Authorities are warning WA residents to prepare emergency kits for up to five days and to avoid "last minute" preparations, despite below-average cyclone predictions for the 201920 season.

While the world is consumed with the terrifying coronavirus pandemic, on March 19 the Trump administration will be marking the 17th anniversary of the U.S. invasion of Iraq by ramping up the conflict there. After an Iran-aligned militia allegedly struck a U.S. base near Baghdad on March 11, the U.S. military carried out retaliatory strikes against five […]

MOTORISTS could be putting themselves at risk of being hit by lorries and heavy goods vehicles at roundabouts in what could become a serious car crash.

Ignat V. Shilov
Sep 1, 2007; 6:1638-1655
Technology

Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
Research

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.

Weerapan Khovidhunkit
Jul 1, 2004; 45:1169-1196
Thematic Reviews

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.

M. M. Kapustei and P. V. Slyusarchuk
Theor. Probability and Math. Statist. 99 (2020), 101-111.
Abstract, references and article information

(University of Adelaide) An international team of scientists led by the University of Adelaide's Davies Research Centre has shown that it is possible to disentangle the DNA sequences of the chromosomes inherited from the mother and the father, to create true diploid genomes from a single individual.

(Smithsonian Tropical Research Institute) Oil pollution is known to cause lethal and sublethal responses on coral communities in the short-term, but its long-term effects have not been widely studied. The Bahia Las Minas oil spill, which contaminated about 40 square kilometers (about 15 square miles) near the Smithsonian's Galeta Point Marine Laboratory in Colon and became the largest recorded near coastal habitats in Panama, served as an opportunity to understand how coral reefs in tropical ecosystems recover from acute contamination over time.

Members Event

Event participants

Professor Michael Cox, Associate Fellow, US and the Americas Programme, Chatham House; Director, LSE IDEAS

Professor Margaret MacMillan, Professor of History, University of Toronto; Emeritus Professor of International History, University of Oxford

Dr Geoff Tily, Senior Economist, TUC; Author, Keynes Betrayed: The General Theory, the Rate of Interest and 'Keynesian' Economics

Chair: Dr Jessica Reinisch, Reader in Modern European History, Birkbeck University of London

Research Event

Event participants

Brigadier General Stephen A. Cheney, CEO, American Security Project; Member, Foreign Affairs Policy Board, US Department of State
Major General Munir Muniruzzaman, President and CEO, Bangladesh Institute of Peace and Security Studies; Former Military Advisor to the President of Bangladesh 
Rear Admiral Neil Morisetti, Director of Strategy, UK Department of Science, Technology, Engineering and Public Policy; University College London; Former UK Government Climate and Energy Security Envoy
Dr Patricia Lewis, Research Director, International Security, Chatham House
Chair: Rt Hon Sir Oliver Letwin MP, Former UK Cabinet Office Minister

An “author pays” publishing model is the only fair way to make biomedical research findings accessible to all, say David Sanders, professor of gastroenterology at Sheffield University, but James Ashton and worries that it can lead to bias in the evidence base towards commercially driven results - as those are the researchers who can pay for open...

High school graduation is a landmark event for students. It also plays an important role in the state accountability systems designed to ensure that schools provide all students a high-quality education. Yet relying on a school's four-year graduation rate for federal accountability purposes can have unintended consequences for English Learners, who may need extra time to graduate.

Meat industry and trade -- Environmental aspects.

London : Longman, Brown, Green, and Longmans, 1842.

Gianluca Finocchio, Johannes Schmidt-Hieber.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 239--271.

Abstract:
Consider the Gaussian sequence model under the additional assumption that a fixed fraction of the means is known. We study the problem of variance estimation from a frequentist Bayesian perspective. The maximum likelihood estimator (MLE) for $sigma^{2}$ is biased and inconsistent. This raises the question whether the posterior is able to correct the MLE in this case. By developing a new proving strategy that uses refined properties of the posterior distribution, we find that the marginal posterior is inconsistent for any i.i.d. prior on the mean parameters. In particular, no assumption on the decay of the prior needs to be imposed. Surprisingly, we also find that consistency can be retained for a hierarchical prior based on Gaussian mixtures. In this case we also establish a limiting shape result and determine the limit distribution. In contrast to the classical Bernstein-von Mises theorem, the limit is non-Gaussian. We show that the Bayesian analysis leads to new statistical estimators outperforming the correctly calibrated MLE in a numerical simulation study.

Natalia Shenkman.

Source: Brazilian Journal of Probability and Statistics, Volume 34, Number 1, 127--135.

Abstract:
While derivations of the characterization of the $d$-variate exchangeable Marshall–Olkin copula via $d$-monotone sequences relying on basic knowledge in probability theory exist in the literature, they contain a myriad of unnecessary relatively complicated computations. We revisit this issue and provide proofs where all undesired artefacts are removed, thereby exposing the simplicity of the characterization. In particular, we give an insightful analytical derivation of the monotonicity conditions based on the monotonicity properties of the survival probabilities.

A. Philip Dawid, Vanessa Didelez

Source: Statist. Surv., Volume 4, 184--231.

Abstract:
We consider the problem of learning about and comparing the consequences of dynamic treatment strategies on the basis of observational data. We formulate this within a probabilistic decision-theoretic framework. Our approach is compared with related work by Robins and others: in particular, we show how Robins’s ‘ G -computation’ algorithm arises naturally from this decision-theoretic perspective. Careful attention is paid to the mathematical and substantive conditions required to justify the use of this formula. These conditions revolve around a property we term stability , which relates the probabilistic behaviours of observational and interventional regimes. We show how an assumption of ‘sequential randomization’ (or ‘no unmeasured confounders’), or an alternative assumption of ‘sequential irrelevance’, can be used to infer stability. Probabilistic influence diagrams are used to simplify manipulations, and their power and limitations are discussed. We compare our approach with alternative formulations based on causal DAGs or potential response models. We aim to show that formulating the problem of assessing dynamic treatment strategies as a problem of decision analysis brings clarity, simplicity and generality.

References:
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Dawid, A. P. (2010). Beware of the DAG! In Proceedings of the NIPS 2008 Workshop on Causality. Journal of Machine Learning Research Workshop and Conference Proceedings ( D. Janzing, I. Guyon and B. Schölkopf, eds.) 6 59–86. http://tinyurl.com/33va7tm

Dawid, A. P. and Didelez, V. (2008). Identifying optimal sequential decisions. In Proceedings of the Twenty-Fourth Annual Conference on Uncertainty in Artificial Intelligence (UAI-08) ( D. McAllester and A. Nicholson, eds.). 113-120. AUAI Press, Corvallis, Oregon. http://tinyurl.com/3899qpp

Dechter, R. (2003). Constraint Processing. Morgan Kaufmann Publishers.

Didelez, V., Dawid, A. P. and Geneletti, S. G. (2006). Direct and indirect effects of sequential treatments. In Proceedings of the Twenty-Second Annual Conference on Uncertainty in Artificial Intelligence (UAI-06) ( R. Dechter and T. Richardson, eds.). 138-146. AUAI Press, Arlington, Virginia. http://tinyurl.com/32w3f4e

Didelez, V., Kreiner, S. and Keiding, N. (2010). Graphical models for inference under outcome dependent sampling. Statistical Science (to appear).

Didelez, V. and Sheehan, N. S. (2007). Mendelian randomisation: Why epidemiology needs a formal language for causality. In Causality and Probability in the Sciences, ( F. Russo and J. Williamson, eds.). Texts in Philosophy Series 5 263–292. College Publications, London.

Eichler, M. and Didelez, V. (2010). Granger-causality and the effect of interventions in time series. Lifetime Data Analysis 16 3–32.

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Geneletti, S. G. (2007). Identifying direct and indirect effects in a non–counterfactual framework. Journal of the Royal Statistical Society: Series B 69 199–215.

Geneletti, S. G. and Dawid, A. P. (2010). Defining and identifying the effect of treatment on the treated. In Causality in the Sciences ( P. M. Illari, F. Russo and J. Williamson, eds.) Oxford University Press (to appear).

Gill, R. D. and Robins, J. M. (2001). Causal inference for complex longitudinal data: The continuous case. Annals of Statistics 29 1785–1811.

Guo, H. and Dawid, A. P. (2010). Sufficient covariates and linear propensity analysis. In Proceedings of the Thirteenth International Workshop on Artificial Intelligence and Statistics, (AISTATS) 2010, Chia Laguna, Sardinia, Italy, May 13-15, 2010. Journal of Machine Learning Research Workshop and Conference Proceedings ( Y. W. Teh and D. M. Titterington, eds.) 9 281–288. http://tinyurl.com/33lmuj7

Henderson, R., Ansel, P. and Alshibani, D. (2010). Regret-regression for optimal dynamic treatment regimes. Biometrics (to appear). doi:10.1111/j.1541-0420.2009.01368.x

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Kang, J. D. Y. and Schafer, J. L. (2007). Demystifying double robustness: A comparison of alternative strategies for estimating a population mean from incomplete data. Statistical Science 22 523–539.

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Lok, J., Gill, R., van der Vaart, A. and Robins, J. (2004). Estimating the causal effect of a time-varying treatment on time-to-event using structural nested failure time models. Statistica Neerlandica 58 271–295.

Moodie, E. M., Richardson, T. S. and Stephens, D. A. (2007). Demystifying optimal dynamic treatment regimes. Biometrics 63 447–455.

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Robins, J. M. (2004). Optimal structural nested models for optimal sequential decisions. In Proceedings of the Second Seattle Symposium on Biostatistics ( D. Y. Lin and P. Heagerty, eds.) 189–326. Springer, New York.

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Robins, J. M. and Wasserman, L. A. (1997). Estimation of effects of sequential treatments by reparameterizing directed acyclic graphs. In Proceedings of the 13th Annual Conference on Uncertainty in Artificial Intelligence ( D. Geiger and P. Shenoy, eds.) 409-420. Morgan Kaufmann Publishers, San Francisco. http://tinyurl.com/33ghsas

Rosthøj, S., Fullwood, C., Henderson, R. and Stewart, S. (2006). Estimation of optimal dynamic anticoagulation regimes from observational data: A regret-based approach. Statistics in Medicine 25 4197–4215.

Shpitser, I. and Pearl, J. (2006a). Identification of conditional interventional distributions. In Proceedings of the 22nd Annual Conference on Uncertainty in Artificial Intelligence (UAI-06) ( R. Dechter and T. Richardson, eds.). 437–444. AUAI Press, Corvallis, Oregon. http://tinyurl.com/2um8w47

Shpitser, I. and Pearl, J. (2006b). Identification of joint interventional distributions in recursive semi-Markovian causal models. In Proceedings of the Twenty-First National Conference on Artificial Intelligence 1219–1226. AAAI Press, Menlo Park, California.

Spirtes, P., Glymour, C. and Scheines, R. (2000). Causation, Prediction and Search, Second ed. Springer-Verlag, New York.

Sterne, J. A. C., May, M., Costagliola, D., de Wolf, F., Phillips, A. N., Harris, R., Funk, M. J., Geskus, R. B., Gill, J., Dabis, F., Miro, J. M., Justice, A. C., Ledergerber, B., Fatkenheuer, G., Hogg, R. S., D’Arminio-Monforte, A., Saag, M., Smith, C., Staszewski, S., Egger, M., Cole, S. R. and When To Start Consortium (2009). Timing of initiation of antiretroviral therapy in AIDS-Free HIV-1-infected patients: A collaborative analysis of 18 HIV cohort studies. Lancet 373 1352–1363.

Taubman, S. L., Robins, J. M., Mittleman, M. A. and Hernán, M. A. (2009). Intervening on risk factors for coronary heart disease: An application of the parametric g-formula. International Journal of Epidemiology 38 1599–1611.

Tian, J. (2008). Identifying dynamic sequential plans. In Proceedings of the Twenty-Fourth Annual Conference on Uncertainty in Artificial Intelligence (UAI-08) ( D. McAllester and A. Nicholson, eds.). 554–561. AUAI Press, Corvallis, Oregon. http://tinyurl.com/36ufx2h

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Jeng-Min Chiou, Yu-Ting Chen, Tailen Hsing.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1430--1463.

Abstract:
Motivated by the study of road segmentation partitioned by shifts in traffic conditions along a freeway, we introduce a two-stage procedure, Dynamic Segmentation and Backward Elimination (DSBE), for identifying multiple changes in the mean functions for a sequence of functional data. The Dynamic Segmentation procedure searches for all possible changepoints using the derived global optimality criterion coupled with the local strategy of at-most-one-changepoint by dividing the entire sequence into individual subsequences that are recursively adjusted until convergence. Then, the Backward Elimination procedure verifies these changepoints by iteratively testing the unlikely changes to ensure their significance until no more changepoints can be removed. By combining the local strategy with the global optimal changepoint criterion, the DSBE algorithm is conceptually simple and easy to implement and performs better than the binary segmentation-based approach at detecting small multiple changes. The consistency property of the changepoint estimators and the convergence of the algorithm are proved. We apply DSBE to detect changes in traffic streams through real freeway traffic data. The practical performance of DSBE is also investigated through intensive simulation studies for various scenarios.

Adriana Coutinho, Rodrigo Lambert, Jérôme Rousseau.

Source: Bernoulli, Volume 26, Number 3, 2021--2050.

Abstract:
We investigate the length of the longest common substring for encoded sequences and its asymptotic behaviour. The main result is a strong law of large numbers for a re-scaled version of this quantity, which presents an explicit relation with the Rényi entropy of the source. We apply this result to the zero-inflated contamination model and the stochastic scrabble. In the case of dynamical systems, this problem is equivalent to the shortest distance between two observed orbits and its limiting relationship with the correlation dimension of the pushforward measure. An extension to the shortest distance between orbits for random dynamical systems is also provided.

Eduard Belitser, Nurzhan Nurushev.

Source: Bernoulli, Volume 26, Number 1, 191--225.

Abstract:
In the general signal$+$noise (allowing non-normal, non-independent observations) model, we construct an empirical Bayes posterior which we then use for uncertainty quantification for the unknown, possibly sparse, signal. We introduce a novel excessive bias restriction (EBR) condition, which gives rise to a new slicing of the entire space that is suitable for uncertainty quantification. Under EBR and some mild exchangeable exponential moment condition on the noise, we establish the local (oracle) optimality of the proposed confidence ball. Without EBR, we propose another confidence ball of full coverage, but its radius contains an additional $sigma n^{1/4}$-term. In passing, we also get the local optimal results for estimation , posterior contraction problems, and the problem of weak recovery of sparsity structure . Adaptive minimax results (also for the estimation and posterior contraction problems) over various sparsity classes follow from our local results.

Roderick J. Little.

Source: Statistical Science, Volume 34, Number 4, 580--583.

Andreas Buja, Lawrence Brown, Richard Berk, Edward George, Emil Pitkin, Mikhail Traskin, Kai Zhang, Linda Zhao.

Source: Statistical Science, Volume 34, Number 4, 523--544.

Abstract:
In the early 1980s, Halbert White inaugurated a “model-robust” form of statistical inference based on the “sandwich estimator” of standard error. This estimator is known to be “heteroskedasticity-consistent,” but it is less well known to be “nonlinearity-consistent” as well. Nonlinearity, however, raises fundamental issues because in its presence regressors are not ancillary, hence cannot be treated as fixed. The consequences are deep: (1) population slopes need to be reinterpreted as statistical functionals obtained from OLS fits to largely arbitrary joint ${x extrm{-}y}$ distributions; (2) the meaning of slope parameters needs to be rethought; (3) the regressor distribution affects the slope parameters; (4) randomness of the regressors becomes a source of sampling variability in slope estimates of order $1/sqrt{N}$; (5) inference needs to be based on model-robust standard errors, including sandwich estimators or the ${x extrm{-}y}$ bootstrap. In theory, model-robust and model-trusting standard errors can deviate by arbitrary magnitudes either way. In practice, significant deviations between them can be detected with a diagnostic test.

This law is going to make a mess sooner rather than later.

Parents generally adapt well to newborn screening results, but reactions to carrier status for X-linked conditions are unknown.

Results suggest that detection and disclosure of FMR1 newborn carrier status may not result in significant adverse events for mothers. (Read the full article)

The Council for Scientific and Industrial Research (CSIR) is also planning to submit additional 450 genome sequence data of coronavirus by May 15, its Director General Shekhar Mande said.

  When configuring touch targets to control other elements of a scene, it’s important to minimize the screen space that the controlling elements occupy. In this way, you can devote more of the Ult...

Chinese genome sequencing company, BGI Genomics (BGI), and Australian health-data expert, Pryzm Health (Pryzm) have announced a collaboration designed to bring genome-related precision health services to Australia.

Slovak-Austrian Chamber of Commerce together with law firm Eversheds Sutherland invites you to a webinar: First practical experience with measures to mitigate the economic consequences of COVID19 in Slovakia. The Slovak republic applied a number of ...

It is reported today in the media that a Deputy District Judge in the South Shields County Court has made a finding against MBNA ("the Creditor") in respect of various aspects of the enforceability of a credit card agreement and a payment protection...

You may recall the recent case of Golden Ocean Group Ltd v Salgaocar Mining Industries PVT Ltd [2011] EWHC 56 (Comm) in which it was argued that a valid guarantee had been given as a result of a chain of emails exchanged between two parties. At...

MLS (Overseas) Limited v The Secretary of State for Defence [2017] EWHC 3389 (TCC) Summary In a recent judgment following a challenge to a competitive procurement process run by the Ministry of Defence (“MoD”) (MLS (Overseas) Limited v T...

1.1 Which Corona related administrative orders must be differentiated in Germany and what are their effects? The local health departments are, on a case-by-case basis, entitled to prohibit the happening of any kind of event that includes a significa...

1.1 What impact might production downtime or circumstances with similar effect have on supply contracts? Reduced production or similar measurements and resulting supply shortages can cause severe problems to distributors or intermediaries, as they ...

Changes to the insolvency, civil and criminal procedural law The German Federal Government is currently planning various support measures for entrepreneurs, sole traders, other small, medium and large companies and credit institutions to mitigate t...

Lessons from the deep past reveal that human-induced warming could create more extreme conditions than Earth has ever experienced

Helium's essential for party balloons, but also for MRI scanners, physics experiments and space rockets. But supplies on Earth are getting dangerously low, warns Chanda Prescod-Weinstein

Title: Low Health Literacy May Have Deadly Consequences
Category: Health News
Created: 4/27/2011 11:00:00 AM
Last Editorial Review: 4/27/2011 12:00:00 AM

Title: Dental Anxiety Has Consequences Beyond Tooth Decay
Category: Health News
Created: 5/3/2017 12:00:00 AM
Last Editorial Review: 5/4/2017 12:00:00 AM

In mammalian cells, alphavirus replication complexes are anchored to the plasma membrane. This interaction with lipid bilayers is mediated through the viral methyl/guanylyltransferase nsP1 and reinforced by palmitoylation of cysteine residue(s) in the C-terminal region of this protein. Lipid content of membranes supporting nsP1 anchoring remains poorly studied. Here, we explore the membrane binding capacity of nsP1 with regard to cholesterol. Using the medically important chikungunya virus (CHIKV) as a model, we report that nsP1 cosegregates with cholesterol-rich detergent-resistant membrane microdomains (DRMs), also called lipid rafts. In search for the critical factor for cholesterol partitioning, we identify nsP1 palmitoylated cysteines as major players in this process. In cells infected with CHIKV or transfected with CHIKV trans-replicase plasmids, nsP1, together with the other nonstructural proteins, are detected in DRMs. While the functional importance of CHIKV nsP1 preference for cholesterol-rich membrane domains remains to be determined, we observed that U18666A- and imipramine-induced sequestration of cholesterol in late endosomes redirected nsP1 to these compartments and simultaneously dramatically decreased CHIKV genome replication. A parallel study of Sindbis virus (SINV) revealed that nsP1 from this divergent alphavirus displays a low affinity for cholesterol and only moderately segregates with DRMs. Behaviors of CHIKV and SINV with regard to cholesterol, therefore, match with the previously reported differences in the requirement for nsP1 palmitoylation, which is dispensable for SINV but strictly required for CHIKV replication. Altogether, this study highlights the functional importance of nsP1 segregation with DRMs and provides new insight into the functional role of nsP1 palmitoylated cysteines during alphavirus replication.

IMPORTANCE Functional alphavirus replication complexes are anchored to the host cell membranes through the interaction of nsP1 with the lipid bilayers. In this work, we investigate the importance of cholesterol for such an association. We show that nsP1 has affinity for cholesterol-rich membrane microdomains formed at the plasma membrane and identify conserved palmitoylated cysteine(s) in nsP1 as the key determinant for cholesterol affinity. We demonstrate that drug-induced cholesterol sequestration in late endosomes not only redirects nsP1 to this compartment but also dramatically decreases genome replication, suggesting the functional importance of nsP1 targeting to cholesterol-rich plasma membrane microdomains. Finally, we show evidence that nsP1 from chikungunya and Sindbis viruses displays different sensitivity to cholesterol sequestering agents that parallel with their difference in the requirement for nsP1 palmitoylation for replication. This research, therefore, gives new insight into the functional role of palmitoylated cysteines in nsP1 for the assembly of functional alphavirus replication complexes in their mammalian host.