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PET/CT imaging with a 18F-labeled galactodendritic unit in a galectin-1 overexpressing orthotopic bladder cancer model

Galectins are carbohydrate-binding proteins overexpressed in bladder cancer (BCa) cells. Dendritic galactose moieties have a high affinity for galectin-expressing tumor cells. We radiolabeled a dendritic galactose carbohydrate with fluorine-18 – 18F-labeled galactodendritic unit 4 – and examined its potential in imaging urothelial malignancies. Methods: The 18F-labeled 1st generation galactodendritic unit 4 was obtained from its tosylate precursor. We conducted in vivo studies in galectin-expressing UMUC3 orthotopic BCa model to determine the ability of 18F-labeled galactodendritic unit 4 to image BCa. Results: Intravesical administration of 18F-labeled galactodendritic unit 4 allowed specific accumulation of the carbohydrate radiotracer in galectin-1 overexpressing UMUC3 orthotopic tumors when imaged with PET. The 18F-labeled galactodendritic unit 4 was not found to accumulate in non-tumor murine bladders. Conclusion: The 18F-labeled galactodendritic unit 4 and similar analogs may be clinically relevant and exploitable for PET imaging of galectin-1 overexpressing bladder tumors.




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FDG-PET/CT identifies predictors of survival in patients with locally advanced cervical carcinoma and para-aortic lymph node involvement to increase treatment

Introduction: To use positron emission tomography coupled with computed tomography (18FDG-PET/CT) to identify a high-risk subgroup requiring therapeutic intensification among patients with locally advanced cervical cancer (LACC) and para-aortic lymph node (PALN) involvement. Methods: In this retrospective multicentric study, patients with LACC and PALN involvement concurrently treated with chemoradiotherapy and extended-field radiotherapy (EFR) between 2006 and 2016 were included. A senior nuclear medicine specialist in PET for gynaecologic oncology reviewed all 18FDG-PET/CT scans. Metabolic parameters including maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were determined for the primary tumour, pelvic lymph nodes and PALN. Associations between these parameters and overall survival (OS) were assessed with Cox's proportional hazards model. Results: Sixty-eight patients were enrolled in the study. Three-year OS was 55.5% (95% CI (40.8-68.0)). When adjusted for age, stage and histology, pelvic lymph node TLG, PALN TLG and PALN SUVmax were significantly associated with OS (p<0.005). Conclusion: FDG-PET/CT was able to identify predictors of survival in the homogeneous subgroup of patients with LACC and PALN involvement, thus allowing therapeutic intensification to be proposed.




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Intraoperative 68Gallium-PSMA Cerenkov Luminescence Imaging for surgical margins in radical prostatectomy - a feasibility study

Objective: To assess the feasibility and accuracy of Cerenkov Luminescence Imaging (CLI) for assessment of surgical margins intraoperatively during radical prostatectomy (RPE). Methods: A single centre feasibility study included 10 patients with high-risk primary prostate cancer (PC). 68Ga-PSMA PET/CT scans were performed followed by RPE and intraoperative CLI of the excised prostate. In addition to imaging the intact prostate, in the first two patients the prostate gland was incised and imaged with CLI to visualise the primary tumour. We compared the tumour margin status on CLI to postoperative histopathology. Measured CLI intensities were determined as tumour to background ratio (TBR). Results: Tumour cells were successfully detected on the incised prostate CLI images as confirmed by histopathology. 3 of 10 men had histopathological positive surgical margins (PSMs), and 2 of 3 PSMs were accurately detected on CLI. Overall, 25 (72%) out of 35 regions of interest (ROIs) proved to visualize a tumour signal according to standard histopathology. The median tumour radiance in these areas was 11301 photons/s/cm2/sr (range 3328 - 25428 photons/s/cm2/sr) and median TBR was 4.2 (range 2.1 – 11.6). False positive signals were seen mainly at the prostate base with PC cells overlaid by benign tissue. PSMA-immunohistochemistry (PSMA-IHC) revealed strong PSMA staining of benign gland tissue, which impacts measured activities. Conclusion: This feasibility showed that 68Ga-PSMA CLI is a new intraoperative imaging technique capable of imaging the entire specimen’s surface to detect PC tissue at the resection margin. Further optimisation of the CLI protocol, or the use of lower-energetic imaging tracers such as 18F-PSMA, are required to reduce false positives. A larger study will be performed to assess diagnostic performance.




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High Resolution Depth-Encoding PET Detector Module with Prismatoid Light Guide Array

Depth-encoding detectors with single-ended readout provide a practical, cost-effective approach for constructing high resolution and high sensitivity PET scanners. However, the current iteration of such detectors utilizes a uniform glass light guide to achieve depth-encoding, resulting in non-uniform performance throughout the detector array due to suboptimal intercrystal light sharing. We introduce Prism-PET, a single-ended readout PET detector module with a segmented light guide composed of an array of prismatoids that introduces enhanced, deterministic light sharing. Methods: High resolution PET detector modules were fabricated with single-ended readout of polished multicrystal lutetium yttrium orthosilicate (LYSO) scintillator arrays directly coupled 4-to-1 and 9-to-1 to arrays of 3.2 x 3.2 mm2 silicon photomultiplier pixels. Each scintillator array was coupled at the non-readout side to a light guide (one 4-to-1 module with a uniform glass light guide, one 4-to-1 Prism-PET module and one 9-to-1 Prism-PET module) to introduce intercrystal light sharing, which closely mimics the behavior of dual-ended readout with the additional benefit of improved crystal identification. Flood histogram data was acquired using a 3 MBq Na-22 source to characterize crystal identification and energy resolution. Lead collimation was used to acquire data at specific depths to determine depth-of-interaction (DOI) resolution. Results: The flood histogram measurements showed excellent and uniform crystal separation throughout the Prism-PET modules while the uniform glass light guide module had performance degradation at the edges and corners. A DOI resolution of 5.0 mm full width at half maximum (FWHM) and energy resolution of 13% were obtained in the uniform glass light guide module. By comparison, the 4-to-1 coupled Prism-PET module achieved 2.5 mm FWHM DOI resolution and 9% energy resolution. Conclusion: PET scanners based on our Prism-PET modules with segmented prismatoid light guide arrays can achieve high and uniform spatial resolution (9-to-1 coupling with ~ 1 mm crystals), high sensitivity, good energy and timing resolutions (using polished crystals and after applying DOI-correction), and compact size (depth-encoding eliminates parallax error and permits smaller ring-diameter).




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Factors predicting metastatic disease in 68Ga-PSMA-11 PET positive osseous lesions in prostate cancer

Bone is the most common site of distant metastatic spread in prostate adenocarcinoma. Prostate-specific membrane antigen uptake has been described in both benign and malignant bone lesions, which can lead to false-positive findings on 68Ga-prostate-specific membrane antigen-11 positron emission tomography (68Ga-PSMA-11 PET). The purpose of this study was to evaluate the diagnostic accuracy of 68Ga-PSMA-11 PET for osseous prostate cancer metastases and improve bone uptake interpretation using semi-quantitative metrics. METHODS: 56 prostate cancer patients (18 pre-prostatectomy, 38 biochemical recurrence) who underwent 68Ga-PSMA-11 PET/MRI or PET/CT examinations with osseous PSMA-ligand uptake were included in the study. Medical records were reviewed retrospectively by board-certified nuclear radiologists to determine true or false positivity based on a composite endpoint. For each avid osseous lesion, biological volume, size, PSMA-RADS rating, maximum standardized uptake value (SUVmax), and ratio of lesion SUVmax to liver, blood pool, and background bone SUVmax were measured. Differences between benign and malignant lesions were evaluated for statistical significance, and cut-off values for these parameters were determined to maximize diagnostic accuracy. RESULTS: Among 56 participants, 13 patients (22.8%) had false-positive osseous 68Ga-PSMA-11 findings and 43 patients (76.8%) had true-positive osseous 68Ga-PSMA-11 findings. Twenty-two patients (39%) had 1 osseous lesion, 18 (32%) had 2-4 lesions, and 16 (29%) had 5 or more lesions. Cut-off values resulting in statistically significant (p<0.005) differences between benign and malignant lesions were: PSMA-RADS ≥4, SUVmax ≥4.1, SUVmax ratio of lesion to blood pool ≥2.11, to liver ≥0.55, and to bone ≥4.4. These measurements corresponded to lesion-based 68Ga-PSMA-11 PET lesion detection rate for malignancy of 80%, 93%, 89%, 21%, 89%, and a specificity of 73%, 73%, 73%, 93%, 60%, respectively. CONCLUSION: PSMA-RADS rating, SUVmax, and SUVmax ratio of lesion to blood pool can help differentiate benign from malignant lesions on 68Ga-PSMA-11 PET. SUVmax ratio to blood pool above 2.2 is a reasonable parameter to support image interpretation and presented superior lesion detection rate and specificity when compared to visual interpretation by PSMA RADS. These parameters hold clinical value by improving diagnostic accuracy for metastatic prostate cancer on 68Ga-PSMA-11 PET/MRI and PET/CT.




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Letter to the Editor: Who was the first doctor to report the Covid-19 outbreak in Wuhan, China?




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Radioiodine Ablation of Remaining Thyroid Lobe in Patients with Differentiated Thyroid Cancer Treated by Lobectomy. A systematic review and meta-analysis.

Purpose: We aimed to conduct a systematic review and meta-analysis of studies reporting the performance of radioactive iodine therapy (131-I therapy) in differentiating thyroid cancer (DTC) patients requiring a completion treatment following lobectomy. We also evaluated the response to 131-I therapy according to 2015ATA guidelines and the adverse events. Methods: A specific search strategy was designed to find articles evaluating the use of I-131 in patients with evidence of DTC after lobectomy. PubMed, CENTRAL, Scopus and Web of Science were searched. The search was updated until January 2020, without language restriction. Data were cross-checked and any discrepancy discussed. A proportion meta-analysis (with 95%CI) was performed using the random-effects model. Meta-regressions on I-131 success were attempted. Results: The pooled success ablation rate was 69% with better results in patients receiving a single administration of about 3.7 GBq; high heterogeneity was found (I2 85%), and publication bias was absent (Egger test: P = 0.57). Incomplete structural responses were recorded in only 14 of 695 (2%) patients enrolled in our analysis. Incomplete biochemical responses were observed in 8 to 24% of patients, with higher rates (24%) in patients receiving low radioiodine activities (~1.1 GBq) and lower rates (from 8 to 18%) in patients receiving higher activities of radioiodine (~3.7 Gbq). Neck pain due to thyroiditis was reported in up to 18% of patients but, in most cases, symptoms resolved after oral paracetamol or a short course of prednisone. Conclusion: Lobar ablation with 131-I is effective especially when high 131I activities are used. However, the rate of incomplete biochemical response to initial treatment appears to be slightly higher than the classical scheme of initial treatment of DTC. "Radioisotopic lobectomy" should be considered for patients with low-to-intermediate risk DTC requiring completion treatment after lobectomy due to specific individual risk factors and/or patient’s preferences.




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Violent Extremist Groups in Africa: Local and Global Factors

Research Event

10 October 2019 - 5:00pm to 6:00pm

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Professor Stig Jarle Hansen, Professor, Norwegian University of Life Sciences; Author, Horn, Sahel and Rift: Fault-lines of the African Jihad
Bulama Bukarti, PhD Candidate, SOAS, University of London; Analyst, Tony Blair Institute for Global Change
Chair: Aoife McCullough, PhD Candidate, LSE

Islamist-inspired radical organizations in Africa have had a historical presence that extends well beyond the more recent emergence of groups including Al Shabaab, Boko Haram, Ansar Dine and Al-Qaeda in the Islamic Maghreb.
  
Despite more than three decades of international efforts to immobilize these organizations, they have proven to be adaptable and resilient, continuing to engage in insurgent campaigns against the state and employing terrorist violence against civilians. As they operate within and across different states and regions, the key to understanding this persistence – as well as the challenges of responding to it – often lies in the interaction between global dynamics and frequently underappreciated local factors.
 
At this event, which will launch the book Horn, Sahel and Rift: Fault-lines of the African Jihad, speakers will discuss key factors leading to the emergence of radical Islamist violence in Africa, its impact and the outlook ahead for African and other actors in addressing these issues.
 
THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED. 

Yusuf Hassan

Parliamentary and Media Outreach Assistant, Africa Programme
+44 (0) 20 7314 3645




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Somalia's Electoral Road-Map and Federal Relations

Research Event

15 November 2019 - 10:30am to 11:30am

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Abdirahman Abdishakur Warsame, Leader, Wadajir Party, Federal Republic of Somalia
Chair: Ahmed Soliman, Research Fellow, Africa Programme, Chatham House

As Somalia heads into an electoral cycle, its political landscape and federal picture appear unstable. The federal government is seeking to implement a feasible electoral model that will further the country’s democratic transition ahead of elections set for late 2020 and early 2021. An expanded and more inclusive process will require an agreement on election modalities and approved electoral law, the completion of the constitutional review and improved security provision.
 
Reconciliation and dialogue between the federal government and federal member states will be critical to making further progress on political, security and economic reforms. Recent contestations in the regions of Jubaland, Galmudug and Puntland do not bode well. Somalia’s political leaders are readying themselves for a tough contest with several opposition parties recently merging to form the Forum for National Parties (FNP), led by former President Sharif Sheikh Ahmed.
 
At this event, the Abdirahman Warsame, leader of the Wadajir Party, will analyse the political and federal transition in Somalia and give his perspective on how to improve the often-fractious relationship between the centre and the regions.
 
THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED.

Sahar Eljack

Programme Administrator, Africa Programme
+ 44 (0) 20 7314 3660




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AMPK Interactome Reveals New Function in Non-homologous End Joining DNA Repair [Research]

Adenosine monophosphate-activated protein kinase (AMPK) is an obligate heterotrimer that consists of a catalytic subunit (α) and two regulatory subunits (β and ). AMPK is a key enzyme in the regulation of cellular energy homeostasis. It has been well studied and is known to function in many cellular pathways. However, the interactome of AMPK has not yet been systematically established, although protein-protein interaction is critically important for protein function and regulation. Here, we used tandem-affinity purification, coupled with mass spectrometry (TAP-MS) analysis, to determine the interactome of AMPK and its functions. We conducted a TAP-MS analysis of all seven AMPK subunits. We identified 138 candidate high-confidence interacting proteins (HCIPs) of AMPK, which allowed us to build an interaction network of AMPK complexes. Five candidate AMPK-binding proteins were experimentally validated, underlining the reliability of our data set. Furthermore, we demonstrated that AMPK acts with a strong AMPK-binding protein, Artemis, in non-homologous end joining. Collectively, our study established the first AMPK interactome and uncovered a new function of AMPK in DNA repair.




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Human Hepatocyte Nuclear Factor 4-{alpha} Encodes Isoforms with Distinct Transcriptional Functions [Research]

HNF4α is a nuclear receptor produced as 12 isoforms from two promoters by alternative splicing. To characterize the transcriptional capacities of all 12 HNF4α isoforms, stable lines expressing each isoform were generated. The entire transcriptome associated with each isoform was analyzed as well as their respective interacting proteome. Major differences were noted in the transcriptional function of these isoforms. The α1 and α2 isoforms were the strongest regulators of gene expression whereas the α3 isoform exhibited significantly reduced activity. The α4, α5, and α6 isoforms, which use an alternative first exon, were characterized for the first time, and showed a greatly reduced transcriptional potential with an inability to recognize the consensus response element of HNF4α. Several transcription factors and coregulators were identified as potential specific partners for certain HNF4α isoforms. An analysis integrating the vast amount of omics data enabled the identification of transcriptional regulatory mechanisms specific to certain HNF4α isoforms, hence demonstrating the importance of considering all isoforms given their seemingly diverse functions.




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A peroxisome deficiency-induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway [Metabolism]

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.




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The mRNA levels of heat shock factor 1 are regulated by thermogenic signals via the cAMP-dependent transcription factor ATF3 [Metabolism]

Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses. We have recently reported a previously unappreciated role for HSF1 in the regulation of energy metabolism in fat tissues; however, whether HSF1 is differentially expressed in adipose depots and how its levels are regulated in fat tissues remain unclear. Here, we show that HSF1 levels are higher in brown and subcutaneous fat tissues than in those in the visceral depot and that HSF1 is more abundant in differentiated, thermogenic adipocytes. Gene expression experiments indicated that HSF1 is transcriptionally regulated in fat by agents that modulate cAMP levels, by cold exposure, and by pharmacological stimulation of β-adrenergic signaling. An in silico promoter analysis helped identify a putative response element for activating transcription factor 3 (ATF3) at −258 to −250 base pairs from the HSF1 transcriptional start site, and electrophoretic mobility shift and ChIP assays confirmed ATF3 binding to this sequence. Furthermore, functional assays disclosed that ATF3 is necessary and sufficient for HSF1 regulation. Detailed gene expression analysis revealed that ATF3 is one of the most highly induced ATFs in thermogenic tissues of mice exposed to cold temperatures or treated with the β-adrenergic receptor agonist CL316,243 and that its expression is induced by modulators of cAMP levels in isolated adipocytes. To the best of our knowledge, our results show for the first time that HSF1 is transcriptionally controlled by ATF3 in response to classic stimuli that promote heat generation in thermogenic tissues.




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Victorian Premier Daniel Andrews announces 175 new tech jobs for Melbourne

State government commits to five-year funding round as software company launches community centre and new jobs.




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Australian public service failing to share information: Public Sector Data Management report

A report has revealed stunning examples of public service inefficiency when it comes to releasing and managing data.




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$212,000 per public service IT contractor, and we're hiring more of them

Contractors cost 80 grand more than public servants, Finance Departments says, and the public service hires more of them.




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Metabolic regulation of the lysosomal cofactor bis(monoacylglycero)phosphate in mice

Gernot F. Grabner
Apr 29, 2020; 0:jlr.RA119000516v1-jlr.RA119000516
Research Articles




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Episode 84 - The Internet of Porn (IoP) Nectome, Galaxy S9 and UK porn age checks

The gang returns with an eclectic mix of tech chat. Can Nectome really download your thoughts - while killing you - to preserve your memories forever in the cloud? We didn't make this up.


Then we discuss the brand new Samsung Galaxy S9, phone cameras and crap AR before discussing how the UK should go about contracting a company to age check porn site users.

 

See acast.com/privacy for privacy and opt-out information.




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Metabolic regulation of the lysosomal cofactor bis(monoacylglycero)phosphate in mice [Research Articles]

Bis(monoacylglycero)phosphate (BMP), also known as lysobisphosphatidic acid (LBPA), is a phospholipid that promotes lipid sorting in late endosomes/lysosomes by activating lipid hydrolases and lipid transfer proteins. Changes in the cellular BMP content therefore reflect an altered metabolic activity of the endo-lysosomal system. Surprisingly, little is known about the physiological regulation of BMP. In this study, we investigated the effects of nutritional and metabolic factors on BMP profiles of whole tissues and  parenchymal and non-parenchymal cells. Tissue samples were obtained from fed, fasted, two-hours refed, and insulin-treated mice, as well as from mice housed at  5°C, 22°C, or 30°C. These tissues exhibited distinct BMP profiles, which were regulated by the nutritional state in a tissue-specific manner. Insulin treatment was not sufficient to mimic refeeding-induced changes in tissue BMP levels indicating that BMP metabolism is regulated by other hormonal or nutritional factors. Tissue fractionation experiments revealed that fasting drastically elevates BMP levels in hepatocytes and pancreatic cells. Furthermore, we observed that the BMP content in brown adipose tissue strongly depends on housing temperatures. In conclusion, our observations suggest that BMP concentrations adapt to the metabolic state in a tissue-and cell type-specific manner in mice. Drastic changes observed in hepatocytes, pancreatic cells, and brown adipocytes suggest that BMP possesses a role in the functional adaption to nutrient starvation and ambient temperature.




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Proteome and phosphoproteome analysis of brown adipocytes reveals that RICTOR loss dampens global insulin/AKT signaling [Research]

Stimulating brown adipose tissue (BAT) activity represents a promising therapy for overcoming metabolic diseases. mTORC2 is important for regulating BAT metabolism, but its downstream targets have not been fully characterized. In this study, we apply proteomics and phosphoproteomics to investigate the downstream effectors of mTORC2 in brown adipocytes. We compare wild-type controls to isogenic cells with an induced knockout of the mTORC2 subunit RICTOR (Rictor-iKO) by stimulating each with insulin for a 30-minute time course. In Rictor-iKO cells, we identify decreases to the abundance of glycolytic and de novo lipogenesis enzymes, and increases to mitochondrial proteins as well as a set of proteins known to increase upon interferon stimulation. We also observe significant differences to basal phosphorylation due to chronic RICTOR loss including decreased phosphorylation of the lipid droplet protein perilipin-1 in Rictor-iKO cells, suggesting that RICTOR could be involved with regulating basal lipolysis or droplet dynamics. Finally, we observe mild dampening of acute insulin signaling response in Rictor-iKO cells, and a subset of AKT substrates exhibiting statistically significant dependence on RICTOR.




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Lebanon: Futile Victory

1 June 2008 , Number 3

For the third time in less than two years, Beirut has been turned into a battleground, with Hizbollah and the opposition taking over the city. The government and its allies did not engage militarily, managing to avoid civil war and becoming a regional battlefield. The Arab League is now trying to sort things out, highlighting the regional and international dimensions.

Nadim Shehadi

Associate Fellow, Middle East and North Africa Programme




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Victory and Memory: WW2 Narratives in Modern Day Russia and Ukraine

Invitation Only Research Event

11 May 2020 - 4:00pm to 5:30pm
Add to Calendar
Nina Tumarkin, Kathryn Wasserman Davis Professor of Slavic Studies; Professor of History; Director, Russian Area Studies Program, Wellesley College
Georgiy Kasianov, Head, Department of Contemporary History and Politics, Institute of History of Ukraine, National Academy of Sciences of Ukraine
Chair: Robert Brinkley, Chairman, Steering Committee, Ukraine Forum, Chatham House
In 2020 the world commemorates the 75th anniversary of the end of World War II. The Russian government has organized a wide range of activities to mark the USSR’s victory, aiming to raise the already prominent role of the USSR to a new level. Moscow also uses its narrative about the war as a propaganda tool. Ukraine, which suffered disproportionally huge human losses and material destruction during WWII, is departing from its Soviet legacy by focusing commemorative efforts on honouring the victims of WWII rather than on glorifying victory. 
 
This event will analyze the evolution of the WWII narratives in Russia and Ukraine in recent years. The panellists will discuss the role of those narratives in shaping national discourses and their implications for the countries' respective futures.
 
This event will be held on the record.

Anna Morgan

Administrator, Ukraine Forum
+44 (0)20 7389 3274

Department/project




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Metallopeptidase Stp1 activates the transcription factor Sre1 in the carotenogenic yeast Xanthophyllomyces dendrorhous [Research Articles]

Xanthophyllomyces dendrorhous is a basidiomycete yeast known as a natural producer of astaxanthin, a carotenoid of commercial interest because of its antioxidant properties. Recent studies indicated that X. dendrorhous has a functional SREBP pathway involved in the regulation of isoprenoid compound biosynthesis, which includes ergosterol and carotenoids. SREBP is a major regulator of sterol metabolism and homeostasis in mammals; characterization in fungi also provides information about its role in the hypoxia adaptation response and virulence. SREBP protease processing is required to activate SREBP pathway functions in fungi. Here, we identified and described the STP1 gene, which encodes a metallopeptidase of the M50 family involved in the proteolytic activation of the transcription factor Sre1 of the SREBP pathway, in X. dendrorhous. We assessed STP1 function in stp1 strains derived from the wild-type and a mutant of ergosterol biosynthesis that overproduces carotenoids and sterols. Bioinformatic analysis of the deduced protein predicted the presence of characteristic features identified in homologs from mammals and fungi. The stp1 mutation decreased yeast growth in the presence of azole drugs and reduced transcript levels of Sre1-dependent genes. This mutation also negatively affected the carotenoid- and sterol-overproducing phenotype. Western blot analysis demonstrated that Sre1 was activated in the yeast ergosterol biosynthesis mutant and that the stp1 mutation introduced in this strain prevented Sre1 proteolytic activation. Overall, our results demonstrate that STP1 encodes a metallopeptidase involved in proteolytic activation of Sre1 in X. dendrorhous, contributing to our understanding of fungal SREBP pathways.




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Problem Notes for SAS®9 - 60332: A SAS 9.4 installation in Update mode notifies you about unwritable files in the "SASHome\SASWebApplicationServer" directory

When you run SAS Deployment Wizard to install or update SAS 9.4 software, the file system is examined. If any files that the wizard needs to delete are found to be locked, they are reported as unwritable f




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Linking risk factors and outcomes in autism spectrum disorder: is there evidence for resilience?




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Lactogens Reduce Endoplasmic Reticulum Stress-induced Rodent and Human {beta}-cell Death and Diabetes Incidence in Akita Mice

Diabetes occurs due to a loss of functional β-cells, resulting from β-cell death and dysfunction. Lactogens protect rodent and human β-cells in vitro and in vivo against triggers of β-cell cytotoxicity relevant to diabetes, many of which converge onto a common pathway, endoplasmic reticulum (ER) stress. However, whether lactogens modulate the ER stress pathway is unknown. This study examines if lactogens can protect β-cells against ER stress and mitigate diabetes incidence in Akita mice, a rodent model of ER stress-induced diabetes, akin to neonatal diabetes in humans. We show that lactogens protect INS1 cells, primary rodent and human β-cells in vitro against two distinct ER stressors, tunicamycin and thapsigargin, through activation of the JAK2/STAT5 pathway. Lactogens mitigate expression of pro-apoptotic molecules in the ER stress pathway that are induced by chronic ER stress in INS1 cells and rodent islets. Transgenic expression of placental lactogen in β-cells of Akita mice drastically reduces the severe hyperglycemia, diabetes incidence, hypoinsulinemia, β-cell death, and loss of β-cell mass observed in Akita littermates. These are the first studies in any cell type demonstrating lactogens modulate the ER stress pathway, causing enhanced β-cell survival and reduced diabetes incidence in the face of chronic ER stress.




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The Effects of B1344, a Novel Fibroblast Growth Factor 21 Analog, on Nonalcoholic Steatohepatitis in Nonhuman Primates

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting PEGylated FGF21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy, and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease, administration of B1344 via subcutaneous injection for eleven weeks caused a profound reduction of hepatic steatosis, inflammation and fibrosis, and amelioration of liver injury and hepatocyte death as evidenced by liver biopsy and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkey, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, administration of B1344 were performed in mice fed with methionine and choline deficiency diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis at a dose-dependent manner. These results provide preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.




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SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation [Protein Synthesis and Degradation]

SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes.




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A Legionella effector kinase is activated by host inositol hexakisphosphate [Enzymology]

The transfer of a phosphate from ATP to a protein substrate, a modification known as protein phosphorylation, is catalyzed by protein kinases. Protein kinases play a crucial role in virtually every cellular activity. Recent studies of atypical protein kinases have highlighted the structural similarity of the kinase superfamily despite notable differences in primary amino acid sequence. Here, using a bioinformatics screen, we searched for putative protein kinases in the intracellular bacterial pathogen Legionella pneumophila and identified the type 4 secretion system effector Lpg2603 as a remote member of the protein kinase superfamily. Employing an array of biochemical and structural biology approaches, including in vitro kinase assays and isothermal titration calorimetry, we show that Lpg2603 is an active protein kinase with several atypical structural features. Importantly, we found that the eukaryote-specific host signaling molecule inositol hexakisphosphate (IP6) is required for Lpg2603 kinase activity. Crystal structures of Lpg2603 in the apo-form and when bound to IP6 revealed an active-site rearrangement that allows for ATP binding and catalysis. Our results on the structure and activity of Lpg2603 reveal a unique mode of regulation of a protein kinase, provide the first example of a bacterial kinase that requires IP6 for its activation, and may aid future work on the function of this effector during Legionella pathogenesis.




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Risk Factors for Diabetic Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study

Barbara H. Braffett
May 1, 2020; 69:1000-1010
Complications




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Predictors of Postpartum Diabetes in Women With Gestational Diabetes Mellitus

Kristian Löbner
Mar 1, 2006; 55:792-797
Pathophysiology




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Diabetes in China: Epidemiology and Genetic Risk Factors and Their Clinical Utility in Personalized Medication

Cheng Hu
Jan 1, 2018; 67:3-11
Perspectives in Diabetes




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Humble Bochy to get well-deserved victory lap

Bruce Bochy announced on Monday that his 25th season as a manager -- his 13th in an absurdly successful run with the Giants -- would be his last. In making the announcement, Bochy is going to give all of us the opportunity to say thanks during a 2019 season that will be something of a victory lap whether he likes it or not.




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The war on drugs has failed: doctors should lead calls for drug policy reform




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Doctors face manslaughter charge for failing to raise alarm over killer nurse




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POSTPONED: Supporting Civic Space: The Role and Impact of the Private Sector

Invitation Only Research Event

16 March 2020 - 11:00am to 5:00pm

Chatham House | 10 St James's Square | London | SW1Y 4LE

A healthy civic space is vital for an enabling business environment. In recognition of this, a growing number of private sector actors are challenging, publicly or otherwise, the deteriorating environment for civic freedoms.

However, this corporate activism is often limited and largely ad hoc. It remains confined to a small cluster of multinationals leaving potential routes for effective coordination and collaboration with other actors underexplored.

This roundtable will bring together a diverse and international group of business actors, civil society actors and foreign policy experts to exchange perspectives and experiences on how the private sector can be involved in issues around civic space. The meeting will provide an opportunity to explore the drivers of – and barriers to – corporate activism, develop a better understanding of existing initiatives, identify good practice and discuss practical strategies for the business community.

This meeting will be the first of a series of roundtables at Chatham House in support of initiatives to build broad alliances for the protection of civic space. 

Attendance at this event is by invitation only. 

PLEASE NOTE THIS EVENT IS POSTPONED UNTIL FURTHER NOTICE. 

Jacqueline Rowe

Programme Assistant, International Law Programme
020 7389 3287




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Chile After the October Uprising

Invitation Only Research Event

13 February 2020 - 8:00am to 9:30am

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Andrés Velasco, Dean of the School of Public Policy, London School of Economics and Political Science
Robert Funk, Assistant Professor of Political Science, University of Chile; Visiting Senior Fellow at the School of Public Policy, London School of Economics and Political Science
Chair: Melissa MacEwen, Manager, Energy, Environment and Resources Programme 

The outbreak of popular discontent in Chile in October of last year caught many observers by surprise. What began as a protest against a metro fare hike has transformed into widespread rejection of the economic and political model in place since the return to democracy in 1990, accompanied with unprecedented violence which raises questions about the state's ability to maintain rule of law. 

Professor Andrés Velasco, Dean of the School of Public Policy at the LSE, and Dr Robert Funk, Assistant Professor of Political Science at the University of Chile will join us for a discussion on the causes of the current protest.

What are the prospects for reform and a return to normality? Is this the end of the much-lauded Chilean model?

Event attributes

Chatham House Rule

US and Americas Programme




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Virtual Roundtable: Tectonic Plates of 2020 – Developments in the US Presidential Race

Invitation Only Research Event

18 March 2020 - 1:00pm to 1:45pm

Event participants

John Zogby, Founder and Senior Partner, John Zogby Strategies
Chair: Dr Lindsay Newman, Senior Research Fellow, US and Americas Programme, Chatham House

This event is part of the Inaugural Virtual Roundtable Series on the US, Americas and the State of the World and will take place virtually only. Participants should not come to Chatham House for these events.

US and Americas Programme




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Diabetes Core Update – October 2019

Diabetes Core Update is a monthly podcast that presents and discusses the latest clinically relevant articles from the American Diabetes Association’s four science and medical journals – Diabetes, Diabetes Care, Clinical Diabetes, and Diabetes Spectrum. Each episode is approximately 20 minutes long and presents 5-6 recently published articles from ADA journals.

Intended for practicing physicians and health care professionals, Diabetes Core Update discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting.

This month we review articles on:

  1. Nasal Glucagon
  2. Incidence of type 2 diabetes in people with a history of hospitalization for major mental illness
  3. Achievement of Target A1C <7.0% after treatment with basal insulin in Randomized Controlled Trials and Clinical Practice
  4. Metformin effect on Coronary endothelial Dysfunction in prediabetic patients with stable angina
  5. Change in cardiovascular health risk and the development of type 2 diabetes and impaired fasting glucose
  6. Association between diabetes HbA1c, glycaemia and development of frailty in the elderly

For more information about each of ADA’s science and medical journals, please visit www.diabetesjournals.org.

Presented by:

Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health

John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Abington Jefferson Health




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Covid-19: Doctors face shortages of vital drugs, gases, and therapeutics, survey finds




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Victory and Memory: WW2 Narratives in Modern Day Russia and Ukraine

Invitation Only Research Event

11 May 2020 - 4:00pm to 5:30pm
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Nina Tumarkin, Kathryn Wasserman Davis Professor of Slavic Studies; Professor of History; Director, Russian Area Studies Program, Wellesley College
Georgiy Kasianov, Head, Department of Contemporary History and Politics, Institute of History of Ukraine, National Academy of Sciences of Ukraine
Chair: Robert Brinkley, Chairman, Steering Committee, Ukraine Forum, Chatham House
In 2020 the world commemorates the 75th anniversary of the end of World War II. The Russian government has organized a wide range of activities to mark the USSR’s victory, aiming to raise the already prominent role of the USSR to a new level. Moscow also uses its narrative about the war as a propaganda tool. Ukraine, which suffered disproportionally huge human losses and material destruction during WWII, is departing from its Soviet legacy by focusing commemorative efforts on honouring the victims of WWII rather than on glorifying victory. 
 
This event will analyze the evolution of the WWII narratives in Russia and Ukraine in recent years. The panellists will discuss the role of those narratives in shaping national discourses and their implications for the countries' respective futures.
 
This event will be held on the record.

Anna Morgan

Administrator, Ukraine Forum
+44 (0)20 7389 3274

Department/project




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Earth Observation, Risk Assessment and Global Change: Implications for the Insurance and Aerospace Sectors

Research Event

16 July 2008 - 2:00pm to 5:15pm

Chatham House, London

This event is organized by Chatham House and the Center for Strategic and International Studies (CSIS).

Keynote speaker:

  • Lindene Patton, Climate Product Officer, Zurich Financial Services
Other speaker highlights:
  • Alexis Livanos, Northrop Grumman
  • Sir David King, University of Oxford
  • Barend Van Bergen, KPMG
  • Mike Keebaugh,Raytheon
  • Peter Stott, UK Met Office
  • Trevor Maynard, Lloyd's
  • Shree Khare, Risk Management Solutions
  • Giovanni Rum, Group on Earth Observations
  • Greg Withee, US National Oceanic and Atmospheric Administration
  • Man Cheung, Marsh Ltd




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Actor Boy Awards pays tribute to those we lost - Event goes online Saturday

Choreographer and designer Barry Moncrieffe; actress Lois Kelly Miller; New York-based broadcaster Gil Bailey; and actor and teacher Carl Samuels will all be remembered with a special tribute at Saturday’s staging of the annual Actor Boy Awards....




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Hysterectomy and your sex life

A hysterectomy is a surgical procedure that’s done to cure serious problems of the uterus (womb), cervix or even the ovaries. Some women fear that having this procedure done will affect their sex life. Will it truly? Let’s find out. “There are...




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Cole: Arb win a bigger victory for players to come

By winning his arbitration case against the Astros, pitcher Gerrit Cole stands to make $2,075,000 more this season than if he'd lost. That's a significant victory for Cole, who will double his salary this year and make $13.5 million, and a significant victory for other players to come, the veteran pitcher said.




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Grumpy old doctors

Those who rise to the top in medicine see themselves as hardworking extroverts with a caring nature, suggests an unscientific analysis of the answers given by contributors to BMJ Confidential. But ask about their pet hates and another, less nurturing, side emerges. We gathered 6 former confidentialists in The BMJ studio to moan over mince...




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Should doctors recommend homeopathy?

A recent review by the Australian National Health and Medical Research Council concluded that “there are no health conditions for which there is reliable evidence that homeopathy is effective”, but Europe currently spends €1bn annually on such remedies - often at the recommendation of doctors. So a recent head to head debate in The BMJ asks,...




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The junior doctor protest

Thousands of NHS staff have demonstrated against the government’s threatened “imposition” of an “unsafe and unfair” contract for junior doctors. At a London rally on Saturday 17 October junior doctors and supporters noisily defended their trade union, as speakers accused England’s health secretary, Jeremy Hunt, of misleading the public about...




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The evidence on doctors strikes and patient harm

Doctors considering strike action may worry about the effect on patients. David Metcalfe and colleagues examine the evidence and find that “patients do not come to serious harm during industrial action provided that provisions are made for emergency care.” Read the full analysis: http://www.bmj.com/content/351/bmj.h6231




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Junior doctors second strike - from the picket line

This week, junior doctors in England have taken industrial action for the second time in as many months after failing to reach agreement with the government over their proposed new contract. Tom Moberley and Abi Rimmer, from BMJ Careers, went to the picket lines at Northwick Park Hospital, and University Hospital Lewisham to talk to the doctors,...