A single transcription factor is sufficient to induce and maintain secretory cell architecture

We hypothesized that basic helix–loop–helix (bHLH) MIST1 (BHLHA15) is a “scaling factor” that universally establishes secretory morphology in cells that perform regulated secretion. Here, we show that targeted deletion of MIST1 caused dismantling of the secretory apparatus of diverse exocrine cells. Parietal cells (PCs), whose function is to pump acid into the stomach, normally lack MIST1 and do not perform regulated secretion. Forced expression of MIST1 in PCs caused them to expand their apical cytoplasm, rearrange mitochondrial/lysosome trafficking, and generate large secretory granules. Mist1 induced a cohort of genes regulated by MIST1 in multiple organs but did not affect PC function. MIST1 bound CATATG/CAGCTG E boxes in the first intron of genes that regulate autophagosome/lysosomal degradation, mitochondrial trafficking, and amino acid metabolism. Similar alterations in cell architecture and gene expression were also caused by ectopically inducing MIST1 in vivo in hepatocytes. Thus, MIST1 is a scaling factor necessary and sufficient by itself to induce and maintain secretory cell architecture. Our results indicate that, whereas mature cell types in each organ may have unique developmental origins, cells performing similar physiological functions throughout the body share similar transcription factor-mediated architectural “blueprints.

Ultrafast all-optical second harmonic wavefront shaping

Optical communication can be revolutionized by encoding data into the orbital angular momentum of light beams. However, state-of-the-art approaches for dynamic control of complex optical wavefronts are mainly based on liquid crystal spatial light modulators or miniaturized mirrors, which suffer from intrinsically slow (mu s-ms) response times. Here, we experimentally realize a hybrid meta-optical system that enables complex control of the wavefront of light with pulse-duration limited dynamics. Specifically, by combining ultrafast polarization switching in a WSe2 monolayer with a dielectric metasurface, we demonstrate second harmonic beam deflection and structuring of orbital angular momentum on the femtosecond timescale. Our results pave the way to robust encoding of information for free space optical links, while reaching response times compatible with real-world telecom applications.Enhancing the data encoding into the orbital angular momentum of light beams could enable faster and more efficient optical communications. This work demonstrates complex control of the second harmonic wavefront with dynamics solely limited by the pulse duration

Which type of tobacco product warning imagery is more effective and sustainable over time?

Objective This study examined smokers’ responses to pictorial health warnings (PHWs) with different types of imagery under natural exposure conditions. Methods Adult smokers from online panels in Canada (n=2357), Australia (n=1671) and Mexico (n=2537) were surveyed every 4 months from 2012 to 2013. Participants were shown PHWs on packs in their respective countries and asked about: (1) noticing PHWs; (2) negative affects towards PHWs; (3) believability of PHWs; (4) PHW-stimulated discussions; and (5) quit motivation due to PHWs. Country-specific generalised estimating equation models regressed these outcomes on time (ie, survey wave), PHW imagery type (ie, symbolic representations of risk, suffering from smoking and graphic depictions of bodily harm) and interactions between them. Results In all countries, PHW responses did not significantly change over time, except for increased noticing PHWs in Canada and Mexico, increased negative affect in Australia and decreased negative affect in Mexico. For all outcomes, symbolic PHWs were rated lower than suffering and graphic PHWs in Canada (the only country with symbolic PHWs). Graphic PHWs were rated higher than suffering PHWs for negative affect (all countries), discussions (Canada) and quit motivation (Australia). Suffering PHWs were rated higher than graphic PHWs for noticing PHWs (Canada), believability (all countries), discussions (AustraliaandMexico) and quit motivation (Mexico). Changes in noticing, believability and discussions varied somewhat by imagery type across countries. Conclusions The different PHW imagery appears to have different pathways of influence on adult smokers. Reactions to specific PHWs are similar over 1–2 years, suggesting that wear-out of PHW effects is due to decreased attention rather than the diminishing effectiveness of content

Effects of Erxian decoction, a Chinese medicinal formulation, on serum lipid profile in a rat model of menopause

<p>Abstract</p> <p>Background</p> <p>The prevalence and risk of cardiovascular disease increase after menopause in correlation with the progression of abnormality in the serum lipid profile and the deprivation of estrogen. <it>Erxian </it>decoction (EXD), a Chinese medicinal formulation for treating menopausal syndrome, stimulates ovarian estrogen biosynthesis. This study investigates whether EXD improves the serum lipid profile in a menopausal rat model.</p> <p>Methods</p> <p>Twenty-month-old female Sprague Dawley rats were treated with EXD and its constituent fractions. Premarin was administered for comparison. After eight weeks of treatment, rats were sacrificed and the serum levels of total cholesterol, triglyceride, high-density-lipoprotein cholesterol and low-density-lipoprotein cholesterol were determined. The hepatic protein levels of 3-hydroxy-3-methyl-glutaryl-CoA reductase and low-density-lipoprotein receptor were assessed with Western blot.</p> <p>Results</p> <p>The serum levels of total cholesterol and low-density-lipoprotein cholesterol were significantly lower in the EXD-treated group than in the constituent fractions of EXD or premarin groups. However, the serum levels of triglyceride and high-density-lipoprotein cholesterol were not significantly different from the control groups. Results from Western blot suggest that EXD significantly down-regulated the protein level of 3-hydroxy-3-methyl-glutaryl-CoA reductase and up-regulated low-density-lipoprotein receptor. <b>Conclusion </b>EXD improves serum lipid profile in a menopausal rat model through the suppression of the serum levels of total cholesterol and low-density-lipoprotein cholesterol, possibly through the down-regulation of the 3-hydroxy-3-methyl-glutaryl-CoA and up-regulation of the low-density-lipoprotein receptor.</p

CD36 maintains the gastric mucosa and associates with gastric disease

The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd3

A randomized phase 2 study of paclitaxel and carboplatin with or without conatumumab for first-line treatment of advanced non-small-cell lung cancer

Introduction: This study evaluated the efficacy, safety, and pharmacokinetics of conatumumab combined with paclitaxel-carboplatin (PC) as first-line treatment for advanced non-small-cell lung cancer (NSCLC). Methods: Patients (aged >18 years) with previously untreated advanced or recurrent NSCLC were randomized 1: 1: 1 (stratified by Eastern Cooperative Oncology Group performance status and disease stage) to receive up to six 3-week cycles of PC combined with conatumumab (arm 1, 3 mg/kg; arm 2, 15 mg/kg) or placebo (arm 3) every 3 weeks. The primary endpoint was progression-free survival (PFS). This study is registered with ClinicalTrials.gov (NCT00534027). Results: Between August 8, 2007 and April 9, 2009, 172 patients were randomized (arm 1, n = 57; arm 2, n = 56; arm 3, n = 59). Median PFS was 5.4 months (95% confidence interval [CI] 4.1-6.3) in arm 1 (hazard ratio [HR] 0.84 [95% CI 0.57-1.24]; p = 0.41), 4.8 months (95% CI 3.2-6.5) in arm 2 (HR 0.93 [0.64-1.35]; p = 0.57), and 5.5 months (95% CI 4.3-5.7) in arm 3. There was an interaction between tumor histology and the effect of conatumumab on PFS (squamous HR 0.47 [0.23-0.94]; nonsquamous HR 1.08 [0.74-1.57]; interaction p = 0.039). The most common grade of three or more adverse events were neutropenia, anemia, and thrombocytopenia. There was no evidence of pharmacokinetic interactions between conatumumab and PC. Of 158 patients assessable for FCGR3A polymorphisms, conatumumab treatment was associated with a trend toward longer overall survival (HR 0.72 [0.43-1.23]) among V-allele carriers (V/V or F/V; n = 54) but not among F-allele homozygotes (n = 34; HR 1.37 [0.66-2.86]). Conclusion: Although well tolerated, the addition of conatumumab to PC did not improve outcomes in unselected patients with previously untreated advanced NSCLC

CD36 maintains the gastric mucosa and associates with gastric disease.

The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36-/-), with Cd36 deletion in parietal cells (PC-Cd36-/-) or in endothelial cells (EC-Cd36-/-). CD36 expresses on corpus ECs, on PC basolateral membranes, and in gastrin and ghrelin cells. Stomachs of Cd36-/- mice have altered gland organization and secretion, more fibronectin, and inflammation. Tissue respiration and mitochondrial efficiency are reduced. Phospholipids increased and triglycerides decreased. Mucosal repair after injury is impaired in Cd36-/- and EC-Cd36-/-, not in PC-Cd36-/- mice, and is due to defect of progenitor differentiation to PCs, not of progenitor proliferation or mature PC dysfunction. Relevance to humans is explored in the Vanderbilt BioVu using PrediXcan that links genetically-determined gene expression to clinical phenotypes, which associates low CD36 mRNA with gastritis, gastric ulcer, and gastro-intestinal hemorrhage. A CD36 variant predicted to disrupt an enhancer site associates (p < 10-17) to death from gastro-intestinal hemorrhage in the UK Biobank. The findings support role of CD36 in gastric tissue repair, and its deletion associated with chronic diseases that can predispose to malignancy