Deciphering Redox Free Radical Mechanisms of 15LOX/PEBP1-Driven Ferroptosis in Skin

This proposal will uncover critical molecular mechanisms governing a new class of death signaling pathway (ie ferroptosis) and its relevance to ultraviolet radiation (UVR)-induced skin injury and cutaneous malignancies. The team will focus on the key role played by protein 15-lipoxygenase (15-LOX) in ferroptosis using a broad interdisciplinary approach. Specifically the team will: (1) Elucidate the local structure around the catalytic site of 15-LOX as well as in a complex of 15-LOX with PEBP1 in order to understand how metal-protein interactions affect 15-LOX function and how PEBP1 binding to 15-LOX opens the active site; (2) Measure the atomic structure and molecular interactions of 15-LOX active site in the presence of newly designed specific inhibitors of 15-LOX/PEBP1 complex in order to understand the mechanism of inhibition; and (3) Characterize the previously unexplored role of 15-LOX/PEBP1 complex in triggering ferroptotic death of skin cells (melanocytes and keratinocytes) and its regulation by selective new inhibitors and melanin biosynthesis. The interdisciplinary team brings together the experts from the School of Arts and Sciences, the School of Medicine and the School of Public Health. The project builds on the expertise of the Kagan group in the discovery and understanding of the biochemical network that underpins ferroptosis. The Saxena group brings in the knowledgebase to measure at the atomic level key interactions that are essential for ferroptosis in order to aid the development of new ferroptosis inhibitors. Finally, the Bunimovich group will expand the mechanistic studies to skin cell models and will explore the relevance of ferroptosis and 15LOX/PEBP1 inhibition in dermatological diseases. Understanding the mechanisms and regulation of ferroptosis in the skin will be critical for the prevention and treatment of radiation and drug-induced skin injury, as well as inflammatory, autoimmune and neoplastic cutaneous diseases such as psoriasis, lupus and melanoma

A challenging diagnosis of penile sarcomatoid squamous cell carcinoma

We report a patient with penile sarcomatoid squamous cell carcinoma (SCC) initially misdiagnosed as condyloma acuminatum. Sarcomatoid SCC is a rare, aggressive, biphasic cancer that often presents a diagnostic challenge and carries a poor prognosis, especially after a delay in diagnosis. Although sarcomatoid SCC may exhibit a broad range of clinical features, the expression of p63 and keratin 34?E12 is a common finding. Our case highlights the importance of accurate clinicopathologic correlation to facilitate a timely diagnosis and management of this rare and highly aggressive malignancy

The optimal sink and the best source in a Markov chain

It is well known that the distributions of hitting times in Markov chains are quite irregular, unless the limit as time tends to infinity is considered. We show that nevertheless for a typical finite irreducible Markov chain and for nondegenerate initial distributions the tails of the distributions of the hitting times for the states of a Markov chain can be ordered, i.e., they do not overlap after a certain finite moment of time. If one considers instead each state of a Markov chain as a source rather than a sink then again the states can generically be ordered according to their efficiency. The mechanisms underlying these two orderings are essentially different though.Comment: 12 pages, 1 figur

Spiers Memorial Lecture: Molecular mechanics and molecular electronics

We describe our research into building integrated molecular electronics circuitry for a diverse set of functions, and with a focus on the fundamental scientific issues that surround this project. In particular, we discuss experiments aimed at understanding the function of bistable [2]rotaxane molecular electronic switches by correlating the switching kinetics and ground state thermodynamic properties of those switches in various environments, ranging from the solution phase to a Langmuir monolayer of the switching molecules sandwiched between two electrodes. We discuss various devices, low bit-density memory circuits, and ultra-high density memory circuits that utilize the electrochemical switching characteristics of these molecules in conjunction with novel patterning methods. We also discuss interconnect schemes that are capable of bridging the micrometre to submicrometre length scales of conventional patterning approaches to the near-molecular length scales of the ultra-dense memory circuits. Finally, we discuss some of the challenges associated with fabricated ultra-dense molecular electronic integrated circuits

Quantitative Real-Time Measurements of DNA Hybridization with Alkylated Nonoxidized Silicon Nanowires in Electrolyte Solution

The quantitative, real-time detection of single-stranded oligonucleotides with silicon nanowires (SiNWs) in physiologically relevant electrolyte solution is demonstrated. Debye screening of the hybridization event is circumvented by utilizing electrostatically adsorbed primary DNA on an amine-terminated NW surface. Two surface functionalization chemistries are compared:  an amine-terminated siloxane monolayer on the native SiO2 surface of the SiNW, and an amine-terminated alkyl monolayer grown directly on a hydrogen-terminated SiNW surface. The SiNWs without the native oxide exhibit improved solution-gated field-effect transistor characteristics and a significantly enhanced sensitivity to single-stranded DNA detection, with an accompanying 2 orders of magnitude improvement in the dynamic range of sensing. A model for the detection of analyte by SiNW sensors is developed and utilized to extract DNA-binding kinetic parameters. Those values are directly compared with values obtained by the standard method of surface plasmon resonance (SPR) and demonstrated to be similar. The nanowires, however, are characterized by higher detection sensitivity. The implication is that SiNWs can be utilized to quantitate the solution-phase concentration of biomolecules at low concentrations. This work also demonstrates the importance of surface chemistry for optimizing biomolecular sensing with silicon nanowires

Electrochemical fabrication of conducting polymer nanowires in an integrated microfluidic system

In this paper, we introduce a new approach for the in situ electrochemical fabrication of an individually addressable array of conducting polymer nanowires (CPNWs) positioned within an integrated microfluidic device and also demonstrate that such an integrated device can be used as a chemical sensor immediately after its construction

A 160-kilobit molecular electronic memory patterned at 10^(11) bits per square centimetre

The primary metric for gauging progress in the various semiconductor integrated circuit technologies is the spacing, or pitch, between the most closely spaced wires within a dynamic random access memory (DRAM) circuit. Modern DRAM circuits have 140nm pitch wires and a memory cell size of 0.0408 μm^2. Improving integrated circuit technology will require that these dimensions decrease over time. However, at present a large fraction of the patterning and materials requirements that we expect to need for the construction of new integrated circuit technologies in 2013 have ‘no known solution’. Promising ingredients for advances in integrated circuit technology are nanowires, molecular electronics and defect-tolerant architectures, as demonstrated by reports of single devices and small circuits. Methods of extending these approaches to large-scale, high-density circuitry are largely undeveloped. Here we describe a 160,000-bit molecular electronic memory circuit, fabricated at a density of 10^(11) bits cm^(-2) (pitch 33 nm; memory cell size 0.0011 mm^2), that is, roughly analogous to the dimensions of a DRAM circuit projected to be available by 2020. A monolayer of bistable, [2]rotaxane molecules 10 served as the data storage elements. Although the circuit has large numbers of defects, those defects could be readily identified through electronic testing and isolated using software coding. The working bits were then configured to form a fully functional random access memory circuit for storing and retrieving information

Predicting Outcomes of Prostate Cancer Immunotherapy by Personalized Mathematical Models

Therapeutic vaccination against disseminated prostate cancer (PCa) is partially effective in some PCa patients. We hypothesized that the efficacy of treatment will be enhanced by individualized vaccination regimens tailored by simple mathematical models.We developed a general mathematical model encompassing the basic interactions of a vaccine, immune system and PCa cells, and validated it by the results of a clinical trial testing an allogeneic PCa whole-cell vaccine. For model validation in the absence of any other pertinent marker, we used the clinically measured changes in prostate-specific antigen (PSA) levels as a correlate of tumor burden. Up to 26 PSA levels measured per patient were divided into each patient's training set and his validation set. The training set, used for model personalization, contained the patient's initial sequence of PSA levels; the validation set contained his subsequent PSA data points. Personalized models were simulated to predict changes in tumor burden and PSA levels and predictions were compared to the validation set. The model accurately predicted PSA levels over the entire measured period in 12 of the 15 vaccination-responsive patients (the coefficient of determination between the predicted and observed PSA values was R(2) = 0.972). The model could not account for the inconsistent changes in PSA levels in 3 of the 15 responsive patients at the end of treatment. Each validated personalized model was simulated under many hypothetical immunotherapy protocols to suggest alternative vaccination regimens. Personalized regimens predicted to enhance the effects of therapy differed among the patients.Using a few initial measurements, we constructed robust patient-specific models of PCa immunotherapy, which were retrospectively validated by clinical trial results. Our results emphasize the potential value and feasibility of individualized model-suggested immunotherapy protocols