RANK Signaling Research Articles

B-cell intrinsic RANK signaling cooperates with TCL1 to induce lineage-dependent B-cell transformation

B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), remain incurable, with MM particularly prone to relapse. Our study introduces a novel mouse model with active RANK signaling and the TCL1 oncogene, displaying both CLL and MM phenotypes. In younger mice, TCL1 and RANK expression expands CLL-like B1-lymphocytes, while MM originates from B2-cells, becoming predominant in later stages and leading to severe disease progression and mortality. The induced MM mimics human disease, exhibiting features like clonal plasma cell expansion, paraproteinemia, anemia, and kidney and bone failure, as well as critical immunosurveillance strategies that promote a tumor-supportive microenvironment. This research elucidates the differential impacts of RANK activation in B1- and B2-cells and underscores the distinct roles of single versus combined oncogenes in B-cell malignancies. We also demonstrate that human MM cells express RANK and that inhibiting RANK signaling can reduce MM progression in a xenotransplantation model. Our study provides a rationale for further investigating the effects of RANK signaling in B-cell transformation and the shaping of a tumor-promoting microenvironment.

PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis.

Epigenetic regulation of metabolism profoundly influences cell fate commitment. During osteoclast differentiation, the activation of RANK signaling is accompanied by metabolic reprogramming, but the epigenetic mechanisms by which RANK signaling induces this reprogramming remain elusive. By transcriptional sequence and ATAC analysis, this study identifies that activation of RANK signaling upregulates PRMT6 by epigenetic modification, triggering a metabolic switching from fatty acids oxidation toward glycolysis. Conversely, Prmt6 deficiency reverses this shift, markedly reducing HIF-1α-mediated glycolysis and enhancing fatty acid oxidation. Consequently, PRMT6 deficiency or inhibitor impedes osteoclast differentiation and alleviates bone loss in ovariectomized (OVX) mice. At the molecular level, Prmt6 deficiency reduces asymmetric dimethylation of H3R2 at the promoters of genes including Ppard, Acox3, and Cpt1a, enhancing genomic accessibility for fatty acid oxidation. PRMT6 thus emerges as a metabolic checkpoint, mediating metabolic switch from fatty acid oxidation to glycolysis, thereby supporting osteoclastogenesis. Unveiling PRMT6's critical role in epigenetically orchestrating metabolic shifts in osteoclastogenesis offers a promising target for anti-resorptive therapy.

ROGER: Ranking-oriented Generative Retrieval

In recent years, various dense retrieval methods have been developed to improve the performance of search engines with a vectorized index. However, these approaches require a large pre-computed index and have limited capacity to memorize all semantics in a document within a single vector. To address these issues, researchers have explored end-to-end generative retrieval models that use a seq-to-seq generative model to directly return identifiers of relevant documents. Although these models have been effective, they are often trained with the maximum likelihood estimation method. It only encourages the model to assign a high probability to the relevant document identifier, ignoring the relevance comparisons of other documents. This may lead to performance degradation in ranking tasks, where the core is to compare the relevance between documents. To address this issue, we propose a ranking-oriented generative retrieval model that incorporates relevance signals in order to better estimate the relative relevance of different documents in ranking tasks. Based upon the analysis of the optimization objectives of dense retrieval and generative retrieval, we propose utilizing dense retrieval to provide relevance feedback for generative retrieval. Under an alternate training framework, the generative retrieval model gradually acquires higher-quality ranking signals to optimize the model. Experimental results show that our approach increasing Recall@1 by 12.9% with respect to the baselines on MS MARCO dataset.

A phase Ib study of JMT103, a receptor activator of NF-kB ligand (RANKL) antibody, in patients (pts) with bone metastases from solid tumors.

e15190 Background: JMT103 is a human IgG4 monoclonal antibody against RANKL and blocks the RANK signaling in osteoclasts, thus suppressing bone resorption. This phase Ib study aims to demonstrate the activity of JMT103 in bone metastases patients with solid tumors. Methods: In this randomized, multi-center, open-label, phase Ib study, adult pts with bone metastases from solid tumors were enrolled and randomized at a 1:1:1 ratio to receive JMT103 subcutaneously at 120mg every 4 weeks (Q4W, Cohort 1), 120mg every 8 weeks (Q8W, Cohort 2) and 180mg Q8W (Cohort 3) up to 49 weeks. The primary endpoint was the percent change from baseline to week 13 in creatinine-adjusted urinary N-telopeptide (uNTx/Cr). Secondary endpoints included safety, anti-drug antibodies (ADA) positivity, the percentage of patients who experienced on-study skeletal-related events (SREs), and ≥ 2-point decreases in pain with Brief Pain Inventory – Short Form. Results: At database lock (Mar. 31, 2023), 295 pts were enrolled; 293 were treated with JMT103 and eligible for efficacy and safety evaluation (96 pts in Cohort 1, 97 pts in Cohort 2, and 100 pts in Cohort 3). The median age was 58 years (Interquartile range [IQR] 51, 66), and the primary tumor types were mainly breast (145, 50%) and prostate cancer (44, 15%). At week 13, the median (IQR) percent change in uNTx/Cr was - 80% (- 93%, - 50%) in Cohort 1, - 73% (- 94%, - 34%) in Cohort 2, and - 76% (- 92%, - 40%) in Cohort 3, respectively. The incidence of SREs in the three cohorts was 3%, 6%, and 7%, respectively. Among the 33 pts in Cohort 1, 35 pts in Cohort 2, and 37 pts in Cohort 3 with baseline pain scores ≥ 2, 61% in Cohort 1, 46% in Cohort 2, and 54% in Cohort 3 experienced ≥ 2-point decreases in pain at the first post-treatment visit (Day 15). For ADA analysis, only 1 (1%) pt in Cohort 2 with a negative result at baseline tested positive after treatment. The table shows the overall summary of the safety profile. Most of TRAEs were low in grade and resolved quickly. The most common TRAEs (any grade) were hypocalcemia (68, 23%), hypophosphatemia (67, 23%), and increased aspartate transaminase (35, 12%). Among the 40 cases of grade-5 TEAE, only 1 was reported as a TRAE (pneumonia); the rest were unrelated to JMT103. Conclusions: Our study demonstrated a promising efficacy of JMT103 in reducing bone metabolism biomarker and a good safety profile with low immunogenicity. Clinical trial information: NCT04630522 . [Table: see text]

Caffeine induces alveolar bone loss in rats submitted to orthodontic movement via activation of receptor activator of nuclear factor ҡB, receptor activator of nuclear factor ҡB ligand, and osteoprotegerin pathway

Caffeine is a widely consumed substance with several effects on bone metabolism. This study aimed to investigate the effect of caffeine on the bone tissue of rats submitted to orthodontic movement. Twenty-five male Wistar rats underwent orthodontic movement (21 days) of the first permanent maxillary molars on the left side. The experimental group (caffeine; n= 13) and control group (n= 12) received caffeine and water, respectively, by gavage. Microcomputed tomography was performed to analyze orthodontic movement. Histologic analysis of the inflammatory infiltrate and osteoclast count by tartrate-resistant acid phosphatase were conducted. Maxilla tissue was evaluated for receptor activator of nuclear factor ҡB (RANK), RANK ligand (RANKL), and osteoprotegerin by immunohistochemistry. Caffeine exhibited a lower bone volume/tissue volume ratio (78.09% ± 5.83%) than the control (86.84% ± 4.89%; P<0.05). Inflammatory infiltrate was increased in the caffeine group compared with the control group (P<0.05). A higher number of tartrate-resistant acid phosphatase-positive cells was observed in the caffeine (9.67 ± 1.73) than in the control group (2.66 ± 0.76; P<0.01). Immunoexpression of RANK and RANKL in the caffeine group was greater than the control (P<0.05). The use of caffeine thermogenic induces alveolar bone loss in rats submitted to orthodontic movement via activation of RANK, RANKL, and osteoprotegerin signaling pathways.

Study on the mechanism of magnesium calcium alloys/mineralized collagen composites mediating macrophage polarization to promote bone repair

Magnesium-based composites are a focal point in biomaterials research. However, the rapid degradation rate of magnesium alloys does not align with the healing time of bone tissue. Additionally, the host reaction caused by magnesium implantation hampers its full osteogenic potential. To maintain an appropriate microenvironment, it is important to enhance both corrosion resistance and osteogenic activity of the magnesium matrix. In this study, a composite scaffold composed of mineralized collagen and magnesium alloy was utilized to investigate the regulatory effect of mineralized collagen on mouse macrophages and evaluate its impact on mouse bone marrow mesenchymal stem cells in terms of osteogenesis, immune response, and macrophage-induced osteogenic differentiation. This experiment examined the biocompatibility of mouse bone marrow mesenchymal stem cells and macrophage-induced osteogenic differentiation in vitro, and examined the expression levels of relevant pathways proteins. Magnesium calcium alloys/mineralized collagen exhibited extensive spreading, facilitated by broad and abundant pseudopodia that firmly adhered them to the material surface and promoted growth and pseudopodia formation. The findings revealed that magnesium calcium alloy/mineralized collagen scaffold materials induced osteogenic differentiation mainly through M2 polarization of macrophages. This effect was mainly mediated by promoting the integrin α2β1-FAK-ERK1/2 signaling pathways and inhibiting the RANK signaling pathways.

Icariin regulates RANKL-induced osteoclast differentiation via the ERα/c-Src/RANK signaling

Osteoporosis (OP) is a common metabolic bone disease. Excessive osteoclastic activity significantly contributes to the development of OP. Icariin (ICA) is a flavonol glycoside derived from herbal plants and possesses curative effects on postmenopausal OP and bone fracture. This study aimed to investigate the effects of ICA on osteoclast differentiation induced by receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) and the involvement of estrogen receptor α (ERα) and RANK signaling cascade in this process. RANKL was used to induce the differentiation of RAW264.7 cells to into osteoclasts. Small interfering RNA technique was used to knockdown ERα in cells. Cell counting kit-8 assay was performed to determine the cytotoxicity of ICA. The number of tartrate-resistant acid phosphatase (TRAP)-positive cells was quantified by TRAP staining. RANKL induced the differentiation of RAW264.7 cells into osteoclasts, while ICA abolished the pro-osteoporotic effect of RANKL. Moreover, ERα knockdown abolished the effects of ICA on RANKL-induced osteoclastogenesis. Further exploration revealed that ICA inhibited the phosphorylation of c-Src in osteoclasts via regulating ERα, while inactivation of c-Src reversed ERα knockdown-promoted osteoclastogenesis. Lastly, ICA inhibited the activation of the mitogen-activated protein kinase signaling pathway and downregulated the expressions of target osteoclastogenic proteins in RANKL-treated RAW 264.7 cells, while ERα knockdown almost completely diminished the effects of ICA. ICA inhibited RANKL-induced osteoclast differentiation via regulating the ERα/c-Src/RANK signaling. These findings elucidated a novel mechanism by which ICA exerts an anti-osteoporotic effect.

Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer risk

Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression, but tissue-specific factors linking these associations remain ill-defined. We observed that stiff breast tissue from women with high mammographic density, who exhibit increased lifetime risk for breast cancer, associates with abundant stem-progenitor epithelial cells. Using genetically engineered mouse models of elevated integrin mechanosignaling and collagen density, syngeneic manipulations, and spheroid models, we determined that a stiff matrix and high mechanosignaling increase mammary epithelial stem-progenitor cell frequency and enhance tumor initiation invivo. Augmented tissue mechanics expand stemness by potentiating extracellular signal-related kinase (ERK) activity to foster progesterone receptor-dependent RANK signaling. Consistently, we detected elevated phosphorylated ERK and progesterone receptors and increased levels of RANK signaling in stiff breast tissue from women with high mammographic density. The findings link fibrosis and mechanosignaling to stem-progenitor cell frequency and breast cancer risk and causally implicate epidermal growth factor receptor-ERK-dependent hormone signaling in this phenotype.

Keeping Up Appearances: An Experimental Investigation of Relative Rank Signaling

Keeping Up Appearances: An Experimental Investigation of Relative Rank Signaling

An LGR4 agonist activates the GSK‑3β pathway to inhibit RANK‑RANKL signaling during osteoclastogenesis in bone marrow‑derived macrophages.

The binding between receptor‑activated nuclear factor‑κB (RANK) and the RANK ligand (RANKL) during osteoclast development is an important target for drugs that treat osteoporosis. The leucine‑rich repeat‑containing G‑protein‑coupled receptor 4 (LGR4) acts as a negative regulator of RANK‑RANKL that suppresses canonical RANK signaling during osteoclast differentiation. Therefore, LGR4 agonists may be useful in inhibiting osteoclastogenesis and effectively treating osteoporosis. In the present study, bone marrow‑derived macrophages and a mouse model of RANKL‑induced bone loss were used to investigate the effect of mutant RANKL (MT RANKL), which was previously developed based on the crystal structure of the RANKL complex. In the present study, the binding affinity of wild‑type (WT) RANKL and MT RANKL to RANK and LGR4 was determined using microscale thermophoresis analysis, and the effect of the ligands on the AKT‑glycogen synthase kinase‑3β (GSK‑3β)‑nuclear factor of activated T cells, cytoplasmic, calcineurin‑dependent 1 (NFATc1) signaling cascade was investigated using western blotting and confocal microscopy. In addition, the expression of LGR4 and the colocalization of LGR4 with MT RANKL were analyzed in a mouse model of RANKL‑induced bone loss. The results showed that in osteoclast precursor cells, MT RANKL bound with high affinity to LGR4 and increased GSK‑3β phosphorylation independently of AKT, resulting in the inhibition of NFATc1 nuclear translocation. In the mouse model, MT RANKL colocalized with LGR4 and inhibited bone resorption. These results indicated that MT RANKL may inhibit RANKL‑induced osteoclastogenesis through an LGR4‑dependent pathway and this could be exploited to develop new therapies for osteoporosis.

Design Website for Digital Promotion SMEs Product by Optimize SEO Techniques

Small and medium-sized enterprises (SMEs) frequently face challenges in effectively promoting and selling their products online. This study aims to develop an optimized website design for digital promotion of SME products, incorporating enhanced search engine optimization (SEO) techniques. The paper first reviews key barriers inhibiting SMEs from harnessing digital channels, including limited expertise and resources in web development, SEO, and online marketing. Core principles of effective website design are then introduced, covering aspects like user-friendly interfaces, high-quality content, efficient site architecture, and responsive layouts. Building on this, SEO best practices are outlined based on an analysis of major ranking signals and algorithmic behavior. An integrated methodology is subsequently proposed for planning and creating SEO-optimized websites tailored to SME product promotion. The methodology incorporates defining goals and KPIs, competitor analysis, keyword research and mapping, optimized content development, technical site optimization, performance tracking, and continuous improvement. To validate the efficacy of this methodology, the study implements it in developing an e-commerce website for a small homemade food business. KPIs including organic traffic, conversions, and revenues are tracked before and after site development. The results demonstrate significant increases across key indicators, highlighting the effectiveness of the proposed approach in bolstering SME digital promotion through optimized website design and SEO. The methodology and findings aim to provide an accessible, impactful framework for SME adoption of digital channels.

Ethanol Extract of Radix Asteris Suppresses Osteoclast Differentiation and Alleviates Osteoporosis.

Radix Asteris, the root of Aster tataricus L. f., is historically significant in East Asian medicine for treating respiratory conditions. Yet, its implications on bone health remain uncharted. This research investigated the impact of an aqueous ethanol extract of Radix Asteris (EERA) on osteoclast differentiation and its prospective contribution to osteoporosis management. We discerned that EERA retards osteoclast differentiation by inhibiting receptor activator of nuclear factor kappa-B ligand (RANKL) expression and obstructing RANKL-induced osteoclastogenesis. EERA markedly suppressed RANKL-induced expression of NFATc1, a pivotal osteoclastogenic factor, via modulating early RANK signaling. EERA's therapeutic potential was underscored by its defense against trabecular bone degradation and its counteraction to increased body and perigonadal fat in ovariectomized mice, mirroring postmenopausal physiological changes. In the phytochemical analysis of EERA, we identified several constituents recognized for their roles in regulating bone and fat metabolism. Collectively, our findings emphasize the potential of EERA in osteoclast differentiation modulation and in the management of osteoporosis and associated metabolic changes following estrogen depletion, suggesting its suitability as an alternative therapeutic strategy for postmenopausal osteoporosis intertwined with metabolic imbalances.

Do honest signals or piercing weapons determine rank in a polygynous ungulate?

Abstract In polygynous ungulates, males are often larger than females and bear more elaborate/larger weapons. Quantifying sexual dimorphism in different traits could provide insights into species-specific evolutionary pathways of sexual selection. Concerning the combination of secondary sexual traits, we found that Himalayan tahr (Hemitragus jemlahicus) is unique among the ~20 species in the tribe Caprini, as its body mass dimorphism is ~2-fold greater than the dimorphism in horn size, whereas horn shape appears to be near-monomorphic. Whilst horns show the same growth rate in both sexes, body mass increases faster in males. Considering age variation, dominant, golden-ruffed males are also heavier than brown-ruffed, lower-ranking males. Unlike most bovids, male–male competition in tahr does not seem to have influenced weapon development, suggesting a lower importance of horns in male–male competition compared to body mass, as their unritualized combat style also suggests. Our study highlights alternative evolutionary pathways occurring in the Caprinae, where intraspecific signals involve different traits, from weapons to pelage features. Accordingly, male tahr use their ruff colour as an ‘honest’ signal of rank.

Luminal Rank loss decreases cell fitness leading to basal cell bipotency in parous mammary glands

Rank signaling pathway regulates mammary gland homeostasis and epithelial cell differentiation. Although Rank receptor is expressed by basal cells and luminal progenitors, its role in each individual cell lineage remains unclear. By combining temporal/lineage specific Rank genetic deletion with lineage tracing techniques, we found that loss of luminal Rank reduces the luminal progenitor pool and leads to aberrant alveolar-like differentiation with high protein translation capacity in virgin mammary glands. These Rank-deleted luminal cells are unable to expand during the first pregnancy, leading to lactation failure and impairment of protein synthesis potential in the parous stage. The unfit parous Rank-deleted luminal cells in the alveoli are progressively replaced by Rank-proficient cells early during the second pregnancy, thereby restoring lactation. Transcriptomic analysis and functional assays point to the awakening of basal bipotency after pregnancy by the induction of Rank/NF-κB signaling in basal parous cell to restore lactation and tissue homeostasis.

RANK ligand converts the NCoR/HDAC3 co-repressor to a PGC1β- and RNA-dependent co-activator of osteoclast gene expression

The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression. Mechanistically, RANK signaling promotes RNA-dependent interaction of the transcriptional co-activator PGC1β with the NCoR/HDAC3 complex, resulting in the activation of PGC1β and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12, which are associated with altered human bone homeostasis, promote NCoR/HDAC3 complex assembly and are necessary for RANKL-induced osteoclast differentiation invitro. These findings may be prototypic for signal-dependent functions of NCoR in other biological contexts.

Panicum miliaceum L. and Bone Healing Properties in Rat Model of Femur Fracture by Activating Phosphate Stimulating Macrophages via BMP2 and RANK Signaling Pathway

Objectives The aim of this study was to investigate the effect of Panicum miliaceum involved in the repair of femur bone fracture in rats. Materials and Methods In this study, 40 Wistar rats in five groups were studied as healthy, rats with lesion induced by surgery in femur (FX), FX rats treated with P. miliaceum extract (FX +100 and 200 P. miliaceum) and FX rats treated with Osteocare syrup (FX + OC). After 40 days, the serum levels of blood calcium (Ca), phosphorus (P), and alkaline phosphatase (ALP) along with activity of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) enzymes, and nitric oxide (NO) level were measured. The serum level of cytokines (IL-6, C-reactive protein [CRP], IL-10, IL-1β, and tumor necrosis factor-α [TNF-α]) was also measured by ELISA. The expression of OPG, RANK, RANKL, and BMP-2 genes and proteins were evaluated by real-time PCR and Western blotting techniques, respectively. Results The results showed that P. miliaceum was able to decrease the activity of ALP enzyme in addition to increasing serum Ca and P levels and GPx, SOD, and CAT activity. P. miliaceum reduces serum IL-6, IL-1β, and TNF-α, and NO levels. Also, the extract of this plant could increase the expression of OPG/RANK/BMP-2 pathway genes and proteins. Conclusion P. miliaceum can be used as a prodrug in traditional medicine to repair bone fractures and osteoporosis.

Harnessing Patient Complaints to Systematically Monitoring Healthcare Concerns through Disproportionality Analysis.

Staff observations are the most common source of data for driving improvements in care. However, the patient perspective should also be considered, and healthcare complaints offer concrete details that health organizations might otherwise overlook and that can highlight areas for learning and improvement in the healthcare system. However, because of the diverse nature of patient complaints, systematic analyses can be challenging. This study aimed to identify and prioritize areas for improvement using a data-driven approach to analysing patient complaints. The Danish version of the Healthcare Complaints Analysis Tool was used to categorize the content of complaint letters. All complaints managed by the national complaints authority, compensation claims to the Patient Compensation Association, and locally managed complaints that were filed directly at Odense University Hospital from 2017 to 2021 were included. Proportional reporting ratios (PRRs) were used to measure and display the top five signals of disproportionality and rank them by excess complaints at the hospital level and when divided into department types. The study included 6366 complaints containing 13 156 problems (on average, 2.1 problems mentioned per complaint letter). Surgical departments had the highest number of complaints (3818), followed by medical (1059), service (439), and emergency departments (239). Signal 1 of disproportionality, relating to quality problems during ward procedures, had the highest excess reporting of 1043 complaints at the hospital level, a PRR of 1.61, and was present in all department types. Signal 2, relating to safety problems during the examination and diagnosis stage, had excess reporting of 699 problems, a PRR of 1.86, and was also present in all department types. Signal 3, relating to institutional problems during admission, had the highest PRR of 3.54 and was found in most department types. Signals 4 and 5, relating to environmental problems during ward procedures and care on the ward, respectively, had PRRs of 1.5 and 1.84 and were present in most department types. The study found that analysing patient complaints can identify potential areas for hospital improvement. The study identified recurring issues in multiple departments, including quality problems during ward procedures, safety problems during the examination, institutional problems during admission, and environmental problems on the ward. The study highlights disproportionality analysis of complaints as a valuable tool to monitor patient concerns systematically.

On Best Low Rank Approximation of Positive Definite Tensors

Tensors, or multi-indexed arrays, play an important role in machine learning and signal processing. These higher-order generalizations of matrices allow for preservation of higher-order structure in data, and low rank decompositions of tensors allow for recovery of underlying information. In many cases, the underlying tensor of interest is positive (semi)definite, i.e., the homogeneous polynomial associated to the tensor has nonnegative evaluation on all inputs. An archetypal problem is that one has a noisy measurement of some low rank signal tensor of interest. This measurement itself does not have low rank, so one must compute a best low rank approximation of the measured tensor to recover component information. As it turns out, the set of tensors of rank less than or equal to is, in general, not closed when , and, as a consequence, best low rank approximations can fail to exist. In the case when a best low rank approximation does not exist, near optimal low rank approximations suffer numerical issues and cannot be used to reliably approximate underlying component information. As a consequence, existence guarantees for best low rank tensor approximations are of great practical and theoretical interest. This article develops deterministic guarantees for the existence of best low rank approximations of tensors which are positive semidefinite. In particular, we show that the set of low rank positive semidefinite tensors is relatively closed as a subset of the set of positive semidefinite tensors. We use this fact to give a deterministic bound which may be used to guarantee the existence of a best low rank approximation of a noisy low rank positive semidefinite tensor. Furthermore, we show that this condition guarantees uniqueness of the canonical polyadic decomposition for best low rank approximations. In addition, for order three tensors, we prove that our bound is sharp and that it can be computed using semidefinite programming. The main results of this article are illustrated through numerical experiments, which show that our bound is highly predictive of numerical issues when attempting to recover underlying component information from a noisy low rank positive semidefinite tensor.

Curcumin suppresses RANKL-induced osteoclast precursor autophagy in osteoclastogenesis by inhibiting RANK signaling and downstream JNK-BCL2-Beclin1 pathway

BackgroundCurcumin ameliorates bone loss by inhibiting osteoclastogenesis. Curcumin inhibits RANKL-promoted autophagy in osteoclast precursors (OCPs), which mediates its anti-osteoclastogenic effect. But the role of RANKL signaling in curcumin-regulated OCP autophagy is unknown. This study aimed to explore the relationship between curcumin, RANKL signaling, and OCP autophagy during osteoclastogenesis. MethodsWe investigated the role of curcumin in RANKL-related molecular signaling in OCPs, and identified the significance of RANK-TRAF6 signaling in curcumin-treated osteoclastogenesis and OCP autophagy using flow sorting and lentiviral transduction. Tg-hRANKL mice were used to observe the in vivo effects of curcumin on RANKL-regulated bone loss, osteoclastogenesis, and OCP autophagy. The significance of JNK-BCL2-Beclin1 pathway in curcumin-regulated OCP autophagy with RANKL was explored via rescue assays and BCL2 phosphorylation detection. ResultsCurcumin inhibited RANKL-related molecular signaling in OCPs, and repressed osteoclast differentiation and autophagy in sorted RANK+ OCPs but did not affect those of RANK− OCPs. Curcumin-inhibited osteoclast differentiation and OCP autophagy were recovered by TRAF6 overexpression. But curcumin lost these effects under TRAF6 knockdown. Furthermore, curcumin prevented the decrease in bone mass and the increase in trabecular osteoclast formation and autophagy in RANK+ OCPs in Tg-hRANKL mice. Additionally, curcumin-inhibited OCP autophagy with RANKL was reversed by JNK activator anisomycin and TAT-Beclin1 overexpressing Beclin1. Curcumin inhibited BCL2 phosphorylation at Ser70 and enhanced protein interaction between BCL2 and Beclin1 in OCPs. ConclusionsCurcumin suppresses RANKL-promoted OCP autophagy by inhibiting signaling pathway downstream of RANKL, contributing to its anti-osteoclastogenic effect. Moreover, JNK-BCL2-Beclin1 pathway plays an important role in curcumin-regulated OCP autophagy.

PO-04-134 STAR MAPPING METHOD TO IDENTIFY ENDO-EPICARDIAL DISSOCIATION AND DRIVING SITES IN PERSISTENT ATRIAL FIBRILLATION

Recurrence rates following ablation for persistent AF (psAF) remain high with the underlying mechanisms complex and poorly understood. Asynchronous activation of the endocardial and epicardial surfaces during AF, defined as endo-epicardial dissociation (EED) may be a driver for AF. We aim to investigate whether using the novel vector mapping approach, Stochastic Trajectory Analysis of Ranked (STAR) signals, endo- epicardial dissociation and early sites of activation (ESA) can be identified. Six (6) patients underwent endo-epicardial AF ablation utilizing the pericardial percutaneous CO2 insufflation technique. Two AdvisorTM HD Grid mapping catheters were placed in corresponding endocardial and epicardial positions in the left atrium. During AF, 30 second segments were recorded at the base of the left atrial appendage, anterior, inferior, left lateral and posterior LA wall. Fifteen (15) corresponding endo-epicardial segments were analysed using STAR maps and assessed for ESA and variation in direction of activation wavefront between the endocardium and epicardium. Activation wavefront direction was defined as dissociated if there was >40-degree difference between activation direction of simultaneous endo-epicardial wavefronts on STAR mapping. For each 30 second recording if there was more than 1 dominant wavefront direction, the 2 most common were used and an average taken. The overall mean difference in angulation of wavefront between the endocardium and epicardium was 71 ± 55 degrees. Nine (9) of 15 STAR maps (53%) showed activation angulation difference of >40 degrees between the endocardial and epicardial wavefront activation. Of these 9, 3 were on the posterior wall, 3 were at the base of the appendage, 2 were on the left lateral wall and 1 was on the anterior wall. ESA was identified in 6 STAR mapped endo and epicardial segments of AF, with 4 of these 6 (67%) ESAs in the epicardium. STAR mapping identifies activation wavefront discrepancy showing EED in multiple sites of the atrium with the majority of ESAs in the epicardial atrial surface.