HDQLIFE: development and assessment of health-related quality of life in Huntington disease (HD).

PURPOSE: Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content. METHODS: New item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD. RESULTS: Moderate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose. CONCLUSIONS: HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.

New measures to capture end of life concerns in Huntington disease: Meaning and Purpose and Concern with Death and Dying from HDQLIFE (a patient-reported outcomes measurement system).

PURPOSE: Huntington disease (HD) is an incurable terminal disease. Thus, end of life (EOL) concerns are common in these individuals. A quantitative measure of EOL concerns in HD would enable a better understanding of how these concerns impact health-related quality of life. Therefore, we developed new measures of EOL for use in HD. METHODS: An EOL item pool of 45 items was field tested in 507 individuals with prodromal or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to establish unidimensional item pools. Item response theory (IRT) and differential item functioning analyses were applied to the identified unidimensional item pools to select the final items. RESULTS: EFA and CFA supported two separate unidimensional sets of items: Concern with Death and Dying (16 items), and Meaning and Purpose (14 items). IRT and DIF supported the retention of 12 Concern with Death and Dying items and 4 Meaning and Purpose items. IRT data supported the development of both a computer adaptive test (CAT) and a 6-item, static short form for Concern with Death and Dying. CONCLUSION: The HDQLIFE Concern with Death and Dying CAT and corresponding 6-item short form, and the 4-item calibrated HDQLIFE Meaning and Purpose scale demonstrate excellent psychometric properties. These new measures have the potential to provide clinically meaningful information about end-of-life preferences and concerns to clinicians and researchers working with individuals with HD. In addition, these measures may also be relevant and useful for other terminal conditions.

The development of a new computer adaptive test to evaluate chorea in Huntington disease: HDQLIFE Chorea.

PURPOSE: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease associated with motor, behavioral, and cognitive deficits. The hallmark symptom of HD, chorea, is often the focus of HD clinical trials. Unfortunately, there are no self-reported measures of chorea. To address this shortcoming, we developed a new measure of chorea for use in HD, HDQLIFE Chorea. METHODS: Qualitative data and literature reviews were conducted to develop an initial item pool of 141 chorea items. An iterative process, including cognitive interviews, expert review, translatability review, and literacy review, was used to refine this item pool to 64 items. These 64 items were field tested in 507 individuals with prodromal and/or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to identify a unidimensional set of items. Then, an item response theory graded response model (GRM) and differential item functioning analyses were conducted to select the final items for inclusion in this measure. RESULTS: EFA and CFA supported the retention of 34 chorea items. GRM and DIF supported the retention of all of these items in the final measure. GRM calibration data were used to inform the selection of a 6-item, static short form and to program the HDQLIFE Chorea computer adaptive test (CAT). CAT simulation analyses indicated a 0.99 correlation between the CAT scores and the full item bank. CONCLUSIONS: The new HDQLIFE Chorea CAT and corresponding 6-item short form were developed using established rigorous measurement development standards; this is the first self-reported measure developed to evaluate the impact of chorea on HRQOL in HD. This development work indicates that these measures have strong psychometric properties; future work is needed to establish test-retest reliability and responsiveness to change.

HDQLIFE: the development of two new computer adaptive tests for use in Huntington disease, Speech Difficulties, and Swallowing Difficulties.

PURPOSE: Huntington disease (HD) is an autosomal dominant neurodegenerative disease which results in several progressive symptoms, including bulbar dysfunction (i.e., speech and swallowing difficulties). Although difficulties in speech and swallowing in HD have a negative impact on health-related quality of life, no patient-reported outcome measure exists to capture these difficulties that are specific to HD. Thus, we developed a new patient-reported outcome measure for use in the Huntington Disease Health-Related Quality of Life (HDQLIFE) Measurement System that focused on the impact that difficulties with speech and swallowing have on HRQOL in HD. METHODS: Five hundred and seven individuals with prodromal and/or manifest HD completed 47 newly developed items examining speech and swallowing difficulties. Unidimensional item pools were identified using exploratory factor analysis and confirmatory factor analysis (EFA and CFA, respectively). Item response theory (IRT) was used to calibrate the final measures. RESULTS: EFA and CFA identified two separate unidimensional sets of items: Speech Difficulties (27 items) and Swallowing Difficulties (16 items). Items were calibrated separately for these two measures and resulted in item banks that can be administered as computer adaptive tests (CATs) and/or 6-item, static short forms. Reliability of both of these measures was supported through high correlations between the simulated CAT scores and the full item bank. CONCLUSIONS: CATs and 6-item calibrated short forms were developed for HDQLIFE Speech Difficulties and HDQLIFE Swallowing Difficulties. These measures both demonstrate excellent psychometric properties and may have clinical utility in other populations where speech and swallowing difficulties are prevalent.

Role of fatty acid transport protein 4 in oleic acid-induced glucagon-like peptide-1 secretion from murine intestinal L cells.

The antidiabetic intestinal L cell hormone glucagon-like peptide-1 (GLP-1) enhances glucose-dependent insulin secretion and inhibits gastric emptying. GLP-1 secretion is stimulated by luminal oleic acid (OA), which crosses the cell membrane by an unknown mechanism. We hypothesized that L cell fatty acid transport proteins (FATPs) are essential for OA-induced GLP-1 release. Therefore, the murine GLUTag L cell model was used for immunoblotting, [(3)H]OA uptake assay, and GLP-1 secretion assay as determined by radioimmunoassay following treatment with OA ± phloretin, sulfo-N-succinimidyl oleate, or siRNA against FATP4. FATP4(-/-) and cluster-of-differentiation 36 (CD36)(-/-) mice received intraileal OA, and plasma GLP-1 was measured by sandwich immunoassay. GLUTag cells were found to express CD36, FATP1, FATP3, and FATP4. The cells demonstrated specific (3)H[OA] uptake that was dose-dependently inhibited by 500 and 1,000 µM unlabeled OA (P < 0.001). Cell viability was not altered by treatment with OA. Phloretin and sulfo-N-succinimidyl oleate, inhibitors of protein-mediated transport and CD36, respectively, also decreased [(3)H]OA uptake, as did knockdown of FATP4 by siRNA transfection (P < 0.05-0.001). OA dose-dependently increased GLP-1 secretion at 500 and 1,000 µM (P < 0.001), whereas phloretin, sulfo-N-succinimidyl oleate, and FATP4 knockdown decreased this response (P < 0.05-0.01). FATP4(-/-) mice displayed lower plasma GLP-1 at 60 min in response to intraileal OA (P < 0.05), whereas, unexpectedly, CD36(-/-) mice displayed higher basal GLP-1 levels (P < 0.01) but a normal response to intraileal OA. Together, these findings demonstrate a key role for FATP4 in OA-induced GLP-1 secretion from the murine L cell in vitro and in vivo, whereas the precise role of CD36 remains unclear.

Dietary conjugated linoleic acid induces lipolysis in adipose tissue of coconut oil-fed mice but not soy oil-fed mice.

Mice fed diets containing conjugated linoleic acid (CLA) are leaner than mice not fed CLA. This anti-obesity effect is amplified in mice fed coconut oil-containing or fat free diets, compared to soy oil diets. The present objective was to determine if CLA alters lipolysis in mice fed different base oils. Mice were fed diets containing soy oil (SO), coconut oil (CO), or fat free (FF) for 6 weeks, followed by 10 or 12 days of CLA or no CLA supplementation. Body fat, tissue weights, and ex vivo lipolysis were determined. Relative protein abundance and activation of perilipin, hormone sensitive lipase (HSL), adipose triglyceride lipase (ATGL), and adipose differentiation related protein (ADRP) were determined by western blotting. CLA feeding caused mice to have less (P < 0.05) body fat than non-CLA fed mice. This was enhanced in CO and FF-fed mice (CLA × oil source, P < 0.05). There was also a CLA × oil source interaction on lipolysis as CO + CLA and FF + CLA-fed mice had increased (P < 0.05) rates of lipolysis but SO + CLA-fed mice did not. However, after 12 days of CLA consumption, activated perilipin was increased (P < 0.05) only in SO + CLA-fed mice and total HSL and ATGL were decreased (P < 0.05) in CO + CLA-fed mice. Therefore, the enhanced CLA-induced body fat loss in CO and FF-fed mice appears to involve increased lipolysis but this effect may be decreasing by 12 days of CLA consumption.

Short communication: Detection of yeast DNA in omasal digesta of dairy cows consuming dried distillers grains and solubles.

Purine analysis is widely used to estimate microbial crude protein (MCP) flow, and the method assumes that all purines contained in feed are degraded in the rumen and that purines detected are of microbial origin. The objectives of our experiment were (1) to determine if DNA from yeast (Saccharomyces cerevisiae) contained in dried distillers grains and solubles (DDGS) escapes degradation in the rumen and (2) to estimate the proportion of yeast DNA compared with total bacterial DNA in omasal samples. Two ruminally fistulated Holstein dairy cows averaging 649 kg (SD = 42.0) and 126 d in milk (SD = 28.9) were fed in a crossover design during 2 periods of 21 d each. Treatments were (1) control, a total mixed ration (TMR) not containing DDGS and (2) a DDGS-based diet, a TMR in which DDGS were included at 30% of diet dry matter (DM). On d 20 and 21 at 0400 and 1600 h, omasal digesta samples were collected via a ruminal cannula, and DNA was extracted from each sample in duplicate. The DNA samples were subjected to a real-time PCR assay to detect the presence of DNA from yeast. Forward and reverse primers and a probe were designed to target a DNA segment contained on the second chromosome of Saccharomyces cerevisiae. Real-time PCR amplification curves indicated the presence of yeast DNA in samples from both treatments. Specifically, the estimate of relative abundance of yeast DNA from digesta samples collected from animals consuming the diet containing DDGS was 9.46 ± 0.67/g of DM and was significantly higher than that from animals consuming no DDGS, which was observed to be 0.091 ± 0.67/g of DM. Omasal samples were also analyzed for total bacterial DNA. Primers and a probe were designed from DNA encoding part of the 16S rRNA. When the DDGS-based diet was fed, the relative abundance of total bacterial DNA tended to increase from 610 to 626±3.82/g of DM. Results suggest that yeast DNA is detected in the omasum and this is increased when cows consume DDGS but it does not represent a significant proportion of total microbial DNA in the omasal digesta samples.

Optical transmission through double-layer, laterally shifted metallic subwavelength hole arrays.

We measure the transmission of IR radiation through double-layer metal films with periodic arrays of subwavelength holes. When the two metal films are placed in sufficiently close proximity, two types of transmission resonances emerge. For the surface plasmon mode, the electromagnetic field is concentrated on the outer surface of the entire metallic layer stack. In contrast, for the guided mode, the field is confined to the gap between the two metal layers. Our measurements indicate that, as the two layers are laterally shifted from perfect alignment, the peak transmission frequency of the guided mode decreases significantly, while that of the surface plasmon mode remains largely unchanged, in agreement with numerical calculations.

Nanopores in solid-state membranes engineered for single molecule detection.

A nanopore is an analytical tool with single molecule sensitivity. For detection, a nanopore relies on the electrical signal that develops when a molecule translocates through it. However, the detection sensitivity can be adversely affected by noise and the frequency response. Here, we report measurements of the frequency and noise performance of nanopores

Differences in mitochondrial efficiency between lines of mice divergently selected for heat loss.

Divergent selection for heat loss was applied to lines of mice for 15 generations (G) in 3 replicates. Selection resumed at G42 and continued through G51 across all replicates. At the end of G51, differences in heat loss and feed intake per unit of BW were approximately 56 and 34%, respectively, between high heat loss (MH) and low heat loss (ML) lines, as a percentage of the control line (MC) mean. Rates of liver mitochondrial respiration states, degree of coupling, and mitochondrial efficiency were measured in G58 using a Clark-type oxygen electrode to investigate possible causes of underlying variation in maintenance requirements. Body composition, BW, liver weight, feed intake, and residual feed intake (RFI) were also measured or calculated. Results reported here represent data from 197 mature male mice from all replicates. There were no differences in BW (P = 0.91) between the selection lines. Selection had an effect on lean percentage (P = 0.02), with MH mice being leaner. Fat percentage differences between the selection lines tended toward significance (P = 0.13). Livers of MH mice were approximately 13% larger than livers of ML mice (P = 0.01). An effect of selection was observed (P < 0.01) in feed intake per unit BW, with MH mice consuming 29% more feed than ML mice in G58. Differences in state 2 and state 4 respiration rates were significant (P = 0.01), whereas state 3 rates approached significance (P = 0.06). Mitochondria of MH mice respired at a greater rate than mitochondria of ML mice in all states of respiration; ML mice had respiratory control ratios that were, on average, 8% greater than MH mice (P = 0.14). Although this difference only tended toward significance, we suspect a greater degree of coupling of mitochondrial processes exists in ML animals. Mice selected for reduced heat loss had ADP:oxygen ratios that were approximately 20% greater than MH mice (P = 0.03). Therefore, greater mitochondrial efficiency was expressed in the ML animals. Within a line-replicate, there was no correlation between ADP:O and feed intake per unit BW (P = 0.71). In addition, no correlation of ADP:O and RFI existed (P = 0.92). Although the selection lines differed in mitochondrial traits, including overall mitochondrial efficiency (ADP:oxygen), these differences were not a significant underlying cause of variation in feed intake per unit BW or in RFI estimates.

Role of resistin in insulin sensitivity in rodents and humans.

Resistin is a potential link between obesity and insulin resistance or type 2 diabetes. In rodents, resistin is primarily expressed in and secreted from mature adipocytes, with some expression in pancreatic islets and portions of the pituitary and hypothalamus. Its secretion can be up-regulated by several factors, including insulin and glucose. The exposure of rodents, or their cells, to resistin results in decreased response to insulin. This is likely in part due to an up-regulation of suppressor of cytokine signaling (SOCS)-3, which interferes with the activation of insulin receptor substrate (IRS)-1. However, in humans resistin is expressed primarily by macrophages and seems to be involved in the recruitment of other immune cells and the secretion of pro-inflammatory factors, including tumor necrosis factor (TNF)alpha. Human resistin may interfere with insulin signaling by stimulating the expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN), which dephosphorylates 3-phosphorylated phosphoinositide (PIP(3)). Resistin also seems to be involved in the development of atherosclerosis in humans by promoting the formation of foam cells and the proliferation and migration of vascular endothelial and smooth muscle cells. Many of the inflammatory related functions of human resistin appear to be regulated by activation of the nuclear factor (NF)kappaB transcription factor. The divergent roles of resistin in humans and rodents are evident by the data presented in this review but they will not be able to be fully understood until the resistin receptor is identified.

The neuroendocrine effects of the TASER X26: a brief report.

INTRODUCTION: Law enforcement officers use conducted electrical weapons (CEW) such as the TASER X26 to control violently resistive subjects. There are no studies in the medical literature examining the effects of these weapons on the human stress response. This is the first study to compare the human stress response to conducted electrical weapons, oleoresin capsicum (O.C.), a cold-water tank immersion, and a defensive tactics drill. METHODS: Subjects were randomized to one of the four interventions studied. Subjects received either a 5-s exposure from the TASER X26 CEW with the probes fired into the back from 7 ft, a 5-s spray of O.C., a skin and mucous membrane irritant, to the eyes, a 45-s exposure of the hand and forearm in a 0 degrees C cold water tank, or a 1-min defensive tactics drill. RESULTS: Alpha-amylase had the greatest increase from baseline at 10-15 min with the defensive tactics drill. Cortisol had the greatest increase at 15-20 min with O.C. Cortisol remained most elevated at 40-60 min in the defensive tactics drill group. CONCLUSIONS: Our preliminary data suggests that physical exertion during custodial arrest may be most activating of the human stress response, particularly the sympathetic-adrenal-medulla axis. This may suggest that techniques to limit the duration of this exertion may be the safest means to apprehend subjects, particularly those at high-risk for in-custody death. Conducted electrical weapons were not more activating of the human stress response than other uses of force.

Controlling the phase delay of light transmitted through double-layer metallic subwavelength slit arrays.

We demonstrate that the phase of light transmitted through double-layer subwavelength metallic slit arrays can be controlled through lateral shift of the two layers. Our samples consist of two aluminum layers, each of which contains an array of subwavelength slits. The two layers are placed in sufficient proximity to allow coupling of the evanescent fields at resonance. By changing the lateral shift between the layers from zero to half the period, the phase of the transmitted electromagnetic field is increased by pi, while the transmitted intensity remains high. Such a controllable phase delay could open new capabilities for nanophotonic devices that cannot be achieved with single-layer structures.

Small-Signal Performance and Modeling of sub-50nm nMOSFETs with f above 460-GHz.

We have fabricated and tested the performance of sub-50nm gate nMOSFETs to assess their suitability for mixed signal applications in the super high frequency (SHF) band, i.e. 3-30GHz. For a 30nm×40 µm×2 device, we found f(T) =465GHz at V(ds)=2V, V(g)=0.67V, which is the highest cut-off frequency reported for a MOSFET produced on bulk silicon substrate so far. However, our measurements of f(max) and noise figure indicate that parasitics impose limitations on SHF operation. We also present a high-frequency ac model appropriate to sub-50nm gate length nanotransistors, which incorporates the effects of the parasitics. The model accurately accounts for measurements of the S and Y parameters in the frequency range from 1 to 50GHz.

The clinician effect on "objective" technical components of the electrodiagnostic consultation.

OBJECTIVE: To examine the impact of clinician factors on technical data within an electrodiagnostic consultation for low-back pain and spinal stenosis. DESIGN: Examiner differences on single-segment paraspinal mapping scores and other findings were examined in a prospective, masked, double-controlled trial involving 150 people aged 55-80 yrs who were selected for no symptoms, back pain, or possible spinal stenosis. RESULTS: Unmasked clinicians were more variable than masked physicians (F2,219 = 4.808, P =or<0.01) and gave lower scores to people they felt had mechanical back pain. The percentage of inadequate segmental scores differed among clinicians (0-16.6%, F8,226 = 4.170, P < 0.001), with fellows having more difficulty than faculty (11.76 +/- 32.38% vs. 0.75 +/- 8.67%) (t233 = 3.753, P < 0.001). Correction of clinician bias improved the relationship between paraspinal score and subjects' ability to walk (weighted regression R = 0.129, B = -0.047, P < 0.001; unweighted regression R = 0.090, B = -0.045, P < 0.001). CONCLUSIONS: Objective testing is adversely affected by clinician factors including prejudgment, experience, and individual idiosyncrasies. Less variation is found in more codified procedures. For electrodiagnostic consultation, correction of variability improves the relationship of test results to disability.

Type I collagen glomerulopathy: postnatal collagen deposition follows glomerular maturation.

In chronic renal disease, the progressive accumulation of collagen and other extracellular matrix proteins in the mesangium results in fibrosis, glomerulosclerosis, and eventual renal failure. Mice deficient in proalpha2(I) collagen are not only a model of osteogenesis imperfecta but also accumulate fibrillar homotrimeric type I collagen in the mesangium. This accumulation spreads to the subendothelial space in the peripheral capillary loops. Picosirius red staining of kidney sections demonstrates that in comparison to wild-type mice, Col1a2-deficient homozygous and heterozygous mice exhibit abnormal glomerular collagen deposition in a gene dosage-dependent manner. The glomerulopathy initiates during the first postnatal week, appears progressive following the pattern of glomerular maturation and results in albuminuria in severely affected animals. In situ hybridization revealed no gross differences in steady-state proalpha1(I) and proalpha2(I) collagen mRNA levels among the three genotypes. Quantitative reverse transcriptase-polymerase chain reaction, however, using whole kidney sections showed a twofold increase in steady-state proalpha1(I) collagen mRNA in 1-month homozygous Col1a2-deficient animals compared with wild-type and heterozygous animals. We suggest that glomerular collagen deposition seen in the osteogenesis imperfecta model mice is, in part, owing to pretranslational mechanisms and may represent an over compensation of wound healing.

Choosing a mouse model to study the molecular pathobiology of Alport glomerulonephritis.

Alport syndrome, caused by mutations that interfere with the normal assembly of the alpha3alpha4alpha5(IV) collagen network in the glomerular basement membrane (GBM), is the most common inherited glomerular disease leading to renal failure. A detailed knowledge of the underlying pathogenic mechanisms is necessary for developing new, more specific, and effective therapeutic strategies aimed at delaying the onset and slowing disease progression. Studies of several dog and mouse models of Alport syndrome have significantly enhanced our understanding of the disease mechanisms and provided systems for testing potential therapies. In the most widely used Col4a3-/- mouse models of autosomal-recessive Alport syndrome (ARAS), the genetic background strongly affects renal survival. One contributing factor may be the strong ectopic deposition of alpha5alpha6(IV) collagen in the GBM of Col4a3-/- mice on the C57BL/6J background, which is almost undetectable on the 129/Sv background. This isoform 'switch' has not been observed in human ARAS, although it had been reported in the dog model of ARAS. In human patients as well as dog and mouse models of X-linked Alport syndrome, the alpha3-alpha6(IV) collagen chains are absent from the GBM. These biochemical differences among Alport animal models provide an opportunity to determine how the molecular makeup of the GBM affects the glomerular function. At the same time, potentially confounding influences of characteristics unique to a particular strain or model should be carefully considered in the design of studies aiming to define key events underlying the pathobiology of Alport glomerular disease.

The growth plate sparing effects of the selective glucocorticoid receptor modulator, AL-438.

Long-term use of glucocorticoids (GC) can cause growth retardation in children due to their actions on growth plate chondrocytes. AL-438, a non-steroidal anti-inflammatory agent that acts through the glucocorticoid receptor (GR) retains full anti-inflammatory efficacy but has reduced negative effects on osteoblasts compared to those elicited by prednisolone (Pred) or dexamethasone (Dex). We have used the murine chondrogenic ATDC5 cell line to compare the effects of AL-438 with those of Dex and Pred on chondrocyte dynamics. Dex and Pred caused a reduction in cell proliferation and proteoglycan synthesis, whereas exposure to AL-438 had no effect. LPS-induced IL-6 production in ATDC5 cells was reduced by Dex or AL-438, showing that AL-438 has similar anti-inflammatory efficacy to Dex in these cells. Fetal mouse metatarsals grown in the presence of Dex were shorter than control bones whereas AL-438 treated metatarsals paralleled control bone growth. These results indicate that the adverse effects Dex or Pred have on chondrocyte proliferation and bone growth were attenuated following AL-438 exposure, suggesting that AL-438 has a reduced side effect profile on chondrocytes compared to other GCs. This could prove important in the search for new anti-inflammatory treatments for children.

Optical transmission through double-layer metallic subwavelength slit arrays.

We present measurements of transmission of infrared radiation through double-layer metallic grating structures. Each metal layer contains an array of subwavelength slits and supports transmission resonance in the absence of the other layer. The two metal layers are fabricated in close proximity to allow coupling of the evanescent field on individual layers. The transmission of the double layer is found to be surprisingly large at particular wavelengths, even when no direct line of sight exists through the structure as a result of the lateral shifts between the two layers. We perform numerical simulations using rigorous coupled wave analysis to explain the strong dependence of the peak transmission on the lateral shift between the metal layers.

Beyond the Gene Chip.

We describe a prospective strategy for reading the encyclopedic information encoded in the genome: using a nanopore in a membrane formed from an MOS-capacitor to sense the charge in DNA. In principle, as DNA permeates the capacitor-membrane through the pore, the electrostatic charge distribution characteristic of the molecule should polarize the capacitor and induce a voltage on the electrodes that can be measured. Silicon nanofabrication and molecular dynamic simulations with atomic detail are technological linchpins in the development of this detector. The sub-nanometer precision available through silicon nanotechnology facilitates the fabrication of the detector, and molecular dynamics provides us with a means to design it and analyze the experimental outcomes.