In 2000 the United States launched the National Nanotechnology Initiative and, along with it, a well-defined set of goals for nanomedicine. This Perspective looks back at the progress made toward ...those goals, within the context of the changing landscape in biomedicine that has occurred over the past 15 years, and considers advances that are likely to occur during the next decade. In particular, nanotechnologies for health-related genomics and single-cell biology, inorganic and organic nanoparticles for biomedicine, and wearable nanotechnologies for wellness monitoring are briefly covered.
The genetic, functional or compositional heterogeneity of healthy and diseased tissues presents major challenges in drug discovery and development. Such heterogeneity hinders the design of accurate ...disease models and can confound the interpretation of biomarker levels and of patient responses to specific therapies. The complex nature of virtually all tissues has motivated the development of tools for single-cell genomic, transcriptomic and multiplex proteomic analyses. Here, we review these tools and assess their advantages and limitations. Emerging applications of single cell analysis tools in drug discovery and development, particularly in the field of oncology, are discussed.
The dynamic nature of the first water adlayers on solid surfaces at room temperature has made the direct detection of their microscopic structure challenging. We used graphene as an atomically flat ...coating for atomic force microscopy to determine the structure of the water adlayers on mica at room temperature as a function of relative humidity. Water adlayers grew epitaxially on the mica substrate in a layer-by-layer fashion. Submonolayers form atomically flat, faceted islands of height 0.37 ± 0.02 nanometers, in agreement with the height of a monolayer of ice. The second adlayers, observed at higher relative humidity, also appear icelike, and thicker layers appear liquidlike. Our results also indicate nanometer-scale surface defects serve as nucleation centers for the formation of both the first and the second adlayers.
Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from ...glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of donai EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA.
Finding faster and simpler ways to screen protein sequence space to enable the identification of new biocatalysts for asymmetric synthesis remains both a challenge and a rate-limiting step in enzyme ...discovery. Biocatalytic strategies for the synthesis of chiral amines are increasingly attractive and include enzymatic asymmetric reductive amination, which offers an efficient route to many of these high-value compounds. Here we report the discovery of over 300 new imine reductases and the production of a large (384 enzymes) and sequence-diverse panel of imine reductases available for screening. We also report the development of a facile high-throughput screen to interrogate their activity. Through this approach we identified imine reductase biocatalysts capable of accepting structurally demanding ketones and amines, which include the preparative synthesis of N-substituted β-amino ester derivatives via a dynamic kinetic resolution process, with excellent yields and stereochemical purities.
During an infection, the body increases the output of mature immune cells in order to fight off the pathogen. Despite convincing evidence that hematopoietic stem and progenitor cells (HSPCs) can ...sense pathogens directly, how this contributes to hematopoietic cell output remains unknown. Here, we have combined mouse models with a single-cell proteomics platform to show that, in response to Toll-like receptor stimulation, short-term HSCs and multipotent progenitor cells produce copious amounts of diverse cytokines through nuclear factor κB (NF-κB) signaling. Interestingly, the cytokine production ability of HSPCs trumps mature immune cells in both magnitude and breadth. Among cytokines produced by HSPCs, IL-6 is a particularly important regulator of myeloid differentiation and HSPC proliferation in a paracrine manner and in mediating rapid myeloid cell recovery during neutropenia. This study has uncovered an important property of HSPCs that enables them to convert danger signals into versatile cytokine signals for the regulation of stress hematopoiesis.
Display omitted
•Undifferentiated HSPCs produce a wide range of cytokines upon stimulation•The cytokine production function of HSPCs is regulated by the TLR/NF-κB axis•HSPCs are significantly more potent cytokine secretors than mature immune cells•Cytokines produced by HSPCs allow efficient myelopoiesis in vitro and in vivo
Zhao et al. reveal that, during an infection, hematopoietic stem and progenitor cells respond directly to Toll-like receptor signaling to produce IL-6 and other cytokines in order to potently stimulate myelopoiesis.
Controlling the thermal conductivity of a material independently of its electrical conductivity continues to be a goal for researchers working on thermoelectric materials for use in energy ...applications and in the cooling of integrated circuits. In principle, the thermal conductivity κ and the electrical conductivity σ may be independently optimized in semiconducting nanostructures because different length scales are associated with phonons (which carry heat) and electric charges (which carry current). Phonons are scattered at surfaces and interfaces, so κ generally decreases as the surface-to-volume ratio increases. In contrast, σ is less sensitive to a decrease in nanostructure size, although at sufficiently small sizes it will degrade through the scattering of charge carriers at interfaces. Here, we demonstrate an approach to independently controlling κ based on altering the phonon band structure of a semiconductor thin film through the formation of a phononic nanomesh film. These films are patterned with periodic spacings that are comparable to, or shorter than, the phonon mean free path. The nanomesh structure exhibits a substantially lower thermal conductivity than an equivalently prepared array of silicon nanowires, even though this array has a significantly higher surface-to-volume ratio. Bulk-like electrical conductivity is preserved. We suggest that this development is a step towards a coherent mechanism for lowering thermal conductivity.
Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell ...phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations.
Display omitted
•Sequencing excludes the selection of an mTORki-resistant genotype in a GBM model•Heterogeneous signaling networks rapidly adapt to mTORki to drive resistance•Resistance-promoting signaling is observed a priori by single-cell analysis•Network analyses point to therapy combinations for long-term disease suppression
Wei et al. utilize single-cell phosphoproteomic analysis of patient-derived glioblastoma models to identify shifts in signaling coordination following short-term treatment with kinase inhibitors, which facilitates the design of combination therapy approaches with reduced resistance and improved efficacy.
We report on the scanning tunneling microscopy study of a new class of corrugations in exfoliated monolayer graphene sheets, that is, wrinkles ∼10 nm in width and ∼3 nm in height. We found such ...corrugations to be ubiquitous in graphene and have distinctly different properties when compared to other regions of graphene. In particular, a “three-for-six” triangular pattern of atoms is exclusively and consistently observed on wrinkles, suggesting the local curvature of the wrinkle provides a sufficient perturbation to break the 6-fold symmetry of the graphene lattice. Through scanning tunneling spectroscopy, we further demonstrate that the wrinkles have lower electrical conductance and are characterized by the presence of midgap states, which is in agreement with recent theoretical predictions. The observed wrinkles are likely important for understanding the electrical properties of graphene.
PDF
