KPT-330 Prevents Aortic Valve Calcification via a Novel C/EBPß Signaling Pathway.

[Figure: see text].

Phenotypic Variation Between Stromal Cells Differentially Impacts Engineered Cardiac Tissue Function.

IMPACT STATEMENT: Understanding the relationship between parenchymal and supporting cell populations is paramount to recapitulate the multicellular complexity of native tissues. Incorporation of stromal cells is widely recognized to be necessary for the stable formation of stem cell-derived cardiac tissues; yet, the types of stromal cells used have varied widely. This study systematically characterized several stromal populations and found that stromal phenotype and morphology was highly variable depending on cell source and exerted differential impacts on cardiac tissue function and induced pluripotent stem cell-cardiomyocyte phenotype. Therefore, the choice of supporting stromal population can differentially impact the phenotypic or functional performance of engineered cardiac tissues.

3D, Reconfigurable, Multimodal Electronic Whiskers via Directed Air Assembly.

A batch-assembly technique for forming 3D electronics on shape memory polymer substrates is demonstrated and is used to create dense, highly sensitive, multimodal arrays of electronic whiskers. Directed air flow at temperatures above the substrate's glass transition temperature transforms planar photolithographically defined resistive sensors from 2D precursors into shape-tunable, deterministic 3D assemblies. Reversible 3D assembly and flattening is achieved by exploiting the shape memory properties of the substrate, enabling context-driven shape reconfiguration to isolate/enhance specific sensing modes. In particular, measurement schemes and device configurations are introduced that allow for the sensing of temperature, stiffness, contact force, proximity, and surface texture and roughness. The assemblies offer highly spatiotemporally resolved, wide-range measurements of surface topology (50 nm to 500 µm), material stiffness (200 kPa to 7.5 GPa), and temperature (0-100 °C), with response times of <250 µs. The development of a scalable process for 3D assembly of reconfigurable electronic sensors, as well as the large breadth and sensitivity of complex sensing modes demonstrated, has applications in the growing fields of 3D assembly, electronic skin, and human-machine interfaces.

Transient Nutrient Deprivation Promotes Macropinocytosis-Dependent Intracellular Bacterial Community Development.

Nutrient limitation restricts bacterial growth in privileged sites such as the middle ear. Transient heme-iron restriction of nontypeable Haemophilus influenzae (NTHI), the major causative agent of chronic and recurrent otitis media (OM), promotes new and diverse phenotypes that can influence planktonic, biofilm, and intracellular lifestyles of NTHI. However, the bacterial responses to nutrient restriction that impact intracellular fate and survival of NTHI are unknown. In this work, we provide evidence for the role of transient heme-iron restriction in promoting the formation of intracellular bacterial communities (IBCs) of NTHI both in vitro and in vivo in a preclinical model of OM. We show that transient heme-iron restriction of NTHI results in significantly increased invasion and intracellular populations that escape or evade the endolysosomal pathway for increased intracellular survival. In contrast, NTHI continuously exposed to heme-iron traffics through the endolysosomal pathway for degradation. The use of pharmacological inhibitors revealed that prior heme-iron status does not appear to influence NTHI internalization through endocytic pathways. However, inhibition of macropinocytosis altered the intracellular fate of transiently restricted NTHI for degradation in the endolysosomal pathway. Furthermore, prevention of macropinocytosis significantly reduced the number of IBCs in cultured middle ear epithelial cells, providing evidence for the feasibility of this approach to reduce OM persistence. These results reveal that microenvironmental cues can influence the intracellular fate of NTHI, leading to new mechanisms for survival during disease progression.IMPORTANCE Otitis media is the most common bacterial infection in childhood. Current therapies are limited in the prevention of chronic or recurrent otitis media which leads to increased antibiotic exposure and represents a significant socioeconomic burden. In this study, we delineate the effect of nutritional limitation on the intracellular trafficking pathways used by nontypeable Haemophilus influenzae (NTHI). Moreover, transient limitation of heme-iron led to the development of intracellular bacterial communities that are known to contribute to persistence and recurrence in other diseases. New approaches for therapeutic interventions that reduce the production of intracellular bacterial communities and promote trafficking through the endolysosomal pathway were revealed through the use of pharmacological inhibition of macropinocytosis. This work demonstrates the importance of an intracellular niche for NTHI and provides new approaches for intervention for acute, chronic, and recurring episodes of otitis media.