OC Function Research Articles

Methodology and Characterization of a 3D Bone Organoid Model Derived from Murine Cells.

Here, we report on the development of a cost-effective, well-characterized three-dimensional (3D) model of bone homeostasis derived from commonly available stocks of immortalized murine cell lines and laboratory reagents. This 3D murine-cell-derived bone organoid model (3D-mcBOM) is adaptable to a range of contexts and can be used in conjunction with surrogates of osteoblast and osteoclast function to study cellular and molecular mechanisms that affect bone homeostasis in vitro or to augment in vivo models of physiology or disease. The 3D-mcBOM was established using a pre-osteoblast murine cell line, which was seeded into a hydrogel extracellular matrix (ECM) and differentiated into functional osteoblasts (OBs). The OBs mineralized the hydrogel ECM, leading to the deposition and consolidation of hydroxyapatite into bone-like organoids. Fourier-transform infrared (FTIR) spectroscopy confirmed that the mineralized matrix formed in the 3D-mcBOM was bone. The histological staining of 3D-mcBOM samples indicated a consistent rate of ECM mineralization. Type I collagen C-telopeptide (CTX1) analysis was used to evaluate the dynamics of OC differentiation and activity. Reliable 3D models of bone formation and homeostasis align with current ethical trends to reduce the use of animal models. This functional model of bone homeostasis provides a cost-effective model system using immortalized cell lines and easily procured supplemental compounds, which can be assessed by measuring surrogates of OB and OC function to study the effects of various stimuli in future experimental evaluations of bone homeostasis.

An Analysis of the Mean Chart Under OC Function for Correlated Data

In this paper, we determine and illustrate the effects of correlation between the observations on the operating characteristics curve, Type-I error and Average Run length. In addition, for different correlated coefficient the control limits have been developed. To study the effect of correlated observations the OC curves, Type-I error, ARL and factor A have been worked out using various equation and values are given in Tables 1 to 4. To give a visual comparison of OC function and ARL, curves have been drawn in Figures 1 to 6. It is found that correlation between observations seriously affected the OC, Type-I error, ARL and factor A for the mean chart when standards are known. When the center line and control limits are based on the large value. Thus, it will be healthy contribution in manufacturing process which tracks important product characteristics in industry.

Optimal design of multiple dependent state repetitive group sampling plan for Inverse Power Lomax distribution

A sampling plan named as Multiple Dependent State Repetitive Group Sampling (MDSRGS) plan is introduced for a time-truncated life test given that the underlying distribution of the product's lifetime is Inverse Power Lomax distribution (IPLD). The proposed sampling plan is developed with the help of two already developed sampling plans (MDS and RGS). The two-point approach OC function known as the producer's risk and customer's risk is used to determine the parameters of the proposed plan. An optimization method is used for different values of customer's risk and producer's risk, for static values of experiment termination ratio and mean ratio, to find out plan parameters (minimum size of the sample, the number of acceptance and rejection, and the number of successive lots). Tables are created for different known values of shape parameters of Inverse Power Lomax distribution. The efficiency of the proposed MDSRGS plan is examined by conducting a comparative study. To accompany the results, graphs are also used for visualizing the average sample and acceptance probabilities with the specific mean ratio. Two real-life applications are also incorporated to demonstrate the operating procedure of the proposed plan.

An Adaptive and Scalable Protection Coordination System of Overcurrent Relays in Distributed-Generator-Integrated Distribution Networks

Integration of distributed generators (DGs) into a distribution network (DN) can cause coordination challenges of overcurrent relays (OCRs) because of different fault-current contributions of DGs as well as the directional change in fault currents. Therefore, the OCRs should be properly coordinated to maintain their adaptability and scalability to protect the DG-integrated distribution network. In this study, an adaptive and scalable protection coordination (ASPC) approach has been developed for the OCRs in a DG-contained distribution network based on two implementation stages. At the first stage, the reliability improvement of fault-current calculation results is performed by determining the min-max confidence interval of fault current for each different fault type, which is the basis for properly selecting tripping and pick-up thresholds of definite-time and inverse-time OC functions in the same OCR. At the second stage, optimization algorithms are used for calculating protection-curve coefficients and Time-Dial Setting (TDS) multiplier for the inverse-time OC functions in the OCR. A real 22 kV DG-integrated distribution network which is simulated by ETAP software is considered a reliable test-bed to validate the proposed ASPC system of OCRs in the multiple-DG-contained distribution network. In addition, the coordination results of OCRs can be obtained by three common optimization algorithms, Particle Swarm Optimization (PSO), Gravitational Search Algorithm (GSA), and Genetic Algorithm (GA). These relay coordination results have shown an effective protection combination of the definite-time OC functions (50P and 50G) and the inverse-time OC functions (51P and 51G) in the same OCR to get the adaptable and scalable DN protection system.

Bayesian Kernel Machine Regression Distributed Lag Models

BACKGROUND AND AIM: Exposures to environmental chemicals during gestation can alter health status later in life. Most studies of maternal exposure to chemicals during pregnancy focus on a single chemical exposure observed at high temporal resolution. Recent research has turned to focus on exposure to mixtures of multiple chemicals, generally observed at a single time point. We consider statistical methods for analyzing data on chemical mixtures that are observed at high temporal resolution. METHODS: We propose a novel method, Bayesian kernel machine regression distributed lag model (BKMR-DLM), that simultaneously accounts for nonlinear associations and interactions among time-varying measures of exposure to mixtures. BKMR-DLM uses a functional weight for each exposure that parameterizes the window of susceptibility corresponding to that exposure within a kernel machine framework that captures non-linear and interaction effects of the multivariate exposure on the outcome. RESULTS:In a simulation, we show that the proposed method can better estimate the exposure-response function and, in high signal settings, can identify critical windows in time during which exposure has an increased association with the outcome. Applying the proposed methods to data from a birth cohort, we found evidence of a negative association between OC and birth weight and that nitrate modifies the OC, EC, and sulfate exposure-response functions. CONCLUSIONS:BKMR-DLM can estimate nonlinear association and higher-order interactions between repeated measures of exposure to a chemical mixture. It can be used to identify critical windows to components of a mixture. KEYWORDS: Air pollution, Birth outcomes, Mixtures, Modeling, Pregnancy outcomes

Robustness of the EWMA Sampling Plan to Non-Normality

The effect of non-normality on the OC function of the sampling plan under EWMA is studied by deriving the OC function for a non-normal population represented by the first four terms of an Edgeworth series.

Scutellarein inhibits RANKL-induced osteoclast formation in vitro and prevents LPS-induced bone loss in vivo.

Osteoporosis, arthritis, Peget's disease, bone tumor, periprosthetic joint infection, and periprosthetic loosening have a common characteristic of osteolysis, which is characterized by the enhanced osteoclastic bone resorptive function. At present, the treatment target of these diseases is to interfere with osteoclastic formation and function. Scutellarein (Scu), a flavonoids compound, can inhibit the progress of tumor and inflammation. However, the role of Scu in inflammatory osteolysis isn't elucidated clearly. Our study showed that Scu inhibited bone destruction induced by LPS in vivo and OC morphology and function induced by RANKL in vitro. Mechanistic studies revealed that Scu suppressed osteoclastic marker gene expression by RANKL-induced, such as Ctsk9, Mmp9, Acp5, and Atp6v0d2. In addition, we found that the inhibition effects of osteoclastogenesis and bone resorption function of Scu were mediated via attenuating NF-κB and NFAT signaling pathways. In conclusion, the results showed that Scu may become a potential new drug for the treatment of inflammatory osteolysis.

On Dodge-Romig Single Sampling Inspection Tables under Average Quality Protection

Objectives: This paper aims at presenting an easy method of designing Single Sampling Plans (SSP) by attributes inspection based on Dodge-Romig method under Average Quality Protection. Methods/Statistical Analysis: A computational algorithm is developed for obtaining the parameters of the SSP, viz., the sample size and the acceptance number. A simple computer programme under the Poisson model for the OC function is developed for the computational algorithm using which the parameters of the SSP for desired levels of Average Outgoing Quality Limit (AOQL). Findings: The sample size and acceptance number constituting the SSP obtained using the procedure described in this paper are found to provide closer values of the desired AOQL and the minimum Average Total Inspection (ATI) than those obtainable from Dodge and Romig. The simple computer programme replaces the huge volumes of tables of Dodge and Romig. The procedure avoids the approximations involved in the original Dodge-Romig method and thus results in better plans. Application/ Improvements: The Single Sampling Plans under average quality protection are applicable in attributes inspection where ever rectification is possible.

Acceptance sampling by variables with life-test objectives

Sampling plans by variables with special references to life-test problems based on Weidull distribution are obtained. The life-test is terminated at the r-th failure. The sampling plan is such that a lot is accepted with a reassigned(high)probability when the specified mean life can be established. OC functions of the plans are obtained and Producer's risk is also discussed. A method of obtaining minimum sample size has been proposed so as to obtain the require number of failures with a prescribed time limit with a given probability .

A small shared epitope-mimetic compound potently accelerates osteoclast-mediated bone damage in autoimmune arthritis (P3090)

Abstract We have recently proposed that the shared epitope (SE) may contribute to rheumatoid arthritis (RA) pathogenesis by acting as a ligand that activates pro-arthritogenic signal transduction events. In order to examine this hypothesis, here we determined the arthritogenic effect of a novel small SE-mimetic compound, c(HS4-4). In this study, we show that c(HS4-4), containing the SE primary sequence motif QKRAA, interacted with the SE receptor calreticulin, potently activated reactive oxygen species (ROS) and nitric oxide (NO) production and markedly facilitated OC differentiation and function in vitro. The pro-osteoclastogenic potency of c(HS4-4) was 100,000 to 1,000,000-fold higher than the potency of a recently described linear SE peptidic ligand. When administered at low-nanogram doses to collagen-induced arthritis (CIA) mice, c(HS4-4) significantly facilitated arthritis onset, increased disease incidence and severity, augmented bone destruction, and increased OC abundance in synovial tissues and osteoclastogenic propensities of bone marrow-derived cells. In conclusion, c(HS4-4), a small SE-mimetic compound with drug-like properties, potently activates OC-mediated bone damage and disease severity in inflammatory arthritis. These findings support the hypothesis that the SE acts as signal transduction ligand that activates an arthritogenic pathway, and attest to the druggability of this pathway.

AVL-292, a Bruton's Tyrosine Kinase Inhibitor Impacts Bone Resorption by Abrogating Osteoclast Sealing Zone Formation in Multiple Myeloma

Abstract 1822The activation of Bruton's tyrosine kinase (Btk), a member of the Tec family of tyrosine kinases regulates B-cell development and activation, and plays a key role in antibody production. Interestingly, Btk and the other Tec kinase family, Tec, regulate OC differentiation via Receptor Activator of Nuclear Factor κ B (RANK) signaling. Moreover, patients with X-linked agammaglobulinemia (XLA) who harbor Btk null mutations have impaired OC function.Here we show that, a potent and specific inhibitor of Btk, AVL-292, inhibits OC function in MM patients. AVL-292 is a highly selective, covalent Btk inhibitor that potently silences Btk enzymatic activity (IC50 < 0.5nM) with high selectivity towards Btk with lack of significant inhibition against other kinases involved in BCR signaling (Syk, Lyn). We examined the mechanism of action of AVL-292 in the context of OCs function. OC derived from MM patient monocytes were assayed with or without AVL-292. Interestingly, OC function was inhibited in the presence AVL-292 as demonstrated by pit formation assay. However, mRNA expression of Cathepsin K and TRAP, markers of OC differentiation, were increased in the presence of AVL-292. These data suggest AVL-292 inhibits OC function without affecting the OC differentiation.It has been shown that BTK and Tec regulation of OC differentiation is related to calcium (Ca2+) signaling by increasing Ca2+ flux through direct phosphorylation of phospholipase C2 (PLCγ2). To delineate the mechanism of action of the BTK inhibitor against OC function, the RANK signaling proteins were detected by western blotting and Ca2+ concentration was measured by flourescence. AVL-292 inhibited phosphorylation of the BTK substrate, PLCγ2 in OCs. This was associated with an inhibition of intracellular Ca2+ release by AVL-292 which otherwise increased with RANKL stimulation in OCs.Given the effect of AVL-292 on RANK signaling we next evaluated its effect on Proline-rich tyrosine Kinase 2 (Pyk2) and c-Src. Pyk2 plays a role in OC activation and localizes to the sealing zone in OC. RANK signaling activates c-Src, which phosphorylates Pyk2. Moreover c-Src controls OC bone resorption by regulating actin organization via cortactin. Interestingly, AVL-292 inhibited c-Src and Pyk2 phosphorylation. Furthermore, AVL-292 inhibited cortactin protein and mRNA expression, and upregulated c-Cbl protein (E3 ubiquitin ligase for c-Src) expression in OCs derived from MM patient monocytes.These data demonstrate that the novel BTK inhibitor AVL-292 inhibits OC function through inhibition of OC sealing zone formation. These results suggest a potential novel mechanism of Btk inhibition with AVL-292 on osteoclast function and therefore bone resorption. Disclosures:Evans:Celgene: Employment. Singh:Celgene: Employment. Westlin:Celgene: Employment. Raje:Onyx: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding.

Molecular Dynamics Simulations of Methane Hydrate Using Polarizable Force Fields

Molecular dynamics simulations of methane hydrate have been carried out using the polarizable AMOEBA and COS/G2 force fields. Properties calculated include the temperature dependence of the lattice constant, the OC and OO radial distribution functions, and the vibrational spectra. Both the AMOEBA and COS/G2 force fields are found to successfully account for the available experimental data, with overall somewhat better agreement with experiment being found for the AMOEBA model. Comparison is made with previous results obtained using TIP4P and SPC/E effective two-body force fields and the polarizable TIP4P-FQ force field, which allows for in-plane polarization only. Significant differences are found between the properties calculated using the TIP4P-FQ model and those obtained using the other models, indicating an inadequacy of restricting explicit polarization to in-plane only.

Evaluating and Implementing 3-Level Control Charts

In some situations, an appropriate quality measure uses three or more discrete levels (rather than an attributes or a variables measure) to classify a product characteristic. In previous work, we refer to such a classification scheme as a multi-level product quality measure, and present a general methodology for the evaluation and implementation of 3-level (conforming, marginal, nonconforming) acceptance sampling plans. In this paper, we apply this classification scheme and methodology for the purpose of evaluating and implementing 3-level control charts. The OC and ARL functions are formulated and integrated into an approximate parameter selection method. Because of the approximation, a manufacturer must overstate their ARL expectations in order to obtain reasonable control chart performance.

Imatinib as a potential antiresorptive therapy for bone disease

AbstractOsteoclasts (OCs) are large multinucleated cells derived from progenitor cells of the monocyte-macrophage lineage. Signal transduction via the macrophage–colony-stimulating factor (M-CSF) receptor, c-fms, is essential for OC formation. Since we have previously demonstrated inhibition of c-fms by imatinib, we examined the effect of imatinib on OC formation and activity. OC formation was not affected by concentrations of 1.0 μM imatinib and lower, but was reduced by 75% at 3.0 μM imatinib. In contrast, both the area of resorption and the number of resorption lacunae were reduced by 80% at 0.3 μM imatinib, and no resorption was observed at concentrations above 3.0 μM. A dose-dependent decrease in receptor activator of nuclear factor κB (RANK) expression was observed in OCs when cultured in the presence of imatinib, providing a mechanism for the decrease in OC function. In vivo analysis of the effect of imatinib on OC activity in adult mice following 8 weeks of imatinib treatment also demonstrated a decrease in OC activity. These results suggest that imatinib may have therapeutic value as an antiosteolytic agent in diseases such as osteoporosis, metastatic bone disease, and multiple myeloma.

Asymptotic Expansion for Sampling Distribution and Sample Size in Statistical Inference III—The Modified Likelihood Ratio Λ-Test in the Noncentral Case

ABSTRACT This is the third article on the subject stated in the title, treating the asymptotic expansion formula for the OC function of the modified Λ-test. According to the idea and approaching procedure in our first article (Siotani et al., 1995), the reference domain of parameters for making the expansion formula valid was set up. Then an approximate upper bound on the absolute error of the treated expanded OC function was constructed numerically and experimentally over the reference domain in such a way that it provides the guarantee for the practical validity of the expanded OC function and method of determining an effective sample size for designing the test procedure satisfying some requirements on the power of the test.

Stromal cell-derived factor-1 binding to its chemokine receptor CXCR4 on precursor cells promotes the chemotactic recruitment, development and survival of human osteoclasts

Osteoclasts (Oc) derive from hematopoietic precursors present in the circulation and bone marrow, and they differentiate into multinucleated bone-resorbing cells in response to the dual essential signals receptor activator of NF-κB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) primarily provided by bone marrow stromal cells (BMSC) and osteoblasts (Ob). However, little is known about signals that direct Oc precursors from the circulation into bone or control their migration within the marrow. Stromal cell-derived factor-1 (SDF-1 or CXCL12) is a chemokine highly expressed by bone endothelium, BMSC, and immature Ob that is essential for the normal homing, early development, and survival of various hematopoietic progenitor cells. We investigated whether SDF-1 and its unique chemokine receptor CXCR4 were involved in regulating human Oc precursor chemotaxis, development, function, or survival. CXCR4 was highly expressed by freshly isolated human monocyte (MN) populations, in vitro generated Oc and Oc-like cells, and mature Oc isolated from human femoral bones. SDF-1 markedly stimulated the chemotactic recruitment of circulating human MN capable of generating bone-resorptive Oc, leading to a 4-fold increase in Oc formation and greater bone pit resorption after their M-CSF + RANKL induced differentiation compared to spontaneously migrating cells. SDF-1 also directly promoted early (but not later) stages of Oc development via stimulating precursor cell numbers, multinucleated cell fusion, increased cell size, and tartrate-resistant acid phosphatase (TRAP) activity in a similar, but non-additive, fashion to M-CSF + RANKL. While SDF-1 did not cause full development of bone-resorbing Oc or stimulate the resorptive function of mature Oc directly, it also did not interfere with any actions promoted by M-CSF + RANKL. In mature human Oc, SDF-1 proved equally as effective as M-CSF + RANKL for preventing Oc apoptosis induced by cytokine withdrawal. In both cases, Oc survival was accompanied by analogous rises in the mRNA ratios for anti-apoptotic Bcl-x L and Bfl-1 relative to pro-apoptotic Bax, and by marked protein suppression of the critical pro-apoptotic signal Bim. These findings demonstrate for the first time that SDF-1 chemoattracts circulating human Oc precursors capable of developing into bone-resorptive Oc, and that it can stimulate MN cell fusion and TRAP activity, mimic M-CSF + RANKL in early osteoclastogenic effects, substitute for M-CSF + RANKL in maintaining the survival of mature human Oc, and suppress Oc expression of Bim protein. Thus, high levels of SDF-1 produced by bone endothelium, BMSC, and Ob may selectively target circulating Oc precursors into bone and stimulate their marrow migration into suitable perivascular stromal sites for their early development, RANKL differentiation, and survival. Consequently, SDF-1 may be a key factor linking bone vascular cells, BMSC, Ob, and Oc in the normal homeostatic regulation of bone development and remodeling.

Exact computation for some sequential tests

Assume that the probability density function for the lifetime of a newly designed product has the form: , for some known H(·). The Exponential ϵ(θ), Rayleigh, and Pareto Pdf's are special cases. A class of continuous-time sequential tests based on the transformed total time on test and the total number of failures is proposed. The use of Steck's (1971) recursions for rectangle probabilities of uniform order statistics simplifies the exact computation for the operating characteristic, the average sample number, and the average failure number. Applications are given to Epstein and Sobel's (1955) continuous-time sequential probability ratio tests (SPRT), Anderson (1960) type of modification to the SPRT, a Bayesian sequential reliability demonstration test (BSRDT) and a predictive sequentila reliability demonstration test (PSRDT). Jeffreys’ prior appears inappropriate for both BSRDT's and PSRDT's. An ad hoc noninformative prior is used for BSRDT's and PSRDT's. Relationship between BSRDT's and PSRDT's is discussed. Numerical examples are given for illustrating the recursion formulas for the OC and ASN functions.

Exact formulas for the oc and asn functions of the sprt for erlang distributions

Let X1, X2,… be independent distributed random variables where is unknown. Using solutions of special integral equations, exact formulae for the operating characteristic as well as for the average sample number of SPRT’s are derived

GERT Analysis of Conditional Repetitive Group Sampling Plan

Introduces a conditional repetitive group sampling plan. The OC and ASN functions are derived by GERT approach. The present development would be a valuable addition to the literature and a useful device to quality control practitioners and also to quality control engineers and plan designers in the development of further new plans.

Estimating expected waiting-time in Weibull SPRT

Abstract The present paper deals with the development of a sequential test plan when lifetime has a Weibull distribution with a known shape parameter. Formulae for the OC function, the ASN function and the EWT function are also given and analysed.