Neutropaenia complications from Ocrelizumab and Rituximab treatment.

Ocrelizumab is an anti-CD20 monoclonal antibody (mAb) that has been shown in phase 3 clinical trials to reduce relapses and disease progression in multiple sclerosis (MS) patients. Prior to the approval of ocrelizumab, rituximab, a chimeric anti-CD20 mAb was used to treat MS. Rituximab is still used to treat MS in many countries outside of Australia and remains mainstay of treatment of many non-MS neuroimmunological and systemic inflammatory diseases. Rituximab is currently used in neuromyelitis optica spectrum disorder (NMOSD) and autoimmune encephalitis, in addition to its widespread usage in hematological malignancies and systemic inflammatory diseases. Ocrelizumab is currently approved in Australia for treatment of relapsing-remitting MS (RRMS). Neutropaenia is a rare complication of both ocrelizumab and rituximab treatment. This case series reports 12 patients who have experienced neutropaenia following ocrelizumab or rituximab treatment and aims to characterize the clinical parameters of neutropaenia experienced by these patients, including the severity and duration of neutropaenia, length of hospital admission, the types of subsequent infections experienced and types of treatment necessary before patients reached count recovery. The unpredictability of neutropaenia and potential for serious infections highlight the need for continued hematological monitoring for patients on B-cell depleting therapies and calls for careful patient counselling to provide guidance on whether to continue such therapies in patients who have experienced related neutropaenia.

HLA-DRB1*15:01 and the MERTK Gene Interact to Selectively Influence the Profile of MERTK-Expressing Monocytes in Both Health and MS.

BACKGROUND AND OBJECTIVES: HLA-DRB1*15:01 (DR15) and MERTK are 2 risk genes for multiple sclerosis (MS). The variant rs7422195 is an expression quantitative trait locus for MERTK in CD14+ monocytes; cells with phagocytic and immunomodulatory potential. We aimed to understand how drivers of disease risk and pathogenesis vary with HLA and MERTK genotype and disease activity. METHODS: We investigated how proportions of monocytes vary with HLA and MERTK genotype and disease activity in MS. CD14+ monocytes were isolated from patients with MS at relapse (n = 40) and 3 months later (n = 23). Healthy controls (HCs) underwent 2 blood collections 3 months apart. Immunophenotypic profiling of monocytes was performed by flow cytometry. Methylation of 35 CpG sites within and near the MERTK gene was assessed in whole blood samples of individuals experiencing their first episode of clinical CNS demyelination (n = 204) and matched HCs (n = 345) using an Illumina EPIC array. RESULTS: DR15-positive patients had lower proportions of CD14+ MERTK+ monocytes than DR15-negative patients, independent of genotype at the MERTK SNP rs7422195. Proportions of CD14+ MERTK+ monocytes were further reduced during relapse in DR15-positive but not DR15-negative patients. Patients homozygous for the major G allele at rs7422195 exhibited higher proportions of CD14+ MERTK+ monocytes at both relapse and remission compared with controls. We observed that increased methylation of the MERTK gene was significantly associated with the presence of DR15. DISCUSSION: DR15 and MERTK genotype independently influence proportions of CD14+ MERTK+ monocytes in MS. We confirmed previous observations that the MERTK risk SNP rs7422195 is associated with altered MERTK expression in monocytes. We identified that expression of MERTK is stratified by disease in people homozygous for the major G allele of rs7422195. The finding that the proportion of CD14+ MERTK+ monocytes is reduced in DR15-positive individuals supports prior data identifying genetic links between these 2 loci in influencing MS risk. DR15 genotype-dependent alterations in methylation of the MERTK gene provides a molecular link between these loci and identifies a potential mechanism by which MERTK expression is influenced by DR15. This links DR15 haplotype to MS susceptibility beyond direct influence on antigen presentation and suggests the need for HLA-based stratification of approaches to MERTK as a therapeutic target.

Rates of John Cunningham virus seroconversion greatly reduced in natalizumab-treated patients during COVID-19-related lockdowns.

BACKGROUND AND PURPOSE: This study was undertaken to retrospectively compare rates of John Cunningham virus (JCV) seroconversion in natalizumab-treated patients before and during COVID-19-related community restrictions. Natalizumab is highly effective therapy for relapsing-remitting multiple sclerosis. Prolonged exposure to natalizumab in JCV-positive patients can cause progressive multifocal leukoencephalopathy, a potentially fatal brain infection. Serial assessment of JCV status is required for patients receiving natalizumab. METHODS: Patients receiving natalizumab at the Royal Melbourne Hospital were assessed for change in JCV serostatus and duration of exposure to natalizumab in two discrete time periods: from 1 February 2012 until 1 February 2017 ("pre-COVID"; n = 128) and from 1 April 2020 until 12 October 2022 ("COVID"; n = 214). A Poisson regression model adjusted for age at natalizumab commencement and sex was used to model seroconversion rate between the two time periods. RESULTS: The pre-COVID JCV seroconversion rate among natalizumab-treated patients at the Royal Melbourne Hospital was 9.08%. Conversely, we found a precipitous decline in JCV seroconversion during COVID lockdown. Annualized seroconversion during COVID-19-related restrictions was 2.01%. The annualized seroconversion rate was 4.7 times higher during the pre-COVID-19 period (95% confidence interval = 2.96-7.45, p < 0.0001) compared to the annualized seroconversion rate during COVID lockdown. Males had a 2× higher rate of seroconversion compared to females. CONCLUSIONS: JCV seroconversion among natalizumab-treated patients was markedly lower during COVID-19-related community restrictions. Restrictions observed in Melbourne were among the longest and most comprehensive implemented worldwide. This suggests the presence of modifiable risk factors that could lower rates of JCV seroconversion among natalizumab-treated patients.

Predicting Infection Risk in Multiple Sclerosis Patients Treated with Ocrelizumab: A Retrospective Cohort Study.

BACKGROUND: Ocrelizumab safety outcomes have been well evaluated in clinical trials and open-label extension (OLE) studies. However, risk factors for infection in patients with multiple sclerosis (MS) receiving ocrelizumab have not been extensively studied in the real-world setting. OBJECTIVE: The aim of this study was to examine factors determining risk of self-reported infections and antimicrobial use in patients receiving ocrelizumab for MS. METHODS: A retrospective, observational cohort study was conducted in patients receiving ocrelizumab at the Royal Melbourne Hospital. Infection type and number were reported by patients, and the associations of potential clinical and laboratory risk factors with self-reported infection and antimicrobial use were estimated using univariate and multivariable logistic regression models. RESULTS: A total of 185 patients were included in the study; a total of 176 infections were reported in 89 patients (46.1%), and antimicrobial use was identified in 47 patients (25.3%). In univariate analyses, a higher serum IgA was associated with reduced odds of infection (OR 0.44, 95% CI 0.25-0.76). In multivariable analyses, older age (OR 0.94, 95% CI 0.88-0.99), higher serum IgA (OR 0.37, 95% CI 0.17-0.80) and higher serum IgG (OR 0.81, 95% CI 0.67-0.99) were associated with reduced odds of infection. Older age (OR 0.85, 95% CI 0.75-0.96) and higher serum IgA (OR 0.23, 95% CI 0.07-0.79) were associated with reduced odds of antimicrobial use, whilst longer MS disease duration (OR 1.22, 95% CI 1.06-1.41) and higher Expanded Disability Status Scale (EDSS) score (OR 1.99, 95% CI 1.02-3.86) were associated with increased odds of antimicrobial use. CONCLUSIONS: Higher serum IgA and IgG and older age were associated with reduced odds of infection. Our findings highlight that infection risk is not uniform in patients with MS receiving ocrelizumab and substantiate the need to monitor immunoglobulin levels pre-treatment and whilst on therapy.

Evaluating the perspective of patients with MS and related conditions on their DMT in relation to the COVID-19 pandemic in one MS centre in Australia.

OBJECTIVE: Patients with Multiple Sclerosis (MS) and on disease modifying therapies (DMTs) that can be immunosuppressive or immunomodulatory form a special group where risk of continuation of DMT needs to be taken into account with risk of contracting Covid-19. This concept can pose a degree of anxiety for patients as well as neurologists. We aimed to evaluate patient perspectives regarding the use of Natalizumab and anti-CD20 therapies (Rituximab and Ocrelizumab) in the context of the COVID-19 pandemic. METHODS: cross-sectional study conducted via voluntary survey filled in by patients with MS and related disorders receiving their infusional treatment in one MS centre in Australia, exploring their concerns regarding their therapy, their therapy and COVID-19, precautions undertaken in response to the pandemic, and factors impacting their decision-making. RESULTS: 170 patients completed the survey. Of patients on Natalizumab, the majority had either no or mild concern regarding their DMT and COVID-19, and of patients on B-cell depleting therapies, again, the majority had no or mild concern, though a slightly higher proportion had a moderate level of concern. Asked to delineate their concerns, an increased risk of contracting COVID-19 was more commonly conveyed than MS-specific factors or poor outcomes pertaining to COVID-19 if contracted, by patients in both groups. Conversely, being invited to specifically consider the possibility of contracting COVID-19 or experience a relapse of MS, almost half of the cohort rated both of equal of concern. More than half of the cohort were self-isolating more stringently than general government advice and government-related resources followed by information provided by patient's neurologist where the commonest means of information to guide decision making. CONCLUSIONS: Whilst a large proportion of patients had some concern regarding the impact of their DMT on COVID-19, whether on their risk of contracting COVID-19 or a theoretical risk for more severe disease, the overall level of concern in most cases was at most mild. Patients on B-cell depleting therapies were more inclined to express a higher level of concern. A similar concern was ascribed to a risk of a relapse or worsening MS symptoms compared to the risk of contracting COVID-19. Such attitudes may underscore a willingness of patients to continue their DMT where benefits outweigh risks during future phases of the COVID-19 pandemic.

Spatially explicit network analysis reveals multi-species annual cycle movement patterns of sea ducks.

Conservation of long-distance migratory species poses unique challenges. Migratory connectivity, that is, the extent to which groupings of individuals at breeding sites are maintained in wintering areas, is frequently used to evaluate population structure and assess use of key habitat areas. However, for species with complex or variable annual cycle movements, this traditional bimodal framework of migratory connectivity may be overly simplistic. Like many other waterfowl, sea ducks often travel to specific pre- and post-breeding sites outside their nesting and wintering areas to prepare for migration by feeding extensively and, in some cases, molting their flight feathers. These additional migrations may play a key role in population structure, but are not included in traditional models of migratory connectivity. Network analysis, which applies graph theory to assess linkages between discrete locations or entities, offers a powerful tool for quantitatively assessing the contributions of different sites used throughout the annual cycle to complex spatial networks. We collected satellite telemetry data on annual cycle movements of 672 individual sea ducks of five species from throughout eastern North America and the Great Lakes. From these data, we constructed a multi-species network model of migratory patterns and site use over the course of breeding, molting, wintering, and migratory staging. Our results highlight inter- and intra-specific differences in the patterns and complexity of annual cycle movement patterns, including the central importance of staging and molting sites in James Bay, the St. Lawrence River, and southern New England to multi-species annual cycle habitat linkages, and highlight the value of Long-tailed Ducks (Calengula haemalis) as an umbrella species to represent the movement patterns of multiple sea duck species. We also discuss potential applications of network migration models to conservation prioritization, identification of population units, and integrating different data streams.

Artelle et al. (2018) miss the science underlying North American wildlife management.

Artelle et al. (2018) conclude that "hallmarks of science" are largely missing from North American wildlife management based on a desk review of selected hunting management plans and related documents found through Internet searches and email requests to state and provincial wildlife agencies. We highlight three fundamental problems that compromise the validity of the conclusions posited: missing information to support selection of "hallmarks of science," confusion about the roles and nature of science and management, and failure to engage effectively with the scientists and managers actively managing wildlife populations in North America.

Experimental Infection of Common Eider Ducklings with Wellfleet Bay Virus, a Newly Characterized Orthomyxovirus.

Wellfleet Bay virus (WFBV), a novel orthomyxovirus in the genus Quaranjavirus, was first isolated in 2006 from carcasses of common eider (Somateria mollissima) during a mortality event in Wellfleet Bay (Barnstable County, Massachusetts, USA) and has since been repeatedly isolated during recurrent mortality events in this location. Hepatic, pancreatic, splenic, and intestinal necrosis was observed in dead eiders. We inoculated 6-week-old common eider ducklings with WFBV in an attempt to recreate the naturally occurring disease. Approximately 25% of inoculated eiders had onset of clinical disease and required euthanasia; an additional 18.75% were adversely affected based on net weight loss during the trial. Control ducklings did not become infected and did not have clinical disease. Infected ducklings with clinical disease had pathologic lesions consistent with those observed during natural mortality events. WFBV was reisolated from 37.5% of the inoculated ducklings. Ducklings surviving to 5 days postinoculation developed serum antibody titers to WFBV.

An Optically Modulated Self-Assembled Resonance Energy Transfer Pass Gate.

We demonstrate an optically controlled molecular-scale pass gate that uses the photoinduced dark states of fluorescent molecules to modulate the flow of excitons. The device consists of four fluorophores spatially arranged on a self-assembled DNA nanostructure. Together, they form a resonance energy transfer (RET) network resembling a standard transistor with a source, channel, drain, and gate. When the gate fluorophore is directly excited, the device is toggled on. Excitons flow freely from the source to the drain, producing strong output fluorescence. Without this excitation, exciton flow through the device is hindered by absorbing paths along the way, resulting in weak output fluorescence. In this Letter, we describe the design and fabrication of the pass gate. We perform a steady-state analysis revealing that the on/off fluorescence ratio for this particular implementation is ∼8.7. To demonstrate dynamic modulation of the pass gate, we toggle the gate excitation on and off and measure the corresponding change in output fluorescence. We characterize the rise and fall times of these transitions, showing that they are faster and/or more easily achieved than other methods of RET network modulation. The pass gate is the first dynamic RET-based logic gate exclusively modulated by dark states and serves as a proof-of-concept device for building more complex RET systems in the future.

Evaluation of harvest and information needs for North American sea ducks.

Wildlife managers routinely seek to establish sustainable limits of sport harvest or other regulated forms of take while confronted with considerable uncertainty. A growing body of ecological research focuses on methods to describe and account for uncertainty in management decision-making and to prioritize research and monitoring investments to reduce the most influential uncertainties. We used simulation methods incorporating measures of demographic uncertainty to evaluate risk of overharvest and prioritize information needs for North American sea ducks (Tribe Mergini). Sea ducks are popular game birds in North America, yet they are poorly monitored and their population dynamics are poorly understood relative to other North American waterfowl. There have been few attempts to assess the sustainability of harvest of North American sea ducks, and no formal harvest strategy exists in the U.S. or Canada to guide management. The popularity of sea duck hunting, extended hunting opportunity for some populations (i.e., special seasons and/or bag limits), and population declines have led to concern about potential overharvest. We used Monte Carlo simulation to contrast estimates of allowable harvest and observed harvest and assess risk of overharvest for 7 populations of North American sea ducks: the American subspecies of common eider (Somateria mollissima dresseri), eastern and western populations of black scoter (Melanitta americana) and surf scoter (M. perspicillata), and continental populations of white-winged scoter (M. fusca) and long-tailed duck (Clangula hyemalis). We combined information from empirical studies and the opinions of experts through formal elicitation to create probability distributions reflecting uncertainty in the individual demographic parameters used in this assessment. Estimates of maximum growth (rmax), and therefore of allowable harvest, were highly uncertain for all populations. Long-tailed duck and American common eider appeared to be at high risk of overharvest (i.e., observed harvest < allowable harvest in 5-7% and 19-26% of simulations, respectively depending on the functional form of density dependence), whereas the other populations appeared to be at moderate risk to low risk (observed harvest < allowable harvest in 22-68% of simulations, again conditional on the form of density dependence). We also evaluated the sensitivity of the difference between allowable and observed harvest estimates to uncertainty in individual demographic parameters to prioritize information needs. We found that uncertainty in overall fecundity had more influence on comparisons of allowable and observed harvest than adult survival or observed harvest for all species except long-tailed duck. Although adult survival was characterized by less uncertainty than individual components of fecundity, it was identified as a high priority information need given the sensitivity of growth rate and allowable harvest to this parameter. Uncertainty about population size was influential in the comparison of observed and allowable harvest for 5 of the 6 populations where it factored into the assessment. While this assessment highlights a high degree of uncertainty in allowable harvest, it provides a framework for integration of improved data from future research and monitoring. It could also serve as the basis for harvest strategy development as management objectives and regulatory alternatives are specified by the management community.

PREVALENCE AND DISTRIBUTION OF WELLFLEET BAY VIRUS EXPOSURE IN THE COMMON EIDER (SOMATERIA MOLLISSIMA).

Between 1998 and 2014, recurrent mortality events were reported in the Dresser's subspecies of the Common Eider ( Somateria mollissima dresseri) on Cape Cod, Massachusetts, US near Wellfleet Harbor. The early die-offs were attributed to parasitism and emaciation, but beginning in 2006 a suite of distinct lesions was observed concomitant with the isolation of a previously unknown RNA virus. This novel pathogen was identified as an orthomyxovirus in the genus Quaranjavirus and was named Wellfleet Bay virus (WFBV). To assess evidence of exposure to this virus in Common Eiders, we conducted a longitudinal study of the prevalence of WFBV antibodies at multiple locations from 2004-14; we collected 2,258 serum samples from six locations and analyzed each using a microneutralization assay. Results corroborate the emergence of WFBV in 2006 based on the first detection of antibodies in that year. Significantly higher prevalence was detected in Common Eiders sampled in Massachusetts compared to those in Maine, Nova Scotia, and Québec. For birds breeding and wintering in Massachusetss, viral exposure varied by age, sex, and season of sampling, and prevalence by season and sex were highly interrelated with greater numbers of antibody-positive males in the autumn and females in the spring. No evidence of viral exposure was detected in the Northern subspecies ( Somateria mollissima borealis). Among the locations sampled, Massachusetts appears to be the epicenter of Common Eider exposure to WFBV. Further research is warranted to understand the factors controlling the epidemiology of WFBV in Massachussetts, including those that may be limiting geographic expansion of this virus.

Fluorescent taggants with temporally coded signatures.

In this paper, resonance energy transfer (RET) networks between chromophores are used to implement fluorescent taggants with temporally coded signatures. Because the temporal signature of such a fluorescent taggant is a phase-type distribution defined by the geometry of its RET network, the taggant design is not constrained by resolvable dyes and has a significantly larger coding capacity than spectrally or lifetime coded fluorescent taggants. Meanwhile, the detection process becomes highly efficient when the signatures are coded in the time domain. The taggant identification method is based on the multinomial distribution of detected photons and Maximum Likelihood Estimation, which guarantees high accuracy even with only a few hundred photons and also applies to a mixture of taggants in multiplex detection. Therefore, these temporally coded fluorescent taggants have great potential for both in situ and Lidar applications.

Self-Assembled Resonance Energy Transfer Keys for Secure Communication over Classical Channels.

Modern authentication and communication protocols increasingly use physical keys in lieu of conventional software-based keys for security. This shift is primarily driven by the ability to derive a unique, unforgeable signature from a physical key. The sole demonstration of an unforgeable key, thus far, has been through quantum key distribution, which suffers from limited communication distances and expensive infrastructure requirements. Here, we show a method for creating unclonable keys by molecular self-assembly of resonance energy transfer (RET) devices. It is infeasible to clone the RET-key due to the inability to characterize the key using current technology, the large number of input-output combinations per key, and the variation of the key's response with time. However, the manufacturer can produce multiple identical devices, which enables inexpensive, secure authentication and communication over classical channels, and thus any distance. Through a detailed experimental survey of the nanoscale keys, we demonstrate that legitimate users are successfully authenticated 99.48% of the time and the false-positives are only 0.39%, over two attempts. We estimate that a legitimate user would have a computational advantage of more than 10(340) years over an attacker. Our method enables the discovery of physical key based multiparty authentication and communication schemes that are both practical and possess unprecedented security.

An enzymatically-sensitized sequential and concentric energy transfer relay self-assembled around semiconductor quantum dots.

The ability to control light energy within de novo nanoscale structures and devices will greatly benefit their continuing development and ultimate application. Ideally, this control should extend from generating the light itself to its spatial propagation within the device along with providing defined emission wavelength(s), all in a stand-alone modality. Here we design and characterize macromolecular nanoassemblies consisting of semiconductor quantum dots (QDs), several differentially dye-labeled peptides and the enzyme luciferase which cumulatively demonstrate many of these capabilities by engaging in multiple-sequential energy transfer steps. To create these structures, recombinantly-expressed luciferase and the dye-labeled peptides were appended with a terminal polyhistidine sequence allowing for controlled ratiometric self-assembly around the QDs via metal-affinity coordination. The QDs serve to provide multiple roles in these structures including as central assembly platforms or nanoscaffolds along with acting as a potent energy harvesting and transfer relay. The devices are activated by addition of coelenterazine H substrate which is oxidized by luciferase producing light energy which sensitizes the central 625 nm emitting QD acceptor by bioluminescence resonance energy transfer (BRET). The sensitized QD, in turn, acts as a relay and transfers the energy to a first peptide-labeled Alexa Fluor 647 acceptor dye displayed on its surface. This dye then transfers energy to a second red-shifted peptide-labeled dye acceptor on the QD surface through a second concentric Förster resonance energy transfer (FRET) process. Alexa Fluor 700 and Cy5.5 are both tested in the role of this terminal FRET acceptor. Photophysical analysis of spectral profiles from the resulting sequential BRET-FRET-FRET processes allow us to estimate the efficiency of each of the transfer steps. Importantly, the efficiency of each step within this energy transfer cascade can be controlled to some extent by the number of enzymes/peptides displayed on the QD. Further optimization of the energy transfer process(es) along with potential applications of such devices are finally discussed.

Cyclic avian mass mortality in the northeastern United States is associated with a novel orthomyxovirus.

UNLABELLED: Since 1998, cyclic mortality events in common eiders (Somateria mollissima), numbering in the hundreds to thousands of dead birds, have been documented along the coast of Cape Cod, MA, USA. Although longitudinal disease investigations have uncovered potential contributing factors responsible for these outbreaks, detecting a primary etiological agent has proven enigmatic. Here, we identify a novel orthomyxovirus, tentatively named Wellfleet Bay virus (WFBV), as a potential causative agent of these outbreaks. Genomic analysis of WFBV revealed that it is most closely related to members of the Quaranjavirus genus within the family Orthomyxoviridae. Similar to other members of the genus, WFBV contains an alphabaculovirus gp64-like glycoprotein that was demonstrated to have fusion activity; this also tentatively suggests that ticks (and/or insects) may vector the virus in nature. However, in addition to the six RNA segments encoding the prototypical structural proteins identified in other quaranjaviruses, a previously unknown RNA segment (segment 7) encoding a novel protein designated VP7 was discovered in WFBV. Although WFBV shows low to moderate levels of sequence similarity to Quaranfil virus and Johnston Atoll virus, the original members of the Quaranjavirus genus, additional antigenic and genetic analyses demonstrated that it is closely related to the recently identified Cygnet River virus (CyRV) from South Australia, suggesting that WFBV and CyRV may be geographic variants of the same virus. Although the identification of WFBV in part may resolve the enigma of these mass mortality events, the details of the ecology and epidemiology of the virus remain to be determined. IMPORTANCE: The emergence or reemergence of viral pathogens resulting in large-scale outbreaks of disease in humans and/or animals is one of the most important challenges facing biomedicine. For example, understanding how orthomyxoviruses such as novel influenza A virus reassortants and/or mutants emerge to cause epidemic or pandemic disease is at the forefront of current global health concerns. Here, we describe the emergence of a novel orthomyxovirus, Wellfleet Bay virus (WFBV), which has been associated with cyclic large-scale bird die-offs in the northeastern United States. This initial characterization study provides a foundation for further research into the evolution, epidemiology, and ecology of newly emerging orthomyxoviruses, such as WFBV, and their potential impacts on animal and/or human health.

DNA-enabled integrated molecular systems for computation and sensing.

CONSPECTUS: Nucleic acids have become powerful building blocks for creating supramolecular nanostructures with a variety of new and interesting behaviors. The predictable and guided folding of DNA, inspired by nature, allows designs to manipulate molecular-scale processes unlike any other material system. Thus, DNA can be co-opted for engineered and purposeful ends. This Account details a small portion of what can be engineered using DNA within the context of computer architectures and systems. Over a decade of work at the intersection of DNA nanotechnology and computer system design has shown several key elements and properties of how to harness the massive parallelism created by DNA self-assembly. This work is presented, naturally, from the bottom-up beginning with early work on strand sequence design for deterministic, finite DNA nanostructure synthesis. The key features of DNA nanostructures are explored, including how the use of small DNA motifs assembled in a hierarchical manner enables full-addressability of the final nanostructure, an important property for building dense and complicated systems. A full computer system also requires devices that are compatible with DNA self-assembly and cooperate at a higher level as circuits patterned over many, many replicated units. Described here is some work in this area investigating nanowire and nanoparticle devices, as well as chromophore-based circuits called resonance energy transfer (RET) logic. The former is an example of a new way to bring traditional silicon transistor technology to the nanoscale, which is increasingly problematic with current fabrication methods. RET logic, on the other hand, introduces a framework for optical computing at the molecular level. This Account also highlights several architectural system studies that demonstrate that even with low-level devices that are inferior to their silicon counterparts and a substrate that harbors abundant defects, self-assembled systems can still outperform conventional systems. Further, the domain, that is, the physical environment, in which such self-assembled computers can operate transcends the usual limitations of silicon machines and opens up new and exciting horizons for their application. This Account also includes a look at simulation tools developed to streamline the design process at the strand, device, circuit, and architectural levels. These tools are essential for understanding how to best manipulate the devices into systems that explore the fundamentally new computing domains enabled by DNA nanotechnology.

Thousand-fold increase in optical storage density by polychromatic address multiplexing on self-assembled DNA nanostructures.

A super-resolution optical storage technique enabled by DNA nanotechnology and the design of resonance energy transfer (RET) networks are demonstrated. The enhancement in storage density stems from non-linear interactions between excitons on the nanostructured RET circuits, which permit large-scale multiplexing with a small set of addressing wavelengths and a single output channel.

Encoded multichromophore response for simultaneous label-free detection.

The self-assembly of molecularly precise nanostructures is widely expected to form the basis of future high-speed integrated circuits, but the technologies suitable for such circuits are not well understood. In this work, DNA self-assembly is used to create molecular logic circuits that can selectively identify specific biomolecules in solution by encoding the optical response of near-field coupled arrangements of chromophores. The resulting circuits can detect label-free, femtomole quantities of multiple proteins, DNA oligomers, and small fragments of RNA in solution via ensemble optical measurements. This method, which is capable of creating multiple logic-gate-sensor pairs on a 2 x 80 x 80-nm DNA grid, is a step toward more sophisticated nanoscale logic circuits capable of interfacing computers with biological processes.

Selective functionalization of arbitrary nanowires.

We report the selective functionalization of uniform and heterostructured nanowires with self-assembled monolayers (SAMs) of (3-mercaptopropyl)trimethoxysilane (MPTMS). The wires were grown electrochemically in anodic aluminum oxide (AAO) templates. Selective deposition and removal of SAMs during nanowire growth permits the decoration of specific regions of the surface along the length of the nanowires. This technique presents a facile method for the tailored functionalization of nanowires, but does not rely on the intrinsic chemical properties of the nanowires as previous methods have.