Inhibition of HIV-1 gene expression by Sam68ΔC: multiple targets but a common mechanism?

Two recent publications have explored the mechanisms by which a mutant of the host protein Sam68 blocks HIV-1 structural protein synthesis and expands its activity to encompass Nef. Although the two studies propose different mechanisms for the responses observed, it is possible that a common activity is responsible. Understanding how this Sam68 mutant discriminates among the multiple viral mRNAs promises to reveal unique properties of HIV-1 RNA metabolism

On the Influence of Alloy Composition on the Additive Manufacturability of Ni-Based Superalloys

The susceptibility of nickel-based superalloys to processing-induced crack formation during laser powder-bed additive manufacturing is studied. Twelve different alloys—some of existing (heritage) type but also other newly-designed ones—are considered. A strong inter-dependence of alloy composition and processability is demonstrated. Stereological procedures are developed to enable the two dominant defect types found—solidification cracks and solid-state ductility dip cracks—to be distinguished and quantified. Differential scanning calorimetry, creep stress relaxation tests at 1000 °C and measurements of tensile ductility at 800 °C are used to interpret the effects of alloy composition. A model for solid-state cracking is proposed, based on an incapacity to relax the thermal stress arising from constrained differential thermal contraction; its development is supported by experimental measurements using a constrained bar cooling test. A modified solidification cracking criterion is proposed based upon solidification range but including also a contribution from the stress relaxation effect. This work provides fundamental insights into the role of composition on the additive manufacturability of these materials

Single molecule quantitation and sequencing of rare translocations using microfluidic nested digital PCR

Cancers are heterogeneous and genetically unstable. New methods are needed that provide the sensitivity and specificity to query single cells at the genetic loci that drive cancer progression, thereby enabling researchers to study the progression of individual tumors. Here, we report the development and application of a bead-based hemi-nested microfluidic droplet digital PCR (dPCR) technology to achieve ‘quantitative’ measurement and single-molecule sequencing of somatically acquired carcinogenic translocations at extremely low levels (<10−6) in healthy subjects. We use this technique in our healthy study population to determine the overall concentration of the t(14;18) translocation, which is strongly associated with follicular lymphoma. The nested dPCR approach improves the detection limit to 1 × 10−7 or lower while maintaining the analysis efficiency and specificity. Further, the bead-based dPCR enabled us to isolate and quantify the relative amounts of the various clonal forms of t(14;18) translocation in these subjects, and the single-molecule sensitivity and resolution of dPCR led to the discovery of new clonal forms of t(14;18) that were otherwise masked by the conventional quantitative PCR measurements. In this manner, we created a quantitative map for this carcinogenic mutation in this healthy population and identified the positions on chromosomes 14 and 18 where the vast majority of these t(14;18) events occur.Trans-National Institutes of Health Genes, Environment and Health Initiative, Biological Response Indicators of Environmental Systems Center Grant [U54 ES016115-01 to M.T.S. and R.A.M.] and National Institute of Environmental Health Sciences Superfund Basic Research Program Grant [P42 ES004705 to M.T.S.]; Canary Foundation and ACS Postdoctoral Fellowship Award in Early Detection [116373-PFTED-08-251-01-SIED to J.S.] from the American Cancer Society; New faculty start-up funds from the University of Kansas (in part to Y.Z.). National Science Foundation Graduate Research Fellowship (to R.N.). Funding for open access charge: National Institutes of Health [U54 ES016115-01]

Avalanches and the Renormalization Group for Pinned Charge-Density Waves

The critical behavior of charge-density waves (CDWs) in the pinned phase is studied for applied fields increasing toward the threshold field, using recently developed renormalization group techniques and simulations of automaton models. Despite the existence of many metastable states in the pinned state of the CDW, the renormalization group treatment can be used successfully to find the divergences in the polarization and the correlation length, and, to first order in an $\epsilon = 4-d$ expansion, the diverging time scale. The automaton models studied are a charge-density wave model and a ``sandpile'' model with periodic boundary conditions; these models are found to have the same critical behavior, associated with diverging avalanche sizes. The numerical results for the polarization and the diverging length and time scales in dimensions $d=2,3$ are in agreement with the analytical treatment. These results clarify the connections between the behaviour above and below threshold: the characteristic correlation lengths on both sides of the transition diverge with different exponents. The scaling of the distribution of avalanches on the approach to threshold is found to be different for automaton and continuous-variable models.Comment: 29 pages, 11 postscript figures included, REVTEX v3.0 (dvi and PS files also available by anonymous ftp from external.nj.nec.com in directory /pub/alan/cdwfigs

DoubleMod and SingleMod: Simple Randomized Secret-Key Encryption with Bounded Homomorphicity

An encryption relation f Z Z with decryption function f 1 is “group-homomorphic” if, for any suitable plaintexts x1 and x2, x1+x2 = f 1( f (x1)+f (x2)). It is “ring-homomorphic” if furthermore x1x2 = f 1( f (x1) f (x2)); it is “field-homomorphic” if furthermore 1=x1 = f 1( f (1=x1)). Such relations would support oblivious processing of encrypted data. We propose a simple randomized encryption relation f over the integers, called DoubleMod, which is “bounded ring-homomorphic” or what some call ”somewhat homomorphic.” Here, “bounded” means that the number of additions and multiplications that can be performed, while not allowing the encrypted values to go out of range, is limited (any pre-specified bound on the operation-count can be accommodated). Let R be any large integer. For any plaintext x 2 ZR, DoubleMod encrypts x as f (x) = x + au + bv, where a and b are randomly chosen integers in some appropriate interval, while (u; v) is the secret key. Here u > R2 is a large prime and the smallest prime factor of v exceeds u. With knowledge of the key, but not of a and b, the receiver decrypts the ciphertext by computing f 1(y) = (y mod v) mod u. DoubleMod generalizes an independent idea of van Dijk et al. 2010. We present and refine a new CCA1 chosen-ciphertext attack that finds the secret key of both systems (ours and van Dijk et al.’s) in linear time in the bit length of the security parameter. Under a known-plaintext attack, breaking DoubleMod is at most as hard as solving the Approximate GCD (AGCD) problem. The complexity of AGCD is not known. We also introduce the SingleMod field-homomorphic cryptosystems. The simplest SingleMod system based on the integers can be broken trivially. We had hoped, that if SingleMod is implemented inside non-Euclidean quadratic or higher-order fields with large discriminants, where GCD computations appear di cult, it may be feasible to achieve a desired level of security. We show, however, that a variation of our chosen-ciphertext attack works against SingleMod even in non-Euclidean fields

Implementation of U.K. Earth system models for CMIP6

We describe the scientific and technical implementation of two models for a core set of experiments contributing to the sixth phase of the Coupled Model Intercomparison Project (CMIP6). The models used are the physical atmosphere-land-ocean-sea ice model HadGEM3-GC3.1 and the Earth system model UKESM1 which adds a carbon-nitrogen cycle and atmospheric chemistry to HadGEM3-GC3.1. The model results are constrained by the external boundary conditions (forcing data) and initial conditions.We outline the scientific rationale and assumptions made in specifying these. Notable details of the implementation include an ozone redistribution scheme for prescribed ozone simulations (HadGEM3-GC3.1) to avoid inconsistencies with the model's thermal tropopause, and land use change in dynamic vegetation simulations (UKESM1) whose influence will be subject to potential biases in the simulation of background natural vegetation.We discuss the implications of these decisions for interpretation of the simulation results. These simulations are expensive in terms of human and CPU resources and will underpin many further experiments; we describe some of the technical steps taken to ensure their scientific robustness and reproducibility

Coronavirus Antibodies in African Bat Species

Asian bats have been identified as potential reservoir hosts of coronaviruses associated with severe acute respiratory syndrome (SARS-CoV). We detected antibody reactive with SARS-CoV antigen in 47 (6.7%) of 705 bat serum specimens comprising 26 species collected in Africa; thus, African bats may harbor agents related to putative group 4 CoV

Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms

Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability