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MARTY NEUMEIER - The Designful Company
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BRENDAN DAWES - Boil, Simmer, Reduce
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DAVID MCCANDLESS - Information Is Beautiful
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SAMANTHA WARREN - The Power and Beauty of Typography
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JOHN GRUBER - The Auteur Theory Of Design
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HANNAH DONOVAN - Jam Session: What Improvisation Can Teach Us About Design
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JAMES BRIDLE - The Value Of Ruins
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TOM COATES - Everything The Network Touches
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Kerning, Orgasms And Those Goddamned Japanese Toothpicks
My CSWE Journey, Part 1
In part 1 of My CSWE Journey blog by Nick Zhang, he discusses his journey on how he achieved his CSWE certificate
Author information
The post My CSWE Journey, Part 1 appeared first on SOLIDWORKS Education Blog.
Myth vs Reality: a look behind the scenes of cash transfers
Cash transfer programmes – regular money payments to poor households - aim to reduce poverty, promote sustainable livelihoods and increase production in the developing world. During the past decade, an increasing number of governments in sub-Saharan Africa have launched cash transfer programmes that target the most vulnerable groups, including subsistence farmers, people with disabilities and HIV/AIDS, as well as families [...]
Myocardial Ischemic Burden and Differences in Prognosis Among Patients With and Without Diabetes: Results From the Multicenter International REFINE SPECT Registry
Prevalence and prognostic impact of cardiovascular disease differ between patients with or without diabetes. We aimed to explore differences in the prevalence and prognosis of myocardial ischemia by automated quantification of total perfusion deficit (TPD) among patients with and without diabetes. Of 20,418 individuals who underwent single-photon emission computed tomography myocardial perfusion imaging, 2,951 patients with diabetes were matched to 2,951 patients without diabetes based on risk factors using propensity score. TPD was categorized as TPD = 0%, 0% < TPD < 1%, 1% ≤ TPD < 5%, 5% ≤ TPD ≤ 10%, and TPD >10%. Major adverse cardiovascular events (MACE) were defined as a composite of all-cause mortality, myocardial infarction, unstable angina, or late revascularization. MACE risk was increased in patients with diabetes compared with patients without diabetes at each level of TPD above 0 (P < 0.001 for interaction). In patients with TPD >10%, patients with diabetes had greater than twice the MACE risk compared with patients without diabetes (annualized MACE rate 9.4 [95% CI 6.7–11.6] and 3.9 [95% CI 2.8–5.6], respectively, P < 0.001). Patients with diabetes with even very minimal TPD (0% < TPD < 1%) experienced a higher risk for MACE than those with 0% TPD (hazard ratio 2.05 [95% CI 1.21–3.47], P = 0.007). Patients with diabetes with a TPD of 0.5% had a similar MACE risk as patients without diabetes with a TPD of 8%. For every level of TPD >0%, even a very minimal deficit of 0% < TPD < 1%, the MACE risk was higher in the patients with diabetes compared with patients without diabetes. Patients with diabetes with minimal ischemia had comparable MACE risk as patients without diabetes with significant ischemia.
MY MUM'S PUMPKIN & DATE SCONES
I have clear memories of being about four year's old standing on a little stool next to my mum while she made batches of these golden scones. I always loved being in the kitchen with her and she was endlessly patient, letting me help mix, stir, roll and shape all manner of things (in this case turning a blind eye when I smuggled little nuggets raw dough and dates into my mouth.) We would chat away as we went and she would explain to me what she was doing. I remember to this day her telling me the secret to making good scones was to use the lightest touch possible when you're mixing the dough together...we had no food processor then so everything was mixed by hand and I loved rubbing the flour and butter together, lifting my hands high as she had taught me to help keep the scones light. Although I whiz these up in a processor now, every so often I make a batch by hand, and am immediately whisked back into that childhood kitchen and can almost feel and see Cooee, my mum, beside me in her wonderful cinch-waisted 60's polka dot dress...it's a wonderful image.
My Mother's Fried Rice
Lorraine Elliott is the author of Not Quite Nigella. You can find her blog at www.notquitenigella.com This recipe was featured on Foodie Tuesday, every 3:30 PM Tuesday, 774 ABC Melbourne Drive show.
My Team vs. Your Team: The Political Arena Lives Up to Its Name
With America divided right down the middle for the third presidential election in a row, most people would not be surprised to hear that Democratic and Republican partisans perceive a widening gap between their presidential choices. In 2004, for example, die-hards in both parties felt that the...
[ Marriage & Divorce ] Open Question : 5 year old doesn’t want to go to her dads?
My step daughter is 5 and her dad lives states away. He calls her maybe once a month (not even on holidays) he hasn’t had her since she was one (when they lived in the same state) he had told my wife if our daughter wanted to see him we could bring her to him but he wasn’t coming to our state. My wife asked him beginning of this year if he’d sign his rights over. He doesn’t talk to her and he was behind on child support. He said no and that we was going to finally pick her up. He is getting married and didn’t include the little one we told him if he is going to get her he needs to tell her that it’s not just him living there and he is getting married. Our daughter was hurt by it that he hid this from her (they’ve been engaged for 4 years). She’s been crying she doesn’t want to go and he isn’t willing to come stay the week here to visit. He said he is taking her back to his state for a month. Yes it’s in their agreement but is there anything we can do? She really doesn’t want to go to a “strangers” house is what my daughter says.
Myocardial Blood Flow and Myocardial Flow Reserve After Cardiac Transplantation: Mistakes in Diagnostic Value and Prognosis
Myeloid HMG-CoA Reductase Determines Adipose Tissue Inflammation, Insulin Resistance, and Hepatic Steatosis in Diet-Induced Obese Mice
Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell–specific reduction of HMG-CoA reductase (Hmgcrm–/m–), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcrm–/m– mice than in control Hmgcrfl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcrm–/m– and Hmgcrfl/fl mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell–specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell–specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.
My first lie
I spoke French for thirteen years I say to him And he smiles. More cheese. Soft night yields to love, Rap is the only hard night sound, The White man is out of his depth, Even in French. He leans forward and whispers in my ear but, The first lie was mine. We’ll count them […]
My name is Henry
The place I used to visit, On bad days, With yoghurt and spoon, Is vacant. The leaves are raked, Into a neat pile, By the bench, And except for the newspaper, Blowing about in the wind, There is no-one here. The river beyond, Is a murky brown, Same as it’s always been, But, Over the […]
Structural basis of specific inhibition of extracellular activation of pro- or latent myostatin by the monoclonal antibody SRK-015 [Molecular Biophysics]
Myostatin (or growth/differentiation factor 8 (GDF8)) is a member of the transforming growth factor β superfamily of growth factors and negatively regulates skeletal muscle growth. Its dysregulation is implicated in muscle wasting diseases. SRK-015 is a clinical-stage mAb that prevents extracellular proteolytic activation of pro- and latent myostatin. Here we used integrated structural and biochemical approaches to elucidate the molecular mechanism of antibody-mediated neutralization of pro-myostatin activation. The crystal structure of pro-myostatin in complex with 29H4-16 Fab, a high-affinity variant of SRK-015, at 2.79 Å resolution revealed that the antibody binds to a conformational epitope in the arm region of the prodomain distant from the proteolytic cleavage sites. This epitope is highly sequence-divergent, having only limited similarity to other closely related members of the transforming growth factor β superfamily. Hydrogen/deuterium exchange MS experiments indicated that antibody binding induces conformational changes in pro- and latent myostatin that span the arm region, the loops contiguous to the protease cleavage sites, and the latency-associated structural elements. Moreover, negative-stain EM with full-length antibodies disclosed a stable, ring-like antigen–antibody structure in which the two Fab arms of a single antibody occupy the two arm regions of the prodomain in the pro- and latent myostatin homodimers, suggesting a 1:1 (antibody:myostatin homodimer) binding stoichiometry. These results suggest that SRK-015 binding stabilizes the latent conformation and limits the accessibility of protease cleavage sites within the prodomain. These findings shed light on approaches that specifically block the extracellular activation of growth factors by targeting their precursor forms.
Myo-Inositol Oxygenase (MIOX) Overexpression Drives the Progression of Renal Tubulo-Interstitial Injury in Diabetes
Conceivably, upregulation of myo-inositol oxygenase (MIOX) is associated with altered cellular redox. Its promoter includes oxidant-response elements, and we also discovered binding sites for XBP-1, a transcription factor of ER stress response. Previous studies indicate that MIOX’s upregulation in acute tubular injury is mediated by oxidant and ER stress. Here, we investigated if hyperglycemia leads to accentuation of oxidant and ER stress, while boosting each other’s activities and thereby augmenting tubulo-interstitial injury/fibrosis. We generated MIOX-overexpressing transgenic (MIOX-TG) and -knockout (MIOX-KO) mice. A diabetic state was induced by streptozotocin administration. Also, MIOX-KO were crossbred with Ins2Akita to generate Ins2Akita/KO mice. MIOX-TG mice had worsening renal functions with kidneys having increased oxidant/ER stress, as reflected by DCF/DHE staining, perturbed NAD/NADH and GSH/GSSG ratios, increased NOX-4 expression, apoptosis and its executionary molecules, accentuation of TGF-β signaling, Smads and XBP-1 nuclear translocation, expression of GRP78 and XBP1 (ER stress markers) and accelerated tubulo-interstitial fibrosis. These changes were not seen in MIOX-KO mice. Interestingly, such changes were remarkably reduced in Ins2Akita/KO mice, and likewise in vitro experiments with XBP1-siRNA. These findings suggest that MIOX expression accentuates while its deficiency shields kidneys from tubulo-interstitial injury by dampening oxidant and ER stress, which mutually enhance each other’s activity.
Myeloid-specific deficiency of pregnane X receptor decreases atherosclerosis in LDL receptor-deficient mice [Research Articles]
The pregnane X receptor (PXR) is a nuclear receptor that can be activated by numerous drugs and xenobiotic chemicals. PXR thereby functions as a xenobiotic sensor to coordinately regulate host responses to xenobiotics by transcriptionally regulating many genes involved in xenobiotic metabolism. We have previously reported that PXR has pro-atherogenic effects in animal models, but how PXR contributes to atherosclerosis development in different tissues or cell types remains elusive. In this study, we generated an LDL receptor-deficient mouse model with myeloid-specific PXR deficiency (PXRMyeLDLR–/–) to elucidate the role of macrophage PXR signaling in atherogenesis. The myeloid PXR deficiency did not affect metabolic phenotypes and plasma lipid profiles, but PXRMyeLDLR–/– mice had significantly decreased atherosclerosis at both aortic root and brachiocephalic arteries compared with control littermates. Interestingly, the PXR deletion did not affect macrophage adhesion and migration properties, but reduced lipid accumulation and foam cell formation in the macrophages. PXR deficiency also led to decreased expression of the scavenger receptor CD36 and impaired lipid uptake in macrophages of the PXRMyeLDLR–/– mice. Further, RNA-Seq analysis indicated that treatment with a prototypical PXR ligand affects the expression of many atherosclerosis-related genes in macrophages in vitro. These findings reveal a pivotal role of myeloid PXR signaling in atherosclerosis development and suggest that PXR may be a potential therapeutic target in atherosclerosis management.
Myeloid-specific deficiency of pregnane X receptor decreases atherosclerosis in LDL receptor-deficient mice
Yipeng Sui
May 1, 2020; 61:696-706
Research Articles
MyGov to feel the audit blowtorch
Human Service to face National Audit Office scrutiny. Again.Structural basis of specific inhibition of extracellular activation of pro- or latent myostatin by the monoclonal antibody SRK-015 [Molecular Biophysics]
Myostatin (or growth/differentiation factor 8 (GDF8)) is a member of the transforming growth factor β superfamily of growth factors and negatively regulates skeletal muscle growth. Its dysregulation is implicated in muscle wasting diseases. SRK-015 is a clinical-stage mAb that prevents extracellular proteolytic activation of pro- and latent myostatin. Here we used integrated structural and biochemical approaches to elucidate the molecular mechanism of antibody-mediated neutralization of pro-myostatin activation. The crystal structure of pro-myostatin in complex with 29H4-16 Fab, a high-affinity variant of SRK-015, at 2.79 Å resolution revealed that the antibody binds to a conformational epitope in the arm region of the prodomain distant from the proteolytic cleavage sites. This epitope is highly sequence-divergent, having only limited similarity to other closely related members of the transforming growth factor β superfamily. Hydrogen/deuterium exchange MS experiments indicated that antibody binding induces conformational changes in pro- and latent myostatin that span the arm region, the loops contiguous to the protease cleavage sites, and the latency-associated structural elements. Moreover, negative-stain EM with full-length antibodies disclosed a stable, ring-like antigen–antibody structure in which the two Fab arms of a single antibody occupy the two arm regions of the prodomain in the pro- and latent myostatin homodimers, suggesting a 1:1 (antibody:myostatin homodimer) binding stoichiometry. These results suggest that SRK-015 binding stabilizes the latent conformation and limits the accessibility of protease cleavage sites within the prodomain. These findings shed light on approaches that specifically block the extracellular activation of growth factors by targeting their precursor forms.
Myeloid-specific deficiency of pregnane X receptor decreases atherosclerosis in LDL receptor-deficient mice [Research Articles]
The pregnane X receptor (PXR) is a nuclear receptor that can be activated by numerous drugs and xenobiotic chemicals. PXR thereby functions as a xenobiotic sensor to coordinately regulate host responses to xenobiotics by transcriptionally regulating many genes involved in xenobiotic metabolism. We have previously reported that PXR has pro-atherogenic effects in animal models, but how PXR contributes to atherosclerosis development in different tissues or cell types remains elusive. In this study, we generated an LDL receptor-deficient mouse model with myeloid-specific PXR deficiency (PXRMyeLDLR–/–) to elucidate the role of macrophage PXR signaling in atherogenesis. The myeloid PXR deficiency did not affect metabolic phenotypes and plasma lipid profiles, but PXRMyeLDLR–/– mice had significantly decreased atherosclerosis at both aortic root and brachiocephalic arteries compared with control littermates. Interestingly, the PXR deletion did not affect macrophage adhesion and migration properties, but reduced lipid accumulation and foam cell formation in the macrophages. PXR deficiency also led to decreased expression of the scavenger receptor CD36 and impaired lipid uptake in macrophages of the PXRMyeLDLR–/– mice. Further, RNA-Seq analysis indicated that treatment with a prototypical PXR ligand affects the expression of many atherosclerosis-related genes in macrophages in vitro. These findings reveal a pivotal role of myeloid PXR signaling in atherosclerosis development and suggest that PXR may be a potential therapeutic target in atherosclerosis management.
Structural basis of specific inhibition of extracellular activation of pro- or latent myostatin by the monoclonal antibody SRK-015 [Molecular Biophysics]
Myostatin (or growth/differentiation factor 8 (GDF8)) is a member of the transforming growth factor β superfamily of growth factors and negatively regulates skeletal muscle growth. Its dysregulation is implicated in muscle wasting diseases. SRK-015 is a clinical-stage mAb that prevents extracellular proteolytic activation of pro- and latent myostatin. Here we used integrated structural and biochemical approaches to elucidate the molecular mechanism of antibody-mediated neutralization of pro-myostatin activation. The crystal structure of pro-myostatin in complex with 29H4-16 Fab, a high-affinity variant of SRK-015, at 2.79 Å resolution revealed that the antibody binds to a conformational epitope in the arm region of the prodomain distant from the proteolytic cleavage sites. This epitope is highly sequence-divergent, having only limited similarity to other closely related members of the transforming growth factor β superfamily. Hydrogen/deuterium exchange MS experiments indicated that antibody binding induces conformational changes in pro- and latent myostatin that span the arm region, the loops contiguous to the protease cleavage sites, and the latency-associated structural elements. Moreover, negative-stain EM with full-length antibodies disclosed a stable, ring-like antigen–antibody structure in which the two Fab arms of a single antibody occupy the two arm regions of the prodomain in the pro- and latent myostatin homodimers, suggesting a 1:1 (antibody:myostatin homodimer) binding stoichiometry. These results suggest that SRK-015 binding stabilizes the latent conformation and limits the accessibility of protease cleavage sites within the prodomain. These findings shed light on approaches that specifically block the extracellular activation of growth factors by targeting their precursor forms.
Proteomics of the Chloroplast Envelope Membranes from Arabidopsis thaliana
Myriam Ferro
May 1, 2003; 2:325-345
Research
My Faith in Nerds: Stronger Than Any Gelatinous Cube
dConstruct 2010: Merlin Mann - "Kerning, Orgasms & Those Goddamned Japanese Toothpicks" (NSFW)
Download the audio | Huffduff it
Let's be honest. I don't go...mmmm...places very often.
I sit in this chair. I go to the Safeway with my daughter. Sometimes, I take the train downtown to get a haircut. I check the mail.
But, by and large, like most nerds, I'm without question, a bit of a shut-in.
Which makes it more than a little ironic that my first trip off the North American continent brought me all the way to Brighton, England's wonderful dConstruct Conference.
Which wonderful conference placed me inside a very royal complex, alone on a very large stage, 90 seconds after being informed I'd better be entertaining, because I'd be conducting my oration on the same spot where, a scant 36 years earlier, ABBA had become international stars by singing an up-tempo number about giving up. So, y'know. No pressure.
Commanded to this location by two of my web heroes, I was told I could speak about whatever I wanted. So, wow, to quote the ladies of ABBA, how could I ever refuse?
Thus, I stood on that stage for over 35 minutes, rambling to 800 talented, creative people about Dungeons & Dragons, japanese toothpicks, torrenting Photoshop, as well as what I used to find myself doing after a long evening of shooting mutants in Stargate.1
But, mostly? Yes. Mostly, I stood on a stage thousands of miles from the chair from which I barely move, and I told a lot of really smart people that they were nerds. I also told them they should get out more.
I swear: it made sense at the time.
Some Serious Talent
My talk about the challenges and opportunities of being a giant nerd seemed well received. Honestly, I'm very happy with how it turned out. But--oh, brother--was I ever up against some heavy hitters. Serious Lou Gehrig shit.
I'll leave it to other, more eloquent folks to tell you what a wonderful day this was. But I will very much suggest you learn this for yourself by listening to the audio of the fantastic talks. Because every one of them is a corker.
Additionally, like I said, Tom Coates put on one of the loveliest slide decks it's ever been my pleasure to see (56MB PDF).
Great speakers, great hosts, wonderful attendees (who aren't above buying a yank a pint [thanks, everybody]).
And, Thanks, dConstruct
I have to admit, I'm kind of over conferences as a thing, which makes it even more crazy when I go to one, and it blows me out of the water with the care and quality of the event, the speakers, and the attendees. dConstruct was absolutely one of those blown-out-of-the-water events.
(photo: happy.apple)
As I learned over and over again--yes, like me--these folks are nerds. But, brother are they ever talented nerds who care and care. Which I just love so much.
I'll take a nerdy bunch of fontdorks and cellists over a splashy mega-conference full of VC pitches and skanks pushing free Red Bull anytime. Anytime.
dConstruct was simply a top-notch operation from end-to-end, and I'm insanely grateful that I was invited to participate. Thanks, Clearleft.
And, you, the reader? If you get the chance next time, go. Heck, I might even leave this chair and go there, myself. Maybe.
I suppose when Dr. Who's over, I could just let these 20-sided dice decide for me. Lemme see...what's my Armor Class and Hit Points...?
Listen for Yourself2
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Hint: Number Three. ↩
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Code for these was stolen wholesale from the dConstruct site. Jeremy, et al - don't hesitate to tell me if that's a problem.Srsly. ↩
”My Faith in Nerds: Stronger Than Any Gelatinous Cube” was written by Merlin Mann for 43Folders.com and was originally posted on September 10, 2010. Except as noted, it's ©2010 Merlin Mann and licensed for reuse under CC BY-NC-ND 3.0. "Why a footer?"
German digital publishing – the Berlin way
My favorite number at the first TOC buchreport in Berlin on April 23rd was 20, as in 20% of the 2.4 million ebook buyers in Germany in 2012 had not bought any books in the previous twelve months, according to …
Drag queen Pissi Myles causes a stir with unexpected appearance at the impeachment hearings
Myles stole the show with a towering blonde wig and shiny red mini-dress.
Angel investing strategies
My friend Jerry Neumann wrote a great post on angel investing strategies, dissecting truth and myth about different betting strategies and sharing his own approach. The question of luck came up and a commenter linked to my work on data-driven patterns of successful … Continue reading
My most favorite math proof ever
Math is beautiful and, sometimes, math becomes even more beautiful with the help of a bit of computer science. My favorite proof of all time combines the two in just such a way. Goal: prove that the cardinality of the … Continue reading
My final Associated Press high school boys basketball ballot
IHSAA basketball: IndyStar's high school insider Kyle Neddenriep ranks boys basketball teams statewide.
My Associated Press high school boys basketball ballot for this week
Bloomington South, Silver Creek, Fort Wayne Blackhawk, Barr-Reeve No. 1 teams on my ballot for this week
My Associated Press high school boys basketball ballot for this week
Bloomington South, Silver Creek, Fort Wayne Blackhawk, Greenwood Christian on top of my ballot
My Associated Press high school boys basketball ballot for this week
Bloomington South, Lawrence North, Lawrence Central top three on my Class 4A ballot this week
My Associated Press high school boys basketball ballot this week
Bloomington South No. 1 on my Class 4A ballot this week
My Associated Press high school boys basketball ballot for this week
Lawrence North, Silver Creek, Fort Wayne Blackhawk, Greenwood Christian on top of my ballot this week
Pacers big man Myles Turner helps his father through coronavirus scare
Myles Turner of the Indiana Pacers discusses coronavirus and how his performance changed after the All-Star break
Mysterious death of tech giant worker in Hamilton County baffles police
David Fouts had a good job at Salesforce and lived a standard middle-class life. That's why police in Hamilton County are baffled by his death.
Mystery author Charles Finch gets stoned, masters Steely Dan and becomes a "candle guy"
In our latest quarantine diary, Charles Finch contemplates Kierkegaard, watches "Love Is Blind," gets the Led out and develops a candle habit.
My therapist's orders: Go on 35 first dates
My therapist was pushing me to date more, which is hard when you're a teacher and can't go out "on a school night." But I'm getting myself out there. L.A. traffic willing.
My fave travel places are closed. I'm still (virtually) visiting
I ache to stay at the Metropol in Moscow, and stroll through the Louvre. For now, videos and photos will have to do.
A more uncertain world than ever for sporting retirees
My retirement came at the very start of the season so it felt like things had dragged on for quite a while for me before I could attempt to cut ties because I had already kicked off the season with the current group.
Why I’m on a rent strike
My landlord in Stuyvesant Town is the private equity giant Blackstone, which happens to be the world’s largest private landlord. Blackstone sent a letter to tenants on March 30th offering a “rental assistance program” during COVID-19. The program just meant tenants can break their lease and move during a pandemic, use their security deposit (and pay it back later), or commit to paying full rent over a longer period of time, if we can prove we’ve suffered economic loss.
Two Cities ~ Two Countries
My wife and I recently visited Niagara Falls this past August in our quest to escape some of the summer heat. I had been there two earlier times as a child and a parent. The town of Niagara has seen…
Travel to Guayaquil
My travels to the largest city of Ecuador where pretty uneventful Nothing went wrong and everything ran pretty smoothly which was nice. I flew from Boston to Miami and from Miami to Guayaquil. At MIA Miami International Airport I met up with Gabriel whi