866 research outputs found
A rare mutation in SMAD9 associated with high bone mass identifies the SMAD-dependent BMP signalling pathway as a potential anabolic target for osteoporosis
Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z-scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome-wide and gene-based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (P-GWAS = 6 x 10(-16); P-GENE = 8 x 10(-17)). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone-derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)-dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss-of-function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. (c) 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research
A2ML1 and otitis media : novel variants, differential expression, and relevant pathways
A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.Peer reviewe
Computational analysis of antibody dynamics identifies recent HIV-1 infection.
CAPRISA, 2017.Abstract available in pdf
2015 Research & Innovation Day Program
A one day showcase of applied research, social innovation, scholarship projects and activities.https://first.fanshawec.ca/cri_cripublications/1002/thumbnail.jp
NeuroBench:A Framework for Benchmarking Neuromorphic Computing Algorithms and Systems
Neuromorphic computing shows promise for advancing computing efficiency and capabilities of AI applications using brain-inspired principles. However, the neuromorphic research field currently lacks standardized benchmarks, making it difficult to accurately measure technological advancements, compare performance with conventional methods, and identify promising future research directions. Prior neuromorphic computing benchmark efforts have not seen widespread adoption due to a lack of inclusive, actionable, and iterative benchmark design and guidelines. To address these shortcomings, we present NeuroBench: a benchmark framework for neuromorphic computing algorithms and systems. NeuroBench is a collaboratively-designed effort from an open community of nearly 100 co-authors across over 50 institutions in industry and academia, aiming to provide a representative structure for standardizing the evaluation of neuromorphic approaches. The NeuroBench framework introduces a common set of tools and systematic methodology for inclusive benchmark measurement, delivering an objective reference framework for quantifying neuromorphic approaches in both hardware-independent (algorithm track) and hardware-dependent (system track) settings. In this article, we present initial performance baselines across various model architectures on the algorithm track and outline the system track benchmark tasks and guidelines. NeuroBench is intended to continually expand its benchmarks and features to foster and track the progress made by the research community
The JWST Galactic Center Survey -- A White Paper
The inner hundred parsecs of the Milky Way hosts the nearest supermassive
black hole, largest reservoir of dense gas, greatest stellar density, hundreds
of massive main and post main sequence stars, and the highest volume density of
supernovae in the Galaxy. As the nearest environment in which it is possible to
simultaneously observe many of the extreme processes shaping the Universe, it
is one of the most well-studied regions in astrophysics. Due to its proximity,
we can study the center of our Galaxy on scales down to a few hundred AU, a
hundred times better than in similar Local Group galaxies and thousands of
times better than in the nearest active galaxies. The Galactic Center (GC) is
therefore of outstanding astrophysical interest. However, in spite of intense
observational work over the past decades, there are still fundamental things
unknown about the GC. JWST has the unique capability to provide us with the
necessary, game-changing data. In this White Paper, we advocate for a JWST
NIRCam survey that aims at solving central questions, that we have identified
as a community: i) the 3D structure and kinematics of gas and stars; ii)
ancient star formation and its relation with the overall history of the Milky
Way, as well as recent star formation and its implications for the overall
energetics of our galaxy's nucleus; and iii) the (non-)universality of star
formation and the stellar initial mass function. We advocate for a large-area,
multi-epoch, multi-wavelength NIRCam survey of the inner 100\,pc of the Galaxy
in the form of a Treasury GO JWST Large Program that is open to the community.
We describe how this survey will derive the physical and kinematic properties
of ~10,000,000 stars, how this will solve the key unknowns and provide a
valuable resource for the community with long-lasting legacy value.Comment: This White Paper will be updated when required (e.g. new authors
joining, editing of content). Most recent update: 24 Oct 202
The ABC130 barrel module prototyping programme for the ATLAS strip tracker
For the Phase-II Upgrade of the ATLAS Detector, its Inner Detector,
consisting of silicon pixel, silicon strip and transition radiation
sub-detectors, will be replaced with an all new 100 % silicon tracker, composed
of a pixel tracker at inner radii and a strip tracker at outer radii. The
future ATLAS strip tracker will include 11,000 silicon sensor modules in the
central region (barrel) and 7,000 modules in the forward region (end-caps),
which are foreseen to be constructed over a period of 3.5 years. The
construction of each module consists of a series of assembly and quality
control steps, which were engineered to be identical for all production sites.
In order to develop the tooling and procedures for assembly and testing of
these modules, two series of major prototyping programs were conducted: an
early program using readout chips designed using a 250 nm fabrication process
(ABCN-25) and a subsequent program using a follow-up chip set made using 130 nm
processing (ABC130 and HCC130 chips). This second generation of readout chips
was used for an extensive prototyping program that produced around 100
barrel-type modules and contributed significantly to the development of the
final module layout. This paper gives an overview of the components used in
ABC130 barrel modules, their assembly procedure and findings resulting from
their tests.Comment: 82 pages, 66 figure
IMPACT-Global Hip Fracture Audit: Nosocomial infection, risk prediction and prognostication, minimum reporting standards and global collaborative audit. Lessons from an international multicentre study of 7,090 patients conducted in 14 nations during the COVID-19 pandemic
Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an
Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis
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