NF2-Related Schwannomatosis (NF2): Molecular Insights and Therapeutic Avenues.

NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2 deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by NF2 deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.

Optical extra-body communication using smartphone cameras for human vital sign transmission.

This paper presents an optical extra-body communication (OEBC) for the transmission of human vital signs in an optical camera communication link. The primary vital signs, such as pulse rate, respiratory rate, body temperature, blood pressure, and peripheral capillary oxygen saturation, are captured from the patient's body. The proposed OEBC system has body sensors installed on various parts of the body for detecting, processing, and communicating the vital sign data. A light-emitting diode (LED) hub is a 4×4 red, green, and blue (RGB) LED array that acts as a coordinator to collect the vital sign data from the sensors and transmit through an optical link, while an android-based smartphone camera is used as the receiver. The proposed OEBC employs color modulation, which assigns colors to each vital sign data and transmits data based on the RGB color combinations. The experiment and simulation results show that the scheme is able to transmit the vital sign data through the optical link with an acceptable bit error rate value of 1.2×10-4 at a peak signal-to-noise ratio value of 15 dB. The proposed OEBC can thus facilitate both reliable and convenient health monitoring in hospital environments.

Patient Mobility Support for Indoor Non-Directed Optical Body Area Networks.

In this paper, a patient mobility support scheme for indoor non-directed optical body area networks (OBAN) is presented. The OBAN is an optical healthcare system where medical sensors are installed on various parts of the patient's body and are connected to an optical coordinator for transmitting the physiological signals via optical wireless links. In the proposed scheme, a white light-emitting diode (LED) was employed as the optical coordinator that was mounted on the patient body, while a photodetector (PD) was used as the receiver installed at the ceiling. We considered three practical mobility scenarios in terms of the location of the coordinator: (i) Shoulder, (ii) wrist, and (iii) both shoulder and wrist. The analytical channel model for multiple reflections in a non-directed OBAN was developed and validated in the form of simulations. In addition, experiments were carried out to verify the effectiveness of the proposed mobility scheme. It was found that the third scenario (shoulder and wrist) performed best, showing a bit error rate (BER) of 1.2 × 10-6 at a distance of 1.25 m. The experimental results demonstrated that the proposed mobility support scheme in the OBAN added an additional degree of freedom to patients with reliable performances.

Experimental demonstration of indoor uplink near-infrared LED camera communication.

In this paper, we present experimental demonstration of an indoor uplink near-infrared LED camera communication (ICC) that employs near-infrared (IR) light as a communication medium and a camera as the receiver. The proposed ICC exploits advantages of the camera receiver to provide wider coverage and accurate indoor positioning in IR communications. Since near-IR light is the communication medium, ICC can safely increase the light intensity compared with other visible light based wireless communication schemes. Unlike previous studies focused on positioning only, the ICC provides practical uplink indoor wireless communication as well as positioning. As in optical camera communications, the blooming effect from slow speed cameras needs to be mitigated in the ICC. An adaptive intensity compensation algorithm is also proposed for reducing this blooming effect. The blooming reduction algorithm is based on the absence of visible light interference in IR communications. Experiments demonstrate that employing an even low-specification webcam and low-power LEDs can provide centimeter-scale accuracy for the user positioning and a data rate of 6.72 kbit/s at a distance of 100 cm.

Preferential Induction of the T Cell Auxiliary Signaling Molecule B7-H3 on Synovial Monocytes in Rheumatoid Arthritis.

B7-H3, a newly identified B7 family member, has functional duality as a co-stimulator and co-inhibitor that fine-tunes T cell-mediated immune responses. Given that B7-H3 expression on human monocytes and dendritic cells is enhanced by inflammatory cytokines, its potential inmmunoregulatory role at sites of inflammation has been suggested. Further, monocytes play crucial roles in the pathophysiology of various inflammatory disorders including autoimmune diseases; however, the immunological role of B7-H3 in rheumatoid arthritis (RA) has not been defined. Thus, we aimed to investigate the possible roles of monocyte B7-H3 in the pathogenesis of RA. Synovial monocytes, but not peripheral monocytes, in RA patients predominantly express surface B7-H3. The 4Ig isoform of B7-H3 is exclusively induced on the cell surface, whereas the 2Ig B7-H3 isoform is constitutively expressed in the intracytoplasmic region of both peripheral and synovial monocytes. B7-H3 knockdown experiments reveal that surface B7-H3 has an inhibitory effect on IFN-γ production in CD4 memory cells. Moreover, surface B7-H3 expression on synovial monocytes inversely correlates with RA clinical parameters. Our findings demonstrate that activation-induced B7-H3 expression on synovial monocytes has the potential to inhibit Th1-mediated immune responses and immunomodulatory roles affecting RA pathogenesis.

Experimental demonstration of highway I2V using visible light communications.

A visible light communication (VLC)-based intelligent transportation system (ITS) has drawn much interest from telematics and automobile industries due to its enhanced safety and cost effectiveness. Within the framework of ITS, vehicle-to-vehicle and infrastructure-to-vehicle (I2V) communications have largely been considered. I2V can be viewed as an important ITS technology that broadcasts traffic information from fixed traffic infrastructure. In this paper, an experimental demonstration of a highway VLC-based I2V system is presented. For robust and reliable detection in the VLC-based I2V, the receiver structure of the proposed system is comprised of an optical filter, a color filter, and a Fresnel lens. We consider two primary atmospheric conditions in the highway I2V, i.e., sunlight and cloud effects. To alleviate these adverse effects, we propose an efficient and robust zone detection (ZD) and adaptive decision threshold (ADT) method. The sunlight effect is reduced predominantly by the ZD, while the cloud effect is lessened significantly by the ADT. The experimental results demonstrate that the proposed method performs well to counter the sunlight and cloud effects. It is found that the proposed ZD and ADT method provides an approximate SNR improvement ranging from 16 to 26 dB, depending upon measurement times of the day.

Smart LED allocation scheme for efficient multiuser visible light communication networks.

In a multiuser bidirectional visible light communication (VLC), a large number of LEDs or an LED array needs to be allocated in an efficient manner to ensure sustainable data rate and link quality. Moreover, in order to support an increasing or decreasing number of users in the network, the LED allocation is required to be performed dynamically. In this paper, a novel smart LED allocation scheme for efficient multiuser VLC networks is presented. The proposed scheme allocates RGB LEDs to multiple users in a dynamic and efficient fashion, while satisfying illumination requirements in an indoor environment. The smart LED array comprised of RGB LEDs is divided into sectors according to the location of the users. The allocated sectors then provide optical power concentration toward the users for efficient and reliable data transmission. An algorithm for the dynamic allocation of the LEDs is also presented. To verify its effective resource allocation feature of the proposed scheme, simulations were performed. It is found that the proposed smart LED allocation scheme provides the effect of optical beamforming toward individual users, thereby increasing the collective power concentration of the optical signals on the desirable users and resulting in significantly increased data rate, while ensuring sufficient illumination in a multiuser VLC environment.

Visible light communication based motion detection.

In this paper, a unique and novel visible light communication based motion detection is presented. The proposed motion detection is performed based on white light LEDs and an array of photodetectors from existing visible light communication (VLC) links, thus providing VLC with three functionalities of illumination, communication and motion detection. The motion is detected by observing the pattern created by intentional obstruction of the VLC link. Experimental and simulation results demonstrate the validity of the proposed VLC based motion detection technique. The VLC based motion detection can benefit smart devices control in VLC based smart home environments.

Optical bidirectional beacon based visible light communications.

In an indoor bidirectional visible light communications (VLC), a line-of-sight (LOS) transmission plays a major role in obtaining adequate performance of a VLC system. Signals are often obstructed in the LOS transmission path, causing an effect called optical shadowing. In the absence of LOS, the performance of the VLC system degrades significantly and, in particular, at uplink transmission this degradation becomes severe due to design constraints and limited power at uplink devices. In this paper, a novel concept and design of an optical bidirectional beacon (OBB) is presented as an efficient model to counter the performance degradation in a non-line-of-sight (NLOS) VLC system. OBB is an independent operating bidirectional transceiver unit installed on walls, composed of red, green, and blue (RGB) light emitting diodes (LEDs), photodetectors (PDs) and color filters. OBB improves the coverage area in the form of providing additional or alternate paths for transmission and enhances the performance of the VLC system in terms of bit error rate (BER). To verify the effectiveness of the proposed system, simulations were carried out under optical shadowing conditions at various locations in an indoor environment. The simulation results and analysis show that the implementation of OBB improves the performance of the VLC system significantly, especially when the LOS bidirectional transmission paths are completely or partially obstructed.

PTX3 stimulates osteoclastogenesis by increasing osteoblast RANKL production.

Pentraxin-3 (PTX3), also known as tumor necrosis factor-stimulated gene 14 (TSG-14), is produced by immune and vascular cells in response to pro-inflammatory signals and is therefore a multipotent inflammatory mediator. The present study showed that during human osteoblast (OB) differentiation, precursor OBs (pOBs), but not mature OB, highly expressed PTX3. TNFα treatment elevated the PTX3 expression of pOBs. When mice were injected with lipopolysaccharide, which induces an inflammatory osteolytic condition characterized by trabecular bone destruction and high osteoclastogenesis, their bone marrow cells expressed elevated levels of PTX3 protein. Exogenous PTX3 did not directly affect osteoclast (OC) or OB differentiation. However, when pOBs and precursor OCs were co-cultured, exogenous PTX3 significantly increased the number of tartrate-resistant acid phosphatase-positive multinucleated cells (i.e., OC cells) by increasing the pOB mRNA expression and protein secretion of RANK ligand (RANKL). This was accompanied with increased Runt-related transcription factor 2 (Runx2) expression in the pOBs. Knock-down of endogenous PTX3 with small-interfering RNA did not change the osteogenic potential of pOBs but suppressed their production of RANKL and reduced osteoclastogenesis. Finally, TNFα treatment of the co-culture elevated PTX3 expression by the pOBs and increased OC formation. This effect was suppressed by PTX3 knock-down by decreasing RANKL expression. Thus, the PTX3-driven increase in the osteoclastogenic potential of pOBs appears to be mediated by the effect of PTX3 on pOB RANKL production. These findings suggest that PTX3 is an inflammatory mediator that contributes to the deteriorating osteolytic condition of inflamed bone. J. Cell. Physiol. 229: 1744-1752, 2014. © 2014 Wiley Periodicals, Inc.

Beclin-1 is required for RANKL-induced osteoclast differentiation.

Beclin-1 plays a critical role in autophagy; however, it also contributes to other biological processes in a non-autophagic manner. Although studies have examined the non-autophagic role of autophagy proteins in the secretory function of osteoclasts (OC), the role of Beclin-1 is unclear. Here, we examined the role of Beclin-1 in OC differentiation, and found that mouse bone marrow macrophages (BMMs) showed increased expression of Beclin-1 upon RANKL stimulation in a p38- and NF-kappa B-dependent manner. During OC differentiation, Beclin-1 localized to the mitochondria, where it was involved in the production of mitochondrial intracellular reactive oxygen species. Knockdown of Beclin-1 in RANKL-primed BMMs led to a significant reduction in RANKL-dependent osteoclastogenesis, which was accompanied by reduced NFATc1 induction. Furthermore, knockdown of Beclin-1 inhibited RANKL-mediated activation of JNK and p38, both of which act downstream of reactive oxygen species, resulting in the suppression of NFATc1 induction. Finally, overexpression of constitutively active NFATc1 rescued the phenotype induced by Beclin-1 knockdown, indicating that Beclin-1 mediates RANKL-induced osteoclastogenesis by regulating NFATc1 expression. These findings show that Beclin-1 plays a non-autophagic role in RANKL-induced osteoclastogenesis by inducing the production of reactive oxygen species and NFATc1.

Progerin, an Aberrant Spliced Form of Lamin A, Is a Potential Therapeutic Target for HGPS.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of the LMNA gene. HGPS affects systemic levels, with the exception of cognition or brain development, in children, showing that cellular aging can occur in the short term. Studying progeria could be useful in unraveling the causes of human aging (as well as fatal age-related disorders). Elucidating the clear cause of HGPS or the development of a therapeutic medicine could improve the quality of life and extend the survival of patients. This review aimed to (i) briefly describe how progerin was discovered as the causative agent of HGPS, (ii) elucidate the puzzling observation of the absence of primary neurological disease in HGPS, (iii) present several studies showing the deleterious effects of progerin and the beneficial effects of its inhibition, and (iv) summarize research to develop a therapy for HGPS and introduce clinical trials for its treatment.

Dysfunction in parkin aggravates inflammatory bone erosion by reinforcing osteoclast activity.

BACKGROUND: Parkin dysfunction associated with the progression of parkinsonism contributes to a progressive systemic skeletal disease characterized by low bone mineral density. However, the role of parkin in bone remodeling has not yet been elucidated in detail. RESULT: We observed that decreased parkin in monocytes is linked to osteoclastic bone-resorbing activity. siRNA-mediated knockdown of parkin significantly enhanced the bone-resorbing activity of osteoclasts (OCs) on dentin without any changes in osteoblast differentiation. Moreover, Parkin-deficient mice exhibited an osteoporotic phenotype with a lower bone volume accompanied by increased OC-mediated bone-resorbing capacity displaying increased acetylation of α-tubulin compared to wild-type (WT) mice. Notably, compared to WT mice, the Parkin-deficient mice displayed increased susceptibility to inflammatory arthritis, reflected by a higher arthritis score and a marked bone loss after arthritis induction using K/BxN serum transfer, but not ovariectomy-induced bone loss. Intriguingly, parkin colocalized with microtubules and parkin-depleted-osteoclast precursor cells (Parkin-/- OCPs) displayed augmented ERK-dependent acetylation of α-tubulin due to failure of interaction with histone deacetylase 6 (HDAC6), which was promoted by IL-1ß signaling. The ectopic expression of parkin in Parkin-/- OCPs limited the increase in dentin resorption induced by IL-1ß, accompanied by the reduced acetylation of α-tubulin and diminished cathepsin K activity. CONCLUSION: These results indicate that a deficiency in the function of parkin caused by a decrease in parkin expression in OCPs under the inflammatory condition may enhance inflammatory bone erosion by altering microtubule dynamics to maintain OC activity.

Inflammatory conversion of quiescent osteoblasts by metastatic breast cancer cells through pERK1/2 aggravates cancer-induced bone destruction.

Disruption of bone homeostasis caused by metastatic osteolytic breast cancer cells increases inflammatory osteolysis and decreases bone formation, thereby predisposing patients to pathological fracture and cancer growth. Alteration of osteoblast function induces skeletal diseases due to the disruption of bone homeostasis. We observed increased activation of pERK1/2 in osteolytic breast cancer cells and osteoblasts in human pathological specimens with aggressive osteolytic breast cancer metastases. We confirmed that osteolytic breast cancers with high expression of pERK1/2 disrupt bone homeostasis via osteoblastic ERK1/2 activation at the bone-breast cancer interface. The process of inflammatory osteolysis modulates ERK1/2 activation in osteoblasts and breast cancer cells through dominant-negative MEK1 expression and constitutively active MEK1 expression to promote cancer growth within bone. Trametinib, an FDA-approved MEK inhibitor, not only reduced breast cancer-induced bone destruction but also dramatically reduced cancer growth in bone by inhibiting the inflammatory skeletal microenvironment. Taken together, these findings suggest that ERK1/2 activation in both breast cancer cells and osteoblasts is required for osteolytic breast cancer-induced inflammatory osteolysis and that ERK1/2 pathway inhibitors may represent a promising adjuvant therapy for patients with aggressive osteolytic breast cancers by altering the shared cancer and bone microenvironment.

Systemic Parathyroid Hormone Enhances Fracture Healing in Multiple Murine Models of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a multisystemic disease that afflicts more than 415 million people globally-the incidence and prevalence of T2DM continues to rise. It is well-known that T2DM has detrimental effects on bone quality that increase skeletal fragility, which predisposes subjects to an increased risk of fracture and fracture healing that results in non- or malunion. Diabetics have been found to have perturbations in metabolism, hormone production, and calcium homeostasis-particularly PTH expression-that contribute to the increased risk of fracture and decreased fracture healing. Given the perturbations in PTH expression and the establishment of hPTH (1-34) for use in age-related osteoporosis, it was determined logical to attempt to ameliorate the bone phenotype found in T2DM using hPTH (1-34). Therefore, the present study had two aims: (i) to establish a suitable murine model of the skeletal fragility present in T2DM because no current consensus model exists; and (ii) to determine the effects of hPTH (1-34) on bone fractures in T2DM. The results of the present study suggest that the polygenic mouse of T2DM, TALLYHO/JngJ, most accurately recapitulates the diabetic osteoporotic phenotype seen in humans and that the intermittent systemic administration of hPTH (1-34) increases fracture healing in T2DM murine models by increasing the proliferation of mesenchymal stem cells. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Suppression of Syk activation by resveratrol inhibits MSU crystal-induced inflammation in human monocytes.

Monosodium urate (MSU) crystals are an endogenous sterile particulate that has been identified as a potent damage-associated molecular pattern (DAMP). In humans, the induction of IL-1ß production through MSU-induced NLRP3 inflammasome activation in monocytes/macrophages is responsible for pathogenesis of gouty arthritis. It was recently reported that in a murine model of this disease, resveratrol decreases MSU-induced recurrent attacks of gouty arthritis. Despite its demonstrated anti-inflammatory effects, the mechanisms underlying resveratrol-mediated repression of IL-1ß production in MSU-activated monocytes remain poorly understood. Here, we show that resveratrol suppresses secretion of active IL-1ß by human primary monocytes stimulated with MSU crystals through suppression of Syk activation. Metabolic labeling and pull-down assays to investigate de novo protein synthesis clearly demonstrated that intracellular pro-IL-1ß synthesis is rapidly repressed in monocytes after resveratrol treatment due to decreased phosphorylation of Syk and p38. Resveratrol also inhibited NLRP3 inflammasome activation in MSU-stimulated monocytes by suppressing oligomerization of ASC. Furthermore, resveratrol exerted a beneficial effect by reducing IL-1ß production and inhibiting neutrophil recruitment in a mouse model of MSU-mediated peritonitis. Our findings suggest that resveratrol exerts anti-inflammatory effects via post-translational regulation of IL-1ß production and, thus, may prove beneficial for the treatment of MSU crystal-mediated sterile inflammation. KEY MESSAGE: Resveratrol has negative effects on pro-IL-1ß synthesis through Syk and p38. Resveratrol inhibits oligomerization of ASC. Resveratrol is beneficial in a mouse model of MSU-induced peritonitis.

Interleukin-32 Gamma Stimulates Bone Formation by Increasing miR-29a in Osteoblastic Cells and Prevents the Development of Osteoporosis.

Interleukin-32 gamma (IL-32γ) is a recently discovered cytokine that is elevated in inflamed tissues and contributes to pathogenic features of bone in human inflammatory rheumatic diseases. Nevertheless, the role of IL-32γ and its direct involvement in bone metabolism is unclear. We investigated the molecular mechanism of IL-32γ in bone remodeling and the hypothetical correlation between IL-32γ and disease activity in osteoporosis patients. Transgenic (TG) mice overexpressing human IL-32γ showed reduced bone loss with advancing age, increased bone formation, and high osteogenic capacity of osteoblast compared to wild-type (WT) mice through the upregulation of miR-29a, which caused a reduction of Dickkopf-1 (DKK1) expression. IL-32γ TG mice were protected against ovariectomy (OVX)induced osteoporosis compared with WT mice. Decreased plasma IL-32γ levels were associated with bone mineral density (BMD) in human patients linked to increased DKK1 levels. These results indicate that IL-32γ plays a protective role for bone loss, providing clinical evidence of a negative correlation between IL-32γ and DKK1 as bone metabolic markers.

Monosodium urate crystal-induced pro-interleukin-1ß production is post-transcriptionally regulated via the p38 signaling pathway in human monocytes.

IL-1ß is a key mediator of sterile inflammation in response to endogenous particulates, a type of damage-associated molecular pattern (DAMPs) molecule derived from damaged cells. Despite the well-known role of sterile particulates such as monosodium urate (MSU) crystals as inflammasome inducers in monocytes/macrophages, little is known regarding how pro-IL-1ß synthesis is induced under sterile inflammatory conditions. We provide evidence that MSU crystals post-transcriptionally induce the rapid production of pro-IL-1ß in human primary monocytes. Metabolic labeling and pull-down assays for newly-synthesized proteins clearly showed that MSU crystals rapidly, within 30 min, induce the synthesis of pro-IL-1ß as well as global proteins. Notably, MSU crystal-induced pro-IL-1ß synthesis is selectively dependent on the p38 MAPK pathway, whereas global protein synthesis is mediated via the mTOR, ERK1/2, and p38 pathways. Furthermore, inhibition of Mnk1, a substrate of p38, blocked MSU crystal-induced pro-IL-1ß synthesis downstream of eIF4E phosphorylation. In addition, the p38 MAPK pathway leading to phosphorylation of MK2 was also critical for stabilization of pro-IL-1ß mRNA following MSU stimulation. Our findings demonstrate that post-transcriptional regulation via p38 MAPK plays a central role in the rapid synthesis of pro-IL-1ß in response to MSU crystals, which is an essential step for IL-1ß production in human monocytes.

High level of interleukin-32 gamma in the joint of ankylosing spondylitis is associated with osteoblast differentiation.

BACKGOUND: The formation of bony spurs and ankylosis is a key pathognomic feature in ankylosing spondylitis (AS) and results in functional impairment. The aim of this study was to investigate the role of IL-32γ in osteoblast (OB) differentiation and its association with the pathogenesis of AS. METHODS: The concentration and expression of IL-32γ were evaluated in synovial fluid and tissue from patients with AS, rheumatoid arthritis (RA) and osteoarthritis (OA), using enzyme-linked immunosorbent assay and immunohistochemistry. To establish whether IL-32γ affects OB differentiation, we used calvarial cells of IL-32γ transgenic (TG) mice or wild-type (WT) mice. To elucidate the mechanism of osteoblastogenesis, levels of regulators were assayed in IL-32γ TG mice and in primary OBs after IL-32γ stimulation. RESULTS: The IL-32γ levels were higher in the synovial fluid of AS patients compared with RA or OA patients and the expression of IL-32 was higher in AS synovia than in RA or OA synovia. Additional IL-32γ stimulation in precursor cells enhanced OB differentiation potentially and IL-32γ TG mice showed higher rates of OB differentiation than WT mice. IL-32γ reduced the expression of DKK-1, a negative regulator, in both WT precursor cells and human OBs and the constitutive expression of DKK-1 was suppressed in calvarial cells from IL-32γ TG mice. CONCLUSIONS: The elevated level of IL-32γ in AS joint could enhance OB differentiation via DKK-1 suppression. Therefore, IL-32γ might be a putative molecular target to prevent the abnormal bone formation in AS.