CD44-targeting hyaluronic acid-selenium nanoparticles boost functional recovery following spinal cord injury.

BACKGROUND: Therapeutic strategies based on scavenging reactive oxygen species (ROS) and suppressing inflammatory cascades are effective in improving functional recovery after spinal cord injury (SCI). However, the lack of targeting nanoparticles (NPs) with powerful antioxidant and anti-inflammatory properties hampers the clinical translation of these strategies. Here, CD44-targeting hyaluronic acid-selenium (HA-Se) NPs were designed and prepared for scavenging ROS and suppressing inflammatory responses in the injured spinal cord, enhancing functional recovery. RESULTS: The HA-Se NPs were easily prepared through direct reduction of seleninic acid in the presence of HA. The obtained HA-Se NPs exhibited a remarkable capacity to eliminate free radicals and CD44 receptor-facilitated internalization by astrocytes. Moreover, the HA-Se NPs effectively mitigated the secretion of proinflammatory cytokines (such as IL-1ß, TNF-α, and IL-6) by microglia cells (BV2) upon lipopolysaccharide-induced inflammation. In vivo experiments confirmed that HA-Se NPs could effectively accumulate within the lesion site through CD44 targeting. As a result, HA-Se NPs demonstrated superior protection of axons and neurons within the injury site, leading to enhanced functional recovery in a rat model of SCI. CONCLUSIONS: These results highlight the potential of CD44-targeting HA-Se NPs for SCI treatment.

Classical calculation of differential cross section for a beam deflected by a concentric refractive index field.

Ray tracing is a fundamental geometric-optics issue which gives a single ray path but seldom presents the collective behavior of light. The optical field distribution usually involves the calculation of an electromagnetic field and is rarely discussed from the perspective of geometric optics. However, in this paper, we show for a concentric medium with spherically symmetric refractive index, how the relative angular distribution of refractive beams can be obtained from the pure classical geometric optics method. As a measurement of the distribution, we introduce the concept of the differential cross section (DCS), which can be calculated from the relation between aiming distance and deflecting the angle of the ray. We present a general method to solve this relation from both Snell's law in a constant medium and the optical Binet equation (OBE) in a gradient-index (GRIN) medium. Even without observing the collective traces, the DCS can independently give a quantitative description for the deflected light density of concentric media at different directions. It may act as a reference index for the design of beam deflector.

Analytical ray tracing based on Hamilton principal function and conjugate variable pairs.

A transformation method based on optical Hamilton equations is proposed for 3D ray tracing in axially inhomogeneous gradient-index (GRIN) media with cylindrical symmetry. For a given GRIN field, the optical conjugate variable pairs of physical space can be transformed into a virtual space by applying canonical transformation. The virtual trace can be simply solved as a uniform expression regardless of what the GRIN field is, and one can inversely transform it into the physical space. The transformation is intimately related to a Hamilton principal function, called the S function, which simultaneously gives the real ray trace and its conjugate. The "conjugate trace" displays the direction cosines of the ray trace and thus shows the information about propagation direction at every point, and it can be independently derived from the S function without knowing the real trace. In addition, as two special dimension-reduction cases, the S function is also applicable for 2D structures with only axial inhomogeneity or cylindrical symmetry.

Ray tracing in concentric gradient-index media: optical Binet equation.

The Binet equation in mechanics describes the orbital geometry of a moving particle under a central force field. In this paper, as its counterpart in optics, we show this formula can be similarly utilized in ray tracing of a gradient-index (GRIN) medium with a concentric field. As an inference of Fermat's principle, this generalization is called the optical Binet equation (OBE). A remarkable advantage of OBE is that it can not only determine the ray trace or concentric GRIN field once one of them is given, but also derive the propagation time inside the medium. As examples, we apply OBE to rays passing through a Maxwell fish-eye lens, Luneburg lens, Eaton lens, concentrator, and hyperbolic deflector, the time delay of which can be calculated once the GRIN field or ray trace equation is solved. The results are well matched with simulations, proving it to be an effective tool in solving problems of the concentric GRIN field.

State evolution formula and stability analysis of a paraxial optical system.

By analyzing the phase vector evolution of a paraxial optical system (POS) with a variational background refractive index, we obtain a continuous dynamic equation, called state evolution formula (SEF), which simultaneously gives the phase vector transformation and ray trajectory inside and outside the optical elements. Compared with ray transfer matrix method, this phase-vector equation is universal in treating problems about propagation and stability of paraxial rays, since it extends the linear and discrete matrix equation to a differential equation. It takes a consistent form for both continuous and discontinuous cases without considering the special rays, even the input and output states present a nonlinear relation. Based on the SEF, we further propose a rigorous criterion about whether a continuous and non-periodic POS is stable. This formula provides a reference model for the theoretical analysis of ray dynamics in geometric and physical optical systems.

Manipulating light trace in a gradient-refractive-index medium: a Lagrangian optics method.

Light propagation obeys Fermat's principle, and an important inference of Fermat's principle is the optical Lagrange equation, from which the light trace can be determined with a given refractive index. Here, we consider the inverse problem of how to derive the refractive index distribution of a planar geometric optical system once the trace is predetermined. Based on the optical Lagrange equation, we propose a dynamic equation model which associates the refractive index with the light trace. With the consideration of a certain trace, we illustrate the process of solving the partial differential equation of refractive index through first integral method. By setting the distribution function of a gradient-refractive-index (GRIN) medium, one can control the light traveling along a desirable curve, adjust the incoming and outgoing rays, and also use the trace to paint geometrics. This method develops the Lagrangian optics in the application of ray dynamic system design, such as lens, beam splitter, metasurface and optical waveguide. It provides a theoretical guidance to manipulate the ray in a GRIN medium.

Photonic magneto-Stark effect based on gradiently modulated magneto-optical medium.

Photons are neutral particles which cannot directly interact with an applied magnetic field, but recent studies show that an effective magnetic field can be created for photons by modulating the background permittivity or using magneto-optical (MO) media. In this paper, we demonstrate that when the permittivity tensor of a MO medium is spatially modulated, it can create an effective magnetic field proportional to the gradient of gyrotropic ratio. This field induces a Lorentz force and gives rise to a photonic magneto-Stark (PMS) effect. We prove this effect occurs once the photon's wave vector and the gradient of gyrotropic ratio are non-parallel, and reaches the maximum when they are perpendicular. The PMS effect provides a new mechanism for wavelength modulation and controlling the direction-dependent propagation of photonic modes.

PEGylated Poly(α-lipoic acid) Loaded with Doxorubicin as a pH and Reduction Dual Responsive Nanomedicine for Breast Cancer Therapy.

Disulfide-containing nanoparticles are promising vehicles for anticancer drug delivery. However, the preparation of disulfide-containing nanoparticles usually relies on complex synthetic procedures. In the present work, a PEGylated poly(α-lipoic acid) (mPEG-PαLA) copolymer was facilely synthesized and used for pH and reduction dual responsive drug delivery. Poly(α-lipoic acid) was prepared by thermal polymerization of α-lipoic acid without any catalyst or solvent and then conjugated with methoxy poly(ethylene glycol) to form the mPEG-PαLA copolymer. The obtained mPEG-PαLA copolymer was amphiphilic, which could self-assemble into nanoparticles (NPs) in aqueous solution. More interestingly, the mPEG-PαLA NPs showed high drug loading efficiency (87.7%) for the cationic drug doxorubicin (DOX). The DOX-loaded NPs (NPs-DOX) exhibited pH and reduction dual responsive drug release behaviors. Moreover, the flow cytometry analysis and confocal laser scanning microscopy confirmed that the drug-loaded nanoparticles could be efficiently internalized and subsequently release DOX in 4T1 cancer cells. As a result, the NPs-DOX displayed favorable antiproliferation efficacy in 4T1 cancer cells (measured by MTT assays). Furthermore, the NPs-DOX showed enhanced antitumor efficacy in a 4T1 tumor-bearing mice model with reduced side toxicities toward normal organs due to the prolonged circulation time and improved biodistribution in vivo. In other words, this work demonstrates that the PEGylated poly(α-lipoic acid) copolymer can be used as a biocompatible and stimuli-responsive nanocarrier for anticancer drug delivery, which may have potential clinical utility.

Cervical intervertebral disc calcification with extreme lateral herniation in a child: T2-weighted signal intensity of the involved disc can be restored to normal.

PURPOSE: The purpose of this case report is to present a very atypical case of cervical intervertebral disc calcification (IDC) with extreme lateral herniated calcification in a child. This is the first ever reported case in which T2-weighted signal intensity of the involved disc was restored to normal after a 2-year follow-up. METHODS: A 10-year-old girl presented with neck pain and right upper limb numbness for 2 months. The initial computed tomography (CT) images on admission showed calcified nucleus pulposus with extreme lateral herniated calcification at the C6-C7 level. Meanwhile, T2-weighted magnetic resonance imaging (MRI) revealed decreased signal intensity of the involved disc. The patient was treated conservatively with nonsteroidal anti-inflammatory drugs and jaw-occipital belt traction for 2 weeks. The cervical CT and MRI scans were repeated at 2-year follow-up. RESULTS: Her clinical symptoms were completely resolved after 2 weeks. At 2-year follow-up, CT and MRI images demonstrated that calcification was completely absorbed and T2-weighted signal intensity of the C6-C7 disc was restored back to normal. CONCLUSION: Cervical IDC combined with extreme lateral herniated calcification is extremely rare in children. The recovery of signal intensity of intervertebral disc on MRI may provide further support to the feasibility of conservative treatment of IDC.

Inactivation of androgen-induced regulator ARD1 inhibits androgen receptor acetylation and prostate tumorigenesis.

Androgen signaling through androgen receptor (AR) is critical for prostate tumorigenesis. Given that AR-mediated gene regulation is enhanced by AR coregulators, inactivation of those coregulators is emerging as a promising therapy for prostate cancer (PCa). Here, we show that the N-acetyltransferase arrest-defect 1 protein (ARD1) functions as a unique AR regulator in PCa cells. ARD1 is up-regulated in human PCa cell lines and primary tumor biopsies. The expression of ARD1 was augmented by treatment with synthetic androgen (R1881) unless AR is deficient or is inhibited by AR-specific siRNA or androgen inhibitor bicalutamide (Casodex). Depletion of ARD1 by shRNA suppressed PCa cell proliferation, anchorage-independent growth, and xenograft tumor formation in SCID mice, suggesting that AR-dependent ARD1 expression is biologically germane. Notably, ARD1 was critical for transcriptionally regulating a number of AR target genes that are involved in prostate tumorigenesis. Furthermore, ARD1 interacted physically with and acetylated the AR protein in vivo and in vitro. Because AR-ARD1 interaction facilitated the AR binding to its targeted promoters for gene transcription, we propose that ARD1 functions as a unique AR regulator and forms a positive feedback loop for AR-dependent prostate tumorigenesis. Disruption of AR-ARD1 interactions may be a potent intervention for androgen-dependent PCa therapy.

In Situ Reaction-Generated Aldehyde-Scavenging Polypeptides-Curcumin Conjugate Nanoassemblies for Combined Treatment of Spinal Cord Injury.

The microenvironment after traumatic spinal cord injury (SCI) involves complex pathological processes, including elevated oxidative stress, accumulated reactive aldehydes from lipid peroxidation, excessive immune cell infiltration, etc. Unfortunately, most of current neuroprotection therapies cannot cope with the intricate pathophysiology of SCI, leading to scant treatment efficacies. Here, we developed a facile in situ reaction-induced self-assembly method to prepare aldehyde-scavenging polypeptides (PAH)-curcumin conjugate nanoassemblies (named as PFCN) for combined neuroprotection in SCI. The prepared PFCN could release PAH and curcumin in response to oxidative and acidic SCI microenvironment. Subsequently, PFCN exhibited an effectively neuroprotective effect through scavenging toxic aldehydes as well as reactive nitrogen and oxygen species in neurons, modulating microglial M1/M2 polarization, and down-regulating the expression of inflammation-related cytokines to inhibit neuroinflammation. The intravenous administration of PFCN could significantly ameliorate the malignant microenvironment of injured spinal cord, protect the neurons, and promote the motor function recovery in the contusive SCI rat model.

Causal effect of physical activity and sedentary behaviors on the risk of osteoarthritis: a univariate and multivariate Mendelian randomization study.

There is still a lot of ambiguity about the link between physical activity (PA), sedentary behaviors (SBs) and osteoarthritis (OA). This study aimed to investigate the causal relationship of PA/SBs on the risk of OA. A univariate and multivariate Mendelian randomization (MR) analysis was conducted to investigate the causal effect of five PA phenotypes and three SB phenotypes on overall OA, knee OA, hip OA, total hip arthroplasty, and total knee arthroplasty (TKA). MR methods used were inverse-variance weighting, MR-Egger regressions, and weighted median. Sensitivity analysis examined horizontal pleiotropy and heterogeneity, and confirmed the reliability of the results. After false discovery rate, light do-it-yourself (DIY) activities decreased the risk for overall OA (OR: 0.32, 95% CI 0.16-0.65), and knee OA (OR: 0.26, 95% CI 0.12-0.51). Resulting in a decreased risk of walking for pleasure on overall OA (OR: 0.87, 95% CI 0.70-1.04) and knee OA (OR: 0.14, 95% CI 0.06-0.32) was also observed. Television viewing, however, significantly increased the risk of OA, knee OA, hip OA, and TKA. MVMR findings revealed independent causal impacts of walking for pleasure and watching television on overall and knee OA, taking into account BMI, smoking, and education. This study suggested that light DIY and walking for pleasure were beneficial for preventing OA, and the risk of OA and TKA increased with prolonged television watching.

Recent advances in endogenous neural stem/progenitor cell manipulation for spinal cord injury repair.

Traumatic spinal cord injury (SCI) can cause severe neurological impairments. Clinically available treatments are quite limited, with unsatisfactory remediation effects. Residing endogenous neural stem/progenitor cells (eNSPCs) tend to differentiate towards astrocytes, leaving only a small fraction towards oligodendrocytes and even fewer towards neurons; this has been suggested as one of the reasons for the failure of autonomous neuronal regeneration. Thus, finding ways to recruit and facilitate the differentiation of eNSPCs towards neurons has been considered a promising strategy for the noninvasive and immune-compatible treatment of SCI. The present manuscript first introduces the responses of eNSPCs after exogenous interventions to boost endogenous neurogenesis in various SCI models. Then, we focus on state-of-art manipulation approaches that enhance the intrinsic neurogenesis capacity and reconstruct the hostile microenvironment, mainly consisting of pharmacological treatments, stem cell-derived exosome administration, gene therapy, functional scaffold implantation, inflammation regulation, and inhibitory element delineation. Facing the extremely complex situation of SCI, combined treatments are also highlighted to provide more clues for future relevant investigations.

Nanomaterials as therapeutic agents to modulate astrocyte-mediated inflammation in spinal cord injury.

Promoting the recovery of neurological function in patients with traumatic spinal cord injury (TSCI) remains challenging. The balance between astrocyte-mediated neurotrophic and pro-inflammatory responses is critical for TSCI repair. Recently, the utilization of nanomaterials has been considerably explored in immunological reconstructive techniques that specifically target astrocyte-mediated inflammation, yielding positive outcomes. In this review, we aim to condense the present knowledge regarding the astrocyte-mediated inflammation following TSCI. We then review the various categories of nanomaterials utilized in the management of astrocyte-mediated inflammation in TSCI and conclude by summarizing their functions and advantages to offer novel insights for the advancement of effective clinical strategies targeting TSCI.

Epigallocatechin-3-gallate selenium nanoparticles for neuroprotection by scavenging reactive oxygen species and reducing inflammation.

Purpose: Spinal cord injury (SCI) is a severely crippling injury. Scavenging reactive oxygen species (ROS) and suppressing inflammation to ameliorate secondary injury using biomaterials has turned into a promising strategy for SCI recuperation. Herein, epigallocatechin-3-gallate selenium nanoparticles (EGCG-Se NP) that scavenge ROS and attenuate inflammation were used for neuroprotection in SCI. Methods: EGCG-Se NP were arranged using a simple redox framework. The size, morphology, and chemical structure of the EGCG-Se NP were characterized. The protective effect of EGCG-Se NP for neuroprotection was examined in cell culture and in an SCI rat model. Results: EGCG-Se NP could promptly scavenge excess ROS and safeguard PC12 cells against H2O2-induced oxidative harm in vitro. After intravenous delivery in SCI rats, EGCG-Se NP significantly improved locomotor capacity and diminished the injury region by safeguarding neurons and myelin sheaths. Component studies showed that the main restorative impact of EGCG-Se NP was due to their ROS-scavenging and anti-inflammatory properties. Conclusion: This study showed the superior neuroprotective effect of EGCG-Se NP through ROS sequestration and anti-inflammatory capabilities. EGCG-Se NP could be a promising and effective treatment for SCI.

Minocycline-Loaded Poly(α-Lipoic Acid)-Methylprednisolone Prodrug Nanoparticles for the Combined Anti-Inflammatory Treatment of Spinal Cord Injury.

PURPOSE: Traumatic spinal cord injury (TSCI) induces a powerful inflammatory response that can significantly exacerbate the extent and severity of neural damage (termed as "secondary injury"). Thus, the suppression of inflammation is crucial for reducing neurological dysfunction following TSCI. However, the conventional anti-inflammatory drugs show limited efficacy because of poor penetration and release kinetics at the injury site. This study describes the design, synthesis, release kinetics, biosafety, and preclinical efficacy of minocycline (MC)-loaded poly(α-lipoic acid)-methylprednisolone (PαLA-MP) prodrug nanoparticles (NPs) for the combined anti-inflammatory treatment of TSCI. METHODS: NPs were produced by conjugating MP to PαLA and then loading MC. The NP structure was confirmed through 1H nuclear magnetic resonance (1H NMR), Fourier transform infrared spectroscopy, ultraviolet-visible absorption spectroscopy, gel permeation chromatography, dynamic light scattering, and transmission electron microscopy. Drug-loading content and efficacy were measured using high-performance liquid chromatography (HPLC) or 1H NMR and release kinetics through HPLC. Biosafety was examined using the MTT assay, cell penetration efficiency using confocal microscopy, and flow cytometry using Cyanine5 (Cy5)-labeled MC-PαLA-MP NPs, effects on injury-induced pro-inflammatory cytokine release using enzyme-linked immunosorbent assays and immunofluorescence, and treatment efficacy by measuring motor recovery in a rat model of TSCI. RESULTS: The MC-PαLA-MP NPs exhibited high biocompatibility and released 81% MC and 54% MP within 24 h under TSCI-like conditions, effectively reducing 40% of pro-inflammatory cytokine release both in cultures and injured rat spinal cord tissues. Systemic injection increased the Basso, Beattie, Bresnahan score of TSCI rats from 2.33 ± 0.52 to 8.83 ± 1.83 in 8 weeks, providing effective neuroprotection and enhanced exercise recovery in the TSCI rats. CONCLUSION: The MC-PαLA-MP NPs can mitigate secondary inflammation and preserve motor function following experimental TSCI, which suggests their potential for clinical application.

Lumbar Facet Joint Effusion on Magnetic Resonance Imaging: Do Different Joint Effusion Images Have Different Clinical Values?

OBJECTIVE: The objective of the study was to explore the significance of the distribution of lumbar facet joint effusion (unilateral or bilateral) and the amount of joint effusion in the process of lumbar degeneration. METHODS: A total of 142 patients with L4-5 lumbar facet joint effusion in our hospital from December 2020 to December 2021 were analyzed retrospectively, including 69 cases of unilateral facet joint effusion and 73 cases of bilateral facet joint effusion. The correlation between joint effusion width, effusion area and lumbar stability, facet joint degeneration grade, lumbar intervertebral disc degeneration index, and lumbosacral angle (LSA) was analyzed. To study the significance of the distribution of joint effusion, the patients were divided into unilateral and bilateral effusion groups. RESULTS: The size of the LSA in the bilateral effusion group was significantly larger than that in the unilateral effusion group (t = 3.6634, P < 0.05). There was a significant difference in the proportion of stability between both groups (P < 0.05). The width of the joint effusion was positively correlated with lumbar stability and the LSA. When the width of the joint effusion was 2 mm, the probability of lumbar instability was 58.1%. The area of joint effusion was positively correlated with lumbar stability and the LSA. When the area of effusion was 0.2 cm2, the probability of lumbar instability was 58.9%. CONCLUSIONS: A bilateral effusion signal is more likely to indicate lumbar instability than a unilateral effusion signal. The distribution width and area of effusion were positively correlated with lumbar stability and LSA.

A Recurrent ADPRHL1 Germline Mutation Activates PARP1 and Confers Prostate Cancer Risk in African American Families.

African American (AA) families have the highest risk of prostate cancer. However, the genetic factors contributing to prostate cancer susceptibility in AA families remain poorly understood. We performed whole-exome sequencing of one affected and one unaffected brother in an AA family with hereditary prostate cancer. The novel non-synonymous variants discovered only in the affected individuals were further analyzed in all affected and unaffected men in 20 AA-PC families. Here, we report one rare recurrent ADPRHL1 germline mutation (c.A233T; p.D78V) in four of the 20 families affected by prostate cancer. The mutation co-segregates with prostate cancer in two families and presents in two affected men in the other two families, but was absent in 170 unrelated healthy AA men. Functional characterization of the mutation in benign prostate cells showed aberrant promotion of cell proliferation, whereas expression of the wild-type ADPRHL1 in prostate cancer cells suppressed cell proliferation and oncogenesis. Mechanistically, the ADPRHL1 mutant activates PARP1, leading to an increased H2O2 or cisplatin-induced DNA damage response for prostate cancer cell survival. Indeed, the PARP1 inhibitor, olaparib, suppresses prostate cancer cell survival induced by mutant ADPRHL1. Given that the expression levels of ADPRHL1 are significantly high in normal prostate tissues and reduce stepwise as Gleason scores increase in tumors, our findings provide genetic, biochemical, and clinicopathological evidence that ADPRHL1 is a tumor suppressor in prostate tissue. A loss of function mutation in ADPRHL1 induces prostate tumorigenesis and confers prostate cancer susceptibility in high-risk AA families. IMPLICATIONS: This study highlights a potential strategy for ADPRHL1 mutation detection in prostate cancer-risk assessment and a potential therapeutic application for individuals with prostate cancer in AA families.

Nanomedicine-Based Therapeutics to Combat Acute Lung Injury.

Acute lung injury (ALI) or its aggravated stage acute respiratory distress syndrome (ARDS) may lead to a life-threatening form of respiratory failure, resulting in high mortality of up to 30-40% in most studies. Although there have been decades of research since ALI was first described in 1967, the clinical therapeutic alternatives for ALI are still in a state of limited availability. Supportive treatment and mechanical ventilation still have priority. Despite some preclinical studies demonstrating the benefit of pharmacological interventions, none of these has been proved completely effective to date. Recent advances in nanotechnology may shed new light on the pharmacotherapy of ALI. Nanomedicine possesses targeting and synergistic therapeutic capability, thus boosting pharmaceutical efficacy and mitigating the side effects. Currently, a variety of nanomedicine with diverse frameworks and functional groups have been elaborately developed, in accordance with their lung targeting ability and the pathophysiology of ALI. The in-depth review of the current literature reveals that liposomes, polymers, inorganic materials, cell membranes, platelets, and other nanomedicine approaches have conferred attractive therapeutic benefits for ALI treatment. In this review, we explore the recent progress in the study of the nanomedicine-based therapy of ALI, presenting various nanomedical approaches, drug choices, therapeutic strategies, and outcomes, thereby providing insight into the trends.

Identification and characterization of putative tumor suppressor NGB, a GTP-binding protein that interacts with the neurofibromatosis 2 protein.

Mutations of the neurofibromatosis 2 (NF2) tumor suppressor gene have frequently been detected not only in schwannomas and other central nervous system tumors of NF2 patients but also in their sporadic counterparts and malignant tumors unrelated to the NF2 syndrome such as malignant mesothelioma, indicating a broader role for the NF2 gene in human tumorigenesis. However, the mechanisms by which the NF2 product, merlin or schwannomin, is regulated and controls cell proliferation remain elusive. Here, we identify a novel GTP-binding protein, dubbed NGB (referring to NF2-associated GTP binding protein), which binds to merlin. NGB is highly conserved between Saccharomyces cerevisiae, Caenorhabditis elegans, and human cells, and its GTP-binding region is very similar to those found in R-ras and Rap2. However, ectopic expression of NGB inhibits cell growth, cell aggregation, and tumorigenicity in tumorigenic schwanomma cells. Down-regulation and infrequent mutation of NGB were detected in human glioma cell lines and primary tumors. The interaction of NGB with merlin impairs the turnover of merlin, yet merlin does not affect the GTPase nor GTP-binding activity of NGB. Finally, the tumor suppressor functions of NGB require merlin and are linked to its ability to suppress cyclin D1 expression. Collectively, these findings indicate that NGB is a tumor suppressor that regulates and requires merlin to suppress cell proliferation.