Parameterizing the Binding Properties of XNA Aptamers Isolated from a Low Stringency Selection.

Machine learning offers a guided approach to aptamer discovery, but more information is needed to develop algorithms that can intelligently identify high-performing aptamers to a broad array of targets. Critical to this effort is the need to experimentally parameterize the difference between low and high affinity binders to a given target. Although classical selection experiments help define the upper limit by converging on a small number of tight binding sequences, very little is known about the lower limit of binding that defines the boundary between binders and nonbinders.

Os(II/III) complex supports pH-insensitive electrochemical DNA-based sensing with superior operational stability than the benchmark methylene blue reporter.

DNA-based electrochemical sensors use redox reporters to transduce affinity events into electrical currents. Ideally, such reporters must be electrochemically reversible, chemically stable for thousands of redox cycles, and tolerant to changing chemical environments. Here we report the first use of an Os(II/III) complex in DNA-based sensors, which undergoes pH-insensitive electron transfer with 35% better operational stability relative to the benchmark methylene blue, making it a promising reporter for continuous molecular monitoring applications where pH fluctuates with time.

Lymphangioleiomyomatosis: a metastatic lung disease.

Lymphangioleiomyomatosis (LAM) is a rare disease affecting women, caused by somatic mutations in the TSC1 or TSC2 genes, and driven by estrogen. Similar to many cancers, it is metastatic, primarily to the lung. Despite its monogenetic nature, like many cancers, LAM is a heterogeneous disease.

Human Cyclophilin B Nuclease Activity Revealed via Nucleic Acid-Based Electrochemical Sensors.

Human cyclophilin B (CypB) is oversecreted by pancreatic cancer cells, making it a potential biomarker for early-stage disease diagnosis. Our group is motivated to develop aptamer-based assays to measure CypB levels in biofluids. However, human cyclophilins have been postulated to have collateral nuclease activity, which could impede the use of aptamers for CypB detection.

A STING agonist preconditions against ischaemic stroke via an adaptive antiviral Type 1 interferon response.

Converging lines of inquiry have highlighted the importance of the Type I antiviral response not only in defending against viruses but also in preconditioning the brain against ischaemic stroke. Despite this understanding, treatments that foster brain resilience by driving antiviral interferon responses have yet to be developed for human use. Studies from our laboratory showed that tilorone, the first human antiviral immunomodulatory agent to be developed, robustly preconditioned against stroke in mice and rats.

Integration of chemically modified nucleotides with DNA strand displacement reactions for applications in living systems.

Watson-Crick base pairing rules provide a powerful approach for engineering DNA-based nanodevices with programmable and predictable behaviors. In particular, DNA strand displacement reactions have enabled the development of an impressive repertoire of molecular devices with complex functionalities. By relying on DNA to function, dynamic strand displacement devices represent powerful tools for the interrogation and manipulation of biological systems.

Kinetics of heterochiral strand displacement from PNA-DNA heteroduplexes.

Dynamic DNA nanodevices represent powerful tools for the interrogation and manipulation of biological systems. Yet, implementation remains challenging due to nuclease degradation and other cellular factors. Use of l-DNA, the nuclease resistant enantiomer of native d-DNA, provides a promising solution.

Nuclease Hydrolysis Does Not Drive the Rapid Signaling Decay of DNA Aptamer-Based Electrochemical Sensors in Biological Fluids.

Electrochemical aptamer-based (E-AB) sensors are a technology capable of real-time monitoring of drug concentrations directly in the body. These sensors achieve their selectivity from surface-attached aptamers, which alter their conformation upon target binding, thereby causing a change in electron transfer kinetics between aptamer-bound redox reporters and the electrode surface. Because, in theory, aptamers can be selected for nearly any target of interest, E-AB sensors have far-reaching potential for diagnostic and biomedical applications.

Heterochiral Nucleic Acid Circuits.

The programmability of DNA/RNA-based molecular circuits provides numerous opportunities in the field of synthetic biology. However, the stability of nucleic acids remains a major concern when performing complex computations in biological environments. Our solution to this problem is L-(deoxy)ribose nucleic acids (L-DNA/RNA), which are mirror images (i.

Mirror-Image Oligonucleotides: History and Emerging Applications.

As chiral molecules, naturally occurring d-oligonucleotides have enantiomers, l-DNA and l-RNA, which are comprised of l-(deoxy)ribose sugars. These mirror-image oligonucleotides have the same physical and chemical properties as that of their native d-counterparts, yet are highly orthogonal to the stereospecific environment of biology. Consequently, l-oligonucleotides are resistant to nuclease degradation and many of the off-target interactions that plague traditional d-oligonucleotide-based technologies; thus making them ideal for biomedical applications.

Ferroptosis in Neurons and Cancer Cells Is Similar But Differentially Regulated by Histone Deacetylase Inhibitors.

Ferroptotic death is a mechanism for tumor suppression by pharmacological inhibitors that target the X transporter (cystine/glutamate antiporter) in a host of non-CNS and CNS tumors. Inhibition of this transporter leads to reduction of cystine uptake, cyst(e)ine deprivation, subsequent depletion of the versatile antioxidant glutathione, and reactive lipid species-dependent death. Accordingly, pharmacological inhibitors of the X transporter can also induce neuronal cell death raising concerns about toxicity in the CNS and PNS if these agents are used for chemotherapy.

Estrogen-activated MDM2 disrupts mammary tissue architecture through a p53-independent pathway.

The Cancer Genome Atlas (TCGA) data indicate that high MDM2 expression correlates with all subtypes of breast cancer. Overexpression of MDM2 drives breast oncogenesis in the presence of wild-type or mutant p53 (mtp53). Importantly, estrogen-receptor positive (ER+) breast cancers overexpress MDM2 and estrogen mediates this expression.

Drosophila insulin and target of rapamycin (TOR) pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo.

Background: Genetic studies in Drosophila melanogaster reveal an important role for Myc in controlling growth. Similar studies have also shown how components of the insulin and target of rapamycin (TOR) pathways are key regulators of growth. Despite a few suggestions that Myc transcriptional activity lies downstream of these pathways, a molecular mechanism linking these signaling pathways to Myc has not been clearly described.

A p53-independent role of Mdm2 in estrogen-mediated activation of breast cancer cell proliferation.

Introduction: Estrogen receptor positive breast cancers often have high levels of Mdm2. We investigated if estrogen signaling in such breast cancers occurred through an Mdm2 mediated pathway with subsequent inactivation of p53.

Methods: We examined the effect of long-term 17β-estradiol (E2) treatment (five days) on the p53-Mdm2 pathway in estrogen receptor alpha (ERα) positive breast cancer cell lines that contain wild-type p53 (MCF-7 and ZR75-1).