cssi/SciSciGPT-SciSciNet huggingface dataset:
Electrostatically driven adsorption of silica nanoparticles on functionalized surfaces.

Adsorption of nanoparticles on solid supports is a scientifically interesting and technologically important phenomenon that has been attracting ever-increasing attention. Formation of particle-based films onto surfaces from stable suspensions is at the center of the development of new devices that utilize the plethora of newly synthesized nanoparticles with exciting properties. In this study we exploit the attractive electrostatic interactions between silica (SiO(2)) nanoparticles and functionalized substrates that display an amine termination in order to devise a simple method for the fabrication of SiO(2) nanoparticle films. Electrostatically controlled adsorption allows for uniform coverage of nanoparticles over large areas. The Stober method (a sol-gel approach) was employed to prepare uniformly sized SiO(2) nanoparticles with a diameter of 50-80 nm. Native oxide-covered silicon wafer substrates were amino-functionalized utilizing the self-assembled monolayer of 3-aminopropyltrimethoxysilane (APS). The adsorption of SiO(2) nanoparticle film onto the silicon wafer substrate was controlled by modulation of the electrostatic interaction between nanoparticles and the substrate. Modification of surface charge of either the SiO(2) NP or the substrate is a crucial step in the process. Thus the effect of APS adsorption time on the surface energy of the substrate was investigated. Also, process parameters such as NP concentration and solvent composition were varied in order to investigate the extent of NP adsorption. Moreover, NaCl was introduced to the SiO(2) suspension as a charge-screening agent to reduce the inter-particle repulsion in the suspension as well as interaction of the particles with the surface. This resulted in denser/thicker films.
Human Cytomegalovirus UL84 Oligomerization and Heterodimerization Domains Act as Transdominant Inhibitors of oriLyt-Dependent DNA Replication: Evidence that IE2-UL84 and UL84-UL84 Interactions Are Required for Lytic DNA Replication

Human cytomegalovirus (HCMV) UL84 encodes a 75-kDa protein required for oriLyt-dependent DNA replication and interacts with IE2 in infected and transfected cells. UL84 localizes to the nucleus of transfected and infected cells and is found in viral replication compartments. In transient assays it was shown that UL84 can interfere with the IE2-mediated transactivation of the UL112/113 promoter of HCMV. To determine whether UL84 protein-protein interactions are necessary for lytic DNA synthesis, we purified UL84 and used this protein to generate a monoclonal antibody. Using this antibody, we now show that UL84 forms a stable interaction with itself in vivo. The point of self-interaction maps to a region of the protein between amino acids 151 and 200, a domain that contains a series of highly charged amino acid residues. Coimmunoprecipitation assays determined that UL84 interacts with a protein domain present within the first 215 amino acids of IE2. We also show that an intact leucine zipper domain of UL84 is required for a stable interaction with IE2 and UL84 leucine zipper mutants fail to complement oriLyt-dependent DNA replication. UL84 leucine zipper mutants no longer interfere with IE2-mediated transactivation of the UL112/113 promoter, confirming that the leucine zipper is essential for a functional interaction with IE2. In addition, we demonstrate that both the leucine zipper and oligomerization domains of UL84 can act as transdominant-negative inhibitors of lytic replication in the transient assay, strongly suggesting that both an IE2-UL84 and a UL84-UL84 interaction are required for DNA synthesis.
Hybrid image and blood sampling input function for quantification of small animal dynamic PET data.

Abstract We describe and validate a hybrid image and blood sampling (HIBS) method to derive the input function for quantification of microPET mice data. The HIBS algorithm derives the peak of the input function from the image, which is corrected for recovery, while the tail is derived from 5 to 6 optimally placed blood sampling points. A Bezier interpolation algorithm is used to link the rightmost image peak data point to the leftmost blood sampling point. To assess the performance of HIBS, 4 mice underwent 60-min microPET imaging sessions following a 0.40–0.50-mCi bolus administration of 18 FDG. In total, 21 blood samples (blood-sampled plasma time–activity curve, bsPTAC) were obtained throughout the imaging session to compare against the proposed HIBS method. MicroPET images were reconstructed using filtered back projection with a zoom of 2.75 on the heart. Volumetric regions of interest (ROIs) were composed by drawing circular ROIs 3 pixels in diameter on 3–4 transverse planes of the left ventricle. Performance was characterized by kinetic simulations in terms of bias in parameter estimates when bsPTAC and HIBS are used as input functions. The peak of the bsPTAC curve was distorted in comparison to the HIBS-derived curve due to temporal limitations and delay in blood sampling, which affected the rates of bidirectional exchange between plasma and tissue. The results highlight limitations in using bsPTAC. The HIBS method, however, yields consistent results, and thus, is a substitute for bsPTAC.
Mutating Conserved Cysteines in the Alphavirus E2 Glycoprotein Causes Virus-Specific Assembly Defects

There are 80 trimeric, glycoprotein spikes that cover the surface of an alphavirus particle. The spikes, which are composed of three E2 and E1 glycoprotein heterodimers, are responsible for receptor binding and mediating fusion between the viral and host-cell membranes during entry. In addition, the cytoplasmic domain of E2 interacts with the nucleocapsid core during the last stages of particle assembly, possibly to aid in particle stability. During assembly, the spikes are nonfusogenic until the E3 glycoprotein is cleaved from E2 in the trans-Golgi network. Thus, a mutation in E2 potentially has effects on virus entry, spike assembly, or spike maturation. E2 is a highly conserved, cysteine-rich transmembrane glycoprotein. We made single cysteine-to-serine mutations within two distinct regions of the E2 ectodomain in both Sindbis virus and Ross River virus. Each of the E2 Cys mutants produced fewer infectious particles than wild-type virus. Further characterization of the mutant viruses revealed differences in particle morphology, fusion activity, and polyprotein cleavage between Sindbis and Ross River virus mutants, despite the mutations being made at corresponding positions in E2. The nonconserved assembly defects suggest that E2 folding and function is species dependent, possibly due to interactions with a virus-specific chaperone.
Using Dyad-Specific Social Stories to Increase Communicative and Social Skills of Preschoolers with Hearing Loss in Self-Contained and Inclusive Settings.

Children with profound hearing loss often do not have the same prelinguistic opportunities for social and communication interaction as peers with typical hearing and benefit from structured opportunities to learn these skills. This study examined the effect of two interventions to improve the communicative and social skills of four preschoolers with hearing loss in two learning environments: a preschool for children who are deaf (oral approach) and an inclusive regular preschool. A social story with a verbal prompt was provided before play (Intervention 1), and a social story with a teacher prompt and verbal prompting and reinforcement during play were provided (Intervention 2). A single-subject design revealed that in the inclusive settings, three of the four participants increased verbal comments and play turns in Interventions 1 and 2, although some changes were slight. In the oral preschool classroom, two showed improvements in target behaviours with both interventions. Generalisation of skills occurr...
Post-perceptual processing during the attentional blink is modulated by inter-trial task expectancies.

The selective processing of goal-relevant information depends on an attention system that can flexibly adapt to changing task demands and expectations. Evidence from visual search tasks indicates that the perceptual selectivity of attention increases when the bottom-up demands of the task increase and when the expectations about task demands engendered by trial history are violated. Evidence from studies of the attentional blink (AB), which measures the temporal dynamics of attention, also indicates that perceptual selectivity during the AB is increased if the bottom-up task demands required are increased. The present work tested whether expectations about task demands engendered by trial history also modulate perceptual selectivity during the AB. Two experiments tested the extent to which inter-trial switches in task demands reduced post-perceptual processing of targets presented during the AB. Experiment 1 indexed post-perceptual processing using the event-related potential (ERP) technique to isolate the context sensitive N400 ERP component evoked by words presented during the AB. Experiment 2 indexed post-perceptual processing using behavioral performance to determine the extent to which personal names survive the AB. The results of both experiments revealed that both electrophysiological (Exp. 1) and behavioral (Exp. 2) indices of post-perceptual processing were attenuated when consecutive trials differed in terms of their perceptual demands. The results are consistent with the notion that the selectivity of attention during the AB is modulated not only by within-trial task demands, but also can be flexibly determined by trial-by-trial expectations.
Perioperative Issues for Surgeons: Improving Patient Safety and Outcomes

This issue of the Surgical Clinics of North America deals with the perioperative concerns of our patients. It covers a wide range of topics from hospital systems issues to specific medical concerns of varying subsets of patients. This issue once again underscores the importance of the surgeon understanding the system in which he or she works. The complexity of the patients we care for is increasing and will likely continue to do so for the balance of our careers. The days when surgeons could (at least according to lore) control everything about their working environment are gone. In fact, many surgeons faced with increasing responsibilities for increased ‘‘productivity,’’ decreasing reimbursement, and an increasing desire for shorter hours have opted to delegate many of the responsibilities that used to be ours. Preoperative ‘‘clearance’’ is something one gets from a medical colleague; total parenteral nutrition is managed by the Metabolic Support Service; operative instruments and supplies are purchased in consolidated contracts. Although it is not necessarily the best use of a surgeon’s time to personally tend to every detail of a patient’s hospitalization or care, we still are responsible for the end result. For better or worse, patients tend to give us more credit than we deserve when things go well and place most of the blame on us when they do not. Ironically, many surgeons are fine with the former and indignant at the latter. Ronald F. Martin, MD
Peperite as a record of early-stage phreatomagmatic fragmentation processes: an example from the Hopi Buttes volcanic field, Navajo Nation, Arizona, USA

Abstract Peperite is the product of near-surface magma–wet sediment mingling. Some peperites are inferred to record ‘frozen’ coarse mixing-stage fuel–coolant interactions (FCIs), and hence can be used in attempts to determine specific parameters related to phreatomagmatic fragmentation, such as water/magma mass ratios, confining pressures, and vent-region hydrology. Two lamprophyric dikes in the Miocene–Pliocene Hopi Buttes volcanic field, Arizona, contain ellipsoidal regions of dilation (buds) associated with peperite. These peperite-rimmed zones occur within identifiable stratigraphic horizons, and at known depths beneath the elevation of the local pre-eruptive surface. The presence of both fluidal and blocky juvenile clasts, combined with physical aspects of the sediment–lamprophyre contacts, suggest that coarse mixing-stage FCI was a potential fragmentation mechanism within these systems. Confining pressures calculated for sites of single buds range from 0.6 to 1.0 MPa. Average inferred water–magma ratios within peperite bodies at the time they formed vary from 0.09 to 0.16, consistent with experimental values for water–melt mixing ratios necessary for explosive heat transfer. A number of factors may have inhibited further explosive activity in these peperite-forming mixing events, including anisotropic saturation of the host sediment, low confining pressures and water/melt ratios, and damped explosive interactions resulting from increased density, viscosity, and surface tension of sediment–water coolants. Nevertheless, these deposits record localized thermohydraulic interactions between magma and wet sediment, and provide valuable information about the geometry and mixing ratios present during peperite formation.
Evolution of Passive Optical Component Technologies for Fiber-Optic Communication Systems

This paper reviews the evolution of passive optical components for fiber-optic communication systems, focusing on the interaction between component technologies and the evolution of fiber-optic systems.
Effects of Music on Physiological Arousal: Explorations into Tempo and Genre

Two experiments explore the validity of conceptualizing musical beats as auditory structural features and the potential for increases in tempo to lead to greater sympathetic arousal, measured using skin conductance. In the first experiment, fast- and slow-paced rock and classical music excerpts were compared to silence. As expected, skin conductance response (SCR) frequency was greater during music processing than during silence. Skin conductance level (SCL) data showed that fast-paced music elicits greater activation than slow-paced music. Genre significantly interacted with tempo in SCR frequency, with faster tempo increasing activation for classical music and decreasing it for rock music. A second experiment was conducted to explore the possibility that the presumed familiarity of the genre led to this interaction. Although further evidence was found for conceptualizing musical beat onsets as auditory structure, the familiarity explanation was not supported.
Parental Alcohol Consumption, Cigarette Smoking, and Risk of Infant Leukemia: a Childrens Cancer Group Study

Background: Whether parental drinking and smoking during pregnancy are associated with an increased risk of cancer in offspring is controversial . There are some indications that maternal alcohol consumption is associated with an elevated risk of acute myeloid leukemia (AML) appearing in very young children. Evidence for an association between maternal smoking during pregnancy and risk of leukemia in offspring has been inconsistent. Purpose: Using data from a Childrens Cancer Group case-control study, we evaluated relationships between infant leukemia risk and parental alcohol consumption and/or cigarette smoking during pregnancy or during the month prior to it. Methods: Three hundred two leukemia cases (203 acute lymphoid leukemias [ALLs], 88 AMLs, and 11 other leukemia types) diagnosed in children at 18 months of age or younger and 558 individually matched, regional (i.e., same telephone area code and exchange number) controls were included in the analysis. Information concerning parental alcohol consumption and smoking behavior during the index pregnancy and during the month prior to it was collected by telephone interviews with the mothers of all case and control subjects and the fathers of 250 case and 361 control subjects. Odds ratios (ORs) were used to measure the risk of infant leukemia associated with parental smoking and drinking; tests for trend were used to assess dose-response relationships. The data were analyzed further after stratifying the leukemia cases according to histologic and morphologic types. Reported P values are from two-sided tests of statistical significance. Results: Maternal drinking during pregnancy (compared with not drinking) was associated with ORs of 1.43 (95% confidence interval [CI] = 1.00-2.04) for ALL and 2.64 (95% CI = 1J6-5.06) for AML. A dose-response relationship was observed for total maternal alcohol consumption during pregnancy and risk of AML (P<.01). Alcohol-related risk appeared to be most pronounced for children who developed AML with a morphology of Ml (myeloblastic with minimal maturation) or M2 (myeloblastic with maturation) (OR = 7.62; 95% CI = 2.03-28.64). Paternal alcohol consumption did not confer an increased risk of infant leukemia. Maternal smoking during pregnancy (compared with not smoking) was negatively associated with infant leukemia risk (OR = 0.66 and 95% CI = 0.46-0.94 for total leukemia; OR = 0.45 and 95% CI = 0.21-0.96 for AML), whereas paternal smoking 1 month prior to pregnancy (compared with not smoking during the same period) was related to an elevated risk of ALL (OR = 1.56; 95% CI = 1.03-2.36). Conclusions: Maternal alcohol consumption during pregnancy increases the risk of infant leukemia, especially AML. Maternal smoking, however, does not elevate risk for either AML or ALL. Implication: The data suggest that in utero exposure to alcohol may contribute to leukemogenesis involving myeloid cells. [J Natl Cancer Inst 1996;88:24-31]
Comparison of Turnip Crinkle Virus RNA-Dependent RNA Polymerase Preparations Expressed in Escherichia coli or Derived from Infected Plants

Turnip crinkle virus (TCV) is a small, plus-sense, single-stranded RNA virus of plants. A virus-coded protein, p88, which is required for replication has been expressed and purified from Escherichia coli. In vitro assays revealed that the recombinant p88 has an RNA-dependent RNA polymerase (RdRp) activity and can also bind to RNA. Deletion of the N-terminal region in p88 resulted in a more active RdRp, while further deletions abolished RdRp activity. Comparison of the E. coli-expressed p88, the N-terminal deletion mutant of p88, and a TCV RdRp preparation obtained from infected plants revealed that these preparations show remarkable similarities in RNA template recognition and usage. Both the recombinant and the plant TCV RdRp preparations are capable of de novo initiation on both plus- and minus-strand satC and satD templates, which are small parasitic RNAs associated with TCV infections. In addition, these RdRp preparations can efficiently recognize the related Tomato bushy stunt virus promoter sequences, including the minus- and plus-strand initiation promoters. Heterologous viral and artificial promoters are recognized poorly by the recombinant and the plant TCV RdRps. Further comparison of the single-component recombinant TCV RdRp and the multicomponent plant TCV RdRp will help dissect the functions of various components of the TCV replicase.
The intradermal test and the plasma card test: a critical assessment of their reliability for diagnosing Schistosoma haematobium infection, and other considerations.

(1971). The intradermal test and the plasma card test: a critical assessment of their reliability for diagnosing Schistosoma haematobium infection, and other considerations. Annals of Tropical Medicine & Parasitology: Vol. 65, No. 4, pp. 505-511.
Three-taxon analysis can always successfully recognize groups based on putative reversals

Three-taxon analysis in it canonical form can always successfully recognize groups based on putative reversals if latter are coded as separate states before three-taxon permutations are derived from conventional matrices. This way of coding removes incongruence from either conventional multistate or three-taxon matrices and makes the discussions about symplesiomorphy as a putative homology unnecessary. The ability of conventional parsimony to recognize reversal-based clades is technically nothing more than grouping by plesiomorphic values. Therefore this solution cannot be accepted as a Cladistic approach to data and must be correctly classified as “post-Hennigian” or “phenetic”. The ability of three-taxon analysis to recognize groups based on the putative reversals may be viewed as a heuristic cladistics attempts to prevent this “phenetic” approach affecting the analysis of the data.
Confidence-Building Measures for Genetically Modified Products: Stakeholder Teamwork on Regulatory Proposals

The introduction of genetically modified products into the human food supply and into other commercial uses is one of the most socially and politically divisive technology issues facing the United States. This article presents a model for confidence building among opposed groups in areas of polarized regulatory conflict generally and details a proposal for confidence building in the genetically modified product arena in particular. The specific proposal entails private industry, activist organizations, and representatives of the public working together on a jointly proposed set of guidelines for improving the quality of genetically modified product regulation.
Interaction of Amphiphilic Molecules with Biological Membranes

The nonspecific interactions of propranolol, timolol, and ethanol with model and sarcoplasmic reticulum membranes were determined utilizing radioisotopic association, differential scanning calorimetry, and neutron diffraction. Differential scanning calorimetry performed on mixtures of these amphiphilic compounds and model membrane bilayers composed of dimyristoyllecithin showed that propranolol was approximately 25 times more lipid-soluble than timolol and at least 100 times more lipid-soluble than ethanol. Neutron diffraction showed that the solvation of propranolol was within the fatty acyl chain region of the lipid bilayer. This solvation correlated with the effect of propranolol to inhibit ATP-dependent calcium transport in isolated rabbit skeletal muscle sarcoplasmic reticulum, a membrane that lacks β-adrenergic receptors. In contrast, the major site of interaction of ethanol was within the aqueous compartment hydrating the sarcoplasmic reticulum membrane. A model for nonspecific drug interaction with the sarcoplasmic reticulum membrane based on the site of interaction of these amphiphiles and their relative potencies to inhibit calcium transport by these membranes is proposed. In principle, this model could be extended to specific drug interactions with membranes.
Model Study of the Therapy of Replenishing Qi and Activating Blood Circulation on Protecting the Brain Impairment Caused by Hypoxic-ischemic Encephalopathy in SD Rats

Objective:To explore the brain protecting effect based on Xuefuzhuyu decoction plus different dosages of Radix Astragali by testing the amount of the nerve growth factor mRNA(NGF mRNA),evaluating neurological behaviors,and observing the pathologic changes of brain tissue in SD rats with hypoxic-ischemic encephalopathy(HIE).To reveal the mechanism of the therapy of replenishing Qi and activating blood circulation.Methods:80 healthy clean SD rats(off weaning for two weeks,weight about 100g,40 male and 40 female rats)were divided into 5 groups(n=16).The control group(also called the feigned operation group),the model group and three Chinese medicine treating groups(also called the operation groups collectively).Bilateral carotis ligature is performed in all groups except control group to establish HIE model.Gastric lavage is performed after operation with normal saline(control and model groups),xuefuzhuyu decoction(Chinese medicine group1),xuefuzhuyu decoction plus 10g radix astragali(Chinese medicine group2) and xuefuzhuyu decoction plus 40g radix astragali(Chinese medicine group3) respectively.Neurological behaviors were observed on the 1st day and the 6th day after operation and evaluated by Zea Longa neural function grading criteria.Brain tissues were obtained after decollation and pathologic changes were examined under light lens after HE dyeing.The amounts of NGF mRNA were tested with quantitative fluorescence RT-PCR.Results:On the 1st day after the operation,compared with control group,all the other groups had remarkable neurological malfunction(P0.05),pathologic changes and significant increase in the amount of NGF mRNA(P0.05).On the 6th day,three Chinese medicine treating groups had remarkable improvement in neurological malfunction,pathologic changes(P0.05) and a significant increase in the amounts of NGF mRNA compared with the model group(P0.05).There is no significant difference among three Chinese medicine groups.Compared with the 1st day,a significant decrease of the amounts of NGF mRNA(P0.05) was found in the model group while neurological malfunction and pathologic changes remains no obvious improvement.For three Chinese medicine treated groups,remarkable improvement has been found both in neurological behavior and pathologic changes(P0.05) while no significant difference in increasing NGF mRNA expression among the three groups.Conclusions:Gastric lavaging xuefuzhuyu decoction with radix astragali can significantly improve both neurological behavior and pathological changes and significantly increase the NGF mRNA expression in SD rats with HIE.Chinese medicine treating group2(gastric lavaging xuefuzhuyu decoction with 10g radix astragali) has the best effect of pathological recovery among all groups.The therapy of replenishing Qi and activating blood circulation is an effective way for protecting the brain impairment caused by hypoxic-ischemic encephalopathy.
Synthesis, Radical Reactivity, and Thermochemistry of Monomeric Cu(II) Alkoxide Complexes Relevant to Cu/Radical Alcohol Oxidation Catalysis

Two new monomeric Cu(II) alkoxide complexes were prepared and fully characterized as models for intermediates in copper/radical mediated alcohol oxidation catalysis: TptBuRCuIIOCH2CF3 with TptBu = hydro-tris(3-tert-butyl-pyrazol-1-yl)borate 1 or TptBuMe = hydro-tris(3-tert-butyl-5-methyl-pyrazol-1-yl)borate 2. These complexes were made as models for potential intermediates in enzymatic and synthetic catalytic cycles for alcohol oxidation. However, the alkoxide ligands are not readily oxidized by loss of H; instead, these complexes were found to be hydrogen atom acceptors. They oxidize the hydroxylamine TEMPOH, 2,4,6-tri-t-butylphenol, and 1,4-cyclohexadiene to the nitroxyl radical, phenoxyl radical, and benzene, with formation of HOCH2CF3 (TFE) and the Cu(I) complexes TptBuRCuI-MeCN in dichloromethane/1% MeCN or 1/2 [TptBuRCuI]2 in toluene. On the basis of thermodynamics and kinetics arguments, these reactions likely proceed through concerted proton–electron transfer mechanisms. Thermochemical analyses gi...
Aggregate and Microcarrier Cultures of Human Pluripotent Stem Cells in Stirred-Suspension Systems

Pluripotent stem cells can differentiate to any cell type and contribute to damaged tissue repair and organ function reconstitution. The scalable culture of pluripotent stem cells is essential to furthering the use of stem cell products in a wide gamut of applications such as screening of candidate drugs and cell replacement therapies. Human stem cell cultivation in stirred-suspension vessels enables the expansion of stem cells and the generation of differentiated progeny in quantities suitable for use in animal models and clinical studies. We describe methods of culturing human pluripotent stem cells in spinner flasks either as aggregates or on microcarriers. Techniques for assessing the quality of the culture and characterizing the cells based on the presentation of pertinent markers are also presented. Spinner flask culture with its relatively low capital and operating costs is appealing to laboratories interested in scaling up their production of stem/progenitor cells.
The Early Life of Joseph Stiglitz

There are few scholars more academically talented, curious, or varied than Joseph Stiglitz. His interest in a broad set of important questions has allowed him to see the forest through the trees and to apply concepts from one area of public finance or economics to many others. His abilities have not gone unnoticed.
Skeletal Muscle Measures as Predictors of Toxicity, Hospitalization, and Survival in Patients with Metastatic Breast Cancer Receiving Taxane-Based Chemotherapy

Purpose: Severe skeletal muscle (SM) loss (sarcopenia), is associated with poor cancer outcomes including reduced survival and increased toxicity. This study investigates SM measures in metastatic breast cancer (MBC) patients receiving first line taxane-based chemotherapy and evaluates associations with treatment toxicity and other outcomes. Experimental Design: Using computerized tomography (CT) images taken for the evaluation of disease burden, skeletal muscle area (SMA) and density (SMD) were measured at the 3rd lumbar vertebrae. Sarcopenia was defined as Skeletal Muscle Index (SMI=SMA / height2) <41. Skeletal Muscle Gauge (SMG) was created by multiplying SMI x SMD. Fisher9s exact tests, t-tests, the Kaplan-Meier method, and Cox regression modeling were used. Results: MBC patients (N=40), median age 55 (rang 34-80), 58% sarcopenic, median SMG 1296 AU (SD 522). Grade 3-4 toxicity was found in 57% of sarcopenic vs 18% of non-sarcopenic patients (p=0.02). Toxicity-related hospitalizations were also higher in sarcopenic patients (39% vs 0%, p=0.005) as were any adverse events -- defined as any grade 3-4 toxicities, hospitalizations, dose reductions, or dose delay -- (74% vs 35%, p=0.02). Low SMG was associated with grade 3-4 toxicity (p=0.04), hospitalization (p=0.01) and time to treatment failure (for progression or toxicity) (p=0.03). Low SMG had a borderline significant association with any adverse event (p=0.06) and overall survival (p=0.07). Conclusions: SM measures are associated with toxicity outcomes and survival in MBC patients receiving first line taxane-based chemotherapy. Further studies are needed to explore how routinely obtained CT scans can be used to individualize dosing and improve treatment planning.
Membranous Nephropathy in the Kidney Allograft

Membranous nephropathy (MN) may occur in a kidney transplant as recurrence of the original disease (rMN) or as a de novo MN (dnMN). rMN often occurs early, within the first year, and often in a mild or subclinical fashion. Recurrence cannot be predicted by clinical features at the time of transplantation. The natural history is increasing proteinuria over time, with less chance for spontaneous remission compared to primary MN (pMN). Antiphospholipase A2 receptor (PLA2R) antibodies should be evaluated in all patients with pMN at the time of transplantation and serially. If titers persist or rise, biopsy is indicated. Irrespective of PLA2R status, any case with proteinuria reaching 1 g/day should be biopsied. No randomized controlled trials have been published regarding treatment of rMN. Observational data support use of rituximab. Given the progressive nature of rMN and lack of spontaneous remissions, a period of observation does not seem justifiable. dnMN occurs with about equal frequency as rMN and shares features of secondary MN in native kidneys. Causes include viral infections (e.g., hepatitis B or C), which should be treated. In some cases, dnMN may represent an atypical alloimmune response. The role of rituximab in dnMN is undefined.
Dynamic Variations in Genetic Integrity Accompany Changes in Cell Fate

Pluripotent stem cells hold the potential to form the basis of novel approaches to treatment of disease in vivo as well as to facilitate the generation of models for human disease, providing powerful avenues to discovery of novel diagnostic biomarkers and/or innovative drug regimens in vitro. However, this will require extensive maintenance, expansion, and manipulation of these cells in culture, which raises a concern regarding the extent to which genetic integrity will be preserved throughout these manipulations. We used a mutation reporter (lacI) transgene approach to conduct direct comparisons of mutation frequencies in cell populations that shared a common origin and genetic identity, but were induced to undergo transitions in cell fate between pluripotent and differentiated states, or vice versa. We confirm that pluripotent cells normally maintain enhanced genetic integrity relative to that in differentiated cells, and we extend this finding to show that dynamic transformations in the relative stringency at which genetic integrity is maintained are associated with transitions between pluripotent and differentiated cellular states. These results provide insight into basic biological distinctions between pluripotent and differentiated cell types that impact genetic integrity in a manner that is directly relevant to the potential clinical use of these cell types.
Abstract 16413: Association of Weight Loss Medications With Cardiometabolic Risk Factors: Systematic Review and Network Meta-Analysis

Background: The average excess weight loss with FDA-approved weight loss drugs ranges from 2.6 to 8.8 kg. However, their efficacy in improving cardiometabolic risk is not known. We assessed this as...
Genetic Basis of Salmonella Enteritidis Pathogenesis in Chickens

Abstract Salmonella Enteritidis (SE) is the predominant cause of the food-borne salmonellosis in humans, in part because this serotype has the unique ability to contaminate chicken eggs without causing discernible illness in the infected birds. Attempts to develop effective vaccines and eradicate SE from chickens are undermined by significant limitations in our current understanding of the genetic basis of pathogenesis of SE in this reservoir host. In this chapter, we summarize the infection kinetics and provide an overview of the current understanding of genetic factors underlying SE infection in the chicken host. We also discuss the important knowledge gaps that, if addressed, will improve our understanding of the complex biology of SE in young chickens and in egg laying hens.
Evaluation of chip morphology during machining of ECAE titanium

Titanium (Ti) and its alloys are currently used extensively in medical and dental applications due to their superior mechanical and physical properties compared to coarse-grained (CG) Ti. However, the presence of alloying elements such as aluminum and vanadium has raised concerns about Ti alloy biocompatibility. Fortunately, equal channel angular extrusion (ECAE)-processed ultrafine-grained (UFG) Ti, which has a grain structure on the submicron level, has emerged as a viable alternative. The substantial reduction in grain size results in distinct material property differences, which may affect the dynamic material behavior. In this study, the chip morphology, which is an indication of the dynamic behavior of materials, of ECAE-processed Ti after machining is evaluated and compared with that of CG Ti. The chip morphology for both Ti materials is found to transform as the cutting speed increases while ECAE Ti has a different shear band spacing, indicating that ECAE Ti responds differently to deformation when compared with CG Ti.
Probing Deep Brain Circuitry: New Advances in in Vivo Calcium Measurement Strategies.

The study of neuronal ensembles in awake and behaving animals is a critical question in contemporary neuroscience research. Through the examination of calcium fluctuations, which are correlated with neuronal activity, we are able to better understand complex neural circuits. Recently, the development of technologies including two-photon microscopy, miniature microscopes, and fiber photometry has allowed us to examine calcium activity in behaving subjects over time. Visualizing changes in intracellular calcium in vivo has been accomplished utilizing GCaMP, a genetically encoded calcium indicator. GCaMP allows researchers to tag cell-type specific neurons with engineered fluorescent proteins that alter their levels of fluorescence in response to changes in intracellular calcium concentration. Even with the evolution of GCaMP, in vivo calcium imaging had yet to overcome the limitation of light scattering, which occurs when imaging from neural tissue in deep brain regions. Currently, researchers have created ...
In Situ Tagged nsp15 Reveals Interactions with Coronavirus Replication/Transcription Complex-Associated Proteins.

Coronavirus (CoV) replication and transcription are carried out in close proximity to restructured endoplasmic reticulum (ER) membranes in replication/transcription complexes (RTC). Many of the CoV nonstructural proteins (nsps) are required for RTC function; however, not all of their functions are known. nsp15 contains an endoribonuclease domain that is conserved in the CoV family. While the enzymatic activity and crystal structure of nsp15 are well defined, its role in replication remains elusive. nsp15 localizes to sites of RNA replication, but whether it acts independently or requires additional interactions for its function remains unknown. To begin to address these questions, we created an in situ tagged form of nsp15 using the prototypic CoV, mouse hepatitis virus (MHV). In MHV, nsp15 contains the genomic RNA packaging signal (P/S), a 95-bp RNA stem-loop structure that is not required for viral replication or nsp15 function. Utilizing this knowledge, we constructed an internal hemagglutinin (HA) tag that replaced the P/S. We found that nsp15-HA was localized to discrete perinuclear puncta and strongly colocalized with nsp8 and nsp12, both well-defined members of the RTC, but not the membrane (M) protein, involved in virus assembly. Finally, we found that nsp15 interacted with RTC-associated proteins nsp8 and nsp12 during infection, and this interaction was RNA independent. From this, we conclude that nsp15 localizes and interacts with CoV proteins in the RTC, suggesting it plays a direct or indirect role in virus replication. Furthermore, the use of in situ epitope tags could be used to determine novel nsp-nsp interactions in coronaviruses. Importance Despite structural and biochemical data demonstrating that the coronavirus nsp15 protein contains an endoribonuclease domain, its precise function during coronavirus infection remains unknown. In this work, we created a novel in situ tagged form of nsp15 to study interactions and localization during infection. This in situ tag was tolerated by MHV and did not affect viral replication. Utilizing this tag, we established that nsp15 localized to sites of replication but not sites of assembly throughout infection. Furthermore, we found that nsp15 interacted with the putative viral primase nsp8 and polymerase nsp12 during CoV infection. The strong association of nsp15 with replication complexes and interactions with replicative CoV enzymes suggest nsp15 is involved in CoV replication. These data and tools developed in this study help elucidate the function of nsp15 during infection and may be used to uncover other novel viral protein interactions.
Extensor Tendon Injuries of the Upper Extremity

Extensor tendon injuries are a common injury in the hand. Causes of injury can include closed trauma, attritional overuse, and lacerations. There are characteristic injuries with each zone of the extensor tendons. Many injuries can be treated with splinting. Thorough comprehension of the injuries and their treatment is best obtained through detailed knowledge of the anatomy of the extensor tendons.
Impact of Physical Activity on Reporting of Childhood Asthma Symptoms.

This study aims to determine the impact of physical activity on asthma symptom reporting among children living in an inner city. Among 147 children aged 5–12 years with physician-diagnosed asthma, we assessed asthma symptoms using twice-daily diaries and physical activity using the physical activity questionnaire for children during three 8-day periods (baseline, 3 and 6 months). Linear, logistic, and quasi-poisson regression models were used to determine the association between physical activity and asthma symptoms; adjusting for age, sex, race, BMI, caregiver’s education, asthma severity, medication use, and season. A 1-unit increase in PAQ score was significantly associated with reporting more nocturnal symptoms [risk ratio (RR): 1.03; 95% CI 1.00–1.06], daytime symptoms (RR: 1.04; 95% CI 1.00–1.09), being bothered by asthma (RR: 1.05; 95% CI 1.00–1.09), and trouble breathing (RR: 1.05; 95% CI 1.00–1.10). Level of physical activity should be taken into account in clinical management of asthma and epidemiological studies of asthma symptom burden.
Abstract B015: An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer

Tumors evolve as they adapt to environmental cues. The principles governing evolution of tumors under the selective pressure of targeted therapy are not well understood. We aimed to evaluate the evolution of resistance and to identify therapeutic modalities that prevent this process in BRAF V600E -mutant tumors. We modeled the selection and propagation of BRAF V600E amplification (BRAF amp ) in patient-derived tumor xenografts (PDX) treated with a direct ERK inhibitor. Single-cell sequencing and multiplex-fluorescence in situ hybridization mapped the emergence of extra-chromosomal amplification in multiple subclones of the same tumor shortly after treatment. The evolutionary selection of BRAF amp is determined by the fitness threshold, the barrier subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for ERK signaling inhibitors, and single-cell sequencing of a melanoma PDX model showed that drugs of the same pathway do not necessarily select for the same subclones. These data suggest that sequential monotherapy is not optimal, but concurrent targeting of RAF, MEK, and ERK, however, imposes a sufficiently high fitness threshold to prevent the propagation of subclones with high-level amplification. Administered on an intermittent schedule, this treatment inhibited tumor growth without apparent toxicity in 11/11-lung cancer and melanoma PDX models with various additional alterations. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose a high fitness threshold, such as our intermittent triple therapy, will likely prevent the evolution of resistance-causing alterations and merit testing in patients. Citation Format: Yaohua Xue, Luciano Martelotto, Timour Baslan, Alberto Vides, Martha Solomon, Kalyani Chadalavada, Elisa DeStanchina, Gouri Nanjangud, Michael Berger, Scott Lowe, Jorge S. Reis-Filho, Neal Rosen, Piro Lito. An approach to suppress the evolution of resistance in BRAF V600E -mutant cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B015.
Cost-effectiveness of three different strategies for the treatment of first recurrent Clostridium difficile infection diagnosed in a community setting.

OBJECTIVE A significant portion of patients with Clostridium difficile infections (CDI) experience recurrence, and there is little consensus on its treatment. With the availability of newer agents for CDI and the added burdens of recurrent disease, a cost-effectiveness analysis may provide insight on the most efficient use of resources. DESIGN A decision-tree analysis was created to compare the cost-effectiveness of 3 possible treatments for patients with first CDI recurrence: oral vancomycin, fidaxomicin, or bezlotoxumab plus vancomycin. The model was performed from a payer's perspective with direct cost inputs and a timeline of 1 year. A systematic review of literature was performed to identify clinical, utility, and cost data. Quality-adjusted life years (QALY) and incremental cost-effectiveness ratios were calculated. The willingness-to-pay (WTP) threshold was set at $100,000 per QALY gained. The robustness of the model was tested using one-way sensitivity analyses and probabilistic sensitivity analysis. RESULTS Vancomycin had the lowest cost ($15,692) and was associated with a QALY gain of 0.8019 years. Bezlotoxumab plus vancomycin was a dominated strategy. Fidaxomicin led to a higher QALY compared to vancomycin, at an incremental cost of $500,975 per QALY gained. Based on our WTP threshold, vancomycin alone was the most cost-effective regimen for treating the first recurrence of CDI. Sensitivity analyses demonstrated the model's robustness. CONCLUSIONS Vancomycin alone appears to be the most cost-effective regimen for the treatment of first recurrence of CDI. Fidaxomicin alone led to the highest QALY gained, but at a cost beyond what is considered cost-effective.
A review of the continuum of drug-induced states of excitation and depression

Simplistic concepts which label a drug as an anesthetic, excitant, hallucinogen, convulsant, anticonvulsant, etc., can be extremely misleading. For example, one could label diethyl ether as a stimulant, euphoriant, hallucinogen or anesthetic. Each description partly characterizes ether at some dose/time period but does not describe the totality of drug action. Another example is phenytoin, which is universally considered to be an anticonvulsant agent, but can induce seizures at high doses. Further, the argument that one action is ‘the’ desired effect and other actions are side effects is likewise misleading. The decision as to which is a desired effect and which is side effect depends upon the desired effect. For example, ophthalmologists dilate the pupil of the eye and paralyze accommodation with atropine. They regard the dry mouth and reduced bladder and gastrointestinal tract excitability as side effects. However, the urologist or gastroenterologist uses atropine because of the latter effects and considers the effects on the eyes to be the side effects. A more satisfactory approach to drug classification would be to describe the continuum of total drug actions which occur according to the dose and time course of effects. The advent of the excessive nonmedical use of drugs makes this reevaluation of central nervous system (CNS) acting drug classes critical.
Examples of Extremal Control

It can be shown (for instance, see Ref. 12.1) that the equations of rectilinear motion of a rocket operating at constant propulsive power are $$ {\mathop x\limits^ \bullet _1}\left( t \right) = u\left( t \right),\;{\mathop x\limits^ \bullet _1}\left( t \right) = {u^2}\left( t \right) $$ (12.1) where t is time, x 1 is velocity, and x 2 is inversely proportional to the mass of the rocket, while u is the acceleration caused by the thrust.
Induction of Midtrimester Abortion by the Combined Method of Continuous Extra Vovular Infusion of Prostaglandin F2α and Intracervical Laminaria Tents

Midtrimester abortion was successfully induced in 55 of 60 patients with continuous extraovular infusion of prostaglandin F 2 α (PGF 2 α ) following the insertion of intracervical laminaria tents. Intravenous oxytocin was also used in 38 (63%) of the 60 patients. The mean induction-abortion time (IAT) was 11.72 hours ± 1.06 SD). Abortion was completed in 40% within 8 hours, 80% within 16 hours, and 93% within 24 hours. The mean total dose of PGF 2 α was 41.9 mg. There was no significant difference in IAT between the parous patients (13.40 hours ± 1.90 SD) and the nulliparous patients (10.41 hours ± 1.13 SD). There was no apparent correlation between IAT and the stages of gestation (12 to 22 weeks). The five patients who failed to abort within 24 to 36 hours underwent uterine evacuation, which was easily accomplished because there was a marked degree of cervical dilatation. Side effects and complications of the technique were few. Endometritis occurred in three patients, two of whom had had intrauterine devices in situ until just prior to the procedure. It appears that this method has a high success rate, an acceptable safety factor, good patient tolerance, and relatively few side effects.