The Bunch-Kaufman factorization is widely accepted as the algorithm of choice for the direct solution of symmetric indefinite linear equations; it is the algorithm employed in both LINPACK and ...LAPACK. It has also been adapted to sparse symmetric indefinite linear systems. While the Bunch--Kaufman factorization is normwise backward stable, its factors can have unusual scaling, with entries bounded by terms depending both on |A| and on $\kappa(A)$. This scaling, combined with the block nature of the algorithm, may degrade the accuracy of computed solutions unnecessarily. Overlooking the lack of a triangular factor bound leads to a further complication in LAPACK such that the LAPACK Bunch--Kaufman factorization can be unstable. We present two alternative algorithms, close cousins of the Bunch-Kaufman factorization, for solving dense symmetric indefinite systems. Both share the positive attributes of the Bunch-Kaufman algorithm but provide better accuracy by bounding the triangular factors. The price of higher accuracy can be kept low by choosing between our two algorithms. One is appropriate as the replacement for the blocked LAPACK Bunch-Kaufman factorization; the other would replace the LINPACK-like unblocked factorization in LAPACK. Solving sparse symmetric indefinite systems is more problematic. We conclude that the Bunch-Kaufman algorithm cannot be rescued effectively in the sparse case. Imposing the constraint of bounding the triangular factors leads naturally to one particular version of the Duff-Reid algorithm, which we show gives better accuracy than Liu's sparse variant of the Bunch-Kaufman algorithm. We extend the work of Duff and Reid in two respects that often provide higher efficiency: a more effective procedure for finding pivot blocks and a stable extension to pivot blocks of size larger than two.
The structure of the membrane-containing bacteriophage PRD1 has been determined by X-ray crystallography at about 4 A resolution. Here we describe the structure and location of proteins P3, P16, P30 ...and P31. Different structural proteins seem to have specialist roles in controlling virus assembly. The linearly extended P30 appears to nucleate the formation of the icosahedral facets (composed of trimers of the major capsid protein, P3) and acts as a molecular tape-measure, defining the size of the virus and cementing the facets together. Pentamers of P31 form the vertex base, interlocking with subunits of P3 and interacting with the membrane protein P16. The architectural similarities with adenovirus and one of the largest known virus particles PBCV-1 support the notion that the mechanism of assembly of PRD1 is scaleable and applies across the major viral lineage formed by these viruses.
Abstract
Many essential cellular processes rely on substrate rotation or translocation by a multi-subunit, ring-type NTPase. A large number of double-stranded DNA viruses, including tailed ...bacteriophages and herpes viruses, use a homomeric ring ATPase to processively translocate viral genomic DNA into procapsids during assembly. Our current understanding of viral DNA packaging comes from three archetypal bacteriophage systems: cos, pac and phi29. Detailed mechanistic understanding exists for pac and phi29, but not for cos. Here, we reconstituted in vitro a cos packaging system based on bacteriophage HK97 and provided a detailed biochemical and structural description. We used a photobleaching-based, single-molecule assay to determine the stoichiometry of the DNA-translocating ATPase large terminase. Crystal structures of the large terminase and DNA-recruiting small terminase, a first for a biochemically defined cos system, reveal mechanistic similarities between cos and pac systems. At the same time, mutational and biochemical analyses indicate a new regulatory mechanism for ATPase multimerization and coordination in the HK97 system. This work therefore establishes a framework for studying the evolutionary relationships between ATP-dependent DNA translocation machineries in double-stranded DNA viruses.
INTRODUCTION
We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within ...neurodegenerative diseases.
METHODS
Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p‐tau)181 and amyloid beta (Aβ)42/40 were measured using ultra‐sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD).
RESULTS
GFAP, NfL, and/or p‐tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p‐tau181 were highly predictive across diseases, p‐tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ42/40.
DISCUSSION
GFAP, NfL, and p‐tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.
The rhesus macaque is an important animal model for AIDS and other infectious diseases. However, the investigation of Fc-mediated Ab responses in macaques is complicated by species-specific ...differences in FcγRs and IgG subclasses relative to humans. To assess the effects of these differences on FcγR-IgG interactions, reporter cell lines expressing common allotypes of human and rhesus macaque FcγR2A and FcγR3A were established. FcγR-mediated responses to B cells were measured in the presence of serial dilutions of anti-CD20 Abs with Fc domains corresponding to each of the four subclasses of human and rhesus IgG and with Fc variants of IgG1 that enhance binding to FcγR2A or FcγR3A. All of the FcγRs were functional and preferentially recognized either IgG1 or IgG2. Whereas allotypes of rhesus FcγR2A were identified with responses similar to variants of human FcγR2A with higher (H131) and lower (R131) affinity for IgG, all of the rhesus FcγR3A allotypes exhibited responses most similar to the higher affinity V158 variant of human FcγR3A. Unlike responses to human IgGs, there was little variation in FcγR-mediated responses to different subclasses of rhesus IgG. Phylogenetic comparisons suggest that this reflects limited sequence variation of macaque IgGs as a result of their relatively recent diversification from a common
gene since humans and macaques last shared a common ancestor. These findings reveal species-specific differences in FcγR-IgG interactions with important implications for investigating Ab effector functions in macaques.
This research developes a numerical model to predict skin burn injury resulting from heat transfer through a protective garment worn by an instrumented manikin exposed to laboratory-controlled flash ...fire exposures. This model incorporates characteristics of the simulated flash fire generated in the chamber and the heat-induced changes in fabric thermophysical properties. The model also accounts for clothing air layers between the garment and the manikin. The model is validated using an instrumented manikin fire test system. Results from the numerical model help contribute to a better understanding of the heat transfer process in protective garments exposed to intense flash fires, and to establishing systematic methods for engineering materials and garments to produce optimum thermal protective performance.
Cells in murine muscle have been reported to differentiate into hematopoietic stem and progenitor cells and thus repopulate the hematopoietic system of an irradiated animal. This activity was ...attributed to muscle stem cells. We used an in vitro and in vivo approach to identify the hematopoietic repopulating activity found in muscle tissue of mice by antibody staining and cell sorting. We confirmed existence of a hematopoietic repopulating cell in muscle tissue, but the data strongly suggest that repopulation is due not to muscle stem cells but to hematopoietic cells present in muscle tissue. Unexpectedly, the blood-forming cells were enriched in muscle relative to their frequency in peripheral blood.
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