cssi/SciSciGPT-SciSciNet huggingface dataset:
Postcolumn Introduction of an Internal Standard for Quantitative LC−MS Analysis

A method for introducing internal standards by direct infusion into the LC effluent for the quantitative LC−MS analysis of environmental samples is described. This postcolumn introduction method was found to be effective in correcting quantitative errors associated with matrix signal suppression. However, unlike surrogate or volumetric internal standards, the performance of the postcolumn method does not depend on the selection of an internal standard that shares identical elution time with the target analyte. As a result, either structural analogues (target analyte derivatives) or isotopically labeled compounds may be applied as effective internal standards. Furthermore, the postcolumn introduction method allows the application of one internal standard to address signal suppression effects for several analytes in a single LC−MS run. In contrast, volumetric and surrogate introduction methods require an isotopically labeled internal standard for each analyte to be quantified.
Observations of 50/60 Hz power line radiation in the low latitude ionosphere detected by the electric field instrument on the C/NOFS satellite

One of the most ubiquitous forms of EM radiation emanating from the earth's surface is that of power line radiation. Associated with the generation of AC electric power, such emissions are typically launched along conducting power lines that may travel hundreds, or even thousands of km, from generating stations. The fundamental frequencies of such emissions are characteristically 50 Hz or 60 Hz, depending on the regional standards for power generation/consumption. The frequency of this radiation is well below that of the plasma frequency of the ionosphere (typically several MHz) and hence is expected to reflect back to the earth and propagate in the waveguide formed by the earth's surface and the bottom ledge of the ionosphere, typically near 100 km. Given that such power lines are widespread on the exposed lithosphere, the leakage of some ELF emissions associated with electric power generation might nevertheless be expected in the ionosphere, in the same manner in which a small fraction of the power associated with ELF Schumann resonances and lightning sferics have been shown to penetrate into the ionosphere. Despite their known frequency signatures and source locations, the direct detection in space (i.e., in the ionosphere) of 50/60 Hz waves associated with terrestrial power line emissions is, to our knowledge, not commonly observed.
Causal reversibility in Bayesian networks

Causal manipulation theorems proposed by Spirtes et al. and Pearl in the context of directed probabilistic graphs, such as Bayesian networks, offer a simple and theoretically sound formalism for predicting the effect of manipulation of a system from its causal model. While the theorems are applicable to a wide variety of equilibrium causal models, they do not address the issue of reversible causal mechanisms, i.e. mechanisms that are capable of working in several directions, depending on which of their variables are manipulated exogenously. An example involving reversible causal mechanisms is the power train of a car: normally the engine moves the transmission which, in turn, moves the wheels; when the car goes down the hill, however, the driver may want to use the power train to slow down the car, i.e. let the wheels move the transmission, which then moves the engine. Some probabilistic systems can also be symmetric and reversible. For example, the noise introduced by a noisy communication channel does n...
Survey of hearing aid fitting practices for children with multiple impairments.

The fitting of amplification on young children with multiple impairments in addition to hearing loss is a challenge faced regularly by audiologists. However, very little has been published on this ...
Are unionized blue collar jobs more hazardous than nonunionized blue collar jobs

The University of Michigan’s Quality of Employment Survey for 1977 (QES) contains 13 questions pertaining to health and safety conditions at the workplace. Using these questions, together with the injury rate associated with the worker’s industry, this study finds evidence that unionized blue collar jobs are more hazardous than nonunionized blue collar jobs whether hazards are defined as resulting in injury or disease. In addition, the evidence suggests that age, schooling, and being female are negatively associated with the probability of holding a hazardous job. Race has no apparent effect on the probability.
Collective flow by the azimuthal correlation of projectile fragments in relativistic heavy-ion collisions.

An analysis that does not require the determination of reaction plane on an event-by-event basis, and involves only azimuthal correlation function of the projectile fragment pairs, has been employed to measure the collective flow of nuclear matter. Using this technique, we study the flow of projectile fragments of charge Z\ensuremath{\ge}2 produced in $^{197}\mathrm{Au}$ induced-emulsion reactions at 10.6A GeV. The collective flow is observed to be the most pronounced in semicentral collisions. The results are compared with those of $^{28}\mathrm{Si}$ at 14.5A GeV, $^{238}\mathrm{U}$ at 0.96A GeV, $^{84}\mathrm{Kr}$ at 1.52A GeV, and $^{56}\mathrm{Fe}$ at 1.7A GeV.
Probing interactions from solvent‐exchangeable protons and monovalent cations with the 1,2‐propanediol‐1‐yl radical intermediate in the reaction of dioldehydrase

The reaction of adenosylcobalamin-dependent dioldehydrase with 1,2-propanediol gives rise to a radical intermediate observable by EPR spectroscopy. This reaction requires a monovalent cation such as potassium ion. The radical signal arises from the formation of a radical pair comprised of the Co(II) of cob(II)alamin and a substrate-related radical generated upon hydrogen abstraction by the 5′-deoxyadenosyl radical. The high-field asymmetric doublet arising from the organic radical has allowed investigation of its composition and environment through the use of EPR spectroscopic techniques. To characterize the protonation state of the oxygen substituents in the radical intermediate, X-band EPR spectroscopy was performed in the presence of D2O and compared to the spectrum in H2O. Results indicate that the unpaired electron of the steady-state radical couples to a proton on the C(1) hydroxyl group. Other spectroscopic experiments were performed, using either potassium or thallous ion as the activating monovalent cation, in an attempt to exploit the magnetic nature of the 205,203Tl nucleus to identify any intimate interaction of the radical intermediate with the activating cation. The radical intermediate in complex with dioldehydrase, cob(II)alamin and one of the activating monovalent cations was observed using EPR, ENDOR, and ESEEM spectroscopy. The spectroscopic evidence did not implicate a direct coordination of the activating cation and the substrate derived radical intermediate.
Controllers and controlled: an analysis of participant constructions of outpatient commitment

This paper utilises qualitative data to examine outpatient commitment from two points of view: clinicians (the controllers) and clients (the controlled). Outpatient commitment is a legal mechanism whereby ‘mentally ill’ individuals are court-ordered to report to their community mental health centre for treatment. In this paper I provide the reader with an understanding of how outpatient commitment works by allowing clinicians and clients to describe the meaning outpatient commitment has for them. While the experience of outpatient commitment varies, and supports the contention that there are multiple definitions of reality, it is clear that in general clinicians favoured the greater control over clients’ outpatient commitment provided and clients were cognisant of the greater liberty it afforded them. This has important theoretical implications for research into medicalisation and social control, in that providers and clients interpret medical dominance and ideology differentially. Consequently I analyse the interpretations of controllers and controlled from those sociological perspectives relevant to the issues of ideology, power, and social control. I conclude by calling for further investigation of those agents who seek to engage in ‘heretical discourse’ (Bourdieu 1991) which challenge dominant medical constructions.
Physical and physiological correlates of behavioral inhibition.

Previous investigations have suggested that the temperamental quality of inhibition is related to the threshold of reactivity to unfamiliar events within certain limbic structures. In earlier work, children in three independent samples who had been selected to be inhibited were more likely to have blue than brown eyes, whereas uninhibited childern were more likely to have brown eyes. The present study, which selected two-year-old children on the basis of eye color (blue or brown) rather than behavior, found a significant association between blue eyes and behavioral inhibition, and between brown eyes and an uninhibited style. Although the inhibited childern were more likely to have a high and stable heart rate than were the uninhibited children, there was no relation between eye color and these cardiac measures. Several interpretations of the association between these temperamental categories and iris pigmentation are proposed.
Assessment and Treatment of Stereotypic Behavior in Children with Autism and Other Developmental Disabilities: A Thirty Year Review.

Abstract A defining feature of children with autism includes stereotypy, characterized as restrictive and repetitive vocal and motor behavior. The current literature review seeks to (a) determine the number of empirical studies using behavioral interventions to treat stereotypy exhibited by children with autism or other pervasive development disorder, (b) identify the assessment techniques used to determine the function of stereotypy, (c) broadly categorize the treatment procedures, (d) summarize findings of other relevant variables (e.g., participant demographics, experimental setting, change agents used, and topography of stereotypy), and (e) determine the number of studies reporting reliability of the independent variables. Results indicate that a wide variety of stereotypies are represented in the published literature. A majority of studies do not rely on a functional assessment to guide intervention planning and consequence-based approaches are the most common treatment technique. Similar to previous research, measurement of reliability of the independent variables is uncommon.
Regional sensitivity of Greenland precipitation to NAO variability

The North Atlantic Oscillation (NAO) is a primary mode of interannual climate variability for the North Atlantic Ocean Basin and influences the climate over much of Europe and parts of North America. Knowledge of past variability of this oscillatory system is essential for efforts to understand, model, and predict future climate variability, particularly under a warming Earth scenario. As Greenland precipitation is modulated by the NAO, ice core-derived accumulation histories are incorporated into multi-proxy reconstructions. New ice core records from Greenland demonstrate that the NAO's influence on accumulation is temporally and spatially variable. The results presented indicate that (1) NAO modulation of accumulation is strongest and most persistent along the west-central side of Greenland, (2) records from central Greenland should be avoided and (3) the spatial character of the precipitation response to NAO variability has been influenced by the 20th century warming in the high Arctic.
The Social Determinants of Health: Why We Should Care

Adina Preda and Kristin Voigt (2015) have written a provocative article that seeks to challenge major aspects of the current consensus on the significant role social determinants play in shaping po...
Nucleotide sequence analysis of 95 kb near the 3′ end of the murine T-cell receptor αδ chain locus: Strategy and methodology

Abstract The nucleotide sequence of a region at the 3′ terminus of the murine T-cell receptor α δ chain locus is presented. This region, which encodes the constant region genes for α and δ chain polypeptides and all 50 joining gene segments for the α chain polypeptide, spans 94,647 bp and includes more than 50 noncoding sequence elements important for T-cell receptor gene rearrangement and expression. DNA sequencing of this region included complete analysis of two cosmid clones and five additional restriction fragments using a random subcloning approach with various manual and automated sequencing strategies. The automated sequencing strategies hold considerable promise for future large-scale DNA sequencing efforts.
Pressure dependence of space charge deposition in piezoelectric polymer foams: simulations and experimental verification

The piezoelectric activity of PQ-50 cellular polypropylene (PP) foam (an example of a so-called ferroelectret) is measured after repeated charging in a nitrogen atmosphere at a range of pressures between 61 and 381 kPa. The results are compared against simulations using a multilayer electromechanical model based on Townsend’s model of Paschen breakdown and a realistic distribution of void heights determined from scanning electron micrographs. The modeled piezoelectric coefficients versus pressure are in good agreement with experimental data when adjusted Paschen coefficients are used, indicating that the Paschen curve for electric breakdown in gases needs to be modified for dielectric barrier discharges in microcavities. The highest d 33 coefficients were achieved for pressures above 251 kPa. For previously uncharged PP foam, the model predicts an optimal charging pressure of 186 kPa.
Chapter 20 Allergen immunotherapy and standardization and stability of allergen extracts

Allergen immunotherapy (IT) enjoyed widespread use for 50 years before the first controlled studies showing efficacy in allergic rhinitis and allergic asthma were published. IT is allergen specific and results are dose dependent: high-dose therapy is superior to low-dose, and very-low-dose IT (as in Rinkel IT) is ineffective. Double-blind, placebo-controlled studies in allergic rhinitis have shown efficacy for crude short ragweed, antigen E, mountain cedar. Cludosporium, timothy, and orchard grasses. Studies in allergic asthma have shown benefits for northern grasses, cat and dog dander, house dust and dust mite, and Cludosporium. Local intranasal IT is effective with both ragweed aqueous and modified extracts. Oral IT with grass pollen capsules is not effective, nor is bacterial vaccine (respiratory stock vaccine). Several studies of IT have established a clinical benefit from placebo at about 30% of patients.
Note on factor analysis

Certain assumptions and procedures basic to factor analysis are examined from the point of view of the mathematician. It is demonstrated that the Hotelling method does not yield meaningful traits, and an example from the theory of gas mixtures with convertible components is cited as evidence. The justification of current methods for determining the adequacy of the reproduction of a correlation matrix by a factorial matrix is questioned, and ax2 criterion, practical only for a small matrix, is proposed. By means of a hypothetical example from geometry, it is shown that results of a Hotelling analysis are necessarily relative to the population at hand. The factorial effects of the adjunction of a “total test” to a group of tests are considered. Some of the general considerations and questions raised are pertinent to types of analysis other than the Hotelling.
On the flow instabilities in the end-wall region of a surface mounted obstacle

Abstract Visualization of flow in the around a surface mounted obstacle revealed that the pressure gradients imposed on the boundary layer amplified the formation of turbulent spots in the end-wall region. It was observed that the juncture vortices exhibited Λ waveform instability even during the stretching phase that was followed by a rapid amplification and formation of a turbulent spot. The turbulent spot spread laterally as it convected past the attachment and corner region of the end-wall flow. At the Reynolds number used in this investigation the instabilities were always initiated in the region where the primary singular point is located.
Effect of day length upon the vegetative growth, maturity, and tuber characters of the Irish potato

1. Studies concerning the effect of length of day were made on vegetative growth, maturity, and yield and smoothness of tubers of the Irish potato when grown under field and controlled conditions. 2. With field and controlled experiments, plantings under short days showed less vegetative growth, matured earlier, and the potatoes were generally smoother. The opposite effects were obtained under long-day conditions; the plants were very vegetative, matured later, tubers had deeper eyes, and were more irregular in shape, although, the total yields were higher. 3. Seedlings representing several family lines were studied and the resulting segregations could be classified as either long or short-day plants. The parental combinations had a marked influence on whether the resulting seedlings would fall into the long or short-day group.
Coastline responses to changing storm patterns

[1] Researchers and coastal managers are pondering how accelerated sea-level rise and possibly intensified storms will affect shorelines. These issues are most often investigated in a cross-shore profile framework, fostering the implicit assumption that coastline responses will be approximately uniform in the alongshore direction. However, experiments with a recently developed numerical model of coastline change on a large spatial domain suggest that the shoreline responses to climate change could be highly variable. As storm and wave climates change, large-scale coastline shapes are likely to shift—causing areas of greatly accelerated coastal erosion to alternate with areas of considerable shoreline accretion. On complex-shaped coastlines, including cuspate-cape and spit coastlines, the alongshore variation in shoreline retreat rates could be an order of magnitude higher than the baseline retreat rate expected from sea-level rise alone.
Surface attached manganese-oxo clusters as potential contrast agents.

Surface attachment of the manganese–oxo cluster known as Mn-12 provided aqueous solution stabilization that allowed investigation of the use of the cluster as an MRI contrast agent.
A standards-based, peer-reviewed teaching award to enhance a medical school's teaching environment and inform the promotions process.

The authors provide the rationale, design, and description of a unique teaching award that has enhanced Baylor College of Medicine's teaching environment and become highly valued by the promotions and tenure (PT increasing the recognition, importance, and value of teaching; encouraging the improvement of teaching skills; and providing a better understanding to others about what medical teachers really do. Of the 214 open-ended responses to survey questions of award recipients, more than half the comments were about the value of the award and its positive effect on promotion.
Detection of bile acids in thin-layer chromatography.

Abstract A spray reagent consisting of anisaldehyde (0.5 ml), glacial acetic acid (50 ml), and concentrated sulfuric acid (1 ml) is a sensitive means of detecting bile acids in thin-layer chromatography. Quantities as small as 1 μg may be easily detected. The bile acids give characteristic colors with this reagent, thus making identification easier.
Development of novel formulations that enhance adenoviral-mediated gene expression in the lung in vitro and in vivo.

Despite remarkable progress in the development of both viral and non-viral gene delivery vec-tors for cystic fibrosis therapy, low efficiency of gene transfer to the airway epithelium is a major obstacle to clinical application. Here we develop formulations that enhance cellular absorption of adenoviral vectors. We selected excipients from a panel of pharmaceutically acceptable com-pounds known to enhance drug absorption. Transduction efficiency of the virus in the presence of each ingredient was assessed in vitro and in vivo. Mannitol and chitosan substantially enhanced transduction efficiency in vitro and augmented expression in vivo by 4 and 8 log units, respectively. The most successful formulation (a blend of sucrose, mannitol, and Pluronic F68) transduced 100% of an A549 cell population in vitro and produced areas of intense gene expression in both large and small airways in vivo with minimal toxicity. Dose response studies also indicate that when placed in this formulation, the viral dose can be lowered by 1/2 log while maintaining superior levels of transgene expression. This formulation also enhanced the physical stability of the virus. No significant loss in titer was detected from a lyophilized formulation after storage at 25°C for 30 days.
Using a Personal Response System to Map Cognitive Efficiency and Gain Insight into a Proposed Learning Progression in Preparatory Chemistry.

Personal response systems (“clickers”) have become an important means for instructors to gauge student learning in large lecture classes. In addition to measuring students’ performance on a particular question, requesting a measure of mental effort from students allows for richer data concerning student learning. This information can be provided to an individual student for a better gauge of his or her understanding of specific content, allowing that student to target his or her studies for subsequent assessments. Mental effort information also provides instructors with an opportunity to consider instructional interventions based on more than just performance. Lastly, using measures of both performance and reported mental effort can provide a better understanding of the learning progression. This paper describes using performance and mental effort data on review items given regularly in lecture with clickers in order to train the students to use the study reports and the mental effort rating system. The combination of high or low clicker performance and high or low mental effort was examined with exam performance and final grade as well as performance within specific content areas. A progression of high–low clicker performance and high–low mental effort and performance on assessments or in the course is discussed.
Impaired oxidation of Nervonic acid in fibroblasts of patients with Zellweger Syndrome and X-linked Adrenoleukodystrophy. † 622

Impaired oxidation of Nervonic acid in fibroblasts of patients with Zellweger Syndrome and X-linked Adrenoleukodystrophy. † 622
Neoadjuvant Chemotherapy Monitoring with Diffuse Optical Measurement of Blood Flow in Breast Tumors

Preliminary results from diffuse optical spectroscopy and diffuse correlation spectroscopy on a patient going through a neoadjuvant chemotherapy demonstrate feasibility to utilize these methods for early response monitoring to the cancer therapy.
Isolating mesoscale coupled ocean-atmosphere interactions in the Kuroshio Extension region

Abstract The Kuroshio Extension region is characterized by energetic oceanic mesoscale and frontal variability that alters the air–sea fluxes that can influence large-scale climate variability in the North Pacific. We investigate this mesoscale air-sea coupling using a regional eddy-resolving coupled ocean–atmosphere (OA) model that downscales the observed large-scale climate variability from 2001 to 2007. The model simulates many aspects of the observed seasonal cycle of OA coupling strength for both momentum and turbulent heat fluxes. We introduce a new modeling approach to study the scale-dependence of two well-known mechanisms for the surface wind response to mesoscale sea surface temperatures (SSTs), namely, the ‘vertical mixing mechanism’ (VMM) and the ‘pressure adjustment mechanism’ (PAM). We compare the fully coupled model to the same model with an online, 2-D spatial smoother applied to remove the mesoscale SST field felt by the atmosphere. Both VMM and PAM are found to be active during the strong wintertime peak seen in the coupling strength in both the model and observations. For VMM, large-scale SST gradients surprisingly generate coupling between downwind SST gradient and wind stress divergence that is often stronger than the coupling on the mesoscale, indicating their joint importance in OA interaction in this region. In contrast, VMM coupling between crosswind SST gradient and wind stress curl occurs only on the mesoscale, and not over large-scale SST gradients, indicating the essential role of the ocean mesocale. For PAM, the model results indicate that coupling between the Laplacian of sea level pressure and surface wind convergence occurs for both mesoscale and large-scale processes, but inclusion of the mesoscale roughly doubles the coupling strength. Coupling between latent heat flux and SST is found to be significant throughout the entire seasonal cycle in both fully coupled mode and large-scale coupled mode, with peak coupling during winter months. The atmospheric response to the oceanic mesoscale SST is also studied by comparing the fully coupled run to an uncoupled atmospheric model forced with smoothed SST prescribed from the coupled run. Precipitation anomalies are found to be forced by surface wind convergence patterns that are driven by mesoscale SST gradients, indicating the importance of the ocean forcing the atmosphere at this scale.
Tragacanth solutions III*: The Effect of pH on the Stability

The effect of pH on the viscosity of tragacanth solutions during storage was studied. Tragacanth solutions exhibited maximum stability near pH 5.
Multiple Chemical Sensitivity (MCS): The Controversy and Relation to Interior Design

It is important for designers to become knowledgeable on multiple chemical sensitivity (MCS) as it relates to indoor air quality (IAQ). It is also important to design spaces and specify materials for the built environment that promotes good IAQ. MCS is a condition in which a person reports sensitivity or intolerance to a number of chemicals and other irritants at very low concentrations (EPA, 2003). Within the medical community, MCS has been controversial, and still is today, regarding its name, definition, diagnosis, and treatment. Some physicians consider MCS a psychological illness or phenomenon, while other physicians and clinical ecologists treat patients with MCS. However, research indicates that many individuals have become ill from chemicals emitted from materials within interior spaces. A consensus on MCS within the medical community is essential. The relevance of MCS for the design community is that many materials used in building construction, interior finishes and furnishings, and products for installations contain chemicals that may trigger MCS. Therefore, it is essential that designers specify safe, healthy materials. Since many designers (architects and interior designers) are working to improve IAQ, they could take the initiative for change by working collaboratively on research with the medical community and individuals with MCS; by educating other designers about appropriate product specifications; and by becoming a legislative advocate.
Surface compression using a space of C 1 cubic splines with a hierarchical basis

A method for compressing surfaces associated with C1 cubic splines defined on triangulated quadrangulations is described. The method makes use of hierarchical bases, and does not require the construction of wavelets.
Estimating tidal current amplitudes outside estuaries and characterizing the zone of estuarine tidal influence

Abstract Tidal currents within many estuaries are stronger than on the adjacent continental shelf. Estuarine tidal influence extends onto the shelf elevating tidal amplitudes above ambient shelf levels over a region outside the estuary. In this paper, a kinematic theory that describes tidal flow in these estuary–shelf tidal interaction zones is derived and tested. Using these results, tidal current amplitudes outside estuaries are estimated and the range and intensity of estuarine tidal influence is characterized. The estimates for the tidal current amplitudes (utide) of the dominant constituent are appropriate for linear or weakly nonlinear systems with predominantly barotropic tides; the ratio of tidal height to water depth is small (η/h≪1) in linear or weakly nonlinear regimes. Within tidal interaction zones, the tidal current amplitude is composed of an ambient shelf part (ua) and an estuary-induced part (ue). The characteristic shelf amplitude far from the estuary is used to set ua. Continuity arguments indicate that ue (averaged over a control volume arc centered on the mouth with radius r and a swath angle of γπ) approximately equals the ratio of the tidal volume flux through the mouth (Vm) and the cross-sectional area of any control volume arc ( u e ≈ V m / γ π r h ¯ ) . This approximation holds where the squared product of the tidal wave number and radial distance is small: (kr)2≪1. For a shelf with constant slope α and small coastal wall depth, the arc-averaged depth is h ¯ ≈ sr (where s=2α/pi for γ=1). For this shelf bathymetry, ue decays with squared radial distance from the estuary mouth. Theoretical predictions are consistent with observed tidal current amplitudes outside the Delaware Bay and Block Island Sound. In both test cases, the estimated and observed amplitudes exhibit an r−2 dependence and decay over a similar distance. The relative importance of estuarine tidal influence is assessed with the tidal interaction index (Ti=ue/ua). The intensity of estuarine influence is characterized by the value of Ti at the mouth (Tim). The extent of an estuary–shelf tidal interaction zone is measured by the interaction radius ri (where Ti=1) and by r∞ (where Ti=0.1). These metrics are used to compare the tidal interaction zone characteristics for the Delaware Bay, Block Island Sound, several other major estuaries, and a small tidal inlet. The kinematic theory can be applied outside other estuaries where only limited tidal information is available or used to interpret observed patterns in tidal amplitudes and characterize the degree of estuarine influence.
Cytoplasmic Forms of Human T-Cell Leukemia Virus Type 1 Tax Induce NF-κB Activation

Human T-cell leukemia virus type 1 (HTLV-1) Tax targets I-κBα and I-κBβ for phosphorylation, ubiquitination, and proteasome-mediated degradation, causing the nuclear translocation of NF-κB/Rel proteins and transcription induction of many cellular genes. The mechanism by which a nuclear protein such as Tax stimulates I-κB phosphorylation and degradation remains unclear. Here, we describe two cytoplasmic mutants of Tax, designated TaxΔN81 and TaxΔN109, from which the domains important for cyclic AMP response element binding factor (CREB) and serum response factor (SRF) binding and nuclear transport have been removed. These mutants were unable to trans activate from the HTLV-1 21-bp repeats or the serum response element in the c-fos promoter. In contrast, they activated NF-κB reporters, suggesting that activation of NF-κB by Tax occurs in the cytoplasm. Incorporation of the nuclear localization signal (NLS) of the simian virus 40 large T antigen into TaxΔN81 and TaxΔN109 redirected both proteins predominantly to the nucleus yet did not restore trans activation via CREB or SRF. The NLS fusion had little effect on TaxΔN81 but reduced NF-κB trans activation by TaxΔN109, possibly because of its proximity to the NF-κB-activating domain of Tax. In contrast to wild-type Tax, the cytoplasmic TaxΔN mutants are not cytotoxic. Stable expression of TaxΔN109 in HeLa cells resulted in a significant reduction in the intracellular level of I-κBα, with the constitutive presence of NF-κB in the nucleus and concomitant activation of the NF-κB enhancer. These results are suggestive of a potential application of the TaxΔN109-like mutants in targeting I-κB degradation and NF-κB activation. Interestingly, a Tax species with a molecular mass similar to that of TaxΔN109 was identified in many HTLV-1-transformed T cells, suggesting that TaxΔN109-like species might play a role in HTLV-1-induced leukemogenesis.
T cell targeted immunotherapy for autoimmune disease

Much emphasis has been placed on the so-called “biologics” in the treatment of immune disorders within the last few years. Here we discuss the expanding horizon of potential strategies for immunotherapies targeting T lymphocytes as key effectors and regulators of autoimmunity. We review emerging reagents in a variety of animal models and human disorders that may offer new therapeutic options in current or modified iterations.
Initiation -Promotion Versus Complete Skin Carcinogenesis in Mice: Importance of Dark Basal Keratinocytes (Stem Cells)

Tumor promotion research has accelerated at an explosive level during the past decade and continues to do so because of its importance to the understanding of the induction of human cancer. Furthermore, the promotion process, being mostly reversible allows one to find very effective ways to prevent cancer. The extensive data available as well as the multistage nature of tumor promotion suggests that this process, which is thought to occur in most tissues where cancer can be induced or occurs spontaneously, may involve the interaction of a number of environmental factors such as chemical, radiation, viruses and diet and nutrition, thus unifying all of the current areas of cancer research. In terms of human cancer, smoking, asbestos, radiation, alcohol and diet, and nutrition just to mention a few, are not thought to have more than a promotional influence in the carcinogenesis process. Here and in later papers we will discuss some important aspects of promotion as well as discuss the possible controversial ...
Perturbation biology nominates upstream–downstream drug combinations in RAF inhibitor resistant melanoma cells

Drugs that target the activity of specific genes could potentially form precise cancer therapies. Some cancers, including the aggressive skin cancer called melanoma, initially respond well to such treatments. However, resistance to drugs develops quickly, leading to the rapid regrowth of the tumors. Resistance can develop in a number of ways. For example, to prevent the drug from working or to compensate for the effects of a drug, cancer cells can adapt their signaling processes or acquire genetic mutations or other modifications that affect how genes are expressed. A well-designed combination of drugs that targets multiple molecular pathways can make it harder for cells to resist treatment, as this limits the number of available ‘escape’ pathways that bypass the drug targets. However, it is difficult to accurately predict how a cell will respond when treated with a particular drug, making it extremely challenging to design effective drug combinations. In 2013, researchers developed a technique to build predictive models of cellular response pathways based on data collected from perturbation experiments followed by mathematical modeling. Now, Korkut et al.—including several of the researchers involved in the 2013 work—have refined this technology and applied it to the problem of preventing drug resistance in cancer cells. Computer simulations that used the mathematical models suggested a particular strategy of ‘upstream–downstream targeting’ in cells that were insensitive to the clinically successful drug vemurafenib (an inhibitor of RAF proteins, which are often mutated in cancers). In the landscape of signaling pathways, the target of the upstream drug is on or near the mutated RAF protein. c-Myc, the indirect target of the downstream drug helps to express genes that trigger signals that cause the cells to grow. Inhibiting both targets in parallel may have the dual advantage of blocking the activation of the tumor-specific growth pathway while reducing the cancer cells' attempts to bypass the activation block. An initial test of the designed drug combination required moving from computer simulations to the laboratory using cell cultures originally derived from melanoma tumors. When Korkut et al. applied the drug combination, the combined treatment successfully blocked cell growth. The results suggest that the data-driven computer modeling strategy termed perturbation biology could be a useful tool for identifying effective cancer drug combinations for further preclinical research, possibly followed by clinical trials.
Generation of Long Internal Gravity Waves in Waveguides by Rising Buoyant Air Masses and Other Sources

Summary The displacement fields generated in an internal gravity wave waveguide between plane rigid walls are compared for two types of source: an explosive point source and a rising buoyant sphere moving at constant speed. It is concluded that for large enough spheres and comparable energy expenditures, the buoyant sphere is a far more efficient source of long internal gravity waves. In particular it appears possible to conclude that, in the case of large events such as nuclear or volcanic explosions in the atmosphere, the rising heated air mass can generate long wavelength (Λ > 500 km) internal gravity waves at ionospheric heights.
Tumour Necrosis Factor α Enhances CCL2 and ICAM-1 Expression in Peripheral Nerve Microvascular Endoneurial Endothelial Cells:

Recruitment and trafficking of autoreactive leucocytes across the BNB (blood-nerve barrier) is an early pathological insult in GBS (Guillain-Barre syndrome), an aggressive autoimmune disorder of the PNS (peripheral nervous system). Whereas the aetiology and pathogenesis of GBS remain unclear, pro-inflammatory cytokines, including TNFα (tumour necrosis factor α), are reported to be elevated early in the course of GBS and may initiate nerve injury by activating the BNB. Previously, we reported that disrupting leucocyte trafficking in vivo therapeutically attenuates the course of an established animal model of GBS. Here, PNMECs (peripheral nerve microvascular endothelial cells) that form the BNB were harvested from rat sciatic nerves, immortalized by SV40 (simian virus 40) large T antigen transduction and subsequently challenged with TNFα. Relative changes in CCL2 (chemokine ligand 2) and ICAM-1 (intercellular adhesion molecule 1) expression were determined. We report that TNFα elicits marked dose- and time-dependent increases in CCL2 and ICAM-1 mRNA and protein content and promotes secretion of functional CCL2 from immortalized and primary PNMEC cultures. TNFα-mediated secretion of CCL2 promotes, in vitro, the transendothelial migration of CCR2-expressing THP-1 monocytes. Increased CCL2 and ICAM-1 expression in response to TNFα may facilitate recruitment and trafficking of autoreactive leucocytes across the BNB in autoimmune disorders, including GBS.
Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis

Expansion of a polyglutamine repeat in huntingtin causes Huntington's disease (HD). Although full-length huntingtin is predominantly distributed in the cytoplasm, N-terminal fragments of huntingtin with expanded polyglutamine tracts are able to accumulate in the nucleus and kill neurons through apoptotic pathways. Transgenic mice expressing N-terminal mutant huntingtin show intranuclear huntingtin accumulation and develop progressive neurological symptoms. Inhibiting caspase-1 can prolong the survival of these HD mice. How intranuclear huntingtin is associated with caspase activation and apoptosis is unclear. Here we report that intranuclear huntingtin induces the activation of caspase-3 and the release of cytochrome c from mitochondria in cultured cells. As a result, cells expressing intranuclear huntingtin undergo apoptosis. We show that intranuclear huntingtin increases the expression of caspase-1, which may in turn activate caspase-3 and trigger apoptosis. We propose that the increased level of caspase-1 induced by intranuclear huntingtin contributes to HD-associated cell death.
The Moderating Effect of Perceived Risk on Consumers’ Evaluations of Product Incongruity: Preference for the Norm

Research supports the existence of a “moderate incongruity effect” such that an option that is moderately inconsistent with an evoked product category schema is sometimes preferred to a congruent option. We propose that perceived risk is an important situational factor that moderates the impact of congruity on evaluations. Three studies show that the positive evaluation of moderately incongruent products, relative to congruent ones, does not appear when there is risk associated with product selection. When consumers perceive high risk associated with a purchase, the moderate incongruity effect is reversed such that the congruent is preferred to the moderately incongruent product. Only in conditions where subjects perceived no real risk did the positive effect of moderate incongruity appear. The limiting effect of perceived risk appears to be due to consumers’ “preferences for the norm” under high‐risk conditions. The set of findings are discussed as they relate to and extend current thinking about the eff...
Lysine-91 of the tetraheme c-type cytochrome CymA is essential for quinone interaction and arsenate respiration in Shewanella sp. strain ANA-3

The tetraheme c-type cytochrome, CymA, is essential for arsenate respiratory reduction in Shewanella sp. ANA-3, a model arsenate reducer. CymA is predicted to mediate electron transfer from quinols to the arsenate respiratory reductase (ArrAB). Here, we present biochemi- cal and physiological evidence that CymA interacts with menaquinol (MQH2) substrates. Fluorescence quench titra- tion with the MQH2 analog, 2-n-heptyl-4-hydroxyquinoline- N-oxide (HOQNO), was used to demonstrate quinol binding of E. coli cytoplasmic membranes enriched with various forms of CymA. Wild-type CymA bound HOQNO with a Kd of 0.1-1 lM. It was also shown that the redox active MQH2 analog, 2,3-dimethoxy-1,4-naphthoquinone (DMNH2), could reduce CymA in cytoplasmic membrane preparations. Based on a CymA homology model made from the NrfH tetraheme cytochrome structure, it was predicted that Lys91 would be involved in CymA-quinol interactions. CymA with a K91Q substitution showed little interaction with HOQNO. In addition, DMNH2-dependent reduction of CymA-K91Q was diminished by 45% compared to wild- type CymA. A DcymA ANA-3 strain containing a plasmid copy of cymA-K91Q failed to grow with arsenate as an electron acceptor. These results suggest that Lys91 is physiologically important for arsenate respiration and support the hypothesis that CymA interacts with menaquinol resulting in the reduction of the cytochrome.
Hoxa9 influences the phenotype but not the incidence of Mll-AF9 fusion gene leukemia

Identification of the targets of mixed lineage leukemia (MLL) fusion genes will assist in understanding the biology of MLL fusion gene leukemias and in development of better therapies. Numerous studies have implicated HOXA9 as one of the possible targets of MLL fusion proteins. To determine if HOXA9 was required for leukemia development by MLL fusion genes, we compared the effects of the Mll-AF9 knock-in mutation in mice in the presence or absence of Hoxa9 . Both groups of mice showed myeloid expansion at 8 weeks and then developed myeloid leukemia with a similar incidence and time course. The leukemia in the mice lacking Hoxa9 generally displayed a more immature myeloid phenotype than that in the mice that were wild-type for Hoxa9. Gene expression profiling revealed that expression of Mll-AF9 led to overexpression of Hoxa5, Hoxa6, Hoxa7, Hoxa9, and Hoxa10. Thus, genes of the Hox-a cluster are important in defining the phenotype but not the incidence of Mll-AF9 leukemia. These results demonstrate that the Mll-AF9 fusion gene disrupts the expression of several Hox genes, none of which as a single gene is likely to be necessary for development of leukemia. Instead, we propose that the “ Hox code” minimally defined by the Hoxa5-a9 cluster is central to MLL leukemogenesis.
Attention moderates the fearlessness of psychopathic offenders.

Background Psychopathic behavior is generally attributed to a fundamental, amygdala-mediated deficit in fearlessness that undermines social conformity. An alternative view is that psychopathy involves an attention-related deficit that undermines the processing of peripheral information, including fear stimuli. Methods We evaluated these alternative hypotheses by measuring fear-potentiated startle (FPS) in a group of 125 prisoners under experimental conditions that 1) focused attention directly on fear-relevant information or 2) established an alternative attentional focus. Psychopathy was assessed using Hare's Psychopathy Checklist-Revised (PCL-R). Results Psychopathic individuals displayed normal FPS under threat-focused conditions but manifested a significant deficit in FPS under alternative-focus conditions. Moreover, these findings were essentially unchanged when analyses employed the interpersonal/affective factor of the PCL-R instead of PCL-R total scores. Conclusions The results provide unprecedented evidence that higher-order cognitive processes moderate the fear deficits of psychopathic individuals. These findings suggest that psychopaths' diminished reactivity to fear stimuli, and emotion-related cues more generally, reflect idiosyncrasies in attention that limit their processing of peripheral information. Although psychopathic individuals are commonly described as cold-blooded predators who are unmotivated to change, the attentional dysfunction identified in this study supports an alternative interpretation of their chronic disinhibition and insensitive interpersonal style.
T‐cell tolerance or function is determined by combinatorial costimulatory signals

Activated in immune responses, T lymphocytes differentiate into effector cells with potent immune function. CD28 is the most prominent costimulatory receptor for T-cell activation. However, absence of CD28 costimulation did not completely impair effector function of CD4 or CD8 T cells. Moreover, increasing number of costimulatory molecules are recently found on antigen-presenting cells to regulate T-cell activation. To understand the molecular mechanisms that determine T-cell function or tolerance, we have collectively examined the roles of positive and negative costimulatory molecules. Antigen-specific naive CD4 and CD8 T cells, only when activated in the absence of both CD28 and ICOS pathways, were completely impaired in effector function. These tolerant T cells not only were anergic with profound defects in TcR signal transduction but also completely lacked expression of effector-specific transcription factors. T-cell tolerance induction in this system requires the action by negative costimulatory molecules; T-cell proliferation and function was partially restored by inhibiting PD-1, B7-H3 or B7S1. This work demonstrates that T-cell function or tolerance is controlled by costimulatory signals.