Transcription activator like effector (TALE)-directed piggyBac transposition in human cells.

Insertional therapies have shown great potential for combating genetic disease and safer methods would undoubtedly broaden the variety of possible illness that can be treated. A major challenge that remains is reducing the risk of insertional mutagenesis due to random insertion by both viral and non-viral vectors. Targetable nucleases are capable of inducing double-stranded breaks to enhance homologous recombination for the introduction of transgenes at specific sequences. However, off-target DNA cleavages at unknown sites can lead to mutations that are difficult to detect. Alternatively, the piggyBac transposase is able perform all of the steps required for integration; therefore, cells confirmed to contain a single copy of a targeted transposon, for which its location is known, are likely to be devoid of aberrant genomic modifications. We aimed to retarget transposon insertions by comparing a series of novel hyperactive piggyBac constructs tethered to a custom transcription activator like effector DNA-binding domain designed to bind the first intron of the human CCR5 gene. Multiple targeting strategies were evaluated using combinations of both plasmid-DNA and transposase-protein relocalization to the target sequence. We demonstrated user-defined directed transposition to the CCR5 genomic safe harbor and isolated single-copy clones harboring targeted integrations

Essential role for proteinase-activated receptor-2 in arthritis

Using physiological, pharmacological, and gene disruption approaches, we demonstrate that proteinase-activated receptor-2 (PAR-2) plays a pivotal role in mediating chronic inflammation. Using an adjuvant monoarthritis model of chronic inflammation, joint swelling was substantially inhibited in PAR-2-deficient mice, being reduced by more than fourfold compared with wild-type mice, with virtually no histological evidence of joint damage. Mice heterozygous for PAR-2 gene disruption showed an intermediate phenotype. PAR-2 expression, normally limited to endothelial cells in small arterioles, was substantially upregulated 2 weeks after induction of inflammation, both in synovium and in other periarticular tissues. PAR-2 agonists showed potent proinflammatory effects as intra-articular injection of ASKH95, a novel synthetic PAR-2 agonist, induced prolonged joint swelling and synovial hyperemia. Given the absence of the chronic inflammatory response in the PAR-2-deficient mice, our findings demonstrate a key role for PAR-2 in mediating chronic inflammation, thereby identifying a novel and important therapeutic target for the management of chronic inflammatory diseases such as rheumatoid arthritis

Efficient Multikernel Hierarchical Compression for Boundary Element Matrices

We present a new scheme that allows for the compression of operators of the combined field integral equation in the low-frequency regime using a hierarchical decomposition that leverages a unified pseudoskeleton approximation of both the single- and the double-layer Green’s function at the quadrature points. Compared with a standard adaptive cross approximation, the numerical results show a reduced memory consump- tion without sacrificing computational run time

Periodicities and Plasma Density Structure of Jupiter’s Dawnside Magnetosphere

The ability to quantify variations in magnetic field topology and density within Jupiter’s magnetosphere is an important step in understanding the overall structure and dynamics. The Juno spacecraft has provided a rich data set in the dawnside magnetosphere. The recent Grid Agnostic MHD for Extended Research Applications (GAMERA) global simulation study by Zhang et al. (2021) showed a highly structured plasmadisc with closed magnetic field lines mapping between the outer dawn-tail flank and the high latitude polar region. To test these model predictions, we examined Juno’s magnetic field data and electron/energetic particle data to categorize portions of orbits 1-15 into one of three regions based on plasma confinement: the flux pileup region, the intermediate region, and the plasmadisc region. For each region we examined periodicities from magnetic field fluctuations and particle density fluctuations on the 1-10 hours time scale. Periodicities on this time scale could relate to internal (e.g. plasmadisc structure) or external processes (e.g. Kelvin-Helmholtz vortices). Similar analysis was performed on the GAMERA simulation with the data split into two regions, an outer (150 \u3e R \u3e 60) region and an inner (R \u3c 60) region. Finally, using published density moments from Huscher et al. (2021) we compared the relative density variations of the Juno moments and the GAMERA simulation to further understand the overall structure and dynamics of the plasmadisc. The agreement between data and simulation supports the existence of such a highly structured plasmadisc

Three-dimensional geometric morphometric analysis of the first metacarpal distal articular surface in humans, great apes and fossil hominins

Understanding the manual abilities of fossil hominins has been a focus of palaeoanthropological research for decades. Of interest are the morphological characteristics of the thumb due to its fundamental role in manipulation, particularly that of the trapeziometacarpal joint. Considerably less attention has been given to the thumb metacarpophalangeal (MCP) joint, which plays a role in stabilizing the thumb during forceful grasps and precision pinching. In this study we use a three-dimensional geometric morphometric approach to quantify the shape of the first metacarpal head in extant hominids (Homo, Pan, Gorilla and Pongo) and six fossil hominin species (Homo neanderthalensis Tabun C1 and La Chappelle-aux-Saints, Homo naledi U.W. 101-1282, Australopithecus sediba MH2, Paranthropus robustus/early Homo SK84, Australopithecus africanus StW 418, Australopithecus afarensis A.L. 333w-39), with the aims of identifying shapes that may be correlated with human-like forceful opposition and determining if similar morphologies are present in fossil hominins. Results show that humans differ from extant great apes by having a distally flatter articular surface, larger epicondyle surface area, and a larger radial palmar condyle. We suggest that this suite of features is correlated with a lower range of motion at the MCP joint, which would enhance the thumbs ability to resist the elevated loads associated with the forceful precision grips typical of humans. Great ape genera are each differentiated by distinctive morphological features, each of which is consistently correlated with the predicted biomechanical demands of their particular locomotor and/or manipulatory habits. Neanderthals and U.W. 101-1282 fall within the modern human range of variation, StW 418, SK 84 and U.W. 88-119 fall in between humans and great apes, and A.L. 333w-39 falls within Pan variation. These results agree with those of traditional linear analyses while providing a more comprehensive quantitative basis from which to interpret the hand functional morphology of extinct hominins

The Locomotion of Babakotia radofilai Inferred From Epiphyseal and Diaphyseal Morphology of the Humerus and Femur

Palaeopropithecids, or “sloth lemurs,” are a diverse clade of large-bodied Malagasy subfossil primates characterized by their inferred suspensory positional behavior. The most recently discovered genus of the palaeopropithecids is Babakotia, and it has been described as more arboreal than Mesopropithecus, but less than Palaeopropithecus. In this article, the withinbone and between-bones articular and cross-sectional diaphyseal proportions of the humerus and femur of Babakotia were compared to extant lemurs, Mesopropithecus and Palaeopropithecus in order to further understand its arboreal adaptations. Additionally, a sample of apes and sloths (Choloepus and Bradypus) are included as functional outgroups composed of suspensory adapted primates and non-primates. Results show that Babakotia and Mesopropithecus both have high humeral/femoral shaft strength proportions, similar to extant great apes and sloths and indicative of forelimb suspensory behavior, with Babakotia more extreme in this regard. All three subfossil taxa have relatively large femoral heads, also associated with suspension in modern taxa. However, Babakotia and Mesopropithecus (but not Palaeopropithecus) have relatively small femoral head surface area to shaft strength proportions suggesting that hind-limb positioning in these taxa during climbing and other behaviors was different than in extant great apes, involving less mobility. Knee and humeral articular dimensions relative to shaft strengths are small in Babakotia and Mesopropithecus, similar to those found in modern sloths and divergent from those in extant great apes and lemurs, suggesting more sloth-like use of these joints during locomotion. Mesopropithecus and Babakotia are more similar to Choloepus in humerofemoral head and length proportions while Palaeopropithecus is more similar to Bradypus. These results provide further evidence of the suspensory adaptations of Babakotia and further highlight similarities to both extant suspensory primates and non-primate slow arboreal climbers and hangers

Higher-spin current multiplets in operator-product expansions

Various formulas for currents with arbitrary spin are worked out in general space-time dimension, in the free field limit and, at the bare level, in presence of interactions. As the n-dimensional generalization of the (conformal) vector field, the (n/2-1)-form is used. The two-point functions and the higher-spin central charges are evaluated at one loop. As an application, the higher-spin hierarchies generated by the stress-tensor operator-product expansion are computed in supersymmetric theories. The results exhibit an interesting universality.Comment: 19 pages. Introductory paragraph, misprint corrected and updated references. CQG in pres