Earlier this year, we announced that Basecamp was committing to getting to carbon negative for our cumulative history and moving forward. Today, I want to share an update on that commitment. Note: I edited this post on Nov 5, 2020 to include the prices paid for all carbon offsets and explain a little more about the… keep reading

20th CCP National Congress: Five issues to watch Expert comment LJefferson 13 October 2022

Interpreters of the Chinese Communist Party’s tea leaves will be paying close attention to the issues that will shape China’s trajectory for the next five years.

Xi Jinping’s expected anointment for an unprecedented third term as general secretary of the Chinese Communist Party (CCP) is likely to generate global headlines when the party’s five-yearly National Congress begins on 16 October.

But with that outcome so widely forecast, interpreters of the CCP’s tea leaves will be paying closer attention to a range of more contested – and sometimes byzantine – issues that will shape China’s trajectory for the next five years, and reverberate around the world.

These are five key issues to watch out for during Xi’s political report, a dry but authoritative account of the CCP’s policy priorities for the next five years, and the subsequent deliberations over personnel appointments.

1. From market economy to ‘common prosperity’

As the world grapples with the economic impact of Russia’s invasion of Ukraine, the Chinese economy is entering particularly choppy waters. China is forecast to grow at a slower rate than the rest of Asia for the first time in more than 30 years, according to the World Bank, as the impact of Xi’s COVID zero policies compounds a growing list of structural and cyclical challenges.

Xi is under pressure to offer some new prescriptions for the world’s second biggest economy, and he is likely to signal further shifts away from the market economics that propelled Chinese growth for decades toward his vision of ‘common prosperity’.

His ambition is to redefine progress, not in terms of producing double-digit growth, but in tackling long-standing challenges such as demographic decline, social inequality and high property prices – thereby meeting ‘people’s ever-growing needs for a better life’.

China’s leader may have arrived at the right diagnosis, but he has so far failed to find measures that deliver common prosperity. He will use the Party Congress to redesign some policy measures, likely putting a stronger focus on the development of rural areas to promote economic dynamism and generate employment opportunities.

2. COVID zero to endure?

While most of the world has opened up and learned to live with COVID-19, China is still pursuing a COVID zero policy that requires frequent lockdowns, stringent movement controls and closed borders. This approach has intensified economic pressures, exacerbated high youth unemployment, and is testing the patience of China’s upwardly mobile middle classes.

Those not employed by the state have been particularly hard hit and it is difficult to see how China’s economy can start to crank up again until Beijing reduces internal restrictions and reconnects with the world.

Xi has championed the COVID zero policy, which Beijing continues to insist is vital to protect vulnerable people and support economic and social stability. So, observers will be playing close attention to his political report for any signs of a possible softening or indications of alternative future pathways for managing the pandemic. But a wholesale shift does not appear to be on the cards.

3. Xi Jinping’s team

Sinologists’ enthusiasm for predicting leadership changes in the CCP is not matched by their ability to do so. The party’s roots as a secret organization ensure that it keeps a tight lid on information about top leaders.

Observers will be closely following appointments to the seven-member Politburo Standing Committee, the apex of power for the CCP and China’s supreme decision-making body. These choices will shape China’s future policy trajectory and give some signals about the extent of Xi’s concentration of power and his future plans.

Names to watch for possible promotion include Xi allies such as He Lifeng, currently head of the National Development Reform Commission, a key economic planning entity, and Zhang Qingwei, currently the party secretary of Hunan, an important and populous province.

As Vice Premier Sun Chunlan, the only woman on the Politburo, reaches the retirement age, there is also likely to be a slot open for her replacement, with Shan Yiqin, the party secretary of Guizhou, one potential option.

Tracking the fate of key Xi allies will also indicate how far he has managed to overturn the collective leadership system he inherited in 2012 and how comprehensively the CCP endorses this more centralized approach to governing China.

4. Taiwan

After the escalating tensions of the last few months, analysts will be looking for any possible change in tone when Xi speaks about Taiwan, a self-governing island that China claims as a renegade province. During the past five years, Xi has approached the outside world with a mix of high-octane rhetoric with pragmatism and patience.

Arguments Over Innovation Capacity Miss How Much the US and China Are Intertwined Expert comment sysadmin 30 May 2018

Most discussions of current US–China trade tensions fundamentally misrepresent the globalized nature of innovation.

Among the many issues at play in the ongoing economic and trade tensions between the US and China are questions of technological capability and innovation.

Two of the main complaints in the US Section 301 report were that American companies have been forced to transfer technology to China and been the subject of cyber espionage. The presentation of the issues in this report has been disputed, but behind it lies concern in the US that Chinese innovative and technological capability is catching up with that in the US, thanks partly to the support of state policies set out in the Made in China 2025 initiative.

One important feature of the package of measures announced by the US last month is that it was designed to contain China’s technological development as much as to reduce the trade deficit, even though the latter has been the focus of President Donald Trump’s rhetoric.

(Some have cast doubt on this picture of Chinese innovation, suggesting that China is more of a ‘fat tech dragon’ whose massive inputs into research and development do not translate into real innovative capacity.)

The problem with the debate comparing Chinese and American technological capability is that it misunderstands or misrepresents the globalized nature of innovation in today’s world.

Contrary to the economic nationalist rhetoric emanating mainly from Washington, and to a lesser extent from Beijing, the US and China are not two separate economies competing for economic hegemony. As part of the globalization of manufacturing and production over the last 40 years and the more recent globalization of consumption, the shape and structure of innovation has also changed.

As we argue in a new paper, the key to understanding this is to think of innovation as being carried out through global or transnational networks linking economic actors, not within separated economies. What the recent phase of globalization has demonstrated is that innovation is achieved most effectively and efficiently when those engaged in innovation are connected not just within national borders but across them.

China has become integrated into these global innovation networks in ways which reflect its relative strengths and weaknesses in research and development. China’s extensive manufacturing ecosystem has enabled its companies to perform well in production-related and efficiency-driven innovation. Moreover the rapid growth in its large and dynamic consumer market provides fertile ground for consumer-related innovation by Chinese and foreign-invested enterprises alike. The rapidly increasing talent pool in China also provides additional human capital for innovation and technology.

Apart from the increased emphasis by Chinese enterprises on innovation, multinationals have also been stepping up their research and development (R&D) efforts in China. These now consitute a significant part of China’s R&D landscape, and are an increasingly important part of the global innovation by multinationals.

Things are of course changing. China’s overall innovation capacity is improving, and there are concerns in both in the US and Europe that Chinese policy is moving backwards towards the promotion of ‘indigenous innovation’ – or self-reliant innovation – and away from openness. In other words, we may be seeing a more ‘techno-nationalist’ China as well as a protectionist US.

China has also been criticized for inadequate protection of intellectual property rights, though the establishment of special courts for such disputes marks a commitment to improve – and the rights of Chinese companies increasingly need protection too.

As the benefits of globalization increasingly come under question, and with some degree of nationalist political pressure in both the West and China, it is not going to be possible – or politically desirable – to do away with national borders when it comes to innovation. But at the same time, the extent to which businesses and consumers have globalized means that fully ‘indigenous’ innovation is not possible, even if it were politically desirable.

EU-China innovation relations, as well as those between Washington and Beijing, therefore need careful management. But both Americans and Europeans should have more confidence in their innovation capability, given the relative strengths and weaknesses of Chinese innovation.

Americans and Europeans should acknowledge and promote the opportunities that come from globally networked innovation processes. Taking advantage of the comparative advantage of all the players in these networks means working with China as an innovation partner.

Roland Bruderer
May 1, 2015; 14:1400-1410
Research

Mathias Uhlén
Dec 1, 2005; 4:1920-1932
Research

Linn Fagerberg
Feb 1, 2014; 13:397-406
Research

Independent Thinking: China protests, North Korea missile tests Audio NCapeling 1 December 2022

Episode seven of our new weekly podcast examines the civil unrest in China and the ongoing development of North Korea’s nuclear weapons programme.

Anti-lockdown protests are sweeping the cities of Beijing, Shanghai, and Guangzhou. What does the unrest say about China’s response to COVID-19? How serious a challenge is it to Xi Jinping’s legitimacy so soon after the Party Congress?

Meanwhile, 2022 has been a record year for Pyongyang’s ballistic missile launches. How far has North Korea’s nuclear programme and its missile systems developed, and what does it mean for the country’s neighbours?

Joining Bronwen Maddox in the studio this week from the Chatham House Asia-Pacific programme are its director Ben Bland and senior research fellow Dr Yu Jie. Joining the panel is special guest Ankit Panda, the Stanton senior fellow at the Carnegie Endowment for International Peace, and editor-at-large for The Diplomat magazine.

About Independent Thinking

A weekly podcast hosted by Chatham House director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

Margrit Schwarz
Sep 1, 1998; 39:1833-1843
Articles

Saverio Cinti
Nov 1, 2005; 46:2347-2355
Research Articles

Chatham House Commission on Democracy and Technology in Europe News Release sysadmin 25 July 2019

Our project on Democracy and Technology in Europe is now entering its final phase. Now we want your help in shaping the final report.

Expert

Webinar: Hong Kong: Dissent in the Age of Coronavirus 17 April 2020 — 12:00PM TO 1:00PM Anonymous (not verified) 8 April 2020

Street protests demanding greater autonomy and democratization in Hong Kong upended the city for seven months last year. However, with the outbreak of the coronavirus in China in late January, the protests quickly died out. What does this mean for the city’s protest movement?

The speaker will argue that, despite the lack of high-profile street rallies, protest in the city is continuing. It is building on and evolving from last year’s protest movement albeit in different forms. At the same time, the Hong Kong authorities, emboldened by a hard line from Beijing, have begun cracking down on activists and protesters in the city as they seek to put a lid on dissent ahead of important Legislative Council elections scheduled for this September.

In this webinar, the speaker will look at the current state of dissent in Hong Kong and prospects for Hong Kong’s future.

This event will be held on the record.

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.

Visual Abstract

Colin T. McDowell
Nov 24, 2020; 0:RA120.002256v1-mcp.RA120.002256
Research

The kinesin-3 family contains the fastest and most processive motors of the three neuronal transport kinesin families, yet the sequence of states and rates of kinetic transitions that comprise the chemomechanical cycle and give rise to their unique properties are poorly understood. We used stopped-flow fluorescence spectroscopy and single-molecule motility assays to delineate the chemomechanical cycle of the kinesin-3, KIF1A. Our bacterially expressed KIF1A construct, dimerized via a kinesin-1 coiled-coil, exhibits fast velocity and superprocessivity behavior similar to WT KIF1A. We established that the KIF1A forward step is triggered by hydrolysis of ATP and not by ATP binding, meaning that KIF1A follows the same chemomechanical cycle as established for kinesin-1 and -2. The ATP-triggered half-site release rate of KIF1A was similar to the stepping rate, indicating that during stepping, rear-head detachment is an order of magnitude faster than in kinesin-1 and kinesin-2. Thus, KIF1A spends the majority of its hydrolysis cycle in a one-head-bound state. Both the ADP off-rate and the ATP on-rate at physiological ATP concentration were fast, eliminating these steps as possible rate-limiting transitions. Based on the measured run length and the relatively slow off-rate in ADP, we conclude that attachment of the tethered head is the rate-limiting transition in the KIF1A stepping cycle. Thus, KIF1A's activity can be explained by a fast rear-head detachment rate, a rate-limiting step of tethered-head attachment that follows ATP hydrolysis, and a relatively strong electrostatic interaction with the microtubule in the weakly bound post-hydrolysis state.

Montgomery Blencowe
Dec 23, 2020; 0:jlr.RA120000713v1-jlr.RA120000713
Research Articles

Anja Jaeschke
Dec 9, 2020; 0:jlr.RA120001141v1-jlr.RA120001141
Research Articles

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

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

Amanda D.V. MacCannell
Nov 18, 2020; 0:jlr.ILR120001204v1-jlr.ILR120001204
Images in Lipid Research

If the OBSMARGINS= or OM= option is specified in an LSMEANS, LSMESTIMATE, or SLICE statement and a user-defined format is applied to any of the effect variables in the OM-data-set , PROC PLM incorrectly stops proce

The LDL receptor-related protein-1 (LRP1) is highly expressed in numerous cell types, and its impairment is associated with obesity, diabetes, and fatty liver disease. However, the mechanisms linking LRP1 to metabolic disease are not completely understood. Here, we compared the metabolic phenotype of C57BL/6J wild type and LRP1 knock-in mice carrying an inactivating mutation in the distal NPxY motif after feeding a low fat (LF) diet or high fat diets with (HFHC) or without (HF) cholesterol supplementation. In response to HF feeding, both groups developed hyperglycemia, hyperinsulinemia, and hyperlipidemia, as well as increased adiposity with adipose tissue inflammation and liver steatosis. However, when animals were fed the HF diet supplemented with cholesterol, the LRP1 NPxY mutation prevents hypercholesterolemia, reduces adipose tissue and brain inflammation, and limits liver progression to steatohepatitis. Nevertheless, insulin signaling is impaired in LRP1 NPxY mutant hepatocytes and this mutation does not protect against HFHC-induced insulin resistance. The selective metabolic improvement observed in HFHC-fed LRP1 NPxY mutant mice is due to an apparent increase of hepatic LDL receptor levels, leading to an elevated rate of plasma lipoprotein clearance and lowering of plasma and hepatic cholesterol levels. The unique metabolic phenotypes displayed by LRP1 NPxY mutant mice in response to HF or HFHC diet feeding indicate an LRP1-cholesterol axis in modulating tissue inflammation. The LRP1 NPxY mutant mouse phenotype differs from phenotypes observed in mice with tissue-specific LRP1 inactivation, thus highlighting the importance of an integrative approach to evaluate how global LRP1 dysfunction contributes to metabolic disease development.

Genome-wide association studies (GWAS) have implicated ~380 genetic loci for plasma lipid regulation. However, these loci only explain 17-27% of the trait variance and a comprehensive understanding of the molecular mechanisms has not been achieved. In this study, we utilized an integrative genomics approach leveraging diverse genomic data from human populations to investigate whether genetic variants associated with various plasma lipid traits, namely total cholesterol (TC), high and low density lipoprotein cholesterol (HDL and LDL), and triglycerides (TG), from GWAS were concentrated on specific parts of tissue-specific gene regulatory networks. In addition to the expected lipid metabolism pathways, gene subnetworks involved in ‘interferon signaling’, ‘autoimmune/immune activation’, ‘visual transduction’, and ‘protein catabolism’ were significantly associated with all lipid traits. Additionally, we detected trait-specific subnetworks, including cadherin-associated subnetworks for LDL, glutathione metabolism for HDL, valine, leucine and isoleucine biosynthesis for TC, and insulin signaling and complement pathways for TG. Finally, utilizing gene-gene relations revealed by tissue-specific gene regulatory networks, we detected both known (e.g. APOH, APOA4, and ABCA1) and novel (e.g. F2 in adipose tissue) key regulator genes in these lipid-associated subnetworks. Knockdown of the F2 gene (Coagulation Factor II, Thrombin) in 3T3-L1 and C3H10T1/2 adipocytes reduced gene expression of Abcb11, Apoa5, Apof, Fabp1, Lipc, and Cd36, reduced intracellular adipocyte lipid content, and increased extracellular lipid content, supporting a link between adipose thrombin and lipid regulation. Our results shed light on the complex mechanisms underlying lipid metabolism and highlight potential novel targets for lipid regulation and lipid-associated diseases.

Bile acids (BAs) have been established as ubiquitous regulatory molecules implicated in a large variety of healthy and pathological processes. However, the scope of BA heterogeneity is often underrepresented in current literature. This is due in part to inadequate detection methods, which fail to distinguish the individual constituents of the BA pool. Thus, the primary aim of this study was to develop a method that would allow the simultaneous analysis of specific C24 BA species, and to apply that method to biological systems of interest. Herein, we describe the generation and validation of an LC-MS/MS assay for quantification of numerous BAs in a variety of cell systems and relevant biofluids and tissue. These studies included the first baseline level assessment for planar BAs, including allocholic acid, in cell lines, biofluids, and tissue in a nonhuman primate (NHP) laboratory animal, Macaca mulatta, in healthy conditions. These results indicate that immortalized cell lines make poor models for the study of BA synthesis and metabolism, whereas human primary hepatocytes represent a promising alternative model system. We also characterized the BA pool of M. mulatta in detail. Our results support the use of NHP models for the study of BA metabolism and pathology in lieu of murine models. Moreover, the method developed here can be applied to the study of common and planar C24 BA species in other systems.

Among the virulence factors in Neisseria infections, a major inducer of inflammatory cytokines is the lipooligosaccharide (LOS). The activation of NF-B via extracellular binding of LOS or lipopolysaccharide (LPS) to the toll-like receptor 4 and its coreceptor, MD-2, results in production of pro-inflammatory cytokines that initiate adaptive immune responses. LOS can also be absorbed by cells and activate intracellular inflammasomes, causing the release of inflammatory cytokines and pyroptosis. Studies of LOS and LPS have shown that their inflammatory potential is highly dependent on lipid A phosphorylation and acylation, but little is known on the location and pattern of these posttranslational modifications. Herein, we report on the localization of phosphoryl groups on phosphorylated meningococcal lipid A, which has two to three phosphate and zero to two phosphoethanolamine substituents. Intact LOS with symmetrical hexa-acylated and asymmetrical penta-acylated lipid A moieties was subjected to high-resolution ion mobility spectrometry MALDI-TOF MS. LOS molecular ions readily underwent in-source decay to give fragments of the oligosaccharide and lipid A formed by cleavage of the ketosidic linkage, which enabled performing MS/MS (pseudo-MS³). The resulting spectra revealed several patterns of phosphoryl substitution on lipid A, with certain species predominating. The extent of phosphoryl substitution, particularly phosphoethanolaminylation, on the 4'-hydroxyl was greater than that on the 1-hydroxyl. The heretofore unrecognized phosphorylation patterns of lipid A of meningococcal LOS that we detected are likely determinants of both pathogenicity and the ability of the bacteria to evade the innate immune system.

Adaptive thermogenesis is highly dependent on uncoupling protein 1 (UCP1), a protein expressed by thermogenic adipocytes present in brown adipose tissue (BAT) and white adipose tissue (WAT). Thermogenic capacity of human and mouse BAT can be measured by positron emission tomography-computed tomography quantifying the uptake of ¹⁸F-fluodeoxyglucose or lipid tracers. BAT activation is typically studied in response to cold exposure or treatment with β-3-adrenergic receptor agonists such as CL316,243 (CL). Currently, it is unknown whether cold-stimulated uptake of glucose or lipid tracers is a good surrogate marker of UCP1-mediated thermogenesis. In metabolic studies using radiolabeled tracers, we found that glucose uptake is increased in mildly cold-activated BAT of Ucp1^–/– versus WT mice kept at subthermoneutral temperature. Conversely, lower glucose disposal was detected after full thermogenic activation achieved by sustained cold exposure or CL treatment. In contrast, uptake of lipoprotein-derived fatty acids into chronically activated thermogenic adipose tissues was substantially increased in UCP1-deficient mice. This effect is linked to higher sympathetic tone in adipose tissues of Ucp1^–/– mice, as indicated by elevated levels of thermogenic genes in BAT and WAT. Thus, glucose and lipoprotein handling does not necessarily reflect UCP1-dependent thermogenic activity, but especially lipid uptake rather mirrors sympathetic activation of adipose tissues.

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.

Le ventre est l’une des parties du corps où il est plus difficile de perdre de la graisse. Souvent, la meilleure solution pour arriver à perdre de la graisse à cet endroit précis du corps consiste à manger sainement et équilibré. Cependant, quels sont les aliments qui brûlent les graisses du ventre sans danger pour la […]

L’article Quels sont les aliments qui brûlent rapidement les graisses du ventre ? est apparu en premier sur Ortho Doc France.

The complexity and dynamics of the immensely heterogeneous glycoproteome of the prostate cancer (PCa) tumour micro-environment remain incompletely mapped, a knowledge gap that impedes our molecular-level understanding of the disease. To this end, we have used sensitive glycomics and glycoproteomics to map the protein-, cell- and tumour grade-specific N- and O-glycosylation in surgically-removed PCa tissues spanning five histological grades (n = 10/grade) and tissues from patients with benign prostatic hyperplasia (n = 5). Quantitative glycomics revealed PCa grade-specific alterations of the oligomannosidic-, paucimannosidic- and branched sialylated complex-type N-glycans, and dynamic remodelling of the sialylated core 1- and core 2-type O-glycome. Deep quantitative glycoproteomics identified ~7,400 unique N-glycopeptides from 500 N-glycoproteins and ~500 unique O-glycopeptides from nearly 200 O-glycoproteins. With reference to a recent Tissue and Blood Atlas, our data indicate that paucimannosidic glycans of the PCa tissues arise mainly from immune cell-derived glycoproteins. Further, the grade-specific PCa glycosylation arises primarily from dynamics in the cellular makeup of the PCa tumour microenvironment across grades involving increased oligomannosylation of prostate-derived glycoproteins and decreased bisecting GlcNAcylation of N-glycans carried by the extracellular matrix proteins. Further, elevated expression of several oligosaccharyltransferase subunits and enhanced N-glycoprotein site occupancy were observed associated with PCa progression. Finally, correlations between the protein-specific glycosylation and PCa progression were observed including increased site-specific core 2-type O-glycosylation of collagen VI. In conclusion, integrated glycomics and glycoproteomics have enabled new insight into the complexity and dynamics of the tissue glycoproteome associated with PCa progression generating an important resource to explore the underpinning disease mechanisms.

The early detection of pancreatic ductal adenocarcinoma is a complex clinical obstacle yet is key to improving the overall likelihood of patient survival. Current and prospective carbohydrate biomarkers CA19-9 and sTRA are sufficient for surveilling disease progression yet are not approved for delineating PDAC from other abdominal cancers and non-cancerous pancreatic pathologies. To further understand these glycan epitopes, an imaging mass spectrometry approach was utilized to assess the N-glycome of the human pancreas and pancreatic cancer in a cohort of PDAC patients represented by tissue microarrays and whole tissue sections. Orthogonally, these same tissues were characterized by multi-round immunofluorescence which defined expression of CA19-9 and sTRA as well as other lectins towards carbohydrate epitopes with the potential to improve PDAC diagnosis. These analyses revealed distinct differences not only in N-glycan spatial localization across both healthy and diseased tissues but importantly between different biomarker-categorized tissue samples. Unique sulfated bi-antennary N-glycans were detected specifically in normal pancreatic islets. N-glycans from CA19-9 expressing tissues tended to be bi-, tri- and tetra-antennary structures with both core and terminal fucose residues and bisecting N-acetylglucosamines. These N-glycans were detected in less abundance in sTRA-expressing tumor tissues, which favored tri- and tetra-antennary structures with polylactosamine extensions. Increased sialylation of N-glycans was detected in all tumor tissues. A candidate new biomarker derived from IMS was further explored by fluorescence staining with selected lectins on the same tissues. The lectins confirmed the expression of the epitopes in cancer cells and revealed different tumor-associated staining patterns between glycans with bisecting GlcNAc and those with terminal GlcNAc. Thus, the combination of lectin-IHC and IMS techniques produces more complete information for tumor classification than the individual analyses alone. These findings potentiate the development of early assessment technologies to rapidly and specifically identify PDAC in the clinic that may directly impact patient outcomes.

Exploring Public International Law Issues with Chinese Scholars – Part Four Other resource sysadmin 30 October 2018

As part of a roundtable series, Chatham House and the China University of Political Science and Law (CUPL) held a two-day roundtable in Beijing on emerging issues of public international law.

The specific objectives were to:

• create a platform for Chinese international law academics working on international human rights law issues to present their thinking and exchange ideas with counterparts from outside China;
• build stronger understanding within the wider international law community of intellectual debates taking place in China about the international human rights system and China’s role within it;
• support networking between Chinese and non-Chinese academics working on international human rights and related areas of international law.

The roundtable forms part of a wider Chatham House project exploring China’s impact on the international human rights system and was inspired by early discussions with a burgeoning community of Chinese academics thinking, writing (mainly in Chinese) and teaching about international human rights law.

For CUPL, one of the largest and most prestigious law schools in China and perhaps the only university in the world with an entire faculty of international law, the initiative is part of a drive to forge partnerships beyond China in the international law field.

The meeting was co-hosted with CUPL and involved 28 participants, consisting of 19 Chinese participants (from six leading research institutions in Beijing and Shanghai) and nine nonChinese participants (from eight leading research institutions in Australia, the Netherlands, the UK, Switzerland, Canada and Singapore).

To ensure continuity while also expanding the expert network being built, the fifth meeting included a mix of participants from the previous meetings and some new participants.

All discussions were held in English under the Chatham House Rule.

An employment judge has cleared the way for Farah Jameel, a former chair of the BMA’s General Practitioners Committee for England (GPCE), to go ahead with claims of discrimination and unfair dismissal against the association over her removal from the post during maternity leave.Jameel, who was elected the first female chair in November 2021, was put on temporary suspension in 2022 after complaints by BMA staff. The BMA told her in August 2023 that her contract was being terminated.The contract described her as a contractor providing consultancy services rather than an employee. But in a preliminary ruling the employment judge Natasha Joffe has held that Jameel was in reality an office holder and an employee, opening the way for her claims to proceed to a full hearing by an employment tribunal.The GPCE passed a vote of no confidence in Jameel in July 2023, as a means of electing a new...

Concerns are mounting over whether the NHS can meet key performance targets this winter, NHS Providers has said, after a survey of trust leaders highlighted pressure on hospitals, ambulance services, and community and mental health teams.1Over nine in 10 of the leaders who responded (96%) said that they were extremely or moderately concerned about the effect of winter pressures on their trust and local area. The most common reasons for concerns related to financial constraints and staffing provision. The top three greatest risks to the provision of high quality patient care over winter were identified as delayed discharge (57%), social care capacity (49%), and acute care bed capacity (43%).NHS Providers surveyed 171 trust leaders from 118 trusts in September and October, accounting for 56% of the provider sector.Most trust leaders (79%) were worried or very worried about whether their trusts had capacity to meet demand for services over the next...

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.

Issues to watch in 2023 The World Today mhiggins.drupal 29 November 2022

From nuclear proliferation to African debt, here are the issues six of our expert contributors expect to make the news in the year ahead.

Europe’s energy outlook

Mike Bradshaw, Professor of Global Energy, Warwick Business School

There is cautious optimism that Europe will endure this winter without an energy crisis. Gas prices have fallen, storage is 95 per cent full, and the autumn was mild. High summer gas prices cut industrial demand but domestic heating demand will be critical over the winter. Already, France’s problematic nuclear fleet and lower hydroelectric output mean Europe is using more gas to generate power. 

Russian pipeline gas supply to southern Europe has fallen by 55 per cent. While Asian demand has fallen, Europe has still paid record prices to secure additional liquefied natural gas (LNG), largely from America but also Russia. European demand for LNG this winter will push prices up, and these will rise even higher if China relaxes its Zero-Covid policy and demand recovers. However, with luck, Europe will avoid power cuts in early 2023. The problem is next winter. With less Russian pipeline gas and a tight LNG market, 90 per cent winter gas storage levels will be much harder to achieve. 

NATO’s resurgence

Alice Billon-Galland, Research Fellow, Europe Programme, Chatham House and one of 14 NATO Young Leaders

In response to Russia’s invasion of Ukraine, NATO adopted a new strategic concept. Member states will reinforce NATO battlegroups and bolster higher readiness forces from 40,000 troops to more than 300,000, while striving to avoid escalation with Russia. Turkey’s attempts to block Sweden and Finland’s NATO membership will preoccupy Jens Stoltenberg, the Secretary-General, until he leaves his post next autumn.

Expect arguments on defence spending in the run-up to the July summit in Vilnius. Although only nine of its 30 members are expected to meet the 2 per cent spending target, the debate is moving towards 3 per cent, in part to reduce dependency on American assets and hedge against the uncertainty of the 2024 US presidential election. Infrastructure vulnerabilities, such as the Nord Stream pipeline sabotage in the Baltic, will also be a focus. Otherwise, NATO ’s eyes will be on China: from its relations with Russia to the threat of cyberattacks.

Universal health reforms

Robert Yates, Executive Director, Centre for Universal Health, Chatham House

In response to the perma-crisis experienced by many populations this past year, some leaders are launching or extending universal health reforms. New left-wing leaders in Chile, Colombia and Brazil have promised to rebuild their publicly financed universal health systems. In Brazil, newly elected president Lula da Silva has pledged to increase public health spending and improve access to medicines. It is hoped Malaysia’s new coalition will carry forward its predecessor’s pledge to raise health spending to 5 per cent of GDP by 2027 to provide a universal package of free health services.

In September, world leaders will discuss universal health coverage at the UN General Assembly. There, Chatham House will publish its Commission for Universal Health report, identifying countries in which crises may trigger new national health programmes. Might this be when a US presidential candidate announces a platform to create a publicly financed health system?

Weapons of mass destruction

Patricia Lewis, Director of the International Security Programme, Chatham House

Since its illegal invasion of Ukraine, Russia has attacked civil nuclear power stations, falsely accused Ukraine of possessing bioweapons and radiological bombs, and threatened to use nuclear weapons. In contrast, NATO has instead demonstrated that deterrence can be highly effective with conventional weaponry. In the coming year, the Kremlin’s nuclear brinkmanship will still be a focus. Washington will try to restart bilateral nuclear negotiations with Moscow and similarly try to engage Beijing.

Following the failure of the nuclear Non-Proliferation Treaty Review Conference to reach consensus in August, the next review cycle will start by looking at strengthening the process. Iran’s nuclear capabilities remain a concern, and North Korea’s nuclear weapons programme is a growing threat. So, we are left with a question: will 2023 be the year of  nuclear conflict or the year when states get busy again on non-proliferation and disarmament?  

Africa’s mounting debt

Joseph Asunka, Chief Executive Officer, Afrobarometer

Inflation is at historic highs in several African economies. Meanwhile, many African countries including Nigeria, Zimbabwe and Democratic Republic of Congo will hold  elections in 2023, driving up public spending, increasing inflationary pressures and exacerbating poverty. According to Afrobarometer data, the proportion of Africans experiencing high levels of poverty has increased from 19 per cent in 2014/2015 to  26 per cent in 2021/2022.

Worse still, many of those countries holding elections are either, like Zimbabwe, in debt distress – that is unable to honour their obligations to creditors – or at high risk of debt distress, like Nigeria. This makes the elections in Zimbabwe and Nigeria critical. The expiration of the World Bank/IMF-backed debt service suspension initiative in 2021 has only amplified this risk. What are viable policy options to tackle this dire economic predicament? A debt service moratorium, debt cancellation and serious attention to fiscal discipline.

Feminist foreign policy

Daniela Philipson García, Co-founder of Internacional Feminista, and a PhD candidate, Monash University

Feminist Foreign Policy (FFP) is under threat. The war in Ukraine led to strengthened military budgets and alliances at odds with FFP’s human security and peace-centred approaches. Sweden’s new right-wing government reversed its FFP. In Mexico, the first Global South country to adopt an FFP, Congress has voted to expand the military’s role to curb cartel-related violence, in contradiction of its FFP. The second anniversary of the US withdrawal from Afghanistan will be a moment to assess how foreign policy, diplomacy and women’s and girls’ rights have been affected globally. 

There is hope. Germany, whose coalition government adopted an FFP in 2021, is to publish more guidelines in the spring. The governments of Colombia and Chile have announced their own FFPs. Colombia’s first National Action Plan on Women, Peace and Security, to be announced at the UN General Assembly in September, is expected to set a standard for a region submerged in violence. 

Preclinical data have shown that ¹⁶¹Tb-labeled peptides targeting the somatostatin receptor are therapeutically more effective for peptide receptor radionuclide therapy than are their ¹⁷⁷Lu-labeled counterparts. To further substantiate this enhanced therapeutic effect, we performed cellular dosimetry to quantify the absorbed dose to the cell nucleus and compared dose–response curves to evaluate differences in relative biological effectiveness in vitro. Methods: CA20948 cell survival was assessed after treatment with [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTATATE (agonist) and with [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTA-LM3 (antagonist) via a clonogenic assay. Cell binding, internalization, and dissociation assays were performed up to 7 d to acquire time-integrated activity coefficients. Separate S values for each type of particle emission (Auger/internal conversion [IC] electrons and β^– particles) were computed via Monte Carlo simulations, while considering spheric cells. Once the absorbed dose to the cell nucleus was calculated, survival curves were fitted to the appropriate linear or linear-quadratic model and corresponding relative biological effectiveness was evaluated. Results: Although the radiopeptide uptake was independent of the radionuclide, [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 delivered a 3.6 and 3.8 times higher dose to the nucleus, respectively, than their ¹⁷⁷Lu-labeled counterparts on saturated receptor binding. This increased nucleus-absorbed dose was mainly due to the additional emission of IC and not Auger electrons by ¹⁶¹Tb. When activity concentrations were considered, both [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 showed a lower survival fraction than did labeling with ¹⁷⁷Lu. When the absorbed dose to the nucleus was considered, no significant difference could be observed between the dose–response curves for [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTATATE. [¹⁶¹Tb]Tb-DOTA-LM3 showed a linear-quadratic dose response, whereas [¹⁶¹Tb]Tb-DOTATATE showed only a linear dose response within the observed dose range, suggesting additional cell membrane damage by Auger electrons. Conclusion: The IC, rather than Auger, electrons emitted by ¹⁶¹Tb resulted in a higher absorbed dose to the cell nucleus and lower clonogenic survival for [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 than for the ¹⁷⁷Lu-labeled analogs. In contrast, [¹⁶¹Tb]Tb-DOTATATE showed no higher dose response than [¹⁷⁷Lu]Lu-DOTATATE, whereas for [¹⁶¹Tb]Tb-DOTA-LM3 an additional quadratic response was observed. Because of this quadratic response, potentially caused by cell membrane damage, [¹⁶¹Tb]Tb-DOTA-LM3 is a more effective radiopeptide than [¹⁶¹Tb]Tb-DOTATATE for labeling with ¹⁶¹Tb.

As Nissan on Thursday reported a roughly half-billion- dollar revenue drop in 2024, the Japanese automaker said it will cut 9,000 jobs and reduce manufacturing capacity by 20%.

Oil giant Shell emerged victorious Tuesday from a Dutch court where it was appealing a ruling ordering it to slash its global carbon emissions by 45% by the end of the decade in line with the Paris climate agreement.

Oil giant Shell emerged victorious Tuesday from a Dutch court where it was appealing a ruling ordering it to slash its global carbon emissions by 45% by the end of the decade in line with the Paris climate agreement.

A large ball python found slithering in the parking lot of a Chili's restaurant in North Carolina turned out to have been an escaped pet missing for two months.

After percolating for roughly a year, NSF has issued the next solicitation for the National Quantum Virtual Lab program — this one focused on design and implementation phases of the […]

The post NSF Issues Next Solicitation and More Detail on National Quantum Virtual Laboratory appeared first on HPCwire.