Cytochrome c oxidase (CcO) reduces O2 to water, coupled with a proton-pumping process. The structure of the O2-reduction site of CcO contains two reducing equivalents, Fea32+ and CuB1+, and suggests that a peroxide-bound state (Fea33+–O−–O−–CuB2+) rather than an O2-bound state (Fea32+–O2) is the initial catalytic intermediate. Unexpectedly, however, resonance Raman spectroscopy results have shown that the initial intermediate is Fea32+–O2, whereas Fea33+–O−–O−–CuB2+ is undetectable. Based on X-ray structures of static noncatalytic CcO forms and mutation analyses for bovine CcO, a proton-pumping mechanism has been proposed. It involves a proton-conducting pathway (the H-pathway) comprising a tandem hydrogen-bond network and a water channel located between the N- and P-side surfaces. However, a system for unidirectional proton-transport has not been experimentally identified. Here, an essentially identical X-ray structure for the two catalytic intermediates (P and F) of bovine CcO was determined at 1.8 Å resolution. A 1.70 Å Fe–O distance of the ferryl center could best be described as Fea34+ = O2−, not as Fea34+–OH−. The distance suggests an ∼800-cm−1 Raman stretching band. We found an interstitial water molecule that could trigger a rapid proton-coupled electron transfer from tyrosine-OH to the slowly forming Fea33+–O−–O−–CuB2+ state, preventing its detection, consistent with the unexpected Raman results. The H-pathway structures of both intermediates indicated that during proton-pumping from the hydrogen-bond network to the P-side, a transmembrane helix closes the water channel connecting the N-side with the hydrogen-bond network, facilitating unidirectional proton-pumping during the P-to-F transition.

Reactive oxygen and nitrogen species have been implicated in many biological processes and diseases, including immune responses, cardiovascular dysfunction, neurodegeneration, and cancer. These chemical species are short-lived in biological settings, and detecting them in these conditions and diseases requires the use of molecular probes that form stable, easily detectable, products. The chemical mechanisms and limitations of many of the currently used probes are not well-understood, hampering their effective applications. Boronates have emerged as a class of probes for the detection of nucleophilic two-electron oxidants. Here, we report the results of an oxygen-18–labeling MS study to identify the origin of oxygen atoms in the oxidation products of phenylboronate targeted to mitochondria. We demonstrate that boronate oxidation by hydrogen peroxide, peroxymonocarbonate, hypochlorite, or peroxynitrite involves the incorporation of oxygen atoms from these oxidants. We therefore conclude that boronates can be used as probes to track isotopically labeled oxidants. This suggests that the detection of specific products formed from these redox probes could enable precise identification of oxidants formed in biological systems. We discuss the implications of these results for understanding the mechanism of conversion of the boronate-based redox probes to oxidant-specific products.

Much of our current knowledge of biological chemistry is founded in the structure-function relationship, whereby sequence determines structure that determines function. Thus, the discovery that a large fraction of the proteome is intrinsically disordered, while being functional, has revolutionized our understanding of proteins and raised new and interesting questions. Many intrinsically disordered proteins (IDPs) have been determined to undergo a disorder-to-order transition when recognizing their physiological partners, suggesting that their mechanisms of folding are intrinsically different from those observed in globular proteins. However, IDPs also follow some of the classic paradigms established for globular proteins, pointing to important similarities in their behavior. In this review, we compare and contrast the folding mechanisms of globular proteins with the emerging features of binding-induced folding of intrinsically disordered proteins. Specifically, whereas disorder-to-order transitions of intrinsically disordered proteins appear to follow rules of globular protein folding, such as the cooperative nature of the reaction, their folding pathways are remarkably more malleable, due to the heterogeneous nature of their folding nuclei, as probed by analysis of linear free-energy relationship plots. These insights have led to a new model for the disorder-to-order transition in IDPs termed “templated folding,” whereby the binding partner dictates distinct structural transitions en route to product, while ensuring a cooperative folding.

The CRISPR/Cas9 nucleases have been widely applied for genome editing in various organisms. Cas9 nucleases complexed with a guide RNA (Cas9–gRNA) find their targets by scanning and interrogating the genomic DNA for sequences complementary to the gRNA. Recognition of the DNA target sequence requires a short protospacer adjacent motif (PAM) located outside this sequence. Given that the efficiency of target location may depend on the strength of interactions that promote target recognition, here we sought to compare affinities of different Cas9 nucleases for their cognate PAM sequences. To this end, we measured affinities of Cas9 nucleases from Streptococcus pyogenes, Staphylococcus aureus, and Francisella novicida complexed with guide RNAs (gRNAs) (SpCas9–gRNA, SaCas9–gRNA, and FnCas9–gRNA, respectively) and of three engineered SpCas9–gRNA variants with altered PAM specificities for short, PAM-containing DNA probes. We used a “beacon” assay that measures the relative affinities of DNA probes by determining their ability to competitively affect the rate of Cas9–gRNA binding to fluorescently labeled target DNA derivatives called “Cas9 beacons.” We observed significant differences in the affinities for cognate PAM sequences among the studied Cas9 enzymes. The relative affinities of SpCas9–gRNA and its engineered variants for canonical and suboptimal PAMs correlated with previous findings on the efficiency of these PAM sequences in genome editing. These findings suggest that high affinity of a Cas9 nuclease for its cognate PAM promotes higher genome-editing efficiency.

Members Event

Event participants

Dr Marja Lehto, Special Rapporteur, International Law Commission, UN
Doug Weir, Research and Policy Director, The Conflict and Environment Observatory
Chair: Elizabeth Wilmshurst CMG, Distinguished Fellow, International Law Programme, Chatham House
 

Invitation Only Research Event

Event participants

Andrew Grant, Carbon Tracker Initiative
Chair: Siân Bradley, Research Fellow, Energy, Environment and Resources, Chatham House

1 April 2020

Considerations of justice and social equity are as important for the circular economy transition as they are in the contexts of low-carbon transitions and digitalization of the economy. This paper sets out the just transition approach, and its relevance in climate change and energy transition debates.

15 April 2020

Invitation Only Research Event

29 November 2019

23 January 2020

Membrane-bound proteins have been proposed to mediate the transport of long-chain FA (LCFA) transport through the plasma membrane (PM). These proposals are based largely on reports that PM transport of LCFAs can be blocked by a number of enzymes and purported inhibitors of LCFA transport. Here, using the ratiometric pH indicator (2',7'-bis-(2-carboxyethyl)-5-(and-6-)-carboxyfluorescein and acrylodated intestinal FA-binding protein-based dual fluorescence assays, we investigated the effects of nine inhibitors of the putative FA transporter protein CD36 on the binding and transmembrane movement of LCFAs. We particularly focused on sulfosuccinimidyl oleate (SSO), reported to be a competitive inhibitor of CD36-mediated LCFA transport. Using these assays in adipocytes and inhibitor-treated protein-free lipid vesicles, we demonstrate that rapid LCFA transport across model and biological membranes remains unchanged in the presence of these purported inhibitors. We have previously shown in live cells that CD36 does not accelerate the transport of unesterified LCFAs across the PM. Our present experiments indicated disruption of LCFA metabolism inside the cell within minutes upon treatment with many of the "inhibitors" previously assumed to inhibit LCFA transport across the PM. Furthermore, using confocal microscopy and a specific anti-SSO antibody, we found that numerous intracellular and PM-bound proteins are SSO-modified in addition to CD36. Our results support the hypothesis that LCFAs diffuse rapidly across biological membranes and do not require an active protein transporter for their transmembrane movement.

Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (^–/–) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women.­

Fatty liver involves ectopic lipid accumulation and dysregulated hepatic oxidative metabolism, which can progress to a state of elevated inflammation and fibrosis referred to as nonalcoholic steatohepatitis (NASH). The factors that control progression from simple steatosis to NASH are not fully known. Here, we tested the hypothesis that dietary vitamin E (VitE) supplementation would prevent NASH progression and associated metabolic alterations induced by a Western diet (WD). Hyperphagic melanocortin-4 receptor-deficient (MC4R^–/–) mice were fed chow, chow+VitE, WD, or WD+VitE starting at 8 or 20 weeks of age. All groups exhibited extensive hepatic steatosis by the end of the study (28 weeks of age). WD feeding exacerbated liver disease severity without inducing proportional changes in liver triglycerides. Eight weeks of WD accelerated liver pyruvate cycling, and 20 weeks of WD extensively upregulated liver glucose and oxidative metabolism assessed by ²H/¹³C flux analysis. VitE supplementation failed to reduce the histological features of NASH. Rather, WD+VitE increased the abundance and saturation of liver ceramides and accelerated metabolic flux dysregulation compared with 8 weeks of WD alone. In summary, VitE did not limit NASH pathogenesis in genetically obese mice, but instead increased some indicators of metabolic dysfunction.

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Cytochrome c oxidase (CcO) reduces O2 to water, coupled with a proton-pumping process. The structure of the O2-reduction site of CcO contains two reducing equivalents, Fea32+ and CuB1+, and suggests that a peroxide-bound state (Fea33+–O−–O−–CuB2+) rather than an O2-bound state (Fea32+–O2) is the initial catalytic intermediate. Unexpectedly, however, resonance Raman spectroscopy results have shown that the initial intermediate is Fea32+–O2, whereas Fea33+–O−–O−–CuB2+ is undetectable. Based on X-ray structures of static noncatalytic CcO forms and mutation analyses for bovine CcO, a proton-pumping mechanism has been proposed. It involves a proton-conducting pathway (the H-pathway) comprising a tandem hydrogen-bond network and a water channel located between the N- and P-side surfaces. However, a system for unidirectional proton-transport has not been experimentally identified. Here, an essentially identical X-ray structure for the two catalytic intermediates (P and F) of bovine CcO was determined at 1.8 Å resolution. A 1.70 Å Fe–O distance of the ferryl center could best be described as Fea34+ = O2−, not as Fea34+–OH−. The distance suggests an ∼800-cm−1 Raman stretching band. We found an interstitial water molecule that could trigger a rapid proton-coupled electron transfer from tyrosine-OH to the slowly forming Fea33+–O−–O−–CuB2+ state, preventing its detection, consistent with the unexpected Raman results. The H-pathway structures of both intermediates indicated that during proton-pumping from the hydrogen-bond network to the P-side, a transmembrane helix closes the water channel connecting the N-side with the hydrogen-bond network, facilitating unidirectional proton-pumping during the P-to-F transition.

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Actually, they weren.t caught together at all their images were put together with software. The shadows cast by the stars. faces give it away: The sun is coming from two different directions on the same beach! More elaborate digital doctoring is detected with mathematics. Calculus, linear algebra, and statistics are especially useful in determining when a portion of one image has been copied to another or when part of an image has been replaced. Tampering with an image leaves statistical traces in the file. For example, if a person is removed from an image and replaced with part of the background, then two different parts of the resulting file will be identical. The difficulty with exposing this type of alteration is that both the location of the replacement and its size are unknown beforehand. One successful algorithm finds these repetitions by first sorting small regions according to their digital color similarity, and then moving to larger regions that contain similar small ones. The algorithm.s designer, a leading digital forensics expert, admits that image alterers generally stay a step ahead of detectors, but observes that forensic advances have made it much harder for them to escape notice. He adds that to catch fakers, At the end of the day you need math.(1) For More Information: Can Digital Photos be Trusted?, Steve Casimiro, Popular Science, October 2005. _______ 1 It May Look Authentic; Here.s How to Tell It Isn't, Nicholas Wade, The New York Times, January 24, 2006.

The outcome of elections that offer more than two alternatives but with no preference by a majority, is determined more by the voting procedure used than by the votes themselves. Mathematicians have shown that in such elections, illogical results are more likely than not. For example, the majority of this group want to go to a warm place, but the South Pole is the group.s plurality winner. So if these people choose their group.s vacation destination in the same way most elections are conducted, they will all go to the South Pole and six people will be disappointed, if not frostbitten. Elections in which only the top preference of each voter is counted are equivalent to a school choosing its best student based only on the number of A.s earned. The inequity of such a situation has led to the development of other voting methods. In one method, points are assigned to choices, just as they are to grades. Using this procedure, these people will vacation in a warm place a more desirable conclusion for the group. Mathematicians study voting methods in hopes of finding equitable procedures, so that no one is unfairly left out in the cold. For more information: Chaotic Elections: A Mathematician Looks at Voting, Donald Saari

The music of most hit songs is pretty well known, but sometimes there are mysteries. One question that remained unanswered for over forty years is: What instrumentation and notes make up the opening chord of the Beatles. "A Hard Day.s Night"? Mathematician Jason Brown - a big Beatles fan - recently solved the puzzle using his musical knowledge and discrete Fourier transforms, mathematical transformations that help decompose signals into their basic parts. These transformations simplify applications ranging from signal processing to multiplying large numbers, so that a researcher doesn.t have to be "working like a dog" to get an answer. Brown is also using mathematics, specifically graph theory, to discover who wrote "In My Life," which both Lennon and McCartney claimed to have written. In his graphs, chords are represented by points that are connected when one chord immediately follows another. When all songs with known authorship are diagrammed, Brown will see which collection of graphs - McCartney.s or Lennon.s - is a better fit for "In My Life." Although it may seem a bit counterintuitive to use mathematics to learn more about a revolutionary band, these analytical methods identify and uncover compositional principles inherent in some of the best Beatles. music. Thus it.s completely natural and rewarding to apply mathematics to the Fab 4 For More Information: Professor Uses Mathematics to Decode Beatles Tunes, "The Wall Street Journal", January 30, 2009..

Normally when creating a digital file, such as a picture, much more information is recorded than necessary-even before storing or sending. The image on the right was created with compressed (or compressive) sensing, a breakthrough technique based on probability and linear algebra. Rather than recording excess information and discarding what is not needed, sensors collect the most significant information at the time of creation, which saves power, time, and memory. The potential increase in efficiency has led researchers to investigate employing compressed sensing in applications ranging from missions in space, where minimizing power consumption is important, to MRIs, for which faster image creation would allow for better scans and happier patients. Just as a word has different representations in different languages, signals (such as images or audio) can be represented many different ways. Compressed sensing relies on using the representation for the given class of signals that requires the fewest bits. Linear programming applied to that representation finds the most likely candidate fitting the particular low-information signal. Mathematicians have proved that in all but the very rarest case that candidate-often constructed from less than a tiny fraction of the data traditionally collected-matches the original. The ability to locate and capture only the most important components without any loss of quality is so unexpected that even the mathematicians who discovered compressed sensing found it hard to believe. For More Information: "Compressed Sensing Makes Every Pixel Count," What's Happening in the Mathematical Sciences, Vol. 7, Dana Mackenzie.

A triple cork is a spinning jump in which the snowboarder is parallel to the ground three times while in the air. Such a jump had never been performed in a competition before 2011, which prompted ESPN.s Sport Science program to ask math professor Tim Chartier if it could be done under certain conditions. Originally doubtful, he and a recent math major graduate used differential equations, vector analysis, and calculus to discover that yes, a triple cork was indeed possible. A few days later, boarder Torstein Horgmo landed a successful triple cork at the X-Games (which presumably are named for everyone.s favorite variable). Snowboarding is not the only sport in which modern athletes and coaches seek answers from mathematics. Swimming and bobsledding research involves computational fluid dynamics to analyze fluid flow so as to decrease drag. Soccer and basketball analysts employ graph and network theory to chart passes and quantify team performance. And coaches in the NFL apply statistics and game theory to focus on the expected value of a play instead of sticking with the traditional Square root of 9 yards and a cloud of dust.

A triple cork is a spinning jump in which the snowboarder is parallel to the ground three times while in the air. Such a jump had never been performed in a competition before 2011, which prompted ESPN.s Sport Science program to ask math professor Tim Chartier if it could be done under certain conditions. Originally doubtful, he and a recent math major graduate used differential equations, vector analysis, and calculus to discover that yes, a triple cork was indeed possible. A few days later, boarder Torstein Horgmo landed a successful triple cork at the X-Games (which presumably are named for everyone.s favorite variable). Snowboarding is not the only sport in which modern athletes and coaches seek answers from mathematics. Swimming and bobsledding research involves computational fluid dynamics to analyze fluid flow so as to decrease drag. Soccer and basketball analysts employ graph and network theory to chart passes and quantify team performance. And coaches in the NFL apply statistics and game theory to focus on the expected value of a play instead of sticking with the traditional Square root of 9 yards and a cloud of dust.

Colin Adams talks about knot theory

In a ground breaking study, an international team of 21 scientists led by Sean Hoban, Ph.D., Conservation Biologist at The Morton Arboretum in Lisle, Illinois, evaluated five genera spanning the plant tree of life (Hibiscus, Magnolia, Pseudophoenix, Quercus and Zamia) to understand how much genetic diversity currently exists in collections in botanical gardens and arboreta worldwide.

A new way of looking at marine evolution over the past 540 million years has shown that levels of biodiversity in our oceans have remained fairly constant, rather than increasing continuously over the last 200 million years, as scientists previously thought.

"The coronavirus pandemic has made abundantly clear that if life is to thrive on this Earth, human and nonhuman, we need cooperation at all scales-global, regional, binational, within a nation, interstate, and in our local communities. And we need to learn how to coexist with and have compassion for our nonhuman relatives-and acknowledge in the midst of this pandemic that bats are not our enemies."

Tropical rainforests are the world's richest land habitats for biodiversity, harbouring stunning numbers of plant and animal species. The Amazon and the Congo basins, together with Asian rainforests, represent only 6 per cent of earth's land surface, and yet more than 50 per cent of global biodiversity can be found under their shade.

We asked Guardian readers living in cities and towns across the world to share their images of the wildlife they can see from their homes. You answered in your droves, from Canada to Cardiff, and here are some of the best.

New Publication: Rules, Procedures and Mechanisms Applicable to Processes under the Cartagena Protocol on Biosafety.

Report of the Fourth Meeting of the Conference of the Parties to the Convention on Biological Diversity Serving as the Meeting of the Parties to the Cartagena Protocol on Biosafety (Advance text)