physics Deep roots: On the 2024 Physics Nobel Prize By www.thehindu.com Published On :: Wed, 09 Oct 2024 00:10:00 +0530 Physics Nobel Prize acknowledges the diverse foundations of AI Full Article Editorial
physics Representations of linear groups [electronic resource] : an introduction based on examples from physics and number theory / Rolf Berndt By darius.uleth.ca Published On :: Wiesbaden : Vieweg, 2007 Full Article
physics Fuchsian reduction [electronic resource] : applications to geometry, cosmology and mathematical physics / Satyanad Kichenassamy By darius.uleth.ca Published On :: Boston : Birkhauser, 2007 Full Article
physics 'Lengthy' physics section kept students on tenterhooks By www.thehindu.com Published On :: Mon, 02 May 2016 09:07:50 +0530 Many of them said they had not prepared thoroughly for AIPMT as it was only ‘an option’ Full Article Bengaluru
physics Physics in 2018 By physicsworld.com Published On :: 2018-01-23T15:51:48Z Physics World journalists discuss what excites them about the year ahead Full Article
physics PhysicsWallah’s revenue jumps to s₹1,940 cr, losses widen on back of rising expenses By www.thehindubusinessline.com Published On :: Thu, 07 Nov 2024 19:25:27 +0530 The company’s consolidated loss stood at 1,131.3 crore in FY24, up from ₹ 84.1 crore recorded in the earlier fiscal period. Full Article Education
physics Inside the underground lab in China tasked with solving a physics mystery By www.thehindu.com Published On :: Wed, 16 Oct 2024 12:15:53 +0530 China’s JUNO will soon start gathering data on neutrinos, a product of nuclear reactions, to help solve one of the biggest mysteries in particle physics Full Article Science
physics Rohini Godbole: a passion for high-energy physics, gender equity By www.thehindu.com Published On :: Thu, 31 Oct 2024 05:30:00 +0530 Prof Godbole was a role model for young researchers, particularly women scientists struggling against gender bias and negative attitudes Full Article Science
physics Topological materials move from the world of theoretical physics to experimental chemistry By cen.acs.org Published On :: 23 Jun 2018 13:15:00 +0000 These exotic materials could find applications in electronics, catalysis, and quantum computing Full Article
physics Solid state physics: Vol. 61 / editors, Henry Ehrenreich, Frans Spaepen By library.mit.edu Published On :: Sun, 10 May 2020 06:31:08 EDT Online Resource Full Article
physics Topological and non-topological solitons in scalar field theories / Yakov M. Shnir (Bogoliubov Laboratory of Theoretical Physics, Moscow) By library.mit.edu Published On :: Sun, 10 May 2020 06:31:08 EDT Barker Library - QC174.26.W28 S46 2018 Full Article
physics [ Physics ] Open Question : Help with a non-uniform moments question...? By answers.yahoo.com Published On :: Sun, 10 May 2020 09:06:24 +0000 Ok, so I have tried and do not get the same as as the book (1.6m). Can someone show the forces diagram or something , please? Full Article
physics Earth's North Magnetic Pole Keeps Drifting towards Siberia, Latest World Magnetic Model Shows | Geophysics, Geoscience - Sci-News.com By www.sci-news.com Published On :: Fri, 27 Dec 2019 08:00:00 GMT Earth's North Magnetic Pole Keeps Drifting towards Siberia, Latest World Magnetic Model Shows | Geophysics, Geoscience Sci-News.com Full Article
physics Center for Astrophysics will play major role in mission to “touch” the Sun By insider.si.edu Published On :: Wed, 15 Sep 2010 11:58:51 +0000 When NASA’s Solar Probe Plus launches before the end of the decade, it will carry a suite of cutting-edge scientific instruments. Only one–the Solar Wind Electrons Alphas and Protons Investigation (SWEAP)–will directly sample the Sun’s outer atmosphere. The post Center for Astrophysics will play major role in mission to “touch” the Sun appeared first on Smithsonian Insider. Full Article Research News Science & Nature Space astronomy astrophysics Smithsonian Astrophysical Observatory Sun
physics Free, online course in physics offered by the Harvard-Smithsonian Center for Astrophysics By insider.si.edu Published On :: Fri, 14 Jan 2011 14:46:31 +0000 "Physics for the 21st Century," a free, on-line course developed at the Harvard-Smithsonian Center for Astrophysics about current research in physics is now available. The post Free, online course in physics offered by the Harvard-Smithsonian Center for Astrophysics appeared first on Smithsonian Insider. Full Article Research News Science & Nature Space astronomy astrophysics Center for Astrophysics | Harvard & Smithsonian science education
physics Harvard-Smithsonian Center for Astrophysics to own and operate ALMA Vertex Prototype Antenna By insider.si.edu Published On :: Tue, 05 Apr 2011 17:56:54 +0000 The Harvard-Smithsonian Center for Astrophysics has been selected by the National Science Foundation as the recipient of a 12-meter (39-foot) radio antenna designed for submillimeter-wavelength astronomy. The ALMA Vertex Prototype Antenna was one of three antennas built as prototypes for the Atacama Large Millimeter Array, a 66-dish radio observatory currently being constructed in Chile. The post Harvard-Smithsonian Center for Astrophysics to own and operate ALMA Vertex Prototype Antenna appeared first on Smithsonian Insider. Full Article Research News Science & Nature Space astronomy biodiversity Center for Astrophysics | Harvard & Smithsonian technology
physics Center for Astrophysics project gets first look through new ALMA telescope By insider.si.edu Published On :: Wed, 05 Oct 2011 17:39:35 +0000 Humanity's most complex ground-based astronomy observatory, the Atacama Large Millimeter/submillimeter Array (ALMA), has officially opened for astronomers at its 16,500-foot high desert plateau in northern Chile. The post Center for Astrophysics project gets first look through new ALMA telescope appeared first on Smithsonian Insider. Full Article Science & Nature Space astronomy astrophysics Center for Astrophysics | Harvard & Smithsonian Smithsonian Astrophysical Observatory
physics Lighthouse of the skies, the Harvard-Smithsonian Center for Astrophysics By insider.si.edu Published On :: Fri, 17 Jun 2011 19:12:48 +0000 A short history of the Harvard-Smithsonian Center for Astrophysics The post Lighthouse of the skies, the Harvard-Smithsonian Center for Astrophysics appeared first on Smithsonian Insider. Full Article Video astronomy astrophysics Center for Astrophysics | Harvard & Smithsonian Smithsonian Astrophysical Observatory
physics Kepler 11: A Six-Planet Sonata by Alex Parker, postdoctoral researcher at the Harvard–Smithsonian Center for Astrophysics By insider.si.edu Published On :: Tue, 14 May 2013 07:48:13 +0000 The post Kepler 11: A Six-Planet Sonata by Alex Parker, postdoctoral researcher at the Harvard–Smithsonian Center for Astrophysics appeared first on Smithsonian Insider. Full Article Video astronomy astrophysics Center for Astrophysics | Harvard & Smithsonian planets Smithsonian Astrophysical Observatory
physics Mid-term Assessment of Astronomy and Astrophysics Decadal Goals – New Report By feedproxy.google.com Published On :: Mon, 15 Aug 2016 05:00:00 GMT While scientists have made remarkable advancements in astronomy and astrophysics since the beginning of this decade – notably the first detection of gravitational waves and the discovery of distant Earth-like planets – unforeseen constraints have slowed progress toward reaching some of the priorities and goals outlined in the Academies’ 2010 decadal survey of these disciplines, says a new report from the National Academies of Sciences, Engineering, and Medicine. Full Article
physics Progress Made Toward Priorities Defined in 2013-2022 Solar and Space Physics Decadal Survey By feedproxy.google.com Published On :: Mon, 03 Feb 2020 05:00:00 GMT NASA, NSF, and NOAA have made substantial progress in implementing the programs recommended in the 2013 decadal survey on solar and space physics (heliophysics) despite a challenging budgetary landscape, says a new midterm assessment from the National Academies of Sciences, Engineering, and Medicine. Full Article
physics The physics behind the animation By www.nsf.gov Published On :: Wed, 27 Jul 2011 16:07:13 +0000 Video: The best animators know that physics will make their animation more lifelike. Full Article Computers
physics Northern lights' physics could aid in nuclear fusion By www.mnn.com Published On :: Tue, 13 May 2014 15:39:19 +0000 The aurora may hold the secret of a magnetic phenomenon related to the nuclear fusion powering the sun. Full Article Energy
physics Physics-defying LEDs light the way to a brighter cleantech future By www.mnn.com Published On :: Thu, 31 May 2012 18:37:28 +0000 A light-emitting diode (LED) developed at MIT operates at 230-percent efficiency. That's not a typo. LEDs will provide 70 percent of the world's general lightin Full Article Research & Innovations
physics Blue LED light discovery wins Nobel Prize in physics By www.livescience.com Published On :: Tue, 07 Oct 2014 13:28:27 +0000 Isamu Akasaki, Hiroshi Amano and Shuji Nakamura have been awarded the Nobel Prize in Physics for their invention of the blue light-emitting diode. Full Article Research & Innovations
physics Walter Koroljow is Celebrated as a Leader in Physics and Mathematics By www.24-7pressrelease.com Published On :: Wed, 29 Apr 2020 07:00:00 GMT Dr. Koroljow has found much success in his decades-spanning career Full Article
physics Ken H. Seto Celebrates More than Five Decades of Success in Physics and Chemical Engineering By www.24-7pressrelease.com Published On :: Fri, 10 Jan 2020 07:00:00 GMT With his renowned "Model Mechanics" theory, Mr. Seto introduced a unified theory for all the forces (including gravity), a new theory of gravity, an improved relativity theory, and the discovery of a new fifth force that is part of gravity. Full Article
physics Social Physics Can Change Your Company (and the World) By hbr.org Published On :: Thu, 24 Apr 2014 19:45:53 -0500 Sandy Pentland, MIT professor, on how big data is revealing the science behind how we work together, based on his book "Social Physics: How Good Ideas Spread." Full Article
physics Physics from hell By Published On :: Was modern physics born in the Inferno? Motion video for an Boston Globe Ideas section about the influence of Dante's Inferno in Galileo Physics Full Article
physics Evaluating the phase dynamics of coupled oscillators via time-variant topological features. (arXiv:2005.03343v1 [physics.data-an]) By arxiv.org Published On :: The characterization of phase dynamics in coupled oscillators offers insights into fundamental phenomena in complex systems. To describe the collective dynamics in the oscillatory system, order parameters are often used but are insufficient for identifying more specific behaviors. We therefore propose a topological approach that constructs quantitative features describing the phase evolution of oscillators. Here, the phase data are mapped into a high-dimensional space at each time point, and topological features describing the shape of the data are subsequently extracted from the mapped points. We extend these features to time-variant topological features by considering the evolution time, which serves as an additional dimension in the topological-feature space. The resulting time-variant features provide crucial insights into the time evolution of phase dynamics. We combine these features with the machine learning kernel method to characterize the multicluster synchronized dynamics at a very early stage of the evolution. Furthermore, we demonstrate the usefulness of our method for qualitatively explaining chimera states, which are states of stably coexisting coherent and incoherent groups in systems of identical phase oscillators. The experimental results show that our method is generally better than those using order parameters, especially if only data on the early-stage dynamics are available. Full Article
physics Modeling nanoconfinement effects using active learning. (arXiv:2005.02587v2 [physics.app-ph] UPDATED) By arxiv.org Published On :: Predicting the spatial configuration of gas molecules in nanopores of shale formations is crucial for fluid flow forecasting and hydrocarbon reserves estimation. The key challenge in these tight formations is that the majority of the pore sizes are less than 50 nm. At this scale, the fluid properties are affected by nanoconfinement effects due to the increased fluid-solid interactions. For instance, gas adsorption to the pore walls could account for up to 85% of the total hydrocarbon volume in a tight reservoir. Although there are analytical solutions that describe this phenomenon for simple geometries, they are not suitable for describing realistic pores, where surface roughness and geometric anisotropy play important roles. To describe these, molecular dynamics (MD) simulations are used since they consider fluid-solid and fluid-fluid interactions at the molecular level. However, MD simulations are computationally expensive, and are not able to simulate scales larger than a few connected nanopores. We present a method for building and training physics-based deep learning surrogate models to carry out fast and accurate predictions of molecular configurations of gas inside nanopores. Since training deep learning models requires extensive databases that are computationally expensive to create, we employ active learning (AL). AL reduces the overhead of creating comprehensive sets of high-fidelity data by determining where the model uncertainty is greatest, and running simulations on the fly to minimize it. The proposed workflow enables nanoconfinement effects to be rigorously considered at the mesoscale where complex connected sets of nanopores control key applications such as hydrocarbon recovery and CO2 sequestration. Full Article
physics Trees and Forests in Nuclear Physics. (arXiv:2002.10290v2 [nucl-th] UPDATED) By arxiv.org Published On :: We present a simple introduction to the decision tree algorithm using some examples from nuclear physics. We show how to improve the accuracy of the classical liquid drop nuclear mass model by performing Feature Engineering with a decision tree. Finally, we apply the method to the Duflo-Zuker model showing that, despite their simplicity, decision trees are capable of improving the description of nuclear masses using a limited number of free parameters. Full Article
physics Evolutionary Dynamics of Higher-Order Interactions. (arXiv:2001.10313v2 [physics.soc-ph] UPDATED) By arxiv.org Published On :: We live and cooperate in networks. However, links in networks only allow for pairwise interactions, thus making the framework suitable for dyadic games, but not for games that are played in groups of more than two players. To remedy this, we introduce higher-order interactions, where a link can connect more than two individuals, and study their evolutionary dynamics. We first consider a public goods game on a uniform hypergraph, showing that it corresponds to the replicator dynamics in the well-mixed limit, and providing an exact theoretical foundation to study cooperation in networked groups. We also extend the analysis to heterogeneous hypergraphs that describe interactions of groups of different sizes and characterize the evolution of cooperation in such cases. Finally, we apply our new formulation to study the nature of group dynamics in real systems, showing how to extract the actual dependence of the synergy factor on the size of a group from real-world collaboration data in science and technology. Our work is a first step towards the implementation of new actions to boost cooperation in social groups. Full Article
physics Nonlinear model reduction: a comparison between POD-Galerkin and POD-DEIM methods. (arXiv:2005.03173v1 [physics.comp-ph]) By arxiv.org Published On :: Several nonlinear model reduction techniques are compared for the three cases of the non-parallel version of the Kuramoto-Sivashinsky equation, the transient regime of flow past a cylinder at $Re=100$ and fully developed flow past a cylinder at the same Reynolds number. The linear terms of the governing equations are reduced by Galerkin projection onto a POD basis of the flow state, while the reduced nonlinear convection terms are obtained either by a Galerkin projection onto the same state basis, by a Galerkin projection onto a POD basis representing the nonlinearities or by applying the Discrete Empirical Interpolation Method (DEIM) to a POD basis of the nonlinearities. The quality of the reduced order models is assessed as to their stability, accuracy and robustness, and appropriate quantitative measures are introduced and compared. In particular, the properties of the reduced linear terms are compared to those of the full-scale terms, and the structure of the nonlinear quadratic terms is analyzed as to the conservation of kinetic energy. It is shown that all three reduction techniques provide excellent and similar results for the cases of the Kuramoto-Sivashinsky equation and the limit-cycle cylinder flow. For the case of the transient regime of flow past a cylinder, only the pure Galerkin techniques are successful, while the DEIM technique produces reduced-order models that diverge in finite time. Full Article
physics Evaluation, Tuning and Interpretation of Neural Networks for Meteorological Applications. (arXiv:2005.03126v1 [physics.ao-ph]) By arxiv.org Published On :: Neural networks have opened up many new opportunities to utilize remotely sensed images in meteorology. Common applications include image classification, e.g., to determine whether an image contains a tropical cyclone, and image translation, e.g., to emulate radar imagery for satellites that only have passive channels. However, there are yet many open questions regarding the use of neural networks in meteorology, such as best practices for evaluation, tuning and interpretation. This article highlights several strategies and practical considerations for neural network development that have not yet received much attention in the meteorological community, such as the concept of effective receptive fields, underutilized meteorological performance measures, and methods for NN interpretation, such as synthetic experiments and layer-wise relevance propagation. We also consider the process of neural network interpretation as a whole, recognizing it as an iterative scientist-driven discovery process, and breaking it down into individual steps that researchers can take. Finally, while most work on neural network interpretation in meteorology has so far focused on networks for image classification tasks, we expand the focus to also include networks for image translation. Full Article
physics Physics-based reliability model for large-scale CMOS circuit design By www.freepatentsonline.com Published On :: Tue, 12 May 2015 08:00:00 EDT This disclosure relates generally to systems and methods for simulating physical active semiconductor components using in silico active semiconductor components. To simulate charge degradation effect(s) in a circuit simulation, a simulated defect signal level is produced. More specifically, the simulated defect signal level simulates at least one charge degradation effect in the in silico active semiconductor component as a function of simulation time and a simulated input signal level of a simulated input signal. As such, the charge degradation effect(s) are simulated externally with respect to the in silico active semiconductor component. In this manner, the in silico active semiconductor component does not need to be reprogrammed in order to simulate charge degradation effects. Full Article
physics Physics and a theory of everything By www.abc.net.au Published On :: Mon, 04 May 2020 20:05:00 +1000 How do you fancy a theory describing everything in the world and the whole universe? Physicists have been trying to find a universal theory for centuries. Progress has been made: BBC’s Jim Al-Khalili describes the three pillars of modern physics: quantum theory, relativity, and thermodynamics. But is physics any closer to finding the ONE theory that explains it all? Full Article Science and Technology Physics
physics Particle Physics Turns to Quantum Computing for Solutions to Tomorrow's Big-Data Problems By feedproxy.google.com Published On :: Wed, 29 Jan 2020 11:15:22 EST Giant-scale physics experiments are increasingly reliant on big data and complex algorithms fed into powerful computers, and managing this multiplying mass of data presents its own unique challenges. To better prepare for this data deluge posed by next-generation upgrades and new experiments, physicists are turning to the fledgling field of quantum computing. Full Article
physics TROLLING PHYSICS By feedproxy.google.com Published On :: Wed, 23 Mar 2011 17:30:00 -0700 TROLLING PHYSICS Existed in comics way before the internet Full Article magnets physics trolling
physics FDA approves ventilator designed by particle physics community By www.princeton.edu Published On :: Tue, 05 May 2020 09:01:00 -0400 Led by Princeton’s Cristian Galbiati, a massive international team worked to design, test and finalize the Mechanical Ventilator Milano (MVM), a low-cost ventilator designed to ease device shortages caused by COVID-19. Full Article
physics The physics of freezing soap bubbles is cooler than you’d think By www.pbs.org Published On :: Freezing soap bubbles look like snow globes. This whimsical effect could help us improve biological freezing techniques—and is incredibly fun to watch. Full Article
physics There will be blood, and physics, too: The messy science of bloodstain pattern analysis By www.pbs.org Published On :: Researchers are using fluid dynamics to try to improve the study of crime scene blood spatter. Full Article
physics Refrigerators of the future may be inspired by the weird physics of rubber By www.pbs.org Published On :: A new refrigeration technique harnesses the ability of rubber and other materials to cool down when released from a tight twist. Full Article
physics Structure-based discovery of a small-molecule inhibitor of methicillin-resistant Staphylococcus aureus virulence [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 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. Full Article
physics A neuroglobin-based high-affinity ligand trap reverses carbon monoxide-induced mitochondrial poisoning [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC–treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning. Full Article
physics Crystallographic and kinetic analyses of the FdsBG subcomplex of the cytosolic formate dehydrogenase FdsABG from Cupriavidus necator [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Formate oxidation to carbon dioxide is a key reaction in one-carbon compound metabolism, and its reverse reaction represents the first step in carbon assimilation in the acetogenic and methanogenic branches of many anaerobic organisms. The molybdenum-containing dehydrogenase FdsABG is a soluble NAD+-dependent formate dehydrogenase and a member of the NADH dehydrogenase superfamily. Here, we present the first structure of the FdsBG subcomplex of the cytosolic FdsABG formate dehydrogenase from the hydrogen-oxidizing bacterium Cupriavidus necator H16 both with and without bound NADH. The structures revealed that the two iron-sulfur clusters, Fe4S4 in FdsB and Fe2S2 in FdsG, are closer to the FMN than they are in other NADH dehydrogenases. Rapid kinetic studies and EPR measurements of rapid freeze-quenched samples of the NADH reduction of FdsBG identified a neutral flavin semiquinone, FMNH•, not previously observed to participate in NADH-mediated reduction of the FdsABG holoenzyme. We found that this semiquinone forms through the transfer of one electron from the fully reduced FMNH−, initially formed via NADH-mediated reduction, to the Fe2S2 cluster. This Fe2S2 cluster is not part of the on-path chain of iron-sulfur clusters connecting the FMN of FdsB with the active-site molybdenum center of FdsA. According to the NADH-bound structure, the nicotinamide ring stacks onto the re-face of the FMN. However, NADH binding significantly reduced the electron density for the isoalloxazine ring of FMN and induced a conformational change in residues of the FMN-binding pocket that display peptide-bond flipping upon NAD+ binding in proper NADH dehydrogenases. Full Article
physics Quantification of the affinities of CRISPR-Cas9 nucleases for cognate protospacer adȷacent motif (PAM) sequences [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 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. Full Article
physics Structural basis of specific inhibition of extracellular activation of pro- or latent myostatin by the monoclonal antibody SRK-015 [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 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. Full Article
physics X-ray structures of catalytic intermediates of cytochrome c oxidase provide insights into its O2 activation and unidirectional proton-pump mechanisms [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 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. Full Article
physics Structural basis of cell-surface signaling by a conserved sigma regulator in Gram-negative bacteria [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 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. Full Article