluke, Calicophoron daubneyi, is a parasitic infection of ruminant livestock which has seen a rapid rise in prevalence throughout Western Europe in recent years. Following ingestion of metacercariae (parasite cysts) by the mammalian host, newly-excysted juveniles (NEJs) emerge and invade the duodenal submucosa which causes significant pathology in heavy infections. The immature larvae then migrate upwards, along the gastrointestinal tract, and enter the rumen where they mature and begin to produce eggs. Despite their emergence, and sporadic outbreaks of acute disease, we know little about the molecular mechanisms used by C. daubneyi to establish infection, acquire nutrients and to avoid the host immune response. Here, transcriptome analysis of four intra-mammalian life-cycle stages, integrated with secretome analysis of the NEJ and adult parasites (responsible for acute and chronic disease respectively), revealed how the expression and secretion of selected families of virulence factors and immunomodulators are regulated in accordance with fluke development and migration. Our data show that whilst a family of cathepsins B with varying S2 sub-site residues (indicating distinct substrate specificities) are differentially secreted by NEJs and adult flukes, cathepsins L and F are secreted in low abundance by NEJs only. We found that C. daubneyi has an expanded family of aspartic peptidases, which is up-regulated in adult worms, although they are underrepresented in the secretome. The most abundant proteins in adult fluke secretions were helminth defence molecules (HDMs) that likely establish an immune environment permissive to fluke survival and/or neutralise pathogen-associated molecular patterns (PAMPs) such as bacterial lipopolysaccharide in the microbiome-rich rumen. The distinct collection of molecules secreted by C. daubneyi allowed the development of the first coproantigen-based ELISA for paramphistomosis which, importantly, did not recognise antigens from other helminths commonly found as co-infections with rumen fluke.




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Proteomic analyses identify differentially expressed proteins and pathways between low-risk and high-risk subtypes of early-stage lung adenocarcinoma and their prognostic impacts [Research]

The histopathological subtype of lung adenocarcinoma (LUAD) is closely associated with prognosis. Micropapillary or solid predominant LUAD tends to relapse after surgery at an early stage, whereas lepidic pattern shows a favorable outcome. However, the molecular mechanism underlying this phenomenon remains unknown. Here, we recruited 31 lepidic predominant LUADs (LR: low-risk subtype group) and 28 micropapillary or solid predominant LUADs (HR: high-risk subtype group). Tissues of these cases were obtained and label-free quantitative proteomic and bioinformatic analyses were performed. Additionally, prognostic impact of targeted proteins was validated using The Cancer Genome Atlas databases (n=492) and tissue microarrays composed of early-stage LUADs (n=228). A total of 192 differentially expressed proteins were identified between tumor tissues of LR and HR and three clusters were identified via hierarchical clustering excluding eight proteins. Cluster 1 (65 proteins) showed a sequential decrease in expression from normal tissues to tumor tissues of LR and then to HR and was predominantly enriched in pathways such as tyrosine metabolism and ECM-receptor interaction, and increased matched mRNA expression of 18 proteins from this cluster predicted favorable prognosis. Cluster 2 (70 proteins) demonstrated a sequential increase in expression from normal tissues to tumor tissues of LR and then to HR and was mainly enriched in pathways such as extracellular organization, DNA replication and cell cycle, and high matched mRNA expression of 25 proteins indicated poor prognosis. Cluster 3 (49 proteins) showed high expression only in LR, with high matched mRNA expression of 20 proteins in this cluster indicating favorable prognosis. Furthermore, high expression of ERO1A and FEN1 at protein level predicted poor prognosis in early-stage LUAD, supporting the mRNA results. In conclusion, we discovered key differentially expressed proteins and pathways between low-risk and high-risk subtypes of early-stage LUAD. Some of these proteins could serve as potential biomarkers in prognostic evaluation.




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Nuclear Disarmament and the Protection of Cultural Heritage

Nuclear Disarmament and the Protection of Cultural Heritage Research paper sysadmin 6 October 2017

States possessing nuclear weapons should be called upon to consider and publish the risks posed to cultural heritage, and their mitigation strategies, in their nuclear-weapons doctrines and policies.

A woman walks on the roof of the Great Mosque of Djenné, a World Heritage Site, after praying. Photo: United Nations.

Summary

  • Renewed risk assessments for nuclear weapons and policies are taking place around the world in light of nuclear modernization and the changing geostrategic environment that is making the use of nuclear weapons more likely. As such the humanitarian impacts of nuclear weapons and tests have received increased attention. However, the effect on cultural heritage has so far been neglected.
  • The potential for armed conflict to destroy cultural heritage has been recognized in international law since 1954. There is significant evidence on the impact of nuclear weapons on cultural heritage including the consequences of their use in Hiroshima and Nagasaki and the effect of nuclear-testing programmes in places of cultural significance since 1945. States that possess nuclear weapons have increased liabilities and responsibilities to protect cultural heritage and cultural rights. The need to protect cultural heritage should strengthen the case for reducing and eliminating nuclear weapons.
  • Failure to take into account the protection of heritage in the development of nuclear weapons policies – including disarmament, non-proliferation and arms-control negotiations – significantly undermines states’ existing commitments to protecting heritage threatened by conflict.
  • Risk assessments of the impact of nuclear weapons on cultural heritage and important cultural artefacts – and methods of preventing such catastrophic damage – should be part of protecting cultural heritage in every country and the subject of informed public debate. A new body of knowledge on the full range of nuclear weapons impacts would introduce a fresh perspective to inform decision-makers, international organizations and the public in thinking about nuclear weapons policies and practices.
  • Risk and resilience frameworks, which provide sets of solutions for risk assessments, would allow assessments of nuclear weapons threats to heritage and highlight vulnerabilities that need to be addressed. Such frameworks would provide a basis for policymakers to identify the world’s cultural heritage most at risk and help develop mitigation strategies to ensure that it is protected. In particular, states possessing nuclear weapons should be called upon to consider and publish the risks posed to cultural heritage, and their mitigation strategies, in their nuclear weapons doctrines and policies, as a contribution to transparency and confidence-building, and as a responsibility to the world’s shared heritage. International organizations, such as the UN Educational, Scientific, and Cultural Organization (UNESCO), have a role to play in bridging security perspectives with protecting cultural heritage.




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Infrastructure Management Contracts: Improving Energy Asset Management in Displacement Settings

Infrastructure Management Contracts: Improving Energy Asset Management in Displacement Settings Research paper sysadmin 17 April 2019

This paper highlights a number of options for managing electricity infrastructure in refugee camps and outlines the challenges, opportunities and operational implications associated with them. It takes the Kalobeyei settlement in Kenya as a case study.

A solar array installed for International Rescue Committee health clinics in Kakuma refugee camp, Kenya. Photo: Kube Energy

  • Building and maintaining electricity infrastructure to power offices, businesses, households and other operations in displacement settings is difficult. It is especially challenging for the Office of the United Nations High Commissioner for Refugees (UNHCR) and its partner agencies, because supplying electricity is not their core business.
  • Private-sector companies exist that are willing and able to develop infrastructure management contracts to provide energy as a service in displacement settings. However, institutional barriers within humanitarian agencies persist, with short budgeting cycles in particular preventing humanitarian agencies from entering into the sorts of long-term service agreements required by the private sector.
  • A number of options exist to leverage the expertise of the private sector through ‘public–private partnership’ (P3) structures. Such mechanisms can promote more efficient management of infrastructure by drawing on private-sector experience and expertise, incentivizing appropriate risk-sharing and providing options to leverage private capital in project development.
  • Field work from the Kalobeyei settlement in Kenya suggests that a solar/diesel hybrid mini-grid solution was the most economical option to power camp services and infrastructure there. Compared to distributed diesel generation, the annual savings in operating costs were estimated at $49,880, with the additional investment paid back within 3.6 years.
  • Humanitarian agencies need to be willing to change their policies to enable long-term service agreements. Alternatively (or, more likely, in conjunction with this option), financial mechanisms such as partial risk guarantees need to be developed to offset some of the risks. This change will need high-level support from donors and humanitarian agencies.
  • Once the first infrastructure management contracts can be signed and tested in displacement locations (through the use of donor funding or otherwise) and associated data collected, it will ease the way for future investments in these types of projects.




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Tectonic Politics: Global Political Risk in an Age of Transformation

Tectonic Politics: Global Political Risk in an Age of Transformation Book sysadmin 7 May 2019

Political risk now affects more markets and countries than ever before and that risk will continue to rise. But traditional methods of managing political risk are no longer legitimate or effective.

In Tectonic Politics, Nigel Gould-Davies explores the complex, shifting landscape of political risk and how to navigate it. He analyses trends in each form of political risk: the power to destroy, seize, regulate, and tax.

He shows how each of these forms reflects a deeper transformation of the global political economy that is reordering the relationship between power, wealth, and values. In a world where everything is political, the craft of engagement is as important as the science of production and the art of the deal.

The successful company must integrate that craft—the engager’s way of seeing and doing—into strategy and culture.

Drawing on a career in academia, business, and diplomacy, Gould-Davies provides corporate leaders, scholars, and engaged citizens with a groundbreaking study of the fastest-rising political risk today. ‘As tectonic plates shape the earth,’ he writes, ‘so tectonic politics forges its governance.’

The book is published as part of the Insights series.

Praise for Tectonic Politics

All economic activity involves political risks, but few economic actors know how to analyze or address them. Nigel Gould-Davies demonstrates the central importance of politics to national and international business, and provides a guide to analyzing political risk. Business people, journalists, policymakers, and scholars will all learn from reading Tectonic Politics.

Jeffry Frieden, Stanfield Professor of International Peace, Harvard University

About the author

Nigel Gould-Davies was an associate fellow of the Russia and Eurasia Programme at Chatham House.

Purchase




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Mycobacteria excise DNA damage in 12- or 13-nucleotide-long oligomers by prokaryotic-type dual incisions and performs transcription-coupled repair [Genomics and Proteomics]

In nucleotide excision repair, bulky DNA lesions such as UV-induced cyclobutane pyrimidine dimers are removed from the genome by concerted dual incisions bracketing the lesion, followed by gap filling and ligation. So far, two dual-incision patterns have been discovered: the prokaryotic type, which removes the damage in 11–13-nucleotide-long oligomers, and the eukaryotic type, which removes the damage in 24–32-nucleotide-long oligomers. However, a recent study reported that the UvrC protein of Mycobacterium tuberculosis removes damage in a manner analogous to yeast and humans in a 25-mer oligonucleotide arising from incisions at 15 nt from the 3´ end and 9 nt from the 5´ end flanking the damage. To test this model, we used the in vivo excision assay and the excision repair sequencing genome-wide repair mapping method developed in our laboratory to determine the repair pattern and genome-wide repair map of Mycobacterium smegmatis. We find that M. smegmatis, which possesses homologs of the Escherichia coli uvrA, uvrB, and uvrC genes, removes cyclobutane pyrimidine dimers from the genome in a manner identical to the prokaryotic pattern by incising 7 nt 5´ and 3 or 4 nt 3´ to the photoproduct, and performs transcription-coupled repair in a manner similar to E. coli.




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Phosphorylation of SMURF2 by ATM exerts a negative feedback control of DNA damage response [DNA and Chromosomes]

Timely repair of DNA double-strand breaks (DSBs) is essential to maintaining genomic integrity and preventing illnesses induced by genetic abnormalities. We previously demonstrated that the E3 ubiquitin ligase SMURF2 plays a critical tumor suppressing role via its interaction with RNF20 (ring finger protein 20) in shaping chromatin landscape and preserving genomic stability. However, the mechanism that mobilizes SMURF2 in response to DNA damage remains unclear. Using biochemical approaches and MS analysis, we show that upon the onset of the DNA-damage response, SMURF2 becomes phosphorylated at Ser384 by ataxia telangiectasia mutated (ATM) serine/threonine kinase, and this phosphorylation is required for its interaction with RNF20. We demonstrate that a SMURF2 mutant with an S384A substitution has reduced capacity to ubiquitinate RNF20 while promoting Smad3 ubiquitination unabatedly. More importantly, mouse embryonic fibroblasts expressing the SMURF2 S384A mutant show a weakened ability to sustain the DSB response compared with those expressing WT SMURF2 following etoposide treatment. These data indicate that SMURF2-mediated RNF20 ubiquitination and degradation controlled by ataxia telangiectasia mutated–induced phosphorylation at Ser384 constitutes a negative feedback loop that regulates DSB repair.




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Ausmus eager to guide Halos as camp opens

Spring Training is officially here for the Angels, with pitchers and catchers reporting to Tempe Diablo Stadium on Tuesday. And there's a new face at manager, with Brad Ausmus replacing longtime skipper Mike Scioscia this offseason.




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Politicians are failing to prepare for next pandemic, warns head of European health agency




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Improving Economic Management for Sustainable Growth in Zambia

Improving Economic Management for Sustainable Growth in Zambia 13 July 2018 — 9:00AM TO 10:00AM Anonymous (not verified) 19 June 2018 Chatham House, London

THIS EVENT IS POSTPONED.

High levels of infrastructure investment funded by commercial loans, against a backdrop of subdued economic growth, resulted in an increase in Zambia’s public external debt from $8.7 billion in 2017 to $9.3 billion in March 2018.

In June 2018 Zambia’s Ministry of Finance announced new austerity measures aimed at reducing the country’s debt burden, as part of an ongoing reform agenda that is hoped to stabilise the economy.

In the meantime Zambia grapples with severe social and development challenges. Decreased spending in health, education and social protection, and poor access in rural areas, have already left Zambia ranked 139th out of 188 countries in the UNDP’s 2016 human development index.

At this meeting Margaret Mwanakatwe, minister of finance, discusses the government’s financial reform agenda, its engagement with creditors and IFIs, and plans for generating sustainable growth and job creation.




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Economic Recovery and Anticorruption in South Africa: Assessing Progress on the Reform Agenda

Economic Recovery and Anticorruption in South Africa: Assessing Progress on the Reform Agenda 4 December 2019 — 3:00PM TO 4:00PM Anonymous (not verified) 25 November 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

South Africa has significant economic potential based on its resource endowment, quality human capital and well-developed infrastructure compared to the region. However, the country’s economic growth rate has not topped 2 per cent since 2013, and in 2018, was below 1 per cent. This has put a strain on citizens and communities in a country that still suffers from structural inequality, poverty and high unemployment. Economic recovery and anti-corruption were the central pillars of President Cyril Ramaphosa’s 2019 electoral campaign and he has set an investment target of $100 billion. However, voters and investors alike are demanding faster and more visible progress from the country’s enigmatic leader who has a reputation for caution and calculation.

At this event, Professor Nick Binedell will discuss the progress of and opposition to the president’s economic reform agenda and the opportunities for international investment to support long term inclusive and sustainable growth in South Africa.

Attendance at this event is by invitation only.




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Inclusion, agency and influence: The role of women in Zimbabwe’s economy

Inclusion, agency and influence: The role of women in Zimbabwe’s economy 8 July 2021 — 3:00PM TO 4:30PM Anonymous (not verified) 2 July 2021 Online

Speakers discuss the changing role of women in Zimbabwe’s economic structures and the priorities for promoting greater economic inclusion, agency and influence of women.

Zimbabwe’s National Development Strategy of 2021-2025 highlights the importance of gender sensitivity in policymaking and of women’s economic participation in attaining the government’s Vision 2030.

However, women have been among the worst affected groups by the devastating effects that COVID-19 has had on Zimbabwe’s already floundering economy, which has exacerbated the challenges they face in economic life, such as access to credit, financial services and social security.

Leveraging existing structures such as women’s groups, micro-finance facilities, education and training, and national gender mechanisms, as well as supporting wider financial and digital inclusion in Zimbabwe, is central for the country’s sustained economic recovery.

This event also focuses on the differing impacts of COVID-19 on women’s economic activities across various sectors, as well as along rural-urban and formal-informal economy lines.

Read a meeting summary

This webinar is part of a series of events in partnership with the Konrad Adenauer Stiftung on Zimbabwe’s economic recovery and reform.

This event will also be broadcast live on the Africa Programme Facebook page.




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RCP warns over shortage of stroke physicians




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Development and validation of outcome prediction models for aneurysmal subarachnoid haemorrhage: the SAHIT multinational cohort study




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GLP-1 agonist shortage will last until end of 2024, government warns




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GLP-1 shortages will not resolve this year, EMA warns, amid concern over off-label use




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Review: Rediscovering Milan Kundera’s European tragedy

Review: Rediscovering Milan Kundera’s European tragedy The World Today mhiggins.drupal 28 March 2023

The Czech writer’s 40-year-old essay on the roots of Russia’s empire-building, ‘A Kidnapped West’, reads all too presciently, writes Stefan Auer.

A Kidnapped West: The Tragedy of Central Europe
Milan Kundera, Faber, £10

‘In November 1956, the director of the Hungarian News Agency, shortly before his office was flattened by artillery fire, sent a telex to the entire world with a desperate message announcing that the Russian attack against Budapest had begun. The dispatch ended with these words: “We are going to die for Hungary and for Europe.”’ Thus, Milan Kundera began his 1983 essay for the French journal Le Débat, reflecting on the 1956 Hungarian Uprising.

A seminal essay

The Czech author might well have written a near-identical passage about the fraught hours immediately after Russia’s invasion of Ukraine in 2022. In the event, Russian tanks failed to occupy Kyiv, unlike Budapest in 1956. Nevertheless, Faber has chosen this moment, 40 years later, to republish Kundera’s seminal essay on Europe and Russian aggression in its original translation for the New York Review of Books by Edmund White. How salient are its observations today?

Thanks to the Cold War, the countries of Central Europe were denied their true destiny, Kundera thought, in the democratic West

The essay’s original French title, ‘Un Occident kidnappé ou la tragédie de l’Europe centrale’ (The Kidnapped West, or the Tragedy of Central Europe), described the fate of Hungary, Czechoslovakia in 1968 and, to an extent, Poland in 1980-81 at the hands of the Soviet Union. Owing to the Cold War division of Europe, the countries of Central Europe were denied their true destiny, Kundera thought, to be an integral part of the liberal, democratic West. Kundera himself fled Czechoslovakia for France in 1975.

The author of The Unbearable Lightness of Being might no longer be as well-known as he was at the height of his fame in the 1980s, but his novels and essays still deserve attention. So, it is pleasing to see Kundera’s masterpiece republished, even as it is awful to witness the enduring relevance of the questions it raises.

What did the Hungarian journalist mean when he declared his willingness to die for Europe, Kundera asked? That ‘Russians, in attacking Hungary, were attacking Europe itself. He was ready to die so that Hungary might remain Hungary and European’. The journalist did indeed die in the uprising.

It is a line that President Volodymyr Zelenskyy and his supporters abroad have echoed time and again: that Ukrainian soldiers are not just dying for their country, they are dying for Europe at large.

Kundera’s suspicion of Russia has been validated. His frustration about the indifference of the West less so

The ‘tragedy’ in Kundera’s essay was that the West didn’t care. ‘Europe hasn’t noticed the disappearance of its cultural home,’ Kundera wrote, ‘because Europe no longer perceives its unity as a cultural unity.’

In other words, as the cultural sphere in Central Europe continued to defy the political restrictions imposed by the Soviet empire, it embodied the western values of freedom and democracy more than the West itself did. The extent to which this analysis remains relevant today will prove decisive for Europe’s future.

As timely as ever

Kundera’s essay is as timely as ever but in ways that both vindicate and challenge his key arguments. His suspicion of Russia has been validated. His frustration about the indifference of the West less so. But the true tragedy of Ukraine would be if the West has not changed sufficiently. So far, the West appears to be doing enough to enable Ukraine to defend itself, but not enough to defeat the aggressor.

[A small nation] is one whose very existence can be put in question at any moment; a small nation can disappear and it knows it

Milan Kundera

Faber has made an excellent decision in combining The Tragedy of Central Europe with a lesser-known text by Kundera: his 1967 speech to the Czech Writers’ Congress given the year before the ill-fated Prague Spring. In it, Kundera addressed what was to become a lifelong preoccupation: the fate of small nations. ‘For Czechs’, Kundera wrote, ‘nothing has ever constituted an indisputable possession – neither their language nor their belonging to Europe.’

Rather than reflecting the size of its territory or population, a small nation ‘is one whose very existence can be put in question at any moment; a small nation can disappear, and it knows it.’ In this way Ukraine, Europe’s largest country, apart from Russia, is fighting to avoid the fate of Kundera’s ‘small nation’.

Historically, the ‘small’ nations of Central Europe were threatened by both Germany and Russia. But after the Second World War, the threat was from the Soviet Union, which for Kundera was indistinguishable from Russia (tacitly including Ukraine). In its expansiveness, Russia was the opposite of Central Europe. While the latter was based on the principle of ‘the greatest variety within the smallest space’, the former represented ‘the smallest variety within the greatest space’.

Kundera was criticized for observations that smack of civilizational racism, yet his bleak view of Russia remains prescient

In this sense, authoritarian communism was the fulfilment of Russian history, Kundera argued, writing that ‘Russian communism vigorously reawakened Russia’s old anti-western obsessions and turned it brutally against Europe’. Vladimir Putin’s Russia appears to build on these same pernicious impulses.

Kundera was widely criticized for observations in his essay that smack of civilizational racism (including by me) describing Russians as fundamentally different from us: ‘Russia knows another (greater) dimension of disaster, another image of space (a space so immense that entire nations are swallowed up in it), another sense of time (slow and patient), another way of laughing, living, and dying’.




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Composite Prediction Score to Interpret Bone Focal Uptake in Hormone-Sensitive Prostate Cancer Patients Imaged with [18F]PSMA-1007 PET/CT

Unspecific bone uptake (UBU) related to [18F]PSMA-1007 PET/CT imaging represents a clinical challenge. We aimed to assess whether a combination of clinical, biochemical, and imaging parameters could predict skeletal metastases in patients with [18F]PSMA-1007 bone focal uptake, aiding in result interpretation. Methods: We retrospectively analyzed [18F]PSMA-1007 PET/CT performed in hormone-sensitive prostate cancer (PCa) patients at 3 tertiary-level cancer centers. A fourth center was involved in performing an external validation. For each, a volume of interest was drawn using a threshold method to extract SUVmax, SUVmean, PSMA tumor volume, and total lesion PSMA. The same volume of interest was applied to CT images to calculate the mean Hounsfield units (HUmean) and maximum Hounsfield units. Clinical and laboratory data were collected from electronic medical records. A composite reference standard, including follow-up histopathology, biochemistry, and imaging data, was used to distinguish between PCa bone metastases and UBU. PET readers with less (n = 2) or more (n = 2) experience, masked to the reference standard, were asked to visually rate a subset of focal bone uptake (n = 178) as PCa metastases or not. Results: In total, 448 bone [18F]PSMA-1007 focal uptake specimens were identified in 267 PCa patients. Of the 448 uptake samples, 188 (41.9%) corresponded to PCa metastases. Ongoing androgen deprivation therapy at PET/CT (P < 0.001) with determination of SUVmax (P < 0.001) and HUmean (P < 0.001) independently predicted bone metastases. A composite prediction score, the bone uptake metastatic probability (BUMP) score, achieving an area under the receiver-operating-characteristic curve (AUC) of 0.87, was validated through a 10-fold internal and external validation (n = 89 bone uptake, 51% metastatic; AUC, 0.92). The BUMP score’s AUC was significantly higher than that of HUmean (AUC, 0.62) and remained high among lesions with HUmean in the first tertile (AUC, 0.80). A decision-curve analysis showed a higher net benefit with the score. Compared with the visual assessment, the BUMP score provided added value in terms of specificity in less-experienced PET readers (88% vs. 54%, P < 0.001). Conclusion: The BUMP score accurately distinguished UBU from bone metastases in PCa patients with [18F]PSMA-1007 focal bone uptake at PET imaging, offering additional value compared with the simple assessment of the osteoblastic CT correlate. Its use could help clinicians interpret imaging results, particularly those with less experience, potentially reducing the risk of patient overstaging.




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The Rise of Molecular Image-Guided Robotic Surgery

Following early acceptance by urologists, the use of surgical robotic platforms is rapidly spreading to other surgical fields. This empowerment of surgical perception via robotic advances occurs in parallel to developments in intraoperative molecular imaging. Convergence of these efforts creates a logical incentive to advance the decades-old image-guided robotics paradigm. This yields new radioguided surgery strategies set to optimally exploit the symbiosis between the growing clinical translation of robotics and molecular imaging. These strategies intend to advance surgical precision by increasing dexterity and optimizing surgical decision-making. In this state-of-the-art review, topic-related developments in chemistry (tracer development) and engineering (medical device development) are discussed, and future scientific robotic growth markets for molecular imaging are presented.




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Turkey-Russia Relations: A Marriage of Convenience?

Turkey-Russia Relations: A Marriage of Convenience? 26 November 2020 — 12:00PM TO 1:30PM Anonymous (not verified) 17 November 2020 Chatham House

Speakers discuss the complex but, so far, durable ties between Putin and Erdogan and the perspectives of each leader. Other issues will include the impact of the Biden presidency and the unfolding situation in Nagorny Karabakh.

This is an online only event

Russia-Turkey relations are governed by a unique dynamic between presidents Vladimir Putin and Recep Tayyip Erdogan. They pursue contrasting objectives in Libya, the Eastern Mediterranean, Caucasus and Ukraine; yet they have managed to compartmentalize their differences to avoid any spill-over into diplomatic, military and economic cooperation.

Erdogan purchased the Russian S400 missile defence system at the cost of ejection from the US-led fourth generation F35 stealth fighter programme; and at the risk of sanctions by Washington. Russia is also proceeding with the construction of the Akkuyu Nuclear Power Plant near Turkey’s Mediterranean coast.




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Supermicro Introduces JBOF Storage Platform Powered by NVIDIA BlueField-3 for Scalable AI and HPC

SAN JOSE, Calif., Oct. 16, 2024 — Supermicro, Inc. is launching a new optimized storage system for high performance AI training, inference and HPC workloads. This JBOF (Just a Bunch […]

The post Supermicro Introduces JBOF Storage Platform Powered by NVIDIA BlueField-3 for Scalable AI and HPC appeared first on HPCwire.




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SDSC Leads Expansion of Open Storage Network to More Campus Computing Sites

Oct. 24, 2024 — The San Diego Supercomputer Center (SDSC), part of the School of Computing, Information and Data Sciences at UC San Diego, has been leading the Open Storage Network (OSN) program for years, and along […]

The post SDSC Leads Expansion of Open Storage Network to More Campus Computing Sites appeared first on HPCwire.




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Strong earthquakes strike Cuba, causing damage and landslides

A pair of strong earthquakes has struck off the southern coast of Cuba, inflicting damage and causing landslides.




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Miami Marlins to hire former L.A. Dodgers coach Clayton McCullough as manager

The Miami Marlins officially hired former Los Angeles Dodgers first base coach Clayton McCullough as their new manager, the franchise announced Monday.




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Pure Storage Embraces Next-Gen Networking for AI with Ultra Ethernet Consortium Membership

SANTA CLARA, Calif., Aug. 13, 2024 — Pure Storage today announced that it joined Ultra Ethernet Consortium (UEC), a Linux Foundation initiative dedicated to building a complete, open, and accessible Ethernet-based […]

The post Pure Storage Embraces Next-Gen Networking for AI with Ultra Ethernet Consortium Membership appeared first on HPCwire.




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Accelerating GPU Based Applications with NVIDIA Validated Magnum IO GPUDirect Storage and Pavilion

What can be achieved using applications such as AI/ML, Deep Learning, and Big Data Analytics has been revolutionized by Magnum IO GPUDirect Storage’s capabilities. Agencies have invested in these solutions […]

The post Accelerating GPU Based Applications with NVIDIA Validated Magnum IO GPUDirect Storage and Pavilion appeared first on HPCwire.




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North Carolina man's age inspires $200,000-winning lottery purchase

A North Carolina man's age turned out to be a lucky number when it inspired him to buy a scratch-off lottery ticket worth $200,000.




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MLPerf Releases Latest Inference Results and New Storage Benchmark

MLCommons this week issued the results of its latest MLPerf Inference (v3.1) benchmark exercise. Nvidia was again the top performing accelerator, but Intel (Xeon CPU) and Habana (Gaudi1 and 2) […]

The post MLPerf Releases Latest Inference Results and New Storage Benchmark appeared first on HPCwire.