cssi/SciSciGPT-SciSciNet huggingface dataset:
Lack of experimental vesicant activity for the anticancer agents cisplatin, melphalan, and mitoxantrone

Cisplatin and L-PAM are DNA-crosslinking anticancer agents which have not been systematically studied for vesicant potential. Mitoxantrone is a new active anthracene-based, DNA intercalator which is undergoing widespread clinical testing for antitumor efficacy in man. These three agents were tested for vesicant activity in dehaired BALB/c mice given ID injections equivalent to human clinical doses. Neither cisplatin (up to 150 mg/m2) nor L-PAM (up to 71 mg/m2) produced any skin necrosis in the mice. The L-PAM solvent (acid/alcohol in propylene glycol) was ulcerogenic if injected undiluted. Mitoxantrone (up to 14 mg/m2) was not ulcerogenic in the mice, although the skin site retained a blue drug discoloration for several weeks. It is concluded that in clinically relevant doses, cisplatin, L-PAM, and mitoxantrone are not vesicants.
Quantitation of oxypurines and allopurinol metabolites in biological fluids by cation-exchange chromatography☆

Abstract Chromatography of urine, cerebrospinal fluid, and deproteinized serum on 30 × 0.9 cm columns of AG 50 permits the convenient separation of hypoxanthine, xanthine, allopurinol, and its metabolites. Quantitation by determination of absorbance at 250 mμ is accurate and can be automated. Column preparation is simple, and the columns can be regenerated and used daily for several months with no loss of resolution.
Agrin gene expression in mouse somatosensory cortical neurons during development in vivo and in cell culture

Agrin is an extracellular matrix protein involved in the formation of the postsynaptic apparatus of the neuromuscular junction. In addition to spinal motor neurons, agrin is expressed by many other neuronal populations throughout the nervous system. Agrin's role outside of the neuromuscular junction, however, is poorly understood. Here we use the polymerase chain reaction to examine expression and alternative splicing of agrin in mouse somatosensory cortex during early postnatal development in vivo and in dissociated cell culture. Peak levels of agrin gene expression in developing cortex coincide with ingrowth of thalamic afferent fibres and formation of thalamocortical and intracortical synapses. Analysis of alternatively spliced agrin messenger RNA variants shows that greater than 95% of all agrin in developing and adult somatosensory cortex originates in neurons, including isoforms that have little or no activity in acetylcholine receptor aggregation assays. The levels of expression of "active" and "inactive" isoforms, however, are regulated during development. A similar pattern of agrin gene expression is also observed during a period when new synapses are being formed between somatosensory neurons growing in dissociated cell culture. Changes in agrin gene expression, observed both in vivo and in vitro, are consistent with a role for agrin in synapse formation in the central nervous system.
Noninvasive control of a robotic arm in multiple dimensions using scalp electroencephalogram

Robotic limbs can enable individuals with impaired mobility and motor system output to interact with their physical environment. Many of these individuals do not have the motor control necessary to utilize their hands to control an assistive device. We hypothesize both healthy and post-stroke individuals can modulate sensorimotor rhythms with motor imagery to control of a human-size robotic arm and hand to complete multi-step grasping tasks using noninvasive EEG signals. Two healthy and one post-stroke subject controlled a robotic arm in two-dimensions to move to a target, grab the target block, and move it to a final location using motor imagery recorded through scalp EEG. Subjects demonstrate successful control of a robotic arm in 2D performance of a multi-step task in a time-limited manner.
Indoor location with Wi-Fi fingerprinting

There are many applications for indoor location determination, from the navigation of hospitals, airports, parking garages and shopping malls, for example, to navigational aids for the blind and visually impaired, targeted advertising, mining, and disaster response. GPS signals are too weak for indoor use, however, making it necessary to investigate other means of navigation. Most approaches such as ultrasound and RFID tags require special hardware to be installed and remain expensive and inconvenient. The solution proposed in this paper makes use of commonly available Wi-Fi networks and runs on ordinary smart phones and tablets without the need to install special hardware. It comprises a calibration stage and a navigation stage. The calibration stage creates a “Wi-Fi fingerprint” for each room of a building. It minimizes the calibration time through the use of waypoints. The navigation stage matches Wi-Fi signals to the fingerprints to determine the user's most likely location. It uses maximum likelihood classification for this matching and takes the building's topology into account through the use of Bayes' Theorem. The system is implemented as a mobile Android app and is easy to use. In testing, it took only an hour to calibrate a home or shopping mall, and the navigation stage yielded the correct location 97.5% of the time in a home and 100% of the time in a mall.
Differentially Flat Designs of Mobile Vehicles With Under-Actuated Manipulator Arms

Differential flatness has been investigated in the context of mobile vehicles for planning and control of their motions. In these models, the wheels are considered to be non-slipping, i.e., the system dynamics is subject to non-holonomic constraints. If a manipulator arm is mounted on such a mobile vehicle, the dynamics becomes highly nonlinear due to the nonlinear coupling between the motions of the mobile vehicle and the manipulator arm. A challenging question is how to perform point-to-point motions of such a system in the state space of the mobile manipulator. If some of the actuators are absent in the mechanical arm, the mobile manipulator becomes under-actuated and consequently even harder to plan and control. This paper presents a methodology for design of mobile vehicles, mounted with under-actuated manipulators operating in a horizontal plane, such that the combined system is differentially flat. In this paper, we show that by appropriate inertia distribution of the links and addition of torsion springs at the joints, a range of under-actuated designs are possible where the underactuated mobile manipulator system is differentially flat. The differential flatness property allows to efficiently solve the problem of trajectory planning and feedback controller design for point to point motions of the system. The proposed method is illustrated by the example of a mobile vehicle with under-actuated three-link manipulator.Copyright © 2007 by ASME
Minority carriers in graphite.

Quantum oscillations as a function of magnetic field in the Hall effect and thermoelectric power are studied in two samples of pressure-annealed pyrolytic graphite. Only the oscillations originating from minority-Fermi-surface carriers are discussed. Frequencies of the de Haas-van Alphen type are measured over a wide range of angles between the magnetic field and the c axis of the Brillouin zone. Results are given graphically and analyzed.
Open Challenges for Consulting Service Lifecycle Management: What Service Research Should learn from Software Lifecycle Management

In the last two decades, research in software engineering has hada focus on software lifecycle management. Rather than a narrowfocus on programming languages environments and softwaredevelopment, researchers are considering the end-to-end lifecycleof software, including design, development, deployment, supportand retirement. Business IT consulting has a similar lifecyclefrom request for proposal, to proposal, delivery, on-goingoperation and retirement. For the past 5 years we have beenworking with IBM Global Business Services to address issues indelivering Business IT services. From this experience, we'veidentified a number of open challenges and have begun workingon solutions and a platform for addressing these challenges. Weare starting with lessons learned in software lifecyclemanagement, and building on them to address challengesparticular to service delivery. For example, like softwarelifecycle management, services lifecycle management requiressupport for end-to-end traceability, coordination between peopleworking on related activities and on hand offs between one phaseof a consulting project and the next. In this paper, we enumeratea set of open challenges for service lifecycle management. Wesuggest how lessons from software lifecycle management can beapplied and give a preliminary report on our implementation ofan open architecture environment to support services lifecyclemanagement.
Approximation of weighted local mean operators

Recently, weighted local mean operators are widely used in image processing, compressive sensing and other areas. A weighted local mean operator changes its characteristics depending on a function content within a local area in order to preserve the function features. The directional diffusion filter and Yaroslavsky neighbourhood filter (also called the sigma filter) are discrete versions of such operators. Although these operators are not convolution ones, due to their sparsity, the corresponding numerical algorithms have simple structure and fast performance. In this paper, we study the approximate properties of the weighted local mean operators, particularly focus on their asymptotic expansions, which are related to non-linear diffusion equations.
Use of Comparative Physical and Sequence Mapping to Annotate Mouse Chromosome 16 and Human Chromosome 21

Abstract Distal mouse chromosome 16 (MMU16) shares conserved linkage with human chromosome 21 (HSA21), trisomy for which causes Down syndrome (DS). A 4.5-Mb physical map extending from Cbr1 to Tmprss2 on MMU16 provides a minimal tiling path of P1 artificial chromosomes (PACs) for comparative mapping and genomic sequencing. Thirty-four expressed sequences were positioned on the mouse map, including 19 that were not physically mapped previously. This region of the mouse:human comparative map shows a high degree of evolutionary conservation of gene order and content, which differs only by insertion of one gene (in mouse) and a small inversion involving two adjacent genes. “Low-pass” (2.2×) mouse sequence from a portion of the contig was ordered and oriented along 510 kb of finished HSA21 sequence. In combination with 68 kb of unique PAC end sequence, the comparison provided confirmation of genes predicted by comparative mapping, indicated gene predictions that are likely to be incorrect, and identified three candidate genes in mouse and human that were not observed in the initial HSA21 sequence annotation. This comparative map and sequence derived from it are powerful tools for identifying genes and regulatory regions, information that will in turn provide insights into the genetic mechanisms by which trisomy 21 results in DS.
Fracture toughness of Si3N4 measured with short bar chevron-notched specimens

The short bar chevron-notched specimen is used to measure the plane strain fracture toughness of hot pressed Si3N4. Specimen proportions and chevron-notch angle are varied, thereby varying the amount of crack extension to maximum load (upon which K sub IC is based). The measured toughness (4.68 + or 0.19 MNm to the 3/2 power) is independent of these variations, inferring that the material has a flat crack growth resistance curve.
Incorporating HIPAA Security Requirements into an Enterprise Security Program

Abstract HIPAA Security regulations are forcing many organizations to secure electronic individually identifiable health information. Some side benefits of such an undertaking are improving information management processes, creating a foundation for compliance with other regulations, and maintaining their level of readiness within a security program that aligns with the HIPAA security risk- based approach. This provides effective, enterprisewide risk management.
The direct determination of rate constants and onsager flow coefficients for non-first-order coupled chemical reactions of any degree of complexity by multispectral chemical relaxation spectrometry

Abstract In an earlier paper, the formulation was given for the direct determination of chemical rate constants for coupled first-order ??? multispectral chemical relaxation. This paper gives the theory for the direct derivation of rate constants and the ??? ??? ???, ??? multispectral relaxation data for chemical systems of any degree of complexity in terms of ??? chemical thermodynamics. The procedures only require in integration of auto- and cross-relaxation data and ??? ???.
Female sexual response to condition-dependent ornaments in the guppy, Poecilia reticulata

. The relationship between male ornamentation, display rate, vigour and female sexual response was investigated in the guppy. Male ornamentation was quantified as the area and number of orange, black and structural colour spots and was calculated using the complexity of a male's colour pattern relative to others in the sample. Male constitution (an individual's physical makeup, comprised of inherited qualities altered by environment) was measured as (1) an individual's prolonged swimming ability, indicating vigour or endurance, and (2) as a calculated condition-factor, indicating general health. Male display rate and attractiveness were determined in a female-response experiment. Male display rate, ornament complexity, and area of orange were correlated with sustained swimming performance, and to a lesser extent, with the condition factor, suggesting that male ornamentation and display rates are condition dependent in guppies. Females responded to males that had significantly higher display rates, more complex ornamentation containing more carotenoid pigments, and higher sustained swimming speeds. The results are interpreted in the framework of the Fisherian and 'good genes' models of female choice.
Functional identification of valerena-1,10-diene synthase, a terpene synthase catalyzing a unique chemical cascade in the biosynthesis of biologically active sesquiterpenes in Valeriana officinalis

Valerian is an herbal preparation from the roots of Valeriana officinalis used as an anxiolytic and sedative and in the treatment of insomnia. The biological activities of valerian are attributed to valerenic acid and its putative biosynthetic precursor valerenadiene, sesquiterpenes, found in V. officinalis roots. These sesquiterpenes retain an isobutenyl side chain whose origin has been long recognized as enigmatic because a chemical rationalization for their biosynthesis has not been obvious. Using recently developed metabolomic and transcriptomic resources, we identified seven V. officinalis terpene synthase genes (VoTPSs), two that were functionally characterized as monoterpene synthases and three that preferred farnesyl diphosphate, the substrate for sesquiterpene synthases. The reaction products for two of the sesquiterpene synthases exhibiting root-specific expression were characterized by a combination of GC-MS and NMR in comparison to the terpenes accumulating in planta. VoTPS7 encodes for a synthase that biosynthesizes predominately germacrene C, whereas VoTPS1 catalyzes the conversion of farnesyl diphosphate to valerena-1,10-diene. Using a yeast expression system, specific labeled [13C]acetate, and NMR, we investigated the catalytic mechanism for VoTPS1 and provide evidence for the involvement of a caryophyllenyl carbocation, a cyclobutyl intermediate, in the biosynthesis of valerena-1,10-diene. We suggest a similar mechanism for the biosynthesis of several other biologically related isobutenyl-containing sesquiterpenes. Background: Therapeutic values of Valeriana officinalis have been associated with sesquiterpenes whose biosynthetic origins have remained enigmatic. Results: A cyclobutenyl intermediate in the catalytic cascade of valerena-1,10-diene synthase is reported. Conclusion: A new class of sesquiterpene synthases for the biosynthesis of sesquiterpenes harboring isobutenyl functional groups is proposed. Significance: Similar catalytic mechanisms from evolutionarily diverse organisms are proposed and portend sources for sesquiterpene diversity.
Toxic shock syndrome after laminaria insertion.

Abstract BACKGROUND: Laminaria tents used to facilitate surgical abortion are rarely associated with significant infectious morbidity. CASE: A parous woman in midpregnancy had laminaria placed in her cervix followed by a second set after 24 hours. Eight hours later, she presented with dyspnea, hives, fever, tachycardia, and hypotension. Antibiotic treatment was initiated and a dilation and evacuation procedure was performed. Amniotic membrane cultures showed a heavy growth of Staphylococcus aureus with staphylococcal enterotoxin C expression, compatible with toxic shock syndrome. CONCLUSION: Laminaria cervical dilation might be associated with toxic shock syndrome.
Consistent condom use among drug-using youth in a high HIV-risk neighbourhood

The objectives of this study were to determine predictors of consistent condom use in heterosexual relationships of young adults who use hard drugs in a neighbourhood with widespread drug-use-connected HIV. We interviewed 196 18-24 year olds who injected drugs or used heroin, cocaine or crack in the prior year and lived in the Bushwick neighbourhood of New York City. Interviews covered sociodemographics, substance use and sexual networks. The unit of analysis is the relationship; the dependent variable measures consistent condom use over the prior 30 days in a given relationship. Consistent condom use was reported in 26% of 377 non-commercial relationships and in all of 22 commercial relationships. Using multiple logistic regression, consistent condom use in non-commercial relationships was more likely in relationships that are not 'very close'; for men (but not women) with peers whose norms are more favourable to condom use; and for subjects who had concurrent sex partners in the last 12 months. In conclusion, we found that: (1) the lack of relationship between the peer norms of drug-using women and their condom use suggests they may have little control over condom use in their relationships-programmes should attempt to empower young women drug users and to develop ways for their peers to influence the men in their lives; (2) epidemiologically, the positive association of concurrency to consistent condom use suggests that condom use may be restricting HIV spread through the community-the presence of consistent condom use in all of the commercial sexual relationships also may restrict HIV spread; (3) prevention efforts should attempt to change peer cultures as a way to develop self-sustaining risk reduction. These changes should include changes in gender roles and power relations.
Grb2-associated binder-1 plays a central role in the hepatocyte growth factor enhancement of hepatoma growth inhibition by K vitamin analog compound 5.

Compound 5 (Cpd 5), a K vitamin analog, has been shown to inhibit Hep3B human hepatoma cell growth in cultures and rat hepatoma growth in vivo through prolonged epidermal growth factor receptor (EGFR)–extracellular response kinase (ERK) phosphorylation, and hepatocyte growth factor (HGF) synergizes with Cpd 5 to enhance the inhibition of Hep3B cell and rat hepatoma growth. To explore the mechanisms mediating the HGF/Cpd 5 synergy, we examined the possible involvement of the Grb2-associated binder-1 (Gab1) docking protein because it interacts with both EGFR and HGF receptor c-Met pathways. We found that HGF enhanced Cpd 5–induced c-Met phosphorylation at Tyr-1349, a binding site for Gab1, resulting in increased c-Met binding to Gab1, and induced strong and prolonged Gab1 tyrosine phosphorylation. Prolonged Gab1 phosphorylation by HGF/Cpd 5 in turn enhanced the ability of Gab1 to bind to protein tyrosine phosphatase SHP2 and enhanced the activation of its downstream mitogen-activated protein kinase pathway. In contrast, this same HGF/Cpd 5 treatment inhibited Gab1 binding to phosphatidylinositol 3-kinase (PI3K), leading to the inactivation of the PI3K-Akt pathway. The inhibition of Akt phosphorylation by HGF/Cpd 5 further activated the Raf-MEK-ERK signaling cascade via an Akt-Raf1 interaction, leading to strong and prolonged ERK phosphorylation. The transfection of Hep3B cells with mutated Gab1 (Gab1 Y627F), which had lost its ability to bind SHP2, antagonized HGF/Cpd 5–induced ERK phosphorylation, whereas the transfection of Hep3B cells with mutated Gab1 3YF, which lost its ability to bind PI3K, further enhanced HGF/Cpd 5–induced ERK phosphorylation and cell growth inhibition. Conclusion: Gab1 plays a central role in regulating HGF/Cpd 5 synergy in their actions on Hep3B cell growth inhibition. (HEPATOLOGY 2007;46:2003–2013.)
Evidence for sympathetic vibrational cooling of translationally cold molecules

Compared with atoms, molecules have a rich internal structure that offers many opportunities for technological and scientific advancement. The study of this structure could yield critical insights into quantum chemistry, new methods for manipulating quantum information, and improved tests of discrete symmetry violation and fundamental constant variation. Harnessing this potential typically requires the preparation of cold molecules in their quantum rovibrational ground state. However, the molecular internal structure severely complicates efforts to produce such samples. Removal of energy stored in long-lived vibrational levels is particularly problematic because optical transitions between vibrational levels are not governed by strict selection rules, which makes laser cooling difficult. Additionally, traditional collisional, or sympathetic, cooling methods are inefficient at quenching molecular vibrational motion. Here we experimentally demonstrate that the vibrational motion of trapped BaCl(+) molecules is quenched by collisions with ultracold calcium atoms at a rate comparable to the classical scattering, or Langevin, rate. This is over four orders of magnitude more efficient than traditional sympathetic cooling schemes. The high cooling rate, a consequence of a strong interaction potential (due to the high polarizability of calcium), along with the low collision energies involved, leads to molecular samples with a vibrational ground-state occupancy of at least 90 per cent. Our demonstration uses a novel thermometry technique that relies on relative photodissociation yields. Although the decrease in vibrational temperature is modest, with straightforward improvements it should be possible to produce molecular samples with a vibrational ground-state occupancy greater than 99 per cent in less than 100 milliseconds. Because sympathetic cooling of molecular rotational motion is much more efficient than vibrational cooling in traditional systems, we expect that the method also allows efficient cooling of the rotational motion of the molecules. Moreover, the technique should work for many different combinations of ultracold atoms and molecules.
The Y-Architecture for On-Chip Interconnect: Analysis and Methodology

The Y architecture for on-chip interconnect is based on pervasive use of 0/spl deg/, 120/spl deg/, and 240/spl deg/ oriented semiglobal and global wiring. Its use of three uniform directions exploits on-chip routing resources more efficiently than traditional Manhattan wiring architecture. This paper gives in-depth analysis of deployment issues associated with the Y architecture. Our contributions are as follows. 1) We analyze communication capability (throughput of meshes) for different interconnect architectures using a multicommodity flow approach and a Rentian communication model. Throughput of the Y architecture is largely improved compared to the Manhattan architecture, and is close to the throughput of the X architecture. 2) We improve existing estimates for the wirelength reduction of various interconnect architectures by taking into account the effect of routing-geometry-aware placement. 3) We propose a symmetrical Y clock tree structure with better total wire length compared to both H and X clock tree structures, and better path length compared to the H tree. 4) We discuss power distribution under the Y architecture, and give analytical and SPICE simulation results showing that the power network in Y architecture can achieve (8.5%) less IR drop than an equally resourced power network in Manhattan architecture. 5) We propose the use of via tunnels and banks of via tunnels as a technique for improving routability for Manhattan and Y architectures.
Seeing voices: High-density electrical mapping and source-analysis of the multisensory mismatch negativity evoked during the McGurk illusion

Seeing a speaker's facial articulatory gestures powerfully affects speech perception, helping us overcome noisy acoustical environments. One particularly dramatic illustration of visual influences on speech perception is the "McGurk illusion", where dubbing an auditory phoneme onto video of an incongruent articulatory movement can often lead to illusory auditory percepts. This illusion is so strong that even in the absence of any real change in auditory stimulation, it activates the automatic auditory change-detection system, as indexed by the mismatch negativity (MMN) component of the auditory event-related potential (ERP). We investigated the putative left hemispheric dominance of McGurk-MMN using high-density ERPs in an oddball paradigm. Topographic mapping of the initial McGurk-MMN response showed a highly lateralized left hemisphere distribution, beginning at 175 ms. Subsequently, scalp activity was also observed over bilateral fronto-central scalp with a maximal amplitude at approximately 290 ms, suggesting later recruitment of right temporal cortices. Strong left hemisphere dominance was again observed during the last phase of the McGurk-MMN waveform (350-400 ms). Source analysis indicated bilateral sources in the temporal lobe just posterior to primary auditory cortex. While a single source in the right superior temporal gyrus (STG) accounted for the right hemisphere activity, two separate sources were required, one in the left transverse gyrus and the other in STG, to account for left hemisphere activity. These findings support the notion that visually driven multisensory illusory phonetic percepts produce an auditory-MMN cortical response and that left hemisphere temporal cortex plays a crucial role in this process.
Decreased Bone Mineral Density Is Correlated with Increased Subclinical Atherosclerosis in Older, but not Younger, Mexican American Women and Men: The San Antonio Family Osteoporosis Study

An association has been reported between cardiovascular disease (CVD) and osteoporosis, perhaps attributable to the presence of common risk factors. To assess this possibility, we measured areal bone mineral density (BMD) and carotid artery intimal medial thickness (IMT), a measure of preclinical atherosclerosis, in 535 women and 335 men from the San Antonio Family Osteoporosis Study. Variance decomposition methods were used to determine whether cross-sectional measures of areal BMD (measured by dual-energy X-ray absorptiometry) of the total hip, spine, and forearm were correlated with IMT, serum lipids, and/or C-reactive protein (CRP), a marker of inflammation, after accounting for known environmental factors. We observed significant inverse correlations of IMT and BMD at all bone sites in women >60 years of age (P 60 years of age (P < 0.001) and positive correlations in men <60 years of age (P = 0.05). Variation in risk factors for CVD, including serum levels of low- and high-density lipoprotein cholesterol, low-density lipoprotein particle size, triglycerides, paraoxonase 1 activity, and CRP did not account for the relationship between BMD and IMT in either older or younger men or women. In summary, our results demonstrate that decreased BMD is correlated with increased IMT in older (but not younger) Mexican American men and women, independent of serum CVD risk factors.
The Cramer-Rao lower bound for directions of arrival of Gaussian cyclostationary signals

The Cramer-Rao lower bound on the variance of estimates of directions of arrival, signal strengths, and carrier frequencies and phases of cyclostationary signals arriving at an array is considered. Numerical evaluations of the bound for the estimates of directions of arrival show that it can be orders of magnitude lower than the corresponding bound for stationary signals, despite the great number of unknown parameters in the former case. Comparisons with the mean squared error of direction estimates obtained by the cyclic least squares algorithm show that the bound is not overly optimistic. >
Frame-Based Packet-Mode Scheduling for Input-Queued Switches

Most packet scheduling algorithms for input-queued switches operate on fixed-sized packets known as cells. In reality, communication traffic in many systems such as Internet runs on variable-sized packets. Motivated by potential savings of segmentation and reassembly, there has been increasing interest in scheduling variable-sized packets in a nonpreemptive manner known as packet-mode scheduling. This paper studies frame-based packet-mode scheduling for better scalability. It first shows that the admissible condition is no longer sufficient for packet-mode scheduling. Then, a relation between the frame size and packet sizes is derived that classifies under what conditions the packet-mode scheduling problem is polynomial solvable or is NP-hard. This relation reveals an interesting result that under various packet size distributions, it may be polynomial solvable even if many different packet sizes occur in the packet set, whereas it may be NP-hard with just two packet sizes present. Finally, as a practical solution, this paper studies how a speedup can help packet-mode scheduling. It is shown that the admissible condition becomes sufficient also when a speedup of two is used. A simple algorithm with a speedup of two is presented.
Relationships between DNA Incorporation, Mutant Frequency, and Loss of Heterozygosity at the TK Locus in Human Lymphoblastoid Cells Exposed to 3′-Azido-3′-deoxythymidine

3'-Azido-3'-deoxythymidine (AZT), a thymidine analogue widely used in the treatment of AIDS patients and for prevention of the onset of AIDS in HIV-seropositive individuals, causes tumors in mice exposed as adults or in utero. The purpose of this study was to investigate the potential mechanisms of AZT mutagenicity and carcinogenicity by quantifying the incorporation of AZT into cellular DNA, measuring AZT-induced thymidine kinase (TK) mutant frequencies (Mfs), and determining the percentage of loss of heterozygosity (LOH) in spontaneous or AZT-induced TK mutants in the human lymphoblastoid cell line, TK6. Cells were exposed to 300 microM AZT for 0, 1, 3, or 6 days, or to 0, 33, 100, 300, or 900 microM AZT for 3 days (n = 5 flasks/group). The effects of exposure concentration on incorporation of AZT into cellular DNA were evaluated by an AZT radioimmunoassay, and the effects of duration and concentration of AZT exposure on the TK Mfs were assessed by a cell-cloning assay. AZT was incorporated into DNA in a dose-related manner at concentrations up to 300 microM, above which no further increase was observed. TK Mf increased with the extended duration and with incremental concentrations of AZT exposure. There was a positive correlation (P = 0.036, coefficient = 0.903) between AZT-DNA incorporation and AZT-induced TK Mfs, suggesting that AZT incorporation into cellular DNA has a direct role in the genotoxicity of AZT. Southern blot analyses indicated that 84% (6.2 x 10(-6)/7.4 x 10(-6)) of AZT-induced mutants were attributable to LOH, consistent with the known mechanism of AZT as a DNA chain terminator. Considering the importance of LOH in human carcinogenesis, AZT-induced LOH warrants further study.
Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12.

Context. —Four genetic loci have been identified as contributing to Alzheimer disease (AD), including the amyloid precursor protein gene, the presenilin 1 gene, the presenilin 2 gene, and the apolipoprotein E gene, but do not account for all the genetic risk for AD. Objective. —To identify additional genetic risk factors for late-onset AD. Design. —A complete genomic screen was performed (N=280 markers). Critical values for chromosomal regional follow-up were aPvalue of.05 or less for affected relative pair analysis or sibpair analysis, a parametric lod score of 1.0 or greater, or both. Regional follow-up included analysis of additional markers and a second data set. Setting. —Clinic populations in the continental United States. Patients. —From a series of multiplex families affected with late-onset (≥60 years) AD ascertained during the last 14 years (National Insititute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria) and for which DNA has been obtained, a subset of 16 families (135 total family members, 52 of whom were patients with AD) was used for the genomic screen. A second subset of 38 families (216 total family members, 89 of whom were patients with AD) was used for the follow-up analysis. Main Outcome Measures. —Linkage analysis results generated using both genetic model-dependent (lod score) and model-independent methods. Results. —Fifteen chromosomal regions warranted initial follow-up. Follow-up analyses revealed 4 regions of continued interest on chromosomes 4,6,12, and 20, with the strongest results observed for chromosome 12. Peak 2-point affecteds-only lod scores (n=54) were 1.3,1.6, 2.7, and 2.2 and affected relative pairsPvalues (n=54) were.04,.03,.14, and.04 forD12S373, D12S1057, D12S1042, and D12S390, respectively. Sibpair analysis (n=54) resulted in maximum lod scores (MLSs) of 1.5,2.6,3.2, and 2.3 for these markers, with a peak multipoint MLS of 3.5. Apriori stratification byAPOEgenotype identified 27 families that had at least 1 member with AD whose genotype did not contain anAPOE*4allele. Analysis of these 27 families resulted in MLSs of 1.0,2.4,3.7, and 3.3 and a peak multipoint MLS of 3.9. Conclusions. —A complete genomic screen in families affected with late-onset AD identified 4 regions of interest after follow-up. Chromosome 12 gave the strongest and most consistent results with a peak multipoint MLS of 3.5, suggesting that this region contains a new susceptibility gene for AD. Additional analyses are necessary to identify the chromosome 12 susceptibility gene for AD and to follow up the regions of interest on chromosomes 4, 6, and 20.
Theoretical studies of silicon-containing molecules

Abstract We report herein, a series of ab initio calculations on various SiH n and Si 2 H n species using generalized valence bond and configuration interactions methods. These results allow systematic estimation of the heats of formation and the enthalpies of reactions for these species. For SiH n compounds, the calculated and experimental energetics are in excellent agreement; we obtain D 300 (H 3 SiH) ‡ 91.6 kcal mol −1 (experiment, 90.3 ± 1), D 300 (SiH) = 68.2 kcal (experiment ⩽70 kcal), and an energy of atomization for SiH 4 of 303.4 kcal mol −1 (experiments yield 307.9). However, for silylene, we find Δ H f = 67 kcal mol −1 , 9 kcal mol −1 higher than the (indirect) experimental value and suggest re-examination of these experiments. We calculate D 300 (H 3 SiSiH 3 ) = 71.7 kcal mol −1 , in good agreement with the experimental value of 73.7 ± 2 kcal mol −1 . Particularly interesting is disilene, where it is found that (i) the ground state is nonplanar ( trans ) (with a barrier to planarization of ≈ 1 kcal mol −1 ), (ii) disilene is stable relative to the isomer silylsilylene (H 3 SiSiH) by about 6 kcal mol −1 , and (iii) the SiSi double bond energy is 56 kcal mol −1 , which is 16 kcal mol −1 weaker than the SiSi single bond in disilane! The origin of this effect is explained in terms of GVB bonding.
On caring for the patient with cancer

An Annual Oration or Discourse has been delivered by distinguished members of the Massachusetts Medical Society in almost uninterrupted sequence since the year 1804. For the 195th Anniversary Meeti...
A mammaglobin-A targeting agent for noninvasive detection of breast cancer metastasis in lymph nodes.

Pathologic axillary lymph node (ALN) status is an important prognostic factor for staging breast cancer. Currently, status is determined by histopathology following surgical excision of sentinel lymph node(s), which is an invasive, time consuming, and costly procedure with potential morbidity to the patient. Here, we describe an imaging platform for noninvasive assessment of ALN status, eliminating the need for surgical examination of patients to rule out nodal involvement. A targeted imaging probe (MamAb-680) was developed by conjugation of a mammaglobin-A–specific monoclonal antibody to a near-infrared fluorescent dye. Using DNA and tissue microarray, mammaglobin-A was validated as a cell-surface target that is expressed in ALN-positive patient samples but is not expressed in normal lymph nodes. In vivo selectivity was determined by i.v. injection of MamAb-680 into mice with mammaglobin-A–positive and -negative mammary fat pad (MFP) tumors; and by peritumoral MFP injection of the targeted imaging probe in mice with spontaneous ALN metastases. Fluorescence imaging showed that probe was only retained in positive tumors and metastases. As few as 1,000 cells that endogenously express mammaglobin-A were detected in ALN, indicating high sensitivity of this method. Translation of this approach offers considerable potential as a noninvasive clinical strategy to stage breast cancer. Cancer Res; 71(3); 1050–9. ©2010 AACR.
DNA Synthesis in Chloroplasts III. THE DNA GYRASE INHIBITORS NALIDIXIC ACID AND NOVOBIOCIN INHIBIT BOTH THYMIDINE INCORPORATION INTO DNA AND PHOTOSYNTHETIC OXYGEN EVOLUTION BY ISOLATED CHLOROPLASTS

The influence of two DNA gyrase inhibitors, nalidixic acid and novobiocin on DNA synthesis in isolated pea chloroplasts was examined by autoradiography and densitometry
Improved aneurysmal subarachnoid hemorrhage outcomes: a comparison of 2 decades at an academic center.

Abstract Objective Management of aneurysmal subarachnoid hemorrhage (aSAH) has evolved over the past 2 decades, including refinement of neurosurgical techniques, availability of endovascular options, and evolution of neurocritical care; their impact on SAH outcomes is unclear. Design/Methods Prospectively collected data of patients with aSAH admitted to Johns Hopkins Medical Institutions between 1991 and 2009 were analyzed. We compared survival to discharge and functional outcomes at initial clinic appointment postdischarge (30-120 days) in patients admitted between 1991 and 2000 (phase 1 [P1]) and 2000 and 2009 (phase 2 [P2]), respectively, using dichotomized Glasgow Outcome Scale (good outcome: Glasgow Outcome Scale 4-5). Results A total of 1134 consecutive patients with aSAH were included in the analysis (P1 46.4%, P2 53.6%). There were higher rates of poor grade Hunt and Hess (P1 23%, P2 28%; P Conclusions Our institutional experience over 2 decades confirms that patients with aSAH have shown significant outcome improvements over time.
Real-time strain rate echocardiographic imaging: temporal and spatial analysis of postsystolic compression in acutely ischemic myocardium.

Abstract Postsystolic compression (PSC) is a sensitive indicator of regional left ventricular ischemic diastolic dysfunction. Quantitative assessment of compression patterns by strain rate imaging could determine the presence and spatial extent of PSC for the detection and analysis of acute ischemic diastolic dysfunction. With the use of a segmental left ventricular model, we evaluated time to compression/expansion crossover (T-CEC) in standard apical views. Data at baseline and after acute left anterior descending coronary artery occlusion were collected from 18 open-chest pigs. We found significant mean prolongation of T-CEC, ranging from 43.9 ± 48.6 ms to 110.8 ± 73.8 ms, in all apical segments and in 2 midventricular (anterior and anteroseptal) segments. Analysis of variance demonstrated that the prolonged T-CEC is spatially consistent with perfusion defect. The temporal and spatial analysis of T-CEC with the use of strain rate imaging is a new noninvasive technique for identification and topographic quantitation of ischemic diastolic dysfunction expressed by PSC. (J Am Soc Echocardiogr 2001;14:360-9.)
Polymorphisms in the MTHFR and VDR genes and skin cancer risk.

Folate and vitamin D have been shown to be influenced by ultraviolet (UV) radiation. UVA radiation can break down plasma folate, whereas vitamin D can be synthesized in UVB-exposed skin. Folate metabolism is involved in DNA synthesis and repair, and vitamin D processes antiproliferative effects. The functions of both nutrients are implicated in skin carcinogenesis. We evaluated genetic polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene (C677T and A1298C) and the vitamin D receptor (VDR) gene (Fok1, Bsm1 and Cdx2) with skin cancer risk in a nested case‐control study within the Nurses’ Health Study [219 melanoma, 286 squamous cell carcinoma (SCC), 300 basal cell carcinoma (BCC) and 873 controls]. No significant associations were observed for the two MTHFR polymorphisms on skin cancer risk. We observed an interaction between the C677T polymorphism and total folate intake on SCC risk (P, interaction ¼ 0.04); the highest risk was observed among women with TT genotype and low folate intake (OR ¼ 2.14; 95% CI ¼ 1.01‐4.50). The VDR Bsm1 BB genotype was significantly associated with an increased SCC risk (OR ¼ 1.51; 95% CI ¼ 1.00‐2.28). An interaction between the Bsm1 polymorphism and total vitamin D intake on SCC was observed, with the highest risk seen in women with the BB genotype and high vitamin D intake (OR ¼ 2.38; 95% CI ¼ 1.22‐4.62) (P, interaction ¼ 0.08). This study suggests a possible role of the polymorphisms in MTHFR and VDR interacting with dietary intakes of folate and vitamin D in skin cancer development, especially for SCC. Due to a large number of comparisons and tests, the possible associations should be interpreted with caution and confirmed by other studies.
Role of Cardiac Catheterization in Infective Endocarditis

The benefits and hazards of catheterization and angiography were evaluated in 19 patients with acute aortic and/or mitral endocarditis and heart failure. In 14 patients (74 percent), the bedside diagnosis of valvular insufficiency and heart failure was proved correct. In three patients with both aortic and mitral valve disease, angiography (without hemodynamic measurements) was necessary to clarify the diagnosis. Angiography detected four aortic aneurysmal erosions that were unsuspected clinically, but missed three others. After angiography, heart failure worsened in two patients with severe progressive aortic insufficiency and one died. Thus, catheterization-angiography was of greatest value if more than one left-sided valve lesion was present, if extravalvular diseases mimicked heart failure, or if extravalvular infection was present Patients with isolated, clear-cut mitral insufficiency usually do not need these diagnostic procedures, and they are probably contraindicated in patients with severe aortic regurgitation with rapidly progressing heart failure.
Performance modeling and prediction for scientific Java applications

With the expansion of the Internet, the grid has become an attractive platform for scientific computing. Java, with a platform-independent execution model and built-in support for distributed computing is an inviting choice for implementation of applications intended for grid execution. Recent work has shown that an accurate performance model combined with a load-balancing scheduling strategy can significantly improve the performance of distributed applications on a heterogeneous computing platform, such as the grid. However, current performance modeling techniques are not suitable for Java applications, as the virtual machine execution model presents several difficulties: 1) a significant amount of time is spent on compilation at the beginning of the execution, 2) the virtual machine continuously profiles and recompiles the code during the execution, 3) garbage collection can have unpredictable effects on memory hierarchy, 4) some applications can spend more time garbage collecting than computing for certain heap sizes and 5) small variations in virtual machine implementation can have a large impact on the application's behavior. In this paper, we present a practical profile-based strategy for performance modeling of Java scientific applications intended for execution on the grid. We introduce two novel concepts for the Java execution model: point of predictability (PoP) and point of unpredictability (PoU). PoP accounts for the volatile nature of the effects of the virtual machine on execution time for small problem sizes. PoU accounts for the effects of garbage collection on certain applications that have a memory footprint that approaches the total heap size. We present an algorithm for determining PoP and PoU for Java applications, given the hardware platform, virtual machine and heap size. We also present a code-instrumentation-based mechanism for building the algorithm complexity model for a given application. We introduce a technique for calibrating this model that is able to accurately predict the execution time of Java programs for problem sizes between PoP and PoU. Our preliminary experiments show that techniques can achieve load balancing with more than 90% average CPU utilization.
Efficient and accurate transient simulation in charge-voltage plane

Transient simulation has traditionally been performed in current-voltage plane (with current and voltage as variables)for verification of integrated circuits and systems. This paper introduces techniques for efficient and accurate transient simulation in charge-voltage plane (with charge and voltage as variables). For integrated circuits, both simulation cost and overhead to increase accuracy are drastically reduced by performing simulations in charge-voltage plane. Adaptively controlled explicit simulation in charge-voltage plane is used to demonstrate the feasibility of the approach. Solution of circuit equations in charge-voltage plane is 10-20 times more efficient than in current-voltage plane. Furthermore, simulation accuracy can be increased at an incremental cost. As a result, ACES in charge-voltage plane provides speedups of 300/spl times/-5000/spl times/ or more over traditional circuit simulators with little or no loss in circuit timing accuracy.
Helicobacter pylori Infection in Gnotobiotic Piglets

Helicobacter pylori, a gram negative microaerophilic urease positive and motile spiral shaped bacterium is the etiologic agent of human chronic superficial (active) gastritis. In humans, H. pylori is the primary cause of gastric ulcers and atrophic gastritis and a probable risk factor for the development of gastric carcinoma and gastric mucosa associated lymphoid tissue (MALT) lymphoma, presumably because of infection induced epithelial cell proliferation and increased mucosal exposure to orally ingested carcinogens in an acid neutral environment in the former and immunogenic overstimulation in the latter. The organism exhibits remarkable genomic variation among bacterial isolates, but genomic homogeneity within infected individuals suggesting that it is not subjected to selectional pressures by the host to ecological competition with other bacterial species. Normal gastric defenses which prevent colonization by most bacteria, do not hinder H. pylori and may restrict delivery of specific antibody or immune cells to the gastric lumen.