What makes a good computer device?

Numerous development projects aimed at replacing the silicon technology that dominates computer logic with a faster alternative have been conducted throughout the past 25 years. None has succeeded. The alternatives are usually based on a device that switches very rapidly, and they neglect many other requirements of computer logic. In this article the essential physical factors that account for the success of transistors in digital applications are identified, as are the factors that are absent in proposed alternative devices.

Physical limits in semiconductor electronics.

Although the limitations of the methods of lithography in use at a particular time are easily recognized and attract substantial attention, experience shows that technological ingenuity keeps pushing them to ever-smaller dimensions. There seems to be no fundamental reason to expect that lithographic limits will not continue to recede. The limits to the advance of miniaturization are to be found in the ability of materials to withstand high electric fields and in the ability of packaging technology to remove heat from active components and provide for power distribution, signal interconnection, and flexible mechanical assembly.

Intracranial calcification after cord blood neonatal transplantation for krabbe disease.

Infantile-onset Krabbe disease results from a deficiency of the lysosomal enzyme galactocerebrosidase and leads to death from profound central and peripheral demyelination. Neonatal hematopoietic cell transplantation may result in near-normal cognitive development and partial rescue of gross motor development. The long-term course of the disorder for treated patients seems to involve slowly progressive neurological impairment. We describe the detailed 3-year outcomes of this experimental procedure using umbilical cord blood in a prenatally-diagnosed newborn with Krabbe disease. Substantial perivascular calcifications and atrophy of the white matter developed in the first year post-transplantation. Despite persistent neuroradiological and electrophysiological evidence of leukodystrophy, at age 3 years she has had only mildly impaired non-motor development and moderately impaired motor skills. The cause of these severe white matter changes may have been due to ongoing Krabbe disease or to effects of the chemotherapy regimen or to an interaction of these factors. Extended long-term follow-up of children neonatally transplanted for Krabbe disease is needed before the full utility and limitations of neonatal transplantation can be determined.

Enzymatic sequence-specific spin labeling of a DNA fragment containing the recognition sequence of EcoRI endonuclease.

Deoxyuridine analogs spin labeled in position 5 have been enzymatically incorporated sequence specifically into an oligodeoxyribonucleotide to form a spin-labeled 26-mer. The 26-mer contains the EcoRI-binding site and two labels which are located symmetrically close to the binding site. The labels are separated from one another far beyond the Heisenberg spin-exchange distance. The local base motion as determined by ESR spectroscopy is of the order of 4 ns in the oligonucleotide duplex. This is the same value as reported earlier for local T motions in polynucleotide duplexes, thereby providing direct experimental evidence that the ESR line shape of spin levels covalently attached to nucleic acids depends primarily on the local dynamics of the nucleic acid building blocks.

Correlation of anti-HIV potency with lipophilicity in a series of cosalane analogs having normal alkenyl and phosphodiester chains as cholestane replacements.

In order to define the role of the cholestane moiety in the anti-HIV agent cosalane, a series of cosalane analogs was synthesized in which the cholestane ring system was replaced by normal alkenyl and phosphodiester substituents having varied chain lengths and lipophilicities. The compounds containing simple alkenyl substituents were found to be more potent as inhibitors of the cytopathic effect of HIV-1 in cell culture than the phosphodiesters. In addition, the potencies of the alkene congeners correlated positively with chain length and lipophilicity of the alkene. The results indicate that the cholestane moiety of cosalane functions as a lipophilic accessory appendage to escort the dichlorodisalicylmethane pharmacophore to a lipid environment.

Carcinogenicity tests of fecapentaene-12 in mice and rats.

Fecapentaenes, a class of direct-acting bacterial mutagens, have been isolated from the feces and intestinal tract of humans on a Western meat-containing diet. Two bioassays to test pure fecapentaene-12 (FP-12) for carcinogenicity were performed. FP-12 in dimethylsulfoxide (DMSO) solution was injected i.p. into newborn ICR/MA mice on days 1, 3, 7, 10, 14 and 21. The mice killed after 21 months had neoplasms in liver, lung, glandular stomach and subcutaneous fibrosarcoma. Intrarectal (i.r.) infusion of FP-12 in an aqueous vehicle into male F344 rats for 71 weeks, and killing the rats after 21 weeks more, displayed no evidence of neoplasia associated with FP-12 exposure. The positive control, N-nitrosomethylurea (NMU), given i.r. as 4 2-mg doses in 2 weeks, as expected, yielded multiple colonic neoplasms in less than 11 months. Fecapentaene may exert its effect in bacteria and in newborn mice through the generation of hydroxy radicals. However, adult rodent and human colon may have adequate biochemical defense mechanisms against low level, even continuous exposures to chemicals like FP-12, and thus be at low risk of neoplasia, as was found.

A comparative study of Scatchard-type and linear lattice models for the analysis of EPR competition experiments with spin-labeled nucleic acids and single-strand binding proteins.

An EPR competition formalism is developed which provides relative affinities of proteins for nucleic acids. Two models for analyzing protein-nucleic acid interactions, one assuming independent binding sites (Model 1) and the other considering site overlap (Model 2), are examined with respect to their validity and limitations. The models are employed to derive affinity ratio relationships which are used to calculate the relative affinities of gene 32, gene 5, and SSB proteins for various nucleic acids. It is determined that although Model 2 must be used when determining absolute binding constants, by taking the ratio of binding constants the site overlap becomes unimportant under conditions of moderate to high cooperativity and relatively small site size. This allows Model 1 to considerably simplify binding analyses. Both models are applied to the single-strand binding proteins of bacteriophage T4 gene 32, bacteriophage fd gene 5, and the Escherichia coli ssb gene, and the results are compared.

The validity of electrophysiological criteria used in selective functional posterior rhizotomy for treatment of spastic cerebral palsy.

Although selective functional posterior rhizotomy (SFPR) is an established procedure for the treatment of spasticity, the electrophysiological criteria used to define which posterior rootlets should be cut have not been standardized. The purpose of this study was to determine the validity of the intraoperative electrophysiological criteria used to select posterior rootlets for sectioning in SFPR. Intraoperative stimulation of posterior lumbosacral nerve roots and rootlets, using a 50-Hz stimulus at threshold intensity, was performed in five nonspastic children (controls) undergoing laminectomy for spinal cord untethering and in 32 spastic patients undergoing SFPR. Electromyographic responses were recorded in the upper and lower limbs, the neck, and the face. The pattern of sustained responses was assessed in detail in 17 additional patients who had previously undergone SFPR and in the five controls. Sustained responses with ipsilateral lower limb extrasegmental spread occurred in both spastic patients and the control group. Contralateral lower limb spread and suprasegmental spread to the upper limbs, neck, and face were found only in spastic children. Sustained responses with an incremental pattern were restricted to the spastic population and correlated well with the extent of contralateral and suprasegmental spread, whereas decremental patterns were not associated with contralateral spread. It is concluded that contralateral and suprasegmental spread into the upper limbs, neck, and face, and incremental responses are probably valid criteria of abnormality.

Spin-labeled nucleotide mobility in the boundary of the EcoRI endonuclease binding site.

A complex consisting of the EcoRI endonuclease site-specifically bound to spin-labeled DNA 26mers was prepared to provide a model system for studying possible conformational changes resulting from protein binding. EPR was used to monitor the mobility of the spin labels that were strategically placed in position 6, 9, or 11 with respect to the dyad axis of the 26mer. These positions are located within the flanking region on either side of the EcoRI hexamer binding site. This allows the monitoring of potential distal structural changes in the DNA helix caused by protein binding. The spectral line shapes indicate that the spin label closest to the EcoRI endonuclease binding site, i.e., in position 6, is most influenced by the binding event. The EPR data are analyzed according to a model that distinguishes between spectral effects due to a change in the hydrodynamic shape of the complex and those resulting from local variations in the spin-label mobility as characterized by a local order parameter S. S reflecting the motional restriction of the spin-labeled base is 0.20 +/- 0.01 for all three oligomers as well as for the two complexes with the label in position 9 or 11, while the position 6 labeled complex yields S = 0.25. To further evaluate the origin of the slightly larger EPR effect observed with position 6 labeled material, molecular dynamics (MD) simulations were used to explore the space accessible to the probes in positions 6, 9, and 11. MD results gave similar nitroxide trajectories for all three labeled 26mers in the absence or presence of EcoRI. Thus, the small position 6 effect is attributed to a structural distortion in the major groove of the DNA at this location possibly corresponding to a bend induced by protein binding. The observation that the spectral changes are small indicates the absence of any significant structural disruption being propagated along the helix as a result of protein binding. Also, the fact that the line shape of the 26mers did not change as expected from hydrodynamic theory in view of the significant increase in molecular volume upon protein binding suggests that there are additional relaxation processes involving the protein and nucleic acid.

MO-F-BRB-04: Fast Estimation of Secondary Particle Therapy Dose Using a Modified Track Repeating Method.

PURPOSE: Charged particle beams are of great interest, because they can achieve highly conformal radiation dose distributions. Despite this, some scattered radiation is inevitably present outside of the target volumes, and is of concern because of risks such as radiogenic cancer. Accurately calculating the secondary dose in regions far from the target volume is very difficult due to extremely low particle fluence and the effect of heterogeneities on particle ranges, making calculations possible only with CPU-week long Monte Carlo runs. By using a modified track repeating method, we demonstrate fast and accurate estimation of secondary dose appropriate for clinical use. METHODS: Primary and secondary particle track databases (including protons, electrons, photons, neutrons, and positrons) were generated with the Geant4 Monte Carlo toolkit. Several new strategies were developed or employed to improve the performance of non- primary particle propagation, including: (1) processing the databases such that only primary tracks producing deep penetrating photons or neutrons were kept and particles falling below transport thresholds were discarded, (2) a search algorithm that can locate a sub-track for a given energy in constant time, (3) multiplying photon and neutron tracks during propagation and scoring using particle 'splitting1. RESULTS: Performance and accuracy were benchmarked against full Monte Carlo calculations (Geant4 and FLUKA). Filtering out tracks that did not produce deep penetrating photons or neutrons did not affect the accuracy of the secondary dose calculation. Preliminary performance analysis indicated 60- 100X speed up over Fluka and 700-1000X speed up over Geant4 with well maintained accuracy. CONCLUSIONS: Estimation of secondary dose from particle therapy has so far been largely an academic exercise. This method for fast estimation of secondary dose brings patient / plan specific information within reach, allowing clinicians to make informed decisions on the potential long-term risks associated with specific dose delivery plans. Partial funding from NSF grant CBET-0853157.

SU-E-T-610: Impact of Variable Beam Spot Size on Treatment Time in Particle Therapy.

PURPOSE: The dosimetric advantage of particle therapy comes with a much higher infrastructure investment and operation costs. Increasing patient throughput is a key factor to manage operation costs. We investigate the impact of variable beam spot sizes on treatment time and discuss the tradeoffs involved. METHODS: The following realistic assumptions were used. (1) The beam traveling speed is independent of the beam spot size. (2) The beam spot is a 2D Gaussian. Changing the beam spot size implies varying the standard deviation. (3) The maximum beam intensity is a constant independent of the beam spot size. Increasing the beam spot reduces the fluence. (4) Varying the beam spot size incurs in a reset time penalty.A 2D tumor was used in the study. Dose calculations were based on pencil beam kernels from GEANT4.The total treatment time is divided into the beam travel time, the beam-on time, andthe time for changing the spot size. RESULTS: We found that: (1) Changing the beam spot size has no impact on the beam-on time, because the maximum beam intensity is independentof the beam spot and increasing the beam spot only reduces the fluence. (2) Larger beam spot size shortens the total travel time inversely proportional to the radius of the beam spot. (3) Plans with different beam spot sizes have similar dosimetric qualities. (4) If higher beam intensity could be used for larger beam spot size, savings in beam-on time would be inversely proportional to the intensity available. CONCLUSIONS: We have studied the interplay among beam intensity, travel time, and beam size reset time for a scanning beam with variable beam spot size. Our initial studies show necessary conditions for and limitations on savings in total treatment times. Further studies are being carried out to find additional time saving sources. Supported in part by NSF CBET-0853157.

Nerve conduction studies and electromyography.

Nerve conduction studies and electromyography can aid in the diagnosis of peripheral nervous system disease. The author reviews various techniques used during electromyography and nerve conduction studies. He reviews briefly peripheral nerve and muscle neuroanatomy and neurophysiology. The author defines terms used in nerve conduction studies and electromyography and relates terminology to the underlying pathophysiology and histopathology. He also reviews briefly typical nerve conduction and electromyographic findings in various diseases.

Detection of internal and overall dynamics of a two-atom-tethered spin-labeled DNA.

DNA motions consist of several components which couple, making their investigation difficult. This study describes an approach for obtaining dynamical information by EPR when spin-labeled nucleic acids are examined. The analysis is accomplished by implementing two motional models. The first model (i.e., dynamic cylinder model) views the spin-labeled helix as a diffusing cylinder containing internal dynamics which are characterized by an order parameter. The second model (i.e., base disk model) provides correlation times describing the diffusion of the spin-labeled base. In each model, the nitroxide motion consists of both global and internal contributions. Dynamic cylinder and base disk simulations of four duplexes containing nitroxides attached to thymidine by a two-atom tether (DUMTA)-(dT)7DUMTA-(dT)7.(dA)15, [(dT)7DUMTA(dT)7]2.(dA)30, [(dT)7DUMTA(dT)7]3.(dA)45, and [(dT)7DUMTA(dT)7]m.-(dA)n--demonstrate the useful application of this approach. From dynamic cylinder simulations, the order parameter for internal motions is found to be independent of the helix length (S = 0.32 +/- 0.01). Previous base disk simulations of a DNA 26mer and polymer labeled with a five-atom-tethered nitroxide seemed to indicate that tau perpendicular was only sensitive to internal dynamics. Results from base disk simulations of DUMTA-labeled DNA indicate that the perpendicular component of the base disk correlation time (tau perpendicular = 1.4-6.2 ns) is sensitive to global dynamics. Thus, tau perpendicular is a quantitative indicator of both internal and global dynamics. Comparison of the two models reveals that tau perpendicular infinity S2 tau rb, where tau rb represents the rigid-body diffusion of the DNA helix. This relationship between S and tau perpendicular provides a framework for studying conformational changes and size-dependent phenomena in spin-labeled nucleic acids. Application of the dynamic cylinder model to a B-Z transition generates distinct values of S for each of the conformations, indicating that Z-DNA is more rigid than B-DNA.

Thermal limitations in optical logic.

The problem of removing the heat produced in logical operations limits the density to which logical elements can be packed in large computers employing many elements. The basic minimum power dissipation in elements that use optical phenomena to perform logic operations is estimated from physical laws. A maximum packing density or, alternatively, a minimum propagation delay between elements can then be estimated.

Exploration of the effects of linker chain modifications on anti-HIV activities in a series of cosalane analogues.

The effects of linker chain modifications were investigated in a series of cosalane analogues. The modifications investigated included: (1) shortening the three-carbon linker chain between the dichlorodisalicylmethane and the cholestane moiety by one carbon atom; (2) lengthening the linker chain by one carbon; (3) hydrogenation of the double bond in the linker chain; (4) changing the point of attachment of the linker chain from C-3 to C-6; (5) insertion of a phosphate between the steroid and the linker chain. With the exception of the phosphate modification, which abolished anti-HIV activity and increased cytotoxicity, the linker chain modifications produced relatively minor changes in anti-HIV activity and increased cytotoxicity, the linker chain modifications produced relatively minor changes in anti-HIV potency. The steroid and attached linker chain of cosalane therefore appear only to provide a general lipophilic appendage for the dichlorodisalicylmethane pharmacophore.

Observations on electrical stimulation of lumbosacral nerve roots in children with and without lower limb spasticity.

Selective functional posterior rhizotomy (SFPR) is a popular operation for the treatment of spasticity in children with cerebral palsy, but the physiologic basis of the procedure is poorly understood. As part of SFPR operations in 60 consecutive children, the responses to electrical stimulation of posterior lumbosacral roots and rootlets, and the corresponding anterior roots were studied. In addition, similar electrical stimulation of posterior roots was performed in four nonspastic "control" children. Sustained responses to 50 Hz stimulation, one of the criteria used to signify abnormality in the spastic children, was found frequently in the "control" children. Contralateral spread to the lower limb muscles and suprasegmental spread to the upper limbs, face, and neck were determined to be the most valid criteria which differentiated abnormal from normal responses. Stimulation of anterior nerve roots at 50 Hz caused sustained responses and ipsilateral lower limb spread, at a low threshold compared to that of corresponding posterior roots. The results of this study bring into question the validity of some of the criteria that are used to select abnormal posterior rootlets in the SFPR procedure, and suggest criteria that may be more valid based on findings in nonspastic children.