Vice President Mike Pence toured a GM facility making hospital ventilators for about an hour Thursday.

2020-03-23 -

Cummins is partnering with Minnesota-based 3M to make filters for use in respirators used during the COVID-19 outbreak.

Source: The Pacers will listen to the government and follow its lead before bringing players back

Source: The Pacers will listen to the government and follow its lead before bringing players back

The transport secretary warns social distancing will mean severely-reduced passenger capacity.

Isle of Wight residents have mixed feelings about being used to test the government's new app.

Racing is scheduled for Greenland, Brazil, Nepal and Senegal, among other places.

In 1961, F1 driver Sir Stirling Moss won the hearts of the nation to be crowned Sportsview Personality winner.

Even Ferrari's F1 drivers feel constrained by the lockdown, but Charles Leclerc wants to give people something to enjoy.

Lewis Hamilton says the lack of racing in Formula 1 so far this year has left him feeling "a big void".

If the Isle of Wight trial is successful, the app could be ready nationwide within weeks, ministers say.

• As the coronavirus-led economic shutdown drags on, many investors have started counseling startups to have more than a years' worth of "runway" to avoid having to raise funding on poor terms.
• But VCs are split on how much startups should be socking away. Some have estimated 18 months oof reserves could suffice, while others say as much as 3 years' worth of runway is ideal.
• The different time frames depends on the age of the startup along with which industry they operate in. Younger startups typically have fewer overhead expenses, while older startups likely have more employees and pricey office leases.
• Also, those companies that may be able to resume work as essential services may need less cash if they are able to generate revenue.
• VCs are uniformly bracing for an economic slowdown, but the severity of downturn is still up for debate. 
• Click here for more BI Prime stories.

Startups are facing what could become the worst economic downturn in several decades, and VCs are begging them to take drastic measures to improve their chances of making it through. 

Most Americans who lived through the 2008 financial crisis will know that a savings stockpile or rainy day fund can mean the difference between surviving and thriving during tough times, but as recent studies have shown, many tech startups and VC firms don't have a similar first-hand experience; many have only known boom times and are now venturing into uncharted waters.

One thing VCs agree on is that startups need to quickly rein in growth plans — ideally as soon as yesterday — and start scrutinizing expenses. Anything nonessential should be cut or suspended indefinitely, headcount should be reduced, and pricey office leases eliminated if possible, all with the goal of extending a startup's "runway."

In Silicon Valley, runway refers to how much cash a startup has on hand to put against its operating expenses. If, for example, a startup has roughly $100,000 in monthly operating expenses and has $1 million in the bank, they are looking at a 10-month runway, assuming revenue stays roughly flat.

In the days before the coronavirus pandemic, a startup's runway dictated when it had to start looking for additional funding. Instead of cutting expenses, the popular solution was to simply put more VC money in the bank. This helped high flying startups like Uber and Airbnb expand at a breakneck pace — VC dollars kept pouring in and the companies remained unprofitable as they chased growth at all costs.

But now, VCs are saying that's no longer an option. Founders Fund general partner Keith Rabois said on a podcast recently that profitability is now being rewarded much more than high-growth. 

For startups that aren't profitable, that means hunkering down and ensuring there are enough reserves to last through the crisis.

So how long does the runway need to be? 

Many VCs that Business Insider has spoken to are advising their startups to have at least 18 months of runway. But some VCs say startups should have upwards of 3 years' of expenses saved up. 

The length of time can vary depending on the startup, one investor told Business Insider, pointing to the startup's age and industry as important factors. An early-stage company with a handful of employees and low-overhead costs might easily stretch a $500,000 seed check, whereas a growth-stage biotech startup with hundreds of employees, expensive hardware, and pricey office space might struggle to make tens of millions of dollars in funding make it through 12 months. Those that can't cut costs will be forced to fundraise with poor terms and risk the dreaded downround. 

"You can always easily dial back up the aggressiveness and risk profile if we get more optimistic visibility, but if you don't take action right away — to preserve capital, cut your burn rate, have fundamentally attractive unit economics, edit the product to make more sense in the new world order — if you don't do those right away, the opportunity to do those things and survive is probably lost forever," Rabois said in the April Talkshow broadcast.

Rabois is in the camp of pessimists, generally speaking, who think the economic downturn will not only drag on through 2020, but could eventually turn into an economic depression the likes of which could rival the Great Depression of the 1930s. He said that his VC peers are starting to rein in the freewheeling deal-making that has defined the last two decades of the Silicon Valley startup ecosystem, and are now treading cautiously. It's time that startups do the same, he said.

SEE ALSO: Lower valuations and a long wait for funding: Two top early-stage VCs dish on how they are counseling startups to withstand long-term economic uncertainty

Join the conversation about this story »

NOW WATCH: Pathologists debunk 13 coronavirus myths

Sadly, the most recent horrors are not an aberration.

Can an app contain the pandemic? Interest is growing in smartphone technology as a potential key to ending lockdowns and reopening economies around the world.

Local news publishers have struggled to monetize spike in consumer interest.

Please visit Search Engine Land for the full article.

Through Hiking the Pacific Crest Trail at 10

The Amateur Traveler talks to Karl Anders who returns to the show to talk about travel to Western Montana and in particular to the majestic Glacier National Park. Karl encourages us to drive the Going to the Sun Highway but then to get off the blacktop and hick some of the back country of the park (preferably in a group large enough to discourage the curiosity of bears). He describes some of his favorite hikes such as the trail to Hidden Lakes. Glacier is often rated as one of the top places in the United States to hike or backpack. The valleys of Glacier are carved by glacial activity although there aren't as many glaciers still in the park. Karl also talks about some nearby destinations like the National Bison Refuge, Bitterroot Valley and nearby Missoula with its museum to Smokejumpers.

Between having had more than enough of the not-so-great indoors and realizing that the grocery store might not always have meat, Americans are increasingly looking to feed themselves by hunting. “People are thinking about where they get their food and how they get their food,” Land Tawney, president of the advocacy group Backcountry Hunters and…

The post Facing Concerns of Meat Shortages, More Americans Turn to Hunting appeared first on The Western Journal.

Part of the Antarctic diary promo for the BBC UK Homepage

A woman in her 90s living at the Bradford Valley Care Community is the latest coronavirus victim in the region.

3 February 2016

Drawing on the findings of a recent workshop exploring a potential conflict between China and Japan over disputed islands, this paper suggests there are significant differences between how the United States and Europe prioritize their interests in the Asia-Pacific.

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

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

Actinobacillus pleuropneumoniae (App) is the etiological agent of acute porcine pneumonia and responsible for severe economic losses worldwide. The capsule polymer of App serotype 1 (App1) consists of [4)-GlcNAc-β(1,6)-Gal-α-1-(PO4-] repeating units that are O-acetylated at O-6 of the GlcNAc. It is a major virulence factor and was used in previous studies in the successful generation of an experimental glycoconjugate vaccine. However, the application of glycoconjugate vaccines in the animal health sector is limited, presumably because of the high costs associated with harvesting the polymer from pathogen culture. Consequently, here we exploited the capsule polymerase Cps1B of App1 as an in vitro synthesis tool and an alternative for capsule polymer provision. Cps1B consists of two catalytic domains, as well as a domain rich in tetratricopeptide repeats (TPRs). We compared the elongation mechanism of Cps1B with that of a ΔTPR truncation (Cps1B-ΔTPR). Interestingly, the product profiles displayed by Cps1B suggested processive elongation of the nascent polymer, whereas Cps1B-ΔTPR appeared to work in a more distributive manner. The dispersity of the synthesized products could be reduced by generating single-action transferases and immobilizing them on individual columns, separating the two catalytic activities. Furthermore, we identified the O-acetyltransferase Cps1D of App1 and used it to modify the polymers produced by Cps1B. Two-dimensional NMR analyses of the products revealed O-acetylation levels identical to those of polymer harvested from App1 culture supernatants. In conclusion, we have established a protocol for the pathogen-free in vitro synthesis of tailored, nature-identical App1 capsule polymers.

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

8 January 2020 , Volume 96, Number 1

8 January 2020 , Volume 96, Number 1

8 January 2020 , Volume 96, Number 1

8 January 2020 , Volume 96, Number 1

8 January 2020 , Volume 96, Number 1

8 January 2020 , Volume 96, Number 1

8 January 2020 , Volume 96, Number 1

8 January 2020 , Volume 96, Number 1

8 January 2020 , Volume 96, Number 1

8 January 2020 , Volume 96, Number 1

6 November 2019 , Volume 96, Number 1

The first issue of International Affairs in 2020 explores the geopolitics of the 'Indo-Pacific' region.

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

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

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

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

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

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

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