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Infection and inflammation induce hepcidin production, reducing intestinal iron uptake and hepatic iron export The relationship between hepcidin, iron, and inflammation in the context of aging is complex Future studies exploring these themes as a basis for liver dysfunction during asparaginase treatment are warranted.

The other transcriptional signature in adults reflects heightened capacity for detoxification and metabolic maintenance rather than de novo production of biomaterial. Maturity to adulthood is accompanied by 4—5-fold reduced pool of free tissue nucleotides as compared with juveniles The current study supports this by showing adults have significantly reduced circulating concentrations of the amino acids that serve as precursors to nucleotide synthesis.

Thus, adults must employ a stress remediation strategy that is fundamentally different from juveniles. MTHFD2 supplies formate as a source of carbon for purine nitrogenous bases 38 , In summary, the hepatic response to asparaginase differs with age although activation of the ISR is conserved during maturity to adulthood. Whereas lipid metabolism, oxidative stress defenses, amino acid metabolism, and inflammation are all processes regulated by the ISR, questions remain regarding how this regulation occurs during asparaginase exposure and whether activation of ISR by asparaginase is important for metabolic control by promoting ATF4 synthesis or via repression of mTOR complex 1 signaling as we recently detailed Future studies should explore the relationship between ISR activation and the pathways and processes that are functionally altered at each age.

Cages contained soft bedding and enrichment. Information about sexes of the animals utilized for the analysis of transcriptome is contained in Tables S1 and S2. Asparaginase was reconstituted from powder, and the reconstituted solution was analyzed for asparaginase activity as described 4. Whole livers were rapidly dissected and frozen in liquid nitrogen for the subsequent biochemical analyses. K, Mountain View, CA according to the manufacturer's instructions.

The images were taken with Fluorchem M imager ProteinSimple , and band densities were quantified using AlphaView software. Absorbance at nm was measured within 10 min. A standard curve was generated using an iron chloride solution according to the manufacturer's instructions. Serum alanine aminotransferase, alkaline phosphatase, serum triglyceride, and total cholesterol were measured using commercially available kits Pointe Scientific, Canton, MI.

Amino acid composition of the serum was determined as described previously The reads were mapped to the mouse genome mm10 with Bowtie 2 and TopHat version 2. Sequencing data for the 8-week cohort of mice were taken from 7. Differences in gene expression were determined using DEseq2 approach and evaluated according to treatment and age of the mice.

Expression values in Tables S1 and S2 are given in transcripts per million TPM , which was calculated according to the following formula,. Principal component analysis was performed on the log 2 -transformed counts normalized for library size as described in the DESeq2 vignette. Statistically significant comparisons main or interaction effects were further assessed using Tukey's HSD. All other measurements were analyzed with Wilcoxon rank-sum test through pairwise comparisons.

The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This article was selected as one of our Editor's Picks. This article contains Tables S1 and S2. National Center for Biotechnology Information , U. Journal List J Biol Chem v. J Biol Chem.

Published online Aug Inna A. Christina C. Emily T. William O. Grace L. William J. Tracy G. Author information Article notes Copyright and License information Disclaimer. Received Jun 21; Revised Aug 6. Abstract Asparaginase is an amino acid—depleting agent used to treat blood cancers. Keywords: eukaryotic initiation factor 2 eIF2 , amino acid, triglyceride, mRNA, development, age-dependent response, asparaginase, hepatic metabolism, integrated stress response, integrated stress response ISR.

Introduction Asparaginase is a drug used in the treatment of acute lymphoblastic leukemia in humans and various lymphoid malignancies in dogs and cats. Results Asparaginase reduces body growth and liver mass in juvenile mice only To identify age-specific hepatic responses following chronic asparaginase exposure, we utilized 2-, 8-, and week-old mice representing preweaned juveniles, young adults, and mature adults, respectively.

Open in a separate window. Figure 1. Age influences the liver transcriptome in response to asparaginase We next sought to examine how asparaginase affects the liver transcriptome across the three age groups Fig. Figure 2. Age influences hepatic lipid metabolism in response to asparaginase Asparaginase-induced liver steatosis was greatest in juveniles, displaying the highest liver triglycerides biochemically alongside intense Oil Red O staining in liver sections Fig. Figure 3. Age influences iron metabolism Examination of the juvenile-specific transcriptional changes in response to asparaginase also indicated increased iron sequestration Figs.

Figure 4. Asparaginase provokes inflammation and alters one-carbon metabolism in adult liver The adult-specific transcriptional response to asparaginase showed elevations in Saa1 and Saa2 transcripts, which encode serum amyloid A1 and A2 proteins Fig. Figure 5. Figure 6. Age alters liver gene expression independent of asparaginase In this analysis, more genes were differentially altered by age versus asparaginase Table S2.

Figure 7. Discussion This study aimed to explore the mechanistic basis for age-related differences to asparaginase in liver, complementing our portfolio of work detailing the metabolic and tissue-specific effects of asparaginase 2 , — 4 , 6 , 7 , 9 , Serum analysis Serum alanine aminotransferase, alkaline phosphatase, serum triglyceride, and total cholesterol were measured using commercially available kits Pointe Scientific, Canton, MI.

Author contributions T. Supplementary Material Supporting Information: Click here to view. References 1. Christ T. Phillipson-Weiner L. Liver Physiol. Wilson G. Reinert R. Bunpo P. Nikonorova I. Al-Baghdadi R. Lomelino C. Kimball S. Somel M. White R. BMC Genomics 16 , Conesa A. Genome Biol. Love M. Huang da W. Szklarczyk D. Nucleic Acids Res. Carraro V. PLoS One 5 , e Science , — Ord D, and Ord T. Cell Res. Jousse C.

Maida A. Averous J. Jin H. Kim B. Sikalidis A. Amino Acids 41 , — Dreesen O. Nucleus 4 , — Liu Z. Zughaier S. Evstafieva A. PLoS One 13 , e Kobayashi M. Haematologica , — PLoS One 3 , e Schiele F. Hijiya N. Lymphoma 57 , — Fan J. Nature , — Ben-Sahra I. Drug Metab.

Kwekel J. BMC Genomics 11 , Boissel N. Young Adult Oncol. Ben Tanfous M. Cancer Res. Orgel E. Caballero-Molada M. Braoudaki M. Schmidt P. Bolla R. Ageing Dev. Pedley A. Trends Biochem. Koufaris C. Cancer Metab. Hedayati M. Hyperthermia 34 , — Concern about the possibility of tighter U. Just this week, Van Eck Associates Corp.

There is also a buzz around Ethereum, the most-actively used blockchain in the world, which is set for a network upgrade that would allow it to process a similar number of transactions as Mastercard Inc. The shift to the new system could curb the total supply of Ether, whose price has quadrupled so far this year.

But that would be followed by a larger drop in the cryptocurrency, he said. Updates prices in the sixth paragraph. For more articles like this, please visit us at bloomberg. To flesh out Biden's tax plan, the Tax Policy Center TPC analyzed the many separate things that have been said about how tax rules would change.

Sentiment is on the rise as the annus horribilis winds to an end. And so, investors are looking forward to Two big factors in market uncertainty are on their way to resolving themselves. First, COVID vaccines are in the works, and two major drug companies have announced that vaccines will be available in a matter of months. The prospect of relief from the coronavirus and a divided government unable to enact extreme or controversial measures promises us a degree of stability that will be welcome.

These are buy-rated equities, with double-digit upside potential for the coming year. LendingTree, Inc. The company offers borrowers options to shop for competitive rates, loan terms, and various financing products. Among the offerings, from multiple financing sources, are credit cards, deposit accounts, and insurance products.

In the third quarter, the company showed mixed fiscal results. Covering this stock for Needham, 5-star analyst Mayank Tandon — rated 66 overall out of more than 7, stock pros — is upbeat despite the recent turndown after the Q3 results. Allegro is new to the stock markets, having held its IPO just this past October.

Vijay Rakesh, 5-star analyst with Mizuho, is clearly bullish on this newly public company. Allegro's xMR sensors and power ICs drive technology platform leadership and enable better performance, accuracy, and control for the growing EV market and Industry 4.

Out of 6 analysts polled in the last 3 months, all 6 are bullish on ALGM. The company boasts over 55 major insurers and more than 62, providers incorporating its service into their networks, giving access to more than 80 million potential patients.

AmWell is another newcomer to the markets. Over In its first quarter trading as a public company, AmWell reported several gains in key metrics. And the company registered over 1. The increase was driven primarily by providers employed by, or affiliated with, AMWL's health systems and payor clients… As the number of providers on the network grows, so does the value of the network; network expansion makes it easier for patients to find the right provider and for providers to find the right patient.

American and Canadian governments provide many of the same types of services for those in retirement, but the subtle differences between the two countries are worth noting. By Bob Ciura with Sure Dividend. The U. The potential for a double-dip recession could bring about another downturn in the stock market. For risk-averse investors, it may make sense to buy high-quality dividend stocks in this climate of uncertainty. For this reason, we recommend income investors looking for stability, consider the Dividend Aristocrats.

Such a long track record of annual dividend increases proves a company's ability to withstand recessions. The following three stocks are all on the list of Dividend Aristocrats. Its most important individual product is Humira, a multi-purpose pharmaceutical that was the top-selling drug in the world last year. AbbVie has performed very well over the course of Revenue was boosted by the Allergan acquisition, as well as growth from new products.

The stock has a high dividend yield of 5. AbbVie stock also appears to be undervalued, trading for a price-to-earnings ratio of 9. This is a fairly low multiple for a highly profitable and growing business. AbbVie's low valuation is likely due to uncertainty regarding its flagship product Humira, which is now facing biosimilar competition in Europe and will lose patent protection in the U.

But AbbVie has long prepared for this by investing in its own new products, and by the Allergan acquisition. This means that if AbbVie's valuation expanded from 8. Walgreens has been under pressure on many fronts, not just the coronavirus pandemic but also from a longer-running downturn for physical retail. Internet-based retailers such as Amazon. This trend was already taking place heading into , and the coronavirus has only accelerated the shift to online shopping.

Still, Walgreens remains highly profitable and continues to grow sales. On October 15th, Walgreens reported Q4 and full-year results for the period ending August 31st, For the quarter, sales increased 2. On a per-share basis, adjusted EPS decreased For the fiscal year, sales increased 2. The company anticipates a recovery in the upcoming year, with fiscal guidance that calls for low single-digit growth in adjusted EPS.

Continuing to grow sales and earnings, albeit at a modest rate, would still allow Walgreens to increase its dividend each year, as it has done for 45 consecutive years. Shares yield 4. The company recorded more than 5 million total domestic wireless net adds along with over 1 million postpaid net additions. Another promising growth catalyst is 5G rollout. This means valuation expansion could boost future shareholder returns by approximately 4.

Including the 7. Benzinga does not provide investment advice. All rights reserved. The Nasdaq hit a high as growth led Wednesday. AMD and Shopify are among several stocks flashing buy signals. But a key gauge suggests investors are getting excessively bullish. When a stock starts dropping, investors have to ask two questions.

First, why it's dropping? Is something wrong with it? Or is it just facing a storm of circumstance, but is otherwise sound? If the latter, then the second question comes into play. Has this stock hit bottom? Lately, some of these analysts have been tapping several apparent down-and-out equities as prime candidates for strong gains.

Employers, insurance brokers, health plans, and retail partnerships all offer benefits to consumers of various stripes — and Benefitfocus offers a tech solution to make benefit administration easy. The company offers a software platform specifically designed to handle the HR and data aspects of benefits programs, from enrollment to management.

This niche can be a two-edged sword, however. In good times, with benefit programs swinging, everyone will want in — but in bad times, Benefitfocus has found itself unable to regain traction. At the same time, there were positive developments. Lincoln Financial Group and PayActive joined Benefitfocus as catalog suppliers, and the company held its first open enrollment with the University of Texas system.

These quarterly results came as Benefitfocus brought in new management. These are major moves, that portend a new outlook at the top.

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They are hotter than a poblano but not terribly so. After getting us to them, a chili rellano with the poblano taste too much like a stuffed green pepper. You are all wrong. Aquachile is a Chilean fish farming company. And yes, there is also an Oaxaca regional pepper called chile de agua.

But it also discusses in more detail the shrimp dish. Champulines a Oaxacan delacacy.. Similar to poblanos. A little more heat, are similar to a bana pepper as well. Found on tlayudas. Or relleno. If im not mistaken campechanas are a giant ant found only in Oaxaca highest regions of ciera del norte..

I like the smaller ones the big ones are to meaty.. Sign up for our newsletter to receive the latest tips, tricks, recipes and more, sent twice a week. By signing up, you agree to our Terms of Use and acknowledge the data practices in our Privacy Policy. You may unsubscribe at any time. General Discussion. Gift Guide. Log In Sign Up. Want to stay up to date with this post? It falls under the jurisdiction of Al-Kasom Regional Council. The uptick in rock-throwing and other attacks along this segment of the highway, and recently similar attacks closer to Arad, signals an ominous change in the local population.

Younger men are no longer heeding the words of the Council of Sheiks and their parents who lived in peace with their Jewish neighbors have difficultly controlling their children. But some of the communities are also under closer scrutiny. Hura is not the only one. Agitators from the Northern Branch of the now-outlawed Islamic Movement made their way straight to Kuseifa as well, another Bedouin town closer to Arad, at the start of the terror wave last October. Within days, Arad residents were shocked to encounter stone-throwing attacks at the entrance to their city — an experience some had never had, one that others had not seen since the days of the second intifada more than a decade ago.

Jews are outnumbered in this region. All of you finger trigger, U. Afterall, simplistic black and white answers and suggestions, always work for and your children if you are lucky to have them. Good Luck! Why can't the police use "undercover" tactics and catch these criminals?

Also, inform the mayors of these villages, that the IDF will demolish the home of anyone caught. Thanks for this informative article. I did not realize that there were problems so close to where we live. I pray it can be stopped and that peace will continue. It is sad about the damage that has been done to cars. Thankfully no one has been injured. Scan this QR code to visit this page online:. This advertisement will close in seconds Or click here to close it.

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