Time: 9:00 AM, Location: E2.010

Mammalian Asn-linked glycans are extensively processed as they transit the secretory pathway to generate diverse glycans on cell surface and secreted glycoproteins. Additional modification of the glycan core by α-1,6-fucose addition to the innermost GlcNAc residue (core fucosylation) is catalyzed by an α-1,6-fucosyltransferase (FUT8). The importance of core fucosylation can be seen in the complex pathological phenotypes of FUT8 null mice, which display defects in cellular signaling, development, and subsequent neonatal lethality. Elevated core fucosylation has also been identified in several human cancers. However, the structural basis for FUT8 substrate specificity remains unknown.Here, using various crystal structures of FUT8 in complex with a donor substrate analog, and with four distinct glycan acceptors, we identify the molecular basis for FUT8 specificity and activity. The ordering of three active site loops corresponds to an increased occupancy for bound GDP, suggesting an induced-fit folding of the donor-binding subsite. Structures of the various acceptor complexes were compared with kinetic data on FUT8 active site mutants and with specificity data from a library of glycan acceptors to reveal how binding site complementarity and steric hindrance can tune substrate affinity. The FUT8 structure was also compared with other known fucosyltransferases to identify conserved and divergent structural features for donor and acceptor recognition and catalysis. These data provide insights into the evolution of modular templates for donor and acceptor recognition among GT-B fold glycosyltransferases in the synthesis of diverse glycan structures in biological systems.

Broad-specificity glycoside hydrolases (GHs) contribute to plant biomass hydrolysis by degrading a diverse range of polysaccharides, making them useful catalysts for renewable energy and biocommodity production. Discovery of new GHs with improved kinetic parameters or more tolerant substrate-binding sites could increase the efficiency of renewable bioenergy production even further. GH5 has over 50 subfamilies exhibiting selectivities for reaction with β-(1,4)–linked oligo- and polysaccharides. Among these, subfamily 4 (GH5_4) contains numerous broad-selectivity endoglucanases that hydrolyze cellulose, xyloglucan, and mixed-linkage glucans. We previously surveyed the whole subfamily and found over 100 new broad-specificity endoglucanases, although the structural origins of broad specificity remained unclear. A mechanistic understanding of GH5_4 substrate specificity would help inform the best protein design strategies and the most appropriate industrial application of broad-specificity endoglucanases. Here we report structures of 10 new GH5_4 enzymes from cellulolytic microbes and characterize their substrate selectivity using normalized reducing sugar assays and MS. We found that GH5_4 enzymes have the highest catalytic efficiency for hydrolysis of xyloglucan, glucomannan, and soluble β-glucans, with opportunistic secondary reactions on cellulose, mannan, and xylan. The positions of key aromatic residues determine the overall reaction rate and breadth of substrate tolerance, and they contribute to differences in oligosaccharide cleavage patterns. Our new composite model identifies several critical structural features that confer broad specificity and may be readily engineered into existing industrial enzymes. We demonstrate that GH5_4 endoglucanases can have broad specificity without sacrificing high activity, making them a valuable addition to the biomass deconstruction toolset.

Africa’s strategic priorities and global role 27 January 2023 — 1:00PM TO 2:00PM Anonymous (not verified) 18 January 2023 Chatham House and Online

At this hybrid event, HE John Dramani Mahama, former president of the Republic of Ghana, will discuss his ideas on the key economic and governance reforms required for economic stability and prosperity across Africa.

Ghana recently became the fourth country, after Chad, Ethiopia and Zambia, to seek debt treatment under the G20 Common Framework in January 2023 – reflecting the culmination of a series of internal and external shocks affecting the wider region, including extreme weather events, the COVID-19 pandemic and the Russia-Ukraine crisis.

Prospects for economic recovery and growth, nevertheless, remain positive in many parts of the continent, with the African Development Bank (AfDB), for example, reforecasting economic growth of 5.5 per cent in East Africa in 2023. Coordinated reforms can help to deepen regional integration and promote long-term economic prosperity, particularly in light of Africa’s evolving regional economic governance structures, notably the fledgling African Continental Free Trade Area (AfCFTA) headquartered in Accra.

At this hybrid event, HE John Dramani Mahama, former president of the Republic of Ghana, will discuss his ideas on the key economic and governance reforms required for economic stability and prosperity across Africa. He will also discuss priorities for regional integration and Africa’s role and responsibilities in global economic governance.

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.

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Litong Nie
Dec 1, 2020; 19:2015-2029
Research

Leandro Xavier Neves
Nov 11, 2020; 0:RA120.002227v1-mcp.RA120.002227
Research

The divalent anion sodium symporter (DASS) family (SLC13) plays critical roles in metabolic homeostasis, influencing many processes, including fatty acid synthesis, insulin resistance, and adiposity. DASS transporters catalyze the Na+-driven concentrative uptake of Krebs cycle intermediates and sulfate into cells; disrupting their function can protect against age-related metabolic diseases and can extend lifespan. An inward-facing crystal structure and an outward-facing model of a bacterial DASS family member, VcINDY from Vibrio cholerae, predict an elevator-like transport mechanism involving a large rigid body movement of the substrate-binding site. How substrate binding influences the conformational state of VcINDY is currently unknown. Here, we probe the interaction between substrate binding and protein conformation by monitoring substrate-induced solvent accessibility changes of broadly distributed positions in VcINDY using a site-specific alkylation strategy. Our findings reveal that accessibility to all positions tested is modulated by the presence of substrates, with the majority becoming less accessible in the presence of saturating concentrations of both Na+ and succinate. We also observe separable effects of Na+ and succinate binding at several positions suggesting distinct effects of the two substrates. Furthermore, accessibility changes to a solely succinate-sensitive position suggests that substrate binding is a low-affinity, ordered process. Mapping these accessibility changes onto the structures of VcINDY suggests that Na+ binding drives the transporter into an as-yet-unidentified conformational state, involving rearrangement of the substrate-binding site–associated re-entrant hairpin loops. These findings provide insight into the mechanism of VcINDY, which is currently the only structurally characterized representative of the entire DASS family.

The plasma membrane of a cell is characterized by an asymmetric distribution of lipid species across the exofacial and cytofacial aspects of the bilayer. Regulation of membrane asymmetry is a fundamental characteristic of membrane biology and is crucial for signal transduction, vesicle transport, and cell division. The type IV family of P-ATPases, or P4-ATPases, establishes membrane asymmetry by selection and transfer of a subset of membrane lipids from the lumenal or exofacial leaflet to the cytofacial aspect of the bilayer. It is unclear how P4-ATPases sort through the spectrum of membrane lipids to identify their desired substrate(s) and how the membrane environment modulates this activity. Therefore, we tested how the yeast plasma membrane P4-ATPase, Dnf2, responds to changes in membrane composition induced by perturbation of endogenous lipid biosynthetic pathways or exogenous application of lipid. The primary substrates of Dnf2 are glucosylceramide (GlcCer) and phosphatidylcholine (PC, or their lyso-lipid derivatives), and we find that these substrates compete with each other for transport. Acutely inhibiting sphingolipid synthesis using myriocin attenuates transport of exogenously applied GlcCer without perturbing PC transport. Deletion of genes controlling later steps of glycosphingolipid production also perturb GlcCer transport to a greater extent than PC transport. In contrast, perturbation of ergosterol biosynthesis reduces PC and GlcCer transport equivalently. Surprisingly, application of lipids that are poor transport substrates differentially affects PC and GlcCer transport by Dnf2, thus altering substrate preference. Our data indicate that Dnf2 exhibits exquisite sensitivity to the membrane composition, thus providing feedback onto the function of the P4-ATPases.

Insulin receptor substrate 2 (IRS2) is an essential adaptor that mediates signaling downstream of the insulin receptor and other receptor tyrosine kinases. Transduction through IRS2-dependent pathways is important for coordinating metabolic homeostasis, and dysregulation of IRS2 causes systemic insulin signaling defects. Despite the importance of maintaining proper IRS2 abundance, little is known about what factors mediate its protein stability. We conducted an unbiased proteomic screen to uncover novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that controls the abundance of key cell cycle regulators. We found that IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G₁. Consistent with the APC/C's role in degrading cell cycle regulators, quantitative proteomic analysis of IRS2-null cells revealed a deficiency in proteins involved in cell cycle progression. We further show that cells lacking IRS2 display a weakened spindle assembly checkpoint in cells treated with microtubule inhibitors. Together, these findings reveal a new pathway for IRS2 turnover and indicate that IRS2 is a component of the cell cycle control system in addition to acting as an essential metabolic regulator.

Using a simple, environment friendly proteome extraction (TOP), we were able to optimize the analysis of clinical samples. Using our TOP method we analyzed a clinical cohort of microsatellite stable (MSS) and unstable (MSI-H) colorectal carcinoma (CRC). We identified a tumor cell specific, STAT1-centered, immune signature expressed by the MSI-H tumor cells. We then showed that long, but not short, exposure to Interferon- induces a similar signature in vitro. We identified 10 different temporal protein expression patterns, classifying the Interferon- protein temporal regulation in CRC. Our data sheds light on the changes that tumor cells undergo under long-term immunological pressure in vivo, the importance of STAT proteins in specific biological scenarios. The data generated could help find novel clinical biomarkers and therapeutic approaches.

Studies in the yeast Saccharomyces cerevisiae have helped define mechanisms underlying the activity of the ubiquitin–proteasome system (UPS), uncover the proteasome assembly pathway, and link the UPS to the maintenance of cellular homeostasis. However, the spectrum of UPS substrates is incompletely defined, even though multiple techniques—including MS—have been used. Therefore, we developed a substrate trapping proteomics workflow to identify previously unknown UPS substrates. We first generated a yeast strain with an epitope tagged proteasome subunit to which a proteasome inhibitor could be applied. Parallel experiments utilized inhibitor insensitive strains or strains lacking the tagged subunit. After affinity isolation, enriched proteins were resolved, in-gel digested, and analyzed by high resolution liquid chromatography-tandem MS. A total of 149 proteasome partners were identified, including all 33 proteasome subunits. When we next compared data between inhibitor sensitive and resistant cells, 27 proteasome partners were significantly enriched. Among these proteins were known UPS substrates and proteins that escort ubiquitinated substrates to the proteasome. We also detected Erg25 as a high-confidence partner. Erg25 is a methyl oxidase that converts dimethylzymosterol to zymosterol, a precursor of the plasma membrane sterol, ergosterol. Because Erg25 is a resident of the endoplasmic reticulum (ER) and had not previously been directly characterized as a UPS substrate, we asked whether Erg25 is a target of the ER associated degradation (ERAD) pathway, which most commonly mediates proteasome-dependent destruction of aberrant proteins. As anticipated, Erg25 was ubiquitinated and associated with stalled proteasomes. Further, Erg25 degradation depended on ERAD-associated ubiquitin ligases and was regulated by sterol synthesis. These data expand the cohort of lipid biosynthetic enzymes targeted for ERAD, highlight the role of the UPS in maintaining ER function, and provide a novel tool to uncover other UPS substrates via manipulations of our engineered strain.

Specific E3 ligases target tumor suppressors for degradation. Inhibition of such E3 ligases may be an important approach to cancer treatment. RNF146 is a RING domain and PARylation-dependent E3 ligase that functions as an activator of the β-catenin/Wnt and YAP/Hippo pathways by targeting the degradation of several tumor suppressors. Tankyrases 1 and 2 (TNKS1/2) are the only known poly-ADP-ribosyltransferases that require RNF146 to degrade their substrates. However, systematic identification of RNF146 substrates have not yet been performed. To uncover substrates of RNF146 that are targeted for degradation, we generated RNF146 knockout cells and TNKS1/2-double knockout cells and performed proteome profiling with label-free quantification as well as transcriptome analysis. We identified 160 potential substrates of RNF146, which included many known substrates of RNF146 and TNKS1/2 and 122 potential TNKS-independent substrates of RNF146. In addition, we validated OTU domain-containing protein 5 and Protein mono-ADP-ribosyltransferase PARP10 as TNKS1/2-independent substrates of RNF146 and SARDH as a novel substrate of TNKS1/2 and RNF146. Our study is the first proteome-wide analysis of potential RNF146 substrates. Together, these findings not only demonstrate that proteome profiling can be a useful general approach for the systemic identification of substrates of E3 ligases but also reveal new substrates of RNF146, which provides a resource for further functional studies.

In quantitative proteomics work, the differences in expression of many separate proteins are routinely examined to test for significant differences between treatments. This leads to the multiple hypothesis testing problem: when many separate tests are performed many will be significant by chance and be false positive results. Statistical methods such as the false discovery rate (FDR) method that deal with this problem have been disseminated for more than one decade. However a survey of proteomics journals shows that such tests are not widely implemented in one commonly used technique, quantitative proteomics using two-dimensional electrophoresis (2-DE). We outline a selection of multiple hypothesis testing methods, including some that are well known and some lesser known, and present a simple strategy for their use by the experimental scientist in quantitative proteomics work generally. The strategy focuses on the desirability of simultaneous use of several different methods, the choice and emphasis dependent on research priorities and the results in hand. This approach is demonstrated using case scenarios with experimental and simulated model data.

Glycosylation is a prevalent, yet heterogeneous modification with a broad range of implications in molecular biology. This heterogeneity precludes enrichment strategies that can be universally beneficial for all glycan classes. Thus, choice of enrichment strategy has profound implications on experimental outcomes. Here we review common enrichment strategies used in modern mass spectrometry (MS)-based glycoproteomic experiments, including lectins and other affinity chromatographies, hydrophilic interaction chromatography (HILIC) and its derivatives, porous graphitic carbon (PGC), reversible and irreversible chemical coupling strategies, and chemical biology tools that often leverage bioorthogonal handles. Interest in glycoproteomics continues to surge as MS instrumentation and software improve, so this review aims to help equip researchers with necessary information to choose appropriate enrichment strategies that best complement these efforts.

Protease activity has been associated with pathological processes that can lead to cancer development and progression. However, understanding the pathological unbalance in proteolysis is challenging since changes can occur simultaneously at protease, their inhibitor and substrate levels. Here, we present a pipeline that combines peptidomics, proteomics and peptidase predictions for studying proteolytic events in the saliva of seventy-nine patients and their association with oral squamous cell carcinoma (OSCC) prognosis. Our findings revealed differences in the saliva peptidome of patients with (pN+) or without (pN0) lymph node metastasis and delivered a panel of ten endogenous peptides correlated with poor prognostic factors plus five molecules able to classify pN0 and pN+ patients (ROC-AUC>0.85). In addition, endo- and exopeptidases putatively implicated in the processing of differential peptides were investigated using cancer tissue gene expression data from publicly repositories reinforcing their association with poorer survival rates and prognosis in oral cancer. The dynamics of the OSCC-related proteolysis was further explored via the proteomic profiling of saliva. This revealed that peptidase/endopeptidase inhibitors exhibited reduced levels in the saliva of pN+ patients, as confirmed by SRM-MS, whilst minor changes were detected in the level of saliva proteases. Taken together, our results indicated that proteolytic activity is accentuated in the saliva of OSCC patients with lymph node metastasis and, at least in part, this is modulated by reduced levels of salivary peptidase inhibitors. Therefore, this integrated pipeline provided better comprehension and discovery of molecular features with implications in the oral cancer metastasis prognosis.

South Africa Needs a Strategic Vision for Its Continent Expert comment sysadmin 24 November 2017

South Africa has the potential to catalyse growth across its sub-region and the continent, but the government must develop a comprehensive strategy that aligns political, ideological and commercial interests.

South Africa’s status as the ‘gateway to Africa’ is under serious threat. Its companies continue to flourish, but complex relationships at home and abroad constrain government capacity to match its economic dominance with political reach and influence.

South Africa’s policies towards the rest of the continent are often accused of being inconsistent and incoherent. It has been a development partner to the region and to international donors; a moral leader, championing human rights and exporting its own model of transition; and an advocate and representative for the continent in international forums. However, it has simultaneously been accused of exploiting its economic dominance at the expense of its neighbours; handicapped by the political debts owed by the ANC to other liberation movements for their assistance in the struggle; and criticized for its arrogance in seeking to position itself as the ‘legitimate’ voice of Africa.

At the same time, reputational risks, a weakened policy environment and poor growth have taken the shine off South Africa’s ‘Gateway to Africa’ rhetoric. South Africa faces considerable domestic economic issues. Growth forecasts have fallen from 1.3 to 0.7 per cent, State owned enterprises are a huge burden on the treasury, and the forecast budget deficit is R50.8 billion (£2.7 billion), at a time when the cost of borrowing is increasing following downgrades of the country’s credit ratings.

Political risk is high, lowering investor confidence. Corruption, poor service delivery and the government’s under-delivery on citizen’s expectations are exacerbating social tensions in a country with expanded unemployment at 36.4 per cent, and one of the highest rates of inequality in the world. McKinsey, KPMG and HSBC have all become entangled in scandal relating to their dealings with government entities that have become ‘captured’ by private interests.

Despite these concerns, South Africa nonetheless remains the backbone of the regional economy, and its firms are key players across the continent. Johannesburg hosts the deepest and most sophisticated capital market on the continent, and Pretoria has one of the highest numbers of diplomatic missions in the world. ESKOM provides around 75 per cent of the electricity contribution to the Southern Africa SADC Power pool – comprising 12 countries, including those as far north as DRC and Tanzania – and South African ports facilitate over half of sub-Saharan Africa’s non-commodity trade with the rest of the world.

Post-apartheid expansion across the continent by South African companies was initially met with resistance, but these relationships have improved significantly – and South African firms retain significant advantages. South African retailers have the scale to incorporate regional producers into continental supply chains, purchasing fresh produce at a competitive price from regional agri-businesses, then re-selling further afield. For example, Zambeef supplies meat from Zambia to Shoprite stores in west Africa.

African companies in turn rely on South Africa as a significant consumer of goods, services and primary commodities. A South African government agreement with the DRC to import about half of the electricity that will be produced by a new grand-scale hydro-power project guaranteed its bankability. Mozambique is looking to maximize the potential of its world-class natural gas reserves by building a pipeline into South Africa, thus benefitting from the purchasing power of South African parastatal electricity utility firm ESKOM.

But South Africa’s status as an economic hegemon is not mirrored in its political relationships. South Africa’s GDP is five times higher than the six countries with which it shares a border, combined. But successive ANC governments have been unable to fully flex this economic muscle. Partly this is a legacy of history. It is not forgotten that the regional economic body, the Southern African Development Community, originated as the organization of Front Line States coordinating efforts to end apartheid, and ZANU-PF officials in Zimbabwe lecture their ANC counterparts on liberation.

The pan-African vision of former president Thabo Mbeki, and promotion of South Africa’s transition as a model for the continent, reflected the values that have driven ANC policy since the end of apartheid. But the coherence of South Africa’s foreign policy has been undermined by conflict and contradiction within the government. Appetite for engagement in Africa is dwindling. The country’s ability to project military influence across the continent is in critical decline. Jacob Zuma’s use of regional political bodies as a means of removing political rivals from domestic politics has corroded goodwill.

A new Africa Programme research paper argues that a fresh approach to South African engagement on the continent is both possible and necessary. South Africa can use its relative economic weight to play a stronger developmental role, leveraging the strengths of its business sector and its financial agencies. But it must match this with stronger and more cooperative political engagement, particularly through cultivating relationships with pivotal states such as Nigeria, Kenya, Ethiopia and Angola.

In December, the ANC will elect a new leader to take the party into elections in 2019. Both leading candidates have international experience – Nkosazana Dlamini-Zuma was the chair of the African Union, and Cyril Ramaphosa has led regional responses to crises in South Sudan, Lesotho and Burundi. South Africa still has considerable foreign policy resources at its disposal. A new strategic vision for Africa that unites the interests of government and business, both domestically and in partner states, can deliver prosperity for both South Africa and the region – and need not contradict the values that have shaped South Africa’s aspirations for the continent in the post-apartheid era.

Europe's strategic choices 2021 4 November 2021 TO 5 November 2021 — 8:00AM TO 5:30PM Anonymous (not verified) 21 September 2021 Ritz Carlton Berlin

The 2021 conference will consider how Europe can navigate its political, economic and security challenges, in the context of the lasting effects of the coronavirus pandemic and an increasingly competitive geopolitical environment.

Registration is a two step process and you will receive a link to register on the conference virtually in advance. Please email if you wish to attend in-person.

The Eighth Annual Europe’s Strategic Choices conference, jointly developed and hosted by Chatham House, the Institute for Security Policy at the University of Kiel and the Konrad-Adenauer-Stiftung, aims to understand the complex set of challenges facing Europe in the areas of security, economic competitiveness, trade, technology, and global influence.

Set against the backdrop of a Europe emerging gradually from the COVID-19 pandemic, this annual forum brings together policymakers, and representatives from business, civil society and academia, to explore how European countries can best respond, individually and collectively to their common challenges in an increasingly competitive geopolitical environment.

The conference will be hosted in hybrid format to enable speakers and participants to join in person and allow others to engage virtually via the Conference Plus digital platform. This format ensures we can connect with a geographically diverse audience whilst incorporating important elements of in person engagement in accordance with German Federal government guidelines.

NATO must now transform old missions into new strategy Expert comment NCapeling 21 June 2022

As the war in Ukraine becomes prolonged and unpredictable, risks for the transatlantic alliance will increase, as will the global shockwaves of the conflict.

As a revitalized NATO alliance deals with a crisis that has major economic and humanitarian as well as military dimensions, the need for it to develop both a European and a global containment strategy grows ever more urgent.

Bolstering NATO’s defences so as to provide the capability to repel any form of Russian attack on land, at sea, in the air, or through space and cyberspace is a key aspect of this strategy as, in recent weeks, more combat forces able to defend territory have taken the form of additional troops, ships, and aircraft reinforcing the Baltic states and the Black Sea coastlines of Poland and Romania.

Ten allies have so far contributed to this effort, placing 40,000 troops under direct NATO command. Those sceptical about the future of the transatlantic security relationship have been confounded by the major role the US has played in this effort, sending parts of the 82nd Airborne Division and 3rd Armoured Division to Poland, and redeploying US Stryker brigades from Germany and Italy to the Baltic states and Romania.

Although many other allies have sent useful assets – such as French and UK aircraft to Romania or German and Netherlands Patriot batteries to Slovakia – the US contribution still surpasses all European efforts put together. The US now has 100,000 troops in Europe, the most it has deployed there since the mid-1990s.

Transitioning from temporary to permanent deployment

NATO has also mobilized its high-readiness Reaction Force for the first time and aims to establish four new multinational battalions in the Black Sea region – with France offering to lead the one in Romania, Italy in Bulgaria, and the Czech Republic in Slovakia. Most of these deployments are on a temporary basis, but the receiving allies would understandably like them to stay longer and for NATO to commit to permanent stationed forces.

Although this would oblige the alliance to break formally from the pledge it made to Moscow in 1997 not to station substantial combat forces or nuclear weapons or build military infrastructure on the territory of its new member states in eastern Europe, this was a political undertaking linked to circumstances prevailing at the time.

Given Russia’s behaviour, there is no reason why NATO should not now abandon it. There is also a question over whether NATO could also repeal the NATO-Russia Founding Act and the NATO-Russia Council, or simply leave them in suspension for a future, more cooperative, and less bellicose Russian regime.

Beyond showing the flag along its eastern flank, NATO does face longer-term issues which need to be clarified in its new Strategic Concept. First is whether to abandon its current strategy of reinforcement and military mobility across Europe – known as the Enhanced Forward Presence in the NATO jargon – in favour of the deployment of heavy armoured brigades or even divisions in fixed positions close to borders.

This will be expensive in the long-run and deprive allies of the flexibility they have enjoyed since the end of the Cold War to use their forces as and where they wish – from deployments in the Sahel or Afghanistan to fighting forest fires or building emergency hospitals for COVID-19 patients at home. The only exception is when they have put forces on rotation into the NATO high readiness forces or the European Union (EU) Battle Groups.

Germany’s commitment gives NATO more options

The decision of Germany to increase its defence spending to two per cent of GDP and to devote €100 billion to modernizing the Bundeswehr makes it technically possible for NATO to move to a Cold War-style forward, armoured defence. But it is unclear how quickly Berlin could raise its new divisions given its problems with procurement and government/industry relations in the defence sector.

It may make more sense for Germany not to launch new acquisition programmes but to buy existing off-the-shelf capabilities – as it has recently done with its decision to buy 35 US F35 aircraft – which other European countries are also acquiring, offering economies of scale and cheaper operating and maintenance costs.

But if Germany abandons ambitious defence projects with France – which prefers a ‘buy European’ approach – such as the Future European Air Combat System, the relationship with France will become strained and French plans for EU self-reliance in the military field put at risk.

As a country averse to war fighting and narrow military approaches to security, it is uncertain how much of the conventional defence burden in NATO Germany would be willing to take on, so this could be the opportunity to create more integrated European units with France, the Benelux, Poland, and Italy, even with the post-Brexit UK.

The UK has doubled the size of its forces in Estonia and sent 1,000 troops to Poland, as well as devoting a substantial portion of its army, navy, and airforce to regular NATO exercises in the Baltic region. London was also the first ally to grant Sweden and Finland a temporary security guarantee pending full integration into the alliance.

NATO will likely settle on a compromise, increasing the size of its battalions on its eastern flank – turning them into battle groups – but giving each one a larger reserve force which will remain in Germany or other European allied countries.

A NATO strategic plan is now needed

The other issue for NATO is to develop a single theatre-wide strategic plan managed by the Supreme Allied Commander, Europe (SACEUR) and the NATO command structure. In reinforcing the alliance’s eastern flank, allies have sent forces to wherever they like and largely under national command, but this would not work in a real war.

NATO must revise its exercises to prepare and train for the new threat level, ensuring its forward deployed forces are fully integrated with local forces and the police and border guards to anticipate and respond to any Russian hybrid war tactics. It also needs to step up its joint planning and interoperability with Sweden and Finland and bring their territories into its standing defence plans.

One thing NATO has done well in this crisis is its political messaging. As Russia has become more threatening and reckless, it has been essential for NATO to be consistent and predictable. Re-affirming its core defensive purpose, calmly rejecting Putin’s nuclear posturing, and refusing to put NATO forces in Ukraine may be frustrating for some but it is vital not to play into Putin’s playbook regarding an ‘aggressive NATO’ or give him the sense he is being pushed into a corner. However, NATO strategic ambiguity can be useful when considering how to respond to a Russian escalation in Ukraine itself, such as using chemical weapons.

The key questions for NATO are:

• What should be the balance between permanently deployed and rotational forces in NATO’s new posture?
• What should be the balance of US/Canadian and European forces in this posture?
• How can the capability development programmes under EU Strategic Autonomy (such as PESCO and the European Defence Fund) be geared to support the European role and responsibility in the alliance? Air and missile defence would seem to be priorities given Russia’s reliance on long range strikes.
• How can the EU’s Strategic Compass, NATO’s next Strategic Concept and the third NATO-EU Joint Declaration be harmonized to bring the two institutions more closely together in responding to Russian hybrid operations and influence campaigns, and in assisting both Ukraine and others such as Georgia and Moldova?
• What should be the balance between forces for collective defence with heavy armour and directed artillery fire, and those for expeditionary missions beyond Europe such as counterterrorism, stabilization and peacekeeping?

NATO is revived and refocused

Although the Russian invasion of Ukraine is a catastrophe for Ukraine and Europe more generally, the multilateral system has discovered a new energy and sense of purpose as NATO has been revived and refocused on its core mission.

The EU and the US have pulled together with daily coordination of their policies and actions, and the EU is also facing up to its geo-political role, as recognizing the EU aspirations of Ukraine, Moldova, and Georgia as well as the countries of the western Balkans shows its responsibility for the security and economic integration of the whole of Europe.

HPC System Administrator University of California Los Angeles Budgeted Pay Scale: Full Salary Range: USD $76,200.00/Yr. - USD $158,800.00/Yr. Department Summary UCLAs Office of Advanced Research Computing (OARC) melds expert staff and technical infrastructure to amplify and accelerate the impact of UCLA research in the age of networked data and computation. OARC expertise and resources are available to all UCLA researchers, who are engaged in digital research and scholarship. We work with faculty, student, and postdoctoral researchers; instructors; and staff and administrators. OARC is a relationship-building organization. We enable digital scholarship through collaborations, partnerships, and networked communities to advance cutting-edge research capabilities at UCLA and beyond. OARC supports and enhances the university mission of education, research, and service through the development and execution of innovative and sustainable technology practices, programs, services, infrastructure, policies, and partnerships. Position Summary HPC System Administrator UCLAs Office of Advanced Research Computing (OARC) supports and enhances the university mission of education, research, and service through the development and execution of innovative and sustainable technology practices, programs, services, infrastructure, policies, and partnerships. The OARC High Performance Computing (HPC) Systems Research Technology Group (RTG) supports thousands of UCLA researchers and over 300 research groups through consultation and the operation of the Hoffman2 High Performance Research Cluster. More information on the Hoffman2 cluster may be found at Hoffman2 Cluster Documentation The Hoffman2 cluster environment consists of approximately 1000 compute nodes, GPU nodes, high speed networking, high-performance storage, backup equipment, and extensive hardware and software support infrastructure, spread across multiple data centers. The HPC System Administrator, as part of the HPC team, will serve as a technical expert supporting OARCs HPC environment in the areas of systems and application software development, HPC cluster system administration and management of the backup system environment. Requires the ability to work from UCLAs Westwood campus as operational demands dictate. FlexWork / hybrid schedules will be considered based on work demands and operational needs. Salary & Compensation *UCLA provides a full pay range. Actual salary offers consider factors, including budget, prior experience, skills, knowledge, abilities, education, licensure and certifications, and other business considerations. Salary offers at the top of the range are not common. Visit https://ucnet.universityofcalifornia.edu/compensation-and-benefits/index.html to discover benefits that start on day one, and https://ucnet.universityofcalifornia.edu/compensation-and-benefits/total-compensation-calculator.html to calculate the total compensation value with benefits. Qualifications • 3 years Experience with software and applications development, Linux system administration, and two or more modern programming languages (e.g. Python, C++, Java). (Required) • Expert knowledge of Python, SQL, bash, git, and associated build systems, libraries, and development tools. Demonstrated knowledge of common programming paradigms (e.g., asynchronous, concurrent, and object-oriented). Demonstrated ability to create high-quality system tools and software. (Required) • Ability to work independently or in a development team, and effectively estimate time and effort required to complete tasks. Ability to analyze, benchmark, debug, and test software in a technically sound manner and to generate clear, readable reports and summaries. (Required) • Demonstrated working knowledge of HPC cluster architectures and concepts (e.g., provisioning, benchmarking, scalability, and parallelizing code) and ability to stay current with industry best practices. (Required) • Detailed knowledge of Red Hat Enterprise Linux and related distributions. Solid system administration skills including scripting, pipelines, and UNIX operating system fundamentals. (Required) • Working knowledge of protocols, applications, and formats including, but not limited to, TCP/IP, HTTP, DHCP, SSH, NFS, JSON, XML, and HTML. (Required) • Demonstrated ability to troubleshoot and debug computing problems including, corrupted data, file management, application software, and operating system problems. Accurately, and independently respond to production problems in multiple complex operating systems and software components. (Required) • Knowledge of validation, verification, and disaster recovery capabilities for both hardware and software. (Required) • Demonstrated skill in writing well-organized, complete, and technically and grammatically correct documents and procedures to be used by technical and non-technical personnel of diverse backgrounds at various levels in the organization, including researchers, peers, and management. (Required) • Demonstrated oral communication and presentation skills sufficient to effectively obtain and impart technical information and explain concepts on a one-to-one basis as well as in meetings with or presentations to multiple clients. (Required) • Demonstrated problem-solving skills and the ability to break down and define complex problems, formulate solutions, identify cause and effect relationships, make appropriate decisions, and communicate concepts clearly and appropriately with researchers and peers. (Required) • Ability to prioritize tasks, prepare project plans, schedules, effectively manage projects in areas of responsibility, complete tasks, projects in a timely manner. Work effectively both independently and as part of a team, follow through follow through on assignments with minimal direction. (Required) • Demonstrated skill in establishing and maintaining cooperative working relationships with staff, students, and vendors. Ability to communicate and interact effectively with persons of diverse backgrounds. (Required) Education, Licenses, Certifications & Personal Affiliations • Bachelors Degree Bachelors degree in computer science, software engineering, or a related field. (Required) And • Masters Degree Masters degree in computer science, software engineering or a related field . (Preferred) Special Conditions for Employment • Background Check: Continued employment is contingent upon the completion of a satisfactory background investigation. • Live Scan Background Check: A Live Scan background check must be completed prior to the start of employment. • COVID and Flu Vaccinations: The position is subject to providing evidence of inoculation. Schedule 8:00 am to 5:00 pm Union/Policy Covered 99-Policy Covered To apply, please visit: https://apptrkr.com/5770145 Application Deadline: 8:50 p.m. on Copyright ©2024 Jobelephant.com Inc. All rights reserved. https://www.jobelephant.com/

In this era, expansion in digital infrastructure capacity is inevitable. Parallel to this, climate change consciousness is also rising, making sustainability a mandatory part of the organization’s functioning. As computing […]

The post Why IT Must Have an Influential Role in Strategic Decisions About Sustainability appeared first on HPCwire.

KAWASAKI, Japan and SANTA CLARA, Calif., Nov. 1, 2024 — Fujitsu and AMD have announced that they have signed a memorandum of understanding (MOU) to form a strategic partnership to […]

The post Fujitsu and AMD to Begin Strategic Partnership to Accelerate Open-source AI initiatives appeared first on HPCwire.

A boom in AI has created a problem for the organizers of the NeurIPS conference, which is considered an essential machine-learning research conference. The sheer number of registrations has overwhelmed […]

The post Lottery to Determine Major AI Conference Attendees Amid Registration Boom appeared first on HPCwire.

Here are strategies for creating strong, respectful, productive relationships between superintendents and school boards.

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Here are strategies for creating strong, respectful, productive relationships between superintendents and school boards.