Deficiency of glucocerebrosidase (GBA), a lysosomal β-glucosidase, causes Gaucher disease. The enzyme hydrolyzes β-glucosidic substrates and transglucosylates cholesterol to cholesterol-β-glucoside. Here we show that recombinant human GBA also cleaves β-xylosides and transxylosylates cholesterol. The xylosyl-cholesterol formed acts as acceptor for subsequent formation of di-xylosyl-cholesterol. Common mutant forms of GBA from patients with Gaucher disease with reduced β-glucosidase activity were similarly impaired in β-xylosidase, transglucosidase and transxylosidase activities, except for a slightly reduced xylosidase/glucosidase activity ratio of N370S GBA and a slightly reduced transglucosylation/glucosidase activity ratio of D409H GBA. XylChol was found to be reduced in spleen from Gaucher disease patients. The origin of newly identified XylChol in mouse and human tissues was investigated. Cultured human cells exposed to exogenous β-xylosides generated XylChol in a manner dependent on active lysosomal GBA but not the cytosol-facing β-glucosidase GBA2. We later sought an endogenous β-xyloside acting as donor in transxylosylation reactions, identifying xylosylated ceramide (XylCer) in cells and tissues that serve as donor in the formation of XylChol. UDP-glucosylceramide synthase (GCS) was unable to synthesize XylChol but could catalyse formation of XylCer. Thus, food-derived β-D-xyloside and XylCer are potential donors for the GBA-mediated formation of XylChol in cells. The enzyme GCS produces XylCer at a low rate. Our findings point to further catalytic versatility of GBA and prompt a systematic exploration of the distribution and role of xylosylated lipids.

Bile acids, which are synthesized from cholesterol by the liver, are chemically transformed along the intestinal tract by the gut microbiota, and the products of these transformations signal through host receptors, affecting overall host health. These transformations include bile acid deconjugation, oxidation, and 7α-dehydroxylation. An understanding of the biogeography of bile acid transformations in the gut is critical because deconjugation is a prerequisite for 7α-dehydroxylation and because most gut microorganisms harbor bile acid transformation capacity. Here, we used a coupled metabolomic and metaproteomic approach to probe in vivo activity of the gut microbial community in a gnotobiotic mouse model. Results revealed the involvement of Clostridium scindens in 7α-dehydroxylation, of the genera Muribaculum and Bacteroides in deconjugation, and of six additional organisms in oxidation (the genera Clostridium, Muribaculum, Bacteroides, Bifidobacterium, Acutalibacter, and Akkermansia). Furthermore, the bile acid profile in mice with a more complex microbiota, a dysbiosed microbiota, or no microbiota was considered. For instance, conventional mice harbor a large diversity of bile acids, but treatment with an antibiotic such as clindamycin results in the complete inhibition of 7α-dehydroxylation, underscoring the strong inhibition of organisms that are capable of carrying out this process by this compound. Finally, a comparison of the hepatic bile acid pool size as a function of microbiota revealed that a reduced microbiota affects host signaling but not necessarily bile acid synthesis. In this study, bile acid transformations were mapped to the associated active microorganisms, offering a systematic characterization of the relationship between microbiota and bile acid composition.

The assembly of the postsynaptic transmitter sensing machinery at inhibitory nerve cell synapses requires the intimate interplay between cell adhesion proteins, scaffold and adaptor proteins, and γ-aminobutyric acid (GABA) or glycine receptors. We developed an in vitro membrane system to reconstitute this process, to identify the essential protein components, and to define their mechanism of action, with a specific focus on the mechanism by which the cytosolic C terminus of the synaptic cell adhesion protein Neuroligin-2 alters the conformation of the adaptor protein Collybistin-2 and thereby controls Collybistin-2-interactions with phosphoinositides (PtdInsPs) in the plasma membrane. Supported hybrid membranes doped with different PtdInsPs and 1,2-dioleoyl-sn-glycero-3-{[N-(5-amino-1-carboxypentyl)iminodiacetic acid]succinyl} nickel salt (DGS-NTA(Ni)) to allow for the specific adsorption of the His6-tagged intracellular domain of Neuroligin-2 (His-cytNL2) were prepared on hydrophobically functionalized silicon dioxide substrates via vesicle spreading. Two different collybistin variants, the WT protein (CB2SH3) and a mutant that adopts an intrinsically 'open' and activated conformation (CB2SH3/W24A-E262A), were bound to supported membranes in the absence or presence of His-cytNL2. The corresponding binding data, obtained by reflectometric interference spectroscopy, show that the interaction of the C terminus of Neuroligin-2 with Collybistin-2 induces a conformational change in Collybistin-2 that promotes its interaction with distinct membrane PtdInsPs.

Despite the continued analysis of HDAC inhibitors in clinical trials, the heterogeneous nature of the protein complexes they target limits our understanding of the beneficial and off-target effects associated with their application. Among the many HDAC protein complexes found within the cell, Sin3 complexes are conserved from yeast to humans and likely play important roles as regulators of transcriptional activity. The presence of two Sin3 paralogs in humans, SIN3A and SIN3B, may result in a heterogeneous population of Sin3 complexes and contributes to our poor understanding of the functional attributes of these complexes. Here, we profile the interaction networks of SIN3A and SIN3B to gain insight into complex composition and organization. In accordance with existing data, we show that Sin3 paralog identity influences complex composition. Additionally, chemical cross-linking MS identifies domains that mediate interactions between Sin3 proteins and binding partners. The characterization of rare SIN3B proteoforms provides additional evidence for the existence of conserved and divergent elements within human Sin3 proteins. Together, these findings shed light on both the shared and divergent properties of human Sin3 proteins and highlight the heterogeneous nature of the complexes they organize.

The goal of clinical proteomics is to identify, quantify, and characterize proteins in body fluids or tissue to assist diagnosis, prognosis, and treatment of patients. In this way, it is similar to more mature omics technologies, such as genomics, that are increasingly applied in biomedicine. We argue that, similar to those fields, proteomics also faces ethical issues related to the kinds of information that is inherently obtained through sample measurement, although their acquisition was not the primary purpose. Specifically, we demonstrate the potential to identify individuals both by their characteristic, individual-specific protein levels and by variant peptides reporting on coding single nucleotide polymorphisms. Furthermore, it is in the nature of blood plasma proteomics profiling that it broadly reports on the health status of an individual – beyond the disease under investigation. Finally, we show that private and potentially sensitive information, such as ethnicity and pregnancy status, can increasingly be derived from proteomics data. Although this is potentially valuable not only to the individual, but also for biomedical research, it raises ethical questions similar to the incidental findings obtained through other omics technologies. We here introduce the necessity of - and argue for the desirability for - ethical and human rights-related issues to be discussed within the proteomics community. Those thoughts are more fully developed in our accompanying manuscript. Appreciation and discussion of ethical aspects of proteomic research will allow for deeper, better-informed, more diverse, and, most importantly, wiser guidelines for clinical proteomics.

Tectonic Politics: Global Political Risk in an Age of Transformation Book sysadmin 7 May 2019

Political risk now affects more markets and countries than ever before and that risk will continue to rise. But traditional methods of managing political risk are no longer legitimate or effective.

In Tectonic Politics, Nigel Gould-Davies explores the complex, shifting landscape of political risk and how to navigate it. He analyses trends in each form of political risk: the power to destroy, seize, regulate, and tax.

He shows how each of these forms reflects a deeper transformation of the global political economy that is reordering the relationship between power, wealth, and values. In a world where everything is political, the craft of engagement is as important as the science of production and the art of the deal.

The successful company must integrate that craft—the engager’s way of seeing and doing—into strategy and culture.

Drawing on a career in academia, business, and diplomacy, Gould-Davies provides corporate leaders, scholars, and engaged citizens with a groundbreaking study of the fastest-rising political risk today. ‘As tectonic plates shape the earth,’ he writes, ‘so tectonic politics forges its governance.’

The book is published as part of the Insights series.

Praise for Tectonic Politics

About the author

Nigel Gould-Davies was an associate fellow of the Russia and Eurasia Programme at Chatham House.

Purchase

• UK (via Amazon)
• Rest of world (via Brookings Institution Press)
• Students (via Browns Books)

Online Disinformation and Political Discourse: Applying a Human Rights Framework Research paper sysadmin 5 November 2019

Although some digital platforms now have an impact on more people’s lives than does any one state authority, the international community has been slow to hold to account these platforms’ activities by reference to human rights law.

This paper examines how human rights frameworks should guide digital technology.

Summary

• Online political campaigning techniques are distorting our democratic political processes. These techniques include the creation of disinformation and divisive content; exploiting digital platforms’ algorithms, and using bots, cyborgs and fake accounts to distribute this content; maximizing influence through harnessing emotional responses such as anger and disgust; and micro-targeting on the basis of collated personal data and sophisticated psychological profiling techniques. Some state authorities distort political debate by restricting, filtering, shutting down or censoring online networks.
• Such techniques have outpaced regulatory initiatives and, save in egregious cases such as shutdown of networks, there is no international consensus on how they should be tackled. Digital platforms, driven by their commercial impetus to encourage users to spend as long as possible on them and to attract advertisers, may provide an environment conducive to manipulative techniques.
• International human rights law, with its careful calibrations designed to protect individuals from abuse of power by authority, provides a normative framework that should underpin responses to online disinformation and distortion of political debate. Contrary to popular view, it does not entail that there should be no control of the online environment; rather, controls should balance the interests at stake appropriately.
• The rights to freedom of thought and opinion are critical to delimiting the appropriate boundary between legitimate influence and illegitimate manipulation. When digital platforms exploit decision-making biases in prioritizing bad news and divisive, emotion-arousing information, they may be breaching these rights. States and digital platforms should consider structural changes to digital platforms to ensure that methods of online political discourse respect personal agency and prevent the use of sophisticated manipulative techniques.
• The right to privacy includes a right to choose not to divulge your personal information, and a right to opt out of trading in and profiling on the basis of your personal data. Current practices in collecting, trading and using extensive personal data to ‘micro-target’ voters without their knowledge are not consistent with this right. Significant changes are needed.
• Data protection laws should be implemented robustly, and should not legitimate extensive harvesting of personal data on the basis of either notional ‘consent’ or the data handler’s commercial interests. The right to privacy should be embedded in technological design (such as by allowing the user to access all information held on them at the click of a button); and political parties should be transparent in their collection and use of personal data, and in their targeting of messages. Arguably, the value of personal data should be shared with the individuals from whom it derives.
• The rules on the boundaries of permissible content online should be set by states, and should be consistent with the right to freedom of expression. Digital platforms have had to rapidly develop policies on retention or removal of content, but those policies do not necessarily reflect the right to freedom of expression, and platforms are currently not well placed to take account of the public interest. Platforms should be far more transparent in their content regulation policies and decision-making, and should develop frameworks enabling efficient, fair, consistent internal complaints and content monitoring processes. Expertise on international human rights law should be integral to their systems.
• The right to participate in public affairs and to vote includes the right to engage in public debate. States and digital platforms should ensure an environment in which all can participate in debate online and are not discouraged from standing for election, from participating or from voting by online threats or abuse.

DNA polymerase from bacteriophage T7 undergoes large, substrate-induced conformational changes that are thought to account for high replication fidelity, but prior studies were adversely affected by mutations required to construct a Cys-lite variant needed for site-specific fluorescence labeling. Here we have optimized the direct incorporation of a fluorescent un-natural amino acid, (7-hydroxy-4-coumarin-yl)-ethylglycine, using orthogonal amber suppression machinery in Escherichia coli. MS methods verify that the unnatural amino acid is only incorporated at one position with minimal background. We show that the single fluorophore provides a signal to detect nucleotide-induced conformational changes through equilibrium and stopped-flow kinetic measurements of correct nucleotide binding and incorporation. Pre-steady-state chemical quench methods show that the kinetics and fidelity of DNA replication catalyzed by the labeled enzyme are largely unaffected by the unnatural amino acid. These advances enable rigorous analysis to establish the kinetic and mechanistic basis for high-fidelity DNA replication.

Thinking out loud: Is disinformation here to stay? 10 November 2022 — 6:00PM TO 6:45PM Anonymous (not verified) 25 October 2022 Chatham House

This event is postponed.

Have you ever wondered how Chatham House researchers approach the big deals that become research? Do you enjoy meeting other Chatham House members and engaging with questions that open your mind? ‘Thinking Out Loud’ invites a small group of members to a live, unscripted discussion with a Chatham House researcher. This in-person event is a way for researchers and members to think out loud to help shape ideas for future research.

Kate Jones, Associate Fellow, International Law Programme at Chatham House will pose some key questions facing how speech is governed in an online world:

• How has big tech influenced the way we think about speech and its limitations?

• Can disinformation be eliminated or even greatly reduced?

• Where should the responsibilities fall between government and business when it comes to speech regulation?

• What might the information landscape look like in 10 years’ time? Should that affect how we tackle disinformation today?

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

Tumor hypoxia, an integral biomarker to guide radiotherapy, can be imaged with ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) hypoxia PET. One major obstacle to its broader application is the lack of standardized interpretation criteria. We sought to develop and validate practical interpretation criteria and a dedicated training protocol for nuclear medicine physicians to interpret ¹⁸F-FMISO hypoxia PET. Methods: We randomly selected 123 patients with human papillomavirus–positive oropharyngeal cancer enrolled in a phase II trial who underwent 123 ¹⁸F-FDG PET/CT and 134 ¹⁸F-FMISO PET/CT scans. Four independent nuclear medicine physicians with no ¹⁸F-FMISO experience read the scans. Interpretation by a fifth nuclear medicine physician with over 2 decades of ¹⁸F-FMISO experience was the reference standard. Performance was evaluated after initial instruction and subsequent dedicated training. Scans were considered positive for hypoxia by visual assessment if ¹⁸F-FMISO uptake was greater than floor-of-mouth uptake. Additionally, SUV_max was determined to evaluate whether quantitative assessment using tumor-to-background ratios could be helpful to define hypoxia positivity. Results: Visual assessment produced a mean sensitivity and specificity of 77.3% and 80.9%, with fair interreader agreement ( = 0.34), after initial instruction. After dedicated training, mean sensitivity and specificity improved to 97.6% and 86.9%, with almost perfect agreement ( = 0.86). Quantitative assessment with an estimated best SUV_max ratio threshold of more than 1.2 to define hypoxia positivity produced a mean sensitivity and specificity of 56.8% and 95.9%, respectively, with substantial interreader agreement ( = 0.66), after initial instruction. After dedicated training, mean sensitivity improved to 89.6% whereas mean specificity remained high at 95.3%, with near-perfect interreader agreement ( = 0.86). Conclusion: Nuclear medicine physicians without ¹⁸F-FMISO hypoxia PET reading experience demonstrate much improved interreader agreement with dedicated training using specific interpretation criteria.

CHANDLER, Ariz., Oct. 23, 2024 — The global edge computing market is expected to grow by more than 30 percent in the next five years, serving mission-critical applications in the […]

The post Microchip Expands 64-Bit Portfolio with High-Performance PIC64HX Microprocessors for Edge Computing appeared first on HPCwire.

About This Webinar Oracle’s next generation HPC architecture with Intel compute instance based on 3rd Generation Intel® Xeon® Scalable processors, code named “Ice Lake”, changes the game for HPC in […]

The post Speed up Innovation with performance gains of up to 42% on the most powerful HPC Cloud appeared first on HPCwire.

When storage is mentioned in an AI or Big Data analytics context, it is assumed to be a high-performance system. In practice, it may not be, and the user eventually […]

The post High-Performance Storage for AI and Analytics Panel appeared first on HPCwire.

The surge in digital transformation across industries has led to exponential data growth, driving a heightened demand for computing power. However, this growth also intensifies concerns about energy consumption and […]

The post Renewable Power Unlock New Efficiencies for High-Performance Computing appeared first on HPCwire.

REDWOOD CITY, Calif., Nov. 4, 2024 — MinIO has announced compelling new optimizations and benchmarks for Arm-based chipsets powering on its object store. These optimizations underscore the relevance of low-power, […]

The post MinIO Optimizes Arm-Based Chipsets for High-Performance AI appeared first on HPCwire.

SAN JOSE, Calif., Nov. 12, 2024 — VDURA, a leader in data infrastructure for AI and HPC, today has announced a groundbreaking release of its VDURA Data Platform software, designed to […]

The post VDURA Unveils Next-Gen Data Platform with Enhanced AI and HPC Performance appeared first on HPCwire.

How do you reach people trapped in a reality shaped by propaganda? Exploring the dark psychology of disinformation, author and academic Peter Pomerantsev draws on lessons from a forgotten World War II operation to suggest strategies for cutting through misinformation and rebuilding trust in facts today.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

Gov. Kate Brown ordered the public release of annual school performance ratings last week after Oregon's biggest newspaper reported that a Brown appointee had delayed the release of the statistical rankings until after the high-stakes gubernatorial election Nov. 6.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.