Rationally Designing the Supramolecular Interfaces of Nanoparticle Superlattices with Multivalent Polymers.

In supramolecular materials, multiple weak binding groups can act as a single collective unit when confined to a localized volume, thereby producing strong but dynamic bonds between material building blocks. This principle of multivalency provides a versatile means of controlling material assembly, as both the number and the type of supramolecular moieties become design handles to modulate the strength of intermolecular interactions. However, in materials with building blocks significantly larger than individual supramolecular moieties (e.g., polymer or nanoparticle scaffolds), the degree of multivalency is difficult to predict or control, as sufficiently large scaffolds inherently preclude separated supramolecular moieties from interacting. Because molecular models commonly used to examine supramolecular interactions are intrinsically unable to examine any trends or emergent behaviors that arise due to nanoscale scaffold geometry, our understanding of the thermodynamics of these massively multivalent systems remains limited. Here we address this challenge via the coassembly of polymer-grafted nanoparticles and multivalent polymers, systematically examining how multivalent scaffold size, shape, and spacing affect their collective thermodynamics. Investigating the interplay of polymer structure and supramolecular group stoichiometry reveals complicated but rationally describable trends that demonstrate how the supramolecular scaffold design can modulate the strength of multivalent interactions. This approach to self-assembled supramolecular materials thus allows for the manipulation of polymer-nanoparticle composites with controlled thermal stability, nanoparticle organization, and tailored meso- to microscopic structures. The sophisticated control of multivalent thermodynamics through precise modulation of the nanoscale scaffold geometry represents a significant advance in the ability to rationally design complex hierarchically structured materials via self-assembly.

Reversible Diffusionless Phase Transitions in 3D Nanoparticle Superlattices.

Nanocomposite tectons (NCTs), polymer brush-grafted nanoparticles that use supramolecular interactions to drive their assembly, form ordered nanoparticle superlattices (NPSLs) with well-defined unit cell symmetries when thermally annealed. In this work, we demonstrate that appropriate assembly and processing conditions can also enable control over the microstructure of NCT lattices by balancing the enthalpic and entropic factors associated with ligand packing and supramolecular bonding during crystallization. Unary systems of NCTs are assembled via the addition of a small molecule capable of binding to multiple nanoparticle ligands; these NCTs initially form face-centered-cubic (FCC) structures in solvents that are favorable for the particles' polymer brushes. However, the FCC lattices undergo a reversible, diffusionless phase transition to body-centered-cubic (BCC) lattices when transferred to a solvent that induces polymer brush collapse. The BCC superlattices maintain the same crystal habit as the parent FCC phase but exhibit significant transformation twinning similar to that seen in martensitic alloys. This previously unseen diffusionless phase transformation in NPSLs enables unique microstructural features in the resulting assemblies, suggesting that NPSLs could serve as models for the investigation of microstructural evolution in crystalline systems and extend our understanding of NPSLs as atomic material analogues.

Improving nanoparticle superlattice stability with deformable polymer gels.

The self-assembly of colloidal nanoparticles into ordered superlattices typically uses dynamic interactions to govern particle crystallization, as these non-permanent bonds prevent the formation of kinetically trapped, disordered aggregates. However, while the use of reversible bonding is critical in the formation of highly ordered particle arrangements, dynamic interactions also inherently make the structures more prone to disassembly or disruption when subjected to different environmental stimuli. Thus, there is typically a trade-off between the ability to initially form an ordered colloidal material and the ability of that material to retain its order under different conditions. Here, we present a method for embedding colloidal nanoparticle superlattices into a polymer gel matrix. This encapsulation strategy physically prevents the nanoparticles from dissociating upon heating, drying, or the introduction of chemicals that would normally disrupt the lattice. However, the use of a gel as the embedding medium still permits further modification of the colloidal nanoparticle lattice by introducing stimuli that deform the gel network (as this deformation in turn alters the nanoparticle lattice structure in a predictable manner). Moreover, encapsulation of the lattice within a gel permits further stabilization into fully solid materials by removing the solvent from the gel or by replacing the solvent with a liquid monomer that can be photopolymerized. This embedding method therefore makes it possible to incorporate ordered colloidal arrays into a polymer matrix as either dynamic or static structures, expanding their potential for use in responsive materials.

Impact of a Comfortable in our Skin interactive workshop on social media awareness and self-confidence in adolescents.

Social media use contributes to body dissatisfaction and reduced quality of life among adolescents. This study examines the impact of social media use and skin conditions on body image and suggests that a Comfortable in Our Skin (CIOS) pilot community-based workshop may promote healthier body image and social media usage among urban adolescents.

The pediatric dermatology psychosocial screen: Promoting psychosocial coping and early identification of mental illness in pediatric dermatology patients.

BACKGROUND/OBJECTIVES: The psychosocial impact of pediatric skin conditions can be difficult to assess accurately. There is currently no way to formally screen and provide stepped care specifically for psychosocial dysfunction or mental illness during dermatology clinics. The Psychosocial Screening Tool for Pediatric Dermatology (PDPS) was designed to identify patients in need of psychosocial support and to promote multidisciplinary care. METHODS: The PDPS was studied at Boston Children's Hospital outpatient dermatology clinics. A pilot study was conducted with 16 participants to assess language and applicability. The validation study included 105 participants aged 8-19 years. Participants completed the PDPS, the Children's Depression Index 2 Short (CDI-2 Short), and three subscales of the Behavior Assessment System for Children 2 (BASC-2) to assess content validity. Model fit from confirmatory factor analysis was evaluated using the root-mean-square error of approximation (RMSEA), Comparative Fit Index (CFI), and Tucker-Lewis Index (TLI). RESULTS: Proper model fit and criterion validity were demonstrated through positively correlating the PDPS and the CDI-2 Short (CFI = 0.972, TLI = 0.969, RMSEA 5.3%) and BASC-2 subscales (RMSEA = 7.2%, CFI = 0.975, TLI = 0.969). Patient resilience was positively correlated with higher scores in each psychosocial domain. CONCLUSIONS: The PDPS is an effective screening tool for resilience versus need for early behavioral/mental health intervention in dermatology patients aged 8-19. The PDPS identifies psychosocial dysfunction and problems patients may not disclose otherwise (bullying, self-harm, social supports, neurodermatitis, and body dysmorphic disorder). Additionally, patients can directly indicate interest in various psychosocial health resources on the PDPS, guiding practitioners in providing comprehensive care.

Nanoparticle Assembly as a Materials Development Tool.

Nanoparticle assembly is a complex and versatile method of generating new materials, capable of using thousands of different combinations of particle size, shape, composition, and ligand chemistry to generate a library of unique structures. Here, a history of particle self-assembly as a strategy for materials discovery is presented, focusing on key advances in both synthesis and measurement of emergent properties to describe the current state of the field. Several key challenges for further advancement of nanoparticle assembly are also outlined, establishing a roadmap of critical research areas to enable the next generation of nanoparticle-based materials synthesis.

Reversal of Bortezomib-Induced Neurotoxicity by Suvecaltamide, a Selective T-Type Ca-Channel Modulator, in Preclinical Models.

This study evaluated suvecaltamide, a selective T-type calcium channel modulator, on chemotherapy-induced peripheral neurotoxicity (CIPN) and anti-cancer activity associated with bortezomib (BTZ). Rats received BTZ (0.2 mg/kg thrice weekly) for 4 weeks, then BTZ alone (n = 8) or BTZ+suvecaltamide (3, 10, or 30 mg/kg once daily; each n = 12) for 4 weeks. Nerve conduction velocity (NCV), mechanical threshold, ß-tubulin polymerization, and intraepidermal nerve fiber (IENF) density were assessed. Proteasome inhibition was evaluated in peripheral blood mononuclear cells. Cytotoxicity was assessed in human multiple myeloma cell lines (MCLs) exposed to BTZ alone (IC50 concentration), BTZ+suvecaltamide (10, 30, 100, 300, or 1000 nM), suvecaltamide alone, or vehicle. Tumor volume was estimated in athymic nude mice bearing MCL xenografts receiving vehicle, BTZ alone (1 mg/kg twice weekly), or BTZ+suvecaltamide (30 mg/kg once daily) for 28 days, or no treatment (each n = 8). After 4 weeks, suvecaltamide 10 or 30 mg/kg reversed BTZ-induced reduction in NCV, and suvecaltamide 30 mg/kg reversed BTZ-induced reduction in IENF density. Proteasome inhibition and cytotoxicity were similar between BTZ alone and BTZ+suvecaltamide. BTZ alone and BTZ+suvecaltamide reduced tumor volume versus the control (day 18), and BTZ+suvecaltamide reduced tumor volume versus BTZ alone (day 28). Suvecaltamide reversed CIPN without affecting BTZ anti-cancer activity in preclinical models.

Nanoparticle Assembly in High Polymer Concentration Solutions Increases Superlattice Stability.

Polymer nanocomposites are made by combining a nanoscale filler with a polymer matrix, where polymer-particle interactions can enhance matrix properties and introduce behaviors distinct from either component. Manipulating particle organization within a composite potentially allows for better control over polymer-particle interactions, and the formation of ordered arrays can introduce new, emergent properties not observed in random composites. However, self-assembly of ordered particle arrays typically requires weak interparticle interactions to prevent kinetic traps, making these assemblies incompatible with most conventional processing techniques. As a result, more fundamental investigations are needed into methods to provide additional stability to these lattices without disrupting their internal organization. The authors show that the addition of free polymer chains to the assembly solution is a simple means to increase the stability of nanoparticle superlattices against thermal dissociation. By adding high concentrations (>50 mg mL-1 ) of free polymer to nanoparticle superlattices, it is possible to significantly elevate their thermal stability without adversely affecting ordering. Moreover, polymer topology, molecular weight, and concentration can also be used as independent design handles to tune this behavior. Collectively, this work allows for a wider range of processing conditions for generating future nanocomposites with complete control over particle organization within the material.

A Phase 2 Proof-of-Concept, Randomized, Placebo-Controlled Trial of CX-8998 in Essential Tremor.

BACKGROUND: Available essential tremor (ET) therapies have limitations. OBJECTIVES: The objective of this study was to evaluate CX-8998, a selective T-type calcium channel modulator, in essential tremor. METHODS: Patients 18-75 years old with moderate to severe essential tremor were randomized 1:1 to receive CX-8998 (titrated to 10 mg twice daily) or placebo. The primary end point was change from baseline to day 28 in The Essential Tremor Rating Assessment Scale performance subscale scored by independent blinded video raters. Secondary outcomes included in-person blinded investigator rating of The Essential Tremor Rating Assessment Scale performance subscale, The Essential Tremor Rating Assessment Scale activities of daily living subscale, and Kinesia ONE accelerometry. RESULTS: The video-rated The Essential Tremor Rating Assessment Scale performance subscale was not different for CX-8998 (n = 39) versus placebo (n = 44; P = 0.696). CX-8998 improved investigator-rated The Essential Tremor Rating Assessment Scale performance subscale (P = 0.017) and The Essential Tremor Rating Assessment Scale activities of daily living (P = 0.049) but not Kinesia ONE (P = 0.421). Adverse events with CX-8998 included dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%). CONCLUSIONS: The primary efficacy end point was not met; however, CX-8998 improved some assessments of essential tremor, supporting further clinical investigation. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Macroscopic materials assembled from nanoparticle superlattices.

Nanoparticle assembly has been proposed as an ideal means to program the hierarchical organization of a material by using a selection of nanoscale components to build the entire material from the bottom up. Multiscale structural control is highly desirable because chemical composition, nanoscale ordering, microstructure and macroscopic form all affect physical properties1,2. However, the chemical interactions that typically dictate nanoparticle ordering3-5 do not inherently provide any means to manipulate structure at larger length scales6-9. Nanoparticle-based materials development therefore requires processing strategies to tailor micro- and macrostructure without sacrificing their self-assembled nanoscale arrangements. Here we demonstrate methods to rapidly assemble gram-scale quantities of faceted nanoparticle superlattice crystallites that can be further shaped into macroscopic objects in a manner analogous to the sintering of bulk solids. The key advance of this method is that the chemical interactions that govern nanoparticle assembly remain active during the subsequent processing steps, which enables the local nanoscale ordering of the particles to be preserved as the macroscopic materials are formed. The nano- and microstructure of the bulk solids can be tuned as a function of the size, chemical makeup and crystallographic symmetry of the superlattice crystallites, and the micro- and macrostructures can be controlled via subsequent processing steps. This work therefore provides a versatile method to simultaneously control structural organization across the molecular to macroscopic length scales.

Multistimuli Responsive Nanocomposite Tectons for Pathway Dependent Self-Assembly and Acceleration of Covalent Bond Formation.

Nanocomposite tectons (NCTs) are a recently developed building block for polymer-nanoparticle composite synthesis, consisting of nanoparticle cores functionalized with dense monolayers of polymer chains that terminate in supramolecular recognition groups capable of linking NCTs into hierarchical structures. In principle, the use of molecular binding to guide particle assembly allows NCTs to be highly modular in design, with independent control over the composition of the particle core and polymer brush. However, a major challenge to realize an array of compositionally and structurally varied NCT-based materials is the development of different supramolecular bonding interactions to control NCT assembly, as well as an understanding of how the organization of multiple supramolecular groups around a nanoparticle scaffold affects their collective binding interactions. Here, we present a suite of rationally designed NCT systems, where multiple types of supramolecular interactions (hydrogen bonding, metal complexation, and dynamic covalent bond formation) are used to tune NCT assembly as a function of multiple external stimuli including temperature, small molecules, pH, and light. Furthermore, the incorporation of multiple orthogonal supramolecular chemistries in a single NCT system makes it possible to dictate the morphologies of the assembled NCTs in a pathway-dependent fashion. Finally, multistimuli responsive NCTs enable the modification of composite properties by postassembly functionalization, where NCTs linked by covalent bonds with significantly enhanced stability are obtained in a fast and efficient manner. The designs presented here therefore provide major advancement for the field of composite synthesis by establishing a framework for synthesizing hierarchically ordered composites capable of complicated assembly behaviors.

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial of CX-8998, a Selective Modulator of the T-Type Calcium Channel in Inadequately Treated Moderate to Severe Essential Tremor: T-CALM Study Design and Methodology for Efficacy Endpoint and Digital Biomarker Selection.

Background: Essential tremor (ET) is a common, progressive neurological syndrome with bilateral upper-limb dysfunction of at least 3-year duration, with or without tremor in other body locations. This disorder has a negative impact on daily function and quality of life. A single oral therapy has been approved by FDA for ET. Off-label pharmacotherapies have inadequate efficacy and poor tolerability with high rates of patient dissatisfaction and discontinuation. Safe and efficacious pharmacotherapies are urgently needed to decrease tremor and improve daily living. T-CALM (Tremor-CAv3 modulation) protocol is designed to assess safety and efficacy of CX-8998, a selective modulator of the T-type calcium channel, for ET therapy. Methods/Design: T-CALM is a phase 2, proof of concept, randomized, double-blind, placebo-controlled trial. Titrated doses of CX-8998 to 10 mg BID or placebo will be administered for 28 days to moderate to severe ET patients who are inadequately treated with existing therapies. The primary endpoint will be change from baseline to day 28 of The Essential Tremor Rating Assessment Performance Subscale (TETRAS-PS). Secondary efficacy endpoints for clinician and patient perception of daily function will include TETRAS Activity of Daily Living (ADL), Quality of Life in Essential Tremor Questionnaire (QUEST), Clinical Global Impression-Improvement (CGI-I), Patient Global Impression of Change (PGIC), and Goal Attainment Scale (GAS). Kinesia One, Kinesia 360, and iMotor will biometrically evaluate motor function and tremor amplitude. Safety will be assessed by adverse events, physical and neurological exams and laboratory tests. Sample size of 43 patients per group is estimated to have 90% power to detect a 5.5-point difference between CX-8998 and placebo for TETRAS-PS. Efficacy analyses will be performed with covariance (ANCOVA) and 2-sided test at 0.05 significance level. Discussion: T-CALM has a unique design with physician rating scales, patient-focused questionnaires and scales and objective motor measurements to assess clinically meaningful and congruent efficacy. Patient perception of ET debilitation and therapy with CX-8998 will be key findings. Overall goal of T-CALM is generation of safety and efficacy data to support a go, no-go decision to further develop CX-8998 for ET. Design of T-CALM may guide future clinical studies of ET pharmacotherapies. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03101241.

Selinexor reduces the expression of DNA damage repair proteins and sensitizes cancer cells to DNA damaging agents.

INTRODUCTION: The goal of this study was to examine the effects of selinexor, an inhibitor of exportin-1 mediated nuclear export, on DNA damage repair and to evaluate the cytotoxic effects of selinexor in combination with DNA damaging agents (DDAs) in cancer cells. RESULTS: Selinexor reduced the expression of DNA damage repair (DDR) proteins. This did not induce significant DNA damage in tested cell lines. Inhibition of DDR protein expression resulted in enhanced cancer cell death when cells were pretreated with DDAs. In contrast, enhanced cell death was not detected in cells that were pretreated with selinexor then with DDAs. In vivo, single-agent selinexor, docetaxel, or cisplatin treatment resulted in 66.7%, 51.5%, and 26.6% tumor growth inhibition (TGI), respectively, in an MDA-MB-231 xenograft model. Consequently, combination treatment with docetaxel or cisplatin followed by selinexor in vivo resulted in 93.9% and 103.4% TGI, respectively. Immunohistochemical staining and immunoblot analysis of tumor sections confirmed reduced expression of DDR proteins. CONCLUSION: Selinexor treatment inhibited DDR mechanisms in cancer cell lines and therefore potentiated DNA damage-based therapy. The sequential combination of DDAs followed by selinexor increased cancer cell death. This combination is superior to each individual therapy and has a mechanistic rationale as a novel anticancer strategy. METHODS: Cancer cells treated with selinexor ± DDAs were analyzed using reverse phase protein arrays, immunoblots, quantitative PCR and immunofluorescence. Mice bearing MDA-MB-231 tumors were treated with subtherapeutic doses of selinexor, cisplatin, docetaxel and selinexor in combination with either cisplatin or docetaxel. Tumor growth was evaluated for 25 days.

Body dysmorphic disorder in pediatric dermatology.

Body dysmorphic disorder is an obsessive-compulsive spectrum disorder involving a perceived defect in physical appearance that most commonly develops in early adolescence and causes significant functional impairment and suicidality at much higher rates than in affected adults. Patients may also present with subthreshold body dysmorphic disorder or obsessive concerns over a diagnosable dermatologic condition, both of which can present similarly to body dysmorphic disorder. Pediatric dermatologists can play an important role in detecting body dysmorphic disorder and body dysmorphic disorder-like symptoms, which may occur in as many as 20% of dermatology patients. Greater awareness of the prevalence, clinical presentation, and effect of these symptoms, as well as better screening tools and greater collaboration with our mental health colleagues, may lead to earlier, more effective intervention.

IL-33 promotes food anaphylaxis in epicutaneously sensitized mice by targeting mast cells.

BACKGROUND: Cutaneous exposure to food allergens predisposes to food allergy, which is commonly associated with atopic dermatitis (AD). Levels of the epithelial cytokine IL-33 are increased in skin lesions and serum of patients with AD. Mast cells (MCs) play a critical role in food-induced anaphylaxis and express the IL-33 receptor ST2. The role of IL-33 in patients with MC-dependent food anaphylaxis is unknown. OBJECTIVE: We sought to determine the role and mechanism of action of IL-33 in patients with food-induced anaphylaxis in a model of IgE-dependent food anaphylaxis elicited by oral challenge of epicutaneously sensitized mice. METHODS: Wild-type, ST2-deficient, and MC-deficient KitW-sh/W-sh mice were epicutaneously sensitized with ovalbumin (OVA) and then challenged orally with OVA. Body temperature was measured by means of telemetry, Il33 mRNA by means of quantitative PCR, and IL-33, OVA-specific IgE, and mouse mast cell protease 1 by means of ELISA. Bone marrow-derived mast cell (BMMC) degranulation was assessed by using flow cytometry. RESULTS: Il33 mRNA expression was upregulated in tape-stripped mouse skin and scratched human skin. Tape stripping caused local and systemic IL-33 release in mice. ST2 deficiency, as well as ST2 blockade before oral challenge, significantly reduced the severity of oral anaphylaxis without affecting the systemic TH2 response to the allergen. Oral anaphylaxis was abrogated in KitW-sh/W-sh mice and restored by means of reconstitution with wild-type but not ST2-deficient BMMCs. IL-33 significantly enhanced IgE-mediated degranulation of BMMCs in vitro. CONCLUSION: IL-33 is released after mechanical skin injury, enhances IgE-mediated MC degranulation, and promotes oral anaphylaxis after epicutaneous sensitization by targeting MCs. IL-33 neutralization might be useful in treating food-induced anaphylaxis in patients with AD.

T-type calcium channel blocker Z944 restores cortical synchrony and thalamocortical connectivity in a rat model of neuropathic pain.

Oscillations are fundamental to communication between neuronal ensembles. We previously reported that pain in awake rats enhances synchrony in primary somatosensory cortex (S1) and attenuates coherence between S1 and ventral posterolateral (VPL) thalamus. Here, we asked whether similar changes occur in anesthetized rats and whether pain modulates phase-amplitude coupling between VPL and S1. We also hypothesized that the suppression of burst firing in VPL using Z944, a novel T-type calcium channel blocker, restores S1 synchrony and thalamocortical connectivity. Local field potentials were recorded from S1 and VPL in anesthetized rats 7 days after sciatic chronic constriction injury (CCI). In rats with CCI, low-frequency (4-12 Hz) synchrony in S1 was enhanced, whereas VPL-S1 coherence and theta-gamma phase-amplitude coupling were attenuated. Moreover, Granger causality showed decreased informational flow from VPL to S1. Systemic or intrathalamic delivery of Z944 to rats with CCI normalized these changes. Systemic Z944 also reversed thermal hyperalgesia and conditioned place preference. These data suggest that pain-induced cortical synchrony and thalamocortical disconnectivity are directly related to burst firing in VPL.

Recent progress in the discovery and development of N-type calcium channel modulators for the treatment of pain.

The importance of voltage-gated calcium channels (VGCCs) in basic physiological processes such as cardiac and neurological function has generated intense interest in these proteins as targets of pharmacological intervention. N-type calcium channels are a subset of VGCCs distinguished by their physiology, pharmacology and significance to the pathology of chronic pain. Despite decades of investigation, only a single drug targeting N-type channel function has entered the marketplace. This review will summarize our current understanding of the biology, physiology and pharmacology of N-type calcium channels and the implication of these features for therapeutic intervention. From this basis of understanding, recent efforts to discover and develop peptide based and small molecule modulators of N-type calcium channel function will be discussed.

Diffuse capillary malformation with overgrowth: a clinical subtype of vascular anomalies with hypertrophy.

BACKGROUND: Categorization of vascular anomalies with overgrowth is evolving rapidly with the aid of massively parallel genomic sequencing; however, accurate clinical diagnosis is still essential. We identified a group of patients with an extensive, diffuse, reticulate capillary malformation (CM) and variable hypertrophy without major complications. OBJECTIVE: We sought to study a subset of patients with diffuse CM to better define prognosis and management. METHODS: Chart review identified 73 patients with diffuse CM who did not fit the criteria for known disorders with CM and/or overgrowth. RESULTS: Soft-tissue or bony overgrowth did not correlate with location, morphology, or intensity of the vascular stain. Patients required periodic follow-up to monitor for leg length discrepancy. They were found to exhibit normal neurologic development and proportionate overgrowth rather than progressive, disproportionate asymmetry or vascular complications. LIMITATIONS: This retrospective review was limited to observations documented at clinic visits; these patients require long-term assessment. Further studies are necessary to accurately assess Wilms tumor risk and clinical outcomes in older adults. CONCLUSION: We propose the term "diffuse capillary malformation with overgrowth" to designate this extensive reticular vascular staining with proportionate overgrowth. We differentiate diffuse capillary malformation with overgrowth from other disorders with CM and hypertrophy.