On November 17, 2023, John Davies, Executive Director, National Security Intelligence Review Agency (NSIRA), presented Building Intelligence Review into National Security: The Canadian Experience for ...this year’s West Coast Security Conference. The key points discussed were the structure and responsibilities of NSIRA, the challenges and experiences of NSIRA in the last four years, and NSIRA’s plans for the future.
Received: 01-20-2024
Revised: 01-29-2024
Abstract Bone bonding is occurring in each of us and all other terrestrial vertebrates throughout life at bony remodeling sites. The surface created by the bone-resorbing osteoclast provides a ...three-dimensionally complex surface with which the cement line, the first matrix elaborated during de novo bone formation, interdigitates and is interlocked. The structure and composition of this interfacial bony matrix has been conserved during evolution across species; and we have known for over a decade that this interfacial matrix can be recapitulated at a biomaterial surface implanted in bone, given appropriate healing conditions. No evidence has emerged to suggest that bone bonding to artificial materials is any different from this natural biological process. Given this understanding it is now possible to explain why bone-bonding biomaterials are not restricted to the calcium–phosphate-based bioactive materials as was once thought. Indeed, in the absence of surface porosity, calcium phosphate biomaterials are not bone bonding. On the contrary, non-bonding materials can be rendered bone bonding by modifying their surface topography. This paper argues that the driving force for bone bonding is bone formation by contact osteogenesis, but that this has to occur on a sufficiently stable recipient surface which has micron-scale surface topography with undercuts in the sub-micron scale-range.
Identifying phenotypes based on high-content cellular images is challenging. Conventional image analysis pipelines for phenotype identification comprise multiple independent steps, with each step ...requiring method customization and adjustment of multiple parameters.
Here, we present an approach based on a multi-scale convolutional neural network (M-CNN) that classifies, in a single cohesive step, cellular images into phenotypes by using directly and solely the images' pixel intensity values. The only parameters in the approach are the weights of the neural network, which are automatically optimized based on training images. The approach requires no a priori knowledge or manual customization, and is applicable to single- or multi-channel images displaying single or multiple cells. We evaluated the classification performance of the approach on eight diverse benchmark datasets. The approach yielded overall a higher classification accuracy compared with state-of-the-art results, including those of other deep CNN architectures. In addition to using the network to simply obtain a yes-or-no prediction for a given phenotype, we use the probability outputs calculated by the network to quantitatively describe the phenotypes. This study shows that these probability values correlate with chemical treatment concentrations. This finding validates further our approach and enables chemical treatment potency estimation via CNNs.
The network specifications and solver definitions are provided in Supplementary Software 1.
william_jose.godinez_navarro@novartis.com or xian-1.zhang@novartis.com.
Supplementary data are available at Bioinformatics online.
Antimicrobial resistance in Staphylococcus aureus is a major public health threat, compounded by emergence of strains with resistance to vancomycin and daptomycin, both last line antimicrobials. Here ...we have performed high throughput DNA sequencing and comparative genomics for five clinical pairs of vancomycin-susceptible (VSSA) and vancomycin-intermediate ST239 S. aureus (VISA); each pair isolated before and after vancomycin treatment failure. These comparisons revealed a frequent pattern of mutation among the VISA strains within the essential walKR two-component regulatory locus involved in control of cell wall metabolism. We then conducted bi-directional allelic exchange experiments in our clinical VSSA and VISA strains and showed that single nucleotide substitutions within either walK or walR lead to co-resistance to vancomycin and daptomycin, and caused the typical cell wall thickening observed in resistant clinical isolates. Ion Torrent genome sequencing confirmed no additional regulatory mutations had been introduced into either the walR or walK VISA mutants during the allelic exchange process. However, two potential compensatory mutations were detected within putative transport genes for the walK mutant. The minimal genetic changes in either walK or walR also attenuated virulence, reduced biofilm formation, and led to consistent transcriptional changes that suggest an important role for this regulator in control of central metabolism. This study highlights the dramatic impacts of single mutations that arise during persistent S. aureus infections and demonstrates the role played by walKR to increase drug resistance, control metabolism and alter the virulence potential of this pathogen.
Pro-fibrotic microenvironments of scars and tumors characterized by increased stiffness stimulate mesenchymal stromal cells (MSCs) to express α-smooth muscle actin (α-SMA). We investigated whether ...incorporation of α-SMA into contractile stress fibers regulates human MSC fate. Sorted α-SMA-positive MSCs exhibited high contractile activity, low clonogenicity, and differentiation potential limited to osteogenesis. Knockdown of α-SMA was sufficient to restore clonogenicity and adipogenesis in MSCs. Conversely, α-SMA overexpression induced YAP translocation to the nucleus and reduced the high clonogenicity and adipogenic potential of α-SMA-negative MSCs. Inhibition of YAP rescued the decreased adipogenic differentiation potential induced by α-SMA, establishing a mechanistic link between matrix stiffness, α-SMA, YAP, and MSC differentiation. Consistent with in vitro findings, nuclear localization of YAP was positively correlated in α-SMA expressing stromal cells of adiposarcoma and osteosarcoma. We propose that α-SMA mediated contraction plays a critical role in mechanically regulating MSC fate by controlling YAP/TAZ activation.
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•The α-SMA-positive myofibroblast fraction of human MSCs exhibits low clonogenicity•Formation of α-SMA stress fibers enhances nuclear translocation of YAP/TAZ in MSCs•α-SMA knockdown favors adipogenesis, while overexpression promotes osteogenesis•α-SMA-mediated lineage choice of MSCs is YAP dependent
In this article, Hinz and colleagues establish a mechanistic link between expression of the myofibroblast-characteristic α-smooth muscle actin isoform, the mechano-responsive transcription factors YAP/TAZ, and MSC fate.
Noninvasive respiratory support at the end of life is controversial, although it is becoming increasingly common. Supplemental oxygen is widely prescribed for palliative care and may help with ...hypoxemic respiratory failure. Noninvasive ventilation has a well-established evidence-based role in the management of respiratory failure due to exacerbations of COPD and cardiogenic pulmonary edema. However, its role during palliative care is unclear, and evidence of support is limited. High-flow nasal cannula oxygen therapy is a new strategy for which there is evidence to support its use for hypoxemic respiratory failure. However, any benefit of the use of high-flow nasal cannula oxygen therapy in the palliative setting is unknown at this time. This review examined evidence relating to the use of noninvasive respiratory support at the end of life.
Androgen insensitivity syndrome Hughes, Ieuan A, Prof; Davies, John D, PhD; Bunch, Trevor I ...
The Lancet,
10/2012, Letnik:
380, Številka:
9851
Journal Article
Recenzirano
Odprti dostop
Androgen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate ...normal concentrations of androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the ligand-activated androgen receptor—a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure.
The Sigmoidal Nature of Bone Anchorage Liddell, Robert S; Davies, John E
The International journal of oral and maxillofacial implants,
2022 Jan-Feb, 2022-01-00, 20220101, Letnik:
37, Številka:
1
Journal Article
Recenzirano
The purpose of this study was to show the full evolution of bone anchorage caused by the growth of secondary stability and to determine which empirical model would provide the best quantitative ...description of this growth.
The retention and anchorage of machined (M), grit-blasted and dual acid etched (BAE), and BAE implants with discrete crystals of calcium phosphate (+DCD) were evaluated with both ex vivo and in vivo methods. Ex vivo evaluation of implant retention was tested by measuring the force required to pull implants out of blood-filled osteotomies formed in bovine bone for up to 1 hour. In vivo measurements of bone anchorage were evaluated by reverse torque testing of implants placed in the proximal metaphysis of rat tibiae up to 28 days after initial placement. Four models were fit to the reverse torque results, and fits were evaluated by Bayesian and Akaike information criteria (BIC and AIC) and analysis of variance (ANOVA).
AIC and BIC were 655.53 and 684.78, 472.53 and 512.74, 477.40 and 513.96, and 470.60 and 507.16 for the monomolecular, Richards, Gompertz, and logistic curves, respectively. Comparison of the Richards and logistic curves by analysis of variance (ANOVA) resulted in a P value of .78. A comparison of the three implant types using the logistic curve found that M implants had an earlier inflection point compared with BAE implants (P = .038), and the BAE+DCD implants had the greatest peak anchorage and were significantly greater than both M (P < .0001) and BAE implants (P = .005).
Bone anchorage was found to follow sigmoidal growth, which was best described by the logistic function. Further comparison of the fit values for the logistic curve shows that both overall anchorage and timing of bone anchorage are influenced by implant surface topography.
Mesenchymal progenitor cells (MPCs) have been isolated from a variety of connective tissues, and are commonly called "mesenchymal stem cells" (MSCs). A stem cell is defined as having robust clonal ...self-renewal and multilineage differentiation potential. Accordingly, the term "MSC" has been criticised, as there is little data demonstrating self-renewal of definitive single-cell-derived (SCD) clonal populations from a mesenchymal cell source.
Here we show that a tractable MPC population, human umbilical cord perivascular cells (HUCPVCs), was capable of multilineage differentiation in vitro and, more importantly, contributed to rapid connective tissue healing in vivo by producing bone, cartilage and fibrous stroma. Furthermore, HUCPVCs exhibit a high clonogenic frequency, allowing us to isolate definitive SCD parent and daughter clones from mixed gender suspensions as determined by Y-chromosome fluorescent in situ hybridization.
Analysis of the multilineage differentiation capacity of SCD parent clones and daughter clones enabled us to formulate a new hierarchical schema for MSC self-renewal and differentiation in which a self-renewing multipotent MSC gives rise to more restricted self-renewing progenitors that gradually lose differentiation potential until a state of complete restriction to the fibroblast is reached.
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