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Introducing Instapaper 4.0 for iPad and iPhone

The lede here is that my pal, Marco, has just released the stellar new 4.0 version of his Instapaper suite.

This is fantastic news, and–as if you needed one more of Marco’s beta testers to say so–I do sincerely hope you’ll mark the occasion (and support his hard work) by purchasing the Instapaper iOS app(s). I promise you’ll be treating yourself to a massive update to an already excellent product.

Now, it’s fortunate and appropriate that you’ll be hearing this advice at length from a lot of people this week. Because, if it’s not already obvious, Marco’s little app (and its associated services) enjoys a rabid fanbase of sundry paragraph cultists who are as eager as I am to spread the word; and, yes, we do want you to join the Reading Nerd cult.

But, I also want to mark the occasion by adding a few thoughts on exactly what Instapaper has done, and continues to do, for me. (As you may already know, I’m a big Marco fan.)

Thing is, I want to tell you how Marco has made a magical machine for people who have decided to read.

Long-Time Fan

For years, Instapaper has been one of the best made, most used, and most beloved apps in my iOS ecosystem. It’s always lived on my iPhone’s home page, and, as you can surmise, that’s because I use Instapaper a lot. Like, a lot a lot. Specifically, I use Instapaper a lot because it helps me do four things extremely well. Four things that work together to make my life a little better.

In that typically annoying mixed order I can’t seem to stop doing, here goes.

2. Deciding WHEN to read

Second, and most obviously, I use Instapaper maybe five to ten times a day to catch up on my reading. Which is great. This is what Instapaper is actually for, right? You read stuff.

Long articles, smaller features, short books, big piles of documentation, and really just anything that I would like to read…later. More saliently, these are things that I have decided to read. This decision part’s important, but more on that in a couple minutes.

But, how does all this “stuff” I’ve decided to read get in to Instapaper?

1. Deciding WHAT to read

See, this is the really important first part. Because as much as I use Instapaper for all manner of reading, its use as an ephemeral destination for mostly ephemeral content wouldn’t be nearly so useful if I didn’t have so many ways to collect all that stuff. So, that flexibility in collecting material is where I end up using some form of Instapaper dozens of times each day.

Examples?

I have a bookmarklet for adding items to Instapaper in 4 browsers on 7 devices. I have (and use the hell out of) the “Send to Instapaper” services that are built in to everything from Google Reader to Reeder to Flipboard to Instacast to Tweetbot to Zite to you name it. I can automate in or out of Instapaper with If This Then That, I can email items directly to Instapaper–hell, I can even just copy a URL from iOS Safari, and paste it directly into the motherscratching Instapaper app.

Suffice it to say, there are many ways to get “stuff” into Instapaper. E.g.:

But, that banner dump only tells part of the story.

Yes, a big part of this is about ubiquity and ease-of-use. But, the practical result is that all those little entrees to Instapaper are available to me everywhere I might need them, and they each represent a single little click that silently adds an item of “stuff” to my Instapaper pile.

Each button is one more simple opportunity for me to decide to read.

3. Deciding WHERE to read

Now, the third part of this magic is less immediately obvious, not least because the reading experience of the Instapaper iOS apps is, for my own purposes, perfect. But, there’s more.

Because, all that support for getting stuff into Instapaper is mirrored by an endless number of ways to get stuff back out. To, in fact, read. That thing I decided to read is now everywhere.

However I ended up deciding to read something, seconds after that *click*, the real magic starts happening, and–through whatever inscrutable black art and transmogrification is happening inside the fearsome celestial engine Marco has made–that decision to read is expressed in the most elegant of results and in a startlingly broad variety of convenient places.

It’s readable on a website; it’s readable on an iPhone, and 2 iPads; it’s readable on a Kindle 3; it’s readable on the crazy number of apps and services that display Instapaper items. And, it’s even preserved for posterity in my private Pinboard archive.

So, for practical purposes, this stuff that I’ve decided to read can now go whooshing through a network of customized tubes, and gently land practically anywhere that well-formed bits may reside.

4. Just…Deciding to Read

I know most of you know these things. I know you’re familiar with the many “Features and Benefits” of Instapaper. And, I even know that most of you reading this are probably already using Instapaper–perhaps even to read this very article.

So, the point here is not simply that Instapaper is flexible, idiot-proof, and sanity-savingly redundant. Although it is all those things and many more.

The point is that my life always gets better when I decide to read things–and then actually read those things I decided to read. This is not a trivial point.

We’re all busy, and we’re all bombarded with 10,000 potential calls on our attention every day. Some days, we handle that better than others. Some days, we don’t handle it all.

All I know, is that, throughout my life, deciding to read has made that life better.

It made my life better at 7 with Henry Huggins. It made my life better at 16 with Slaughterhouse-Five. It made my life better at 20 with Absalom, Absalom!. And, it made my life way better at 25 with A Confederacy of Dunces (cf.).

And, now, for the past few years–following over a decade during which I read way more href tags than actual prose paragraphs–my life has gotten better, in part, due to Instapaper. I’ve finally gotten my hands around this “too much stuff” issue, at least insofar as it relates to words of theoretical interest. Now, I know where it goes. It goes into Instapaper.

Because, now? Yeah. Twenty-some years after a college career sucking down over 1,000 pages a week, I am finally returning to reading a lot more. Because, I am deciding to read a lot more. Instapaper means there’s no excuse for not reading a lot more. Period.

How about you?

What Are YOU Deciding?

When you’re in line at the ATM or the professional sporting event, what do you do?

If you’re like a lot of people, you hit your mobile device like a pigeon on a goddamned pellet. Then, you decide what happens.

You can decide to throw birds at pigs. You can decide to check in on which strangers are pretending to like you today. You may even decide to see what you would look like if you were really fat.

Thing is, you could also decide to read. Just for a couple minutes. Maybe more. Maybe less. Who knows. It’s your decision.

A Nudge Towards “Better”

But, if you have followed the circuitous skeins of yarn comprising this little sweater you’ve been reading, it comes down to this:

If you’ve decided that you want to read, Marco’s app will really help you. He’s removed any phony barriers you’ve built about “not having time” or “not having it with you” or “not knowing where to put it.” There are no excuses, apart from the superficial animated ones you’ve constructed out of cartoon birds.

As for me? In the last week alone, I decided to read a lot of things in Instapaper. A small sampling:

I decided to read about an American family’s educational experiment in Russia.

I decided to read about what Heidegger means by Being-in-the-World.

I decided to read about why toasters are so bad.

I decided to read about responsive web design.

I decided to read about why Charlie Kaufman wrote Being John Malkovich.

I decided to read about how Open Data could make San Francisco Public Transportation better.

I decided to read about how John Siracusa remembers Steve Jobs.

I decided, and then I read. I read, and I read.

So, thanks, Marco. You’ve made my life better by making it easier to decide to read. Then, you made it way easier to do the actual reading.

And, to you–the kind readers-of-prose-paragraphs who were inexplicably patient enough to decide to read this long article–please consider supporting Marco’s work.

Please get an account at Instapaper and, if you have an iOS dingus, please do buy the Instapaper app.

In addition to having exquisite taste in app icons and a lovely speaking voice, Marco’s just a very good human. And, good humans more than deserve our support.

Buy Instapaper 4.0 by Marco Arment.

Shao-En Ong
May 1, 2002; 1:376-386
Research

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.

Allostery exploits the conformational dynamics of enzymes by triggering a shift in population ensembles toward functionally distinct conformational or dynamic states. Allostery extensively regulates the activities of key enzymes within biosynthetic pathways to meet metabolic demand for their end products. Here, we have examined a critical enzyme, 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS), at the gateway to aromatic amino acid biosynthesis in Mycobacterium tuberculosis, which shows extremely complex dynamic allostery: three distinct aromatic amino acids jointly communicate occupancy to the active site via subtle changes in dynamics, enabling exquisite fine-tuning of delivery of these essential metabolites. Furthermore, this allosteric mechanism is co-opted by pathway branchpoint enzyme chorismate mutase upon complex formation. In this study, using statistical coupling analysis, site-directed mutagenesis, isothermal calorimetry, small-angle X-ray scattering, and X-ray crystallography analyses, we have pinpointed a critical node within the complex dynamic communication network responsible for this sophisticated allosteric machinery. Through a facile Gly to Pro substitution, we have altered backbone dynamics, completely severing the allosteric signal yet remarkably, generating a nonallosteric enzyme that retains full catalytic activity. We also identified a second residue of prime importance to the inter-enzyme communication with chorismate mutase. Our results reveal that highly complex dynamic allostery is surprisingly vulnerable and provide further insights into the intimate link between catalysis and allostery.

James M. Ntambi
Sep 1, 1999; 40:1549-1558
Reviews

Jorge H. Capdevila
Feb 1, 2000; 41:163-181
Reviews

Gijs den Besten
Sep 1, 2013; 54:2325-2340
Reviews

Margrit Schwarz
Sep 1, 1998; 39:1833-1843
Articles

James E. Balmer
Nov 1, 2002; 43:1773-1808
Reviews

K Schoonjans
May 1, 1996; 37:907-925
Reviews

William R. Morrison
Oct 1, 1964; 5:600-608
Articles

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.

Geranylgeranoic acid (GGA) originally was identified in some animals and has been developed as an agent for preventing second primary hepatoma. We previously have also identified GGA as an acyclic diterpenoid in some medicinal herbs. Recently, we reported that in human hepatoma-derived HuH-7 cells, GGA is metabolically labeled from ¹³C-mevalonate. Several cell-free experiments have demonstrated that GGA is synthesized through geranylgeranial by oxygen-dependent oxidation of geranylgeraniol (GGOH), but the exact biochemical events giving rise to GGA in hepatoma cells remain unclear. Monoamine oxidase B (MOAB) has been suggested to be involved in GGOH oxidation. Here, using two human hepatoma cell lines, we investigated whether MAOB contributes to GGA biosynthesis. Using either HuH-7 cell lysates or recombinant human MAOB, we found that: 1) the MAO inhibitor tranylcypromine dose-dependently downregulates endogenous GGA levels in HuH-7 cells; and 2) siRNA-mediated MAOB silencing reduces intracellular GGA levels in HuH-7 and Hep3B cells. Unexpectedly, however, CRISPR/Cas9-generated MAOB-KO human hepatoma Hep3B cells had GGA levels similar to those in MAOB-WT cells. A sensitivity of GGA levels to siRNA-mediated MAOB downregulation was recovered when the MAOB-KO cells were transfected with a MAOB-expression plasmid, suggesting that MAOB is the enzyme primarily responsible for GGOH oxidation and that some other latent metabolic pathways may maintain endogenous GGA levels in the MAOB-KO hepatoma cells. Along with the previous findings, these results provide critical insights into the biological roles of human MAOB and provide evidence that hepatic MAOB is involved in endogenous GGA biosynthesis via GGOH oxidation.

Adipocytes take up long chain FAs through diffusion and protein-mediated transport, whereas FA efflux is considered to occur by diffusion. To identify potential membrane proteins that are involved in regulating FA flux in adipocytes, the expression levels of 55 membrane transporters without known function were screened in subcutaneous adipose samples from obese patients before and after bariatric surgery using branched DNA methodology. Among the 33 solute carrier (SLC) transporter family members screened, the expression of 14 members showed significant changes before and after bariatric surgery. One of them, Slc43a3, increased about 2.5-fold after bariatric surgery. Further investigation demonstrated that Slc43a3 is highly expressed in murine adipose tissue and induced during adipocyte differentiation in primary preadipocytes and in OP9 cells. Knockdown of Slc43a3 with siRNA in differentiated OP9 adipocytes reduced both basal and forskolin-stimulated FA efflux, while also increasing FA uptake and lipid droplet accumulation. In contrast, overexpression of Slc43a3 decreased FA uptake in differentiated OP9 cells and resulted in decreased lipid droplet accumulation. Therefore, Slc43a3 seems to regulate FA flux in adipocytes, functioning as a positive regulator of FA efflux and as a negative regulator of FA uptake.

Aos primeiros sinais de visão embaçada, as hipóteses mais frequentes sempre são miopia, astigmatismo, hipermetropia. Mas esses sintomas podem indicar outra doença ocular chamada ceratocone - uma deformidade progressiva da córnea, que assume o formato...

The post Visão embaçada e distorcida nem sempre é miopia: fique atento aos sinais do ceratocone appeared first on Saúde Próspera.

Guillermo E. Umpierrez
Jan 1, 2002; 15:
Articles

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.