Nf1 haploinsufficiency alters myeloid lineage commitment and function, leading to deranged skeletal homeostasis

Although nullizygous loss of NF1 leads to myeloid malignancies, haploinsufficient loss of NF1 (Nf1) has been shown to contribute to osteopenia and osteoporosis which occurs in approximately 50% of neurofibromatosis type 1 (NF1) patients. Bone marrow mononuclear cells of haploinsufficient NF1 patients and Nf1(+/-) mice exhibit increased osteoclastogenesis and accelerated bone turnover; however, the culprit hematopoietic lineages responsible for perpetuating these osteolytic manifestations have yet to be elucidated. Here we demonstrate that conditional inactivation of a single Nf1 allele within the myeloid progenitor cell population (Nf1-LysM) is necessary and sufficient to promote multiple osteoclast gains-in-function, resulting in enhanced osteoclastogenesis and accelerated osteoclast bone lytic activity in response to proresorptive challenge in vivo. Surprisingly, mice conditionally Nf1 heterozygous in mature, terminally differentiated osteoclasts (Nf1-Ctsk) do not exhibit any of these skeletal phenotypes, indicating a critical requirement for Nf1 haploinsufficiency at a more primitive/progenitor stage of myeloid development in perpetuating osteolytic activity. We further identified p21Ras-dependent hyperphosphorylation of Pu.1 within the nucleus of Nf1 haploinsufficient myelomonocytic osteoclast precursors, providing a novel therapeutic target for the potential treatment of NF1 associated osteolytic manifestations

Parathyroid Hormone Hormone-Related Protein and the PTH Receptor Regulate Angiogenesis of the Skin

In developing organs, parathyroid hormone (PTH)/parathyroid hormone-related protein (PTHrP) receptor (PPR) signaling inhibits proliferation and differentiation of mesenchyme-derived cell types resulting in control of morphogenic events. Previous studies using PPR agonists and antagonists as well as transgenic overexpression of the PPR ligand PTHrP have suggested that this ligand receptor combination might regulate the anagen to catagen transition of the hair cycle. To further understand the precise role of PTHrP and the PPR in the hair cycle, we have evaluated hair growth in the traditional K14-PTHrP (KrP) and an inducible bitransgenic PTHrP mice. High levels of PTHrP trangene expression limited to the adult hair cycle resulted in the production of shorter hair shafts. Morphometric analysis indicated that reduced proliferation in the matrix preceded the appearance of thinner hair follicles and shafts during late anagen. CD31 staining revealed that the late anagen hair follicles of the KrP mice were surrounded by reduced numbers of smaller diameter capillaries as compared to controls. Moreover, the fetal skins of the PTHrP and PPR knockouts (KOs) had reciprocal increases in the length, diameter, and density of capillaries. Finally, crossing the KrP transgene onto a thrombospondin-1KO background reversed the vascular changes as well as the delayed catagen exhibited by these mice. Taken together, these findings suggest that PTHrP's influence on the hair cycle is mediated in part by its effects on angiogenesis

Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution.

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

High-Level Semantic Optimization of Numerical Codes

This paper presents a mathematical framework to exploit the semantic properties of matrix operations in loop-based numerical codes. The heart of this framework is an algebraic language called the Abstract Matrix Form which a compiler can use to reason about matrix computations in terms of loop nests, high-level matrix operations, and intermediate forms. We demonstrate how this framework may be used to detect and exploit matrix products in loop-based languages such as FORTRAN and MATLAB, and discuss the resulting performance benefits. 1 Introduction Algebraic properties of scalar integer and floating point operations are used by most compilers to optimize programs. These properties enable compilers to reduce of the strength of expressions, enhance the power of common subexpression elimination, and verify the legality of certain loop transformations [2]. Although matrices are also endowed with a rich algebra, it is less common for compilers to exploit matrix algebra to optimize program..

A Case for Source-Level Transformations in MATLAB

In this paper, we discuss various performance overheads in MATLAB codes and propose different program transformation strategies to overcome them. In particular, we demonstrate that high-level source-to-source transformations of MATLAB programs are effective in obtaining substantial performance gains regardless of whether programs are interpreted or later compiled into C or FORTRAN. We argue that automating such transformations provides a promising area of future research. 1 Introduction MATLAB is a programming language and development environment which is popular in many application domains like signal processing and computational finance that involve matrix computations. There are many reasons for its popularity. First, MATLAB is a relatively high-level, untyped language in which matrices are a built-in data type with a rich set of primitive operations. Second, MATLAB programs are interpreted, making MAT- 0 This work was supported by NSF grants CCR-9720211, EIA-9726388 and ACI-9870..

Look Left, Look Right, Look Left Again: An Application of Fractal Symbolic Analysis to Linear Algebra Code Restructuring

Fractal symbolic analysis is a symbolic analysis technique for verifying the legality of program transformations. It is strictly more powerful than dependence analysis# for example, it can be used to verify the legalityofblocking LU factorization with pivoting, a task for which dependence analysis is inadequate. In this paper, weshow how fractal symbolic analysis can be used to convert between left-looking and rightlooking versions of three kernels of central importance in computational science: triangular solve, Cholesky factorization, and LU factorization with pivoting

Fractal Symbolic Analysis for Program Transformations (*new file*)

Restructuring compilers use dependence analysis to prove that the meaning of a program is not changed by a transformation. A well-known limitation of dependence analysis is that it examines only the memory locations read and written by a statement, and does not assume any particular interpretation for the operations in that statement. Exploiting the semantics of these operations enables a wider set of transformations to be used, and is critical for optimizing important codes such as LU factorization with pivoting. Symbolic execution of programs enables the exploitation of such semantic properties, but it is intractable for all but the simplest programs. In this paper, we propose a new form of symbolic analysis for use in restructuring compilers. Fractal symbolic analysis compares a program and its transformed version by repeatedly simplifying these programs until symbolic analysis becomes tractable, ensuring that equality of simplified programs is sufficient to guarantee equality of the original programs. We present a prototype implementation of fractal symbolic analysis, and show how it can be used to optimize the cache performance of LU factorization with pivoting

Left-looking to right-looking and vice versa: An application of fractal symbolic analysis to linear algebra code restructuring

Abstract. We have recently developed a new program analysis strategy called fractal symbolic analysis that addresses some of limitations of techniques such as dependence analysis. In this paper, we showhow fractal symbolic analysis can be used to convert between left-looking and right-looking versions of three kernels of central importance in computational science: Cholesky factorization, LU factorization with pivoting, and triangular solve.