Simone Cecchini and Rudolf Zeidler
Trans. Amer. Math. Soc. 377 (), 5271-5288.
Abstract, references and article information

Gabriele Benedetti, Johanna Bimmermann and Kai Zehmisch
Proc. Amer. Math. Soc. 152 (), 5367-5372.
Abstract, references and article information

Sudip Ranjan Bhuia
Proc. Amer. Math. Soc. 152 (), 5249-5263.
Abstract, references and article information

Thoracic great vessels such as the aorta and subclavian arteries are formed through dynamic remodeling of embryonic pharyngeal arch arteries (PAAs). Previous work has shown that loss of a basic helix-loop-helix transcription factor Hey1 in mice causes abnormal fourth PAA development and lethal great vessel anomalies resembling congenital malformations in humans. However, how Hey1 mediates vascular formation remains unclear. In this study, we revealed that Hey1 in vascular endothelial cells, but not in smooth muscle cells, played essential roles for PAA development and great vessel morphogenesis in mouse embryos. Tek-Cre–mediated Hey1 deletion in endothelial cells affected endothelial tube formation and smooth muscle differentiation in embryonic fourth PAAs and resulted in interruption of the aortic arch and other great vessel malformations. Cell specificity and signal responsiveness of Hey1 expression were controlled through multiple cis-regulatory regions. We found two distal genomic regions that had enhancer activity in endothelial cells and in the pharyngeal epithelium and somites, respectively. The novel endothelial enhancer was conserved across species and was specific to large-caliber arteries. Its transcriptional activity was regulated by Notch signaling in vitro and in vivo, but not by ALK1 signaling and other transcription factors implicated in endothelial cell specificity. The distal endothelial enhancer was not essential for basal Hey1 expression in mouse embryos but may likely serve for Notch-dependent transcriptional control in endothelial cells together with the proximal regulatory region. These findings help in understanding the significance and regulation of endothelial Hey1 as a mediator of multiple signaling pathways in embryonic vascular formation.

CD81 plays a central role in a variety of physiological and pathological processes. Recent structural analysis of CD81 indicates that it contains an intramembrane cholesterol-binding pocket and that interaction with cholesterol may regulate a conformational switch in the large extracellular domain of CD81. Therefore, CD81 possesses a potential cholesterol-sensing mechanism; however, its relevance for protein function is thus far unknown. In this study we investigate CD81 cholesterol sensing in the context of its activity as a receptor for hepatitis C virus (HCV). Structure-led mutagenesis of the cholesterol-binding pocket reduced CD81–cholesterol association but had disparate effects on HCV entry, both reducing and enhancing CD81 receptor activity. We reasoned that this could be explained by alterations in the consequences of cholesterol binding. To investigate this further we performed molecular dynamic simulations of CD81 with and without cholesterol; this identified a potential allosteric mechanism by which cholesterol binding regulates the conformation of CD81. To test this, we designed further mutations to force CD81 into either the open (cholesterol-unbound) or closed (cholesterol-bound) conformation. The open mutant of CD81 exhibited reduced HCV receptor activity, whereas the closed mutant enhanced activity. These data are consistent with cholesterol sensing switching CD81 between a receptor active and inactive state. CD81 interactome analysis also suggests that conformational switching may modulate the assembly of CD81–partner protein networks. This work furthers our understanding of the molecular mechanism of CD81 cholesterol sensing, how this relates to HCV entry, and CD81's function as a molecular scaffold; these insights are relevant to CD81's varied roles in both health and disease.

Investigations of bacterial resistance strategies can aid in the development of new antimicrobial drugs as a countermeasure to the increasing worldwide prevalence of bacterial antibiotic resistance. One such strategy involves the TipA class of transcription factors, which constitute minimal autoregulated multidrug resistance (MDR) systems against diverse antibiotics. However, we have insufficient information regarding how antibiotic binding induces transcriptional activation to design molecules that could interfere with this process. To learn more, we determined the crystal structure of SkgA from Caulobacter crescentus as a representative TipA protein. We identified an unexpected spatial orientation and location of the antibiotic-binding TipAS effector domain in the apo state. We observed that the α6–α7 region of the TipAS domain, which is canonically responsible for forming the lid of antibiotic-binding cleft to tightly enclose the bound antibiotic, is involved in the dimeric interface and stabilized via interaction with the DNA-binding domain in the apo state. Further structural and biochemical analyses demonstrated that the unliganded TipAS domain sterically hinders promoter DNA binding but undergoes a remarkable conformational shift upon antibiotic binding to release this autoinhibition via a switch of its α6–α7 region. Hence, the promoters for MDR genes including tipA and RNA polymerases become available for transcription, enabling efficient antibiotic resistance. These insights into the molecular mechanism of activation of TipA proteins advance our understanding of TipA proteins, as well as bacterial MDR systems, and may provide important clues to block bacterial resistance.

Arabinogalactan proteins (AGPs) are plant proteoglycans with functions in growth and development. However, these functions are largely unexplored, mainly because of the complexity of the sugar moieties. These carbohydrate sequences are generally analyzed with the aid of glycoside hydrolases. The exo-β-1,3-galactanase is a glycoside hydrolase from the basidiomycete Phanerochaete chrysosporium (Pc1,3Gal43A), which specifically cleaves AGPs. However, its structure is not known in relation to its mechanism bypassing side chains. In this study, we solved the apo and liganded structures of Pc1,3Gal43A, which reveal a glycoside hydrolase family 43 subfamily 24 (GH43_sub24) catalytic domain together with a carbohydrate-binding module family 35 (CBM35) binding domain. GH43_sub24 is known to lack the catalytic base Asp conserved among other GH43 subfamilies. Our structure in combination with kinetic analyses reveals that the tautomerized imidic acid group of Gln263 serves as the catalytic base residue instead. Pc1,3Gal43A has three subsites that continue from the bottom of the catalytic pocket to the solvent. Subsite −1 contains a space that can accommodate the C-6 methylol of Gal, enabling the enzyme to bypass the β-1,6–linked galactan side chains of AGPs. Furthermore, the galactan-binding domain in CBM35 has a different ligand interaction mechanism from other sugar-binding CBM35s, including those that bind galactomannan. Specifically, we noted a Gly → Trp substitution, which affects pyranose stacking, and an Asp → Asn substitution in the binding pocket, which recognizes β-linked rather than α-linked Gal residues. These findings should facilitate further structural analysis of AGPs and may also be helpful in engineering designer enzymes for efficient biomass utilization.

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.

Purpose: The ⁶⁸Ga-PSMA PET/CT is a commonly used imaging modality in prostate cancers. However, few studies have compared the diagnostic efficiency between ⁶⁸Ga-PSMA and ¹⁸F-FDG PET/CT and evaluated whether a heterogeneous metabolic phenotype (especially PSMA-FDG+ lesions) exists in patients with castration-resistant prostate cancer (CRPC). We determined the added value of ¹⁸F-FDG PET/CT compared to ⁶⁸Ga-PSMA PET/CT in CRPC patients and identified CRPC patients who may benefit from additional ¹⁸F-FDG PET/CT. Methods: Data of 56 patients with CRPC who underwent both ⁶⁸Ga-PSMA and ¹⁸F-FDG PET/CT from May 2018 to February 2021 were retrospectively analysed. Patients were classified into two groups with or without PSMA-FDG+ lesions. The differences in patient characteristics between the two groups and predictors of patients who having at least one PSMA-FDG+ lesion were analysed. Results: Although both the detection rate (75.0% vs. 51.8%, P = 0.004) and positive lesion number (135 vs. 95) of ⁶⁸Ga-PSMA PET/CT were higher than ¹⁸F-FDG PET/CT, there were still 13/56 (23.2%) patients with at least one PSMA-FDG+ lesion. The prostate-specific antigen (PSA) and Gleason score were both higher in the patients with PSMA-FDG+ lesions than in those without PSMA-FDG+ lesions (P = 0.04 and P<0.001, respectively). Multivariate regression analysis showed that the Gleason score (≥8) and PSA (≥7.9 ng/mL) were associated with the detection rate of patients who had PSMA-FDG+ lesions (P = 0.01 and P = 0.04, respectively). The incidences of having PSMA-FDG+ lesions in low-probability (Gleason score<8 and PSA<7.9 ng/mL), medium-probability (Gleason score≥8 and PSA<7.9 ng/mL or Gleason score<8 and PSA≥7.9 ng/mL), and high-probability (Gleason score≥8 and PSA≥7.9 ng/mL) groups were 0%, 21.7%, and 61.5%, respectively (P<0.001). Conclusion: Gleason score and PSA are significant predictors for PSMA-FDG+ lesions, and CRPC patients with high Gleason score and PSA may benefit from additional ¹⁸F-FDG PET/CT.

PREAMBLE

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote the science, technology, and practical application of nuclear medicine. The European Association of Nuclear Medicine (EANM) is a professional nonprofit medical association that facilitates communication worldwide between individuals pursuing clinical and research excellence in nuclear medicine. The EANM was founded in 1985. The EANM was founded in 1985. SNMMI and EANM members are physicians, technologists, and scientists specializing in the research and practice of nuclear medicine.

The SNMMI and EANM will periodically define new guidelines for nuclear medicine practice to help advance the science of nuclear medicine and to improve the quality of service to patients throughout the world. Existing practice guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated.

Each practice guideline, representing a policy statement by the SNMMI/EANM, has undergone a thorough consensus process in which it has been subjected to extensive review. The SNMMI and EANM recognize that the safe and effective use of diagnostic nuclear medicine imaging requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guideline by those entities not providing these services is not authorized.

These guidelines are an educational tool designed to assist practitioners in providing appropriate care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, both the SNMMI and the EANM caution against the use of these guidelines in litigation in which the clinical decisions of a practitioner are called into question.

The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by the physician or medical physicist in light of all the circumstances presented. Thus, there is no implication that an approach differing from the guidelines, standing alone, is below the standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the guidelines.

The practice of medicine includes both the art and the science of the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditions make it impossible to always reach the most appropriate diagnosis or to predict with certainty a particular response to treatment.

Therefore, it should be recognized that adherence to these guidelines will not ensure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources, and the needs of the patient to deliver effective and safe medical care. The sole purpose of these guidelines is to assist practitioners in achieving this objective.

Visual Abstract

Visual Abstract

Visual Abstract

Visual Abstract

Visual Abstract

Ka-Won Kang
Nov 30, 2020; 0:RA120.002169v1-mcp.RA120.002169
Research

Post-transcriptional modifications of pre-mRNAs expand the diversity of proteomes in higher eukaryotes. In the brain, these modifications diversify the functional output of many critical neuronal signal molecules. In this study, we identified a brain-specific A-to-I RNA editing that changed glutamine to arginine (Q/R) at exon 20 and an alternative splicing of exon 4 in Tmem63b, which encodes a ubiquitously expressed osmosensitive cation channel. The channel isoforms lacking exon 4 occurred in ∼80% of Tmem63b mRNAs in the brain but were not detected in other tissues, suggesting a brain-specific splicing. We found that the Q/R editing was catalyzed by Adar2 (Adarb1) and required an editing site complementary sequence located in the proximal 5' end of intron 20. Moreover, the Q/R editing was almost exclusively identified in the splicing isoform lacking exon 4, indicating a coupling between the editing and the splicing. Elimination of the Q/R editing in brain-specific Adar2 knockout mice did not affect the splicing efficiency of exon 4. Furthermore, transfection with the splicing isoform containing exon 4 suppressed the Q/R editing in primary cultured cerebellar granule neurons. Thus, our study revealed a coupling between an RNA editing and a distant alternative splicing in the Tmem63b pre-mRNA, in which the splicing plays a dominant role. Finally, physiological analysis showed that the splicing and the editing coordinately regulate Ca2+ permeability and osmosensitivity of channel proteins, which may contribute to their functions in the brain.

Genta Kakiyama
Dec 1, 2020; 61:1629-1644
Research Articles

Abudukadier Abulizi
Dec 1, 2020; 61:1565-1576
Research Articles

Ying Zou
Dec 1, 2020; 61:1589-1604
Research Articles

An error might occur when you use the SAS 9 BULKLOAD= and BULKEXTRACT= options load data to or extract data from HP Neoview on the HP Itanium platform. The problem occurs because Hewlett-Packard changed the name of one of

In SAS Merchandise Financial Planning, custom time frame-based data versions do not aggregate correctly when referenced in worksheets with standard hierarchy levels. The data does not aggregate correctly from l

In SAS Infrastructure for Risk Management, the message "ERROR: Could not move and link one or more files to..." occurs while running a job-flow instance if an orphaned folder exists in the persistent area.

This article has been withdrawn by the authors as part of this review overlapped with the contents of Pietrangelo A and Ridgway ND. 2018. Cellular and Molecular Life Sciences. 75; 3079-98.

NAFLD is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to NASH remain unclear. This lack of knowledge leads to a decreased ability to find relevant animal models, predict disease progression, or develop clinical treatments. In the current study, we used multiple mouse models of NAFLD, human correlation data, and selective gene overexpression of steroidogenic acute regulatory protein (StarD1) in mice to elucidate a plausible mechanistic pathway for promoting the transition from NAFL to NASH. We show that oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the "acidic/alternative" pathway of cholesterol metabolism. Specifically, we report data showing that an inability to upregulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury. This metabolic pathway, initiated and exacerbated by insulin resistance, offers insight into approaches for the treatment of NAFLD.

Beiging of white adipose tissue (WAT) has beneficial effects on metabolism. Although it is known that beige adipocytes are active in lipid catabolism and thermogenesis, how they are regulated deserves more explorations. In this study, we demonstrate that stearoyl-CoA desaturase 1 (SCD1) in subcutaneous WAT (scWAT) responded to cold stimulation and was able to promote mobilization of triacylglycerol [TAG (triglyceride)]. In vitro studies showed that SCD1 promoted lipolysis in C3H10T1/2 white adipocytes. The lipolytic effect was contributed by one of SCD1’s products, oleic acid (OA). OA upregulated adipose TAG lipase and hormone-sensitive lipase expression. When SCD1 was overexpressed in the scWAT of mice, lipolysis was enhanced, and oxygen consumption and heat generation were increased. These effects were also demonstrated by the SCD1 knockdown experiments in mice. In conclusion, our study suggests that SCD1, known as an enzyme for lipid synthesis, plays a role in upregulating lipid mobilization through its desaturation product, OA.

Microsomal triglyceride transfer protein (MTTP) deficiency results in a syndrome of hypolipidemia and accelerated NAFLD. Animal models of decreased hepatic MTTP activity have revealed an unexplained dissociation between hepatic steatosis and hepatic insulin resistance. Here, we performed comprehensive metabolic phenotyping of liver-specific MTTP knockout (L-Mttp^–/–) mice and age-weight matched wild-type control mice. Young (10–12-week-old) L-Mttp^–/– mice exhibited hepatic steatosis and increased DAG content; however, the increase in hepatic DAG content was partitioned to the lipid droplet and was not increased in the plasma membrane. Young L-Mttp^–/– mice also manifested normal hepatic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps, no PKC activation, and normal hepatic insulin signaling from the insulin receptor through AKT Ser/Thr kinase. In contrast, aged (10-month-old) L-Mttp^–/– mice exhibited glucose intolerance and hepatic insulin resistance along with an increase in hepatic plasma membrane sn-1,2-DAG content and PKC activation. Treatment with a functionally liver-targeted mitochondrial uncoupler protected the aged L-Mttp^–/– mice against the development of hepatic steatosis, increased plasma membrane sn-1,2-DAG content, PKC activation, and hepatic insulin resistance. Furthermore, increased hepatic insulin sensitivity in the aged controlled-release mitochondrial protonophore-treated L-Mttp^–/– mice was not associated with any reductions in hepatic ceramide content. Taken together, these data demonstrate that differences in the intracellular compartmentation of sn-1,2-DAGs in the lipid droplet versus plasma membrane explains the dissociation of NAFLD/lipid-induced hepatic insulin resistance in young L-Mttp^–/– mice as well as the development of lipid-induced hepatic insulin resistance in aged L-Mttp^–/– mice.

Co-fractionation MS (CF-MS) is a technique with potential to characterize endogenous and unmanipulated protein complexes on an unprecedented scale. However this potential has been offset by a lack of guidelines for best-practice CF-MS data collection and analysis. To obtain such guidelines, this study thoroughly evaluates novel and published Saccharomyces cerevisiae CF-MS data sets using very high proteome coverage libraries of yeast gold standard complexes. A new method for identifying gold standard complexes in CF-MS data, Reference Complex Profiling, and the Extending 'Guilt-by-Association' by Degree (EGAD) R package are used for these evaluations, which are verified with concurrent analyses of published human data. By evaluating data collection designs, which involve fractionation of cell lysates, it is found that near-maximum recall of complexes can be achieved with fewer samples than published studies. Distributing sample collection across orthogonal fractionation methods, rather than a single high resolution data set, leads to particularly efficient recall. By evaluating 17 different similarity scoring metrics, which are central to CF-MS data analysis, it is found that two metrics rarely used in past CF-MS studies – Spearman and Kendall correlations – and the recently introduced Co-apex metric frequently maximize recall, whereas a popular metric—Euclidean distance—delivers poor recall. The common practice of integrating external genomic data into CF-MS data analysis is also evaluated, revealing that this practice may improve the precision and recall of known complexes but is generally unsuitable for predicting novel complexes in model organisms. If studying nonmodel organisms using orthologous genomic data, it is found that particular subsets of fractionation profiles (e.g. the lowest abundance quartile) should be excluded to minimize false discovery. These assessments are summarized in a series of universally applicable guidelines for precise, sensitive and efficient CF-MS studies of known complexes, and effective predictions of novel complexes for orthogonal experimental validation.

The development of the HUPO-PSI's (Proteomics Standards Initiative) standard data formats and MIAPE (Minimum Information About a Proteomics Experiment) guidelines should improve proteomics data sharing within the scientific community. Proteomics journals have encouraged the use of these standards and guidelines to improve the quality of experimental reporting and ease the evaluation and publication of manuscripts. However, there is an evident lack of bioinformatics tools specifically designed to create and edit standard file formats and reports, or embed them within proteomics workflows. In this article, we describe a new web-based software suite (The ProteoRed MIAPE web toolkit) that performs several complementary roles related to proteomic data standards. Firstly, it can verify the reports fulfill the minimum information requirements of the corresponding MIAPE modules, highlighting inconsistencies or missing information. Secondly, the toolkit can convert several XML-based data standards directly into human readable MIAPE reports stored within the ProteoRed MIAPE repository. Finally, it can also perform the reverse operation, allowing users to export from MIAPE reports into XML files for computational processing, data sharing or public database submission. The toolkit is thus the first application capable of automatically linking the PSI's MIAPE modules with the corresponding XML data exchange standards, enabling bidirectional conversions. This toolkit is freely available at http://www.proteored.org/MIAPE/.

Extracellular vesicle (EV) proteins from acute myeloid leukemia (AML) cell lines were analyzed using mass spectrometry. The analyses identified 2450 proteins, including 461 differentially expressed proteins (290 upregulated and 171 downregulated). CD53 and CD47 were upregulated and were selected as candidate biomarkers. The association between survival of patients with AML and the expression levels of CD53 and CD47 at diagnosis was analyzed using mRNA expression data from The Cancer Genome Atlas database. Patients with higher expression levels showed significantly inferior survival than those with lower expression levels. Enzyme-linked immunosorbent assay results of the expression levels of CD53 and CD47 from EVs in the bone marrow of patients with AML at diagnosis and at the time of complete remission with induction chemotherapy revealed that patients with downregulated CD53 and CD47 expression appeared to relapse less frequently. Network model analysis of EV proteins revealed several upregulated kinases, including LYN, CSNK2A1, SYK, CSK, and PTK2B. The potential cytotoxicity of several clinically applicable drugs that inhibit these kinases was tested in AML cell lines. The drugs lowered the viability of AML cells. The collective data suggest that AML-derived EVs could reflect essential leukemia biology.

Gender, think-tanks and international affairs: A toolkit Other resource NCapeling 9 February 2021

Encouraging a more gender-sensitive approach for think-tank activities such as convening and debate, research and analysis, and communications and publishing.

Compiled by staff at Chatham House, the Centre for Feminist Foreign Policy and the British American Security Information Council, the toolkit provides think-tanks with guidance on ways of adapting organizational structures, activities and practices in order to embed greater awareness of gender issues and adopt gender-sensitive approaches throughout their work.

The toolkit is designed for all people working in international affairs think-tanks, regardless of role, experience or level of seniority. It will be particularly useful for those think-tanks that are just beginning the process of raising greater awareness of gender issues internally, as well as for those that have already begun to make changes but wish to expand this work further.

The work to develop the toolkit came as a response to the commonly gendered nature of think-tanks and their activities. The toolkit recognizes the discrimination and under-representation that women often experience within the sector, as well as the relative absence of women among executive leadership, governance structures and senior researcher positions in many think-tanks.

The toolkit’s focus on gender is a starting point for wider intersectional analysis and action within the think-tank community. Embedding inclusive research, convening and communication practices is not just ‘the right thing to do’. When diversity and inclusion initiatives succeed, organizations are more resilient, innovative and better at decision-making.

While there has already been incremental change within think-tanks, the toolkit’s authors intend that their work will build on the important body of research and practices that already exist by encouraging think-tanks to examine their own processes and develop ways of working that focus not just on women’s representation, but on the structures and systems that perpetuate biases and inequalities.

Brad Ausmus held his first media session of the spring on the day pitchers and catchers officially reported on Tuesday, giving updates on rehabbing players such as Shohei Ohtani, Albert Pujols and Zack Cozart.

Shohei Ohtani remains a must-watch player for Angels fans in 2019, and his recovery from Tommy John surgery will be worth monitoring throughout the season as he prepares to pitch again in '20.

Shohei Ohtani, who is aiming for a return in May as a designated hitter but won't pitch in 2019, isn't able to participate in the on-field workouts with his teammates, but has progressed to swinging the bat and working out indoors.

The 2019 MLB season feels so close now. Spring Training has begun. Players are taking the field. So it's time to rank the best of the best.

After Ohtani's nearly unprecedented two-way success during his American League Rookie of the Year campaign last year, more clubs are looking into the possibility of having players who can both pitch and play a position. Walsh fits that bill, as he has been a power-hitting first baseman and outfielder in the Minors, but he's made 10 pitching appearances over the past three seasons as well. The Angels are experimenting with him doing both this spring and this upcoming season.

Shohei Ohtani is continuing to make progress in his rehab from Tommy John surgery. On Sunday, he said he is hopeful he'll be able to start hitting off a tee in the next week.

Tsvangirai Leaves an Important Political Legacy in Southern Africa Expert comment sysadmin 21 February 2018

The story of Zimbabwe’s ‘people’s champion’ offers a powerful example to a region in need of new political compromises.

The death of Movement for Democratic Change (MDC) leader Morgan Tsvangirai is a loss for Zimbabwe. In nearly three decades of speaking truth to power, Tsvangirai helped to change his nation and the region.

Southern Africa’s new politics

His death marks a period of transition for regional governments and opposition parties alike. The Zuma era has ended in South Africa while Mozambique, Namibia and Angola have also seen political transitions, pushing modernization agendas to appeal to young citizenries that increasingly see politics in separate terms from the liberationist struggles of the previous generation.

Regional opposition movements also face winds of change: the longstanding opposition leader in the Democratic Republic of the Congo, Etienne Tshekedi, passed away in 2017, and Mozambique’s Afonso Dhlakama and Kenya’s Raila Odinga are both aging. These movements similarly need to appeal to a younger audience or risk losing relevance.

From trade unionist to opposition leader

Tsvangirai’s career is an eloquent illustration of these challenges. Born in Buhera in rural eastern Zimbabwe, Tsvangirai worked in textiles and mining before politics – diverse experience which gave him crucial exposure to the lives of ordinary people across the country. In his early years, he also worked for ZANU-PF, before leaving to forge his own political path. He became increasingly active in mining politics, rising to the executive of the National Mineworker’s Union and, in 1989, to secretary-general of the powerful Zimbabwe Congress of Trade Unions.

In the late 1990’s, Zimbabwe was riven by questions over land, war veterans, the Congo conflict, a shrinking economy and growing doubts about ZANU-PF itself. Opposition leaders of the time could not answer them; those such as Edgar Tekere and Margaret Dongo struggled to win support beyond their local constituencies, and liberation leader Joshua Nkomo’s ZAPU had been merged with ZANU-PF in the 1987 Unity Accord.

But in 2000, Zimbabwe’s ‘perfect storm’ of a divisive constitutional referendum, land redistribution and a June election made Tsvangirai and the newly minted MDC, formed in 1999, a national rival to ZANU-PF. Through subsequent national elections in 2002, 2005, 2008 and 2013, Zimbabwe remained polarized between competing visions of Zimbabwe future: ZANU-PF’s powerful black liberationist politics of identity and the opposition’s equally compelling liberal democracy agenda.

Tsvangirai’s achievement was to provide a credible alternative to liberation icon Robert Mugabe. Tsvangirai also resuscitated Zimbabwe’s tradition of urban nationalism, and was a successor to Benjamin Burombo and other mid-century Zimbabwean urban leaders. Tsvangirai would in turn be a touchstone for contemporary urban activists Evans Mawarire, Linda Masarira and others.

From opposition to coalition

The political struggle for Zimbabwe became global, with Mugabe and Tsvangirai both winning support from rival international power blocs. In March 2007, pictures of a beaten and bloodied Tsvangirai helped to galvanize support for the MDC in the 2008 elections. But the disputed result and violent subsequent run-off between Tsvangirai and Mugabe led the regional community to push both men into a coalition government, with Tsvangirai as prime minister.

Despite continuous ructions, the Government of National Unity (GNU) held, and stabilized Zimbabwe’s collapsed economy, until 2013. Although often politically out-manoeuvred by Mugabe, Tsvangirai deserves credit for getting the opposition a share of political power and for holding his nerve against many who wanted to collapse the GNU.

Tsvangirai was no saint; his complicated love life, and tacit approval of violent attacks on party dissenters, do him no credit. More importantly, the MDC neglected its grassroots supporters during the GNU, and paid the price in its comprehensive 2013 electoral defeat. But although diminished, Tsvangirai remained Zimbabwe’s most popular opposition politician, and the MDC’s new leaders will have quite a task ahead of them, even if they have been planning since his courageous 2016 public admission of colon cancer.

The MDC after Tsvangirai

Nelson Chamisa, one of the three MDC vice presidents, has now been appointed as acting president by the party’s national committee. Chamisa inherits a fractured and fractious party, and one which has also fallen out with the Tsvangirai family. The other two vice presidents, Thokozani Khupe and Elias Mudzuri, have also set their sights on party leadership.

At 40, Chamisa, an orator with grassroots appeal, has a huge task. With general elections due by July, he has to unite the party, counter Zimbabwe’s rising ethno-politics, prove himself as leader of a broader opposition coalition and take on a resurgent President Emmerson Mnangagwa and ZANU-PF.

Electorally, the opposition’s strongest card has always been the urban vote and the economy. But Mnangagwa has fast forwarded a comprehensive economic reform and internationalist agenda. This, and Mugabe’s exit, have forced Chamisa, Joice Mujuru and other opposition leaders to play catch-up. Zimbabwe’s elections, the first since 2000 without Mugabe and Tsvangirai as contenders, will be of global interest as the country navigates the new political dynamics.

The people’s champion

Morgan Tsvangirai’s resilience earned him respect from friends and foes alike, with Zimbabwe’s President Mnangagwa and Vice President Constantino Chiwenga visiting him at home a few weeks ago. A former nominee for the Nobel Peace Prize, Tsvangirai, popularly known by his totem of ‘Save’ and also called mudhara [the old man] deserves national hero status. He will certainly be remembered as the ‘people’s champion’, and a pioneer in bridging the generational and ideological fissures that have shaped Southern Africa’s politics.

With their leader now gone, the turbulent MDC will undoubtedly be hoping for a ‘remembrance vote’ in his memory to carry them through the elections. But beyond that, his story offers a powerful example to a region in need of new political compromises.

The role of think tanks amid political uncertainty 9 May 2023 — 6:00PM TO 7:00PM Anonymous (not verified) 13 April 2023 Chatham House and Online

Think tank leaders discuss how persistent and new forms of political uncertainty impact on their work and what can they do to counter it.  

Think tanks play a crucial role in supporting better public policy to address the most pressing global and local challenges. However, the recent rise in political turbulence poses a significant challenge to this work. Not only must the work of think tanks help counter political uncertainty but that uncertainty often threatens their ability to work effectively, and in some cases, their survival.

Polarized elections, regional instability, the rise of populism, shrinking civic space, eroding democracies, weakened institutions and public distrust are just some of the tricky contexts and issues raised by think tank leaders in the latest think tank state of the sector report. 

This event is being held in collaboration with On Think Tanks ahead of the On Think Tanks Conference.

Join us for a thought-provoking discussion at Chatham House on the major sources and consequences of political uncertainty in the world today and the critical role of think tanks in responding to and countering it. 

Key questions to be addressed during this discussion include:

• How does political uncertainty look like today?
• What can think tanks do to operate within uncertain contexts? 
• What are their roles: should they build the middle ground, support political parties, rally behind social demands?  
• Will think tanks be able to maintain their reliability and credibility in an increasingly polarized political environment?
• What can think tanks do to contribute to greater political stability?

As with all member events, questions from the audience drive the conversation.

A drinks reception will immediately follow this event.

Ukraine exposes Europe’s double standards for refugees Expert comment NCapeling 30 March 2022

As European governments provide swift protection assurances to those fleeing Ukraine, non-European asylum-seekers continue to face violence at the EU’s borders.

One month after Russia’s invasion of Ukraine, the European Union (EU) already faces its largest refugee crisis since World War Two, with more than ten million people having fled their homes – 6.5 million displaced within Ukraine and 3.9 million escaping to neighbouring countries.

Acting quickly and decisively, European governments have opened borders and European citizens have opened their homes in an unprecedented showing of solidarity towards refugees. But, with all eyes on Ukraine, the Greek coastguard continues to illegally push back asylum-seekers crossing from Turkey while Spanish police forcefully repel those who dare to jump the fence in Melilla.

The painful contrast exposes the double standards in the EU’s approach to refugees. With Europe’s grim history of restrictive asylum policies, it is wishful thinking that the warm welcome to Ukrainians will extend to all asylum-seekers. The EU solidarity to displaced Ukrainians illustrates the deeply politicized – and often discriminatory – nature of providing refugee protection.

However, the hope is this turning point in European history can at least set an important precedent for treating refugees more humanely. Undoubtedly, EU solidarity towards people fleeing the horrors of Putin’s war is critically important and the initial response is positive in its efforts to meet immense humanitarian needs.

Solidarity with Ukrainians

The EU activation of the Temporary Protection Directive (TPD) is a significant step towards a more humane protection regime and fairer responsibility-sharing among member states. Without the need for the examination of individual applications, those fleeing Ukraine can access harmonized rights across the EU for three years – including residence, housing, medical assistance, and access to the labour market and education.

The TPD is also a move away from the strict ‘Dublin’ rules which put the pressure of hosting refugees onto the countries of ‘first arrival’. Ironically, the fiercest opponents of intra-EU solidarity, such as Poland and Hungary, are the ones benefiting from this change now but, in the case of Ukraine, geographical proximity and shared histories must be considered when analysing Europe’s response.

Eastern European and Baltic countries share a post-Soviet history and fear of Russian aggression, and Ukrainians already enjoyed 90 days of visa-free travel in the EU – with a large diaspora, many have established networks across Europe. But even considering these distinctive connections with Ukrainian displacement, the initial response still shows that European countries have both the political will and the capacity to host refugees.

Unlike the usual – often media-fuelled – narratives of refugee ‘invasions’ into Europe, the waves of women and children leaving Ukraine prompted a surge of humanitarian action but they are also a chilling reality check of Europe’s double standards.

The EU has used agreements with countries such as Turkey and Libya to prevent arrivals and outsource asylum responsibilities, while border violence, detention, and lengthy asylum procedures await the few asylum seekers who manage to enter Europe from the Middle East, Asia, and Africa.

These ‘fortress Europe’ legacies have even undercut the humanitarian response in Ukraine, with reports of incidents of discrimination towards people of colour at the EU borders being condemned by the United Nations (UN) and the African Union (AU), the media facing allegations of racist reporting, and comments from Bulgarian PM Kiril Petkov providing a stark reminder of the islamophobia, racism, and history of colonization which still pervades European asylum policies.

Foreign policy also influences how EU leaders treat the right to asylum, as the geopolitics of Europe’s efforts to create a united front against Russian aggression is an undercurrent to the prompt European response to Ukrainians. But only a few months ago, non-European asylum-seekers trapped in freezing forests at the Poland-Belarus border were used as political pawns by Belarusian leader Aliaksandr Lukashenka and then dehumanised as a ‘hybrid attack’ by EU leaders.

A turning point for asylum in Europe?

Despite entrenched discriminatory precedents, it is worth looking ahead at this moment of reckoning. Although policy changes remain far off, the unity shown over Ukraine can help reshape and refocus political efforts towards increased responsibility-sharing among EU member states – the perennial ‘hot potato’ of the EU asylum system.

The U.S. Food and Drug Administration has determined commonly used oral phenylephrine is "not effective" and has proposed its removal from over-the-counter nasal decongestants.

Oct. 31, 2024 — SNIA is pleased to return to SC24 as part of the Open Standards Pavilion, Booth 1815. At SC24, five SNIA groups and six SNIA Alliance and Collaboration […]

The post SNIA to Lead Panel on AI and HPC Innovation Standards at SC24 appeared first on HPCwire.

All-Pro left tackle Tristan Wirfs and tight ends Sam LaPorta and Dalton Kincaid were among key players injured in Week 10 of the NFL season.

BEAVERTON, Ore., Oct. 29, 2024 — Ultra Accelerator Link (UALink) Consortium, led by Board Members from AMD, Amazon Web Services (AWS), Astera Labs, Cisco, Google, Hewlett Packard Enterprise (HPE), Intel, Meta […]

The post Ultra Accelerator Link Consortium Launches with Industry Leaders, Opens Membership to Drive AI Connectivity Standards appeared first on HPCwire.

After much anticipation, the National Institute of Standards and Technology (NIST) issued its first Post Quantum Cryptography (PQC) standards today. They are intended to defeat efforts by quantum computers powerful […]

The post NIST Issues Post Quantum Cryptography Standards and Calls for their Adoption appeared first on HPCwire.