Yueming Hu
Dec 11, 2020; 0:jlr.RA120000919v1-jlr.RA120000919
Research Articles

Akemi Kakino
Nov 3, 2020; 0:jlr.RA120000767v1-jlr.RA120000767
Research Articles

For data that is being loaded from a SAS Stored Process Server, an insertion process might fail to a MySQL database with a warning, as well as an error message that says "During insert: Incorrect datetime value…"

An error might occur when you use the SAS 9 BULKLOAD= and BULKEXTRACT= options load data to or extract data from HP Neoview on the HP Itanium platform. The problem occurs because Hewlett-Packard changed the name of one of

     Lens and tear film lipids are as unique as the systems they reside in. The major lipid of the human lens is dihydrosphingomylein, found in quantity only in the lens. The lens contains a cholesterol to phospholipid molar ratio as high as 10:1, more than anywhere in the body. Lens lipids contribute to maintaining lens clarity, and alterations in lens lipid composition due to age are likely to contribute to cataract. Lens lipid composition reflects adaptations to the unique characteristics of the lens: no turnover of lens lipids or proteins; the lowest amount of oxygen than any other tissue and contains almost no intracellular organelles. The tear film lipid layer (TFLL) is also unique. The TFLL is a thin, 100 nm layer of lipid on the surface of tears covering the cornea that contributes to tear film stability. The major lipids of the TFLL are wax esters and cholesterol esters that are not found in the lens. The hydrocarbon chains associated with the esters are longer than those found anywhere in the body, as long as 32 carbons, and many are branched. Changes in the composition and structure of the 30,000 different moieties of TFLL contribute to the instability of tears. The focus of the current review is how spectroscopy has been used to elucidate the relationships between lipid composition, conformational order and function and the etiology of cataract and dry eye.

Adiponectin, an adipocyte-derived protein, has anti-atherogenic and anti-diabetic effects, but how it confers the anti-atherogenic effects is not well understood. To study the anti-atherogenic mechanisms of adiponectin, we examined whether it interacts with atherogenic low-density lipoprotein (LDL) to attenuate LDL’s atherogenicity. L5, the most electronegative subfraction of LDL, induces atherogenic responses similarly to copper-oxidized LDL (oxLDL). Unlike native LDL endocytosed via the LDL receptor, L5 and oxLDL are internalized by cells via the lectin-like oxidized LDL receptor-1 (LOX-1). Using enzyme-linked immunosorbent assays (ELISAs), we showed that adiponectin preferentially bound oxLDL but not native LDL. In Chinese hamster ovary (CHO) cells transfected with LOX-1 or LDL receptor, adiponectin selectively inhibited the uptake of oxLDL but not of native LDL, respectively. Furthermore, adiponectin suppressed the internalization of oxLDL in human coronary artery endothelial cells (HCAECs) and THP-1–derived macrophages. Western blot analysis of human plasma showed that adiponectin was abundant in L5 but not in L1, the least electronegative subfraction of LDL. Sandwich ELISAs with anti-adiponectin and anti–apolipoprotein B antibodies confirmed the binding of adiponectin to L5 and oxLDL. In LOX-1–expressing CHO cells, adiponectin inhibited cellular responses to oxLDL and L5, including nuclear factor-B activation and ERK phosphorylation. In HCAECs, adiponectin inhibited oxLDL-induced endothelin-1 secretion and ERK phosphorylation. Conversely, oxLDL suppressed the adiponectin-induced activation of adenosine monophosphate–activated protein kinase in COS-7 cells expressing adiponectin receptor AdipoR1. Our findings suggest that adiponectin binds and inactivates atherogenic LDL, providing novel insight into the anti-atherogenic mechanisms of adiponectin.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism by inducing the degradation of hepatic low-density lipoprotein receptor (LDLR). Plasma PCSK9 has two main molecular forms: a 62-kDa mature form (PCSK9_62) and a 55-kDa, furin-cleaved form (PCSK9_55). PCSK9_55 is considered less active than PCSK9_62 in degrading LDLR. We aimed to identify the site of PCSK9_55 formation (intra- vs. extracellular) and to further characterize the LDLR-degradative function of PCSK9_55 relative to PCSK9_62. Co-expressing PCSK9_62 with furin in cell culture induced formation of PCSK9_55, most of which was found in the extracellular space. Under the same conditions we found that: i) adding a cell-permeable furin inhibitor preferentially decreased the formation of PCSK9_55 extracellularly; ii) using pulse-chase, we observed the formation of PCSK9_55 exclusively extracellularly in a time-dependent manner. A recombinant form of PCSK9_55 was efficiently produced but displayed impaired secretion that resulted in its intracellular trapping. However, the non-secreted PCSK9_55 was able to induce degradation of LDLR, though with 50% lower efficiency compared with PCSK9_62. Collectively, our data show that PCSK9_55 is generated in the extracellular space, and that intracellular PCSK9_55 is not secreted but retains the ability to degrade the LDLR through an intracellular pathway.

Apolipoproteins C-I, C-II and C-III interact with ApoE to regulate lipoprotein metabolism and contribute to Alzheimer’s disease pathophysiology. In plasma, apoC-I and C-II exist as truncated isoforms, while apoC-III exhibits multiple glycoforms. This study aimed to 1. delineate apoC-I, C-II and C-III isoform profiles in CSF and plasma in a cohort of non-demented older individuals (n = 61), and 2. examine the effect of APOE4 on these isoforms and their correlation with CSF Aβ42, a surrogate of brain amyloid accumulation. The isoforms of the apoCs were immunoaffinity enriched and measured with MALDI-TOF mass spectrometry, revealing a significantly higher percentage of truncated apoC-I and apoC-II in CSF compared to matched plasma, with positive correlation between CSF and plasma. A greater percentage of monosialylated and disialylated apoC-III isoforms was detected in CSF, accompanied by a lower percentage of the two non-sialylated apoC-III isoforms, with significant linear correlations between CSF and plasma. Furthermore, a greater percentage of truncated apoC-I in CSF, and apoC-II in plasma and CSF, was observed in individuals carrying at least one apoE E4 allele. Increased apoC-I and apoC-II truncations were  associated with lower CSF Aβ42. Finally, monosialylated apoC-III was lower, and disialylated apoC-III greater in the CSF of E4 carriers. Together, these results reveal distinct patterns of the apoCs isoforms in CSF, implying CSF-specific apoCs processing. These patterns were accentuated in APOE E4 allele carriers, suggesting an association between APOE4 genotype and Alzheimer’s disease pathology with apoCs processing and function in the brain.

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.

Microtubules are polymers composed of αβ-tubulin subunits that provide structure to cells and play a crucial role in in the development and function of neuronal processes and cilia, microtubule-driven extensions of the plasma membrane that have sensory (primary cilia) or motor (motile cilia) functions. To stabilize microtubules in neuronal processes and cilia, α tubulin is modified by the posttranslational addition of an acetyl group, or acetylation. We discovered that acetylated tubulin in microtubules interacts with the membrane sphingolipid, ceramide. However, the molecular mechanism and function of this interaction are not understood. Here, we show that in human iPS cell-derived neurons, ceramide stabilizes microtubules, which indicates a similar function in cilia. Using proximity ligation assays, we detected complex formation of ceramide with acetylated tubulin in C. reinhardtii flagella and cilia of human embryonic kidney (HEK293T) cells, primary cultured mouse astrocytes, and ependymal cells. Using incorporation of palmitic azide and click chemistry-mediated addition of fluorophores, we show that a portion of acetylated tubulin is S-palmitoylated. S-palmitoylated acetylated tubulin is colocalized with ceramide-rich platforms (CRPs) in the ciliary membrane, and it is coimmunoprecipitated with Arl13b, a GTPase that mediates transport of proteins into cilia. Inhibition of S-palmitoylation with 2-bromo palmitic acid or inhibition of ceramide biosynthesis with fumonisin B1 reduces formation of the Arl13b-acetylated tubulin complex and its transport into cilia, concurrent with impairment of ciliogenesis. Together, these data show, for the first time, that CRPs mediate membrane anchoring and interaction of S-palmitoylated proteins that are critical for cilium formation, stabilization, and function. 

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.

Extracellular vesicles (EVs) secreted by the epididymal epithelium transfer to spermatozoa key proteins that are essential in promoting motility and subsequent fertilization success. Using the domestic cat model, the objectives were to (1) characterize and compare protein content of EVs between segments of the epididymis, and (2) compare EV protein compositions between normo- and teratospermic individuals (producing >60% of abnormal spermatozoa). Epididymal EVs from adult cats were isolated and assessed via liquid chromatography tandem MS. Both male types shared 3008 proteins in total, with 98 and 20 EV proteins unique to normospermic and teratospermic males, respectively. Expression levels of several proteins changed between epididymal segments in both male types. Several proteins in both groups were related to sperm motility (e.g. hexokinase 1, adenylate kinase isoenzyme) and zona pellucida or oolemma binding (e.g. disintegrin and metalloproteinase domain proteins, zona binding proteins 1 and 2). Interestingly, seven cauda-derived EV proteins trended downward in teratospermic compared with normospermic males, which may relate to poor sperm quality. Collective results revealed, for the first time, EV proteins related to sequential sperm maturation with differences observed between normospermic and teratospermic individuals.

Contrairement à ce qu’on pourrait croire, bien plus de femmes se préoccupent de leurs poids et y font attention. Pour ces femmes, comprendre ce qu’est un indice de masse corporelle (IMC) normal peut permettre de maintenir une bonne santé et savoir quand faire appel à un médecin pour leurs poids. C’est quoi l’IMC ou indice de masse […]

L’article Quel est l’IMC normal pour une femme ? est apparu en premier sur Ortho Doc France.

This article provides an introduction to Fourier transform-based mass spectrometry (FTMS). The key performance characteristics of FTMS, mass accuracy and resolution, are presented in the view of how they impact the interpretation of measurements in proteomic applications. The theory and principles of operation of two types of mass analyzer, Fourier transform ion cyclotron resonance and Orbitrap, are described. Major benefits as well as limitations of FTMS technology are discussed in the context of practical sample analysis, and illustrated with examples included as figures in this text and in the accompanying slide set. Comparisons highlighting the performance differences between the two mass analyzers are made where deemed useful in assisting the user with choosing the most appropriate technology for his/her application. Recent developments of these high-performing mass spectrometers are mentioned to provide a future outlook.

As the capability of mass spectrometry-based proteomics has matured, tens of thousands of peptides can be measured simultaneously, which has the benefit of offering a systems view of protein expression. However, a major challenge is that with an increase in throughput, protein quantification estimation from the native measured peptides has become a computational task. A limitation to existing computationally-driven protein quantification methods is that most ignore protein variation, such as alternate splicing of the RNA transcript and post-translational modifications or other possible proteoforms, which will affect a significant fraction of the proteome. The consequence of this assumption is that statistical inference at the protein level, and consequently downstream analyses, such as network and pathway modeling, have only limited power for biomarker discovery. Here, we describe a Bayesian model (BP-Quant) that uses statistically derived peptides signatures to identify peptides that are outside the dominant pattern, or the existence of multiple over-expressed patterns to improve relative protein abundance estimates. It is a research-driven approach that utilizes the objectives of the experiment, defined in the context of a standard statistical hypothesis, to identify a set of peptides exhibiting similar statistical behavior relating to a protein. This approach infers that changes in relative protein abundance can be used as a surrogate for changes in function, without necessarily taking into account the effect of differential post-translational modifications, processing, or splicing in altering protein function. We verify the approach using a dilution study from mouse plasma samples and demonstrate that BP-Quant achieves similar accuracy as the current state-of-the-art methods at proteoform identification with significantly better specificity. BP-Quant is available as a MatLab ® and R packages at https://github.com/PNNL-Comp-Mass-Spec/BP-Quant.

Thyroglobulin (Tg) is a secreted iodoglycoprotein serving as the precursor for T3 and T4 hormones. Many characterized Tg gene mutations produce secretion-defective variants resulting in congenital hypothyroidism (CH). Tg processing and secretion is controlled by extensive interactions with chaperone, trafficking, and degradation factors comprising the secretory proteostasis network. While dependencies on individual proteostasis network components are known, the integration of proteostasis pathways mediating Tg protein quality control and the molecular basis of mutant Tg misprocessing remain poorly understood. We employ a multiplexed quantitative affinity purification–mass spectrometry approach to define the Tg proteostasis interactome and changes between WT and several CH-variants. Mutant Tg processing is associated with common imbalances in proteostasis engagement including increased chaperoning, oxidative folding, and engagement by targeting factors for ER-associated degradation (ERAD). Furthermore, we reveal mutation-specific changes in engagement with N-glycosylation components, suggesting distinct requirements for one Tg variant on dual engagement of both oligosaccharyltransferase complex isoforms for degradation. Modulating dysregulated proteostasis components and pathways may serve as a therapeutic strategy to restore Tg secretion and thyroid hormone biosynthesis.

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.

In nucleotide excision repair, bulky DNA lesions such as UV-induced cyclobutane pyrimidine dimers are removed from the genome by concerted dual incisions bracketing the lesion, followed by gap filling and ligation. So far, two dual-incision patterns have been discovered: the prokaryotic type, which removes the damage in 11–13-nucleotide-long oligomers, and the eukaryotic type, which removes the damage in 24–32-nucleotide-long oligomers. However, a recent study reported that the UvrC protein of Mycobacterium tuberculosis removes damage in a manner analogous to yeast and humans in a 25-mer oligonucleotide arising from incisions at 15 nt from the 3´ end and 9 nt from the 5´ end flanking the damage. To test this model, we used the in vivo excision assay and the excision repair sequencing genome-wide repair mapping method developed in our laboratory to determine the repair pattern and genome-wide repair map of Mycobacterium smegmatis. We find that M. smegmatis, which possesses homologs of the Escherichia coli uvrA, uvrB, and uvrC genes, removes cyclobutane pyrimidine dimers from the genome in a manner identical to the prokaryotic pattern by incising 7 nt 5´ and 3 or 4 nt 3´ to the photoproduct, and performs transcription-coupled repair in a manner similar to E. coli.

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.

The origin recognition complex (ORC), composed of six subunits, ORC1–6, binds to origins of replication as a ring-shaped heterohexameric ATPase that is believed to be essential to recruit and load MCM2–7, the minichromosome maintenance protein complex, around DNA and initiate DNA replication. We previously reported the creation of viable cancer cell lines that lacked detectable ORC1 or ORC2 protein without a reduction in the number of origins firing. Here, using CRISPR-Cas9–mediated mutations, we report that human HCT116 colon cancer cells also survive when ORC5 protein expression is abolished via a mutation in the initiator ATG of the ORC5 gene. Even if an internal methionine is used to produce an undetectable, N terminally deleted ORC5, the protein would lack 80% of the AAA+ ATPase domain, including the Walker A motif. The ORC5-depleted cells show normal chromatin binding of MCM2–7 and initiate replication from a similar number of origins as WT cells. In addition, we introduced a second mutation in ORC2 in the ORC5 mutant cells, rendering both ORC5 and ORC2 proteins undetectable in the same cells and destabilizing the ORC1, ORC3, and ORC4 proteins. Yet the double mutant cells grow, recruit MCM2–7 normally to chromatin, and initiate DNA replication with normal number of origins. Thus, in these selected cancer cells, either a crippled ORC lacking ORC2 and ORC5 and present at minimal levels on the chromatin can recruit and load enough MCM2–7 to initiate DNA replication, or human cell lines can sometimes recruit MCM2–7 to origins independent of ORC.

All 30 Major League teams will wear special "MLB 150" patches on their uniforms for the entire 2019 season in honor of the 150th anniversary of the 1869 Cincinnati Red Stockings, the first openly all-salaried professional baseball team.

All 30 Major League teams will wear special "MLB 150" patches on their uniforms for the entire 2019 season in honor of the 150th anniversary of the 1869 Cincinnati Red Stockings, the first openly all-salaried professional baseball team.

South Africa's Land Reform Quandary: Scenarios and Policy 10 July 2018 — 10:00AM TO 11:00AM Anonymous (not verified) 13 June 2018 Chatham House, London

Slow delivery on expectations of land redistribution in South Africa has once again put the issue at the forefront of political debate in the country. A parliamentary public consultation process will consider whether constitutional change is required to accelerate expropriation without compensation. Policymakers face dual - often opposing - pressures due to investors’ fears of negative economic impacts as well as citizens’ frustrations over persistent inequality and hardship. State land and tribal trust land remain contentious issues for rural economic development, but with two thirds of the population now living in urban areas policy responses must be as cognizant of the country’s future as it is of its past.

At this meeting, Terence Corrigan, project manager at the South African Institute of Race Relations, will discuss the current debates on expropriation and present the institute’s latest research on future scenarios of land reform in South Africa.

Attendance at this event is by invitation only.

Higher Education in South Africa: Demands for Inclusion and the Challenges of Reform 17 October 2018 — 5:00PM TO 6:00PM Anonymous (not verified) 18 September 2018 Chatham House, London

Economic Reform and Recovery in Zimbabwe 8 October 2018 — 2:30PM TO 3:30PM Anonymous (not verified) 4 October 2018 Chatham House, London

Political Reform in Angola: Challenges and Priorities for Elected Officials 31 October 2018 — 4:00PM TO 5:00PM Anonymous (not verified) 26 October 2018 Chatham House, London

Angola’s reformulated National Assembly has passed a series of legislative reforms since elections in August 2017, in which the ruling MPLA won a majority of 150 seats to the 51 held by the UNITA leading opposition party.

Many of the changes have targeted the revitalization of an underperforming economy and improved governance: in June 2018 parliament approved a new private investment law aimed at diversifying Angola’s fiscal base beyond oil revenues while new legislation in May mandated the return of illicitly exported capital of over $100,000.

As the appetite for measurable progress across all sectors of society remains high, and with newly constituted municipal elections scheduled for 2020, inclusive and accountable political debate will remain critical to Angola’s future.

At the event, a cross-party delegation discuss the role of the National Assembly in affecting political change and the importance of maintaining open dialogue among opposing voices to address the challenges facing Angola.

Economic Recovery and Anticorruption in South Africa: Assessing Progress on the Reform Agenda 4 December 2019 — 3:00PM TO 4:00PM Anonymous (not verified) 25 November 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

South Africa has significant economic potential based on its resource endowment, quality human capital and well-developed infrastructure compared to the region. However, the country’s economic growth rate has not topped 2 per cent since 2013, and in 2018, was below 1 per cent. This has put a strain on citizens and communities in a country that still suffers from structural inequality, poverty and high unemployment. Economic recovery and anti-corruption were the central pillars of President Cyril Ramaphosa’s 2019 electoral campaign and he has set an investment target of $100 billion. However, voters and investors alike are demanding faster and more visible progress from the country’s enigmatic leader who has a reputation for caution and calculation.

At this event, Professor Nick Binedell will discuss the progress of and opposition to the president’s economic reform agenda and the opportunities for international investment to support long term inclusive and sustainable growth in South Africa.

Attendance at this event is by invitation only.

Angola's Business Promise: Evaluating the Progress of Privatization and Other Economic Reforms 21 January 2020 — 2:30PM TO 3:30PM Anonymous (not verified) 16 January 2020 Chatham House | 10 St James's Square | London | SW1Y 4LE

Minister Nunes Júnior will discuss the progress of the Angolan government’s economic stabilization plans and business reform agenda including the privatization of some state-owned enterprises. These reforms could expand Angola’s exports beyond oil and stimulate new industries and more inclusive economic growth.

THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED.

POSTPONED: Pursuing Economic Reform and Growth in South Africa: the view from the African National Congress 18 March 2020 — 10:30AM TO 11:30AM Anonymous (not verified) 3 March 2020 Chatham House | 10 St James's Square | London | SW1Y 4LE

The government of South Africa is pursuing a programme of reform to revitalize the economy, strengthen institutions and combat corruption. The State of the Nation Address (SONA) on 13 February and the budget speech of 26 February represent the most significant articulation of the government’s economic strategy. Central to this is the government’s plans for the energy sector, which is fundamental for reviving the economy, and the reform of State Owned Enterprises (SOEs). But questions remain about possible divergence of the approach taken by government ministers from the policy position of the ruling party, the African National Congress (ANC), and what this might mean for the sustainability and progress of reform.

At this event, Paul Mashatile, Treasurer General of the ANC, will discuss the party’s assessment of reform efforts to date and priorities for delivering on inclusive growth.

PLEASE NOTE THIS EVENT IS POSTPONED UNTIL FURTHER NOTICE.

South Africa's Economic Reform and Employment in the Context of the Coronavirus Pandemic 3 September 2020 — 3:00PM TO 4:00PM Anonymous (not verified) 26 August 2020 Online

President of COSATU, Zingiswa Losi, discusses the organization’s priorities for protecting jobs and workers, and working with other stakeholders to build a sustainable post-pandemic economy.

Employment in South Africa fell by an estimated 18 per cent between February and April 2020. The measures imposed to control the spread of COVID-19 suffocated an already weak economy and unemployment has hit a new high.

The stated aims of the government’s economic reform plans include the support of job creation in labour intensive industries, but the reform of the state and rebalancing of the economy and fiscus could lead to further job losses in state agencies and enterprises.

Protecting jobs while ensuring the health and safety of workers are dual priorities, and require the joint commitment and ‘social compact’ of labour, business and government.

Zambia’s political and economic reform and recovery 5 November 2021 — 11:30AM TO 12:30PM Anonymous (not verified) 2 November 2021 Chatham House and Online

At this event, HE Hakainde Hichilema, president of the Republic of Zambia, discusses his vision for Zambia’s development and long-term political and economic reform and recovery.

Zambia’s new administration, following the general elections of August 2021, faces a daunting challenge of reversing economic contraction, lowering income-eroding inflation, and addressing the unsustainable national debt.

The country has been one of the few to seek debt restructuring under the G20’s new Common Framework for Debt Treatments, and its immediate priorities include a prospective agreement with the International Monetary Fund (IMF).

Young Zambians are eager for jobs and improved living standards. But the government’s ambition to create more jobs and achieve middle-income status will depend on both attracting new investment into its copper sector and pursuing a programme of economic diversification supporting growth beyond the mining industry.

Addressing these economic concerns will also need to be supported by a programme of political reform and rehabilitation of citizens’ trust in the state.

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.

Weathering the storm: The UK’s role in the world today 29 November 2022 — 12:00PM TO 1:00PM Anonymous (not verified) 7 November 2022 Chatham House and Online

In conversation with David Miliband, examining the risks and opportunities for the UK in a critical year ahead. 

With a new government in the midst of a global order in flux, the UK’s position in the world needs re-examining.

Just 20 months since the UK’s Integrated Review on international policy and security, Britain’s global blueprint is being reviewed and updated in light of major global developments.

Today, Brexit and the Russia’s invasion of Ukraine require adjustments to the UK’s strategic thinking and positioning in the world.

As the economic and political turmoil of previous weeks begins to abate, this is an important moment to once again determine Britain’s role in Europe and beyond. 
 
Realigning British foreign policy in a rapidly shifting international order will be a major challenge for the new administration.  

International Rescue Committee’s CEO and President, and former UK Foreign Secretary, David Miliband, examines the risks and opportunities for a critical year ahead. 
 
Key questions include:

• What are the crucial decisions the UK needs to make in the coming 12 months?
• What should the UK’s priorities be for its role in the world? How should it project itself amidst geopolitical fracturing?
• How can Britain best respond to humanitarian crises around the world?
• Does the UK have the strategic and economic clout to keep up with its foreign policy and development commitments?

As with all Chatham House member events, questions from members drive the conversation.

Read the transcript. 

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...

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.

Quantification of ¹⁸F-FDG PET images is useful for accurate diagnosis and evaluation of various brain diseases, including brain tumors, epilepsy, dementia, and Parkinson disease. However, accurate quantification of ¹⁸F-FDG PET images requires matched 3-dimensional T₁ MRI scans of the same individuals to provide detailed information on brain anatomy. In this paper, we propose a transfer learning approach to adapt a pretrained deep neural network model from amyloid PET to spatially normalize ¹⁸F-FDG PET images without the need for 3-dimensional MRI. Methods: The proposed method is based on a deep learning model for automatic spatial normalization of ¹⁸F-FDG brain PET images, which was developed by fine-tuning a pretrained model for amyloid PET using only 103 ¹⁸F-FDG PET and MR images. After training, the algorithm was tested on 65 internal and 78 external test sets. All T₁ MR images with a 1-mm isotropic voxel size were processed with FreeSurfer software to provide cortical segmentation maps used to extract a ground-truth regional SUV ratio using cerebellar gray matter as a reference region. These values were compared with those from spatial normalization-based quantification methods using the proposed method and statistical parametric mapping software. Results: The proposed method showed superior spatial normalization compared with statistical parametric mapping, as evidenced by increased normalized mutual information and better size and shape matching in PET images. Quantitative evaluation revealed a consistently higher SUV ratio correlation and intraclass correlation coefficients for the proposed method across various brain regions in both internal and external datasets. The remarkably good correlation and intraclass correlation coefficient values of the proposed method for the external dataset are noteworthy, considering the dataset’s different ethnic distribution and the use of different PET scanners and image reconstruction algorithms. Conclusion: This study successfully applied transfer learning to a deep neural network for ¹⁸F-FDG PET spatial normalization, demonstrating its resource efficiency and improved performance. This highlights the efficacy of transfer learning, which requires a smaller number of datasets than does the original network training, thus increasing the potential for broader use of deep learning–based brain PET spatial normalization techniques for various clinical and research radiotracers.

The peptide hormone ghrelin is produced in cardiomyocytes and acts through the myocardial growth hormone secretagogue receptor (GHSR) to promote cardiomyocyte survival. Administration of ghrelin may have therapeutic effects on post–myocardial infarction (MI) outcomes. Therefore, there is a need to develop molecular imaging probes that can track the dynamics of GHSR in health and disease to better predict the effectiveness of ghrelin-based therapeutics. We designed a high-affinity GHSR ligand labeled with ¹⁸F for imaging by PET and characterized its in vivo properties in a canine model of MI. Methods: We rationally designed and radiolabeled with ¹⁸F a quinazolinone derivative ([¹⁸F]LCE470) with subnanomolar binding affinity to GHSR. We determined the sensitivity and in vivo and ex vivo specificity of [¹⁸F]LCE470 in a canine model of surgically induced MI using PET/MRI, which allowed for anatomic localization of tracer uptake and simultaneous determination of global cardiac function. Uptake of [¹⁸F]LCE470 was determined by time–activity curve and SUV analysis in 3 regions of the left ventricle—area of infarct, territory served by the left circumflex coronary artery, and remote myocardium—over a period of 1.5 y. Changes in cardiac perfusion were tracked by [¹³N]NH₃ PET. Results: The receptor binding affinity of LCE470 was measured at 0.33 nM, the highest known receptor binding affinity for a radiolabeled GHSR ligand. In vivo blocking studies in healthy hounds and ex vivo blocking studies in myocardial tissue showed the specificity of [¹⁸F]LCE470, and sensitivity was demonstrated by a positive correlation between tracer uptake and GHSR abundance. Post-MI changes in [¹⁸F]LCE470 uptake occurred independently of perfusion tracer distributions and changes in global cardiac function. We found that the regional distribution of [¹⁸F]LCE470 within the left ventricle diverged significantly within 1 d after MI and remained that way throughout the 1.5-y duration of the study. Conclusion: [¹⁸F]LCE470 is a high-affinity PET tracer that can detect changes in the regional distribution of myocardial GHSR after MI. In vivo PET molecular imaging of the global dynamics of GHSR may lead to improved GHSR-based therapeutics in the treatment of post-MI remodeling.

Unspecific bone uptake (UBU) related to [¹⁸F]PSMA-1007 PET/CT imaging represents a clinical challenge. We aimed to assess whether a combination of clinical, biochemical, and imaging parameters could predict skeletal metastases in patients with [¹⁸F]PSMA-1007 bone focal uptake, aiding in result interpretation. Methods: We retrospectively analyzed [¹⁸F]PSMA-1007 PET/CT performed in hormone-sensitive prostate cancer (PCa) patients at 3 tertiary-level cancer centers. A fourth center was involved in performing an external validation. For each, a volume of interest was drawn using a threshold method to extract SUV_max, SUV_mean, PSMA tumor volume, and total lesion PSMA. The same volume of interest was applied to CT images to calculate the mean Hounsfield units (HU_mean) and maximum Hounsfield units. Clinical and laboratory data were collected from electronic medical records. A composite reference standard, including follow-up histopathology, biochemistry, and imaging data, was used to distinguish between PCa bone metastases and UBU. PET readers with less (n = 2) or more (n = 2) experience, masked to the reference standard, were asked to visually rate a subset of focal bone uptake (n = 178) as PCa metastases or not. Results: In total, 448 bone [¹⁸F]PSMA-1007 focal uptake specimens were identified in 267 PCa patients. Of the 448 uptake samples, 188 (41.9%) corresponded to PCa metastases. Ongoing androgen deprivation therapy at PET/CT (P < 0.001) with determination of SUV_max (P < 0.001) and HU_mean (P < 0.001) independently predicted bone metastases. A composite prediction score, the bone uptake metastatic probability (BUMP) score, achieving an area under the receiver-operating-characteristic curve (AUC) of 0.87, was validated through a 10-fold internal and external validation (n = 89 bone uptake, 51% metastatic; AUC, 0.92). The BUMP score’s AUC was significantly higher than that of HU_mean (AUC, 0.62) and remained high among lesions with HU_mean in the first tertile (AUC, 0.80). A decision-curve analysis showed a higher net benefit with the score. Compared with the visual assessment, the BUMP score provided added value in terms of specificity in less-experienced PET readers (88% vs. 54%, P < 0.001). Conclusion: The BUMP score accurately distinguished UBU from bone metastases in PCa patients with [¹⁸F]PSMA-1007 focal bone uptake at PET imaging, offering additional value compared with the simple assessment of the osteoblastic CT correlate. Its use could help clinicians interpret imaging results, particularly those with less experience, potentially reducing the risk of patient overstaging.

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.

SAN JOSE, Calif., Oct. 16, 2024 — Supermicro, Inc. is launching a new optimized storage system for high performance AI training, inference and HPC workloads. This JBOF (Just a Bunch […]

The post Supermicro Introduces JBOF Storage Platform Powered by NVIDIA BlueField-3 for Scalable AI and HPC appeared first on HPCwire.

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.

The Miami Marlins officially hired former Los Angeles Dodgers first base coach Clayton McCullough as their new manager, the franchise announced Monday.

Gerry Faust, who won five Ohio high school football state titles before taking over as coach at Notre Dame in the early 1980s, has died, his family announced. He was 89.

Large-scale scientific research labs and academic institutions are utilizing high performance computing to accelerate sequencing, simulations, and analytics for research, learning, and discovery.  File data volumes are growing rapidly, and […]

The post Accelerating Research Innovation with Qumulo’s File Data Platform appeared first on HPCwire.