RK Tangirala
Nov 1, 1995; 36:2320-2328
Articles

Undercurrents: The Oversight Board's Trump decision, and Merkel's legacy Audio bhorton.drupal 25 June 2021

Was Facebook right to suspend Trump? And how will Merkel be remembered?

In the wake of the storming of Capitol Hill on 6 January 2021, social media platforms took steps to remove former President Donald Trump from their websites for infringing community standards. This step was welcomed by many, but also raised serious questions about the power of social media companies to limit free speech and censor elected officials. The suspension of President Trump from Facebook was referred to the Oversight Board, an independent body of experts set up to scrutinise the platform’s content moderation decisions.  

In this episode, Ben speaks to Thomas Hughes and Kate Jones about the outcome of the Oversight Board’s inquiry into the Trump suspension, and the wider implications for content moderation on social media.  

Then Lara is joined by Hans Kundnani to assess the political outlook in Germany and reflect on the legacy of outgoing Chancellor Angela Merkel.  

Rhodopsin is a canonical class A photosensitive G protein–coupled receptor (GPCR), yet relatively few pharmaceutical agents targeting this visual receptor have been identified, in part due to the unique characteristics of its light-sensitive, covalently bound retinal ligands. Rhodopsin becomes activated when light isomerizes 11-cis-retinal into an agonist, all-trans-retinal (ATR), which enables the receptor to activate its G protein. We have previously demonstrated that, despite being covalently bound, ATR can display properties of equilibrium binding, yet how this is accomplished is unknown. Here, we describe a new approach for both identifying compounds that can activate and attenuate rhodopsin and testing the hypothesis that opsin binds retinal in equilibrium. Our method uses opsin-based fluorescent sensors, which directly report the formation of active receptor conformations by detecting the binding of G protein or arrestin fragments that have been fused onto the receptor's C terminus. We show that these biosensors can be used to monitor equilibrium binding of the agonist, ATR, as well as the noncovalent binding of β-ionone, an antagonist for G protein activation. Finally, we use these novel biosensors to observe ATR release from an activated, unlabeled receptor and its subsequent transfer to the sensor in real time. Taken together, these data support the retinal equilibrium binding hypothesis. The approach we describe should prove directly translatable to other GPCRs, providing a new tool for ligand discovery and mutant characterization.

Haiyong Wang
Math. Comp. 93 (), 2861-2884.
Abstract, references and article information

Denise Uwamariya and Xiangfeng Yang
Theor. Probability and Math. Statist. 111 (), 167-179.
Abstract, references and article information

T. A. Suslina
St. Petersburg Math. J. 35 (), 537-570.
Abstract, references and article information

The police have arrested an individual in the probe surrounding two bags of cash that allegedly fell from a Beryllium security vehicle en route to the Norman Manley International Airport in Kingston last week. 

Aspergillus terreus is an allergenic fungus, in addition to causing infections in both humans and plants. However, the allergens in this fungus are still unknown, limiting the development of diagnostic and therapeutic strategies. We used a proteomic approach to search for allergens, identifying 16 allergens based on two-dimensional immunoblotting with A. terreus susceptible patient sera. We further characterized triose-phosphate isomerase (Asp t 36), one of the dominant IgE (IgE)-reactive proteins. The gene was cloned and expressed in Escherichia coli. Phylogenetic analysis showed Asp t 36 to be highly conserved with close similarity to the triose-phosphate isomerase protein sequence from Dermatophagoides farinae, an allergenic dust mite. We identified four immunodominant epitopes using synthetic peptides, and mapped them on a homology-based model of the tertiary structure of Asp t 36. Among these, two were found to create a continuous surface patch on the 3D structure, rendering it an IgE-binding hotspot. Biophysical analysis indicated that Asp t 36 shows similar secondary structure content and temperature sensitivity with other reported triose-phosphate isomerase allergens. In vivo studies using a murine model displayed that the recombinant Asp t 36 was able to stimulate airway inflammation, as demonstrated by an influx of eosinophils, goblet cell hyperplasia, elevated serum Igs, and induction of Th2 cytokines. Collectively, our results reveal the immunogenic property of Asp t 36, a major allergen from A. terreus, and define a new fungal allergen more broadly. This allergen could serve as a potent candidate for investigating component resolved diagnosis and immunotherapy.

Zinc is a critical element for insulin storage in the secretory granules of pancreatic beta cells. The islet-specific zinc transporter ZnT8 mediates granular sequestration of zinc ions. A genetic variant of human ZnT8 arising from a single nonsynonymous nucleotide change contributes to increased susceptibility to type-2 diabetes (T2D), but it remains unclear how the high risk variant (Arg-325), which is also a higher frequency (>50%) allele, is correlated with zinc transport activity. Here, we compared the activity of Arg-325 with that of a low risk ZnT8 variant (Trp-325). The Arg-325 variant was found to be more active than the Trp-325 form following induced expression in HEK293 cells. We further examined the functional consequences of changing lipid conditions to mimic the impact of lipid remodeling on ZnT8 activity during insulin granule biogenesis. Purified ZnT8 variants in proteoliposomes exhibited more than 4-fold functional tunability by the anionic phospholipids, lysophosphatidylcholine and cholesterol. Over a broad range of permissive lipid compositions, the Arg-325 variant consistently exhibited accelerated zinc transport kinetics versus the Trp-form. In agreement with the human genetic finding that rare loss-of-function mutations in ZnT8 are associated with reduced T2D risk, our results suggested that the common high risk Arg-325 variant is hyperactive, and thus may be targeted for inhibition to reduce T2D risk in the general populations.

Visual Abstract

Kyle Swovick
Dec 28, 2020; 0:RA120.002301v1-mcp.RA120.002301
Research

If the response variable is in the CLASS statement variable list before the class variables that also appear in the MODEL statement, and an OM-data-set is used, least squares means results for several of the statistical procedures are incorrect.

In SAS Merchandise Financial Planning, custom time frame-based data versions do not aggregate correctly when referenced in worksheets with standard hierarchy levels. The data does not aggregate correctly from l

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

Kir2.1, a strong inward rectifier potassium channel encoded by the KCNJ2 gene, is a key regulator of the resting membrane potential of the cardiomyocyte and plays an important role in controlling ventricular excitation and action potential duration in the human heart. Mutations in KCNJ2 result in inheritable cardiac diseases in humans, e.g. the type-1 Andersen-Tawil syndrome (ATS1). Understanding the molecular mechanisms that govern the regulation of inward rectifier potassium currents by Kir2.1 in both normal and disease contexts should help uncover novel targets for therapeutic intervention in ATS1 and other Kir2.1-associated channelopathies. The information available to date on protein-protein interactions involving Kir2.1 channels remains limited. Additional efforts are necessary to provide a comprehensive map of the Kir2.1 interactome. Here we describe the generation of a comprehensive map of the Kir2.1 interactome using the proximity-labeling approach BioID. Most of the 218 high-confidence Kir2.1 channel interactions we identified are novel and encompass various molecular mechanisms of Kir2.1 function, ranging from intracellular trafficking to cross-talk with the insulin-like growth factor receptor signaling pathway, as well as lysosomal degradation. Our map also explores the variations in the interactome profiles of Kir2.1^WT versus Kir2.1^314-315, a trafficking deficient ATS1 mutant, thus uncovering molecular mechanisms whose malfunctions may underlie ATS1 disease. Finally, using patch-clamp analysis, we validate the functional relevance of PKP4, one of our top BioID interactors, to the modulation of Kir2.1-controlled inward rectifier potassium currents. Our results validate the power of our BioID approach in identifying functionally relevant Kir2.1 interactors and underline the value of our Kir2.1 interactome as a repository for numerous novel biological hypotheses on Kir2.1 and Kir2.1-associated diseases.

After successful completion of the Human Genome Project (HGP), HUPO has recently officially launched a global Human Proteome Project (HPP) which is designed to map the entire human protein set. Given the presence of about 30% undisclosed proteins out of 20,300 protein gene products, a systematic global effort is necessary to achieve this goal with respect to protein abundance, distribution, subcellular localization, interaction with other biomolecules, and functions at specific time points. As a general experimental strategy, HPP groups employ the three working pillars for HPP: mass spectrometry, antibody capture, and bioinformatics tools and knowledge base. The HPP participants will take advantage of the output and cross-analyses from the ongoing HUPO initiatives and a chromosome-based protein mapping strategy, termed C-HPP with many national teams currently engaged. In addition, numerous biologically-driven projects will be stimulated and facilitated by the HPP. Timely planning with proper governance of HPP will deliver a protein parts list, reagents and tools for protein studies and analyses, and a stronger basis for personalized medicine. HUPO urges each national research funding agency and the scientific community at large to identify their preferred pathways to participate in aspects of this highly promising project in a HPP consortium of funders and investigators.

Cells continually degrade and replace damaged proteins. However, the high energetic demand of protein turnover generates reactive oxygen species (ROS) that compromise the long-term health of the proteome. Thus, the relationship between aging, protein turnover and energetic demand remains unclear. Here, we used a proteomic approach to measure rates of protein turnover within primary fibroblasts isolated from a number of species with diverse lifespans including the longest-lived mammal, the bowhead whale. We show that organismal lifespan is negatively correlated with turnover rates of highly abundant proteins. In comparison to mice, cells from long-lived naked mole rats have slower rates of protein turnover, lower levels of ATP production and reduced ROS levels. Despite having slower rates of protein turnover, naked mole rat cells tolerate protein misfolding stress more effectively than mouse cells. We suggest that in lieu of rapid constitutive turnover, long-lived species may have evolved more energetically efficient mechanisms for selective detection and clearance of damaged proteins.

Odubel Herrera smiled and patted his stomach. The paunch that he carried into Spring Training 2018 is no longer there. Herrera has reported to camp leaner and, as he said Friday morning at Spectrum Field, motivated to bounce back from the worst season of his four-year career.

VOLUME 279 (2004) PAGES 33438–33446For Fig. 1B, the second, third, and fifth panels were mistakenly duplicated during article preparation as no yeast colonies were observed in these conditions. The corrected images are presented in the revised Fig. 1B. This correction does not affect the results or conclusions of the work. The authors apologize for the error.jbc;295/50/17382/F1F1F1Figure 1B.

VOLUME 289 (2014) PAGES 6604–6618In Fig. 4G, in the foxi1 panel, the images in Fig. 4G, i and l, corresponding to “smad1 MO” and “smad5 MO + samd1/9 mRNA” samples, respectively, were inadvertently reused during figure preparation. This error has now been corrected using images pertaining to each treatment and sample. This correction does not affect the results or conclusions of the work.jbc;295/52/18650/F4F1F4Figure 4G.

American democracy in 2022: Trump, insurrection, and midterm elections 31 October 2022 — 2:00PM TO 3:00PM Anonymous (not verified) 7 October 2022 Online

How much has Donald Trump changed US politics and democracy, and will Trump and ‘Trumpism’ be more or less significant in the years ahead?

America’s democracy is divided, polarized and fragmenting. Inequality and internal division have a long history. But Trump’s lasting influence on the Republican party, and politics more broadly, continues to leave a mark. Repeated denials of President Joe Biden’s 2020 election win, wrapped in claims of electoral fraud, have eroded faith in the democratic institutions.

The memories of 6 January are still fresh, reminding all of the dangers posed by such actions. All told, America’s democracy has taken a beating in recent years.

To help make sense of the events over recent years and consequences for the coming mid-terms, Peter Baker and Susan Glasser (authors of The Divider: Trump in the White House 2017–2021) walk through in detail how the American politics of today has been arrived at.

Key questions discussed include:

• What has been learned from the January 6 Committee?

• Is there a likelihood of a similar event in the future?

• When and how will Trump lose his influence over the Republican party? 

• What are the broader ramifications of the Trump era?

• What did the events of 6 January mean for America’s relationships globally?

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

Read the transcript. 

Undercurrents: Europe's far-right educational institutions Audio bhorton.drupal 8 October 2021

In Hungary, France and Spain, new political movements from the far-right are attempting to reshape their education systems.

Under the supportive eye of Prime Minister Viktor Orbán, the recently established National University of Public Service seeks to embed nationalist illiberal values in a new generation of Hungarian students. Meanwhile in France and Spain, far-right public figure Marion Maréchal has turned away from the electoral politics of the Front Nationale to set up a new conservative research institute, ISSEP.

Both of these developments represent a challenge to the liberal values which underpin the existing international order. To find out more, Ben spoke with Professor Dorit Geva and Dr Felipe Santos, whose recent article in International Affairs considers the implications of this illiberal educational turn. 

This analysis aimed to identify clinical factors associated with positivity on repeat ⁶⁸Ga-PSMA-11 PET/CT after a negative scan in patients with recurrent prostate cancer (PCa) under observation. Methods: This single-center, retrospective analysis included patients who underwent at least 2 ⁶⁸Ga-PSMA-11 PET/CT scans (PET1 and PET2) at UCLA between October 2016 and June 2021 for recurrent PCa with negative PET1 and no PCa-related treatments between the 2 scans. Using Prostate Cancer Molecular Imaging Standardized Evaluation criteria to define negative and positive scans, the final cohort was divided into PET2-negative (PET2-Neg) and PET2-positive (PET2-Pos). The same PET1 was used twice in the more than 2 PET cases with inclusion criteria fulfilled. Patient characteristics and clinical parameters were compared between the 2 cohorts using Mann–Whitney U test and Fisher exact test. Areas under the curve (AUCs) of the receiver operating characteristic and the Youden index were computed to determine the discrimination ability of statistically significant factors and specific cut points that maximized sensitivity and specificity, respectively. Results: The final analysis included 83 sets of 2 PET/CT scans from 70 patients. Thirty-nine of 83 (47%) sets were PET2-Neg, and 44 of 83 (53%) sets were PET2-Pos. Prostate-specific antigen (PSA) increased from PET1 to PET2 for all 83 (100%) sets of scans. Median PSA at PET1 was 0.4 ng/mL (interquartile range, 0.2–1.0) and at PET2 was 1.6 ng/mL (interquartile range, 0.9–3.8). We found higher serum PSA at PET2 (median, 1.8 vs. 1.1 ng/mL; P = 0.015), absolute PSA difference (median, 1.4 vs. 0.7 ng/mL; P = 0.006), percentage of PSA change (median, +270.4% vs. +150.0%: P = 0.031), and median PSA velocity (0.044 vs. 0.017 ng/mL/wk, P = 0.002) and shorter PSA doubling time (DT; median, 5.1 vs. 8.3 mo; P = 0.006) in the PET2-Pos cohort than in the PET2-Neg cohort. Receiver operating characteristic curves showed cutoffs for PSA at PET2 of 4.80 ng/mL (sensitivity, 34%; specificity, 92%; AUC, 0.66), absolute PSA difference of 0.95 ng/mL (sensitivity, 62%; specificity, 71%; AUC, 0.68), percentage of PSA change of a positive 289.50% (sensitivity, 48%; specificity, 82%; AUC, 0.64), PSA velocity of 0.033 ng/mL/wk (sensitivity, 57%; specificity, 80%; AUC, 0.70), and PSA DT of 7.91 mo (sensitivity, 71%; specificity, 62%; AUC, 0.67). Conclusion: Patients with recurrent PCa under observation after a negative ⁶⁸Ga-PSMA-11 PET/CT scan with markedly elevated serum PSA levels and shorter PSA DT are more likely to have positive findings on repeat ⁶⁸Ga-PSMA-11 PET/CT.

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.

The tumor marker cancer antigen 15-3 (CA 15-3) is that most commonly used to monitor metastatic breast cancer during active therapy and surveillance for disease recurrence after treatment. The association of CA 15-3 and ¹⁸F-FDG PET/CT findings can be considered complementary, since any significant rise may indicate the presence of disease and imaging is able to map the tumor sites. Although current guidelines do not recommend the routine performance of CA 15-3 in asymptomatic patients being followed up after definitive breast cancer treatment, most oncologists perform serial assessment of the tumor markers as part of routine follow-up of patients. The aim of this study was to evaluate the correlation between CA 15-3 levels and ¹⁸F-FDG PET/CT scan findings in patients with recurrent breast cancer. Methods: This was a cross-sectional study with data collected retrospectively. Patients being evaluated for breast cancer recurrence with ¹⁸F-FDG PET/CT imaging and CA 15-3 level were included. Evaluation of the association between CA 15-3 levels and ¹⁸F-FDG PET/CT scan findings was then done. Results: In total, 154 cases were included in this study; 62 patients had recurrence (positive) on the ¹⁸F-FDG PET/CT scans, whereas 92 patients had normal (negative) findings on follow-up ¹⁸F-FDG PET/CT scans. There was an association between CA 15-3 levels and the presence or absence of recurrence on ¹⁸F-FDG PET/CT scans, with 84.4% (27/32) of patients who had elevated CA 15-3 levels having disease recurrence on ¹⁸F-FDG PET/CT and 84.4% (27/32) of patients who had elevated CA 15-3 levels having disease recurrence on ¹⁸F-FDG PET/CT as well as a correlation with the burden of metastases. Most patients with disease recurrence on ¹⁸F-FDG PET/CT, however, had normal CA 15-3 levels. Conclusion: Higher CA 15-3 levels correlate with breast cancer recurrence on ¹⁸F-FDG PET/CT as well as with burden of metastasis. Notably, CA 15-3 levels within the reference range do not exclude breast cancer disease recurrence since more than half of patients with recurrence had normal CA 15-3 levels. ¹⁸F-FDG PET/CT should therefore be considered in patients with suspected breast cancer recurrence but normal CA 15-3 levels.

BARCELONA, Spain, Nov. 7, 2024 — Codee, a provider of software developer tools for automated code review and testing specializing in correctness, modernization and optimization of Fortran/C/C++ code, is pleased […]

The post Do IT Now and Codee Partner to Enhance Code Correctness, Modernization and Optimization appeared first on HPCwire.

Nov. 11, 2024 — University of Sydney quantum researchers Dominic Williamson and Nouédyn Baspin have revealed a new architecture for managing errors that emerge in the operation of quantum computers. Their […]

The post University of Sydney Scientists Unveil Quantum Code to Enhance Error Correction with Fewer Qubits appeared first on HPCwire.

Amy Coney Barrett succeeds the late Justice Ruth Bader Ginsburg in time to hear arguments in two cases being watched in the education community.

Nov. 12—Jarrett Gronski wasn't expecting to cry the morning before playing Wayne State. Like most athletes, the Bemidji State football team's senior running back has his pregame rituals. But that routine shook out a little differently before the Beavers' game against the Wildcats. John Gronski — Jarrett's father and a prolific running back for BSU back in the late 1980s — was officially ...