Numerous zinc ectoenzymes are metalated by zinc and activated in the compartments of the early secretory pathway before reaching their destination. Zn transporter (ZNT) proteins located in these compartments are essential for ectoenzyme activation. We have previously reported that ZNT proteins, specifically ZNT5–ZNT6 heterodimers and ZNT7 homodimers, play critical roles in the activation of zinc ectoenzymes, such as alkaline phosphatases (ALPs), by mobilizing cytosolic zinc into these compartments. However, this process remains incompletely understood. Here, using genetically-engineered chicken DT40 cells, we first determined that Zrt/Irt-like protein (ZIP) transporters that are localized to the compartments of the early secretory pathway play only a minor role in the ALP activation process. These transporters included ZIP7, ZIP9, and ZIP13, performing pivotal functions in maintaining cellular homeostasis by effluxing zinc out of the compartments. Next, using purified ALP proteins, we showed that zinc metalation on ALP produced in DT40 cells lacking ZNT5–ZNT6 heterodimers and ZNT7 homodimers is impaired. Finally, by genetically disrupting both ZNT5 and ZNT7 in human HAP1 cells, we directly demonstrated that the tissue-nonspecific ALP-activating functions of both ZNT complexes are conserved in human cells. Furthermore, using mutant HAP1 cells, we uncovered a previously-unrecognized and unique spatial regulation of ZNT5–ZNT6 heterodimer formation, wherein ZNT5 recruits ZNT6 to the Golgi apparatus to form the heterodimeric complex. These findings fill in major gaps in our understanding of the molecular mechanisms underlying zinc ectoenzyme activation in the compartments of the early secretory pathway.

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.

Recent studies using mouse models suggest that interaction between the gut microbiome and IL-17/IL-22 producing cells plays a role in the development of metabolic diseases. We investigated this relationship in humans using data from the prediabetes study of the Integrated Human Microbiome Project (iHMP). Specifically, we addressed the hypothesis that early in the onset of metabolic diseases there is a decline in serum levels of IL-17/IL-22, with concomitant changes in the gut microbiome. Clustering iHMP study participants on the basis of longitudinal IL-17/IL-22 profiles identified discrete groups. Individuals distinguished by low levels of IL-17/IL-22 were linked to established markers of metabolic disease, including insulin sensitivity. These individuals also displayed gut microbiome dysbiosis, characterized by decreased diversity, and IL-17/IL-22-related declines in the phylum Firmicutes, class Clostridia, and order Clostridiales. This ancillary analysis of the iHMP data therefore supports a link between the gut microbiome, IL-17/IL-22 and the onset of metabolic diseases. This raises the possibility for novel, microbiome-related therapeutic targets that may effectively alleviate metabolic diseases in humans as they do in animal models.

Over the last several years it has become clear that higher order assemblies on membranes, exemplified by signalosomes, are a paradigm for the regulation of many membrane signaling processes. We have recently combined two-color direct stochastic optical reconstruction microscopy (dSTORM) with the (Clus-DoC) algorithm that combines cluster detection and colocalization analysis to observe the organization of 5-lipoxygenase (5-LO) and 5-lipoxygenase–activating protein (FLAP) into higher order assemblies on the nuclear envelope of mast cells; these assemblies were linked to leukotriene (LT) C4 production. In this study we investigated whether higher order assemblies of 5-LO and FLAP included cytosolic phospholipase A2 (cPLA2) and were linked to LTB4 production in murine neutrophils. Using two- and three-color dSTORM supported by fluorescence lifetime imaging microscopy we identified higher order assemblies containing 40 molecules (median) (IQR: 23, 87) of 5-LO, and 53 molecules (62, 156) of FLAP monomer. 98 (18, 154) molecules of cPLA2 were clustered with 5-LO, and 77 (33, 114) molecules of cPLA2 were associated with FLAP. These assemblies were tightly linked to LTB4 formation. The activation-dependent close associations of cPLA2, FLAP, and 5-LO in higher order assemblies on the nuclear envelope support a model in which arachidonic acid is generated by cPLA2 in apposition to FLAP, facilitating its transfer to 5-LO to initiate LT synthesis.

In cyanobacteria, metabolic pathways that use the nitrogen-rich amino acid arginine play a pivotal role in nitrogen storage and mobilization. The N-terminal domains of two recently identified bacterial enzymes: ArgZ from Synechocystis and AgrE from Anabaena, have been found to contain an arginine dihydrolase. This enzyme provides catabolic activity that converts arginine to ornithine, resulting in concomitant release of CO2 and ammonia. In Synechocystis, the ArgZ-mediated ornithine–ammonia cycle plays a central role in nitrogen storage and remobilization. The C-terminal domain of AgrE contains an ornithine cyclodeaminase responsible for the formation of proline from ornithine and ammonia production, indicating that AgrE is a bifunctional enzyme catalyzing two sequential reactions in arginine catabolism. Here, the crystal structures of AgrE in three different ligation states revealed that it has a tetrameric conformation, possesses a binding site for the arginine dihydrolase substrate l-arginine and product l-ornithine, and contains a binding site for the coenzyme NAD(H) required for ornithine cyclodeaminase activity. Structure–function analyses indicated that the structure and catalytic mechanism of arginine dihydrolase in AgrE are highly homologous with those of a known bacterial arginine hydrolase. We found that in addition to other active-site residues, Asn-71 is essential for AgrE's dihydrolase activity. Further analysis suggested the presence of a passage for substrate channeling between the two distinct AgrE active sites, which are situated ∼45 Å apart. These results provide structural and functional insights into the bifunctional arginine dihydrolase–ornithine cyclodeaminase enzyme AgrE required for arginine catabolism in Anabaena.

VOLUME 295 (2020) PAGES 1898–1914Yichen Zhong's name was misspelled. The correct spelling is shown above.

This special issue focuses on Diabetes, Covid-19 and Inpatient Management.

Recorded April 3, 2020.

This podcast will cover:

1. Risk with Diabetes of Covid-19 and Complications of Covid-19
2. Management of Hyperglycemia during Covid-19 Infection
3. Sub-cutaneous Insulin for DKA
4. CGM in the Hospital Setting
5. Diabetes Education in the Hospital During Covid-19

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.

Presented by:

Irl Hirsch, MD, Professor of Medicine, University of Washington, Seattle

Guillermo E. Umpierrez, MD, CDE, Professor of Medicine, Emory University, Atlanta Georgia

This special issue focuses on Diabetes, Covid-19 and Inpatient Management.

Recorded April 14, 2020.

This podcast will cover:

1. Inpatient Medication Management for Persons Admitted with Diabetes
2. Outpatient Medication Management for Persons with Diabetes
   1. Hypoglycemic Medication Management
   2. ACE and ARBs
   3. NSAIDs

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.

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

Dr. Joshua Neumiller, Vice Chair & Allen I. White Distinguished Associate Professor of Pharmacotherapy at Washington State University

This special issue focuses on Answering Questions about Inpatient Care During Covid 19, a follow-up discussion to the Townhall meeting discussing inpatient care. 

Recorded April 15, 2020.

This podcast will cover:

1. Subcutaneous Insulin Infusions
2. CGM use in the inpatient setting
3. Insulin Infusion pumps in the inpatient setting
4. Inpatient Glycemic Control - what are the recommendations?
5. Oral Medications
6. Hydroxychloroquine adverse effects in persons with diabetes

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.

Presented by:

Robert Eckel, MD
ADA President, Medicine & Science

Irl Hirsch, MD
University of Washington

Mary Korytkowski, MD
University of Pittsburgh

Jamaica’s senior men’s ice hockey team’s historic championship win at last year’s Amerigol LATAM Cup is memorialised in a Canadian sports yearbook published earlier this year. The team copped the championship in its first international outing...

Invitation Only Research Event

Event participants

Leonid Gozman, President, Perspective Foundation

There’s a starfish in my tooth he says, A golden starfish nestling in the reef, Infecting the coral and, I’m in the deep blue ocean, Among sea creatures, Yellow and purple jellyfish, Undulating in the current, Stingrays swooping by, Luminescent seaweed hangs over caves, Like electric blue curtains, At a tatoo parlour. An octopus rakes […]

Customer Database Management Software, Customer Management Software, Customer Database Software in Mumbai, Customer Database Management Software in Pune, Customer Database Management Software in Ahmedabad, India.

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Salesfundaa is award-winning Order Management Software and Order Management Software company in Mumbai, Pune, Ahmedabad, India. We are providing cloud-based oredr management solution optimizes costs, dispatching, scheduling and reporting.

Research Event

Event participants

Dr Jon Gibbins, Senior Lecturer in the Department of Mechanical Engineering, Imperial College London
Jim Footner, Senior Climate Change Campaigner, Greenpeace

23 May 2011

Research Event

Event participants

Dr Fatima Denton, Director, Special Initiatives Division, UN Economic Commission for Africa
Dr Chukwumerije Okereke, Associate Professor, University of Reading
Douglas Brew, Director External Affairs, Communications and Sustainable Living for Africa, Unilever
Chair: Bob Dewar, Associate Fellow, Africa Programme, Chatham House

22 October 2015

Supreme Ventures Racing and Entertainment Limited, operators of Caymanas Track, has announced the re-opening of the main track, effective tomorrow. The company said in a press release on Thursday evening that the track will be opened for two days...

Multimorbidity presents a number of different challenges, for the patients living with the conditions, but also for the health professionals caring for them in systems that often are not designed with these more complex needs in mind. Emma Wallace, general practice lecturer, and Susan Smith, a professor of general practice at the Royal College of...

Bone pain is the most common type of pain from cancer and is present in around one third of patients with bone metastases, currently, improvements in cancer treatments mean that many patients are living with metastatic cancer for several years. Christopher Kane, NIHR academic clinical fellow in palliative medicine at Leeds University School of...

Some apps have the potential to encourage healthier habits and are accessible to most people, argues Iltifat Husain, but Des Spence notes the lack of any evidence of effectiveness and the potential for encouraging unnecessary anxiety. Read more about in our head to head "Can healthy people benefit from health apps?" -...

The future of health and social care looks certain to be a defining issue in the forthcoming UK general election. Social care has been subject to deep public spending cuts, raising concerns about the sustainability of services in the future. Whoever wins the next election will need to grapple with providing joined up health and social care...

Pleural effusions are common, with an estimated 1-1.5 million new cases in the United States and 200 000-250 000 in the United Kingdom each year. Rahul Bhatnagar, academic clinical lecturer at the University of Bristol, describes how pleural effusions may be investigated and treated in the community and secondary care, with a particular focus on...

Nick Oliver, consultant diabetologist at Imperial Healthcare NHS Trust and Philippa Cooper, who has type I diabetes, join us to explain how structured education works for patients, and give tips on self management. Read the full review: http://www.bmj.com/content/352/bmj.i998

Providing information to enable informed choices about healthcare sounds immediately appealing to most of us. But Minna Johansson, GP trainee and PhD student at the University of Gothenburg, argues that preventive medicine and expanding disease definitions have changed the ethical premises of informed choice and our good intentions may...

You’ll have read in a clinical trial “Most patients had an acceptable adverse-event profile.” Or that a drug “has a manageable and mostly reversible safety profile.” And that “the tolerability was good overall.” In this podcast, Bishal Gyawali (@oncology_bg) joins us to describe what events those terms were actually describing in cancer drug...

Burnout is a problem in healthcare - it’s a problem for individuals, those who experience it and decide to leave a career they formerly loved, but it’s also a problem for our healthcare system. Burnout is associated with an increase in medical errors, and poor quality of care. Fundamentally it’s a patient safety issue. But, unlike other patient...

In this week’s episode, we discuss bystander guilt, convergence, brain hacks and “how you can sneeze on someone’s brain from anywhere in the world”. How can GPs cope with the myriad worries around treating patients during the current pandemic, both on the frontline and in general practice? How do we recognise and break unhelpful anxious behaviour...

Steven M Haffner
Jun 1, 1992; 41:715-722
Original Article

Long-term hyperglycemia in patients with diabetes leads to human serum albumin (HSA) glycation, which may impair HSA function as a transport protein and affect the therapeutic efficacy of anticoagulants in patients with diabetes. In this study, a novel mass spectrometry approach was developed to reveal the differences in the profiles of HSA glycation sites between patients with diabetes and healthy subjects. K199 was the glycation site most significantly changed in patients with diabetes, contributing to different interactions of glycated HSA and normal HSA with two types of anticoagulant drugs, heparin and warfarin. An in vitro experiment showed that the binding affinity to warfarin became stronger when HSA was glycated, while HSA binding to heparin was not significantly influenced by glycation. A pharmacokinetic study showed a decreased level of free warfarin in the plasma of diabetic rats. A preliminary retrospective clinical study also revealed that there was a statistically significant difference in the anticoagulant efficacy between patients with diabetes and patients without diabetes who had been treated with warfarin. Our work suggests that larger studies are needed to provide additional specific guidance for patients with diabetes when they are administered anticoagulant drugs or drugs for treating other chronic diseases.

GEORGETOWN, Guyana, CMC – The Guyana government Friday confirmed that US$4.9 million had been deposited into the Natural Resources Fund as a result of the first royalty payment for the country’s crude oil. Finance Minister, Winston...

THE EDITOR, Madam: TO THE Jamaican Government: there are no trade laws that say you have to buy poison – foreign chicken, beef, produce and other agricultural staples are poisonous. They are chock-full of hormones, antibiotics, fillers, excess...

Invitation Only Research Event

Event participants

Paula Hodges QC, Partner; Head, Global Arbitration Practice, Herbert Smith Freehills
Stéphane Brabant, Partner; Chairman, Africa Practice Group, Herbert Smith Freehills

29 October 2014

The Ghanaian government has taken a number of important steps to reduce illegal logging and related trade but a number of enforcement and administrative challenges remain, as well as broader governance challenges including corruption.

Research Event

Event participants

Toby Fisher, Barrister, Landmark Chambers; Representative of the South African Human Rights Commission, Marikana Commission of Inquiry
Gary White, Director of Operations, Ineqe Group; Expert Witness on Policing, Marikana Commission of Inquiry
Chair: Muzong Kodi, Associate Fellow, Africa Programme

The Arizona Diamondbacks agreed to terms on a contract extension with manager Torey Lovullo on Tuesday.

¹⁸F-DCFPyL (2-(3-{1-carboxy-5-[(6-¹⁸F-fluoropyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) is a promising PET radiopharmaceutical targeting prostate-specific membrane antigen (PSMA). We present our experience with this single-academic-center prospective study evaluating the positivity rate of ¹⁸F-DCFPyL PET/CT in patients with biochemical recurrence (BCR) of prostate cancer (PC). Methods: We prospectively enrolled 72 men (52–91 y old; mean ± SD, 71.5 ± 7.2) with BCR after primary definitive treatment with prostatectomy (n = 42) or radiotherapy (n = 30). The presence of lesions compatible with PC was evaluated by 2 independent readers. Fifty-nine patients had scans concurrent with at least one other conventional scan: bone scanning (24), CT (21), MR (20), ¹⁸F-fluciclovine PET/CT (18), or ¹⁸F-NaF PET (14). Findings from ¹⁸F-DCFPyL PET/CT were compared with those from other modalities. Impact on patient management based on ¹⁸F-DCFPyL PET/CT was recorded from clinical chart review. Results: ¹⁸F-DCFPyL PET/CT had an overall positivity rate of 85%, which increased with higher prostate-specific antigen (PSA) levels (ng/mL): 50% (PSA < 0.5), 69% (0.5 ≤ PSA < 1), 100% (1 ≤ PSA < 2), 91% (2 ≤ PSA < 5), and 96% (PSA ≥ 5). ¹⁸F-DCFPyL PET detected more lesions than conventional imaging. For anatomic imaging, 20 of 41 (49%) CT or MRI scans had findings congruent with ¹⁸F-DCFPyL, whereas ¹⁸F-DCFPyL PET was positive in 17 of 41 (41%) cases with negative CT or MRI findings. For bone imaging, 26 of 38 (68%) bone or ¹⁸F-NaF PET scans were congruent with ¹⁸F-DCFPyL PET, whereas ¹⁸F-DCFPyL PET localized bone lesions in 8 of 38 (21%) patients with negative results on bone or ¹⁸F-NaF PET scans. In 8 of 18 (44%) patients, ¹⁸F-fluciclovine PET had located the same lesions as did ¹⁸F-DCFPyL PET, whereas 5 of 18 (28%) patients with negative ¹⁸F-fluciclovine findings had positive ¹⁸F-DCFPyL PET findings and 1 of 18 (6%) patients with negative ¹⁸F-DCFPyL findings had uptake in the prostate bed on ¹⁸F-fluciclovine PET. In the remaining 4 of 18 (22%) patients, ¹⁸F-DCFPyL and ¹⁸F-fluciclovine scans showed different lesions. Lastly, 43 of 72 (60%) patients had treatment changes after ¹⁸F-DCFPyL PET and, most noticeably, 17 of these patients (24% total) had lesion localization only on ¹⁸F-DCFPyL PET, despite negative results on conventional imaging. Conclusion: ¹⁸F-DCFPyL PET/CT is a promising diagnostic tool in the work-up of biochemically recurrent PC, given the high positivity rate as compared with Food and Drug Administration–approved currently available imaging modalities and its impact on clinical management in 60% of patients.

¹⁸F-PSMA-1007 is a novel prostate-specific membrane antigen (PSMA)–based radiopharmaceutical for imaging prostate cancer (PCa). The aim of this study was to compare the diagnostic accuracy of ¹⁸F-PSMA-1007 with ⁶⁸Ga-PSMA-11 PET/CT in the same patients presenting with newly diagnosed intermediate- or high-risk PCa. Methods: Sixteen patients with intermediate- or high-risk PCa underwent ¹⁸F-PSMA-1007 and ⁶⁸Ga-PSMA-11 PET/CT within 15 d. PET findings were compared between the 2 radiotracers and with reference-standard pathologic specimens obtained from radical prostatectomy. The Cohen -coefficient was used to assess the concordance between ¹⁸F-PSMA-1007 and ⁶⁸Ga-PSMA-11 for detection of intraprostatic lesions. The McNemar test was used to assess agreement between intraprostatic PET/CT findings and histopathologic findings. Sensitivity, specificity, positive predictive value, and negative predictive value were reported for each radiotracer. SUV_max was measured for all lesions, and tumor-to-background activity was calculated. Areas under receiver-operating-characteristic curves were calculated for discriminating diseased from nondiseased prostate segments, and optimal SUV cutoffs were calculated using the Youden index for each radiotracer. Results: PSMA-avid lesions in the prostate were identified in all 16 patients with an almost perfect concordance between the 2 tracers ( ranged from 0.871 to 1). Aside from the dominant intraprostatic lesion, similarly detected by both radiotracers, a second less intense positive focus was detected in 4 patients only with ¹⁸F-PSMA-1007. Three of these secondary foci were confirmed as Gleason grade 3 lesions, whereas the fourth was shown on pathologic examination to represent chronic prostatitis. Conclusion: This pilot study showed that both ¹⁸F-PSMA-1007 and ⁶⁸Ga-PSMA-11 identify all dominant prostatic lesions in patients with intermediate- or high-risk PCa at staging. ¹⁸F-PSMA-1007, however, may detect additional low-grade lesions of limited clinical relevance.