Patterning of multicomponent elastic shells by gaussian curvature.

Recent findings suggest that shell protein distribution and the morphology of bacterial microcompartments regulate the chemical fluxes facilitating reactions which dictate their biological function. We explore how the morphology and component patterning are coupled through the competition of mean and gaussian bending energies in multicomponent elastic shells that form three-component irregular polyhedra. We observe two softer components with lower bending rigidities allocated on the edges and vertices while the harder component occupies the faces. When subjected to a nonzero interfacial line tension, the two softer components further separate and pattern into subdomains that are mediated by the gaussian curvature. We find that this degree of fractionation is maximized when there is a weaker line tension and when the ratio of bending rigidities between the two softer domains ≈2. Our results reveal a patterning mechanism in multicomponent shells that can capture the observed morphologies of bacterial microcompartments, and moreover, can be realized in synthetic vesicles.

Microscopically segregated ligand distribution in co-assembled peptide-amphiphile nanofibers.

Peptide amphiphiles (PAs) self-assemble into cylindrical nanofibers with applications in protein purification, tissue engineering, and regenerative medicine. For these applications, functionalized PAs are often co-assembled with oppositely charged filler PAs. Finding the conditions at which these fibers are homogeneously mixed or segregated is crucial for the required application. We co-assemble negative C12VVEE fillers and positive C12VVKK-OEG4-Z33 ligands, which are important for antibody purifications. Our results show that the ligands tend to cluster and locally segregate in the fiber surfaces. The Z33s are overall neutral and form large aggregates in bulk solution due to short range attractions. However, full segregation of the C12VVKK-OEG4-Z33 is not observed in the cylindrical surface due to the electrostatic penalty of forming large domains of similarly charged molecules. This is commensurate with previous theoretical predictions, showing that the competition between short-range attractive interactions and long-range electrostatic repulsions leads to pattern formation in cylindrical surfaces. This work offers valuable insight into the design of functionalized nanofibers for various biomedical and chemical applications.

Proteomimetic Polymers Trigger Potent Antigen-Specific T Cell Responses to Limit Tumor Growth.

Elicitation of effective antitumor immunity following cancer vaccination requires the selective activation of distinct effector cell populations and pathways. Here we report a therapeutic approach for generating potent T cell responses using a modular vaccination platform technology capable of inducing directed immune activation, termed the Protein-like Polymer (PLP). PLPs demonstrate increased proteolytic resistance, high uptake by antigen-presenting cells (APCs), and enhanced payload-specific T cell responses. Key design parameters, namely payload linkage chemistry, degree of polymerization, and side chain composition, were varied to optimize vaccine formulations. Linking antigens to the polymer backbone using an intracellularly cleaved disulfide bond copolymerized with a diluent amount of oligo(ethylene glycol) (OEG) resulted in the highest payload-specific potentiation of antigen immunogenicity, enhancing dendritic cell (DC) activation and antigen-specific T cell responses. Vaccination with PLPs carrying either gp100, E7, or adpgk peptides significantly increased the survival of mice inoculated with B16F10, TC-1, or MC38 tumors, respectively, without the need for adjuvants. B16F10-bearing mice immunized with gp100-carrying PLPs showed increased antitumor CD8+ T cell immunity, suppressed tumor growth, and treatment synergy when paired with two distinct stimulator of interferon gene (STING) agonists. In a human papillomavirus-associated TC-1 model, combination therapy with PLP and 2'3'-cGAMP resulted in 40% of mice completely eliminating implanted tumors while also displaying curative protection from rechallenge, consistent with conferment of lasting immunological memory. Finally, PLPs can be stored long-term in a lyophilized state and are highly tunable, underscoring the unique properties of the platform for use as generalizable cancer vaccines.

Type specimens, taxonomic history, and genetic analysis of the Japanese dancing mouse or waltzer, Muswagneri variety rotans Droogleever Fortuyn, 1912 (Mammalia, Muridae).

In the present paper, the existence and location of the type series of the Japanese dancing mouse or waltzer, Muswagneri variety rotans Droogleever Fortuyn, 1912, are established, and a lectotype is designated. Available type specimens are measured, and some morphological parameters, sex, and general condition of the specimens are recorded. A literature survey was conducted, and an attempt is made to clarify the position of M.wagneri variety rotans in the taxonomy of Mus. A genetic analysis suggests that the type series of the Japanese dancing mouse represent a crossbred, or derivation of a crossbred, between the original Japanese dancing mouse of Musmusculusmolossinus Temminck 1844 origin and European fancy or laboratory mice of Musmusculusdomesticus Schwarz & Schwarz, 1943 origin. Much of their genome was replaced and occupied by Musmusculusdomesticus type genome, probably through extensive breeding with European mice.

Experiences of racism in the U.S. - A perspective from Asian & Pacific Islander, Black, Latina, and Middle Eastern women.

Introduction: Racism is a critical social determinant of health because it can have a direct impact on health and well-being, as well as infiltrate systems, policies, and practices. Few studies have explored the similarities and differences of experiences with racism and health between different minoritized groups. The objective of this paper is to examine how racism influences life experiences from the perspectives of Asian & Pacific Islander, Black, Latina, and Middle Eastern women. Methods: Eleven online racially/ethnically homogeneous focus groups with a total of 52 participants were conducted in the U.S., with representation from the North, South, and West coast. The online focus groups were recorded, transcribed, and two were translated into English (from Vietnamese and Spanish). The data was coded through NVivo and analyzed through a series of team meetings to establish themes. Results: Participants reported experiences of racism and discrimination, including physical and verbal personal attacks. They shared the role of microaggressions in their daily life, along with the ubiquitous anti-Black sentiment discussed in every group. Our participants discussed the complexities of intersectionality in their experience of discrimination, specifically regarding immigration status, language spoken, and gender. Participants also reported the role of direct racism and vicarious racism (e.g., the experiences with racism of friends or family, awareness of racist incidents via the news) in affecting their mental health. Some effects were fear, stress, anxiety, depression, and self-censoring. For participants in the Black and Latina focus groups, mental health stressors often manifested into physical issues. Discussion: Understanding the nuances in experiences across racial/ethnic groups is beneficial in identifying potential interventions to prevent and address racism and its negative health impacts.

Electric fields near undulating dielectric membranes.

Dielectric interfaces are crucial to the behavior of charged membranes, from graphene to synthetic and biological lipid bilayers. Understanding electrolyte behavior near these interfaces remains a challenge, especially in the case of rough dielectric surfaces. A lack of analytical solutions consigns this problem to numerical treatments. We report an analytic method for determining electrostatic potentials near curved dielectric membranes in a two-dimensional periodic "slab" geometry using a periodic summation of Green's functions. This method is amenable to simulating arbitrary groups of charges near surfaces with two-dimensional deformations. We concentrate on one-dimensional undulations. We show that increasing membrane undulation increases the asymmetry of interfacial charge distributions due to preferential ionic repulsion from troughs. In the limit of thick membranes, we recover results mimicking those for electrolytes near a single interface. Our work demonstrates that rough surfaces generate charge patterns in electrolytes of charged molecules or mixed-valence ions.

Enhanced phoretic self-propulsion of active colloids through surface charge asymmetry.

Charged colloidal particles propel themselves through asymmetric fluxes of chemically generated ions on their surface. We show that asymmetry in the surface charge distribution provides an additional mode of self-propulsion at the nanoscale for chemically active particles that produce ionic species. Particles of sizes smaller than or comparable to the Debye length achieve directed self-propulsion through surface charge asymmetry even when ionic flux is uniform over its surface. Janus nanoparticles endowed with both surface charge and ionic flux asymmetries result in enhanced propulsion speeds of the order of µm/s or higher. Our work suggests an alternative avenue for specifying surface properties that optimize self-propulsion in ionic media.

Restructuring a passive colloidal suspension using a rotationally driven particle.

The interaction between passive and active/driven particles has introduced a new way to control colloidal suspension properties from particle aggregation to crystallization. Here, we focus on the hydrodynamic interaction between a single rotational driven particle and a suspension of passive particles near the floor. Using experiments and Stokesian dynamics simulations that account for near-field lubrication, we demonstrate that the flow induced by the driven particle can induce long-ranged rearrangement in a passive suspension. We observe an accumulation of passive particles in front of the driven particle and a depletion of passive particles behind the driven particle. This restructuring generates a pattern that can span a range more than 10 times the driven particles radius. We further show that size scale of the pattern is only a function of the particles height above the floor.

Reexpansion of charged nanoparticle assemblies in concentrated electrolytes.

Electrostatic forces in solutions are highly relevant to a variety of fields, ranging from electrochemical energy storage to biology. However, their manifestation in concentrated electrolytes is not fully understood, as exemplified by counterintuitive observations of colloidal stability and long-ranged repulsions in molten salts. Highly charged biomolecules, such as DNA, respond sensitively to ions in dilute solutions. Here, we use non-base-pairing DNA-coated nanoparticles (DNA-NP) to analyze electrostatic interactions in concentrated salt solutions. Despite their negative charge, these conjugates form colloidal crystals in solutions of sufficient divalent cation concentration. We utilize small-angle X-ray scattering (SAXS) to study such DNA-NP assemblies across the full accessible concentration ranges of aqueous CaCl2, MgCl2, and SrCl2 solutions. SAXS shows that the crystallinity and phases of the assembled structures vary with cation type. For all tested salts, the aggregates contract with added ions at low salinities and then begin expanding above a cation-dependent threshold salt concentration. Wide-angle X-ray scattering (WAXS) reveals enhanced positional correlations between ions in the solution at high salt concentrations. Complementary molecular dynamics simulations show that these ion-ion interactions reduce the favorability of dense ion configurations within the DNA brushes below that of the bulk solution. Measurements in solutions with lowered permittivity demonstrate a simultaneous increase in ion coupling and decrease in the concentration at which aggregate expansion begins, thus confirming the connection between these phenomena. Our work demonstrates that interactions between charged objects continue to evolve considerably into the high-concentration regime, where classical theories project electrostatics to be of negligible consequence.

Inhibiting the Keap1/Nrf2 Protein-Protein Interaction with Protein-Like Polymers.

Successful and selective inhibition of the cytosolic protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associating protein 1 (Keap1) can enhance the antioxidant response, with the potential for a therapeutic effect in a range of settings including in neurodegenerative disease (ND). Small molecule inhibitors have been developed, yet many have off-target effects, or are otherwise limited by poor cellular permeability. Peptide-based strategies have also been attempted to enhance specificity, yet face challenges due to susceptibility to degradation and lack of cellular penetration. Herein, these barriers are overcome utilizing a polymer-based proteomimetics. The protein-like polymer (PLP) consists of a synthetic, lipophilic polymer backbone displaying water soluble Keap1-binding peptides on each monomer unit forming a brush polymer architecture. The PLPs are capable of engaging Keap1 and displacing the cellular protective transcription factor Nrf2, which then translocates to the nucleus, activating the antioxidant response element (ARE). PLPs exhibit increased Keap1 binding affinity by several orders of magnitude compared to free peptides, maintain serum stability, are cell-penetrant, and selectively activate the ARE pathway in cells, including in primary cortical neuronal cultures. Keap1/Nrf2-inhibitory PLPs have the potential to impact the treatment of disease states associated with dysregulation of oxidative stress, such as NDs.

Vigilance and Protection: How Asian and Pacific Islander, Black, Latina, and Middle Eastern Women Cope with Racism.

BACKGROUND: Research is needed to fully investigate the differential mechanisms racial and ethnic groups use to deal with ongoing intersectional racism in women's lives. The aim of this paper was to understand how Asian American and Pacific Islander, Black, Latina, and Middle Eastern women experience racism-from personal perceptions and interactions to coping mechanisms and methods of protection. METHODS: A purposive sample of 52 participants participated in 11 online racially/ethnically homogeneous focus groups conducted throughout the USA. A team consensus approach was utilized with codebook development and thematic analysis. RESULTS: The findings relate to personal perceptions and interactions related to race and ethnicity, methods of protection against racism, vigilant behavior based on safety concerns, and unity across people of color. A few unique concerns by group included experiences of racism including physical violence among Asian American Pacific Islander groups, police brutality among Black groups, immigration discrimination in Latina groups, and religious discrimination in Middle Eastern groups. Changes in behavior for safety and protection include altering methods of transportation, teaching their children safety measures, and defending their immigration status. They shared strategies to help racial and ethnic minorities against racism including mental health resources and greater political representation. All racial and ethnic groups discussed the need for unity, solidarity, and allyship across various communities of color but for it to be authentic and long-lasting. CONCLUSION: Greater understanding of the types of racism specific groups experience can inform policies and cultural change to reduce those factors.

Transformations in crystals of DNA-functionalized nanoparticles by electrolytes.

Colloidal crystals have applications in water treatments, including water purification and desalination technologies. It is, therefore, important to understand the interactions between colloids as a function of electrolyte concentration. We study the assembly of DNA-grafted gold nanoparticles immersed in concentrated electrolyte solutions. Increasing the concentration of divalent Ca2+ ions leads to the condensation of nanoparticles into face-centered-cubic (FCC) crystals at low electrolyte concentrations. As the electrolyte concentration increases, the system undergoes a phase change to body-centered-cubic (BCC) crystals. This phase change occurs as the interparticle distance decreases. Molecular dynamics analysis suggests that the interparticle interactions change from strongly repulsive to short-range attractive as the divalent-electrolyte concentration increases. A thermodynamic analysis suggests that increasing the salt concentration leads to significant dehydration of the nanoparticle environment. We conjecture that the intercolloid attractive interactions and dehydrated states favour the BCC structure. Our results gain insight into salting out of colloids such as proteins as the concentration of salt increases in the solution.

Outcomes and Associated Extracardiac Malformations in Neonates from Colombia with Severe Congenital Heart Disease.

Congenital heart disease (CHD) is a common structural anomaly, affecting ~ 1% of live births worldwide. Advancements in medical and surgical management have significantly improved survival for children with CHD, however, extracardiac malformations (ECM) continue to be a significant cause of morbidity and mortality. Despite clinical significance, there is limited literature available on ECM in neonates with CHD, especially from Latin America. A cross-sectional study of neonates with severe CHD evaluated by the medical-surgical board team at Fundación Cardiovascular de Colombia from 2014 to 2019 was completed to characterize morbidity, mortality, surgical outcomes, and ECM. Demographics and surgical outcomes were compared between neonates with and without ECM. Medical record data were abstracted and descriptive statistical analysis was performed. Of 378 neonates with CHD, 262 had isolated CHD (69.3%) and 116 had ECM (30.7%). The most common ECM was gastrointestinal (n = 18, 15.5%) followed by central nervous system (n = 14, 12%). Most neonates required a biventricular surgical approach (n = 220, 58.2%). Genetic testing was performed more often for neonates with ECM (n = 65, 56%) than neonates with isolated CHD (n = 14, 5.3%). Neonates with ECM had lower birth weight, longer hospital stays, and higher postsurgical complications rates. There was no difference in survival between groups. Overall, Screening for ECM in neonates with CHD is important and identification of ECM can guide clinical decision-making. These findings have important implications for pediatric healthcare providers, especially in low- and middle-income countries, where the burden of CHD is high and resources for managing CHD and extracardiac malformations may be limited.

Induced phase transformation in ionizable colloidal nanoparticles.

Acid-base equilibria directly influence the functionality and behavior of particles in a system. Due to the ionizing effects of acid-base functional groups, particles will undergo charge exchange. The degree of ionization and their intermolecular and electrostatic interactions are controlled by varying the pH and salt concentration of the solution in a system. Although the pH can be tuned in experiments, it is hard to model this effect using simulations or theoretical approaches. This is due to the difficulty in treating charge regulation and capturing the cooperative effects in a colloidal suspension with Coulombic interaction. In this work, we analyze a suspension of ionizable colloidal particles via molecular dynamics (MD) simulations, along with Monte Carlo simulations for charge regulation (MC-CR) and derive a phase diagram of the system as a function of pH. It is observed that as pH increases, particles functionalized with acid groups change their arrangement from face-centered cubic (FCC) packing to a disordered state. We attribute these transitions to an increase in the degree of charge polydispersity arising from an increase in pH. Our work shows that charge regulation leads to amorphous solids in colloids when the mean nanoparticle charge is sufficiently high.

PDZ scaffolds regulate extracellular vesicle production, composition, and uptake.

Extracellular vesicles (EVs) are membrane-limited organelles mediating cell-to-cell communication in health and disease. EVs are of high medical interest, but their rational use for diagnostics or therapies is restricted by our limited understanding of the molecular mechanisms governing EV biology. Here, we tested whether PDZ proteins, molecular scaffolds that support the formation, transport, and function of signal transduction complexes and that coevolved with multicellularity, may represent important EV regulators. We reveal that the PDZ proteome (ca. 150 proteins in human) establishes a discrete number of direct interactions with the tetraspanins CD9, CD63, and CD81, well-known EV constituents. Strikingly, PDZ proteins interact more extensively with syndecans (SDCs), ubiquitous membrane proteins for which we previously demonstrated an important role in EV biogenesis, loading, and turnover. Nine PDZ proteins were tested in loss-of-function studies. We document that these PDZ proteins regulate both tetraspanins and SDCs, differentially affecting their steady-state levels, subcellular localizations, metabolism, endosomal budding, and accumulations in EVs. Importantly, we also show that PDZ proteins control the levels of heparan sulfate at the cell surface that functions in EV capture. In conclusion, our study establishes that the extensive networking of SDCs, tetraspanins, and PDZ proteins contributes to EV heterogeneity and turnover, highlighting an important piece of the molecular framework governing intracellular trafficking and intercellular communication.