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

Leigh Anderson
Apr 1, 2006; 5:573-588
Research

Philip L. Ross
Dec 1, 2004; 3:1154-1169
Research

Ronald M. Krauss
Jan 1, 1982; 23:97-104
Articles

Expert

An Attack on the ‘One Country, Two Systems’ Principle in Hong Kong Expert comment sysadmin 11 January 2016

The disappearance of publisher Lee Bo may mark the beginning of the end of Beijing’s commitment to uphold the framework that provides the territory with a high degree of autonomy.

The disappearance of a publisher in Hong Kong, Lee Bo, who owns a well-known bookshop that sells books critical of Chinese leaders, is a landmark event and potentially a historical turning point for Hong Kong. It is not clear if this happened at the behest of the senior Chinese leadership. But if those responsible for the disappearing of Lee are not punished, it will be clear that their acts are condoned by the authorities.

This is deeply worrying as it gravely undermines the ‘one country, two systems’ framework, which provides Hong Kong with high degree of autonomy from Beijing. Under the Sino-British Agreement of 1984 and Hong Kong’s Basic Law, which govern relations between Hong Kong and China, the rights of Hong Kong citizens are meant to be protected within the territory. Mainland Chinese authorities do not have the legal power to arrest or detain an individual in, or remove anyone from, Hong Kong.

The Chinese know the limit of their legal authority in Hong Kong. Hence, Lee was quietly disappeared, rather than openly arrested. But that it happened at all may mark the beginning of the end of Beijing’s commitment to uphold the ‘one country, two systems’ framework – a relationship that requires Beijing to tolerate, if not respect, the judicial integrity and the way of life in Hong Kong.

Do we know for sure that Lee was ‘disappeared’ by China’s security apparatus? Before he disappeared, Lee said in an interview that he knew he had been watched and that his emails were accessed by Chinese agents, and that he would not travel to the mainland as a result. And we know that Lee’s travel documents are all in his home; yet he is now supposedly in China ‘assisting the authorities in an investigation’ into something unspecified. This explanation comes from a fax sent to Lee’s wife, probably intended by the Chinese authorities to put an end to speculation. But why would Chinese authorities work with Lee, a British citizen who carries no travel documents and would thus have broken the law by entering China? The circumstantial evidence is strong enough to show that whether he was taken by Chinese officers or someone else, his removal from Hong Kong to China must have received official endorsement.

Should the rest of the world be concerned about this? Hong Kong is a major financial center that services the world economy, and it can do so largely because it enjoys judicial independence and the high degree of autonomy under the ‘one country, two systems’ framework. It is also a shining example of how the rights and scope of development for individuals can be respected in a Chinese community. Should the ‘one country, two systems’ framework be undermined, Hong Kong as we know it will be no more.

Beijing’s quick response in requiring Lee to fax his family may come across as ham-fisted and callous, but it also demonstrates that it had not expected the strong backlash to Lee’s disappearance. A strong and well-articulated international response that brings the matter to Xi’s attention may persuade him that it is in China’s best interest to put a stop to this process of undermining the ‘one country, two systems’ framework. Given Hong Kong’s importance to the global economy, this should be a priority for the international community.

This article was originally published in the Diplomat.

To comment on this article, please contact Chatham House Feedback

Víctor González-Aguilera, Alvaro Liendo, Pedro Montero and Roberto Villaflor Loyola
Trans. Amer. Math. Soc. 377 (), 5483-5511.
Abstract, references and article information

Friedrich Haslinger
Proc. Amer. Math. Soc. 152 (), 5219-5227.
Abstract, references and article information

Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor that limits excessive T cell responses. Cancer cells have evolved to evade these immunoregulatory mechanisms by upregulating PD-1 ligands and preventing T cell–mediated anti-tumor responses. Consequently, therapeutic blockade of PD-1 enhances T cell–mediated anti-tumor immunity, but many patients do not respond and a significant proportion develop inflammatory toxicities. To improve anti-cancer therapy, it is critical to reveal the mechanisms by which PD-1 regulates T cell responses. We performed global quantitative phosphoproteomic interrogation of PD-1 signaling in T cells. By complementing our analysis with functional validation assays, we show that PD-1 targets tyrosine phosphosites that mediate proximal T cell receptor signaling, cytoskeletal organization, and immune synapse formation. PD-1 ligation also led to differential phosphorylation of serine and threonine sites within proteins regulating T cell activation, gene expression, and protein translation. In silico predictions revealed that kinase/substrate relationships engaged downstream of PD-1 ligation. These insights uncover the phosphoproteomic landscape of PD-1–triggered pathways and reveal novel PD-1 substrates that modulate diverse T cell functions and may serve as future therapeutic targets. These data are a useful resource in the design of future PD-1–targeting therapeutic approaches.

11 August 2020

17 September 2020

Alison M. Kurimchak
Dec 1, 2020; 19:2068-2089
Research

Multiple sclerosis (MS) is a CNS disease characterized by immune-mediated demyelination and progressive axonal loss. MS-related CNS damage and its clinical course have two main phases: active and inactive/progressive. Reliable biomarkers are being sought to allow identification of MS pathomechanisms and prediction of its course. The purpose of this study was to identify sphingolipid (SL) species as candidate biomarkers of inflammatory and neurodegenerative processes underlying MS pathology. We performed sphingolipidomic analysis by HPLC-tandem mass spectrometry to determine the lipid profiles in post mortem specimens from the normal-appearing white matter (NAWM) of the normal CNS (nCNS) from subjects with chronic MS (active and inactive lesions) as well as from patients with other neurological diseases. Distinctive SL modification patterns occurred in specimens from MS patients with chronic inactive plaques with respect to NAWM from the nCNS and active MS (Ac-MS) lesions. Chronic inactive MS (In-MS) lesions were characterized by decreased levels of dihydroceramide (dhCer), ceramide (Cer), and SM subspecies, whereas levels of hexosylceramide and Cer 1-phosphate (C1P) subspecies were significantly increased in comparison to NAWM of the nCNS as well as Ac-MS plaques. In contrast, Ac-MS lesions were characterized by a significant increase of major dhCer subspecies in comparison to NAWM of the nCNS. These results suggest the existence of different SL metabolic pathways in the active versus inactive phase within progressive stages of MS. Moreover, they suggest that C1P could be a new biomarker of the In-MS progressive phase, and its detection may help to develop future prognostic and therapeutic strategies for the disease.

Tandem mass tag (TMT) is a multiplexing technology widely-used in proteomic research. It enables relative quantification of proteins from multiple biological samples in a single MS run with high efficiency and high throughput. However, experiments often require more biological replicates or conditions than can be accommodated by a single run, and involve multiple TMT mixtures and multiple runs. Such larger-scale experiments combine sources of biological and technical variation in patterns that are complex, unique to TMT-based workflows, and challenging for the downstream statistical analysis. These patterns cannot be adequately characterized by statistical methods designed for other technologies, such as label-free proteomics or transcriptomics. This manuscript proposes a general statistical approach for relative protein quantification in MS- based experiments with TMT labeling. It is applicable to experiments with multiple conditions, multiple biological replicate runs and multiple technical replicate runs, and unbalanced designs. It is based on a flexible family of linear mixed-effects models that handle complex patterns of technical artifacts and missing values. The approach is implemented in MSstatsTMT, a freely available open-source R/Bioconductor package compatible with data processing tools such as Proteome Discoverer, MaxQuant, OpenMS, and SpectroMine. Evaluation on a controlled mixture, simulated datasets, and three biological investigations with diverse designs demonstrated that MSstatsTMT balanced the sensitivity and the specificity of detecting differentially abundant proteins, in large-scale experiments with multiple biological mixtures.

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the up-regulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC.

Ankylosing Spondylitis (AS) is a common, inflammatory rheumatic disease, which primarily affects the axial skeleton and is associated with sacroiliitis, uveitis and enthesitis. Unlike other autoimmune rheumatic diseases, such as rheumatoid arthritis or systemic lupus erythematosus, autoantibodies have not yet been reported to be a feature of AS. We therefore wished to determine if plasma from patients with AS contained autoantibodies and if so, characterize and quantify this response in comparison to patients with Rheumatoid Arthritis (RA) and healthy controls. Two high-density nucleic acid programmable protein arrays expressing a total of 3498 proteins were screened with plasma from 25 patients with AS, 17 with RA and 25 healthy controls. Autoantigens identified were subjected to Ingenuity Pathway Analysis in order to determine patterns of signalling cascades or tissue origin. 44% of patients with Ankylosing Spondylitis demonstrated a broad autoantibody response, as compared to 33% of patients with RA and only 8% of healthy controls. Individuals with AS demonstrated autoantibody responses to shared autoantigens, and 60% of autoantigens identified in the AS cohort were restricted to that group. The AS patients autoantibody responses were targeted towards connective, skeletal and muscular tissue, unlike those of RA patients or healthy controls. Thus, patients with AS show evidence of systemic humoral autoimmunity and multispecific autoantibody production. Nucleic Acid Programmable Protein Arrays constitute a powerful tool to study autoimmune diseases.

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.

Electrospray ionization is today the most widely used ionization technique in chemical and bio-chemical analysis. Interfaced with a mass spectrometer it allows to investigate the molecular composition of liquid samples. With electrospray a large variety of chemical substances can be ionized. There is no limitation in mass which enables even the investigation of large non-covalent protein complexes. Its high ionization efficiency profoundly changed bio-molecular sciences because proteins can be identified and quantified on trace amounts in a high throughput fashion. This review article focusses mainly on the exploration of the underlying ionization mechanism. Some ionization characteristics are discussed which are related to this mechanism. Typical spectra of peptides, proteins and non-covalent complexes are shown and the quantitative character of spectra is highlighted. Finally the possibilities and limitations in measuring the association constant of bivalent non-covalent complexes are described.

Protein tyrosine kinases (PTKs) play key roles in cellular signal transduction, cell cycle regulation, cell division, and cell differentiation. Dysregulation of PTK-activated pathways, often by receptor overexpression, gene amplification, or genetic mutation, is a causal factor underlying numerous cancers. In this study, we have developed a parallel reaction monitoring (PRM)-based assay for quantitative profiling of 83 PTKs. The assay detects 308 proteotypic peptides from 54 receptor tyrosine kinases and 29 nonreceptor tyrosine kinases in a single run. Quantitative comparisons were based on the labeled reference peptide method. We implemented the assay in four cell models: 1) a comparison of proliferating versus epidermal growth factor (EGF)-stimulated A431 cells, 2) a comparison of SW480Null (mutant APC) and SW480APC (APC restored) colon tumor cell lines, and 3) a comparison of 10 colorectal cancer cell lines with different genomic abnormalities, and 4) lung cancer cell lines with either susceptibility (11-18) or acquired resistance (11-18R) to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. We observed distinct PTK expression changes that were induced by stimuli, genomic features or drug resistance, which were consistent with previous reports. However, most of the measured expression differences were novel observations. For example, acquired resistance to erlotinib in the 11-18 cell model was associated not only with previously reported upregulation of MET, but also with upregulation of FLK2 and downregulation of LYN and PTK7. Immunoblot analyses and shotgun proteomics data were highly consistent with PRM data. Multiplexed PRM assays provide a targeted, systems-level profiling approach to evaluate cancer-related proteotypes and adaptations. Data are available through Proteome eXchange Accession PXD002706.

Recent advances in MS-based proteomics have vastly increased the quality and scope of biological information that can be derived from human samples. These advances have rendered current workflows increasingly applicable in biomedical and clinical contexts. As proteomics is poised to take an important role in the clinic, associated ethical responsibilities increase in tandem with the impact on the health, privacy, and well-being of individuals. Here we conducted and report a systematic literature review of ethical issues in clinical proteomics. We add our perspectives from a background of bioethics, the results of our accompanying paper extracting individual-sensitive results from patient samples, and the literature addressing similar issues in genomics. The spectrum of potential issues ranges from patient re-identification to incidental findings of clinical significance. The latter can be divided into actionable and unactionable findings. Some of these have the potential to be employed in discriminatory or privacy-infringing ways. However, incidental findings may also have great positive potential. A plasma proteome profile, for instance, could inform on the general health or disease status of an individual regardless of the narrow diagnostic question that prompted it. We suggest that early discussion of ethical issues in clinical proteomics is important to ensure that eventual regulations reflect the considered judgment of the community as well as to anticipate opportunities and problems that may arise as the technology matures further.

Can diplomacy advance human rights? 25 April 2023 — 4:00PM TO 5:00PM Anonymous (not verified) 7 March 2023 Chatham House and Online

How is diplomacy contributing to advancing human rights through the multilateral system?

The international human rights system has come under significant pressure in recent years. Russia’s invasion of Ukraine and the US-China rivalry have created difficult political pressures, while major global challenges including climate change and global inequality demand answers. Effective diplomacy on human rights has become increasingly difficult, with incentives stacked against bold action.

The relationship between diplomacy and human rights is an uneasy one. Diplomacy is an art of negotiation, persuasion and compromise. Human rights are tightly defined and universal. The relationship between the two may seem paradoxical, but in the context of an unstable world order, it has never been more important.

In the 75th anniversary year of the Universal Declaration of Human Rights, this discussion will explore the critical role of diplomacy in advancing human rights in the future.

• What are the critical human rights challenges today? What is the role of diplomacy in addressing them?

• What is the impact of intensifying competition between the US and China on the human rights system?

• Is there an opening for more leadership emerging from the Global South?

• What is the future of the human rights system in the context of this polarized world?

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

Here we go again: Russia’s energy ‘diplomacy’ in Moldova Expert comment LJefferson 6 December 2021

The gas crisis shows that while the new Moldovan government may wish for geopolitics to go away, they are a weapon Russia will deploy at will.

In October, Moldova came under the spotlight when Russia, its primary provider of gas, slashed supplies by a third and refused to extend the existing contract.

The crisis was resolved at the end of October when Russia and Moldova signed a new contract, in which Moscow has used Moldova’s gas dependence to extract geopolitical concessions, weaken the new pro-western Chisinau government and drive a wedge between the EU and Moldova.

A chronic failure to reform

Moldova became a classic case of state capture when political elites – including nominally pro-European political elites – engaged in massive rent-extraction.

Up until 2020, when pro-reform forces came to power, Moldovan politics offered rapid route to riches for both the nominally pro-European parties and the pro-Russian Socialist Party; each was responsible for playing up ethnic and geopolitical cleavages in the country to mobilize votes and shore up legitimacy.

These predatory elites hollowed out Moldova economically and politically by a chronic failure to reform, in particular the energy sector which became a major source of rent.

However, this started to change when the pro-reform forces came to power as a result of the 2020 presidential and then 2021 parliament elections. The pro-reformist Maia Sandu defeated the incumbent president Igor Dodon (58 per cent to 42 per cent) in November of that year. And then her party got 58 per cent of the vote in the parliamentary elections which followed in July 2021.

Her Party of Action’s (PAS) winning formula was to focus on corruption and domestic reforms – rather than playing the ‘geopolitical’ card, a favourite strategy of their predecessors. As Sandu put it, the elections marked ‘the end of the reign of thieves in Moldova’.

A gas crisis is initiated  

Russia’s response to these results was to initiate a gas crisis. Up until the victory of the pro-reform forces, Russia had annually renewed a gas contract signed in 2007. However, in September 2021, Russia refused to renew the contract as it had done many times before and instead insisted on a new contract, which allowed Russia to create linkages between energy prices, debt settlement, a halt on energy market reforms and, it can be logically inferred, further integration with the EU.

Moldova’s national energy company, Moldovgaz, is 63.5 per cent de facto owned by Gazprom with the Moldovan government owning the remaining 35.5 per cent. (Moldova was forced to give Gazprom a controlling stake when faced with a cut in supplies in January 2006). It is therefore hardly surprising that no efforts were made to de-monopolise the sector and diversify energy supplies.

This lack of modernization can be explained by the somewhat surreal fact that in any negotiations and planning, Moldovagaz – majority owned by Gazprom – represents the Moldovan side in negotiations with Gazprom. So, when it came to signing of the new five-year contract in October 2021, Russia, through Gazprom, was able to institute a contract which made gas prices conditional on various geopolitical conditions.

It is noteworthy that Moldova’s original 2007 gas contract had been renewed annually despite the supposed accrual of debt. However, the very nature of this debt is suspect. While Moldova’s debt is said to be approximately $700 million, the debt of the much smaller breakaway Transnistria was around $7.3 billion.

The exact level and source of the debt remain murky. Russia appears to be making Moldova liable to repay at least some of Transnistria’s debt while only demanding the debt settlement with Moldova, but not with Transnistria.

High stakes for Moscow

Moreover, the contract is used to derail liberalisation of the energy market in line with EU’s energy market rules (through the so-called unbundling of supplies and distribution) which Moldova had committed itself to since the country joined the Energy Community in 2010.

Referring to ‘the non-application of forced reorganization and sanctions against Moldovagaz’, the new gas contract forces Moldova to postpone implementing the unbundling of supplies and distribution by making it conditional on resolving the energy debt.

Furthermore, Moldova ominously agreed to create an ‘intergovernmental commission on economic cooperation’ with Russia, which effectively blocks Moldova’s economic integration with the EU. (This demand is hardly new as Russia previously requested, and was granted, a seat at the negotiating table on a bilateral trade agreement between the EU and Ukraine. The trilateral EU-Ukraine-Russia negotiations have made it clear that Russia is seeking a veto over European integration of all neighbouring countries.)  

Targeting Moldova’s new reformist government reflects high personal stakes for Moscow. Moldova’s caretaker (kurator) in the Kremlin is Dimitrii Kozak, who in 2003 masterminded the so-called ‘Kozak Memorandum’. This sought to reintegrate breakaway Transnistria into a Moldova-Transnistria federation.

It was thwarted at the last minute but the Russian leadership has not given up on its plan. Now using his position as the deputy head of Presidential Administration, Kozak is masterminding Russia’s rehashed policy towards Moldova and has attempted to bring back his Memorandum as a political blueprint for a ‘settlement’.

Russia’s heavy-handed energy ‘diplomacy’

The new Moldovan government is caught in a crossfire of domestic expectations and Russian geopolitical demands. The gas crisis shows that while the new government may wish for geopolitics to go away, they are a weapon Russia will deploy at will.

The Moldovan government is brand new so it has relatively little experience of dealing with Russia’s heavy-handed ‘energy diplomacy’. But the EU has been on the receiving end of this before – this is a direct replica of Russia’s strategy toward Armenia and Ukraine – and neither ended well for the target countries or for the EU.

So, Russia’s plans for Moldova are likely to have similar consequences for the EU’s latest attempts to be a convincing foreign policy actor. 

In AI, time is money. Top AI players are spending billions to create computing infrastructures to satisfy that need for speed. However, these companies are bottlenecked by computing constraints at […]

The post Ayar Labs CEO: Optical Chiplets Coming to SOCs Soon appeared first on HPCwire.

Around 3% of people are thought to hear voices when there is no one talking.

Nearly everyone in behavioral marketing and influence marketing was surprised when Dr. Robert Cialdini, the “godfather” of persuasion science and the creator of the celebrated Six Principles of Influence, introduced a seventh principle, Unity. In fact, in 2014 I asked Cialdini if, thirty years after completing his seminal book, Influence, he’d add on another one or […]

The post What is Unity, Cialdini’s 7th Principle? appeared first on Neuromarketing.

Human sleep exhibits multiple, recurrent temporal regularities, ranging from circadian rhythms to sleep stage cycles and neuronal oscillations during nonrapid eye movement sleep. Moreover, recent evidence revealed a functional role of aperiodic activity, which reliably discriminates different sleep stages. Aperiodic activity is commonly defined as the spectral slope of the 1/frequency (1/f) decay function of the electrophysiological power spectrum. However, several lines of inquiry now indicate that the aperiodic component of the power spectrum might be better characterized by a superposition of several decay processes with associated timescales. Here, we determined multiple timescales, which jointly shape aperiodic activity using human intracranial electroencephalography. Across three independent studies (47 participants, 23 female), our results reveal that aperiodic activity reliably dissociated sleep stage-dependent dynamics in a regionally specific manner. A principled approach to parametrize aperiodic activity delineated several, spatially and state-specific timescales. Lastly, we employed pharmacological modulation by means of propofol anesthesia to disentangle state-invariant timescales that may reflect physical properties of the underlying neural population from state-specific timescales that likely constitute functional interactions. Collectively, these results establish the presence of multiple intrinsic timescales that define the electrophysiological power spectrum during distinct brain states.

The Tripartite organizations (FAO, OIE, WHO) invite partners to join public discussion on the establishment of the AMR Multi-Stakeholder Partnership Platform.

Credit: David Marshall, University of Bristol

An OM worker from Latin America uses his carpentry skills to disciple young men in their faith and give them better employment opportunities for the future.

OM teams in five countries along the Mekong River in South East Asia are focusing on discipling local believers to see them equipped to share about Jesus with those who have never heard His name.

Students in grades 3-12 gain hands-on 3D CAD experience designing scale-model remote-controlled cars

Students design real-world projects such as a moveable floor on a floating hospital in South America using SOLIDWORKS 3D CAD and COSMOS design analysis software

The Discipleship course in Malawi challenges students to own their faith and apply it in their daily lives.

During the OM's Ride 2 Transform 2017 cycle tour, 17 cyclists biked 550 kilometres around southern Malawi, distributing AudioBibles and praying.

Sport creates a platform for evangelism and discipleship in Ukraine.

A number of dismissed lottery officials who have lodged appeals, as well as suspended officials, continue to draw salaries.

OM intentionally disciples Cambodian staff so that they, in turn, can disciple others.

The film follows three Indianapolis adults as they seek to overcome obstacles on the path to earning an educational credential that they missed earlier.

In schools that use corporal punishment, students with disabilities and black students are disproportionately more likely to be hit than their peers, finds a new report by the Southern Poverty Law Center.

No studies sufficiently answer the question, finds the GAO, which means debates over whether newer restorative-justice approaches help or harm safety are likely to continue.