The financial disruptions from the coronavirus pandemic are growing. April brings new challenges for renters, homeowners and small-business owners.

The pilot told deputies he had mechanical difficulties and had to make a rough landing in the cornfield.

Former England, Yorkshire, Nottinghamshire and Derbyshire batsman Brian Bolus dies aged 86.

Jurgen Klinsmann steps down as Germany coach after two years in charge and is replaced by assistant coach Joachim Loew.

One of the hardest tasks in Earth observation is tracking tiny changes in the shape of the ground.

Smart Spring Yard Care That's Also Stylish

A Canadian grocery chain says its introducing a fleet of intelligent grocery carts that scan and weigh products as customers place them in the cart.

Michel will face a Chicago Bears defense that stops opposing rushers a league-low 13 percent of the time.

Government spending grew at its fastest pace since the Great Recession.

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The devices have reached 50% of US homes, but fallen flat as a channel

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Yesterday was a really fun day spent at Nokia World, the Finnish handset maker’s annual shindig. Conveniently, this year it was held in my home city of London and I got to cover the event for TechCrunch Europe. On day one, Nokia unveiled three new smartphones running Symbian^3, the C6, C7 and E7, which I [...]

Traveling with Small Children

The Amateur Traveler talks to Deanna about cruising to Alaska aboard a small boat from Cruise West In a nights ashore / days at sea program.

Hear about travel to Tasmania in Australia as the Amateur Traveler talks to Robert Reid, the Offbeat Observer for National Geographic Traveler, about his recent trip to Van Diemen’s Land.

“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"

The Northern Pudu (Pudu mephistophiles) is the world's smallest deer. This little inhabitant of the Andes Mountains weighs in at only 3 to 6 kg, or 7 to 13 pounds. The Northern Pudu lives and plays across Columbia, Ecuador, and Peru. They prefer to stay in the higher elevations of the Andes Mountain range. Most of them live at least 2000 meters above sea level. The climate here is a temperate rainforest, with a wet winter and arid summer.

What Do They Look Like?

These little deer have a stocky body and slim legs. They average 32 - 35 cm, or 13 - 14 inches tall. They are approximately 85 cm or 33 inches long. They are slightly larger than a small house dog or a large cat. They have a Southern branch of the family that lives in Chili and Argentina. This species is slightly larger. Their fur is thick, stiff and lays close to the body. They range in color from a reddish brown to a darker brown. The males sport backward curving antlers that do not split.

How Do They Survive?

The Pudu is a solitary animal interacting socially only to mate. They are nocturnal by nature and thrive on leaves, shrubs, sprouts, blossoms and bark. They do not eat meat. They are adept at climbing, jumping and sprinting which helps them evade predators. They tend to move slowly and purposefully through the lush climate, utilizing dense vegetation to hide. Predators include owls, foxes, and large wild cats.

How Many Young Do They Have?

Mating season is short, lasting from April to May each year. Once done they return to their solitary existence. The female Pudu carries her young six to seven months. Most mothers have only one baby, but twins do occur with some regularity. Pudu young will stay with their Mommas for between 8 - 12 months before heading out on their own. Most of them have an average lifespan of 8 - 10 years.

Why Are They Endangered?

The Pudu is listed as vulnerable on the ICUN red list. The main causes of death are disease, loss of habitat, and over hunting. The Pudu is prone to become infected with various types of worms such as the round worm and heart worms. The worms multiply rapidly overcoming their small bodies. Loss of habitat has lead to a decline in mating and death from road accidents. Adding to the problem are hunters. The Pudu is eagerly sought due to the skill needed to track and kill them. Conservationist are working to restore and preserve the habitat for these precious little deer.

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.

Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B–E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B–E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS–PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.

N. Leigh Anderson
Apr 1, 2004; 3:311-326
Research

Ivan Matic
Jan 1, 2008; 7:132-144
Research

Hasmik Keshishian
Dec 1, 2007; 6:2212-2229
Research

Leigh Anderson
Apr 1, 2006; 5:573-588
Research

N. Leigh Anderson
Nov 1, 2002; 1:845-867
Reviews/Perspectives

Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development.

Invitation Only Research Event

Research Event

Event participants

HE Dr Motsoahae Thomas Thabane, Prime Minister of Lesotho
Chair: Ian Lucas MP, Shadow Minister for Africa and the Middle East

Oswald Quehenberger
Nov 1, 2010; 51:3299-3305
Research Articles

WS Harris
Jun 1, 1989; 30:785-807
Reviews

Ronald M. Krauss
Jan 1, 1982; 23:97-104
Articles

AR Tall
Aug 1, 1993; 34:1255-1274
Reviews

John A. Glomset
Mar 1, 1968; 9:155-167
Reviews

Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development.

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.

The formation and properties of liquid-ordered (Lo) lipid domains (rafts) in the plasma membrane are still poorly understood. This limits our ability to manipulate ordered lipid domain-dependent biological functions. Giant plasma membrane vesicles (GPMVs) undergo large-scale phase separations into coexisting Lo and liquid-disordered lipid domains. However, large-scale phase separation in GPMVs detected by light microscopy is observed only at low temperatures. Comparing Förster resonance energy transfer-detected versus light microscopy-detected domain formation, we found that nanodomains, domains of nanometer size, persist at temperatures up to 20°C higher than large-scale phases, up to physiologic temperature. The persistence of nanodomains at higher temperatures is consistent with previously reported theoretical calculations. To investigate the sensitivity of nanodomains to lipid composition, GPMVs were prepared from mammalian cells in which sterol, phospholipid, or sphingolipid composition in the plasma membrane outer leaflet had been altered by cyclodextrin-catalyzed lipid exchange. Lipid substitutions that stabilize or destabilize ordered domain formation in artificial lipid vesicles had a similar effect on the thermal stability of nanodomains and large-scale phase separation in GPMVs, with nanodomains persisting at higher temperatures than large-scale phases for a wide range of lipid compositions. This indicates that it is likely that plasma membrane nanodomains can form under physiologic conditions more readily than large-scale phase separation. We also conclude that membrane lipid substitutions carried out in intact cells are able to modulate the propensity of plasma membranes to form ordered domains. This implies lipid substitutions can be used to alter biological processes dependent upon ordered domains.

The CuMasks have undergone strict testing and certification processes before the product will be distributed to help people combat the COVID-19 virus, Secretary for Innovation & Technology Alfred Sit said today.

Mr Sit’s remarks came amid public concerns over the safety of the free reusable face masks that the Government plans to distribute to all Hong Kong citizens.

Addressing reporters after attending a radio programme this morning, Mr Sit said: “The product has gone through a very comprehensive and clear testing and certification process.

“The product can fully comply with the American Society for Testing & Materials (ASTM) F2100 Level 1 requirement, so that the product can fully meet the need of protecting our people from COVID-19.

“I have to emphasise that this whole process must be done by proper laboratories and that’s what we have done.”

Mr Sit noted that a dedicated website on the CuMask has been set up that contains information on the testing reports of the masks.

“For those people who may not have a complete understanding about our product, they may go to our website so that they can see the reports and certificates.

“I fully hope this product can help our people to combat COVID-19.That’s what we would like to do."

Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B–E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B–E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS–PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.

The actin cytoskeleton is extremely dynamic and supports diverse cellular functions in many physiological and pathological processes, including tumorigenesis. However, the mechanisms that regulate the actin-related protein 2/3 (ARP2/3) complex and thereby promote actin polymerization and organization in cancer cells are not well-understood. We previously implicated the proline-rich 11 (PRR11) protein in lung cancer development. In this study, using immunofluorescence staining, actin polymerization assays, and siRNA-mediated gene silencing, we uncovered that cytoplasmic PRR11 is involved in F-actin polymerization and organization. We found that dysregulation of PRR11 expression results in F-actin rearrangement and nuclear instability in non-small cell lung cancer cells. Results from molecular mechanistic experiments indicated that PRR11 associates with and recruits the ARP2/3 complex, facilitates F-actin polymerization, and thereby disrupts the F-actin cytoskeleton, leading to abnormal nuclear lamina assembly and chromatin reorganization. Inhibition of the ARP2/3 complex activity abolished irregular F-actin polymerization, lamina assembly, and chromatin reorganization due to PRR11 overexpression. Notably, experiments with truncated PRR11 variants revealed that PRR11 regulates F-actin through different regions. We found that deletion of either the N or C terminus of PRR11 abrogates its effects on F-actin polymerization and nuclear instability and that deletion of amino acid residues 100–184 or 100–200 strongly induces an F-actin structure called the actin comet tail, not observed with WT PRR11. Our findings indicate that cytoplasmic PRR11 plays an essential role in regulating F-actin assembly and nuclear stability by recruiting the ARP2/3 complex in human non-small cell lung carcinoma cells.

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.