Queen Elizabeth wore a neon green outfit to her 90th birthday party. What could go wrong? Oh right, the internet...

Architecture firm Atelier Riri has reaped the energy-saving benefits of Indonesia’s tropical climate in their design of the House at Serpong, a climate-responsive suburban house in Jakarta. After conducting solar studies and site analyses, the architects crafted the four-story home with strategically placed voids, windows, elevated gardens and solar shading devices to reduce unwanted solar gain and take advantage of natural cooling. The home was built primarily of natural materials that give the building a warm and tactile feel.[...]

An inspiring beacon of humanitarian architecture has arrived to one of the poorest and most remote regions of Nepal — the new Bayalpata Hospital in Accham. Opened earlier this month to replace an aged and overrun clinic, the new hospital is a model of sustainable rural health made possible through a collaboration between the government of Nepal and NGO Possible Health. New York City-based Sharon Davis Design crafted the 7.5-acre campus, which is built primarily from locally sourced rammed earth and powered by rooftop solar panels.[...]

With all of her plans cancelled because of the crisis that’s hit our planet recently, Jacoba Niepoort decided to use her own home to create murals.

“I wanted to use the spaces we were in to create parallel individual works.”

Together with Miami-based artist Alex Void and the Void Projects’ creative team, Niepoort curated Home MuralFest, which inspired many artists around the world to paint on the walls of their living rooms, studios, and garden sheds.

Check out the various murals over at Colossal.

(Image Credit: David de la Mano/ Void Projects/ Colossal)

(Image Credit: Helen Bur and Erin Holly/ Void Projects/ Colossal)

Princeton historian Rhae Lynn Barnes reflects on teaching and service during the coronavirus outbreak and the history website she launched for educators.

A county-by-county analysis of the United States by Princeton University researchers suggests that rural counties with high populations of people over 60 and limited access to health care facilities could eventually be among the hardest hit by the coronavirus pandemic.

Environmental News FOR IMMEDIATE RELEASE

California's rural areas are in revolt against Gov. Gavin Newsom's statewide coronavirus rules, which make little sense in burgs such as Bieber.

Sasha Frere-Jones, a leading voice on music, language and culture, is joining the Los Angeles Times as cultural critic at large, Editor Davan Maharaj and Managing Editor S.

Some women are giving their hair a break, while others are learning the basics.

Schools in rural parts of the state are struggling not only to teach but to reach students. Many lack internet access and rely on schools for food.

81-year-old Ben Barcelona is L.A.'s most devoted museum-goer. But what happens when the coronavirus shutters culture in California?

L.A. developers pay fees to support public arts programs. Councilman David Ryu has proposed turning that fund into relief grants for arts groups.

Books about nature to read while avoiding the coronavirus — from classics by John McPhee and Annie Dillard to the upcoming "Book of Eels."

WEEK five, or is it six, if anyone's still counting, and yet another fiercely competitive trend in social isolating has emerged.

For a while now many European governments have resorted to austerity measures to deal with the recession and financial crises affecting them. This may have either been by choice, or pressured from the outside.

However, as has been warned countless times, excessive austerity rarely works. Furthermore, focusing on debts and deficits appears to miss the point that the economic problems were caused by a collapse in markets and banking sector in particular, resulting in less revenues for governments; not necessarily an excessive overspend by governments.

Some of the policies being forced through even when evidence appears to show they do not work lead many to think that austerity and structural adjustment policies are being ideologically pushed for — just as they were on most of the developing countries for almost 2 decades with devastating results.

Indeed, in the US, investigations have found billionaires pouring hundreds of millions of dollars on campaigns to fix the debt making it appear as a grassroots movement. Fixing the debt of course happens to leave the elite less affected, so it works to their advantage to push for something like that.

Without more focus on appropriate economic growth, there is a real risk in going backwards, and even undermining democracy.

The global financial crisis page on this web site has been updated with new sections and videos on this issue.

Read full article: Global Financial Crisis

QUIZ night can still take place even while the UK is on lockdown. Express.co.uk has compiled some of the best natural world questions for your family quiz night.

On 29 July 2019, we published an article originally headlined "Islamic Caliphate in rural England: 35000 to pledge allegiance in mass conversion ceremony".

THE summer that just keeps giving had the swallows all in a flutter last week. On the south coast of the Isle of Wight hundreds streamed past me and my family as we walked over the downs, enchanted by dart-like birds racing over the white cliffs and the green sward. Yet they were flying north-east instead of south towards Africa. Some were even coming in from the sea instead of heading out over the Channel.

Woolpert, Inc. is a cutting-edge national architecture, engineering and geospatial (AEG) firm that delivers value to clients by blending engineering excellence with innovative technology and geospatial applications. Woolpert was recently certified as an Employer of Choice by Great Place To Work , w

DONAN, an industry leader in Forensic Engineering, currently has an opening for an experienced Forensic Engineer with either Civil or Structural Engineering experience to cover our Dallas, TX area. This is an opportunity which allows you to work from home while working full time hours and collabora

Managing Engineer Structural The New York City School Construction Authority (NYCSCA) designs, builds and renovates public school buildings throughout all of the five (5) boroughs. We have excellent opportunities for talented and experienced Structural Engineers to join the NYCSCA Team. This

HVAC Engineers and Structural Engineers The New York City School Construction Authority (NYCSCA) designs, builds and renovates public school buildings throughout all of the five (5) boroughs. We have excellent opportunities for talented and experienced HVAC and Structural Engineers to join the NY

This is a great opportunity with a multi-service Civil Engineering firm that is seeking a Senior Bridge Engineer to join their team. The Senior Bridge Engineer serves as a lead designer and project manager in the Structural Design Department producing new and rehabilitated highway bridges and ot

Structural Engineer/Programmer SDS/2 (d.b.a., "Design Data Corporation") is seeking two (2) civil engineers, for their Lincoln, Nebraska, location, with knowledge of structural steel and computer programming who can analyze, develop, modify, enhance, and/or write computer code while incorporatin

Morocco is somewhere I'd wanted to visit for a while. At its closest point, Morocco is less than 10 miles from Europe, and yet the country held a fascinating allure for me. Its culture is a centuries-old mix of Berber, Arab and Mediterranean influences, and all of these combine to create somewhere with a very distinctive and fascinating culture. Matthew Carey writes for Express.co.uk about his experience in Marrakech...

The “digital divide” is back in the news, with both Democratic presidential candidates and incumbent government officials promising billions to provide high-speed Internet to millions of Americans in rural areas who don’t currently have access to it at home. The digital divide, however, is not a rural problem.

It wasn’t one of my proudest moments when, a week before Christmas last year, I was hunched over my smartphone towards the back of the famous Hamley’s Toy Store on London’s Regent Street, composure tethered to an elusive bar of …

The 2019 Chatham House Prize is awarded to Sir David Attenborough and Julian Hector, head of BBC Studios Natural History Unit, for the galvanizing impact of the Blue Planet II series on tackling ocean plastic pollution.

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.

In cyanobacteria, metabolic pathways that use the nitrogen-rich amino acid arginine play a pivotal role in nitrogen storage and mobilization. The N-terminal domains of two recently identified bacterial enzymes: ArgZ from Synechocystis and AgrE from Anabaena, have been found to contain an arginine dihydrolase. This enzyme provides catabolic activity that converts arginine to ornithine, resulting in concomitant release of CO2 and ammonia. In Synechocystis, the ArgZ-mediated ornithine–ammonia cycle plays a central role in nitrogen storage and remobilization. The C-terminal domain of AgrE contains an ornithine cyclodeaminase responsible for the formation of proline from ornithine and ammonia production, indicating that AgrE is a bifunctional enzyme catalyzing two sequential reactions in arginine catabolism. Here, the crystal structures of AgrE in three different ligation states revealed that it has a tetrameric conformation, possesses a binding site for the arginine dihydrolase substrate l-arginine and product l-ornithine, and contains a binding site for the coenzyme NAD(H) required for ornithine cyclodeaminase activity. Structure–function analyses indicated that the structure and catalytic mechanism of arginine dihydrolase in AgrE are highly homologous with those of a known bacterial arginine hydrolase. We found that in addition to other active-site residues, Asn-71 is essential for AgrE's dihydrolase activity. Further analysis suggested the presence of a passage for substrate channeling between the two distinct AgrE active sites, which are situated ∼45 Å apart. These results provide structural and functional insights into the bifunctional arginine dihydrolase–ornithine cyclodeaminase enzyme AgrE required for arginine catabolism in Anabaena.

7 January 2020

Dawn L. Brasaemle
Dec 1, 2007; 48:2547-2559
Thematic Reviews

Motor protein-based active transport is essential for mRNA localization and local translation in animal cells, yet how mRNA granules interact with motor proteins remains poorly understood. Using an unbiased yeast two–hybrid screen for interactions between murine RNA-binding proteins (RBPs) and motor proteins, here we identified protein interaction with APP tail-1 (PAT1) as a potential direct adapter between zipcode-binding protein 1 (ZBP1, a β-actin RBP) and the kinesin-I motor complex. The amino acid sequence of mouse PAT1 is similar to that of the kinesin light chain (KLC), and we found that PAT1 binds to KLC directly. Studying PAT1 in mouse primary hippocampal neuronal cultures from both sexes and using structured illumination microscopic imaging of these neurons, we observed that brain-derived neurotrophic factor (BDNF) enhances co-localization of dendritic ZBP1 and PAT1 within granules that also contain kinesin-I. PAT1 is essential for BDNF-stimulated neuronal growth cone development and dendritic protrusion formation, and we noted that ZBP1 and PAT1 co-locate along with β-actin mRNA in actively transported granules in living neurons. Acute disruption of the PAT1–ZBP1 interaction in neurons with PAT1 siRNA or a dominant-negative ZBP1 construct diminished localization of β-actin mRNA but not of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) mRNA in dendrites. The aberrant β-actin mRNA localization resulted in abnormal dendritic protrusions and growth cone dynamics. These results suggest a critical role for PAT1 in BDNF-induced β-actin mRNA transport during postnatal development and reveal a new molecular mechanism for mRNA localization in vertebrates.

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.

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.

Cell-surface signaling (CSS) in Gram-negative bacteria involves highly conserved regulatory pathways that optimize gene expression by transducing extracellular environmental signals to the cytoplasm via inner-membrane sigma regulators. The molecular details of ferric siderophore-mediated activation of the iron import machinery through a sigma regulator are unclear. Here, we present the 1.56 Å resolution structure of the periplasmic complex of the C-terminal CSS domain (CCSSD) of PupR, the sigma regulator in the Pseudomonas capeferrum pseudobactin BN7/8 transport system, and the N-terminal signaling domain (NTSD) of PupB, an outer-membrane TonB-dependent transducer. The structure revealed that the CCSSD consists of two subdomains: a juxta-membrane subdomain, which has a novel all-β-fold, followed by a secretin/TonB, short N-terminal subdomain at the C terminus of the CCSSD, a previously unobserved topological arrangement of this domain. Using affinity pulldown assays, isothermal titration calorimetry, and thermal denaturation CD spectroscopy, we show that both subdomains are required for binding the NTSD with micromolar affinity and that NTSD binding improves CCSSD stability. Our findings prompt us to present a revised model of CSS wherein the CCSSD:NTSD complex forms prior to ferric-siderophore binding. Upon siderophore binding, conformational changes in the CCSSD enable regulated intramembrane proteolysis of the sigma regulator, ultimately resulting in transcriptional regulation.

Knowledge of the molecular events in mitochondrial DNA (mtDNA) replication is crucial to understanding the origins of human disorders arising from mitochondrial dysfunction. Twinkle helicase is an essential component of mtDNA replication. Here, we employed atomic force microscopy imaging in air and liquids to visualize ring assembly, DNA binding, and unwinding activity of individual Twinkle hexamers at the single-molecule level. We observed that the Twinkle subunits self-assemble into hexamers and higher-order complexes that can switch between open and closed-ring configurations in the absence of DNA. Our analyses helped visualize Twinkle loading onto and unloading from DNA in an open-ringed configuration. They also revealed that closed-ring conformers bind and unwind several hundred base pairs of duplex DNA at an average rate of ∼240 bp/min. We found that the addition of mitochondrial single-stranded (ss) DNA–binding protein both influences the ways Twinkle loads onto defined DNA substrates and stabilizes the unwound ssDNA product, resulting in a ∼5-fold stimulation of the apparent DNA-unwinding rate. Mitochondrial ssDNA-binding protein also increased the estimated translocation processivity from 1750 to >9000 bp before helicase disassociation, suggesting that more than half of the mitochondrial genome could be unwound by Twinkle during a single DNA-binding event. The strategies used in this work provide a new platform to examine Twinkle disease variants and the core mtDNA replication machinery. They also offer an enhanced framework to investigate molecular mechanisms underlying deletion and depletion of the mitochondrial genome as observed in mitochondrial diseases.

Invitation Only Research Event

Lipid rafts are small, dynamic membrane areas characterized by the clustering of selected membrane lipids as the result of the spontaneous separation of glycolipids, sphingolipids, and cholesterol in a liquid-ordered phase. The exact dynamics underlying phase separation of membrane lipids in the complex biological membranes are still not fully understood. Nevertheless, alterations in the membrane lipid composition affect the lateral organization of molecules belonging to lipid rafts. Neural lipid rafts are found in brain cells, including neurons, astrocytes, and microglia, and are characterized by a high enrichment of specific lipids depending on the cell type. These lipid rafts seem to organize and determine the function of multiprotein complexes involved in several aspects of signal transduction, thus regulating the homeostasis of the brain. The progressive decline of brain performance along with physiological aging is at least in part associated with alterations in the composition and structure of neural lipid rafts. In addition, neurodegenerative conditions, such as lysosomal storage disorders, multiple sclerosis, and Parkinson’s, Huntington’s, and Alzheimer’s diseases, are frequently characterized by dysregulated lipid metabolism, which in turn affects the structure of lipid rafts. Several events underlying the pathogenesis of these diseases appear to depend on the altered composition of lipid rafts. Thus, the structure and function of lipid rafts play a central role in the pathogenesis of many common neurodegenerative diseases.

Sovereign nations typically measure economic success in terms of GDP (income) but this approach is risky as it fails to track and measure the impact of this on nature. Inclusive wealth, on the other hand captures financial and produced capital, but also the skills in our workforce (human capital), the cohesion in our society (social capital) and the value of our environment (natural capital).

http://www.biodiversityislife.net/