Relationship Between Product Features and the Prices of e-Cigarette Devices Sold in Web-Based Vape Shops: Comparison Study Using a Linear Regression Model.

BACKGROUND: Open-system electronic cigarette (EC) product features, such as battery capacity, maximum output wattage, and so forth, are major components that drive product costs and may influence use patterns. Moreover, continued innovation and monitoring of product features and prices will provide critical information for designing appropriate taxation policies and product regulations. OBJECTIVE: This study will examine how product features are associated with the prices of devices sold in web-based vape shops. METHODS: We draw samples from 5 popular, US-based, web-based vape shops from April to August 2022 to examine starter kits, device-only products, and e-liquid container-only products. We implemented a linear regression model with a store-fixed effect to examine the association between device attributes and prices. RESULTS: EC starter kits or devices vary significantly by type, with mod prices being much higher than pod and vape pen prices. The prices of mod starter kits were even lower than those of mod devices, suggesting that mod starter kits are discounted in web-based vape shops. The price of mod kits, mod device-only products, and pod kits increased as the battery capacity and output wattage increased. For vape pens, the price was positively associated with the volume size of the e-liquid container. On the other hand, the price of pod kits was positively associated with the number of containers. CONCLUSIONS: A unit-based specific tax, therefore, will impose a higher tax burden on lower-priced devices such as vape pens or pod systems and a lower tax burden on mod devices. A volume- or capacity-based specific tax on devices will impose a higher tax burden on vape pens with a larger container size. Meanwhile, ad valorem taxes pegged to wholesale or retail prices would apply evenly across device types, meaning those with advanced features such as higher battery capacities and output wattage would face higher rates. Therefore, policy makers could manipulate tax rates by device type to discourage the use of certain device products.

Preclinical characterization of a novel investigational monoclonal antibody CM313 with potent CD38-positive cell killing activity.

Introduction: CM313 is currently under clinical investigation for treatments of multiple myeloma, systemic lupus erythematosus, and immune thrombocytopenia. We aimed to report the preclinical profile of the novel therapeutic anti-CD38 monoclonal antibody (mAb) CM313, with an emphasis on the difference with other CD38-targeting mAb. Methods: The binding of CM313 to CD38 recombinant protein across species was assessed using ELISA. The binding of CM313 to CD38-positive (CD38+) cells was detected using flow cytometry assays. CM313-induced complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and apoptosis on different CD38+ cells were assessed by LDH release assays or flow cytometry assays. The effect of CM313 on CD38 enzymatic activity was measured using fluorescence spectroscopy. CM313 immunotoxicity in human blood was assessed using flow cytometry assays, ELISA, and LDH release assays. Anti-tumor activity of CM313 was assessed in multiple mouse xenograft models. Safety profile of CM313 were evaluated in cynomolgus monkeys and human CD38 transgenic (B-hCD38) mice. Results: There exist unique sequences at complementarity-determining regions (CDR) of CM313, which facilitates its affinity to CD38 is consistently higher across a spectrum of CD38+ cell lines than daratumumab. In vitro studies showed that CM313 induces comparable killing activity than daratumumab, including ADCC, CDC, ADCP, apoptosis induced by Fc-mediated cross-linking, and effectively inhibited the enzymatic activity of CD38. However, CM313 showed more potent CDC than isatuximab. In vivo, CM313 dose-dependently inhibited xenograft tumor growth, both as a monotherapy and in combination with dexamethasone or lenalidomide. Furthermore, CM313 was well tolerated with no drug-related clinical signs or off-target risks, as evidenced by 4-week repeat-dose toxicology studies in cynomolgus monkeys and B-hCD38 mice, with the later study showing no observed adverse effect level (NOAEL) of 300mg/kg once weekly. Discussion: CM313 is a novel investigational humanized mAb with a distinct CDR sequence, showing comparable killing effects with daratumumab and stronger CDC activity than isatuximab, which supports its clinical development.

Cost Comparison and Spending on Tobacco Products: Evidence from A Nationally Representative Sample of Adult E-Cigarette Users.

Background: Over 20 states and local jurisdictions in the U.S. have imposed e-cigarette taxes. It is important to evaluate how adult vapers, including those who also smoke respond to e-cigarette taxation. The purpose of this study is to examine factors associated with adult vapers' cost perception of e-cigarettes relative to cigarettes and budget allocations between two products. Methods: We recruited a nationally representative sample of 801 adult e-cigarette users in the U.S., who participated in an online survey in April and May 2023. Nested-ordered logit models and ordinary least squares regressions were used in the analysis. Results: On average, monthly e-cigarette spending was $82.22, and cigarette spending was $118.77 among dual users. Less frequent e-cigarette use and higher state-level e-cigarette taxes were associated with perceiving smoking as cheaper than vaping. Age and exclusive use of tank systems were associated with perceiving vaping as cheaper than smoking. Exclusive use of tank systems was also associated with lower e-cigarette spending. Adults who used e-cigarettes more frequently preferred to report weekly budget on e-cigarettes ( p < 0.01), and among dual users, everyday smokers preferred to report weekly (versus monthly) budget on cigarettes compared to someday smokers ( p < 0.001). Conclusion: Among US adult vapers, frequencies of tobacco use and e-cigarette device type are closely related to cost measures; and e-cigarette taxes are associated with cost perception of e-cigarettes relative to cigarettes, suggesting potential financial disincentive for vaping. Policymaker may consider imposing differential taxes by e-cigarette product types due to their different costs to consumers.

The association between excise taxes and smoking and vaping transitions-Findings from the 2016-2020 ITC United States surveys.

BACKGROUND: While a growing number of studies examined the effect of e-cigarette (EC) excise taxes on tobacco use behaviors using cross-sectional surveys or sales data, there are currently no studies that evaluate the impact of EC taxes on smoking and vaping transitions. METHODS: Using data from the US arm of the 2016-2020 International Tobacco Control Four Country Smoking and Vaping Survey (ITC 4CV), we employed a multinomial logit model with two-way fixed effects to simultaneously estimate the impacts of cigarette/EC taxes on the change in smoking and vaping frequencies. RESULTS: Our benchmark model suggests that a 10 % increase in cigarette taxes led to an 11 % reduction in smoking frequencies (p < 0.01), while EC taxes did not have a significant effect on smoking frequencies. CONCLUSION: Our findings suggest that increasing cigarette taxes may serve as an effective means of encouraging people who smoke to cut back on smoking or quit smoking. The impact of increasing EC taxes on smoking transitions is less certain at this time.

How to Identify e-Cigarette Brands Available in the United States During 2020-2022: Development and Usability Study.

BACKGROUND: Prior studies have demonstrated that the e-cigarette market contains a large number of brands. Identifying these existing e-cigarette brands is a key element of market surveillance, which will further assist in policy making and compliance checks. OBJECTIVE: To facilitate the surveillance of the diverse product landscape in the e-cigarette market, we constructed a semantic database of e-cigarette brands that have appeared in the US market as of 2020-2022. METHODS: In order to build the brand database, we searched and compiled e-cigarette brands from a comprehensive list of retail channels and sources, including (1) e-liquid and disposable brands sold in web-based stores, (2) e-cigarette brands sold in brick-and-mortar stores and collected by the Nielsen Retail Scanner Data, (3) e-cigarette brands compiled by Wikipedia, (4) self-reported e-cigarette brands from the 2020 International Tobacco Control Four-Country Smoking and Vaping (ITC 4CV) US survey, and (5) e-cigarette brands on Twitter. We also estimated the top 5 e-cigarette brands by sales volume in brick-and-mortar stores, by the frequency and variety of offerings in web-based shops, and by the frequency of self-reported brands from the 2020 ITC 4CV US survey. RESULTS: As of 2020-2022, a total of 912 e-cigarette brands have been sold by various retail channels. During 2020-2022, the top 5 brands are JUUL, vuse, njoy, blu, and logic in brick-and-mortar stores; blu, king, monster, twist, and air factory for e-liquids in web-based stores; hyde, pod mesh, suorin, vaporlax, and xtra for disposables sold in web-based stores; and smok, aspire, vaporesso, innokin, and eleaf based on self-reported survey data. CONCLUSIONS: As the US Food and Drug Administration enforces the premarket tobacco market authorization, many e-cigarette brands may become illegal in the US market. In this context, how e-cigarette brands evolve and consolidate in different retail channels will be critical for understanding the regulatory impacts on product availability. Our semantic database of e-cigarette brands can serve as a useful tool to monitor product and marketplace development, conduct compliance checks, assess manufacturers' marketing behaviors, and identify regulatory impacts.

How do users compare the costs between nicotine vaping products and cigarettes? Findings from the 2016-2020 International Tobacco Control United States surveys.

BACKGROUND AND AIMS: Nicotine vaping products (NVPs) can potentially help adult tobacco users quit smoking. This study evaluated how adult consumers compare the costs between NVPs and cigarettes. METHOD: We used data from the US arm of the 2016-2020 International Tobacco Control Four Country Smoking and Vaping (ITC 4CV) surveys to perform a multinomial logit model with two-way fixed effects to measure how perceived cost comparisons are associated with NVP and cigarette taxes, use patterns, NVP device types and individual sociodemographic factors. RESULTS: Higher cigarette taxes are associated with a greater likelihood of perceiving NVPs and cigarettes as costing the same for the overall population and among people who exclusively smoke, and a lower likelihood of perceiving NVPs as more expensive among people who exclusively vape, compared with lower cigarette taxes. Pre-filled cartridge and tank users are more likely to perceive NVPs as less expensive than cigarettes, compared with people who use other types of NVPs. The associations between taxes and perceived cost comparison were more pronounced among males, younger and low-income populations. CONCLUSIONS: Higher cigarette taxes are associated with perceived financial incentives for nicotine vaping products (NVPs) over cigarettes, whereas NVP taxes are not associated with perceived cost comparison between NVPs and cigarettes.

The Association Between the License Fee Increase and the Density of Tobacco Retailers in California-A Segmented Interrupted Time-Series Analysis by Income and Race/Ethnicity.

INTRODUCTION: On May 9, 2016, the State of California passed a law to increase the licensing fee for tobacco retailers from a one-time-only fee of $100 to an annual fee of $265, effective on June 9, 2016. This study investigates the association between this fee increase and retailer densities by neighborhood income and race/ethnicity characteristics. METHODS: We obtained quarterly data on the number of active tobacco retailer licenses from 2011 to 2020 in every zip code in California from the California Department of Tax and Fee Administration. These data were then linked to zip code-level income, race/ethnicity, and population measures. We used a single-group segmented interrupted time-series analysis to assess the association between the increase in licensing fees and retailer densities by neighborhood income and race/ethnicity. RESULTS: After the implementation of the annual licensing fees, the retailer density decreased both immediately and gradually. Specifically, the retailer density dropped by 0.47 in the first quarter following the intervention. Compared to the pre-intervention time trend, the retailer density decreased quarterly by 0.05. Furthermore, the impacts of increasing licensing fees were more pronounced in low-income and the majority Black zip codes. CONCLUSIONS: Given that higher smoking prevalence is associated with greater tobacco outlet density, the licensing fee increase could be an effective policy tool to reduce tobacco use among economically disadvantaged and minority Black communities, thereby addressing tobacco-use disparities. IMPLICATIONS: This study used the single-group segmented interrupted time-series analysis to assess the association between the licensing fee increase and tobacco retailer densities by neighborhood income and race/ethnicity. We found that this licensing fee increase was associated with reduced retailer densities and the total number of active retailers right after the implementation. We further found that the annual licensing fee policy had a continuous effect in reducing tobacco retailer densities in all zip codes. The impacts of increasing licensing fees were more pronounced in low-income and majority of Black zip codes.

Hyperbranched Dynamic Crosslinking Networks Enable Degradable, Reconfigurable, and Multifunctional Epoxy Vitrimer.

Degradation and reprocessing of thermoset polymers have long been intractable challenges to meet a sustainable future. Star strategies via dynamic cross-linking hydrogen bonds and/or covalent bonds can afford reprocessable thermosets, but often at the cost of properties or even their functions. Herein, a simple strategy coined as hyperbranched dynamic crosslinking networks (HDCNs) toward in-practice engineering a petroleum-based epoxy thermoset into degradable, reconfigurable, and multifunctional vitrimer is provided. The special characteristics of HDCNs involve spatially topological crosslinks for solvent adaption and multi-dynamic linkages for reversible behaviors. The resulting vitrimer displays mild room-temperature degradation to dimethylacetamide and can realize the cycling of carbon fiber and epoxy powder from composite. Besides, they have supra toughness and high flexural modulus, high transparency as well as fire-retardancy surpassing their original thermoset. Notably, it is noted in a chance-following that ethanol molecule can induce the reconstruction of vitrimer network by ester-exchange, converting a stiff vitrimer into elastomeric feature, and such material records an ultrahigh modulus (5.45 GPa) at -150 °C for their ultralow-temperature condition uses. This is shaping up to be a potentially sustainable advanced material to address the post-consumer thermoset waste, and also provide a newly crosslinked mode for the designs of high-performance polymer.

Hyperbranched Polyborosiloxanes: Non-traditional Luminescent Polymers with Red Delayed Fluorescence.

Non-traditional fluorescent polymers have attracted significant attention for their excellent biocompatibility and diverse applications. However, designing and preparing non-traditional fluorescent polymers that simultaneously possess long emission wavelengths and long fluorescence lifetime remains challenging. In this study, a series of novel hyperbranched polyborosiloxanes (P1-P4) were synthesized. As the electron density increases on the monomer diol, the optimal emission wavelengths of the P1-P4 polymers gradually red-shift to 510, 570, 575, and 640 nm, respectively. In particular, P4 not only exhibits red emission but also demonstrates delayed fluorescence with a lifetime of 9.73 µs and the lowest critical cluster concentration (1.76 mg/mL). The experimental results and theoretical calculations revealed that the synergistic effect of dual heteroatom-induced electron delocalization and through-space O⋅⋅⋅O and O⋅⋅⋅N interaction was the key factor contributing to the red-light emission with delayed fluorescence. Additionally, these polymers showed excellent potential in dual-information encryption. This study provides a universal design strategy for the development of unconventional fluorescent polymers with both delayed fluorescence and long-wavelength emission.

How cigarette excise tax pass-through to prices responds to the uptake and evolution of e-cigarettes (ECs).

BACKGROUND: How excise taxes are passed through to prices determines whether tax policies will be effective in changing smoking behaviours. Though previous literature has documented that cigarette taxes are overly shifted to prices, there is limited evidence on how cigarette tax pass-through to prices is affected by the uptake and evolution of e-cigarettes (ECs) in the US market. OBJECTIVE: This study investigates how cigarette excise tax pass-through rate varied by price levels (the 25th, 50th, and 75th percentile prices) and the uptake and evolution of ECs. METHODS: Tax pass-through rates were assessed using ordinary least squares regressions while controlling for state, year and month fixed effects. Different trends were then tested for the pre-EC uptake era (2006-2011), EC uptake era (2012-2016) and the evolution of nicotine salt-based ECs era (2017 and later). FINDINGS: Cigarette excise taxes were fully shifted to the 25th and 50th percentile prices and overly shifted to the 75th percentile prices at a 1:1.1 rate. While cigarette excise taxes had a continuous impact on raising prices, the tax pass-through rates were lower for lower priced cigarettes, and states imposed lower taxes. CONCLUSIONS: Continuing to raise cigarette taxes may be needed to create financial incentives to encourage people who smoke to switch to ECs. In addition, continuing to raise cigarette taxes and additional pricing policies such as price promotion restrictions are needed to increase retail prices and reduce price minimisation opportunities.

E3 ligase MG53 suppresses tumor growth by degrading cyclin D1.

Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors. Here we show that in colorectal and gastric cancer patients, MG53 is downregulated in more than 80% of tumors compared to the normal gastrointestinal tissues from the same patient, and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival. Mechanistically, MG53 catalyzes the K48-linked ubiquitination and subsequent degradation of cyclin D1. Thus, increased expression of MG53 leads to cell cycle arrest at G1, and thereby markedly suppresses cancer cell proliferation in vitro as well as tumor growth in mice with xenograft tumors or AOM/DSS induced-colorectal cancer. Consistently, MG53 deficiency results in accumulation of cyclin D1 protein and accelerates cancer cell growth both in culture and in animal models. These findings define MG53 as a tumor suppressor via facilitating cyclin D1 degradation, highlighting the therapeutic potential of targeting MG53 in treating cancers with dysregulated cyclin D1 turnover.

Nonconventional Luminescent Piperazine-Containing Hyperbranched Polysiloxanes with Pure n-electron.

Nonconventional luminogens with high quantum yield (QY) possess very potential applications in various fields. However, the preparation of such luminogens remains a great challenge. Herein, the first example of piperazine-containing hyperbranched polysiloxane exhibiting blue and green fluorescence is reported under the irradiation of different excitation wavelength and a high QY of 20.9%. The density functional theory (DFT) calculations and experimental results revealed that the through-space conjugation (TSC) within the clusters of N and O atoms is produced via the induction of multiple intermolecular hydrogen bonds and flexible SiO units, which is accountable for the fluorescence. Meanwhile, the introduction of the rigid piperazine units not only rigidifies the conformation, but also enhances the TSC. In addition, the fluorescence of both P1 and P2 shows concentration-, excitation-, and solvent-dependent emission, especially exhibits significant pH-dependent emission and obtains an ultrahigh QY of 82.6% at pH 5. The synthetic luminogens show excellent applications in fluorescence detection for Fe3+ and Co2+ , information encryption, and fluorescent film. This study provides a novel strategy to rationally design high-efficiency nonconventional luminogens.

The miR-183 Cluster: Biogenesis, Functions, and Cell Communication via Exosomes in Cancer.

Cancer is one of the leading causes of human death. MicroRNAs have been found to be closely associated with cancer. The miR-183 cluster, comprising miR-183, miR-96, and miR-182, is transcribed as a polycistronic miRNA cluster. Importantly, in most cases, these clusters promote cancer development through different pathways. Exosomes, as extracellular vesicles, play an important role in cellular communication and the regulation of the tissue microenvironment. Interestingly, the miR-183 cluster can be detected in exosomes and plays a functional regulatory role in tumor development. Here, the biogenesis and functions of the miR-183 cluster in highly prevalent cancers and their relationship with other non-coding RNAs are summarized. In addition, the miR-183 cluster in exosomes has also been discussed. Finally, we discuss the miR-183 cluster as a promising target for cancer therapy. This review is expected to provide a new direction for cancer treatment.

What types of e-liquid products were more likely to offer price promotions?

INTRODUCTION: The present study empirically examined the association between price discounts and product attributes of e-liquids sold by online retailers. METHODS: We analysed 14 000 e-liquid products from five major online e-cigarette retailers between April and May 2021 to determine the association between price discounts and product attributes such as nicotine level and form, flavour and vegetable glycerine/propylene glycol ratio. A fixed-effects model was used in the analysis and discounts were calculated in US cents/mL of e-liquid volume. RESULTS: Out of 14 407 e-liquid products, 92.5% were offered at a discounted price. On average, the price discount for the 13 324 products that had discounts was 16.84 cents/mL across the five stores. Among the three forms of nicotine (salt, freebase and nicotine free), salt e-liquids had the highest average price discount. CONCLUSION: Our findings suggest that e-liquids with salt nicotine have a higher average price discount when sold online, which may influence consumer purchasing behaviour. Further research is needed to assess the potential impact of these discounts on youth and adult tobacco use. Policymakers may consider implementing measures to limit online price discounts for e-liquids as a means of reducing sales among young people.

Source identification and apportionment of ambient particulate matter in Beijing using an advanced computer-controlled scanning electron microscopy (CCSEM) system.

The use of electron microscopy to analyze the morphology, composition, and sources of atmospheric particles has been studied extensively worldwide. However, in China, there are few studies on single-particle source analysis based on computer-controlled scanning electron microscopy (CCSEM) technology for a large number of particles, and the related technical methods need to be established and improved. In this study, ambient particulate matter (PM) was collected simultaneously from urban, suburban, and background areas of Beijing in spring 2018 and subsequently characterized using the IntelliSEM-EPAS™ technology (an advanced CCSEM software). The deposition velocity model was used to deduce the size distribution and calculate the concentration of ambient PM. Based on the k-means algorithm and empirical rules, all particles investigated were quantitatively apportioned to nine major sources, including soil/road dust, carbonates-silicates, carbonates, irregular carbonaceous particles, irregular iron oxides, combustion/industry, calcium sulfate, secondary particles, and salt-related particles. The size-resolved contributions (mass and number) of different sources were calculated. For example, soil/road dust (65.1 %), carbonate-silicate (16.1 %), and carbonate (7.1 %) were the top three sources contributing to PM10 mass. This study was the first localized application of IntelliSEM-EPAS technology in China, demonstrating its great promise in PM source apportionment. For further accurate and refined source apportionment, it is essential to build localized individual particle source profiles.

Hyperbranched Polyborate: A Non-conjugated Fluorescent Polymer with Unanticipated High Quantum Yield and Multicolor Emission.

Non-conjugated fluorescent polymers have attracted great attention due to their excellent biocompatibility and environmental friendliness. However, it remains a huge challenge to obtain a polymer with high fluorescence quantum yield (QY) and multicolor emission simultaneously. Herein, we reported three kinds of nonaromatic hyperbranched polyborates (P1-P3) with multicolor emission, surprisingly, P2 also exhibits an unanticipated high QY (54.1 %). The natural bond orbital (NBO) analysis and density functional theory (DFT) calculation results revealed that the synergistic effect of rigid BO3 planar and flexible carbon chain, as well as the through-space dative bond in supramolecular aggregate, were the key factors contributing to the ultrahigh QY of P2. Moreover, the applications of P2 in Fe3+ ions detection and cell imaging were also investigated. This work provides a new perspective for designing non-conjugated fluorescent polymers with both high QY and multicolor emission.

Kynurenine Pathway Metabolites as Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that deteriorates cognitive function. Patients with AD generally exhibit neuroinflammation, elevated beta-amyloid (Aß), tau phosphorylation (p-tau), and other pathological changes in the brain. The kynurenine pathway (KP) and several of its metabolites, especially quinolinic acid (QA), are considered to be involved in the neuropathogenesis of AD. The important metabolites and key enzymes show significant importance in neuroinflammation and AD. Meanwhile, the discovery of changed levels of KP metabolites in patients with AD suggests that KP metabolites may have a prominent role in the pathogenesis of AD. Further, some KP metabolites exhibit other effects on the brain, such as oxidative stress regulation and neurotoxicity. Both analogs of the neuroprotective and antineuroinflammation metabolites and small molecule enzyme inhibitors preventing the formation of neurotoxic and neuroinflammation compounds may have potential therapeutic significance. This review focused on the KP metabolites through the relationship of neuroinflammation in AD, significant KP metabolites, and associated molecular mechanisms as well as the utility of these metabolites as biomarkers and therapeutic targets for AD. The objective is to provide references to find biomarkers and therapeutic targets for patients with AD.

MG53 E3 Ligase-Dead Mutant Protects Diabetic Hearts From Acute Ischemic/Reperfusion Injury and Ameliorates Diet-Induced Cardiometabolic Damage.

Cardiometabolic diseases, including diabetes and its cardiovascular complications, are the global leading causes of death, highlighting a major unmet medical need. Over the past decade, mitsugumin 53 (MG53), also called TRIM72, has emerged as a powerful agent for myocardial membrane repair and cardioprotection, but its therapeutic value is complicated by its E3 ligase activity, which mediates metabolic disorders. Here, we show that an E3 ligase-dead mutant, MG53-C14A, retains its cardioprotective function without causing metabolic adverse effects. When administered in normal animals, both the recombinant human wild-type MG53 protein (rhMG53-WT) and its E3 ligase-dead mutant (rhMG53-C14A) protected the heart equally from myocardial infarction and ischemia/reperfusion (I/R) injury. However, in diabetic db/db mice, rhMG53-WT treatment markedly aggravated hyperglycemia, cardiac I/R injury, and mortality, whereas acute and chronic treatment with rhMG53-C14A still effectively ameliorated I/R-induced myocardial injury and mortality or diabetic cardiomyopathy, respectively, without metabolic adverse effects. Furthermore, knock-in of MG53-C14A protected the mice from high-fat diet-induced metabolic disorders and cardiac damage. Thus, the E3 ligase-dead mutant MG53-C14A not only protects the heart from acute myocardial injury but also counteracts metabolic stress, providing a potentially important therapy for the treatment of acute myocardial injury in metabolic disorders, including diabetes and obesity.

Functional and Adaptive Significance of Promoter Mutations That Affect Divergent Myocardial Expressions of TRIM72 in Primates.

Cis-regulatory elements play important roles in tissue-specific gene expression and in the evolution of various phenotypes, and mutations in promoters and enhancers may be responsible for adaptations of species to environments. TRIM72 is a highly conserved protein that is involved in energy metabolism. Its expression in the heart varies considerably in primates, with high levels of expression in Old World monkeys and near absence in hominids. Here, we combine phylogenetic hypothesis testing and experimentation to demonstrate that mutations in promoter are responsible for the differences among primate species in the heart-specific expression of TRIM72. Maximum likelihood estimates of lineage-specific substitution rates under local-clock models show that relative to the evolutionary rate of introns, the rate of promoter was accelerated by 78% in the common ancestor of Old World monkeys, suggesting a role for positive selection in the evolution of the TRIM72 promoter, possibly driven by selective pressure due to changes in cardiac physiology after species divergence. We demonstrate that mutations in the TRIM72 promoter account for the differential myocardial TRIM72 expression of the human and the rhesus macaque. Furthermore, changes in TRIM72 expression alter the expression of genes involved in oxidative phosphorylation, which in turn affects mitochondrial respiration and cardiac energy capacity. On a broader timescale, phylogenetic regression analyses of data from 29 mammalian species show that mammals with high cardiac expression of TRIM72 have high heart rate, suggesting that the expression changes of TRIM72 may be related to differences in the heart physiology of those species.

MiR-199a-5p suppresses non-small cell lung cancer via targeting MAP3K11.

MicroRNAs (miRNAs) comprise a class of short, non-coding RNAs that directly target 3'UTR of mRNA, causing subsequent degradation or suppression of translation. Here, we verified that miR-199a-5p was significantly down-regulated in mouse NSCLC tissues and human patient samples. To further study the function of miR-199a-5p, lentivirus system was adopted to construct stably over-expressing miR-199a-5p A549, SPC-A1 and H1299 cell lines. Then, miR-199a-5p played a tumor suppression role via directly targeting MAP3K11 gene in non-small cell lung cancer (NSCLC). Elevated miR-199a-5p suppressed cell proliferation and arrested cell cycle in G1 phase. We found that MAP3K11 was negatively correlated with miR-199a-5p in NSCLC patient tissues and mouse xenograft tumors. Our results suggest that miR-199a-5p together with its target gene MAP3K11 is a key factor and constitutes a complicated regulation network in NSCLC.