The hydrolysis of triglycerides in triglyceride-rich lipoproteins by LPL is critical for the delivery of triglyceride-derived fatty acids to tissues, including heart, skeletal muscle, and adipose tissues. Physiologically active LPL is normally bound to the endothelial cell protein glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), which transports LPL across endothelial cells, anchors LPL to the vascular wall, and stabilizes LPL activity. Disruption of LPL-GPIHBP1 binding significantly alters triglyceride metabolism and lipid partitioning. In this study, we modified the NanoLuc® Binary Technology split-luciferase system to develop a novel assay that monitors the binding of LPL to GPIHBP1 on endothelial cells in real time. We validated the specificity and sensitivity of the assay using endothelial lipase and a mutant version of LPL and found that this assay reliably and specifically detected the interaction between LPL and GPIHBP1. We then interrogated various endogenous and exogenous inhibitors of LPL-mediated lipolysis for their ability to disrupt the binding of LPL to GPIHBP1. We found that angiopoietin-like (ANGPTL)4 and ANGPTL3-ANGPTL8 complexes disrupted the interactions of LPL and GPIHBP1, whereas the exogenous LPL blockers we tested (tyloxapol, poloxamer-407, and tetrahydrolipstatin) did not. We also found that chylomicrons could dissociate LPL from GPIHBP1 and found evidence that this dissociation was mediated in part by the fatty acids produced by lipolysis. These results demonstrate the ability of this assay to monitor LPL-GPIHBP1 binding and to probe how various agents influence this important complex.

When you run 32-bit SAS on Windows and disconnect from the Oracle database server, you might see the error: "ERROR: ORACLE disconnect error: ORA-03135: connection lost contact."

When users are defined in multiple groups associated with grid options set mappings, the first grid option set that is returned by the metadata search chain takes precedence. Only one grid options set mapping is used

When you bulk load data into a Google BigQuery database, you might encounter this error: "Error while reading data, error message: CSV table encountered too many errors, giving up...Error detected while parsing row starting at position: 0...Data

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

Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.

The transcription factor forkhead box P3 (FOXP3) is a biomarker for regulatory T cells and can also be expressed in cancer cells, but its function in cancer appears to be divergent. The role of hepatocyte-expressed FOXP3 in hepatocellular carcinoma (HCC) is unknown. Here, we collected tumor samples and clinical information from 115 HCC patients and used five human cancer cell lines. We examined FOXP3 mRNA sequences for mutations, used a luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its tumor-inhibitory capability, and changed cellular responses to histone deacetylase (HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3 mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC.

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

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

Many chemicals and cellular processes cause oxidative stress that can damage lipids, proteins, or DNA (1). To quickly sense and respond to this ubiquitous threat, organisms have evolved enzymes that neutralize harmful oxidants such as reactive oxygen species and electrophilic compounds (including xenobiotics and their breakdown products) in cells.These antioxidant enzymes include GSH S-transferase (GST),2 NADPH:quinone oxidoreductase 1, thioredoxin, hemeoxygenase-1, and others (2, 3). Many of these proteins are commonly expressed in cells exposed to oxidative stress.The antioxidant response element (ARE) is a major regulatory component of this cellular stress response. The ARE is a conserved, 11-nucleotide-long DNA motif present in the 5'-flanking regions of many genes encoding antioxidant proteins. The laboratory of Cecil Pickett (Fig. 1) at the Merck Frosst Centre for Therapeutic Research in Quebec discovered ARE, a finding reported in the early 1990s in two JBC papers recognized as Classics here (4, 5).jbc;295/12/3929/F1F1F1Figure 1.Cecil Pickett (pictured) and colleagues first described the ARE motif, present in the 5' regions of many genes whose expression is up-regulated by oxidative stress and xenobiotics. Photo courtesy of Cecil Pickett.ARE's discovery was spurred in large part by Pickett's career choice. After completing a PhD in biology and a 2-year postdoc at UCLA in the mid-1970s, he began to work in the pharmaceutical industry.Recruited to Merck in 1978 by its then head of research and development (and later CEO), Roy Vagelos, “I became interested in how drug-metabolizing enzymes were induced by various xenobiotics,” Pickett says.According to Pickett, Vagelos encouraged researchers at the company...

Attack your assailant with the baguette, You are carrying in your hand. Soft weapon. Transgender toilet, Beat the crap out of the hoodlum, male Or female, Black or white, think Not you must explain, Why, during the attack Men should not wear, Flaming pink knickers, demand The sex of the person approaching, On the dark […]

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Four companies involved in one of America’s “largest price-fixing cases” are now behind the anti-malaria drug touted by Donald ‘The Great Impeached’ Trump as a snake-oil, cure-all treatment for COVID-19, caused by the novel coronavirus. Several...

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

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

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

Fertility awareness based methods of contraception are increasingly being used for pregnancy prevention. In the US, the proportion of contraceptive users who choose such methods has grown from 1% in 2008 to approximately 3% in 2014.  Relative to other methods of pregnancy prevention, however, substantial misinformation exists around fertility...

We're taking a break from the usual Talk Evidence to focus on the new corona virus that has emerged in China. With a brand new disease, we have to build our evidence base from scratch - basic virology, epidemiology, pathogenicity, transmissibility, and ultimately treatment are all unknowns. In this episode of Talk Evidence, we're trying to get...

Joachim Spranger
Mar 1, 2003; 52:812-817
Pathophysiology

KINGSTOWN, St Vincent, CMC – The St Vincent and the Grenadines Government has denied a United States-based airline permission to land, dashing hopes that an estimated 300 nationals employed with a US-based cruise line would have arrived home...

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

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

Jake Lamb's education at first base hit another checkpoint during Monday's initial full-squad workout when he went through bunt drills for the first time.

As the D-backs went through fielding drills Tuesday, Yasmany Tomas spent his time at first base rather than in the outfield.

PET using radiolabeled prostate-specific membrane antigen (PSMA) is now being more widely adopted as a valuable tool to evaluate patients with prostate cancer (PC). Recently, 3 different criteria for interpretation of PSMA PET were published: the European Association of Nuclear Medicine (EANM) criteria, the Prostate Cancer Molecular Imaging Standardized Evaluation criteria, and the PSMA Reporting and Data System. We compared these 3 criteria in terms of interreader, intrareader, and intercriteria agreement. Methods: Data from 104 patients prospectively enrolled in research protocols at our institution were retrospectively reviewed. The cohort consisted of 2 groups: 47 patients (mean age, 64.2 y old) who underwent Glu-NH-CO-NH-Lys-(Ahx)-[⁶⁸Ga(HBED-CC)] (⁶⁸Ga-PSMA11) PET/MRI for initial staging of biopsy-proven intermediate- or high-risk PC, and 57 patients (mean age, 70.5 y old) who underwent ⁶⁸Ga-PSMA11 PET/CT because of biochemically recurrent PC. Three nuclear medicine physicians independently evaluated all ⁶⁸Ga-PSMA11 PET/MRI and PET/CT studies according to the 3 interpretation criteria. Two of them reevaluated all studies 6 mo later in the same manner and masked to the initial reading. The Gwet agreement coefficient was calculated to evaluate interreader, intrareader, and intercriteria agreement based on the following sites: local lesion (primary tumor or prostate bed after radical prostatectomy), lymph node metastases, and other metastases. Results: In the PET/MRI group, interreader, intrareader, and intercriteria agreement ranged from substantial to almost perfect for any site according to all 3 criteria. In the PET/CT group, interreader agreement ranged from substantial to almost perfect except for judgment of distant metastases based on the PSMA Reporting and Data System (Gwet agreement coefficient, 0.57; moderate agreement), in which the most frequent cause of disagreement was lung nodules. Intrareader agreement ranged from substantial to almost perfect for any site according to all 3 criteria. Intercriteria agreement for each site was also substantial to almost perfect. Conclusion: Although the 3 published criteria have good interreader and intrareader reproducibility in evaluating ⁶⁸Ga-PSMA11 PET, there are some factors causing interreader disagreement. Further work is needed to address this issue.

In bacteria, the restart of stalled DNA replication forks requires the DNA helicase PriA. PriA can recognize and remodel abandoned DNA replication forks, unwind DNA in the 3'-to-5' direction, and facilitate the loading of the helicase DnaB onto the DNA to restart replication. Single-stranded DNA–binding protein (SSB) is typically present at the abandoned forks, but it is unclear how SSB and PriA interact, although it has been shown that the two proteins interact both physically and functionally. Here, we used atomic force microscopy to visualize the interaction of PriA with DNA substrates with or without SSB. These experiments were done in the absence of ATP to delineate the substrate recognition pattern of PriA before its ATP-catalyzed DNA-unwinding reaction. These analyses revealed that in the absence of SSB, PriA binds preferentially to a fork substrate with a gap in the leading strand. Such a preference has not been observed for 5'- and 3'-tailed duplexes, suggesting that it is the fork structure that plays an essential role in PriA's selection of DNA substrates. Furthermore, we found that in the absence of SSB, PriA binds exclusively to the fork regions of the DNA substrates. In contrast, fork-bound SSB loads PriA onto the duplex DNA arms of forks, suggesting a remodeling of PriA by SSB. We also demonstrate that the remodeling of PriA requires a functional C-terminal domain of SSB. In summary, our atomic force microscopy analyses reveal key details in the interactions between PriA and stalled DNA replication forks with or without SSB.

A limited number of fans will be allowed to enter ballparks for games in Taiwan for the first time this season as stay-at-home orders continue to loosen amid the coronavirus pandemic.

Playing in Taiwan once was a last option Justin Nicolino had to continue a professional baseball career. Now the former Miami Marlins pitcher is one of many ex-MLB players who provide entertainment for U.S. sports fans.

UFC 249 will be sandwiched between 14 live baseball broadcasts out of South Korea and Taiwan this weekend for American sports fans to watch as they wait for major sports leagues to return.

Joseph Tran
Oct 1, 2012; 30:173-178
Practical Pointers

OBJECTIVE

Type 2 diabetes mellitus (T2DM) is associated with dyslipidemia, but the detailed alterations in lipid species preceding the disease are largely unknown. We aimed to identify plasma lipids associated with development of T2DM and investigate their associations with lifestyle.

OBJECTIVE

Many patients with hyperglycemic crises present with combined features of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). The implications of concomitant acidosis and hyperosmolality are not well known. We investigated hospital outcomes in patients with isolated or combined hyperglycemic crises.

OBJECTIVE

Previous randomized trials found that treating periodontitis improved glycemic control in patients with type 2 diabetes (T2D), thus lowering the risks of developing T2D-related microvascular diseases and cardiovascular disease (CVD). Some payers in the U.S. have started covering nonsurgical periodontal treatment for those with chronic conditions, such as diabetes. We sought to identify the cost-effectiveness of expanding periodontal treatment coverage among patients with T2D.

OBJECTIVE

To analyze the differences in health care costs according to glycemic control in people with type 2 diabetes.

A "Shoeless" Joe Jackson baseball card from 1910 sold at auction for $492,000 this week.

The handout covers strategies for helping prevent the transmission of suspected respiratory disease in the dental health care setting and answers frequently asked questions related to the virus, based on guidelines from the Centers for Disease Control and Prevention.

OBJECTIVE

To determine the risk of cardiovascular disease (CVD), microvascular complications, and mortality in patients with type 2 diabetes who subsequently develop obstructive sleep apnea (OSA) compared with patients with type 2 diabetes without a diagnosis of OSA.

OBJECTIVE

To examine whether low baseline diastolic blood pressure (DBP) modifies the effects of intensive systolic blood pressure (SBP) lowering on cardiovascular outcomes in type 2 diabetes mellitus (T2DM).

With the U.S. administration calling for the United States to adopt a more “merit-based” immigrant selection system, this conversation focused on what policymakers should consider in designing—and managing—immigrant selection systems in a time of intense labor-market and demographic change.

Asian baseball, Grimes' baby, scary invasive insects -- how well did you follow the news this week? Take the UPI News Quiz for May 8, 2020.

MPI and OECD experts discuss what policymakers should consider in designing and managing immigrant selection systems in a time of intense labor-market and demographic change.

The Trump administration’s plan to create a "merit-based" U.S. immigration system, lessening the longstanding focus on family reunification in favor of more economic migrants, has met with a lackluster response from Democrats and Republicans alike. This Policy Beat article explores how the Trump proposal would reshape immigration to the United States, and how it compares to selection systems in other countries and past debates about changing the U.S. system.

With displacement at a record high, governments around the world are looking for ways to jumpstart, expand, or maximize the impact of their refugee resettlement programs. Yet the evidence base regarding the effectiveness of such programs is particularly thin. This report maps the monitoring and evaluation gaps that exist and identifies areas where further research could help inform policymakers' actions.

Marking the release of an MPI Europe report commissioned as part of the EU-FRANK project, this webinar examines critical gaps in the research and evaluation of refugee resettlement programs and recommendations for improving evidence gathering and knowledge sharing between resettlement countries.