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“Distraction,” Simplicity, and Running Toward Shitstorms

It can scarcely be denied that the supreme goal of all theory is to make the irreducible basic elements as simple and as few as possible without having to surrender the adequate representation of a single datum of experience.

—Albert Einstein, “On the Method of Theoretical Physics” (1934)

Context: Last week, I pinched off one of my typically woolly emails in response to an acquaintance whom I admire. He’s a swell guy who makes things I love, and he'd written, in part, to express concern that my recent Swift impersonation had been directed explicitly at something he'd made. Which, of course, it hadn’t—but which, as I'll try to discuss here, strikes me as irrelevant.

To paraphrase Bogie, I played it for him, so now I suppose I might as well play it for you.


(n.b.: Excerpted, redacted, munged, and heavily expanded from my original email)

There are at least a couple things that mean a lot to me that I'm still just not very good at.

  • Make nuanced points in whatever way they need to be made; even if that ends up seeming “un-nuanced”
  • Never explain yourself.

I want to break both these self-imposed rules privately with you here. [Editor’s Note: Um.] Because, I hope to nuance the shit out of some fairly un-nuanced points. And, to do that, I'll also (reluctantly) need to explain myself. But, here goes.

First [regarding my goofing on “distraction-free writing environments”] I think there are some GIANT distinctions at play here that a lot of folks may not find nearly as obvious as I do:

  1. Tool Mastery vs. Productivity Pr0n – Finding and learning the right tools for your work vs solely dicking around with the options for those tools is just so important, but also so different. And, admittedly, it’s almost impossible to contrast those differences in terms of hard & fast rules that could be true for all people in all situations. But, that doesn’t make the difference any less qualitatively special or real.

    Similarly…
  2. Self-Help Vs. “Self”–“Help” – Solving the problem that caused the problem that caused the problem that caused the symptom we eventually noticed. Huge. Arguably, peerless.

    • Viz.: How many of us ignore the actual cause of our problem in favor of just reading dozens of blog posts about how to “turbocharge” its most superficial symptoms? Sick.
  3. Focus & Play – Yes, focusing on important work is, as Ford used to say, Job 1. But, that focus benefits when we maintain the durable and unapologetic sense of play that affords true creativity and fosters an emergence of context and connection that’s usually killed by stress. BUT.

    • Again, what conceivable “rule” could ever serve to immutably declare that “THIS goofing-off is critical for hippocampal plasticity” vs. “THAT goofing-off is just dumb, distracting bullshit?”
    • Impossible. Because drawing those kinds of distinctions is one of our most important day-to-day responsibilities. Decisions are hard, and there’s no app or alarm gadget that can change that.

      • Although, they certainly can help mask the depth of the underlying problem that made them seem so—what’s the parlance?—“indispensable”.
      • Think: Elmo Band-Aids for that unsightly pancreatic tumor.
  4. Reducing Distraction through Care (Rather than braces, armatures, and puppet strings). Removing interruptions and external distractions that harm your work or life? Great. Counting on your distraction-removal tool to supplement your non-existent motivation to do work that will never get done anyway? Pathetic.

    • Frankly, this is a big reason I'm so galled when anyone touts their tool/product/service as being the poor, misunderstood artist’s new miracle medicine—rather than just admitting they've made a slightly different spoon.
    • Because, let’s be honest: although most of us have plenty of perfectly serviceable spoons, everybody knows collecting cutlery is way more fun than using it to swallow yucky medicine.
  5. Using a System Vs. Becoming a System. Having a system or process for getting work done vs. making the iteration of that system or process a replacement for the work. This is just…wow…big.

    But, maybe most importantly to me…

  6. Embracing the Impossibles. Getting past these or any other intellectual koans by simply accepting life’s innumerable and unresolvable paradoxes, hypocrisies, and impossibilities as God-given gifts of creative constraint. Rather than, say, a mimeographed page of long division problems that must be solved for a whole number, n.

    • I just can’t ever get away from this one. For me, it’s what everything inevitably comes back to.
    • The very definition of our jobs is to solve the right problem at the right level for the right reason—based on a combination of the best info we have for now and a clear-eyed dedication to never pushing an unnecessary rock up an avoidable hill.
    • YET, we keep force-feeding the monster that tells us to fiddle and fart and blame the Big Cruel World whenever we face work that might threaten our fragile personal mythology.

      • “Sigh. I wish I could finally start writing My Novel….Ooooooh, if only I had a slightly nicer pen…and Zeus loved me more….”

All that stuff? That there’s a complex set of ideas to talk about for many complex reasons—not least of which being how many people either despise or (try to) deny the unavoidable impact of ol' number six.

But, here’s the thing: as much as saying so pisses anybody off, I think the topics we're NOT talking about whenever we disappear into Talmudic scholarship about “full-screen mode” or “minimalist desks” or whatever constitutes a “zen habit”—those shunned topics are precisely the things that I believe are most mind-blowingly critical to our real-world happiness as humans.

In fact, I believe that to such a degree that helping provide a voice for those unpopular topics that can be heard over the din is now (what passes for) my career. I really believe these deeper ideas are worth socializing on any number of levels and in many media. Even when it’s inconvenient and slightly disrespectful of someone’s business model.

So, that’s what I try to do. I talk about these things. Seldom by careful design. Often poorly. But, always because they each mean an awful lot to me.

[…]

But, no matter how I end up saying whatever the hell I say, I believe in saying it not simply to be liked or followed or revered as a “nice guy” who pushes out shit-tons of whatever to “help people.”

Because, believe me, friend, a great many of those apparently “nice guys” swarming around the web “helping people” these days are ass-fucking their audience for nickels and calling it a complimentary colonoscopy. And, while I absolutely think that in itself is empirically wrong, I also think it’s just as important to say that it’s wrong. Sometimes, True Things need to be said.

Which in this instance amounts to saying, a) selling people a prettier way to kinda almost but not really write is not, in the canonical sense, “nice”—but, far worse, b) leaving your starry-eyed customers with the nauseatingly misguided impression that their “distraction” originates from anyplace but their own busted-ass brain is really not “helping.” Not on any level. It is, literally, harmful.

“Helping” a junkie become more efficient at keeping his syringe loaded is hardly “nice.”

It’s the opposite of nice. And, it’s the opposite of helpful. These are my True Things.

And, to me, saying your True Things also means not watering down the message you care about in order to render it incapable of even conceivably hurting someone’s feelings—or of even conceivably losing you even one teeny-tiny slice of that precious “market share.”

Well, that’s the price, and I'm fine paying it—best money I've ever spent.

But, it also means trusting your audience by letting each of them decide to add water only as they choose to—by never corrupting the actual concentrate in a way that might make it less useful to the smartest or most eager 5% of people who'd like to try using it undiluted. Because, at that point, you're not only abandoning the coolest people you have the honor of serving—you risk becoming a charlatan.

And, that’s precisely what you become when you start to iteratively inbreed the kind of fucktard audience for whom daily buffets of weak swill and beige assurance are life’s most gratifying reward.

Sure. Those poor bastards may never end up using any of that watery information to do anything more ambitious than turbocharging their most regrettable symptoms. But, who’s the last person in the universe who’s going to grab them by the ears and tell them to get back to work? Exactly—that same “nice guy” whose livelihood now depends on keeping infantalized strangers addicted to his “help.”

Holy shit—no way could I ever live with that. It’s so wrong, it’s not even right. ESC, ESC, ESC!

[…]

Okay. So anyhow, there’s a really long-winded, overly generous, and extremely pompous way of trying to say I don’t know how to do what I do except how I do it. But, I do genuinely feel awful when innocent people feel they have been publicly humiliated or berated simply because I'm some dick who hates people.

Which has to be my favorite irony of all.

When I was a kid, I thought my Mom was “mean” not to let me play in traffic on busy Galbraith Road. Today, I'm not simply grateful that she had the strength and resolve to be so “mean”—I actually can’t imagine how sad it would be to not have people in your life who care enough about your long-term welfare to tell you to stop fucking around in traffic. To where you eventually might start even seeking 12x-daily safety hacks from some of the very same drivers whose recklessness may eventually kill you. Wow.

[…]

Admitting when life is complicated or things aren’t shiny and happy all the time strikes me as a wonderfully sane and adult way to conduct one’s life. That there are so many folks offended by even the existence of this anarchic idea is not a problem I can solve.

No more than I can wish useless email away or pray hard enough that it never rains on anyone’s leaky roof. All out of scope.

And, then, I jizzed on at length about how much I admire the recipient’s work. Which I do.


Good work doesn’t need a cookie

I may admire your work, too. Especially if you care a lot about that work and don’t overly sweat peoples' opinions of it. Most definitely including my own.

For these purposes, it doesn’t really matter whether we're friends and, honestly, it doesn’t even matter whether I love, use, or agree with everything you do, say, or make in a given day.

It doesn’t matter because good work doesn’t need me to love it. Like tornadoes and cold sores, good work happens with total disregard to whether I'm “into it.”

But, conversely, let’s stipulate that the points-of-view undergirding our opinions—again, including mine—will and should survive either agreement or lack of agreement with equivalently effortless ease. Because, like really good work, a really good point-of-view doesn’t require another person’s benediction.

Guess we'll have to disagree to agree

Now, to be only vaguely clearer here, I'm not posting this circuitous ego dump in the service of altering your opinion of either me, my friend, his work, or practically anything else for that matter.

But, I would love it if we could all be more okay with the fact that real life means that we do each have a different, sometimes incongruous, and often totally incompatible point-of-view. Yes. Even you have a point-of-view that someone despises. Ready to change it now? Jesus, I sure hope not.

Then, to be only slightly more clear, I'm also not advocating for that fakey brand of web-based kum ba ya that gets trotted out alternately as “tolerance” or “inclusion” or some styrofoam miniature of “civility.”

I'm absolutely not against all of those things when authentically practiced, but I'm also really skeptical of the well-branded peacemakers who are forever appointing themselves the Internet’s “Now-Now-Let’s-All-Pretend-We're-Just-Saying-the-Same-Useless-Thing-Here” den mothers.

Because we're not all saying the same things. Not at all.

And, it infantalizes some important conversations when we tacitly demand that any instance of honest disagreement be immediately horseshat into a photo opp where some thought leader gets to hoist everyone’s hands in the air like he’s fucking Jimmy Carter.

Nope. Not saying that.

Who will you really rely on?

What I AM saying is that alllllll this seemingly unrelated stuff is absolutely related—that the pattern of not relying on other people for anything you really care about is arguably the great-grandaddy of every useful productivity, creativity, or self-help pattern.

Where’s this matter? Pretty much everywhere you have any sort of stake:

  • Don’t rely on other people to remove your totally fake “distractions.”
  • Don’t rely on other people to pat your beret, re-tie your cravat, and make you a nice cocoa whenever that mean man on the internet points out that your “distractions” are totally fake. (Which they are)
  • Don’t rely on other people to tell you when or whether you have enough information.
  • Don’t rely on other people to define your job.
  • Don’t rely on other people to “design your lifestyle.”
  • Don’t rely on other people to decide when your opinions are acceptable.
  • Don’t rely on other people to tell you when you're allowed to be awesome.
  • Don’t rely on other people to make you care.
  • Don’t even rely on other people to tell you what you should or shouldn’t rely on.

Yes. I went there.

Because that’s the point. These hypocrisies, paradoxes, and ambiguities that people get so wound up about—that many of us are constantly (impotently) trying to resolve—cannot be resolved.

Because, yeah: all of these harrowingly unsolvable problems are immune to new notebooks and less-distracting applications and shinier systems and “nicer” self-“help” and pretty much anything else that is not, specifically, you walking straight into the angriest and least convenient shitstorm you can find and getting your ass kicked until the storm gets bored with kicking it.

Then, you find an even angrier storm. Then, another. And, so on.

“Get the fuck off of my obstacle, Private Pyle!”

Doing that annoying hard stuff is how you grow, get better, and learn what real help looks like. Even if that’s not the answer you wanted to hear. You get better by getting your ass out of your RSS reader and fucking making things until they suck less. Not by buying apps.

You don’t whine about distractions, or derail yourself over needing a nicer pencil sharpener, or aggravate your chronic creative diabetes by starting another desperate waddle to the self-help buffet. No. You work.

And, for what it’s worth, just like you can’t get to the moon by eating cheese, you'll also never leave boot camp with your original scrote intact by telling your drill sergeant to try using more honey than vinegar.

No. That sergeant’s job is to make you miserable. It’s his job to break down your callow conceits about what’s supposed to be easy and fair. It’s his job to emotionally pummel you into giving up and becoming a Marine.

You? You're not there to give the sergeant notes; you're there to sleep two hours a night, then not mind getting beaten for 20 hours until a decent Marine starts to fall out.

Who knows? He may even surprise you by introducing a surprisingly effective “distraction-free learning environment.”

“Tee ell dee ahr, Professor Brainiac.”

Like most humans, I like things I can understand. Like most readers, I love specificity. Like most thinkers, I love clarity. Like most students, I love relevance and practicality. And, like most busy people, believe it or not, I actually do really like it when someone gets straight to the point.

But, here’s the problem. If my 2-year-old daughter asks me about time travel, and I blithely announce, “E=mc2”, I will have said something that is entirely specific, clear, relevant, practical, and/or straight-to-the-point. For somebody.

But, not so much for my daughter. And, to be honest, not even to any useful degree for me.

She'd probably either laugh derisively at me (which she’s great at), or she'd pause and ask, “Whuh dat?” (which she’s even better at).

Thing is, her understanding that jumble of characters less than me—and my understanding it WAY less than Professor Al—has zero impact on the profundity, truth, beauty, or impact of the man’s theory.

Sure. You could quite accurately fault me for being a smartass and a poseur, and you could even berate my toddler for her unaccountably shallow understanding of Modern Physics. But, in any case, you can’t really blame either Albert or his theory.

You're turbocharging nothing

Specifically, Albert can’t begin to tell us what he really knows if we don’t understand math.

So, let’s say this theory you've been hearing about really interests you. And, let’s also pretend, just for the sake of the analogy, that you haven’t completed Calculus III (212) or Quantum Mechanics (403) or even something as elementary as, say, Advanced Astrophysics II (537). I know you have. Obviously. But, let’s pretend. Where do you start?

Well, you could read some tips about learning math. You could find a list of 500 indispensable resources for indispensable math resources. You could buy a new “distraction-free math environment.” Heck, there’s actually nothing to stop you from just declaring yourself a “math expert.” Congratulations, Professor.

Thing is: you still don’t know math.

Which means you still can’t really understand the theory—no more than a pathetic Liberal Arts refugee like me or a dullard Physics ignoramus like my kid can really grok relativity.

Difference is, you will have blown a lot of time hoping that actual expertise follows non-existent effort—while my daughter and I get to remain total novices without charge. Only, we don’t get all mad at the theory as a result; a staggering number of fake math experts do.

I mean, be honest—after all that recreational non-work and make-believe dedication almost trying to kinda learn math sorta—you might actually get frustrated at how brazenly Al defies your fondness for shortcuts by continuing to rely on so many terms and proofs and blah-blah-blah that you still just don’t understand. So annoying.

You may simply decide that Albert Einstein’s a huge dick for never saying things that can be completely understood solely by scanning a headline.

EPIC EINSTEIN FAIL, amirite?

You never really know what you didn’t know until you know it

But, Al just told the truth.

Problem is, Al’s truth not only requires fancy things in order to be truly understood—the more of those fancy things you take away from his truth, the less true it gets. And, by the time it’s been diluted to the point where you're comfortable that you understand it? You'd be understanding the wrong thing. Even I can understand that.

But, not one bit of any of this is Al’s fault. Al doesn’t get to control who uses, abuses, gets, or doesn’t get what he said or why it matters. Especially since he’s been dead for over fifty years.

All I know is, regardless of who has ears to hear it on a given day, it would be to Al’s credit never to mangle something important in order to get it into terms everybody’s ready to handle without actually trying.

And God bless him for never agreeing that your “distractions” to learning math are his problem.

So, yeah, if you only need to hand in a crappy 5-page paper, you could certainly Cliff’s Notes your way through Borges, Eliot, or Joyce in an afternoon, and feel like you haven’t missed a thing. Trouble is, if you did care even a little, it’s impossible to even say how much you're missing since you can’t be bothered to soldier through the source text. The text itself is the entire point.

Even the wonderfully cogent and readable layman’s explanations Einstein himself provided don’t really get to the nut, the application, and the implications of his real theory.

That all takes real math.

That “single datum of experience” matters

Sometimes, complex or difficult things stop being true when you try to make them too simple. Sometimes, you have to actually get laid to understand why people think sex is such a thing. Sometimes, you need to learn some Greek if you really want to understand The Gospel of John. And, yeah, sometimes, you're going to have to just work unbelievably hard at whatever you claim to care about before anyone can begin to help you get any better—or less “distracted”—at it.

The part I really know is what doesn’t work. Reading Penthouse Forum won’t help you CLEP out of Vaginal Intercourse 101. Watching a Rankin-Bass cartoon about the Easter Bunny will teach you very little about the intricacies of transubstantiation. And, if you can’t be troubled to care so much about your work that you reflexively force distractions away, dicking around with yet another writing application will merely aggravate the problem. Ironic, huh?

These quantum mechanics of personal productivity are rife with such frustrating “paradoxes.”

These are True Things.

Achieving expertise and doing creative work is all horribly complicated and difficult and paradoxical and frustrating and recursive and James Joyce-y—and any guide, blog, binary, guru, or “nice guy” that tries to suggest otherwise is probably giving you a complimentary colonoscopy. Do the math.

Want a new syllabus? Sure:

Run straight into your shitstorm, my friends. Reject the impulse to think about work, rather than finishing it. And, open your heart to the remote possibility that any mythology of personal failure that involves messiahs periodically arriving to make everything “easy” for you might not really be helping your work or your mental health or your long-standing addiction to using tools solely to ship new excuses.

Learn your real math, and any slide rule will suffice. Try, make, and do until you quit noticing the tools, and if you still think you need new tools, go try, make, and do more.

If you can pull off this deceptively simple and millennia-old pattern, you'll eventually find that—god by dying god—any partial truth that’s supported your treasured excuses for not working will be replaced by a no-faith-required knowledge that you're really, actually, finally getting better at something you care about.

Which is just sublimely un-distracting.


Dedication

This article is dedicated to my friend, Greg Knauss. No, he’s not the app guy–he’s just a good man who does good work, who accidentally/unintentionally helped me write this rant. He also happens to be a fella who could teach anyone a thing or two about writing with distractions. Thanks, Greg.

“Distraction,” Simplicity, and Running Toward Shitstorms” was written by Merlin Mann for 43Folders.com and was originally posted on October 05, 2010. Except as noted, it's ©2010 Merlin Mann and licensed for reuse under CC BY-NC-ND 3.0. "Why a footer?"




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Labour Party Conference – International affairs networking brunch

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Hosted by Sir Simon Fraser, Chairman of Chatham House.

This event is taking place at the Hilton Hotel, Grace 1 Suite, Liverpool.

You are warmly invited to join us for an exclusive networking brunch at the 2024 Labour Party Conference.

Sir Simon Fraser, Chairman of Chatham House, and Olivia O’Sullivan, Director of Chatham House’s UK in the World Programme, will deliver opening remarks, followed by an interactive networking session where you will have the chance to engage with a wide range of stakeholders. Join us to connect with key senior parliamentary, corporate and media attendees at the Labour Party Conference.

This event will be taking place outside of the secure zone.




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Is Myanmar Running Out of Time?

Is Myanmar Running Out of Time? 17 February 2020 — 1:00PM TO 2:00PM Anonymous (not verified) 10 January 2020 Chatham House | 10 St James's Square | London | SW1Y 4LE

Just a few years ago the West was celebrating what appeared to be the conclusion of a quarter-century long contest between Myanmar’s democrats and a military dictatorship. Today, the country stands charged with genocide at the International Court of Justice, with Aung San Suu Kyi leading the defence. Is Myanmar a democratic transition gone awry? Or something else entirely?

The speaker will argue that Myanmar is not the simple morality tale often portrayed. It has instead become the stage for some of the world’s most pressing challenges such as climate change, explosive inequality and rising populism, the impact of social media; and the rise of China as the next global superpower.

In this context, are 20th century democratic institutions and free-market reforms the correct remedy for a country plagued by the legacies of colonialism, decades of civil war, tyranny and a predatory economic system? The speaker will offer a prognosis for Myanmar’s future, assessing the question of whether it will become Asia’s next failed state.

This event will be held off the record.





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Malawi’s Re-Run Election is Lesson for African Opposition

1 July 2020

Fergus Kell

Projects Assistant, Africa Programme
The overturning of the result in the fresh presidential contest sets a bold precedent for the continent, as a process built upon the resilience of democratic institutions and the collective spirit of opposition.

2020-07-01-Malawi-Chakwera-Election

Lazarus Chakwera, leader of the Malawi Congress Party (MCP) arriving at the Mtandire suburb of the capital Lilongwe for an election rally. Photo by AMOS GUMULIRA/AFP via Getty Images.

Malawi is only the second African country to annul a presidential election, after Kenya in 2017. It is the first in which the opposition has won the re-run.

The initial May 2019 vote had narrowly returned incumbent Peter Mutharika to the presidency. But in February 2020 a landmark ruling by Malawi’s constitutional court annulled the result citing ‘widespread, systematic and grave’ irregularities, including the now-infamous use of corrective fluid in vote tallying, and the Malawi Electoral Commission’s (MEC) failure to address complaints before announcing results. New elections were ordered within 150 days.

In a decisive contrast with the previous year, the fresh polls on 23 June saw the coming together of Lazarus Chakwera of the Malawi Congress Party (MCP) and running mate Saulos Chilima of the United Transformation Movement (UTM) to head a coalition of nine opposition parties - having fiercely competed as the leading challengers previously.

The constitutional court ruling had also changed Malawi’s electoral system, replacing a first-past-the-post model with one demanding an outright majority, which further encouraged the regional power bases of Malawi’s opposition to cast ego aside and work in alliance with each other.

In tandem with a slick digital campaign, the new alliance travelled widely to hold rallies across what is one of the world’s youngest countries, while the elderly Mutharika remained largely confined to the capital. It would be a strategy that ultimately delivered Chakwera to the presidency, polling 58 per cent of votes to Mutharika’s 39.

Political opposition elsewhere in Africa should take note from Malawi’s coalition - dialogue, not division, can offer a genuine path to change, especially in those countries with less favourable institutional conditions. Neighbouring Zambia would certainly do well to heed this example ahead of a pivotal election of its own in 2021.

A victory built on institutional precedent

Yet the story here is not only about throwing out an incumbent: Malawians had already done so twice before, rejecting sitting presidents at the polls in 1994 and 2014. It is also not unfamiliar to see public opinion and the judiciary work in parallel to uphold the constitution: former president Bakili Muluzi was twice blocked from abolishing term limits by popular demonstration during his second term, and again prevented from running for a third time in 2009 by the constitutional court.

The new result did not arise as the foregone conclusion of a judicial miracle. Rather, throughout the re-run process Malawi has had to repeatedly draw upon the strength of its broad-based institutional foundations. The image of the constitutional court judges arriving to deliver their annulment verdict in February wearing bulletproof vests under their robes was a stark reminder that this was never the easy route to take.

In contrast to many other African states, Mutharika was unable to call upon military support as the Malawi Defence Forces (MDF) had moved to shield protesting citizens and protect the judiciary since the 2019 election. The MDF also had previous form in this respect, having defended then-vice president Joyce Banda’s constitutional right to assume the presidency after the incumbent’s death in 2012.

And this institutional resilience from the army would facilitate a smooth and mostly peaceful election process during the re-run, despite Mutharika attempts to intervene by replacing the MDF’s commander and his deputy in March 2020.

Just ten days before the fresh vote the Mutharika government switched focus back to the country’s legal system by attempting to enforce the premature retirement of Malawi’s chief justice, only to be blocked by the high court. Even as unofficial tallies trickled in, Mutharika’s Democratic Progressive Party (DPP) demanded the MEC annul the result: claiming their monitors were intimidated in MCP strongholds, and requesting unlawful access to scrutinise null and void votes.

Headed by a new chairperson, this time the MEC displayed enormous patience in the verification process and openly tackled complaints, now mainly from the DPP. On social media, Malawians celebrated the contrast between images of tally sheets from 2019 and the re-run.

Writing a new chapter

There are lessons here too for international partners. UK diplomacy played a subtle role in encouraging Mutharika to accept the legal process - he was invited to appear at the UK-Africa Investment Summit in January - while also helping promoting early dialogue among opposition parties.

At a time of pressure for UK engagement to offer clear strategic value, the impact of less easily quantifiable forms of influence should not be overlooked, especially as international observer missions effectively went missing in the discredited 2019 election. Preliminary statements back then from the Commonwealth, European Union, African Union and Southern African Development Community (SADC) struck a mostly congratulatory tone and were non-committal on the issues that would prove decisive in the court ruling. None went on to release their final reports.

Malawi must now start to move beyond election mode. Though COVID-19 cases remain low by global standards, a budget already heavily dependent on foreign aid and hampered by 18 months of political uncertainty will be slashed further by the pandemic’s impact. The IMF has predicted GDP growth of just 1% in 2020, down from a pre-coronavirus projection of 5%.

As it inherits a major balance of payments crisis, mounting debt and with no tourism revenue to fall back on, the new government will need to use its political capital to push for immediate reform. But it must not forget the core tenet of its campaign. The coalition that defeated Mutharika united the MCP’s rural support base with the middle-class urban following of the UTM. This spirit of unity and inclusion must be expanded and focus on long-term recovery. On this undertaking – unlike the polls – there will be no opportunity for a re-run.




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Quantitative proteomics reveal neuron projection development genes ARF4, KIF5B and RAB8A associated with Hirschsprung disease

Qin Zhang
Nov 17, 2020; 0:RA120.002325v1-mcp.RA120.002325
Research




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Antibodies play essential roles in both diagnostics and therapeutics. Epitope mapping is essential to understand how an antibody works and to protect intellectual property. Given the millions of antibodies for which epitope information is lacking, there is a need for high-throughput epitope mapping. To address this, we developed a strategy, Antibody binding epitope Mapping (AbMap), by combining a phage displayed peptide library with next generation sequencing. Using AbMap, profiles of the peptides bound by 202 antibodies were determined in a single test, and linear epitopes were identified for >50% of the antibodies. Using spike protein (S1 and S2)-enriched antibodies from the convalescent serum of one COVID-19 patient as the input, both linear and conformational epitopes of spike protein specific antibodies were identified. We defined peptide-binding profile of an antibody as the Binding Capacity (BiC). Conceptually, the BiC could serve as a systematic and functional descriptor of any antibody. Requiring at least one order of magnitude less time and money to map linear epitopes than traditional technologies, AbMap allows for high-throughput epitope mapping and creates many possibilities.




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Quantitative proteomics reveal neuron projection development genes ARF4, KIF5B and RAB8A associated with Hirschsprung disease [Research]

Hirschsprung disease (HSCR) is a heterogeneous group of neurocristopathy characterized by the absence of the enteric ganglia along a variable length of the intestine. Genetic defects play a major role in the pathogenesis of HSCR while family studies of pathogenic variants in all the known genes (loci) only demonstrate incomplete penetrance and variable expressivity for unknown reasons. Here, we applied large-scale, quantitative proteomics of human colon tissues from 21 patients using iTRAQ method followed by bioinformatics analysis. Selected findings were confirmed by parallel reaction monitoring (PRM) verification. At last the interesting differentially expressed proteins were confirmed by western blot. A total of 5341 proteins in human colon tissues were identified. Among them, 664 proteins with >1.2-fold difference were identified in 6 groups: groups A1 and A2 pooled protein from the ganglionic and aganglionic colon of male, long-segment HSCR patients (L-HSCR, n=7); groups B1 and B2 pooled protein from the ganglionic and aganglionic colon of male, short-segment HSCR patients (S-HSCR, n=7); and groups C1 and C2 pooled protein from the ganglionic and aganglionic colon of female, S-HSCR patients (n=7). Based on these analyses, 49 proteins from 5 pathways were selected for PRM verification, including ribosome, endocytosis, spliceosome, oxidative phosphorylation and cell adhesion. The downregulation of three neuron projection development genes ARF4, KIF5B and RAB8A in the aganglionic part of the colon were verified in 15 paired colon samples using WB. The findings of this study will shed new light on the pathogenesis of HSCR and facilitate the development of therapeutic targets.




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