This was nonsense at the time (2022), but more importantly you can imagine what other nonsense Jeremy Peters - and his editors - believe.

Picture this. Walking down 135th street in Harlem, you spot a park in the distance. As you walk closer, you hear a basketball bouncing and kids yelling. It’s a small, outdoor court, well-maintained with fresh paint and a sturdy chain-link fence surrounding it. The ball is constantly in motion, being passed, dribbled, and shot from […]

"Most people do not get a clear opportunity to vote against Communism and prevent a historical evil from taking hold. We have that opportunity. Vote Trump." — James Lindsay

Hardcover, Paperback, Kindle, Audio – January 1, 1993

Hardcover – Large Print, June 8, 2023

Photo by freestocks The issue of rape-related pregnancies is a crucial yet often-overlooked aspect of the broader debate surrounding abortion access. As more states implement strict abortion bans, the implications for survivors of sexual violence become increasingly severe and far-reaching. When Hadley Duvall was just 12 years old, she was raped and impregnated by her stepfather. […]

The post Forced to Carry: The Reality of Rape-Related Pregnancies in a Post-Roe World appeared first on Feminist Majority Foundation.

Read The Vape Landscape In Bad Shape

Customer: "I want a pack of Virginia Tobacco Juul pods."
Me: "You have ID?"
Customer: "Oh, I don't have one. Let me get my mom."

Read The Vape Landscape In Bad Shape

The post The Essential Guide to Low-Light Landscape Photography appeared first on Digital Photography School. It was authored by Natalie Denton (nee Johnson).

Low-light landscape photography offers a unique challenge for photographers. On the one hand, a landscape lit by softer, subtler light can result in the kind of magical shots that go beyond more conventional photos. On the other hand, capturing these scenes requires a careful approach and a keen understanding of camera settings. But don’t fret! […]

The post The Essential Guide to Low-Light Landscape Photography appeared first on Digital Photography School. It was authored by Natalie Denton (nee Johnson).

The post 12 Tips for Stunning Urban Landscape Photography appeared first on Digital Photography School. It was authored by Leanne Cole.

Urban landscape photography is all about taking the chaotic complexity of a city and turning it into well-ordered, beautiful compositions. But if you’re just a beginner – or even if you’re a more experienced city shooter – you may struggle to get solid results. After all, cities are often messy, unstructured, and full of movement; […]

The post 12 Tips for Stunning Urban Landscape Photography appeared first on Digital Photography School. It was authored by Leanne Cole.

Los Angeles, often hailed as the entertainment capital of the world, is not only a hub for the film and music industries but also a fascinating canvas of urban design. The city's architectural landscape reflects a rich tapestry woven with threads of history, culture, and innovation. As one navigates the vast expanse of Los Angeles, it becomes apparent that the city's design is a dynamic fusion of tradition and modernity.[...]

Plant-based paper has been used for thousands of years, but exactly how is it created from trees?

The 9 a.m. service on Monday, Nov. 11, will also be livestreamed.

I learned to create decorative painted papers from Paulus Berensohn, Albie Smith, Lynne Perrella, Anne Bagby, and others by taking wonderful workshops from them in the 1990s, and soon adapted their techniques to making books with beadwork inserted into the covers, like the one below. I use my painted papers on the book covers and for signature covers, which look great with this type of binding.

But after moving to the island where I've lived for 20 years now, I gradually got into quilting and textile arts, kept the beadwork going, and cut way back on painting. Until now!

Inspired, cajoled, and arm-twisted by one of the Textile Guild members, who wants to learn how to paint papers and make books like mine, I agreed to teach a workshop (2 days of painting and 2 days of bookmaking) for the guild members. Of course, since I hadn't painted for many years, I first had to get back into practice. Yay! What fun I've been having, painting in my shed (thankfully heated). The paper below is my favorite of about 20 painted in the last two weeks. The size is 18 x 24 inches. (Please click to see the details!)

And below are two more to go with it.  The paper above will be used for a book cover, even though it will be hard for me to cut it up. The two papers below will be cut (horizontally) into thirds, and used as signature covers. For those unfamiliar with bookmaking, a signature is a section of papers within a book. Each of the six signatures in my book will be covered with this decorative paper.


It's a fun, playful, and experimental process to paint like this, easier for me than it would be to paint figuratively (landscape, still life, or people). With this type of painting, I just mix matte medium with a color or two of acrylic paint, and apply it by rolling, stamping, stenciling in layers. I keep adding layers until I like it, at which point it's a finished paper. There is always at least part of each paper that pleases me enough to use it for bookmaking and paper arts.

These are the basic supplies and tools I use to paint the papers:

1.) Although acrylic paints and this method can be used to paint on almost any surface or paper, I usually paint on 80-90# drawing paper to make decorative papers.

2.) I prefer using a roller to apply background colors or glazes, rather than a brush. My favorite, purchased online from Dick Blick Art Supplies, is a 2.2"  dense foam roller.

3.) Assorted stamps and stencils. I carve a lot of my own stamps, as you will see below, but sometimes also use commercial stamps. Note that commercial rubber stamps with fine detail for stamping with inks do not work well with acrylics, as the paint clogs the fine lines, ruining the stamp.

4.) Assorted materials, such as a notched adhesive-spreader, coarse sea-sponge, webbed food packaging materials, and bubble wrap are useful to print, texture, and stencil.

5.) Acrylic paints. I use heavy-body paint (rather than fluid acrylics) of student-grade or better quality.

6.) Matte medium and glazing medium (slow drying) are added to extend the paint.

I know, maybe you're thinking I should do a video tutorial. OK. You set it up, and I'll do it. In the meantime, I'd rather be painting...  Here are three more recently painted papers for your viewing pleasure (I hope).



The one directly above is my attempt to emulate batik fabric from India. I had a bedspread back in the hippy 60s with a burgundy design on a mustard yellow background, the memory of which was the inspiration for this paper. I carved all of the stamps used to make it.

I love to carve my own stamps, and sometimes cut my own stencils as well. Let's take a look at that process. It's quite easy really, requiring only a block of Speedy-Carve (or other high-density rubber carving block), and a Speed-Ball Carving tool. Designs can be free cut, drawn right on the carving block, or transferred from a tracing. Here's a fairly decent tutorial on the stamp carving process.

Designs? Well, everywhere I look I see possibilities for carving more stamps! Recently, visiting a fabric store with my quilting buddies, I spied a fat quarter of batik fabric with a luscious design. Here is the fabric:

And here is the stamp I carved from a tracing I made of the central flower. The stamp is the same size as on the fabric, about 3" in diameter.

I also cut a stencil, which you can see below. A friend had a commercial stencil of these three leaves, which I really liked. After borrowing her stencil to use on one of my papers, I traced the painted image, and cut out my own stencil. The tool in this image is a Speed-Ball cutter, which I use to carve the rubber to make stamps.

You've already seen (way above) the whole sheet of paper I painted using just this stamp and stencil, but here's a detail. If you click to enlarge, you can see more about how I paint in layers, first the background colors, next the leaves, then a different color over-stencil on the leaves, and last the flowers.

If you like to play with paint, you might want to give it a try! Here are just a few more of my recently painted papers to tempt you...





I'll be teaching a 2-day bookmaking workshop in mid-May using papers like these to create three different books. There may still be a spot or two available in the class. If you are interested, you can contact me for more information.

You may want to visit my website to see more about my handmade books and painted papers. And there are several earlier posts here on Beadlust with pictures of books made with painted decorative papers and beading by my students, as well as other related topics. Here are a few of them:

1. Wedding book
2. Lisa's book (from a workshop I taught in Wisconsin); her fabulous website is here.
3. Susan's book (from a workshop I taught in Wisconsin)
4. painting papers for making Christmas cards
5. Using symbols in our art and symbols in acrylic painting  
6. Using these techniques to paint with dyes on fabric and more fabric paint/dye examples

Susan Anderson took my bookmaking/painting/beading workshop twice at the Coupeville Art Center. These are the papers for her first book, and if you click to enlarge, you can also see her finished book.

And, to close this post, here is a photo of some of the handmade books I've created over the years... most of them utilize decorative painted papers and bead embroidery.

Thanks for sticking with me to the end of this long post :)!

tataata has added a photo to the pool:

We all know the struggle – sometimes, no matter how hard we hit the gym or watch our diet, there’s that stubborn tummy bulge that just won’t budge. But don’t worry, we’ve got your back (or should I say, your front?)!  Today, we’re diving into the world of tummy control shapewear, those magical pieces that ... Read more

The post Enhance Your Silhouette: The Top Picks for Best Tummy Control Shapewear appeared first on Star Two.

In the 1700s, an enslaved man named Onesimus shared a novel way to stave off smallpox during the Boston epidemic. Here’s his little-told story, and how the Atlantic slave trade and Indigenous medicine influenced early modern science.

From the ancient origins of zero to the paradox of motion, NOVA’s teaching resources immerse students in the wonder of math.

Ronan credits her parents and the filmmakers she worked with as a child for keeping acting fun. She stars as a woman struggling with addiction in The Outrun and as a World War II mother in Blitz.

The FEMA official who was just fired for telling workers to avoid homes impacted by the hurricanes in Florida if they had Trump signs says that it was not “isolated” and that FEMA workers were instructed to do it in the Carolinas too. (X) The American people must get justice. Indict and convict. So, apparently this …

A group of teenagers in Fife have been making a documentary about the impact of disposable vapes.

The Prince of Wales is on a trip in South Africa promoting his Earthshot environmental prize.

Dozens of videos involving a senior civil servant in Equatorial Guinea have flooded social media, shocking people in the country.

Trump has started filling key White House roles, starting with Susie Wiles as his chief of staff.

Uber Safari is launching this week, offering riders in Cape Town the opportunity to go on a one-day game drive to a private reserve for $200.

We are doing what we do best when something threatens the consumer supply chain: rushing to buy mountains of toilet paper. Experts say the dockworkers' strike won't result in shortages, but the panic-buying might so long as the panic-buying lasts.

"They cleaned out the toilet paper at my local Walmart in Virginia.

— Read the rest

The post Toilet paper buying panic recommences as dockworkers strike appeared first on Boing Boing.

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.

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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.

Mekka Newspaper, Mecca, Saudi Arabia: Oct. 28, 2022 It was my distinct honor to Arabic receive a wonderful review by Mecca Newspaper, one of the oldest newspapers in the Middle East. I am deeply grateful and humbled to be part of the historic reformation and renaissance taking place in the Middle East. When Mecca newspaper […]

An important mechanism of resistance to β-lactam antibiotics is via their β-lactamase–catalyzed hydrolysis. Recent work has shown that, in addition to the established hydrolysis products, the reaction of the class D nucleophilic serine β-lactamases (SBLs) with carbapenems also produces β-lactones. We report studies on the factors determining β-lactone formation by class D SBLs. We show that variations in hydrophobic residues at the active site of class D SBLs (i.e. Trp105, Val120, and Leu158, using OXA-48 numbering) impact on the relative levels of β-lactones and hydrolysis products formed. Some variants, i.e. the OXA-48 V120L and OXA-23 V128L variants, catalyze increased β-lactone formation compared with the WT enzymes. The results of kinetic and product studies reveal that variations of residues other than those directly involved in catalysis, including those arising from clinically observed mutations, can alter the reaction outcome of class D SBL catalysis. NMR studies show that some class D SBL variants catalyze formation of β-lactones from all clinically relevant carbapenems regardless of the presence or absence of a 1β-methyl substituent. Analysis of reported crystal structures for carbapenem-derived acyl-enzyme complexes reveals preferred conformations for hydrolysis and β-lactone formation. The observation of increased β-lactone formation by class D SBL variants, including the clinically observed carbapenemase OXA-48 V120L, supports the proposal that class D SBL-catalyzed rearrangement of β-lactams to β-lactones is important as a resistance mechanism.

Earlier this month when Alicea Samaru-Brown walked across the stage at The University of the West Indies (UWI) graduation, she beamed with pride. Her husband, Dennis Brown, and her son, Orlando Brown, cheered the loudest from the audience and this...

The Clarendon police have arrested and charged 25-year-old landscaper Anthony Marshall, of Lamparth district, Trout Hall in the parish for allegedly stealing oranges from a property in his community on Sunday.

Youth innovation can help shape the future of African cities Expert comment LToremark 16 August 2022

To meet the challenges of rapid urbanization, African governments must harness the potential of young innovators to help shape the future of African cities.

It is projected that 1.3 billion people will be living in Africa’s cities by 2050, an increase of almost 1 billion from today, and largely driven by young people migrating to urban centres in search of work. As the continent’s urban population grows, cities will need to adapt by nurturing new economic ecosystems to create jobs, while managing the environmental, social and political pressures that urbanization brings.

The evolution of Africa’s cities is critical for meeting the demands of its youth population and must be co-created with them. Africa’s young innovators are already proving to be an asset in shaping the future of African cities and, if they are allowed to flourish, they could be at the forefront of finding much-needed solutions to the continent’s vast urban challenges.

Growing tech hubs

African countries are increasingly benefitting from growth in technology ecosystems, which are often clustered within cities. There are currently more than 600 tech hubs helping to incubate innovative solutions across cities in Africa. Between 2015 and 2020, the number of start-ups receiving funding grew six times faster than the global average. In 2021 alone, start-ups raised over $4billion in funding – twice as much as in 2020.

But significant challenges remain. While the number of new start-ups is an encouraging indication of the entrepreneurialism and creativity of Africa’s youth, job creation on the level required will demand that they grow and scale up to generate more and higher quality jobs. Research on scaling up in Africa is sparse but research by Endeavor suggests that in Nairobi – one of Africa’s top tech ecosystems – only 5 per cent of companies are able to sustain growth of 20 per cent or more each year, yet they created 72 per cent of new jobs in the previous three years. For Africa to fully harness the potential of digital innovation, making cities the best place for young people to launch ideas and grow them into thriving businesses must become a priority policy for African governments. 

Barriers to scale

On the most basic level, business growth needs access to the services that make cities more liveable and help both urban residents and firms become more productive, such as healthcare, transport, water and sanitation. African cities already struggle to provide their residents – in particular the poorest and most vulnerable – with equitable, reliable, affordable and quality access to these services, in a sustainable manner. And these challenges will only get more acute as urban populations rise rapidly, often without any kind of integrated planning.

For example, an estimated 70-80 per cent of municipal solid waste in Africa is recyclable, yet only about 4 per cent is currently recycled, with more than 90 per cent of waste ending up in uncontrolled dumpsites and landfills. As Africa’s urban population grows, these conditions are likely to worsen – unless there is urgent action. New technology has the potential to help by creating a positive feedback loop between innovation, service delivery and growth. For example, to bridge the waste management gap, innovators are exploring various tech-enabled circular economy models. These solutions are often ground-breaking and have the potential to leapfrog traditional waste management infrastructure. Crucially, they are also formalizing a largely informal sector and creating new jobs.

Across the continent, start-ups like Kaltani, Mr Green Africa and Freetown Waste Transformers build processing facilities to turn waste into energy or reusable products, such as construction materials. Others, like Scrapays, Regenize and Soso Care, are helping households and businesses sell off their recycled materials for cash and virtual currencies or exchange them for critical services, such as micro health insurance premiums. Such start-ups help empower informal waste pickers or agents with tech-enabled tools and target low-income urban communities that would not normally prioritize recycling.

Help or hindrance from the top?

But Africa’s young people cannot do this alone – government decision-makers must become catalysts for entrepreneurial leadership. This requires nurturing a mindset that sees young innovators as Africa’s biggest resource, not a threat. While the importance of young people to Africa’s development is acknowledged in various high-level regional treaties, patterns of inhibition and outright hostility from political ‘elites’ suggest that the disruptive nature of technology start-ups and their access to significant capital through venture capital funding models – unlike existing rent-seeking business models with government control – threatens the political establishment.

The growing use of tech solutions also leads to increased transparency and efficiency of service delivery, which in turn leads to increased demand for government accountability and pressure to adopt more liberal policies. Until there is a shift towards catalysing entrepreneurial leadership, there is a stronger incentive for political elites to leverage their powers to co-opt successful technology businesses, or otherwise try to control them for political gain, than let them flourish. This shift in mindset will be critical to unlocking the full potential of Africa’s young innovators.

Visual Abstract

On October 24 and 25, SophosAI presents ideas on how to use models large and small—and defend against malignant ones.

Alison M. Kurimchak
Dec 1, 2020; 19:2068-2089
Research

Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.

The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.

Nicholas D. LeBlond
Dec 1, 2020; 61:1697-1706
Research Articles

The dysregulation of myeloid-derived cell metabolism can drive atherosclerosis. AMP-activated protein kinase (AMPK) controls various aspects of macrophage dynamics and lipid homeostasis, which are important during atherogenesis. Using LysM-Cre to drive the deletion of both the α1 and α2 catalytic subunits (MacKO), we aimed to clarify the role of myeloid-specific AMPK signaling in male and female mice made acutely atherosclerotic by injection of AAV vector encoding a gain-of-function mutant PCSK9 (PCSK9-AAV) and WD feeding. After 6 weeks of WD feeding, mice received a daily injection of either the AMPK activator A-769662 or a vehicle control for an additional 6 weeks. Following this (12 weeks total), we assessed myeloid cell populations and differences between genotype or sex were not observed. Similarly, aortic sinus plaque size, lipid staining, and necrotic area did not differ in male and female MacKO mice compared with their littermate floxed controls. Moreover, therapeutic intervention with A-769662 showed no treatment effect. There were also no observable differences in the amount of circulating total cholesterol or triglyceride, and only minor differences in the levels of inflammatory cytokines between groups. Finally, CD68+ area and markers of autophagy showed no effect of either lacking AMPK signaling or AMPK activation. Our data suggest that while defined roles for each catalytic AMPK subunit have been identified, complete deletion of myeloid AMPK signaling does not significantly impact atherosclerosis. Additionally, these findings suggest that intervention with the first-generation AMPK activator A-769662 is not able to stem the progression of atherosclerosis.

Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the up-regulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC.

The development of the HUPO-PSI's (Proteomics Standards Initiative) standard data formats and MIAPE (Minimum Information About a Proteomics Experiment) guidelines should improve proteomics data sharing within the scientific community. Proteomics journals have encouraged the use of these standards and guidelines to improve the quality of experimental reporting and ease the evaluation and publication of manuscripts. However, there is an evident lack of bioinformatics tools specifically designed to create and edit standard file formats and reports, or embed them within proteomics workflows. In this article, we describe a new web-based software suite (The ProteoRed MIAPE web toolkit) that performs several complementary roles related to proteomic data standards. Firstly, it can verify the reports fulfill the minimum information requirements of the corresponding MIAPE modules, highlighting inconsistencies or missing information. Secondly, the toolkit can convert several XML-based data standards directly into human readable MIAPE reports stored within the ProteoRed MIAPE repository. Finally, it can also perform the reverse operation, allowing users to export from MIAPE reports into XML files for computational processing, data sharing or public database submission. The toolkit is thus the first application capable of automatically linking the PSI's MIAPE modules with the corresponding XML data exchange standards, enabling bidirectional conversions. This toolkit is freely available at http://www.proteored.org/MIAPE/.

Subsidies and Sustainable Agriculture: Mapping the Policy Landscape Research paper sysadmin 10 December 2019

Agricultural subsidies shape production and consumption patterns, with potentially significant effects on poverty, nutrition and other sustainability concerns. This paper maps the different types of support provided by governments to the agricultural sector, and highlights some of the complex political economy dynamics that underpin the relevant policies.

Summary

• Agricultural subsidies, a mainstay of government policy, have a large part in shaping production and consumption patterns, with potentially significant effects as regards poverty, food security, nutrition, and other sustainability concerns such as climate change, land use practices and biodiversity.
• There are multiple types of direct and indirect support provided by governments to various actors in the agricultural sector; and in terms of political economy, there are complex dynamics underpinning the policies that sustain these subsidies.
• Overall, subsidies targeting producers have the most significant effect on production, and the greater trade-distorting effect. These subsidies promote domestic production and discourage imports, leading to overproduction that is largely disposed of on the international market, with the help of export subsidies. This can tend to intensify negative environmental agricultural practices, such as cultivating marginal land, unsustainable types of intensification, or incentivizing excessive pesticide and fertilizer use.
• On the other hand, producer subsidies that are not tied to output of a specific commodity (i.e. delinked) have far fewer distorting impacts and could help to deliver sustainable outcomes. For example, this type of subsidies can require crop diversification or be linked to conservation of permanent grassland.
• Subsidies that enable transfers to consumers, for example through food stamp programmes, also serve to delink production from consumption, can foster healthier diets, can play an important role in delivering food accessibility and security among low-income groups, and can represent one of the less trade-distorting subsidies.
• If subsidies are to be reformed to help promote healthier diets and encourage more sustainable production, it is essential to understand not only the type and amount of support that key countries provide, but also the domestic dynamics that can shape such policies.
• While price support, input subsidies or investment aids remain the central pillars of programmes in large developing countries such as Brazil, China or India, other economies – notably including the EU and Japan – focus on direct payments, support for general services and set-aside schemes, as well as significant border protection. The US, for its part, has tended to focus on subsidized insurance schemes and food programmes for poorer consumers.
• If subsidies are to deliver policy objectives, their design and implementation should delink production from consumption. For example, consumer subsidies designed to deliver nutrition and food security, or payments for environmental services to enable more environmentally friendly production systems, could prove to be the most effective, least trade-distorting means of achieving more sustainable and equitable agricultural production.
• The political economy of food means that the removal of subsidies is often highly sensitive, and tends to be met with significant resistance. However, reform that delinks support from production through a gradual transition process could ultimately prove successful in delivering effective subsidy schemes.
• Effective subsidy schemes must by design be truly result- and performance-based, supported by robust and objective indicators. At the same time, engaging multiple actors along key commodity value chains – including leading importing and exporting countries, traders and transporters – could lead to the development of international, commodity-specific arrangements that are able to deliver effective nutrition and sustainability goals.

Russia's war: How will it shape the region's future? 1 December 2022 — 9:00AM TO 6:00PM Anonymous (not verified) 17 August 2022 Chatham House and Online

This conference takes a deep-dive into the implications of the war for the wider region.

You will receive an email in advance of the conference with further details on accessing the event.

The video on this page is of the opening session only. To view all the session videos, please visit the conference playlist on YouTube.

How will Russia’s war shape the region’s future?

Russia’s latest invasion of Ukraine is on such a scale that it will have a seismic effect on all the countries that once formed the Soviet empire. Vladimir Putin’s decisions have accelerated trends across the region leading to unintended consequences.

Now it is more crucial than ever – not only for those concerned with the region’s economic and democratic development, but for all those with a stake in the future security of Europe.

For some states, this will mean a faster break from the legacy of the USSR and from Russia’s ‘Geopathological embrace‘ while, for others, maybe even a fresh start at democracy and good governance.

In isolated cases, the war will conceivably hasten assimilation with Russia. But the two principal combatants, Ukraine and Russia, will diverge even further. Ukraine, though fighting for its survival now, will at least get the opportunity to ‘build back better’ if it achieves some form of victory.

Whatever the course of the war, however, Russia’s aspirations to be a global power again are doomed as it is gradually deglobalized from Western structures.

This conference analyses:

• How Russia’s war will affect the broader regional economy and whether this will hasten Vladimir Putin’s exit
• What to hope for, what to fear and the key trends that will dominate the region going forward.
• Unique expertise in an independent forum on what’s at stake for Europe.