Nucleic acids and proteins are the fundamental biopolymers that support all life on Earth. Nucleic acids store large amounts of information in nucleobase sequences while peptides and proteins utilize diverse amino acid functional groups to adopt complex structures and perform wide-ranging activities. Although nature has evolved machinery to read the nucleic acid code and translate it into amino acid code, the extant biopolymers are restricted to encoding amino acid or nucleotide sequences separately, limiting their potential applications in medicine and biotechnology. Here we describe the design, synthesis, and stimuli-responsive assembly behavior of a bilingual biopolymer that integrates both amino acid and nucleobase sequences into a single peptide nucleic acid (PNA) scaffold to enable tunable storage and retrieval of tertiary structural behavior and programmable molecular recognition capabilities. Incorporation of a defined sequence of amino acid side-chains along the PNA backbone yields amphiphiles having a "protein code" that directs self-assembly into micellar architectures in aqueous conditions. However, these amphiphiles also carry a "nucleotide code" such that subsequent introduction of a complementary RNA strand induces a sequence-specific disruption of assemblies through hybridization. Together, these properties establish bilingual PNA as a powerful biopolymer that combines two information systems to harness structural responsiveness and sequence recognition. The PNA scaffold and our synthetic system are highly generalizable, enabling fabrication of a wide array of user-defined peptide and nucleotide sequence combinations for diverse future biomedical and nanotechnology applications.
Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that may cause opportunistic infections in susceptible hosts. Lung infections in immunocompetent persons with structural lung disease are most common, while disseminated disease occurs primarily in immunocompromised individuals. Human disease caused by certain species, such as Mycobacterium avium complex, Mycobacterium abscessus, and Mycobacterium kansasii, is increasing in incidence and varies by geographic distribution. The spectrum of NTM disease varies widely in presentation and clinical outcome, but certain patterns can be organized into clinical phenotypes. Treatment options are limited, lengthy, and often toxic. The purpose of this case-based review is to provide non-clinician scientists with a better understanding of human NTM disease with an aim to stimulate more research and development.
Controlling the structure and activity
of nucleic acids dramatically
expands their potential for application in therapeutics, biosensing,
nanotechnology, and biocomputing. Several methods have been developed
to impart responsiveness of DNA and RNA to small-molecule and light-based
stimuli. However, heat-triggered control of nucleic acids has remained
largely unexplored, leaving a significant gap in responsive nucleic
acid technology. Moreover, current technologies have been limited
to natural nucleic acids and are often incompatible with polymerase-generated
sequences. Here we show that glyoxal, a well-characterized compound
that covalently attaches to the Watson–Crick–Franklin
face of several nucleobases, addresses these limitations by thermoreversibly
modulating the structure and activity of virtually any nucleic acid
scaffold. Using a variety of DNA and RNA constructs, we demonstrate
that glyoxal modification is easily installed and potently disrupts
nucleic acid structure and function. We also characterize the kinetics
of decaging and show that activity can be restored via tunable thermal
removal of glyoxal adducts under a variety of conditions. We further
illustrate the versatility of this approach by reversibly caging a
2′-O-methylated RNA aptamer as well as synthetic
threose nucleic acid (TNA) and peptide nucleic acid (PNA) scaffolds.
Glyoxal caging can also be used to reversibly disrupt enzyme–nucleic
acid interactions, and we show that caging of guide RNA allows for
tunable and reversible control over CRISPR-Cas9 activity. We also
demonstrate glyoxal caging as an effective method for enhancing PCR
specificity, and we cage a biostable antisense oligonucleotide for
time-release activation and titration of gene expression in living
cells. Together, glyoxalation is a straightforward and scarless method
for imparting reversible thermal responsiveness to theoretically any
nucleic acid architecture, addressing a significant need in synthetic
biology and offering a versatile new tool for constructing programmable
nucleic acid components in medicine, nanotechnology, and biocomputing.
All drugs except for tralokinumab showed improvements in FEV, ACQ, and AQLQ. Only reslizumab and dupilumab were associated with statistically significant reductions in asthma exacerbation rates.
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