cssi/SciSciGPT-SciSciNet huggingface dataset:
Promoting α-secretase cleavage of beta-amyloid with engineered proteolytic antibody fragments

Deposition of beta-amyloid (Aβ) is considered as an important early event in the pathogenesis of Alzheimer's Disease (AD), and reduction of Aβ levels by various therapeutic approaches is actively being pursued. A potentially non-inflammatory approach to facilitate clearance and reduce toxicity is to hydrolyze Aβ at its α-secretase site. We have previously identified a light chain fragment, mk18, with α-secretase-like catalytic activity, producing the 1–16 and 17–40 amino acid fragments of Aβ40 as primary products, although hydrolysis is also observed following other lysine and arginine residues. To improve the specific activity of the recombinant antibody by affinity maturation, we constructed a single chain variable fragment (scFv) library containing a randomized CDR3 heavy chain region. A biotinylated covalently reactive analog mimicking α-secretase site cleavage was synthesized, immobilized on streptavidin beads, and used to select yeast surface expressed scFvs with increased specificity for Aβ. After two rounds of selection against the analog, yeast cells were individually screened for proteolytic activity towards an internally quenched fluorogenic substrate that contains the α-secretase site of Aβ. From 750 clones screened, the two clones with the highest increase in proteolytic activity compared to the parent mk18 were selected for further study. Kinetic analyses using purified soluble scFvs showed a 3- and 6-fold increase in catalytic activity (kcat/KM) toward the synthetic Aβ substrate compared to the original scFv primarily due to an expected decrease in KM rather than an increase in kcat. This affinity maturation strategy can be used to select for scFvs with increased catalytic specificity for Aβ. These proteolytic scFvs have potential therapeutic applications for AD by decreasing soluble Aβ levels in vivo. © 2009 American Institute of Chemical Engineers. Biotechnol. Prog., 2009
Underlying disease stress augments plasma and tissue adrenomedullin (AM) responses to endotoxin: colocalized increases in AM and inducible nitric oxide synthase within pancreatic islets.

Rapid onset metabolic impairments accompany the initiation of the acute phase response to many disease stresses, whereas more chronic metabolic perturbations may prolong the recovery period. In the present experiment the application of a mild endotoxin challenge [lipopolysaccharide (LPS)] alone or additive to a chronic subclinical parasitic infection (Sarcocystis cruzi; LPS 1 PI) in calves was used as a model to investigate and define a dynamic axis coordinated between adrenomedullin (AM) and nitric oxide in response to immune challenge. Plasma AM and NO2/NO3 concentration responses after LPS (0.45 mg/kg, iv) were rapid in onset and of higher magnitude and longer duration in PI 1 LPS calves than in those challenged with LPS alone. The post-LPS increase in plasma insulin was significantly greater in PI 1 LPS than in LPS; following refeeding of calves, insulin secretion was most blunted in PI 1 LPS calves, consistent with the inhibitory effects of NO and AM on insulin secretion. A more chronic response to the immune challenge (organ specific) was in evidence in tissues harvested 24 h after LPS challenge. Where lung and liver showed no immunostaining for inducible nitric oxide (iNOS), iNOS immunostaining was present in the pancreas, localized to islets only. The percentages of iNOS-immunopositive cells in islets were 1.7%, 21%, 6.7%, and 24% for control (C; saline infused), PI, LPS, and PI 1 LPS calves, respectively. AM immunostaining was not evident in the liver and was present, but not differentially affected by treatment, in airway epithelium in the lung. The number of islet cells with positive immunostaining for AM was increased in LPS, PI, and PI 1 LPS calves. The percentages of AM-immunopositive cells in islets were 8%, 27%, 20%, and 33% for C, PI, LPS, and PI 1 LPS, respectively. Immunostaining for AM and iNOS was colocalized with cells positive for pancreatic polypeptide. By triple label confocal fluorescence immunocytochemistry, colocalization of intense AM and iNOS immunostaining was confirmed in peripheral islet cells. A weaker, more diffuse iNOS signal was also apparent in insulin-containing cells in PI 1 LPS. We conclude that chronic low level infection potentiates the severity of metabolic perturbations that arise with additive sudden onset immune challenge, as can occur with bacterial toxins. These metabolic disturbances are reflected in and possibly mediated by early onset increases in plasma tumor necrosis factor-a, insulin, and AM and up-regulated iNOS activity. These acute complications rapidly progress into a more chronic state characterized by diminished insulin response to feeding stimulus and colocalized increases in pancreatic islet AM and iNOS. The pancreatic responses in AM and iNOS may play a major role in mediating prolonged disturbances in nutrient use by tissues through their influences on temporal patterns of pancreatic hormone secretion during chronic illness. (Endocrinology 140: 5402‐5411, 1999)
The induced axial vector coupling for muon-neutrino electron scattering in weak vector-like models

Abstract The recent negative findings of parity-violation searches in atomic physics have enhanced interest in weak-interaction models characterized by purely vectorial couplings for the electron and muon neutral currents. Even for such models. however, axial couplings of order α arise already from one-loop corrections. We analyze these induced couplings in the context of ν μ +e→ ν μ +e scattering.
Right Pulmonary Vein Potentials Recorded from the Posterior Right Atrial Endocardium: Human Case Report and Validation in a Porcine Model

A 33-year-old woman underwent successful catheter ablation of an atrial tachycardia emanating from deep within a large right superior pulmonary vein (RSPV). A previous ablation attempt in this patient had failed, during which radiofrequency energy applications were made to the posterior right atrium only. The mistaken impression of a right atrial source for this tachycardia was due to RSPV potentials that were recorded during mapping in a region of the posterior right atrium contiguous to the vein ("contiguity region"). To further evaluate this, we performed activation mapping and radiofrequency ablation in atria of healthy pigs. Similar to the reported case, "biatrial" potentials were recorded from both left and right aspects of the contiguity region. Radiofrequency energy application altered only the potential emanating from the atrium in which the lesion was applied. Histologic analysis confirmed that the lesion was limited to this atrium. It is concluded that, due to their proximity, electrical activity in the RSPV may be recorded from certain areas of the posterior right atrium, and vice versa. In the reported case of left atrial tachycardia, this led to the mistaken impression of right atrial tachycardia.
A proposal for a new HIV-1 DLS structural model

The dimer initiation site/dimer linkage sequence (DIS/DLS) region of the human immunodeficiency virus type 1 (HIV-1) RNA genome is suggested to play essential roles at various stages of the viral life cycle. Through a novel assay we had recently developed, we reported on the necessary and sufficient region for RNA dimerization in the HIV-1 virion. Using this system, we performed further detailed mapping of the functional base pairs necessary for HIV-1 DLS structure. Interestingly, the study revealed a previously unnoticed stem formation between two distantly positioned regions. Based on this and other findings on functional base pairing in vivo, we propose new 3D models of the HIV-1 DLS which contain a unique pseudoknot-like conformation. Since this pseudoknot-like conformation appears to be thermodynamically stable, forms a foundational skeleton for the DLS and sterically restricts the spontaneous diversification of DLS conformations, its unique shape may contribute to the viral life cycle and potentially serve as a novel target for anti-HIV-1 therapies.
Synthesis of new building blocks for boron-rich oligomers in boron neutron capture therapy (BNCT). I.

Abstract The synthesis of carborane-containing subunits for use in the construction of boronated oligophosphates via solid phase synthesis is described.
Microbial transformations of tin and tin compounds

The use of organotins for agricultural and industrial purposes and in the marine environment has been increasing steadily for more than 20 years. Recently, reliable methodologies have been developed to permit quantification of individual molecular species of organotins in cultures and in the environment. Particular attention has been given to methyltins which can be formed abiotically and by microorganisms, and to tributyltins which are toxic components of effective antifouling paints. In the aquatic environment tin, tributyltins and other organotins accumulate in the surface microlayer, in sediments, and on suspended particulates. Tin compounds are toxic to a variety of organisms and some aquatic organisms can bioaccumulate them. When tin compounds, particularly di-or tri-substituted tins, enter an ecosystem, a portion of the microbial population is killed. Among the survivors are organisms which can methylate inorganic or organic tins, but the relative contribution of biotic and abiotic mechanisms is not clear. While many details of methylations and demethylations need to be worked out, it is clear that transformations of tins can influence the toxicity, volatility and mobility of tin in natural ecosystems. Tributyltins can be debutylated by microorganisms, and hydroxybutyl tins may be intermediates, as they are in mammalian systems. Little is known of the potential and probable microbial transformations of other economically important organotins, but the transformations should be studied for they may have industrial and environmental importance.
Coenzyme A-Independent Transacylation in Amnion-Derived (WISH) Cells

Abstract Total membranes or microsomal fractions prepared from the amnion-derived WISH cell line posses a coenzyme A-independent transacylase activity. The transacylase utilizes 1-alkenyl- and 1-alkyl-2-lysoglycerophospholipids as preferred accepters. Marginal transacylation was observed with 1-acyl-2-lysoglycerophospholipids. The reaction occurred in the presence of ethylene glycol bis(β-aminoethyl ether)- N , N ′-tetraacetic acid and was not affected by phospholipase A 2 inhibitors. Both 1-acyl- or 1-alkyl-glycerophosphocholines containing an arachidonoyl residue in the sn -2 position were effective as donors, while 2-oleoyl- or 2-palmitoyl-glycerophosphocholines were ineffective. The presence of the transacylase, the specificity of the substrates, and the stability of the 1-alkenyl bond provide a biochemical model that may explain the increased proportion of a highly enriched arachidonate-containing phosphatidylethanolamine-plasmalogens fraction that is found in amnion at term.
Behavioural responses to predators and predation risk in four species of larval anurans

Tadpoles of four anuran species show interspecific behavioural differences that could explain differential predation on these species in artificial ponds. Replicated observations of tadpoles in aquaria revealed that the spring peeper, Hyla crucifer, is quiescent and benthic; Fowler's toad, Bufo woodhousei, is active and benthic; the grey treefrog, Hyla versicolor, is active and pelagic; and the Pine Barrens tree frog, Hyla andersonii, is intermediate in activity and microhabitat position. Species with high activity levels survived poorly in independent artificial pond predation studies, relative to less active species. Costs of low activity level may include poor competitive ability, and/or slow development with increased risk of death from pond drying. Comparisons of tadpole behaviour in aquaria with and without predators present demonstrate that all four species decrease activity with a salamander, the red-spotted newt, Notophthalmus viridescens, and a fish, the black-banded sunfish, Enneacanthus obesus. Hyla andersonii became more benthic with these predators. Hyla versicolor and H. andersonii decreased conspicuous activities in response to a dragonfly naiad, Pantala. Bufo woodhousei responded to E. obesus even though B. woodhousei tadpoles are unpalatable to fish. Inactive H. crucifer responded less to predators than other species but survived well with predators. Baseline prey activity levels (observed in the absence of predators) may be more important than shifts in activity levels in response to predators in determining differential predation.
Schooling in Mass Society.

A changed society makes necessary changed schools, which in turn make necessary new research modes and paradigms.
Linear elasticity of planar delaunay networks. Part II: Voigt and Reuss bounds, and modification for centroids

The linear elastic Delaunay network model developed in a previous paper is used to obtain further results on mechanical properties of graph-representable materials. First, we investigate the error involved in the uniform strain approximation — a computationally inexpensive approach widely employed in the determination of effective moduli of granular and fibrous media. Although this approximation gives an upper bound on the macroscopic moduli, it results in very good estimates of their second order statistics. In order to derive a lower bound another window definition has to be introduced. Also, an energy-based derivation of both bounds is given. The final result relates to a modification of a Delaunay network so that its vertices correspond to the centroids of cells of the corresponding Voronoi tessellation; an increase of effective moduli and a decrease of their scatter are observed.
A mechanism for a class of solar coronal disturbances

A new ideal magnetohydrodynamic (MHD) model is used to examine the dynamical response of the upper solar atmosphere to the injection of cold mass from the photosphere, a surge perturbation. Theoretical results show that mass ejections from the photosphere will form loop structures with internally-moving plasma blobs, which is due to the mass injections from both legs in active regions leading to a reflection of waves at the top of the loop. The mass-loaded loop will remain as long as ejection continues, and will excite MHD waves propagating outward to the upper atmosphere, which may trigger a class of coronal disturbances.
The peripheral sympathetic nervous system in rat strains selectively bred for differences in response to stress

Male rats of two Maudsley Nonreactive sublines, the MNRA/Har and MNR/Har strains, both selected for low levels of open-field defecation (OFD), exhibit higher concentrations of norepinephrine (NE) in descending and transverse colon than Maudsley Reactive (MR/Har) males, selected for high levels of OFD. These differences in NE concentration in regions of the gastrointestinal system involved in defecation support the hypothesis that genetic selection for differences in OFD in the Maudsley strains has been mediated by alterations in their peripheral sympathetic nervous system (SNS). Rats of one Nonreactive subline (MNRA/Har) also had higher NE concentrations than MR/Har animals in small intestine and submaxillary gland; thus, previous data on other organs (heart, spleen, adrenal) and the present findings show that the differences in NE concentration between MR/Har and the MNRA/Har subline have been found in most peripheral tissues studied and may reflect a widespread influence of genes on the SNS. On the other hand, differences in tissue NE concentration between MR/Har and the other Nonreactive subline (MNR/Har) were restricted to descending and transverse colon in the present study. Thus, when considering strain variation in the SNS across all three Maudsley strains the present results suggest that both general and organ-specific factors contribute to their determination.
Complement 1q-binding protein inhibits the mitochondrial permeability transition pore and protects against oxidative stress-induced death

Opening of the MPT (mitochondrial permeability transition) pore is a critical event in mitochondrial-mediated cell death. However, with the exception of CypD (cyclophilin D), the exact molecular composition of the MPT pore remains uncertain. C1qbp (complement 1q-binding protein) has recently been hypothesized to be an essential component of the MPT pore complex. To investigate whether C1qbp indeed plays a critical role in MPT and cell death, we conducted both gain-of-function and loss-of-function experiments in MEFs (mouse embryonic fibroblasts). We first confirmed that C1qbp is a soluble protein that localizes to the mitochondrial matrix in mouse cells and tissues. Similarly, overexpression of C1qbp in MEFs using an adenovirus resulted in its exclusive localization to mitochondria. To our surprise, increased C1qbp protein levels actually suppressed H2O2-induced MPT and cell death. Antithetically, knockdown of endogenous C1qbp with siRNA (small interfering RNA) sensitized the MEFs to H2O2-induced MPT and cell death. Moreover, we found that C1qbp could directly bind to CypD. Therefore C1qbp appears to act as an endogenous inhibitor of the MPT pore, most likely through binding to CypD, and thus protects cells against oxidative stress.
DIVERSIFICATION, DOUBLE LEVERAGE, AND THE COST OF CAPITAL

Public utility regulators choose between “double leverage” and “independent company” approaches to determine the cost of equity capital for electric utility holding companies that have diversified and telephone holding companies that have diversified and issued parent debt. Dissimilarities between these two approaches result in significant differences in cost of capital estimates, in allowed rates of return, and in prices of utility services. No valid support for the “double leverage” approach is found after an analysis of descriptive examples and a general theoretical examination of the two approaches compared against established goals of rate of return regulation. The “independent company” approach is shown to be universally correct. The authors suggest, therefore, that only the “independent company” approach should be employed in rate of return cases of regulated public utilities whose parents own subsidiaries with unequal risk and/or whose parent has its own debt.
The eight genes of bacteriophages φX174 and S13 and comparison of the phage-specified proteins

Abstract Complementation tests between phages S13 and φX174 show that the two phages have at least eight homologous essential genes. Gel electrophoresis of the phage-specified proteins give results which are very similar for the two phages.
The influence of age and genetics on natural resistance to experimentally induced feline infectious peritonitis

Naturally occurring feline infectious peritonitis (FIP) is usually fatal, giving the impression that immunity to the FIP virus (FIPV) is extremely poor. This impression may be incorrect, because not all cats experimentally exposed to FIPV develop FIP. There is also a belief that the incidence of FIP may be affected by a number of host, virus, and environmental cofactors. However, the contribution of these cofactors to immunity and disease incidence has not been determined. The present study followed 111 random-bred specific pathogen free (SPF) cats that were obtained from a single research breeding colony and experimentally infected with FIPV. The cats were from several studies conducted over the past 5 years, and as a result, some of them had prior exposure to feline enteric coronavirus (FECV) or avirulent FIPVs. The cats were housed under optimized conditions of nutrition, husbandry, and quarantine to eliminate most of the cofactors implicated in FIPV infection outcome and were uniformly challenge exposed to the same field strain of serotype 1 FIPV. Forty of the 111 (36%) cats survived their initial challenge exposure to a Type I cat-passaged field strains of FIPV. Six of these 40 survivors succumbed to FIP to a second or third challenge exposure, suggesting that immunity was not always sustained. Exposure to non-FIP-inducing feline coronaviruses prior to challenge with virulent FIPV did not significantly affect FIP incidence but did accelerate the disease course in some cats. There were no significant differences in FIP incidence between males and females, but resistance increased significantly between 6 months and 1 or more years of age. Genetic testing was done on 107 of the 111 infected cats. Multidimensional scaling (MDS) segregated the 107 cats into three distinct families based primarily on a common sire(s), and resistant and susceptible cats were equally distributed within each family. Genome-wide association studies (GWAS) on 73 cats that died of FIP after one or more exposures (cases) and 34 cats that survived (controls) demonstrated four significant associations after 100k permutations. When these same cats were analyzed using a sib-pair transmission test, three of the four associations were confirmed although not with genome-wide significance. GWAS was then done on three different age groups of cases to take into account age-related resistance, and different associations were observed. The only common and strong association identified between the various GWAS case configurations was for the 34.7-45.8Mb region of chromosome A3. No obvious candidate genes were present in this region.
Solar Energetic Fe Charge State Measurements: Implications for Acceleration by Coronal Mass Ejection--driven Shocks

A variety of studies have demonstrated that large (gradual) solar energetic particle (SEP) events are produced by shocks driven by fast coronal mass ejections (CMEs). As the CME-driven shocks propagate through the corona and interplanetary space, they accelerate energetic particles from ambient plasma. A key piece of evidence supporting the CME-driven shock acceleration scenario is the SEP Fe mean charge state measurements from ~1 MeV nucleon-1 to 200-600 MeV nucleon-1, which are consistent with each other and imply acceleration in either the high corona or interplanetary space. However, the SEP Fe mean ionic charge state measurements are generally inconsistent with typical quasi-stationary interstream or coronal hole solar wind Fe charge state measurements, despite the fact that gradual SEP time profiles indicate that shock acceleration subsequent to departure from the corona dominates the SEP observations. These Fe results indicate that neither overtaken solar wind nor charge state biasing of the solar wind as it is swept up and accelerated by the shock are the dominant component accelerated by the CME-driven shock. We suggest that the dominant component for both the plasma and SEP populations appears to be expelled "coronal" plasma stored in the so-called sheath region (between the CME and the shock front), and that swept-up solar wind generally makes only a minor contribution to the SEPs. The only concurrent observation of SEP and solar wind charge states made to date (by instruments on board ISEE 3 in 1978 September) supports this view. We suggest that coordinated SEP and solar wind charge state observations should be given high priority by state-of-the-art instruments currently deployed on board the Solar Anomalous Magnetospheric Particle Explorer, Wind, and the Solar and Heliospheric Observatory.
Enhancing Mental Health Treatment Engagement for Vulnerable Older Populations

Mental disorders are common in late life and are associated with extensive personal and societal costs. Developing and implementing health services models that improve engagement in effective treatments may reduce disparities in outcomes for older adults with mental disorders. However, while a number of effective treatments exist, many older adults, especially from underserved communities, may not be benefitting from them. Novel strategies that improve treatment engagement may not only improve outcomes but also provide opportunities for older adults to participate in cutting-edge research. Moreover, older adults may greatly benefit from emerging health services initiatives such as the Patient-Centered Outcomes Research Initiative (PCORI) that are focused on patient-centered care as well as new policies for caring for vulnerable populations (e.g., dual-eligibles). We will review cutting-edge health services research tailored to older adults with mental disorders, with a particular focus on novel strategies that are aimed to improve treatment engagement and reduce disparities in outcomes. The focus will be on emerging issues in the use of peer and other non-clinical providers as well as information technology to both engage and tailor mental health treatments across a wide range of older populations including Veterans, persons of color, and those with medical complexity. The potential policy implications of these emerging health services strategies will be discussed within the context of new initiatives including the Patient-Centered Outcomes Research Initiative and those who are dually covered under Medicare and Medicaid (i.e., dual-eligibles). Faculty Disclosures: Colin A. Depp, PhD Nothing to disclose Ariel Gildengers, MD Nothing to disclose Amy Kilbourne, PhD, MPH Nothing to disclose Martha Sajatovic, MD Research Support: GlaxoSmithKline N/A Research Support: Pfizer N/A Research Support: Merck N/A Research Support: AstraZeneca N/A EVOLVING ROLES FOR GERIATRIC MENTAL HEALTH PROVIDERS IN THE 21ST CENTURY HEALTHCARE SYSTEM Joel E. Streim, MD; David W. Oslin, MD; Benjamin Liptzin, MD; Gary S. Moak, MD University of Pennsylvania, Philadelphia, PA Philadelphia VA Medical Center, Philadelphia, PA Baystate Medical Center, Springfield, MA Tufts University, Boston, MA Moak Center for Health Aging, Westborough, MA University of Massachusetts, Wooster, MA S14 Am J Geriatr Psychiatry 21:3, Supplement 1
Texture segregation by visual cortex: Perceptual grouping, attention, and learning

A neural model called dARTEX is proposed of how laminar interactions in the visual cortex may learn and recognize object texture and form boundaries. The model unifies five interacting processes: region-based texture classification, contour-based boundary grouping, surface filling-in, spatial attention, and object attention. The model shows how form boundaries can determine regions in which surface filling-in occurs; how surface filling-in interacts with spatial attention to generate a form-fitting distribution of spatial attention, or attentional shroud; how the strongest shroud can inhibit weaker shrouds; and how the winning shroud regulates learning of texture categories, and thus the allocation of object attention. The model can discriminate abutted textures with blurred boundaries and is sensitive to texture boundary attributes like discontinuities in orientation and texture flow curvature as well as to relative orientations of texture elements. The model quantitatively fits the Ben-Shahar and Zucker [Ben-Shahar, O. & Zucker, S. (2004). Sensitivity to curvatures in orientation-based texture segmentation. Vision Research, 44, 257-277] human psychophysical data on orientation-based textures. Surface-based attentional shrouds improve texture learning and classification: Brodatz texture classification rate varies from 95.1% to 98.6% with correct attention, and from 74.1% to 75.5% without attention. Object boundary output of the model in response to photographic images is compared to computer vision algorithms and human segmentations.
Toward a Contemporary Doctrine of the Immanent Trinity: Karl Barth and the Present Discussion

What is the purpose of a doctrine of the immanent Trinity? Broadly speaking it aims to recognize, uphold and respect God's freedom. Without theoretical and practical awareness of this freedom all theological statements about the significance of created existence become ambiguous and constitute merely human attempts to give meaning to creation using theological categories.
High-Pressure Chemistry of Carbon Nitride Materials

The composition and properties of the sp2-bonded carbon nitride precursor paracyanogen (pCN) has been studied at high pressures and temperatures. Paracyanogen decomposes to carbon and molecular nitrogen with the decomposition temperature increasing with pressure over the range of 3 to 19 GPa. Prior to decomposition, pCN can be transformed to an atmospheric-pressure quenchable phase that is more than 25% higher in density and over an order of magnitude harder than the starting material. Structural analysis of this quenchable phase shows, however, that it consists of a sp2-bonded network. In addition, the decomposition kinetics of paracyanogen have been studied in detail. Rapid, self-propagating decomposition occurs above a threshold temperature. Below this, decomposition rates exhibit an Arrhenius behavior with activation energy and volume of 2.7 eV and 3.9 A3, respectively The decomposition rates depend on the nitrogen density and decrease significantly with lower nitrogen concentration. Kinetic effects favoring a graphite-like, sp2-bonded structure may preclude the high-pressure synthesis of superhard, sp3-bonded carbon nitride solids below their thermodynamic stability limit, unless an optimally designed precursor is employed.
Independence diagrams: A technique for data visualization

An important issue in data visualization is the recognition of complex dependencies between attributes. Past techniques for identifying attribute dependence include correlation coefficients, scatterplots, and equi-width histograms. These techniques are sen- sitive to outliers, and often are not sufficiently informative to identify the kind of attribute dependence present. We propose a new ap- proach, which we call independence diagrams. We divide each at- tribute into ranges; for each pair of attributes, the combination of these ranges defines a two-dimensional grid. For each cell of this grid, we store the number of data items in it. We display the grid, scaling each attribute axis so that the displayed width of a range is proportional to the total number of data items within that range. The brightness of a cell is proportional to the density of data items in it. As a result, both attributes are independently normalized by fre- quency, ensuring insensitivity to outliers and skew, and allowing specific focus on attribute dependencies. Furthermore, indepen- dence diagrams provide quantitative measures of the interaction be- tween two attributes, and allow formal reasoning about issues such as statistical significance. We have addressed several technical challenges in making independence diagrams work, ranging from the treatment of categorical attributes to visual artifacts of cell-to- pixel mapping. Our experimental evaluation, using both AT&T and synthetic data, shows that independence diagrams allow the easy identification of various kinds of attribute dependence that would be difficult to identify using conventional techniques. © 2000 SPIE and IS&T. (S1017-9909(00)01704-9)
Translating costimulation blockade to the clinic: lessons learned from three pathways

As the recognition that costimulatory signals are critical for optimal T-cell activation, proliferation, and differentiation, there has been an explosion in the study of costimulatory molecules and their roles in enhancing anti-donor T-cell responses following transplantation. Here, we focus on the bench-to-beside translation of blocking agents designed to target three critical costimulatory pathways: the CD28/CD80/CD86 pathway, the CD154/CD40 pathway, and the lymphocyte function associated antigen-1/intercellular adhesion molecule pathway. While blockade of each of these pathways proved promising in inhibiting donor-reactive T-cell responses and promoting long-term graft survival in murine models of transplantation, the progression of development of therapeutic agents to block these pathways has each taken a slightly different course. Both logistical and biological pitfalls have accompanied the translation of blockers of all three pathways into clinically applicable therapies, and the development of costimulatory blockade as a substitute for current standard-of-care calcineurin inhibitors has by no means reached completion. Collaboration between both the basic and clinical arenas will further propel the development of costimulation blockers currently in the pipeline, as well as of novel methods to target these critical pathways during transplantation.
Holding Homebuilders Liable for Personal Injury and Property Damage Caused by Defective Material: Chinese Drywall Case

AbstractFaced with the stark reality that Chinese drywall manufacturers might not respond to American judgments, some homeowners affected by Chinese drywall excluded them from their lawsuits. Instead, these homeowners sought redress exclusively from homebuilders. This paper focuses on this unique approach of suing only the homebuilder that built the home with defective Chinese drywall and proposes that homeowners be given the opportunity to utilize the same legal theories available to other product consumers. This paper provides relevant background information on the subject matter and presents four common legal theories homeowners can use against homebuilders. The paper provides existing law for each legal theory and analogous case law involving other defective construction materials. Finally, in the conclusions section, the paper provides a discussion on why homeowners should sue homebuilders exclusively and how the courts should respond to the Chinese drywall problem.
Role of Toll-Like Receptor Signaling in the Apoptotic Response of Macrophages to Yersinia Infection

Macrophages encode several Toll-like receptors (TLRs) that recognize bacterial components, such as lipoproteins (TLR2) or lipopolysaccharides (TLR4), and activate multiple signaling pathways. Activation of transcription factor NF-κB by TLR2 or TLR4 signaling promotes proinflammatory and cell survival responses. Alternatively, TLR2 or TLR4 signaling can promote apoptosis if the activation of NF-κB is blocked. The gram-negative bacterial pathogen Yersinia pseudotuberculosis secretes into macrophages a protease (YopJ) that inhibits the activation of NF-κB and promotes apoptosis. We show that primary macrophages expressing constitutively active inhibitor κB kinase β (IKKβ) are completely resistant to YopJ-dependent apoptosis, indicating that YopJ inhibits signaling upstream of IKKβ. Apoptosis is reduced two- to threefold in TLR4−/− macrophages infected with Y. pseudotuberculosis, while the apoptotic response of TLR2−/− macrophages to Y. pseudotuberculosis infection is equivalent to that of wild-type macrophages. Therefore, TLR4 is the primary source of apoptotic signaling in Yersinia-infected macrophages. Our results also show that a small percentage of macrophages can die as a result of an apoptotic process that is YopJ dependent but does not require TLR2 or TLR4 signaling.
(R)‐(+)‐3,4‐Dimethylcyclohex‐2‐en‐1‐one

(2R,5R)-(+)-trans-Dihydrocarvone Copper(II) acetate monohydrate Ferrous sulfate heptahydrate R-(+)-6-Methoxycyclo-2-en-1-one Methyllithium-lithium bromide (6R)-(+)-1,6-Dimethylcyclohex-2-en-1-ol Pyridinium chlorochromate Keywords: dimethylcyclohexenone; waste disposal; cyclohexenone; Ender's methodology; asymmetric synthesis; natural products; irones Essential oils; perfumes
Optimistically building a consensus sequence using F-inexact matches (DNA)

Biological and physical limitations require that DNA be sequenced in fragments. During the process of sequencing the DNA, errors are occasionally introduced. This paper addresses the problem of reconstructing the original DNA sequence given only the fragments that may contain errors. The authors give a new algorithm based on suffix arrays to solve the problem of reconstructing the original DNA sequence. A worst-case and expected-case time analysis of the algorithm is presented. A program based on this algorithm is used to reconstruct the human beta globin region on chromosome 11 (HUMHBB in GenBank) when given a set of 300 to 500 mers drawn randomly from the HUMHBB locus. >
Effects of microstructure on oxygen permeation in some perovskite oxides

The effects of microstructure on the oxygen permeation in SrCo{sub 0.8}Fe{sub 0.2}O{sub 3{minus}{delta}} (SCFO) and La{sub 0.2}Sr{sub 0.8}Fe{sub 0.8}Cr{sub 0.2}O{sub 3} (LSFCO) was investigated using disc samples fabricated under different processing conditions. The microstructure of LSFCO remained unchanged when the sintering temperature was increased from 1,300 to 1,450 C, but the average grain size of SCFO increased considerably when the sintering temperature was increased from 930 to 1,200 C. The change in grain size was found to have a strong effect on the oxygen permeation flux in SCFO, which increased considerably as the grain size was decreased. This indicates that the contribution of the grain boundary diffusion to the steady state oxygen flux in SCFO is substantial and grain boundaries provide faster diffusion paths in oxygen permeation through the samples.
Nilpotent approximation and nilpotentization for under-actuated systems on matrix Lie groups

Develops a method for constructing nilpotent approximations for local representations of invariant systems on matrix Lie groups via a simple operation on the structure constants of the associated Lie algebra. The crucial role such nilpotent approximations play for the problem of feedback nilpotentization is discussed. The presented ideas are illustrated with an example modeling the kinematics of an under-actuated rigid body.
Simultaneous state, Vt and Tox assignment for total standby power minimization

Standby leakage current minimization is a pressing concern for mobile applications that rely on standby modes to extend battery life. Also, gate oxide leakage current (I/sub gate/) has become comparable to subthreshold leakage (I/sub sub/) in 90 nm technologies. In this paper, we propose a new method that uses a combined approach of sleep-state, threshold voltage (V/sub t/ and gate oxide thickness (T/sub ox/) assignments in a dual-V/sub t/ and dual-T/sub ox/ process to minimize both I/sub sub/ and I/sub gate/. Using this method, total leakage current can be dramatically reduced since in a known state in standby mode, only certain transistors are responsible for leakage current and need to be considered for high-V/sub t/ or thick-T/sub ox/ assignment. We formulate the optimization problem for simultaneous state, V/sub t/ and T/sub ox/ assignments under delay constraints and propose two practical heuristics. We implemented and tested the proposed methods on a set of synthesized benchmark circuits. Results show an average leakage current reduction of 5a-6X and 2-3X compared to previous approaches that only use state or state+V/sub t/ assignment, respectively, with small delay penalties.
How scientists view the public, the media and the political process

We review past studies on how scientists view the public, the goals of communication, the performance and impacts of the media, and the role of the public in policy decision-making. We add to these...
Cytogenetic and molecular localization of tipE: A gene affecting sodium channels in Drosophila melanogaster

Voltage-sensitive sodium channels play a key role in nerve cells where they are responsible for the increase in sodium permeability during the rising phase of action potentials. In Drosophila melanogaster a subset of temperature-sensitive paralytic mutations affect sodium channel function. One such mutation is temperature-induced paralysis locus E (tipE), which has been shown by electrophysiology and ligand binding studies to reduce sodium channel numbers. Three new gamma-ray-induced tipE alleles associated with either visible deletions in 64AB or a translocation breakpoint within 64B2 provide landmarks for positional cloning of tipE. Beginning with the flanking cloned gene Ras2, a 140-kb walk across the translocation breakpoint was completed. Germline transformation using a 42-kb cosmid clone and successively smaller subclones localized the tipE gene within a 7.4-kb genomic DNA segment. Although this chromosome region is rich in transcripts, only three overlapping mRNAs (5.4, 4.4, and 1.7 kb) lie completely within the smallest rescuing construct. The small sizes of the rescuing construct and transcripts suggest that tipE does not encode a standard sodium channel alpha-subunit with four homologous repeats. Sequencing these transcripts will elucidate the role of the tipE gene product in sodium channel functional regulation.
New technologies, old practices: the traditional use of electronic courseware in the changing geography of the classroom

Electronic course management software has emerged as a significant aspect of instructional technology infrastructure among institutions of higher education. This study sought to investigate the ways in which electronic courseware is being adopted by higher educational institutions, and how this technological change might impact the role of the instructor and the geography of the classroom. Results summarizing general trends in the use of an electronic courseware system in one large private research university are reported and impacts on changing pedagogical practices are discussed.
Cascaded over- and under-coupled resonators (COUR): reducing group delay dispersion and overcoming the sensitivity-bandwidth trade-off

Cascaded over- and under-coupled resonators (COUR) result in slow light followed by fast light. COUR can be used as a notch filter and phase modulator that overcomes the trade-offs of extinction-ratio-group-delay and sensitivity-bandwidth.
Emotion, Emotion Regulation, and Psychopathology An Affective Science Perspective

Many psychiatric disorders are widely thought to involve problematic patterns of emotional reactivity and emotion regulation. Unfortunately, it has proven far easier to assert the centrality of "emotion dysregulation" than to rigorously document the ways in which individuals with various forms of psychopathology differ from healthy individuals in their patterns of emotional reactivity and emotion regulation. In the first section of this article, we define emotion and emotion regulation. In the second and third sections, we present a simple framework for examining emotion and emotion regulation in psychopathology. In the fourth section, we conclude by highlighting important challenges and opportunities in assessing and treating disorders that involve problematic patterns of emotion and emotion regulation.
Advancing a Family Perspective in Health Research: Models and Methods

In this essay we review and respond to four problems that have impeded the application of family theory to health research: the difficulty in translating family concepts to empirical health research; the confusion and uncertainty in measuring "wholes" and "parts" of a family in a single health project; the apparent conflict between circular-causal and linear perspectives in model building; and the putative, implicit "violation" of a family perspective by the employment of certain data management and design strategies. We argue that current, complex conceptualizations of the family have to be matched with equally complex research designs and methods, and that techniques are available to reach these goals. We distinguish between theoretical models and research methods, and review several strategies, design issues, and alternatives for data analysis. Throughout, we point to 1) the need to maintain consistency among theory, construct, and indicator, 2) the employment of multidimensional family assessment in health research, and 3) the use of readily available but infrequently used methods and procedures for appreciating the richness of multivariate family data.
Scaling time warp-based discrete event execution to 104 processors on a Blue Gene supercomputer

Lately, important large-scale simulation applications, such as emergency/event planning and response, are emerging that are based on discrete event models. The applications are characterized by their scale (several millions of simulated entities), their fine-grained nature of computation (microseconds per event), and their highly dynamic inter-entity event interactions. The desired scale and speed together call for highly scalable parallel discrete event simulation (PDES) engines. However, few such parallel engines have been designed or tested on platforms with thousands of processors. Here an overview is given of a unique PDES engine that has been designed to support Time Warp-style optimistic parallel execution as well as a more generalized mixed, optimistic-conservative synchronization. The engine is designed to run on massively parallel architectures with minimal overheads. A performance study of the engine is presented, including the first results to date of PDES benchmarks demonstrating scalability to as many as 16,384 processors, on an IBM Blue Gene supercomputer. The results show, for the first time, the promise of effectively sustaining very large scale discrete event execution on up to 104 processors.
Importance of good nonlinear analysis

Nonlinear analysis is becoming a popular tool for performance evaluation of structural systems at the life safety and collapse prevention levels. The challenge is to develop analytical tools and component models that make it possible to conduct such analysis with a sufficient degree of confidence. An exact replication of reality is desirable but not critical because of many sources of uncertainty, such as ground motion intensity and frequency content, and modeling uncertainties, which cannot be eliminated by the most accurate analysis. As summarized in this paper, there are several options to nonlinear analysis, and the simplest one that gets close to reality is usually the best one. Observation of behavior during the analysis (whether pushover or time history) is perhaps more important than a rigorous quantitative evaluation based on maximum recorded force or deformation values. In the author's opinion, the main objective of nonlinear analysis is to understand behavior rather than fulfill code-specified limit values. This paper presents arguments why this is a critical issue, even though it is understood that reality in engineering practice usually dictates priority to fulfilling code specified limits.
External memory best-first search for multiple sequence alignment

Multiple sequence alignment (MSA) is a central problem in computational biology. It is well known that MSA can be formulated as a shortest path problem and solved using heuristic search, but the memory requirement of A* makes it impractical for all but the smallest problems. Partial Expansion A* (PEA*) reduces the memory requirement of A* by generating only the most promising successor nodes. However, even PEA* exhausts available memory on many problems. Another alternative is Iterative Deepening Dynamic Programming, which uses an uninformed search order but stores only the nodes along the search frontier. However, it too cannot scale to the largest problems. In this paper, we propose storing nodes on cheap and plentiful secondary storage. We present a new general-purpose algorithm, Parallel External PEA* (PE2A*), that combines PEA* with Delayed Duplicate Detection to take advantage of external memory and multiple processors to solve large MSA problems. In our experiments, PE2A* is the first algorithm capable of solving the entire Reference Set 1 of the standard BAliBASE benchmark using a biologically accurate cost function. This work suggests that external best-first search can effectively use heuristic information to surpass methods that rely on uninformed search orders.