Islamic radicalisation in Central Asia 18 September 2024 — 10:00AM TO 11:30AM Anonymous (not verified) 20 August 2024 Chatham House and Online

Experts analyse rising foreign recruitment, current counter-radicalisation efforts and challenge past Chatham House predictions made of the Central Asia region.

In 2014, Chatham House released a report titled The Myth of Post-Soviet Muslim Radicalisation in the Central Asian Republics. At that time, a significant, Western-funded counter-radicalisation industry was addressing what was believed to be a major issue of Islamic violent extremism in the region.

Over the past decade, two key developments have occurred. First, Western interest in the region has declined in favour of traditional geopolitical concerns. Second, while violent extremism incidents within Central Asia remain rare, there has been a notable recruitment of Central Asians by foreign groups, with several attacks carried out by Central Asians overseas.

In this event, the original report’s authors, John Heathershaw and David Montgomery, will discuss whether the report’s arguments are still valid and how we might answer these questions today.

This raises several questions:

• What did the report accurately predict, and where did it fall short?
• How can we explain the lack of violent extremist organisations (VEOs) within Central Asia but the presence of Central Asians in VEOs abroad?
• Could repression by Central Asian states both domestically and transnationally have contributed to this issue?
• What, if anything, can the counter-radicalisation industry do today to address this problem more effectively?

Please note that in-person places are limited. Please wait for confirmation before participating. 

The amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)–linked RNA-binding protein called FUS (fused in sarcoma) has been implicated in several aspects of RNA regulation, including mRNA translation. The mechanism by which FUS affects the translation of polyribosomes has not been established. Here we show that FUS can associate with stalled polyribosomes and that this association is sensitive to mTOR (mammalian target of rapamycin) kinase activity. Specifically, we show that FUS association with polyribosomes is increased by Torin1 treatment or when cells are cultured in nutrient-deficient media, but not when cells are treated with rapamycin, the allosteric inhibitor of mTORC1. Moreover, we report that FUS is necessary for efficient stalling of translation because deficient cells are refractory to the inhibition of mTOR-dependent signaling by Torin1. We also show that ALS-linked FUS mutants R521G and P525L associate abundantly with polyribosomes and decrease global protein synthesis. Importantly, the inhibitory effect on translation by FUS is impaired by mutations that reduce its RNA-binding affinity. These findings demonstrate that FUS is an important RNA-binding protein that mediates translational repression through mTOR-dependent signaling and that ALS-linked FUS mutants can cause a toxic gain of function in the cytoplasm by repressing the translation of mRNA at polyribosomes.

Yue Chen
May 1, 2007; 6:812-819
Research

David A. Mitchell
Jun 1, 2006; 47:1118-1127
Thematic Reviews

L. Oeding
Trans. Moscow Math. Soc. 83 (), 227-250.
Abstract, references and article information

Knockout mouse models have been extensively used to study the antiviral activity of IFIT (interferon-induced protein with tetratricopeptide repeats). Human IFIT1 binds to cap0 (m7GpppN) RNA, which lacks methylation on the first and second cap-proximal nucleotides (cap1, m7GpppNm, and cap2, m7GpppNmNm, respectively). These modifications are signatures of “self” in higher eukaryotes, whereas unmodified cap0-RNA is recognized as foreign and, therefore, potentially harmful to the host cell. IFIT1 inhibits translation at the initiation stage by competing with the cap-binding initiation factor complex, eIF4F, restricting infection by certain viruses that possess “nonself” cap0-mRNAs. However, in mice and other rodents, the IFIT1 orthologue has been lost, and the closely related Ifit1b has been duplicated twice, yielding three paralogues: Ifit1, Ifit1b, and Ifit1c. Although murine Ifit1 is similar to human IFIT1 in its cap0-RNA–binding selectivity, the roles of Ifit1b and Ifit1c are unknown. Here, we found that Ifit1b preferentially binds to cap1-RNA, whereas binding is much weaker to cap0- and cap2-RNA. In murine cells, we show that Ifit1b can modulate host translation and restrict WT mouse coronavirus infection. We found that Ifit1c acts as a stimulatory cofactor for both Ifit1 and Ifit1b, promoting their translation inhibition. In this way, Ifit1c acts in an analogous fashion to human IFIT3, which is a cofactor to human IFIT1. This work clarifies similarities and differences between the human and murine IFIT families to facilitate better design and interpretation of mouse models of human infection and sheds light on the evolutionary plasticity of the IFIT family.

Heme oxygenase-2 (HO2) and -1 (HO1) catalyze heme degradation to biliverdin, CO, and iron, forming an essential link in the heme metabolism network. Tight regulation of the cellular levels and catalytic activities of HO1 and HO2 is important for maintaining heme homeostasis. HO1 expression is transcriptionally regulated; however, HO2 expression is constitutive. How the cellular levels and activity of HO2 are regulated remains unclear. Here, we elucidate the mechanism of post-translational regulation of cellular HO2 levels by heme. We find that, under heme-deficient conditions, HO2 is destabilized and targeted for degradation, suggesting that heme plays a direct role in HO2 regulation. HO2 has three heme binding sites: one at its catalytic site and the others at its two heme regulatory motifs (HRMs). We report that, in contrast to other HRM-containing proteins, the cellular protein level and degradation rate of HO2 are independent of heme binding to the HRMs. Rather, under heme deficiency, loss of heme binding to the catalytic site destabilizes HO2. Consistently, an HO2 catalytic site variant that is unable to bind heme exhibits a constant low protein level and an enhanced protein degradation rate compared with the WT HO2. Finally, HO2 is degraded by the lysosome through chaperone-mediated autophagy, distinct from other HRM-containing proteins and HO1, which are degraded by the proteasome. These results reveal a novel aspect of HO2 regulation and deepen our understanding of HO2's role in maintaining heme homeostasis, paving the way for future investigation into HO2's pathophysiological role in heme deficiency response.

The synthesis of cholesterol requires more than 20 enzymes, many of which are intricately regulated. Post-translational control of these enzymes provides a rapid means for modifying flux through the pathway. So far, several enzymes have been shown to be rapidly degraded through the ubiquitin–proteasome pathway in response to cholesterol and other sterol intermediates. Additionally, several enzymes have their activity altered through phosphorylation mechanisms. Most work has focused on the two rate-limiting enzymes: 3-hydroxy-3-methylglutaryl CoA reductase and squalene monooxygenase. Here, we review current literature in the area to define some common themes in the regulation of the entire cholesterol synthesis pathway. We highlight the rich variety of inputs controlling each enzyme, discuss the interplay that exists between regulatory mechanisms, and summarize findings that reveal an intricately coordinated network of regulation along the cholesterol synthesis pathway. We provide a roadmap for future research into the post-translational control of cholesterol synthesis, and no doubt the road ahead will reveal further twists and turns for this fascinating pathway crucial for human health and disease.

Visual Abstract

Visual Abstract

Charlotte A. G. H. van Gelder
Dec 1, 2020; 19:1952-1967
Research

Daniel J. Geiszler
Dec 1, 2020; 0:TIR120.002216v1-mcp.TIR120.002216
Technological Innovation and Resources

In SAS Customer Intelligence Studio,  when you add  Reply- node variable values in the Define Value dialog box, you might notice that two identically labeled data-grid variables are

The organic anion transporters (OATs) and organic anion–transporting polypeptides (OATPs) belong to the solute carrier (SLC) transporter superfamily and play important roles in handling various endogenous and exogenous compounds of anionic charge. The OATs and OATPs are often implicated in drug therapy by impacting the pharmacokinetics of clinically important drugs and, thereby, drug exposure in the target organs or cells. Various mechanisms (e.g. genetic, environmental, and disease-related factors, drug-drug interactions, and food-drug interactions) can lead to variations in the expression and activity of the anion drug-transporting proteins of OATs and OATPs, possibly impacting the therapeutic outcomes. Previous investigations mainly focused on the regulation at the transcriptional level and drug-drug interactions as competing substrates or inhibitors. Recently, evidence has accumulated that cellular trafficking, post-translational modification, and degradation mechanisms serve as another important layer for the mechanisms underlying the variations in the OATs and OATPs. This review will provide a brief overview of the major OATs and OATPs implicated in drug therapy and summarize recent progress in our understanding of the post-translational modifications, in particular ubiquitination and degradation pathways of the individual OATs and OATPs implicated in drug therapy.

Protein synthesis on the endoplasmic reticulum (ER) requires the dynamic coordination of numerous cellular components. Together, resident ER membrane proteins, cytoplasmic translation factors, and both integral membrane and cytosolic RNA-binding proteins operate in concert with membrane-associated ribosomes to facilitate ER-localized translation. Little is known, however, regarding the spatial organization of ER-localized translation. This question is of growing significance as it is now known that ER-bound ribosomes contribute to secretory, integral membrane, and cytosolic protein synthesis alike. To explore this question, we utilized quantitative proximity proteomics to identify neighboring protein networks for the candidate ribosome interactors SEC61β (subunit of the protein translocase), RPN1 (oligosaccharyltransferase subunit), SEC62 (translocation integral membrane protein), and LRRC59 (ribosome binding integral membrane protein). Biotin labeling time course studies of the four BioID reporters revealed distinct labeling patterns that intensified but only modestly diversified as a function of labeling time, suggesting that the ER membrane is organized into discrete protein interaction domains. Whereas SEC61β and RPN1 reporters identified translocon-associated networks, SEC62 and LRRC59 reporters revealed divergent protein interactomes. Notably, the SEC62 interactome is enriched in redox-linked proteins and ER luminal chaperones, with the latter likely representing proximity to an ER luminal chaperone reflux pathway. In contrast, the LRRC59 interactome is highly enriched in SRP pathway components, translation factors, and ER-localized RNA-binding proteins, uncovering a functional link between LRRC59 and mRNA translation regulation. Importantly, analysis of the LRRC59 interactome by native immunoprecipitation identified similar protein and functional enrichments. Moreover, [³⁵S]-methionine incorporation assays revealed that siRNA silencing of LRRC59 expression reduced steady state translation levels on the ER by ca. 50%, and also impacted steady state translation levels in the cytosol compartment. Collectively, these data reveal a functional domain organization for the ER and identify a key role for LRRC59 in the organization and regulation of local translation.

Amino acid hydroxylation is a common post-translational modification, which generally regulates protein interactions or adds a functional group that can be further modified. Such hydroxylation is currently considered irreversible, necessitating the degradation and re-synthesis of the entire protein to reset the modification. Here we present evidence that the cellular machinery can reverse FIH-mediated asparagine hydroxylation on intact proteins. These data suggest that asparagine hydroxylation is a flexible and dynamic post-translational modification akin to modifications involved in regulating signaling networks, such as phosphorylation, methylation and ubiquitylation.

At neuronal synapses, activation of group I metabotropic glutamate receptors (mGluR1/5) triggers a form of long-term depression (mGluR-LTD) that relies on new protein synthesis and the internalization of AMPA-type glutamate receptors. Dysregulation of these processes has been implicated in the development of mental disorders such as autism spectrum disorders and therefore merit a better understanding on a molecular level. Here, to study mGluR-induced signaling pathways, we integrated quantitative phosphoproteomics with the analyses of newly synthesized proteins via bio-orthogonal amino acids (azidohomoalanine) in a pulsed labeling strategy in cultured hippocampal neurons stimulated with DHPG, a specific agonist for group I mGluRs. We identified several kinases with important roles in DHPG-induced mGluR activation, which we confirmed using small molecule kinase inhibitors. Furthermore, changes in the AMPA receptor endocytosis pathway in both protein synthesis and protein phosphorylation were identified, whereby Intersectin-1 was validated as a novel player in this pathway. This study revealed several new insights into the molecular pathways downstream of group I mGluR activation in hippocampal neurons, and provides a rich resource for further analyses.

The histidine kinase Hik33 plays important roles in mediating cyanobacterial response to divergent types of abiotic stresses including cold, salt, high light (HL), and osmotic stresses. However, how these functions are regulated by Hik33 remains to be addressed. Using a hik33-deficient strain (hik33) of Synechocystis sp. PCC 6803 (Synechocystis) and quantitative proteomics, we found that Hik33 depletion induces differential protein expression highly similar to that induced by divergent types of stresses. This typically includes downregulation of proteins in photosynthesis and carbon assimilation that are necessary for cell propagation, and upregulation of heat shock proteins, chaperons, and proteases that are important for cell survival. This observation indicates that depletion of Hik33 alone mimics divergent types of abiotic stresses, and that Hik33 could be important for preventing abnormal stress response in the normal condition. Moreover, we found the majority of proteins of plasmid origin were significantly upregulated in hik33, though their biological significance remains to be addressed. Together, the systematically characterized Hik33-regulated cyanobacterial proteome, which is largely involved in stress responses, builds the molecular basis for Hik33 as a general regulator of stress responses.

Open searching has proven to be an effective strategy for identifying both known and unknown modifications in shotgun proteomics experiments. Rather than being limited to a small set of user-specified modifications, open searches identify peptides with any mass shift that may correspond to a single modification or a combination of several modifications. Here we present PTM-Shepherd, a bioinformatics tool that automates characterization of PTM profiles detected in open searches based on attributes such as amino acid localization, fragmentation spectra similarity, retention time shifts, and relative modification rates. PTM-Shepherd can also perform multi-experiment comparisons for studying changes in modification profiles, e.g. in data generated in different laboratories or under different conditions. We demonstrate how PTM-Shepherd improves the analysis of data from formalin-fixed paraffin-embedded samples, detects extreme underalkylation of cysteine in some datasets, discovers an artefactual modification introduced during peptide synthesis, and uncovers site-specific biases in sample preparation artifacts in a multi-center proteomics profiling study.

Review: Islam's role in shaping Europe The World Today rsoppelsa.drupal 1 February 2022

Maryyum Mehmood on a work that recasts the role of Muslim minorities

Muslims and the Making of Modern Europe
Emily Greble, Oxford University Press, £26.99

When discussing the historical role of Muslims in Europe, most authors focus on Muslims in the western part of the continent, many of whom arrived as immigrant settlers from Muslim-majority nations. As a result, Muslims are easily identifiable as a foreign ‘other’. 

Emily Greble takes a different trajectory. In Muslims and the Making of Modern Europe, Greble centres her analysis on south-eastern European Muslims who are native to the region and, despite this fact, have still been subject to continuous stigmatization. 

In light of the present-day political tensions and targeted attacks on Muslims in Bosnia, which has seen inter-ethnic and religious hostility at its worst in 30 years, Greble’s nuanced retelling of the region’s social and political landscape has renewed urgency. Her work serves as a refreshing intervention to the literature on various fronts. It subverts stereotypical assumptions promulgated by the ‘Eastern Question’, whereby Muslims are portrayed as a simple ethnic minority living under colonial rule. Instead, Greble shows how they are a marginalized indigenous group that is by no means a monolithic, homogeneous entity. 

By uncovering the history of the region through the lens of Muslims, Greble highlights their capabilities as agents of change. Muslims were not just passive subjects but active citizens whose engagement was vital in the framing of social norms, political, ethical and legislative structures. 

Greble’s neatly crafted thesis serves as a counterpunch to a decades-long clash-of-civilizations discourse, which pits Muslims of the region as Ottoman outsiders to be scapegoated as and when deemed necessary. 

The author offers a proposition that while secularism was the overarching aim of the new European state-project, the role of religion, especially marginalized or ‘othered’ religious communities cannot be overlooked or relegated to a simple ‘minority’ issue. 

This argument is laid out in three historical parts, beginning with the post-Ottoman transition of power (1878-1921), to the Yugoslav nation-building project (1918-1941) and finally to the political overhaul in a post-Second World War Europe (1941-1949).

Most historical analyses of the region focus on state actions towards Muslim minorities. Greble points out that such an approach is lacking because it is riddled with institutional biases from the very sources and methods used to understand them. 

Instead, the author takes Muslims, their lived realities and agency as her starting point and effectively manages to avoid such pitfalls.

What is most remarkable about this book is Greble’s self-reflective approach to confronting such a sensitive topic with great care.

Almost every chapter begins with an insightful and deeply personal historical account from a Muslim from the region which sets the scene for Greble’s assessment of key social, political and legal struggles.

With an enriching methodology, Greble explores the topic through first and second-hand accounts of how Muslims manoeuvred in both the secular realm and within religious spaces, such as madrasas (Islamic seminaries), waqfs (local community funds), muftis and ulemas (religious scholar), and the shariah courts. As a result, the reader is shown how Muslims affected change and steered the trajectory of constitutional democracies in Europe at key historical junctures. 

By taking this lens, Greble does not just offer another retelling of the significance of the 1878 Congress of Berlin, which enabled the demarcation of new territorial boundaries in a post-Ottoman world, but also conveys the story of how Muslims contributed to the emerging narratives around citizenship. 

Crucially, we are exposed to Muslim leadership as more than just a docile, homogenous grouping, but a defining entity that shaped the European citizenship project by refashioning both imperial secular norms, as well as Islamic jurisprudential rulings to suit their unique context, as opposed to a remnant of bygone Ottoman rule. 

A fundamental difference that sets this book apart from other contemporary work on the topic is that the author brings forth multiple intra-faith complexities found within Muslim groups of the region, from revivalist to reformists, and all else in between. The fluctuating relationship between the traditionalist ulema, muftis and qadis (religious scholars, clergy and judges) and the secular state powers is intricately captured across most chapters in this book. 

At times, the ulema would be seen to bandy with the state to acculturate Muslims to the emerging polities of the region. As Greble shows, muftis in 1914 travelled across southern Serbia giving dawah (missionary work) to locals to encourage them to support the Serbian state. Similarly, qadis in Montenegro in 1902 reassured local Muslims that by following the law of the land, they would be guaranteed their ‘shariah rights’, which were loosely defined by the Muslim clergy. 

This created a paradox for the states: the role of nation-building and liberalizing orthodox religious communities was given to conservative clerics who, in turn, were gatekeepers setting the boundaries and thus interpreted and applied Islam to preserve their position of power. The consequences were twofold. As Greble suggests, ‘instead of becoming more tied to secular structures of state and society – through centralized law, conscription, political representation – Muslims in formerly Ottoman lands were becoming more deeply bound to Islam’. 

Simultaneously, the rhetoric used further embedded Muslims firmly as a minority. 

Ironically in contrast, it was the liberal reformist thinkers who, sometimes, stood in opposition to the state regimes. Such internal divisions within Muslim spaces became more overtly discernible under communist rule, wherein members of the same Muslim community fought in different camps. 

For instance, the author notes how some were aligned with the communist regime, while others were fighting with the allied forces and many were still backing revivalist Islamic groups. In light of this, what is perhaps most intriguing is how the communist takeover in 1945 managed to tear down any seemingly progressive movement that benefited the region’s Muslims. And it brought them back to square one, with the scrapping of shariah law and the removal of a mufti-led judiciary. Such crackdowns caused greater frenzy among the region’s Muslims and led to resistance movements in the form of activism and insurgencies. 

Ultimately, the author offers a complex perspective not only of Balkan Muslims and their lived experiences, but also, the implications of this upon wider society and the states themselves.

Greble’s remapping of the historical underpinnings of the tale of Muslims and the Making of Modern Europe is not just a clear example of how Muslims are not a foreign entity to the region, but a call to overturn the entrenched Great Replacement theory which uses this foreign ‘othering’ to further prejudice and calls for the ousting of Muslims and other minorities from Europe, a land which has forever been their home.
 

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