cssi/SciSciGPT-SciSciNet huggingface dataset:
Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold.

Effective delivery of therapeutic drugs into the human brain is one of the most challenging tasks in central nervous system drug development because of the blood–brain barrier (BBB). To overcome the BBB, both passive permeability and efflux transporter liability of a compound must be addressed. Herein, we report our optimization related to BBB penetration of neuronal nitric oxide synthase (nNOS) inhibitors toward the development of new drugs for neurodegenerative diseases. Various approaches, including enhancing lipophilicity and rigidity of new inhibitors and modulating the pKa of amino groups, have been employed. In addition to determining inhibitor potency and selectivity, crystal structures of most newly designed compounds complexed to various nitric oxide synthase isoforms have been determined. We have discovered a new analogue (21), which exhibits not only excellent potency (Ki < 30 nM) in nNOS inhibition but also a significantly low P-glycoprotein and breast-cancer-resistant protein substrate liabi...
One EMR to Go Please

The confiuence of consumer technologies and electronic health records has resulted in levels of mobility for clinicians previously not seen. In the short span of about 90 days, Partners HealthCare delivered a mobile app, enabling providers to use their consumer smart phones to securely access the organization’s electronic medical record. The mobile EHR app (mEHR) has heavily leveraged existing enterprise architecture, providing for high levels of security, availability, and agility.
Preresolution Drinking Problem Severity Profiles Associated with Stable Moderation Outcomes of Natural Recovery Attempts.

BACKGROUND Higher problem severity contraindicates moderation drinking in treatment samples, but has not been well investigated in natural recovery samples with more prevalent moderation outcomes, nor have single studies assessed multiple severity indicators. Therefore, we integrated 5 prospective studies of recent natural recovery attempts to identify multi-indicator profiles that distinguished moderation from abstinence or unstable resolution involving relapse. The study evaluated whether moderation was distinguished by a generalized lower severity profile or whether more complex profiles better differentiated outcomes. METHODS Community-dwelling problem drinkers in the southeastern United States (N = 616, 67% male, 65% white, mean age = 46.5 years) enrolled soon after stopping alcohol misuse without treatment were followed prospectively for a year. Outcome predictors assessed at enrollment included preresolution drinking practices, alcohol-related problems, alcohol dependence, and a behavioral economic measure of the reward value of drinking based on preresolution spending on alcohol versus saving for the future. RESULTS Latent profile analysis of severity indicators supported a 4-profile solution: (i) global low risk on all indicators, (ii) global high risk on all indicators, (iii) high risk limited to drinking practices only, and (iv) high risk limited to alcohol dependence and alcohol-related problems only. Outcomes differed by profile membership (p < 0.01). Multinomial logistic regression analyses showed that the global low risk and heavy drinking risk only profiles were associated with stable moderation during the 1-year follow-up. The high dependence and alcohol problems risk profile was associated with both abstinence and relapse during the follow-up (ps < 0.05). CONCLUSIONS Consistent with prior research, moderation was associated with lower alcohol dependence, problems, and reward value. Participants who simply drank heavily and did not have elevated risk on other indicators also had a higher probability of moderation. Results support using multidimensional severity indicators that encompass functional variables in addition to drinking practices to predict outcomes.
A Statewide Tiered System for Screening and Diagnosis of Autism Spectrum Disorder

Although autism spectrum disorder (ASD) can be reliably detected in the second year of life, the average age of diagnosis is 4 to 5 years. Limitations in access to timely ASD diagnostic evaluations delay enrollment in interventions known to improve developmental outcomes. As such, developing and testing streamlined methods for ASD diagnosis is a public health and research priority. In this report, we describe the Early Autism Evaluation (EAE) Hub system, a statewide initiative for ASD screening and diagnosis in the primary care setting. Development of the EAE Hub system involved geographically targeted provision of developmental screening technical assistance to primary care, community outreach, and training primary care clinicians in ASD evaluation. At the EAE Hubs, a standard clinical pathway was implemented for evaluation of children, ages 18 to 48 months, at risk for ASD. From 2012 to 2018, 2076 children were evaluated (mean age: 30 months; median evaluation wait time: 62 days), and 33% of children received a diagnosis of ASD. Our findings suggest that developing a tiered system of developmental screening and early ASD evaluation is feasible in a geographic region facing health care access problems. Through targeted delivery of education, outreach, and intensive practice-based training, large numbers of young children at risk for ASD can be identified, referred, and evaluated in the local primary care setting. The EAE Hub model has potential for dissemination to other states facing similar neurodevelopmental health care system burdens. Implementation lessons learned and key system successes, challenges, and future directions are reviewed.
Self-Stabilizing Silicon Nitride Lightsails

We report a design for a microscopic lightsail prototype that allows for passive stabilization in the radiation-pressure dominated regime. Stable dynamics of our silicon nitride structure are predicted for initial tilts of up to ±10°.
Geometrical Scaling Limits of Heat-Assisted Magnetic Recording

System-level requirements for heat-assisted magnetic recording at high areal density are presented in this article. The primary factors that affect bit error rate (BER) are spatial, or media, signal-to-noise ratio (SNR), reader SNR, and channel bit density (CBD). Spatial SNR is largely determined by the interaction between the writer properties and the media properties. For example, how well the thermal gradient matches the grain size. Spatial SNR also depends on how well the reader cross-track resolution matches the track pitch, and the quality of the written pattern. For any given level of spatial SNR, there exists a combination of CBD and reader SNR that results in the desired level of performance. This article elucidates some of the tradeoffs that may be needed to maintain BER as areal density increases, for different bit aspect ratio scenarios. For very high areal density, we show that the geometrical requirements are extremely aggressive, which will most likely require significant invention in head and drive architecture design.
Observation impacts on the Mid-Atlantic Bight front and cross-shelf transport in 4D-Var ocean state estimates: Part II – the Pioneer Array

Abstract The Regional Ocean Modeling System (ROMS) 4-dimensional variational (4D-Var) data assimilation system was used to compute ocean state estimates of the Mid-Atlantic Bight (MAB). A three-level nested grid configuration was employed with horizontal resolution successively enhanced from 7 km down to 800 m at the innermost nest. This captures the dynamics on space- and time-scales ranging from the Gulf Stream western boundary current down to the rapidly evolving and energetic sub-mesoscale circulation. This is a companion study to Levin et al. (2020) which examined the overall impacts of the entire observing system on shelf-break exchange. This follow-on study specifically focuseson the impact of the in situ elements of the ocean observing system on the 4D-Var analyses. The particular focus here is on the Pioneer Array, a high-density observing system in the MAB designed to measure the multi-scale nature of shelf-break exchange processes. Building on Levin et al. (2020), it is found that the relative impact of observations from different components of the Pioneer Array depends on the scales of motion that are resolved by each nested grid. This is in apparent agreement with the linear theory of geostrophic adjustment despite the O(1) Rossby number. The synergy between the observations from different observing platforms has also been quantified by comparing the observation impacts with the sensitivity of the 4D-Var analyses to changes in the observing array. It is found that while some observations do not have a significant direct impact on the analyses, they nevertheless provide essential information about the presence of circulation features, corroborating that measured by other sensors. Thus, the individual parts of the observing system can borrow strength from each other. Finally, the contribution of each component of the observing system to the expected error in the 4D-Var analyses was also quantified, where the critical role played by the Pioneer Array moorings in resolving the sub-mesoscale circulation is again highlighted.
Abstract P225: Health Care Access And Health Indicators In Puerto Rico Pre- And Post- Hurricane Maria: Analysis Of Data From 2015-2018 Behavioral Risk Factor Surveillance System

Background: In September 2017, Hurricane Maria devastated Puerto Rico (PR), in what is now regarded as one of the worst natural disasters in United States (US) history. Natural disasters can impact...
Can Digital Games Teach Scientific Inquiry?: A Case of How Affordances Can Become Constraints

Digital games are increasingly being used to teach the processes of scientific inquiry. These games often make at least one of four key assumptions about scientific inquiry: that inquiry is a problem-solving process which is value-neutral, bounded by strict subject-matter constraints, and conducted by practitioners separable from society. However, feminist, STS, and pragmatist scholars have demonstrated the flawed nature of these assumptions. They highlight instead that: inquiry is a process of problematization that is value-laden, unbounded by subject-matter, and conducted by practitioners who socially, politically, and culturally situated. In this paper, I argue that three of the key affordances of digital games-their procedural, evaluative, and fictional qualities-can constrain their ability to teach inquiry understood as such. I examine these affordances and their relationship to the nature of scientific inquiry through a design case examining our game Solaria designed to teach students how to inquire into the development of solar cells. Specifically, I ask: To what extent can the procedural, evaluative, and fictional affordances of digital games (designed to teach students about solar cells) support the learning of scientific inquiry as a problematizing, situated, and value-laden process, unbounded by subject-matter constraints? I discuss how these affordances of games supported but ultimately limited the design of the game by trivializing real situations, predetermining criteria for progress, and distancing students from real-world risks and responsibilities, respectively. In conclusion, I briefly discuss how understanding these limitations can support the design of educational environments to complement digital games for teaching scientific inquiry.
Chapter 3 – Work of Fishery Scientists

The chapter describes the work of fishery scientists. Initially, fishery scientists were employed by fishery resource agencies for research as well as to teach fishery research. Today, they are employed in fishery resource agencies to collect and evaluate facts concerning the resources and enforce laws and agency regulations. This chapter evaluates the work carried out in intergovernmental fishery commissions and councils, such as the North Atlantic fisheries commission, to collect and publish information. Fishery scientists are also privately employed in fishing companies, fish health services, and environmental research. They work in universities, museums, and research stations in departments teaching and doing research in sciences related to fisheries. The fishery scientists work in agencies with water impoundments, which include urban water departments, irrigation districts, and public hydropower agencies in managing water consumption, water intakes, or water release below the impoundments in ways that favor fish production. Based on the above facts, the scope of work for fishery scientists has expanded from research to professional application of fishery science to diverse environmental and business problems.
Attraction of wild‐like and colony‐reared Bactrocera cucurbitae (Diptera:Tephritidae) to cuelure in the field

The attraction of wild tephritids to semiochemical-based lures is the ideal basis for trap network design in detection programmes, but in practice, mass-reared colony insects are usually used to determine trap efficiency. For Bactrocera cucurbitae Coquillett, a lower response by wild males compared with colony-derived individuals, usually used to estimate attraction parameters, could mean that the sensitivity of detection networks targeting this pest is reduced. We describe the results of mark–release–recapture experiments with wild- and colony-derived B. cucurbitae males in a grid of cuelure-baited traps within a macadamia nut orchard in Hawaii Island designed to quantify the attraction of cuelure to each fly type. For colony males, we estimate a 65% probability of capture at 27 m, intermediate with previous estimates on the attraction of methyl eugenol to Bactrocera dorsalis Hendel (36 m) and trimedlure to Ceratitis capitata Wiedemann (14 m) at the same site. Results suggest similar response over distance by wild-derived B. cucurbitae compared with colony in the field, but there may be qualitative differences in response between wild and colony based on very low response of wild males in a standard bioassay of attraction. For both fly types, the estimates of attraction in the smaller of two grid sizes tested were lower than for the larger spacing, suggesting trap competition was a factor at an intertrap distance of 75 m. Dispersal patterns within the grid were generally to the south for the colony-derived males and more variable for the wild-derived males. In neither case was the direction of recapture correlated with the prevailing direction of the wind.
Interactions between the lateral hypothalamus and the periaqueductal gray

Anatomical and physiological experiments were conducted to characterize the interactions between the lateral hypothalamus (LH) and the periaqueductal gray (PAG) and to determine the role of neurotensin in their interaction. Anatomical studies using injection of Phaseolus vulgaris leucoagglutinin into the LH showed an extensive projection to the ventromedial and the ventrolateral PAG and a less dense projection to the medial and dorsal parts of this region. Physiological experiments were performed on both deeply and lightly anesthetized animals. Electrical stimulation of the LH caused excitation of PAG cells with an onset latency of approximately 14 msec. There was a strong correlation between the response of PAG cells to electrical stimulation and injection of glutamic acid into the LH. Electrical or chemical stimulation of the LH produced an increase in tail flick latency in the lightly anesthetized animals that outlasted the stimulation period. There was a strong correlation between the response of PAG cells to electrical and chemical stimulation of the LH and their response to pressure-injected neurotensin. It is concluded that an excitatory projection from the LH to PAG exists which may involve neurotensin. This pathway may be involved in the analgesia produced by LH stimulation.
Foucault's Normative Epistemology

As this essay will argue, and as this epigraph should suggest, epistemology was a central concern of Michel Foucault's. By denying the conflation of knowledge with power, and consistently maintaining a dyadic relationship ("power/knowledge") rather than a relationship in which power eclipses knowledge, Foucault maintains that knowledge requires its own analysis irreducible to the strategic maneuvers of power. But clearly, given Foucault's political critique of numerous truth claims, to say that Foucault has an epistemology raises the question of what the term epistemology could mean in relation to Foucault's work. The term is often conflated with positivism by continental philosophers, Foucault included, or otherwise used as an oversimplified foil against which a historical approach to the various ways in which knowledge has been defined can be brought up for discussion. "Epistemology," by this caricature, has to approach the question of knowledge as a transcendent entity, akin to Plato's Ideal Forms. But this is not the way many influential analytic philosophers approach it today, from Brandom to Van Fraasen.
Abstract Modeling and Formal Verification of Microprocessors

Moore's Law continues to drive a severe increase in the number of transistors that can be integrated onto a single microprocessor chip. Computer architects and designers continue to look for ways to take advantage from it to produce ever more complex microprocessors. Meanwhile, market forces are dictating a shorter time to market, a proliferation of product and steeper volume ramps in production. However, it is evident that logic correctness is one of the main challenges that computer engineers usually face during the design and validation of such systems. In the last 20 years, researchers and industrial experts invented several modeling and validation technologies, such as logic simulation, fast hardware emulation engines, and formal methods. However the design size and complexity continue to grow and outstrip what the validation techniques can do for producing high quality and correct systems. As a results, the validation problem is becoming more complex to solve and is indeed the main limiter for producing a high quality silicon products. Design abstraction and high level modeling is a fundamental design strategy to cope with system complexity. The basic idea is to hide design implementation details, while focusing on design specification, capturing the pure logic properties and behaviors of the system. Doing this, we believe that the size of the design model can be dramatically decreased because none functional or physical properties of the design are excluded. Therefore the design representation is purely logical and have a clear semantics which it becomes easier to understand, easier and faster to validate using dynamic or formal techniques, so design errors can be detected earlier before going into detailed implementation and thus avoid a costly design iterations due to late soundness issues. In this talk we will present abstract modeling techniques and their verification challenges. In particular we will describe the Abstract State Machines approach for modeling and verification of high level models. In addition we will outline several research topics in this domain to encourage the academic community to take an active part in exploring and developing new verification methods that can cope with the increasing complexity of microprocessors' design.
Structured Interacting Computations

Today, concurrency is ubiquitous, in desktop applications, client-server systems, workflow systems, transaction processing and web services. Design of concurrent systems, particularly in the presence of communication failures, time-outs and interrupts, is still difficult and error-prone. Theoretical models of concurrency focus on expressive power and simplicity, but do not provide high-level constructs suitable for programming. We have been developing a theory, called Orc (for orchestration), and its practical applications. In this paper, we describe our philosophy in designing Orc. The guiding principle is to structure a concurrent program in a hierarchical manner, and permit interactions among subsystems in a controlled fashion. The interactions are described by value passing ; the mode of communication (i.e., whether the value is passed over a channel or kept as shared data, etc.) is left unspecified.
Skirting the Ethical Line: The Quandary of Online Legal Forms

Technology is advancing and its progress has not left the legal profession unaffected.2 Websites are one of the most effective means of reaching the public at large, so much so that it is more common for a law firm to have a website than not to have one—firms without a website are at an incredible marketing disadvantage as compared to those firms that have one.3 In recent years, however, lawyers’ use of websites has gone beyond making a firm’s presence known—their websites now allow the public to generate their own legal documents by simply filling out a standardized form online, resulting in saved expenses, but also creating the potential for future trouble.4
Co‐targeting androgen receptor and DNA for imaging and molecular radiotherapy of prostate cancer: In vitro studies

BACKGROUND The androgen receptor (AR) axis, the key growth and survival pathway in prostate cancer, remains a prime target for drug development. 5-Radioiodo-3′-O-(17β-succinyl-5α-androstan-3-one)-2′-deoxyuridin-5′-yl phosphate (RISAD-P) is the AR-seeking reagent developed for noninvasive assessment of AR and proliferative status, and for molecular radiotherapy of prostate cancer with Auger electron-emitting radionuclides. METHODS RISAD-P radiolabeled with 123I, 124I, and 125I were synthesized using a common stannylated precursor. The cellular uptake, subcellular distribution, and radiotoxicity of 123I-, 124I-, and 125IRISAD-P were measured in LNCaP, DU145, and PC-3 cell lines expressing various levels of AR. RESULTS The uptake of RISAD-P by prostate cancer cells is proportional to AR levels and independent of the radionuclide. The intracellular accumulation of radioactivity is directly proportional to the extracellular concentration of RISAD-P and the duration of exposure. Initially, RISAD-P is trapped in the cytoplasm. Within 24 hr, radioactivity is associated exclusively with DNA. The RISAD-P radiotoxicity is determined by the radionuclide; however, the cellular responses are directly proportional to the AR expression levels. LNCaP cells expressing high levels of AR are killed at the rate of up to 60% per day after a brief 1 hr RISAD-P treatment. For the first time, the AR expression in PC-3 and DU 145 cells, generally reported as AR-negative, was quantitated by the ultra sensitive RISAD-P-based method. CONCLUSIONS RISAD-P is a theranostic drug, which targets AR. Its subcellular metabolite participates in DNA synthesis. RISAD-P is a promising candidate for imaging of the AR expression and tumor proliferation as well as molecular radiotherapy of prostate cancer. Prostate 74: 1634–1646, 2014. © 2014 Wiley Periodicals, Inc.
Changes in premovement activity in primary somatosensory cortex differ when monkeys make hand movements in response to visual vs vibratory cues

Rhesus monkeys were taught to make identical wrist flexion and extension movements in response to either a visual cue or to vibratory cues. Changes in firing rates that were not stimulus-associated but preceded the movements were measured for each primary somatosensory cortical neuron recorded under the two stimulus cued conditions. The onset of the premovement activity changes and the magnitude of these changes differed when visually cued trials were compared with vibratory cued trials that resulted in the same behavioral response. In general, the magnitudes of premovement activity changes were less and the onset of these changes occurred earlier for vibratory cued trials than for the corresponding trials triggered by the visual stimulus. These findings support the hypothesis that centrally generated modulatory influences arriving at primary somatosensory cortical neurons prior to movement onset may differ, depending upon the modality of the stimulus which signals that a movement may be initiated.
Declustering of Clustered Preferential Sampling for Histogram and Semivariogram Inference

Measurements of attributes obtained more as a consequence of business ventures than sampling design frequently result in samplings that are preferential both in location and value, typically in the form of clusters along the pay. Preferential sampling requires preprocessing for the purpose of properly inferring characteristics of the parent population, such as the cumulative distribution and the semivariogram. Consideration of the distance to the nearest neighbor allows preparation of resampled sets that produce comparable results to those from previously proposed methods. A clustered sampling of size 140, taken from an exhaustive sampling, is employed to illustrate this approach.
High-efficiency planar Schottky diode based submillimeter-wave frequency multipliers optimized for high-power operation

We report on a new series of millimeter and submillimeter-wave frequency multipliers specifically optimized for very high-power operation in order to meet the requirements of next generation terahertz instruments for Astrophysics, Planetary science, Earth science and radar imaging applications. New frequency multiplier chips have been designed and fabricated in the 100 GHz to 1 THz range focusing on higher power operation. Initial tests have shown efficiencies of around 30% for a single-chip 105–120 GHz tripler, and 25% for a single-chip 170–200 GHz doubler, when pumped with 500 mW. These results correspond to a factor of 2–3 improvement with regards to previous designs at these frequencies. Similar improvements are expected for the new designs at higher frequencies.
Immuno-spin trapping of a post-translational carboxypeptidase B1 radical formed by a dual role of xanthine oxidase and endothelial nitric oxide synthase in acute septic mice

Post-translational modification of proteins due to exposure to radicals and other reactive species are markers of metabolic and inflammatory oxidative stress such as sepsis. This study uses the nitrone spin-trap DMPO and a combination of immuno-spin trapping and mass spectrometry to identify in vivo products of radical reactions in mice. We report the detection of dose-dependent production of DMPO-carboxypeptidase B1 (CPB1) adducts in the spleens of mice treated with lipopolysaccharide (LPS). Additionally, we report significant detection of DMPO-CPB1 adducts in mice experiencing normal physiological conditions. Treatments with inhibitors and experiments with knock-out mice indicate that xanthine oxidase and endothelial nitric oxide synthase are important sources of the reactive species that lead to CPB1 adduct formation. We also report a significant loss of CPB1 activity following LPS challenge in conjunction with an increase in CPB1 protein accumulation. This suggests the presence of a possible mechanism for CPB1 activity loss with compensatory protein production.
Virus-templated assembly of porphyrins into light-harvesting nanoantennae.

Biological molecules can be used as versatile templates for assembling nanoscale materials because of their unique structures and chemical diversities. Supramolecular organization of molecular pigments, as is found in the natural light-harvesting antenna, has drawn attention for its potential applications to sensors, photocatalytic systems, and photonic devices. Here we show the arrangement of molecular pigments into a one-dimensional light-harvesting antenna using M13 viruses as scaffolds. Chemical grafting of zinc porphyrins to M13 viruses induces distinctive spectroscopic changes, including fluorescence quenching, the extensive band broadening and small red shift of their absorption spectrum, and the shortened lifetime of the excited states. Based on these optical signatures we suggest a hypothetical model to explain the energy transfer occurring in the supramolecular porphyrin structures templated with the virus. We expect that further genetic engineering of M13 viruses can allow us to coassemble othe...
Hiding the word: examining the relationship between a new measure of religiosity and sexual behavior

The relationship between religiosity and sexual behavior has been previously investigated, but researchers have not examined the relationship between the intellectual dimension of religiosity and sexual behavior. In this study, we developed an intellectual measure of religiosity, Hiding the Word (HTW), and examined whether it accounted for variation in the sexual behavior of college students, beyond that for which age and a generic measure of religiosity could account. Results showed, after accounting for age and generic religiosity, HTW made a significant contribution to distinguishing between students who had, and those who had not, engaged in various sexual behaviors. For females, this was the case in three of the five behaviors examined (all except receiving oral sex and participating in unprotected penile-vaginal intercourse at most recent sexual encounter), and for males, two of the four behaviors (sexual intercourse and anal intercourse). HTW was less of a factor in accounting for variation in the frequency of participation. For males, HTW was significant for the frequency of participation in penile-vaginal intercourse, receiving oral sex, and the number of sexual partners in the last month. For females, HTW was significant only for the number of sexual partners in the last month. Thus, religiosity, and specifically HTW, seems to play more of a role in determining whether or not a person has participated in behavior, rather than in the frequency of participation.
Solubility properties of reduced and oxidized ascorbate as determinants of membrane permeation.

Abstract The oil/water distribution coefficients of ascorbic acid and dehydro- L -ascorbic acid have been determined and compared with values for mannitol and lauric acid. In general, the relative degrees of hydrophobicity of the compounds evaluated are lauric acid ⪢ mannitol ≊ dehydro- L -ascorbic acid > ascorbic acid . These findings and recent reports from transport studies do not support the conceot that dehydro- L -ascorbic acid is very hydrophobic and crosses cell membranes rapidly by simple diffusion.
Association of Interpersonal Cognitive Complexity with Communication Skill in Marriage: Moderating Effects of Marital Distress

Little research has examined the influence of social cognition on communicative behaviors that spouses exhibit in conversational interactions. The present study examined the associations between interpersonal cognitive complexity and three marital communication skills: communication effectiveness (generating messages that have the desired outcome), predictive accuracy (anticipating accurately the effects of a message on a receiver), and perceptual accuracy (correctly inferring the intent of a message source). The study also evaluated whether marital distress moderated associations between cognitive complexity and communication skills. Participants (60 couples) discussed a problem from their own marriage and a vignette from the Inventory of Marital Conflicts (Olson & Ryder, 1970) using the communication box. Cognitive complexity was moderately associated with perceptual accuracy, weakly associated with communication effectiveness, and not associated with predictive accuracy. Subsidiary analyses revealed that associations between cognitive complexity and the communication skills were generally stronger in the subsample of distressed couples than in the subsample of nondistressed couples.
Comparison of linear and branched peptide forms (MAPs) in the induction of T helper responses to point-mutated ras immunogens.

Abstract The utility of multiple antigenic peptides (MAPs) for the induction of antibody and cellular immune responses in animal models has been demonstrated for a variety of peptide epitopes involved in human disease. However, little is known about immune responses to MAPs constructed with antigenic tumor epitopes, nor has peptide specificity in branched forms been addressed. A potentially important advantage of the MAP system over linear peptide immunogens for clinical applications is elimination of the need for a protein carrier with its associated toxicity and immunogenicity. Here, we examined cellular immune responses followingin vivoadministration of MAPs incorporating a 13-mer T helper epitope from point-mutated ras p21 (ras V12) and compared the potency of the responses to that of the linear peptide. The Gly → Val mutation in position 12, which is associated with a range of human carcinomas, represents a useful system for evaluating the specificity of the immune response. In initial studies with the point-mutated linear peptide epitope, optimalin vitroproliferation responses were obtained following sc administration of the peptide in a squalane-containing adjuvant formulation. Comparative immunization studies using point-mutated MAPs bearing two, four, or eight branches were administered either in saline or in adjuvant. These studies showed that adjuvant was required for the induction of cellular immune responses using both linear and all three forms of branched peptides. Moreover, there was no apparent advantage of using any of the MAPs vs linear peptide when equivalent mass amounts were administered, i.e., the intensity of the immune response was no greater using any of the branched structures compared to the linear form. Specificity of thein vivoresponses for both the linear and the MAP immunogens was demonstrated by the higher stimulation indices observedin vitroin the presence of the mutant ras V12 vs the normal ras G12 linear peptide. No apparent cellular immune response to the MAP core structure itself was observed. However, a nonspecific response to the two-branched MAP2G12 structure was observed in some assays, the nature of which is unknown at this time. This work represents the first reported investigation of a cellular immune response using MAP immunogens incorporating a tumor-specific peptide epitope and demonstrates that linear peptides are as efficient as three different MAP structures in the generation of specific T cell responses.
Perception of images moving at saccadic velocities during saccades and during fixation

During saccadic eye movements, images of external objects move rapidly across the retina. Small, unpredictable displacements imposed upon a target moving at saccadic velocity were detected with equal accuracy when (1) the retinal image velocity was caused by an eye movement, or (2) when the same velocity was produced during fixation (simulated saccadic conditions). The results provide no evidence of a specific non-visual suppression of vision during saccades, nor of any other compensatory modification of afferent visual inflow which might contribute to our sense of directional stability during saccades.
Nozzle Orientation Effects and Nonlinear Interactions Between Twin Jets of Complex Geometry

In this paper we focus on understanding the behavior of twin nozzles of complex geometry in various yaw orientations. To the best of our knowledge there are no published studies addressing the effects of nozzle orientation on the coupling of twin jets of complex exit geometry. We study the behavior of 1) uniform-exit rectangular nozzles, 2) single-beveled nozzles in a codirected configuration, and 3) single-beveled nozzles in a contradirected configuration. Experiments were carried out at fully expanded Mach numbers ranging from 1.28 to 1.72. Bevel angles of 10 and 30 deg were considered, and microphones located at the nozzle exit plane quantified the coupling using both linear and nonlinear spectral-analysis methods. Nonlinear characteristics were quantified using the nonlinear interaction density metric with a cross-bicoherence cut-off threshold of 0.4. The following interesting results emerged from this study: 1) When nozzles having uniform rectangular exits are yawed, the sound-pressure levels in the internozzle region reduce as the yaw angles are increased, and, at a very high yaw angle, the symmetric coupling regime that existed at the high fully expanded Mach number range (without yaw) is replaced by an antisymmetric coupling regime in the same range. 2) Geometrically similar exits from uniform-exit rectangular nozzles and beveled nozzles in the contradirected configuration showed similar characteristics when studied using linear techniques. However, they revealed information that was hitherto unknown when studied using nonlinear spectral-analysis techniques. It is believed that the results presented in this paper will provide benchmark data to those simulating/designing complex-geometry nozzle systems.
"PSEUDO T3/2" LAW FOR MAGNETIC SURFACES INTERFACES AND SUPERLATTICES

Classical spin-wave theory predicts that the surface magnetisation MS(T) decreases with temperature twice as fast as in the bulk. It is shown that this result which contradicts experiment breaks down at temperatures as low as 1 % TC. The local MS(T) above these temperatures obeys a "pseudo T3/2" law whose prefactor is determined by the local exchange. It is shown that "pseudo T3/2" law holds also for magnetic interfaces and superlattices.
The MARCKS protein plays a critical role in phosphatidylinositol 4,5-bisphosphate metabolism and directed cell movement in vascular endothelial cells.

The MARCKS protein (myristoylated alanine-rich C kinase substrate) is an actin- and calmodulin-binding protein that is expressed in many mammalian tissues. The role of MARCKS in endothelial signaling responses is incompletely understood. We found that siRNA-mediated knockdown of MARCKS in cultured endothelial cells abrogated directed cell movement in a wound healing assay. We used biochemical and cell imaging approaches to explore the role of MARCKS in endothelial signal transduction pathways activated by insulin. Insulin treatment of vascular endothelial cells promoted the dose- and time-dependent phosphorylation of MARCKS. Cell imaging and hydrodynamic approaches revealed that MARCKS is targeted to plasmalemmal caveolae and undergoes subcellular translocation in response to insulin. Insulin treatment promoted an increase in levels of the signaling phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) in plasmalemmal caveolae. The insulin-stimulated increase in caveolar PIP2 was blocked by siRNA-mediated knockdown of MARCKS, as determined using both biochemical assays and imaging studies using FRET-based PIP2 biosensors. The critical role of PIP2 in MARCKS responses was explored by examining the PIP2- and actin-binding proteins Arp2/3 and N-WASP. Insulin promoted the rapid and robust phosphorylation of both N-WASP and Arp2/3, but these phosphorylation responses were markedly attenuated by siRNA-mediated MARCKS knockdown. Moreover, MARCKS knockdown effectively abrogated N-WASP activation in response to insulin, as determined using a FRET-based N-WASP activity biosensor. Taken together, these studies show that MARCKS plays a key role in insulin-dependent endothelial signaling to PIP2 and is a critical determinant of actin assembly and directed cell movement in the vascular endothelium.
Reinforced composite resin foundations for endodontically treated teeth.

Abstract An endodontically treated tooth having a healthy periodontium can contribute long service to the oral apparatus. A reinforced composite resin dowel and core provides the needed reinforcement to combat the effects of occlusal stresses. This allows an endodontically treated tooth to serve the patient as a normal tooth.
"Brown bag" simulations to teach drug utilization review.

Objective. To teach drug utilization review (DUR) skills to pharmacy students and assess their abilities and confidence before and after training.Design. Profile reviews and online and live drug-utilization-review activities of increasing difficulty were incorporated into the first (P1), second (P2), and third (P3) years of the Pharmacy Skills Training Laboratory sequence in a doctor of pharmacy (PharmD) curriculum.Assessment. An online survey instrument was administered to gauge how comfortable students were with specific DUR skills before and after the activities. Students’ confidence in performing specific DUR skills improved after completing the activities.Conclusion. Profile reviews, as well as online and live medication reviews, gave students numerous opportunities to practice drug utilization review skills throughout the first 3 years of the pharmacy curriculum. Students’ confidence in performing specific drug utilization review skills improved after the activities. Students’ ability to perform the...
Alternative chemical-based synthesis routes and characterization of nano-scale particles

Different nano-scale particles have been synthesized by alternative routes: nitrates dehydratation and oxide, or co-formed oxides, reduction by hydrogen. Chemical-based synthesis routes are described and thermodynamics studies and kinetics data are presented to support the feasibility for obtaining single-phase oxides and co-formed two-phase oxides. In addition, the reduction reaction has been applied to successfully produce metal/ceramic nanocomposites. Structural characterization has been carried out by means of X-ray diffraction and, more extensively, transmission electron microscopy operating in conventional diffraction contrast mode (CTEM) and high-resolution mode (HRTEM). Nano-scale size distribution of oxide particles is well demonstrated together with their defect-free structure in the lower range, around 20 nm, size. Structural features related to the synthesized nano-composites are also presented.
Cardiac Myosin Binding Protein-C (MYBP-C) Impedes Actin Filament Motility on Native Mouse Ventricular Thick Filaments Only Within the C-Zone

MyBP-C is a potent modulator of cardiac contractility and is localized to two distinct regions (C-zones) flanking the myosin thick filament (TF) bare zone. To determine whether MyBP-C modulates actomyosin motion generation over the entire length of the TF or only within the C-zones, we isolated native mouse ventricular TFs by mechanical and proteolytic dispersion. Negatively-stained EM images showed 1.6µm long TFs with defined central bare zones. TFs contained intact MyBP-C, confirmed by western blotting with domain specific antibodies. In a total internal reflectance microscopy based motility assay, TFs were imaged using fluorescent ATP and the velocity of fluorescent shards of actin filaments was measured over the entire length of TFs at 100 µM ATP and 20°C. Four distinct velocities were observed, presumably corresponding to motion toward and away from the bare zone, over regions with and without MyBP-C, the average velocity of which was similar to that generated by monomeric myosin in the motility assay (1.0±0.1µm/s). Limiting our analysis to bare zone directed motility, actin moved at 1.8±0.1µm/s starting from the TF end and slowed abruptly to 1.0±0.1µm/s at 285±8nm from the bare zone. In contrast, bare zone directed motility on TFs from MyBP-C knockout mice demonstrated only one velocity (1.7±0.1µm/s), equal to the faster velocity on wildtype (WT) TFs, suggesting the slow velocity on the WT TFs is due to MyBP-C. Similarly, only one bare zone directed velocity (1.9±0.1µm/s) was observed on WT TFs after N-terminal proteolytic truncation of the MyBP-C with calpain to within the MyBP-C motif (C1-C2 linker). We conclude that the N-terminal domains of MyBP-C directly modulate actomyosin motion generation only in a ∼285nm region of the thick filament, presumably the C-zone, where MyBP-C is localized.
A new method for precise determination of iron, zinc and cadmium stable isotope ratios in seawater by double-spike mass spectrometry

The study of Fe, Zn and Cd stable isotopes (δ(56)Fe, δ(66)Zn and δ(114)Cd) in seawater is a new field, which promises to elucidate the marine cycling of these bioactive trace metals. However, the analytical challenges posed by the low concentration of these metals in seawater has meant that previous studies have typically required large sample volumes, highly limiting data collection in the oceans. Here, we present the first simultaneous method for the determination of these three isotope systems in seawater, using Nobias PA-1 chelating resin to extract metals from seawater, purification by anion exchange chromatography, and analysis by double spike MC-ICPMS. This method is designed for use on only a single litre of seawater and has blanks of 0.3, 0.06 and <0.03 ng for Fe, Zn and Cd respectively, representing a 1-20 fold reduction in sample size and a 4-130 decrease in blank compared to previously reported methods. The procedure yields data with high precision for all three elements (typically 0.02-0.2‰; 1σ internal precision), allowing us to distinguish natural variability in the oceans, which spans 1-3‰ for all three isotope systems. Simultaneous extraction and purification of three metals makes this method ideal for high-resolution, large-scale endeavours such as the GEOTRACES program.
Minimum zone separation functionals: The spatial case

Abstract The minimum radial separation measure associated with a convex polytope is computed using basic geometric techniques and an exhaustive search procedure. The minimum volume difference center extends an analogous measure in the plane, and a new measure, the minimum surface-area difference, is defined and computed. The separation functionals associated with perfect cubic forms and regular polytope shapes, as well as a generalized family of convex perfect form are computed for an arbitrary three-dimensional measurement data set. Examples are used to illustrate the methodology and computational experience is described.
Minding the gap: R&D in the Linux kernel

The Linux kernel, since its inception in 1991, has captured the interest of many thousands of developers and millions of users. It recently celebrated its 16th anniversary, includes many millions of lines of code, and is used in production systems around the world. It is also advancing at an increasingly rapid pace, undergoing many changes every single day. Indeed the kernel's importance to many large corporations has sparked a high level of contribution by those companies [3] [4], including the employment of many core kernel developers. Recently Linus Torvalds published statistics relating to contributions to the kernel over the past three years: 96,885 patches attributed to 4068 distinct authors have been accepted [5].
Vibrational spectra of phosphiran, phosphiran-1-d1 and phosphiran-2,3-d4

Abstract Infrared spectra (250–4000 cm −1 ) have been obtained on gas phase samples of phosphiran, phosphiran-1- d 1 , and phosphiran-2,3- d 4 . The Raman spectrum of a liquid sample of phosphiran has also been recorded and polarization data obtained. Frequency shifts in the spectra of the deuterated derivatives, Raman polarization data, vapor phase band contours, and characteristic group frequencies have been utilized in making the vibrational assignments for the phosphiran molecule.