Announced back in July, Nokia’s new flagship N8 smartphone began shipping on the last day of September to those that had pre-ordered the device (it’s now available on most UK networks). As did the first review units sent out with almost military provision to chosen technology bloggers, this writer included. Having already declared “Nokia is [...]

Introducing tenthings.me What started off as a bit of fun on a long New Year’s day weekend, has launched as TenThings.me: … a place to share (up to) ten things about yourself that your friends and co-workers might not know. It’s in part inspired by the recent viral hit threewords.me but also an old blogging [...]

On paper at least, Nokia’s E6 smartphone could have been designed just for me. It keeps most of the design cues and form-factor first seen on the E71 and its successor the E72 – easy one handed operation, great physical QWERTY keyboard, rock solid build (well, the E71 at least), superb call quality, free turn-by-turn [...]

Nokia World, London - Having jumped off of a burning platform and into Redmond’s arms – a story that I (partially) broke on TechCrunch back in February this year – Nokia this morning finally took the wraps off its much anticipated entry into the Windows Phone world with two new devices: The flagship Lumia 800 [...]

I’m not entirely sure who the Samsung Galaxy Note is aimed at, but as somebody who gets to observe from the sidelines, this is one fun, functional and loveable device — although it comes at an out of contract price of around £450-500 upwards, give or take. The biggest talking point of the Galaxy Note is its [...]

As long as we have garbage, we'll never run out of oil, thanks to a technology called thermal depolymerization process (TDP).

The Book-of-the-Month Club is still going strong after more than 90 years, despite the rise and fall of mega-bookstores (and the advent of Amazon.com). But that's not all: you can get a monthly subscription to just about anything.

Do you have the equivalent of a will for all your digital possessions—photos, email, online accounts, and all the rest? If not, you should, and we have a book that shows you what to do. Plus, Interesting Thing of the Day readers can save 30% on it.

Outfit a spacecraft with a huge but incredibly lightweight mirror, and it can travel indefinitely, without fuel, at speeds that eventually exceed those of conventional rocket-powered craft.

It's one thing to give a storm like a hurricane or typhoon a name, but it's another to assign a proper name to wind of a certain type in a certain season and location.

The water level is rising in Venice, while the buildings are sinking. An ambitious plan is underway to save the ancient city from an untimely demise.

If you love to travel and have a few million spare dollars, you can buy a condo on any of several luxury cruise ships and live there year-round, taking your home with you as you sail around the world.

When you think of deadly animals, you may picture lions, hippos, or even mosquitos. But watch out for the real killer: snails.

Digital cameras make it easy to take way too many pictures. Need help sorting, organizing, storing, and managing them? We've got a great book for you—and Interesting Thing of the Day readers can save 30% on it.

My attempts at building a time machine having failed thus far, I find myself with too few hours in the day. So ITotD will be on a (hopefully brief) hiatus while I take care of business.

Last week an email hit my inbox with a simple and powerful sentiment. “I miss your writing,” it said. The person who sent it was a longtime reader of this site. I miss writing too. But there’s a reason I’ve been quiet here and on other platforms – I wrote a very short post about … Continue reading "Why Politics, Why Now?"

Something’s been bugging me about Tik Tok. I’ve almost downloaded it about a dozen times over the past few months. But I always stop short. I don’t have a ton of time (here’s why) so forgive me as I resort to some short form tricks here. To wit: China employs a breathtaking model of state-driven … Continue reading "Tik Tok, Tick Tock…Boom."

This past year, I predicted the fall of both Zuck and Trump, not to mention the triumph of cannabis and rationale markets. But in 2019, the sociopaths won – bigly. Damn, was I wrong. One year ago this week, I sat down to write my annual list of ten or so predictions for the coming … Continue reading "Predictions Review: Trump, Zuck Crush My Optimism In 2019"

A new year brings another run at my annual predictions: For 17 years now, I’ve taken a few hours to imagine what might happen over the course of the coming twelve months. And my goodness did I swing for the fences last year — and I pretty much whiffed. Batting .300 is great in the majors, but it … Continue reading "Predictions 2020: Facebook Caves, Google Zags, Netflix Sells Out, and Data Policy Gets Sexy"

Google’s (and now Alphabet’s) CEO opines in the FT (sub required) on why AI needs to be regulated, joining the chorus of tech leaders who have taken the apparent high road when it comes to regulation, even as governments around the world have shown next to no ability to actually regulate anything (well, I guess … Continue reading "Sundar Pichai in the FT: Please Regulate Us (And Good Luck with All That)"

Andrew Yang has dropped out, which means the presidential campaign just got a lot less fun (you must watch this appreciation from The Recount, embedded above). The race also lost a credible and important voice on issues related to the impact of technology on our society.  The fact that Yang’s campaign didn’t make it past … Continue reading "For Now, America Just Doesn’t Want to Think That Hard"

Who’s Really Behind That “Death of the Techlash” Narrative?   One of my least favorite kinds of journalism is the easy win. It’s the kind of story that just lands in your lap. It feels contrarian, yet of the moment, it’s often predicated by the appearance of a primary source dangling easy data, and unlike most … Continue reading "Will The Coronavirus Save Big Tech?"

“Outbreaks have sparked riots and propelled public-health innovations, prefigured revolutions and redrawn maps.” – The New Yorker, April 2020 “Nothing will be the same.”  That’s the overwhelming takeaway I’ve heard from dozens of conversations I’ve had with C-suite leaders, physicians, policy experts and media professionals these past few weeks.  When it comes to the business … Continue reading "An Open Letter To American Corporations: It’s Good Business (and Smart Marketing) To Support Quality Journalism"

As the coronavirus crisis built to pandemic levels in early March, a relatively unknown tech company confronted a defining opportunity. Zoom Video Communications, a fast-growing enterprise videoconferencing platform with roots in both Silicon Valley and China, had already seen its market cap grow from under $10 billion to nearly double that. As the coronavirus began … Continue reading "New Research Shows Why and How Zoom Could Become an Advertising Driven Business"

If you’ve read Shoshana Zuboff’s Surveillance Capitalism, you likely agree that the most important asset for a data-driven advertising platform is consumer engagement. That engagement throws off data, that data drives prediction models, those models inform algorithms, those algorithms drive advertising engines, and those engines drive revenue, which drives profit. And profit, of course, drives … Continue reading "Zoom Is YouTube, Instagram, and WhatsApp – All in Two Months."

Like what you see? We’d love you to Share, Like, and Comment on Facebook! Conservative Intel has partnered with Pat Cross Cartoons! Pat loves drawing, America, and the Big Man upstairs. His work aims to combine these three elements into a petri dish and see what happens. We hope you will find his work thought-provoking, insightful, profound, and […]

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This week: Suddenly, shockingly, it’s Biden’s to lose Dem primary voters abruptly pulled back from socialism Democrats suddenly get a top candidate for #MTSEN President 2020 Super Tuesday: Pete Buttigieg and Amy Klobuchar knew they could not win. But they realized they could help Bernie Sanders win if they stayed in the race for Super […]

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This week: Sanders’s last gasp Coronavirus threatens to upend election calculus Sessions trails in runoff President 2020 Democrats: The consensus of the pundits is that Joe Biden won Sunday’s (mercifully audience-free) debate on points. But even if Bernie Sanders had laid him out flat, it wouldn’t have been enough to stop the former vice president’s […]

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This week: Biden has won — Sanders just has to admit it Political consequences of coronavirus Congress struggles with how to deal with the plague The world’s news is now clearly dominated by coronavirus. Everything — commerce, social life, and yes, even politics — has been put on hold.  Well, that last bit is not […]

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To our readers: We hope you are safe and well. Please exercise care, especially for the sake of your older loved ones, who are at greater risk if they contract coronavirus. This week: Pelosi loses the week Politics of coronavirus end up surprisingly good for Trump Biden faces his own #MeToo allegation House showdown: There […]

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A very Happy Passover and Easter to all our subscribers. This week: Uncertainties prevent post-pandemic planning Democrats postpone convention Wisconsin supreme court race is on for Tuesday Coronavirus pandemic: Americans are just now getting used to the new realities of social distancing and work (or study) from-home-if-at-all. But what the nation needs next is a […]

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=This week: Blacks, not white socialists, are the Democratic Party’s lifeblood Biden’s campaign is coronavirus’ most prominent victim Behind the story of Wisconsin’s strange, last-minute election drama Sanders: Bernie Sanders failed to build on or improve his 2016 showing in the presidential race for one simple reason: He didn’t win black votes. If you are […]

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This week: Negative coronavirus coverage slightly depressing Trump’s rating U.S. has fared well compared to most developing countries Republicans lose after insisting on Wisconsin vote President 2020 Naturally, coronavirus continues to dominate the national discussion, drowning out any mention or thought of the presidential election. Democratic and media efforts to make President Trump the inventor […]

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This week: Value of COVID ‘lockdowns’ about to be tested. Biden fearful over Trump’s fundraising Kansas GOP panics over crowded primary field President 2020 Coronavirus: In most of America, it really does appear that the coronavirus “curve” has been flattened, as people hoped. Thus, in seeking as swift a return to normalcy as possible, President […]

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May 4, 2020 This week: Biden finally forced to address rape accusation Won’t release his office records The Amash factor President 2020 Joe Biden: News consumers have become deeply fatigued by the coronavirus. Many people just don’t want to read or hear any more about it. It has come to the attention of multiple news […]

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People are always curious about work-from-home (WFH), remote working setups. So, I posted a Basecamp message asking our employees to share a photo of their home office, desk, table, whatever. Here’s what came in. First, the ask: And the answers, in the order they came in: Andy Didorosi, Marketing Justin White, Programmer Jonas Downey, Designer… keep reading

David and I spent nearly 2-hours giving a livestream tour of our very own Basecamp account. We wanted to show you how Basecamp uses Basecamp to run projects, communicate internally, share announcements, know what everyone’s working on, build software, keep up socially, and a whole bunch more. Our entire company runs on Basecamp, and this… keep reading

In this livesteam, David and I answer audience questions about how to work remotely. At Basecamp we’ve been working remotely for nearly 20 years, so we have a lot of experience to share. This nearly 2-hour video goes into great detail on a wide variety of topics. Highly recommended if you’re trying to figure out… keep reading

For many, moving from everyone’s-working-from-the-office to everyone’s-working-at-home isn’t so much a transition as it is a scramble. A very how the fuck? moment. That’s natural. And people need time to figure it out. So if you’re in a leadership position, bake in time. You can’t expect people to hit the ground running when everything’s different.… keep reading

We had originally planned to release HEY, our new email service, in April. There was the final cycle to finish the features, there was a company meetup planned for the end of the month to celebrate together, we’d been capacity testing extensively, and the first step of a marketing campaign was already under way. But… keep reading

The vast majority of web applications should start life as a Majestic Monolith: A single codebase that does everything the application needs to do. This is in contrast to a constellation of services, whether micro or macro, that tries to carve up the application into little islands each doing a piece of the overall work.… keep reading

Spring is emerging in the US and as part of our company spring cleaning, we took a peek at our product policies, noticed some cobwebs, and got out the duster. You can read our current product policies here. Besides rewriting sections to be more readable, we made four substantive changes: 1. We’ve consolidated our policies… keep reading

Basecamp’s newest product HEY has lived on Kubernetes since development first began. While our applications are majestic monoliths, a product like HEY has numerous supporting services that run along-side the main app like our mail pipeline (Postfix and friends), Resque (and Resque Scheduler), and nginx, making Kubernetes a great orchestration option for us. As you… keep reading

There’s no perfect process for hiring great programmers, but there are plenty of terrible ways to screw it up. We’ve rejected the industry stables of grilling candidates in front of a whiteboard or needling them with brain teasers since the start at Basecamp. But you’re not getting around showing real code when applying for a… keep reading

We’ve been teaching people how to do remote work well for the better part of two decades. We wrote a whole book about the topic in 2013, called REMOTE: Office Not Required. Basecamp has been a remote company since day one, and our software is sold as an all-in-one toolkit for remote work. Yeah, we’re… keep reading

Systemic infection and proliferation of intracellular pathogens require the biogenesis of a growth-stimulating compartment. The gastrointestinal pathogen Salmonella enterica commonly forms highly dynamic and extensive tubular membrane compartments built from Salmonella-modified membranes (SMMs) in diverse host cells. Although the general mechanism involved in the formation of replication-permissive compartments of S. enterica is well researched, much less is known regarding specific adaptations to different host cell types. Using an affinity-based proteome approach, we explored the composition of SMMs in murine macrophages. The systematic characterization provides a broader landscape of host players to the maturation of Salmonella-containing compartments and reveals core host elements targeted by Salmonella in macrophages as well as epithelial cells. However, we also identified subtle host specific adaptations. Some of these observations, such as the differential involvement of the COPII system, Rab GTPases 2A, 8B, 11 and ER transport proteins Sec61 and Sec22B may explain cell line-dependent variations in the pathophysiology of Salmonella infections. In summary, our system-wide approach demonstrates a hitherto underappreciated impact of the host cell type in the formation of intracellular compartments by Salmonella.

Acute myeloid leukemia (AML) is a clonal disorder arising from hematopoietic myeloid progenitors. Aberrantly activated tyrosine kinases (TK) are involved in leukemogenesis and are associated with poor treatment outcome. Kinase inhibitor (KI) treatment has shown promise in improving patient outcome in AML. However, inhibitor selection for patients is suboptimal.

In a preclinical effort to address KI selection, we analyzed a panel of 16 AML cell lines using phosphotyrosine (pY) enrichment-based, label-free phosphoproteomics. The Integrative Inferred Kinase Activity (INKA) algorithm was used to identify hyperphosphorylated, active kinases as candidates for KI treatment, and efficacy of selected KIs was tested.

Heterogeneous signaling was observed with between 241 and 2764 phosphopeptides detected per cell line. Of 4853 identified phosphopeptides with 4229 phosphosites, 4459 phosphopeptides (4430 pY) were linked to 3605 class I sites (3525 pY). INKA analysis in single cell lines successfully pinpointed driver kinases (PDGFRA, JAK2, KIT and FLT3) corresponding with activating mutations present in these cell lines. Furthermore, potential receptor tyrosine kinase (RTK) drivers, undetected by standard molecular analyses, were identified in four cell lines (FGFR1 in KG-1 and KG-1a, PDGFRA in Kasumi-3, and FLT3 in MM6). These cell lines proved highly sensitive to specific KIs. Six AML cell lines without a clear RTK driver showed evidence of MAPK1/3 activation, indicative of the presence of activating upstream RAS mutations. Importantly, FLT3 phosphorylation was demonstrated in two clinical AML samples with a FLT3 internal tandem duplication (ITD) mutation.

Our data show the potential of pY-phosphoproteomics and INKA analysis to provide insight in AML TK signaling and identify hyperactive kinases as potential targets for treatment in AML cell lines. These results warrant future investigation of clinical samples to further our understanding of TK phosphorylation in relation to clinical response in the individual patient.

Human leukocyte antigen (HLA) B*51:01 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly genetically associated with Behcet's disease (BD). Previous studies have defined two subgroups of HLA-B*51 peptidome containing proline (Pro) or alanine (Ala) at position 2 (P2). Little is known about the unconventional non-Pro/Ala2 HLA-B*51-bound peptides. We aimed to study the features of this novel subpeptidome, and investigate its regulation by ERAP1. CRISPR-Cas9 was used to generate an HLA-ABC-triple knockout HeLa cell line (HeLa.ABC-KO), which was subsequently transduced to express HLA-B*51:01 (HeLa.ABC-KO.B51). ERAP1 was silenced using lentiviral shRNA. Peptides bound to HLA-B*51:01 were eluted and analyzed by mass spectrometry. The characteristics of non-Pro/Ala2, Pro2, and Ala2 peptides and their alteration by ERAP1 silencing were investigated. Effects of ERAP1 silencing on cell surface expression of HLA-B*51:01 were studied using flow cytometry. More than 20% of peptides eluted from HLA-B*51:01 lacked Pro or Ala at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared with the Pro2 and Ala2 subpeptidomes and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant leucine at position ). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to ~40%, increased the percentage of longer (10-mer and 11-mer) peptides eluted from HLA-B*51:01 complexes, and abrogated the predominance of leucine at P1. Interestingly knockdown of ERAP1 altered the length and N-terminal residue usage of non-Ala2&Pro2 and Ala2 but not the Pro2 peptides. Finally, ERAP1 silencing regulated the expression levels of cell surface HLA-B*51 in a cell-type-dependent manner. In conclusion, we have used a novel methodology to identify an unconventional but surprisingly abundant non-Pro/Ala2 HLA-B*51:01 subpeptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.

The redox-based modifications of cysteine residues in proteins regulate their function in many biological processes. The gas molecule H₂S has been shown to persulfidate redox sensitive cysteine residues resulting in an H₂S-modified proteome known as the sulfhydrome. Tandem Mass Tags (TMT) multiplexing strategies for large-scale proteomic analyses have become increasingly prevalent in detecting cysteine modifications. Here we developed a TMT-based proteomics approach for selectively trapping and tagging cysteine persulfides in the cellular proteomes. We revealed the natural protein sulfhydrome of two human cell lines, and identified insulin as a novel substrate in pancreatic beta cells. Moreover, we showed that under oxidative stress conditions, increased H₂S can target enzymes involved in energy metabolism by switching specific cysteine modifications to persulfides. Specifically, we discovered a Redox Thiol Switch, from protein S-glutathioinylation to S-persulfidation (RTS^GS). We propose that the RTS^GS from S-glutathioinylation to S-persulfidation is a potential mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.