cssi/SciSciGPT-SciSciNet huggingface dataset:
Quantitation of mitoxantrone accumulation, efflux and modulation in MDR human MDA-MB-435 cancer cells

531 Drug resistance of cancer cells remains one of the major obstacles to successful chemotherapy. Overexpression of P-glycoprotein in cancer cells causes resistance of cancer cells to a number of structurally and functionally diverse anticancer agents, i.e. Multidrug Resistance (MDR). Previously, we have reported that decreased uptake and increased efflux of doxorubicin (DOX) in MDR-1 transduced human MDA-MB-435 cancer cells (MDR cells) compared to wild type MDA-MB-435 cells. We identified that nuclei in MDR cells were the main target site in decreasing DOX uptake and increasing DOX efflux by Pgp. In the current study, we have determined accumulation and efflux of the fluorescent anticancer drug mitoxantrone (MX), in wild type MDA-MB-435 cells and MDR cells, and quantified the inhibition of Pgp modulators on MX uptake and efflux in the MDR cells. MDA-MB-435 cells grown on cover slips were sequentially perfused with culture medium, containing MX for two hours, and then fresh culture medium for an additional hour. Serial images at two-minute intervals were collected and analyzed (Metamorph™ software) as mean MX fluorescent intensity per pixel in regions of the nucleus or cytoplasm of the cells. MDR cancer cells were also pretreated with Pgp inhibitors before perfusion as described above. Our results showed that accumulation of MX in MDR cells were three times less than that in the wild type cells. When pretreated with Pgp modulators, verapamil, cyclosporine A, and PSC833, MDR cells had at least the same MX accumulation level as the wild type cells. MX entered into wild type and MDR cells slowly. Although there was about 2.5-time greater MX uptake in wild type cells versus MDR cells, unlike DOX, MX nuclear steady state uptake was similar to its cytosol uptake in MDR cells, indicating intracellular targets of MX and DOX may differ and Pgp may function differently on MX and DOX. MX was mostly effluxed from MDR cells after its removal from perfusates while under the same condition it remained in wild type cells. Results from cell perfusion studies showed that the Pgp inhibitor, PSC833 increased MX uptake and reduced its efflux in MDR cells. These results suggest active MDR function is present in the MDR cells. We conclude that Pgp decreases MX uptake and increases MX efflux in MDR human MDA-MB-435 cells and compared to DOX, MX may have different cellular targets and interact differently with Pgp.
The influence of pulmonary vascular pressures on lung diffusing capacity during incremental exercise in healthy aging

Alveolar-capillary surface area for pulmonary gas exchange falls with aging, causing a reduction in lung diffusing capacity for carbon monoxide (DLCO). However, during exercise additional factors may influence DLCO, including pulmonary blood flow and pulmonary vascular pressures. First, we sought to determine the age-dependent effect of incremental exercise on pulmonary vascular pressures and DLCO. We also aimed to investigate the dependence of DLCO on pulmonary vascular pressures during exercise via sildenafil administration to reduce pulmonary smooth muscle tone. Nine younger (27 ± 4 years) and nine older (70 ± 3 years) healthy subjects performed seven 5-min exercise stages at rest, 0 (unloaded), 10, 15, 30, 50, and 70% of peak workload before and after sildenafil. DLCO, cardiac output (Q), and pulmonary artery and wedge pressure (mPAP and mPCWP; subset of participants) were collected at each stage. mPAP was higher (P = 0.029) and DLCO was lower (P = 0.009) throughout exercise in older adults; however, the rate of rise in mPAP and DLCO with increasing Q was not different. A reduction in pulmonary smooth muscle tone via sildenafil administration reduced mPAP, mPCWP, and the transpulmonary gradient (TPG = mPAP-mPCWP) in younger and older subjects (P < 0.001). DLCO was reduced following the reduction in mPAP and TPG, regardless of age (P < 0.001). In conclusion, older adults successfully adapt to age-dependent alterations in mPAP and DLCO. Furthermore, DLCO is dependent on pulmonary vascular pressures, likely to maintain adequate pulmonary capillary recruitment. The rise in pulmonary artery pressure with aging may be required to combat pulmonary vascular remodeling and maintain lung diffusing capacity, particularly during exercise.
Maternal-Fetal Genetic Interactions, Imprinting, and Risk of Placental Abruption

Maternal genetic variations, including variations in mitochondrial biogenesis (MB) and oxidative phosphorylation (OP), have been associated with placental abruption (PA). However, the role of maternal-fetal genetic interactions (MFGI) and parent-of-origin (imprinting) effects in PA remain unknown. We investigated MFGI in MB-OP, and imprinting effects in relation to risk of PA. Among Peruvian mother-infant pairs (503 PA cases and 1,052 controls), independent single nucleotide polymorphisms (SNPs), with linkage-disequilibrium coefficient
Super-Resolution Imaging of Clickable Graphene Nanoribbons Decorated with Fluorescent Dyes

The functional integration of atomically defined graphene nanoribbons (GNRs) into single-ribbon electronic device architectures has been limited by access to nondestructive high-resolution imaging techniques that are both compatible with common supports such as Si or Si/SiO2 wafers and capable of resolving individual ribbons in dilute samples. Conventional techniques such as scanning probe (AFM, STM) or electron microscopy (SEM, TEM) have been restricted by requisite sample preparation techniques that are incompatible with lithographic device fabrication. Here we report the design and synthesis of ultralong (∼10 μm) cove-type GNRs (cGNRs) featuring azide groups along the edges that can serve as a universal handle for late-stage functionalization with terminal alkynes. Copper-catalyzed click-chemistry with Cy5 fluorescent dyes gives rise to cGNRs decorated along the edges with fluorescent tags detectable by optical microscopy. The structures of individual dye-functionalized cGNRs spin-coated from a dilute solution onto transparent and opaque insulating substrates were resolved using diffraction-limited fluorescence microscopy and super-resolution microscopy (SRM) imaging techniques. Analysis of SRM images reveals an apparent width of cGNRs in the range 40-50 nm and lengths in excess of 10 μm, the longest GNRs imaged to date. Isolated cGNRs can even be distinguished from bundles and larger aggregates as long as the center-to-center distance is greater than the apparent width.
Coping with AIDS in Hemophilia

Hemophilia is a lifelong, chronic disease caused by a deficiency of a clotting factor in the blood. The bleeding episodes caused by that deficiency, especially hemorrhages into the joints, have been the source of pain, suffering, and death to the people who inherited it, from ancient times until just the last half of this century.
Patron-Driven Acquisition of Print Monographs and Music Scores: A Pilot Program Case Study

This article focuses on the context and mechanics of a patron-driven acquisition plan for print music scores and monographs at a large American university. The article analyzes, discusses, and compares, the purchasing and usage trends of the print patron-driven acquisition plan with traditional selection methods. Teaching faculty are using the patron-driven acquisition of print music materials to fill research needs, and to find scores and books for teaching and course reserve use. Compared to firm-order monograph and score purchases, print titles acquired through patron-driven acquisition are circulating sooner after arrival in the collection indicating that the need of the patron has been served in a timely and efficient manner.
The history and future of neurological care

Oliver Sacks9s inexhaust­ible curiosity, his sharpness of wit, and his special ability to create, maintain, and write about meaningful friendships, often with his patients, lent his writing humane, uncommon compassion. All of these most endearing qualities are on full display in Everything in Its Place: First Loves and Last Tales, a posthumous collection of Sacks9s essays. But understanding why his ability to tell stories possessed such resonance requires another tale all together. Historian Anne Harrington offers a version of that story in her latest masterpiece, Mind Fixers: Psy­chiatry9s Troubled Search for the Biology of Mental Illness. Her book, not about Sacks but focused on his historical context, complements his col­lection of essays by providing a readable, revisionist synthesis that shows that mind and brain medicine has not come as far as we imagine or wish.
Race and the jury

The jury is one of our most democratic institutions. A random sample of the community is asked to render an impartial verdict in a case after hearing evidence from both sides. The notion that ordinary men and women of good will can and will exercise good judgment is basic to our tradition of government by the people. Furthermore, a jury’s verdict is assumed to reflect the collective sentiments and conscience of the community and therefore carries a legitimacy that cannot be attained by experts, no matter how intelligent and skillful they may be.
Interleukin (IL)-1β and IL-10 Host Responses in Patients With Staphylococcus aureus Bacteremia Determined by Antimicrobial Therapy

Background Patient interleukin (IL)-1β and IL-10 responses early in Staphylococcus aureus bacteremia (SaB) are associated with bacteremia duration and mortality. We hypothesized that these responses vary depending on antimicrobial therapy, with particular interest in whether the superiority of β-lactams links to key cytokine pathways. Methods Three medical centers included 59 patients with SaB (47 methicillin-resistant S. aureus [MRSA], 12 methicillin-sensitive S. aureus [MSSA]) from 2015-2017. In the first 48 hours, patients were treated with either a β-lactam (n = 24), including oxacillin, cefazolin, or ceftaroline, or a glyco-/lipopeptide (n = 35), that is, vancomycin or daptomycin. Patient sera from days 1, 3, and 7 were assayed for IL-1β and IL-10 by enzyme-linked immunosorbent assay and compared using the Mann-Whitney U test. Results On presentation, IL-10 was elevated in mortality (P = .008) and persistent bacteremia (P = .034), while no difference occurred in IL-1β. Regarding treatment groups, IL-1β and IL-10 were similar prior to receiving antibiotic. Patients treated with β-lactam had higher IL-1β on days 3 (median +5.6 pg/mL; P = .007) and 7 (+10.9 pg/mL; P = .016). Ex vivo, addition of the IL-1 receptor antagonist anakinra to whole blood reduced staphylococcal killing, supporting an IL-1β functional significance in SaB clearance. β-lactam-treated patients had sharper declines in IL-10 than vancomycin or daptomycin -treated patients over 7 days. Conclusions These data underscore the importance of β-lactams for SaB, including consideration that the adjunctive role of β-lactams for MRSA in select patients helps elicit favorable host cytokine responses.
Facing a Hypervelocity Asteroid Impact Disaster: To Deflect or Evacuate?☆

Abstract Understanding of the near-Earth asteroid impact hazard has been evolving. As larger near-Earth objects (NEOs) are retired from concern by the Spaceguard Survey, as new search strategies oriented toward short-term warning are brought on line, as we understand the increasing danger from NEOs in the 15 m to 40 m size range, and in the aftermath of the 2013 Chelyabinsk impact disaster, attention necessarily must shift toward dealing with the most likely dangerous impacts, those in the range of Chelyabinsk to Tunguska. Appropriate responses to predicted impacts by smaller NEOs involve civil defense and emergency planning endeavors. Deflection of an NEO's trajectory by spacecraft impact, or other means, is becoming a less likely type of mitigation than evacuation. We need more research on the environmental and human consequences of diverse types of hypervelocity NEOs interacting with the Earth's atmosphere, oceans, and land surfaces.
Vanquishing Ventilator Associated Events by Re-emphasizing Evidence Based Practices

Background Patients on mechanical ventilation are at a high risk for a variety of serious complications, including infections that can increase the duration of ventilation, length of hospital stay and morbidity and mortality. In early 2019, our facility noted a significant increase in ventilator-associated events (VAEs) with a total of four (4) events in all of 2018 to seven (7) events in the first six months of 2019. Methods A multidisciplinary work group was formed and an evidence-based quality improvement (EBQI) project was implemented to ensure the Society of Healthcare Epidemiology of America (SHEA) guidelines for prevention of ventilator-associated pneumonia practices were being followed. Collaboration by respiratory therapists (RT) and registered nurses (RN) was determined to be a priority in order to ensure daily interruption of sedation (DIS) and spontaneous breathing trials (SBTs) were completed. Respiratory therapists played a critical role in ensuring positive end-expiratory pressures (PEEP) were set appropriately for the patient's body mass index. Staff re-education on the best practices of DIS, SBT, oral care and changing of oral care kits at a specified time was carried out. The Infection Preventionist performed daily audits of ventilated patients and practices. The goal was to reduce the number of VAEs by 50% in the last six months of 2019. Confounding variables were determined to be existing co-morbidities prior to mechanical ventilation and admitting diagnosis. Results To date, data from June 2019 to mid-November 2019 has demonstrated a significant decrease in VAEs. Only one VAE, a ventilator-associated condition (VAC), occurred in early November 2019. Since June 2019, our VAEs have decreased by 85% since implementation of the EBQI project. Conclusions Going back to the basics and evidence-based guidelines through a multidisciplinary work group and EBQI project which stressed staff education, RT and RN collaboration and appropriate ventilator settings has helped significantly reduce our VAE rate.
Abstract 5818: The immortalization process as a therapeutic target

Normal human somatic cells have a finite lifespan and intact tumor suppressor barriers, whereas most carcinoma cells have gained immortality and overcome multiple tumor suppressor barriers. We have developed a comprehensive human mammary epithelial cell (HMEC) culture system to examine the alterations involved in the transition from normal finite to malignant immortal; such data can suggest prevention strategies. Our studies have indicated that HMEC initially encounter a stress-associated senescence barrier (stasis) enforced by retinoblastoma (RB). Errors in the RB pathway allow stasis bypass; similar errors are seen early in progression in vivo. Replicative senescence due to telomere erosion is a second extremely stringent barrier, with critically short telomeres leading to genomic instability. Overcoming this barrier requires reactivation of endogenous telomerase, similar to what is seen in high-grade DCIS in vivo. Resulting immortal HMEC are resistant to oncogene-induced-senescence, and exposure to oncogenes that cause finite cells to senesce, can now give rise to malignancy, underscoring the critical importance of the immortalization step in progression. Also like DCIS, the molecular properties of our non/pre-malignant immortal HMEC lines are more similar to malignant immortal than normal finite cells, highlighting the abnormal, cancer-like qualities of immortalized cells. We suggest this similarity is due to a novel process that we have discovered to be involved in cancer-associated immortal transformation, that we have called conversion. HMEC that gain an error permissive for telomerase reactivation still need to undergo additional changes to assume the cancer-associated immortal phenotype: expression of sufficient telomerase activity to maintain short telomeres, mean TRF ~4 kb (which is shorter than what is present in normal finite cells). Conversion appears initiated by a mean TRF of Citation Format: Martha R. Stampfer, Tara Fresques, Sun-Young Lee, Mark LaBarge, James Garbe. The immortalization process as a therapeutic target [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5818.
Identification of important factors in an inpatient fall risk prediction model to improve the quality of care using EHR and electronic administrative data: A machine-learning approach.

Abstract Background Inpatient falls, many resulting in injury or death, are a serious problem in hospital settings. Existing falls risk assessment tools, such as the Morse Fall Scale, give a risk score based on a set of factors, but don’t necessarily signal which factors are most important for predicting falls. Artificial intelligence (AI) methods provide an opportunity to improve predictive performance while also identifying the most important risk factors associated with hospital-acquired falls. We can glean insight into these risk factors by applying classification tree, bagging, random forest, and adaptive boosting methods applied to Electronic Health Record (EHR) data. Objective The purpose of this study was to use tree-based machine learning methods to determine the most important predictors of inpatient falls, while also validating each via cross-validation. Materials and methods A case-control study was designed using EHR and electronic administrative data collected between January 1, 2013 to October 31, 2013 in 14 medical surgical units. The data contained 38 predictor variables which comprised of patient characteristics, admission information, assessment information, clinical data, and organizational characteristics. Classification tree, bagging, random forest, and adaptive boosting methods were used to identify the most important factors of inpatient fall-risk through variable importance measures. Sensitivity, specificity, and area under the ROC curve were computed via ten-fold cross validation and compared via pairwise t-tests. These methods were also compared to a univariate logistic regression of the Morse Fall Scale total score. Results In terms of AUROC, bagging (0.89), random forest (0.90), and boosting (0.89) all outperformed the Morse Fall Scale (0.86) and the classification tree (0.85), but no differences were measured between bagging, random forest, and adaptive boosting, at a p-value of 0.05. History of Falls, Age, Morse Fall Scale total score, quality of gait, unit type, mental status, and number of high fall risk increasing drugs (FRIDs) were considered the most important features for predicting inpatient fall risk. Conclusions Machine learning methods have the potential to identify the most relevant and novel factors for the detection of hospitalized patients at risk of falling, which would improve the quality of patient care, and to more fully support healthcare provider and organizational leadership decision-making. Nurses would be able to enhance their judgement to caring for patients at risk for falls. Our study may also serve as a reference for the development of AI-based prediction models of other iatrogenic conditions. To our knowledge, this is the first study to report the importance of patient, clinical, and organizational features based on the use of AI approaches.
Current Challenges and Future Directions in Diffusion MRI: From Model- to Data- Driven Analysis

Diffusion weighted MRI is a prominent non-invasive modality to probe in vivo tissue micro- and macro-structure and has been widely applied throughout neuro- and body imaging. The promise of micro-scale analyses has been in the creation of virtual biopsies that provide information in place of physical histology, while tractography and its related methods offer maps of the neuronal wiring through virtual dissection. While both approaches have had strong successes at the group level, specificity and sensitivity at the individual dataset/single subject level have been more elusive. Herein, we reflect on current challenges and potential future directions in the context of a futurist piece. As such, we go beyond the reasonably well-established science to offer hypotheses/postulates/challenges to encourage discussion and exploration. We postulate that there are transformative opportunities available if we complement our perspective of diffusion MRI as a signal that is explained by a tractable biophysical model with one in which data driven machine learning can inform us about detection, localization, and assessment of both normal and abnormal brain tissue in both local (voxels) and global connectivity. Towards this end, this manuscript describes challenges associated with achieving virtual biopsy (i.e., microstructural modeling) and virtual dissection (i.e., fiber tractography) and suggests opportunities to use data-driven techniques to improve modeling geometry, to learn features of the signal that may prove useful as biomarkers, and to harmonize signal, techniques, and datasets to improve tissue characterization.
The random-field specific heat critical behavior at high magnetic concentration: Fe0.93Zn0.07F2

Abstract The specific heat critical behavior is measured and analyzed for a single crystal of the random-field Ising system Fe 0.93 Zn 0.07 F 2 using pulsed heat and optical birefringence techniques. This high magnetic concentration sample does not exhibit the severe scattering hysteresis at low temperature seen in lower concentration samples and its behavior is therefore that of an equilibrium random-field Ising model system. The equivalence of the behavior observed with pulsed heat techniques and optical birefringence is established. The critical peak appears to be a symmetric, logarithmic divergence, in disagreement with random-field model computer simulations. The random-field specific heat scaling function is determined.
Mother-infant interactions and infant intake during breastfeeding versus bottle-feeding expressed breast milk.

Bottle-fed infants are at higher risk for rapid weight gain compared with breastfed infants. Few studies have attempted to disentangle effects of feeding mode, milk composition and relevant covariates on feeding interactions and outcomes. The objective of the present study was to compare effects of breastfeeding directly at the breast versus bottle-feeding expressed breast milk on feeding interactions. Mothers with <6-month-old infants (n = 47) participated in two counterbalanced, feeding observations. Mothers breastfed their infants directly from the breast during one visit (breast condition) and bottle-fed their infants expressed breast milk during the other (bottle condition). Masked raters later coded videos using the Nursing Child Assessment Parent-Child Interaction Feeding Scale. Infant intake was assessed. Mothers self-reported sociodemographic characteristics, infant feeding patterns (i.e. percentage of daily feedings from bottles) and level of pressuring feeding style. Mother and infant behaviours were similar during breast and bottle conditions. Percent bottle-feeding moderated effects of condition on intake (P = 0.032): greater percent bottle-feeding predicted greater intake during the bottle compared with breast condition. Effects of feeding mode were not moderated by parity or pressuring feeding style, but, regardless of condition, multiparous mothers fed their infants more than primiparous mothers (P = 0.028), and pressuring feeding style was positively associated with infant intake (P = 0.045). Findings from the present study do not support the hypothesis that feeding mode directly impacts dyadic interaction for predominantly breastfeeding mothers and infants, but rather suggest between-subject differences in feeding experiences and styles predict feeding outcomes for this population.
Who Is a Parent

This short essay, published as the opening piece in an issue of the ABA Family Advocate devoted to child custody, addresses parentage. It details the various paths to parental recognition across U.S. jurisdictions: adoption, presumed parentage, biological/genetic parentage, intended parentage (in the context of assisted reproduction), and functional (or de facto) parentage. By explaining how each path to parentage operates with examples from state law, this essay reveals important trends in the American legal system. Increasingly, states have accommodated changing family patterns and have recognized parents even when they break from the conventional norms of the biological, marital, and heterosexual family.
In vitro spheroplast and L form induction within the pathogenic nocardiae

Abstract Six strains of Nocardia asteroides, two strains of N. caviae, and two strains of N. braziliensis were grown in medium supplementted with glycine, lysozyme, D-cycloserine, glycine plus lysozyme, and glycine plus D-cycloserine. It was shown that three strains of N. asteroides, and two strains of N. caviae, readily formed spheroplasts and/or protoplasts when grown in the presence of glycine plus either lysozyme or D-cycloserine. This process was studied by both phase contrast microscopy and electron microscopy. The induced cultures were then plated on hypertonic medium for the isolation of L-forms. It was shown that the organisms differed greatly in their ability to produce spheroplasts and subsequently grew as L-forms or transitional-phase variants.
A Model for Some Subcortical DTI Planar and Linear Anisotropy

Linear anisotropy, planar anisotropy and isotropy [1] are used as metrics for different kinds of diffusion in diffusion imaging. While linear anisotropy is reported to correlate to coherent neural fiber structures, the cause for planar anisotropy remains ambiguous. We hypothesize that overlapping linear structures and partial-volume averaging generate the planar anisotropy. We identify a subcortical region containing both linear and planar anisotropy in a human volumetric diffusion tensor image (DTI), propose a model of the anatomy and of the imaging process, and calculate simulated diffusion images of the anatomical model that qualitatively agree with the human DTI. Regions of planar anisotropy are common immediately beneath the cortex. Choosing one such region as representative, we model the anatomy with isotropic regions and linearly anisotropic structures. From the possibly overlapping model structures we simulate the diffusion imaging process, generating a series of diffusion weighted images (DWIs) of the anatomical structures. We then fit the DTI from these simulated DWIs and visualize it. The visualization agrees qualitatively with the visualization of a subcortical human DTI.
Integration of field emitter arrays into spacecraft systems

Field Emitter Arrays (FEAs) are being developed for electron emission in electrodynamic tether applications. Instead of a single hot (i.e. high powered) emitter or a gas dependant plasma contactor, FEA systems consist of many (up to millions per square centimeter) of small (micron-level) cathode/gate pairs on a semiconductor wafer that effect cold emission at a relatively low voltage. Each individual cathode emits only micro-amp level currents, but a functional array is capable of multiple amp levels. This potentially provides a low power, relatively inexpensive technique for the amp level current emissions required for electrodynamic tether propulsion systems. Critical issues in the development of FEA systems which are discussed here are survivability in ionospheric and spacecraft environments, emission efficiency (i.e. power required to overcome space charge limits in the ionosphere), and electrical integration requirements. Tests of FEA devices are being conducted to evaluate their performance and results to date from these tests will be presented here.
The effect of cyclosporine on urinary kallikrein excretion in patients with rheumatoid arthritis.

The effect of cyclosporine (6 to 8 mg/kg/24 hr) on urinary kallikrein excretion is summarized for 9 patients with rheumatoid arthritis using a specific kallikrein radioimmunoassay. Baseline serum creatinine and BUN values were within the normal range for all patients, and baseline kallikrein excretion rates were either normal (n = 5) or more than two S.D. below the mean of the normal group (n = 4). The patients with normal baseline values excreted significantly less urinary kallikrein three and six months after cyclosporine therapy was started, but all of them completed the six-month protocol. Patients in the subgoup with low baseline values also decreased their kallikrein excretion in response to cyclosporine therapy, and two of the four in this group experienced elevations of BUN such that therapy was terminated. In a low-dose (3 mg/kg/24 hr) open extension that followed the initial trial, kallikrein excretion decreased by almost 50% at least one month before any change in serum creatinine was observed. The data suggest that changes in urinary kallikrein excretion rates may be an indicator or predictor of cyclosporine nephrotoxicity. Decreased kallikrein excretion rates could also be a factor in the diminished renal blood flow reported in patients treated with cyclosporine.
Carboxypeptidase H. A regulatory peptide-processing enzyme produced by human hepatoma Hep G2 cells.

Human hepatoma (Hep G2) cells have been shown to secrete nanogram quantities of carboxypeptidase N (Grimwood, B. G., Plummer, T. H., Jr., and Tarentino, A. (1988) J. Biol. Chem. 263, 14397–14401). A second carboxypeptidase with an acidic pH optimum (pH 5.5) is also secreted at levels 2-3-fold greater than carboxypeptidase N. This enzyme was partially purified from the conditioned medium and compared with pure bovine pituitary carboxypeptidase H. The two enzymes behaved in a similar fashion in DE52 ion-exchange chromatography and on gel filtration, with the Hep G2 enzyme being slightly larger than the bovine pituitary enzyme (52–54 versus 50–52 kDa). Both enzymes hydrolyzed COOH-terminal basic amino acids from typical synthetic substrates as well as from natural leuenkephalin peptides and were identical based on pH activity profiles, inhibition by EDTA or guanidinoethyl mercaptosuccinic acid, and stimulation by Co2+ ions. Inhibition of enzyme secretion from Hep G2 cells by tunicamycin indicated that the Hep G2 enzyme was glycosylated. This finding was confirmed by a parallel deglycosylation of the Hep G2 and bovine pituitary carboxypeptidase H enzymes with peptide-N4-(N-acetyl-β-glucosaminyl)asparagine amidase F. Immunoblots using mouse antiserum to bovine pituitary carboxypeptidase H revealed that the Hep G2 enzyme was immunocross-reactive with the bovine enzyme but was slightly larger in size (54 versus 52 kDa). Continuous [35S]methionine labeling and purification to near homogeneity using an affinity matrix corroborated the observations that the secreted Hep G2 carboxypeptidase H was slightly larger than bovine pituitary carboxypeptidase H. The Hep G2-secreted enzyme in pulse-chase experiments was initially detected intracellularly after a 15-min pulse as a single protein of about 54 kDa and was present in the 30-min chase medium with no evidence for pre- or postsecretion proteolytic processing. The human adrenergic cell line IMR-32 continuously labeled with [35S]methionine also secreted carboxypeptidase H of the same size as the Hep G2 enzyme.
Management of Change

The sections in this article are 1 Computer-Aided Design 2 Background 3 Restructuring Design Work Through CAD 4 Discussion
Analyst Forecast Properties, Financial Distress, and Business Risk

This study examines the validity of using analyst forecast properties to proxy for information quality. The results suggest that dispersion and error measures are strongly related to financial distress and business risk. Firms with losses, earnings declines, and volatile earnings have a strong tendency towards high dispersion and error. Furthermore, forecast biases are predictable. Firms with low dispersion or error measures have relatively little forecast optimism, while firms with high dispersion or error measures have high amounts of forecast optimism. This finding is driven by loss firms, which tend to have greater dispersion and error. Caution should thus be employed when using dispersion and error measures to proxy for the quality of the information environment.
Brain stem reticular units: Synaptic responses to stimulation within the ascending reticular pathways

Abstract When the ascending reticular axonal system is stimulated, the responses of distal structures (e.g., the cerebral cortex) appear to outlast the stimulus; these long-lasting effects could reflect the intrinsic nature of the distal structure, or the response could reflect an interaction among the reticular cells which tends to prolong the effects of stimulation. To examine the latter hypothesis, single units with ascending axons (projecting units) were recorded in the cat rostral rhombencephalon in acute experiments conducted under halothane-nitrous oxide anesthesia. Stimulation of areas to or through which axons of reticular neurons projected (midbrain tegmentum and lower tectum, medial thalamus, and basal forebrain) produced a consistent and specific response which was elicited only from these areas: suppression of spontaneous activity which was typically elicited from several areas having ascending axons. One-half of these responses were accompanied by a short latency-single spike synaptic excitation. Stimulating areas more than 1.0 mm from the ascending trajectory nerver produced this response, whereas the number of responses was directly related to the number of projecting axons identified in any one experiment from a given site. Thus, the predominant effect of stimulating within the ascending axonal trajectory was suppression of spontaneous activity in the projecting units, not an ‘en cascade’ activation of these units; on the contrary, the only type of excitation encountered was a single, short latency spike. Therefore, any effects of stimulation within the ascending reticular pathway which appear to outlast the stimulus (as previously described in the literature) cannot be ascribed to a reverberating (excitatory) circuit among projecting units. A possible source of the synaptic responses of projecting units is a retrograde activation of collaterals interconnecting the reticular cells. If such interaction exists, it is specifically distributed among cells with ascending axons, as the responses were only observed in a very few units not identified by antidromic excitation; however, other evidence is adduced to support the belief that these few units were projecting units whose axons were beyond the reach of the stimulating electrodes. Furthermore, the axons may be bundled such that units with axons nearest that of a given projecting unit give rise to the most extensive synaptic interactions; the activation of these nearby axons suppresses spontaneous activity, while axons farther away have a greater possibility of being excitatory in nature. Should such a medium for interaction exist, reticular collateral interactions might be seen to exist specifically for the purpose of decreasing the activity of cells destined for similar rostral target structures.
Oxygen electroreduction in perfluorinated sulphonyl imides

The electroreduction of oxygen in perfluorinated sulphonyl imides has been studied with the emphasis on the identification of alternate acid electrolytes which could replace the presently used phosphoric acid as an electrolyte in H2−O2 fuel cells. The activity for oxygen reduction on smooth platinum and gas-fed, high surface area platinum-catalysed electrodes (10% platinum loading on XC-72 carbon support) has been examined. The polarization of the air cathode in the micro-fuel cell in bis(trifluoromethanesulphonyl)imide is 40 mV more positive compared to phosphoric acid at 100 mA cm−2, presumably due to the increased solubility of oxygen and lower tendency of bis(trifluoromethanesulphonyl)imide to adsorb on the platinum catalyst. The related bis(fluorosulphonyl)imide is unstable in water and the hydrolysis products adsorb strongly on the catalytic sites, resulting in poor performance.
Googling suicide: surfing for suicide information on the Internet.

OBJECTIVE: This study examined the types of resources a suicidal person might find through search engines on the Internet. We were especially interested in determining the accessibility of potentially harmful resources, such as pro-suicide forums, as such resources have been implicated in completed suicides and are known to exist on the Web. METHOD: Using 5 popular search engines (Google, Yahoo!, Ask.com, Lycos, and Dogpile) and 4 suicide-related search terms (suicide, how to commit suicide, suicide methods, and how to kill yourself), we collected quantitative and qualitative data about the search results. The searches were conducted in August and September 2006. Several coraters assigned codes and characterizations to the first 30 Web sites per search term combination (and"sponsored links"on those pages), which were then confirmed by consensus ratings. Search results were classified as being pro-suicide, anti-suicide, suicide-neutral, not a suicide site, or error (i.e., page would not load). Additional information was collected to further characterize the nature of the information on these Web sites. RESULTS: Suicide-neutral and anti-suicide pages occurred most frequently (of 373 unique Web pages, 115 were coded as suicide-neutral, and 109 were anti-suicide). While pro-suicide resources were less frequent (41 Web pages), they were nonetheless easily accessible. Detailed how-to instructions for unusual and lethal suicide methods were likewise easily located through the searches. CONCLUSION: Mental health professionals should ask patients about their Internet use. Depressed, suicidal, or potentially suicidal patients who use the Internet may be especially at risk. Clinicians may wish to assist patients in locating helpful, supportive resources online so that patients' Internet use may be more therapeutic than harmful. Language: en
Location strategies of broad-line retailers: an empirical investigation☆

Abstract This research is an exploratory investigation into location strategies used by broad-line specialist retailers. Location data for 86 broad-line specialists in the home repair and office supply category located in three southeast metropolitan areas are analyzed. Using distance as a measure of retail structure, it is shown that broad-line specialist retailers tend to locate close to general merchandise retailers. Also, broad-line specialists employ two location strategies with respect to other broad-line specialists—proximity (locating close to a competing broad-line specialist) and distancing (not locating close to a competing broad-line specialist). Moreover, the adoption of proximity or distancing as a location strategy depends upon market characteristics. Broad-line specialists tend to use proximity in trade areas with high income, high population density, high per capita income, with younger populations, and high home ownership. Managerial implications and suggestions for future research are offered.
Geochronologic and paleomagnetic evidence defining the relationship between the Miocene Hiko and Racer Canyon tuffs, eccentric outflow lobes from the Caliente caldera complex, southeastern Great Basin, USA

Outflow sheets of the Hiko tuff and the Racer Canyon tuff, which together extend over approximately 16 000 km2 around the Caliente caldera complex in southeastern Nevada, have long been considered to be products of simultaneous or near-simultaneous eruptions from inset calderas in the west and east ends, respectively, of the caldera complex. New high-precision 40Ar/39Ar geochronology and paleomagnetic data demonstrate that emplacement of the uppermost part of the Racer Canyon tuff at 18.33±0.03 Ma was nearly synchronous with emplacement of the single outflow cooling unit of the much larger overlying Hiko tuff at 18.32±0.04 Ma. Based on comparison with the geomagnetic polarity time scale derived from the sea-floor spreading record, we conclude that emplacement of the first of several outflow cooling units of the Racer Canyon tuff commenced approximately 0.5 m.y. earlier. Only one paleomagnetic polarity is found in the Hiko tuff, but at least two paleomagnetic reversals have been found in the Racer Canyon tuff. The two formations overlap in only one place, at and near Panaca Summit northeast of the center of the Caliente caldera complex; here the Hiko tuff is stratigraphically above the Racer Canyon tuff. This study demonstrates the power of combining 40Ar/39Ar and paleomagnetic data in conjunction with phenocryst compositional modes to resolve problematic stratigraphic correlations in complex ash-flow sequences where use of one method alone might not eliminate ambiguities.
Type 1 interferons and antiviral CD8 T-cell responses.

Type 1 interferons (IFNs) were the first cytokines discovered and include IFNβ, >ten forms of IFNα, and several other related molecules that all bind to the same type 1 IFN receptor (IFN1R). Type 1 IFNs are commonly referred to as “viral” IFNs because they can be induced directly by virus infections, in contrast to “immune” IFN, or IFNγ, which is synthesized after receptor engagement of T cells and natural killer (NK) cells during immune responses. Type 1 IFNs get induced by viral nucleic acids and proteins acting on cellular signaling molecules such as Toll-like receptors and RNA helicases, which, in turn, release transcription factors into the nucleus. Mice lacking IFN1R appear normal in a pathogen-free environment but are extraordinarily susceptible to virus infections [1]. This susceptibility is partially due to IFN-regulated genes that suppress viral replication, but type 1 IFNs also have many immunoregulatory properties that could also affect host susceptibility to infection.
T4 bacteriophage tRNAGly.

Abstract The nucleotide sequence of T4 tRNA Gly is: pGCGGAUAUCGUAUAAUG m GDAUUACCUCAGACUUCCAAψCUGAUGAUGUGAGTψCGAUUCUCAUUAUCCGCUCCA-OH. The sequence is compared with the sequences of five other tRNA Gly species.
Thermodynamic Analysis of ZrB2–SiC Oxidation: Formation of a SiC-Depleted Region

A thermodynamic model was developed to explain the formation of a SiC-depleted layer during ZrB2–SiC oxidation in air at 1500°C. The proposed model suggests that a structure consisting of (1) a silica-rich layer, (2) a Zr-rich oxidized layer, and (3) a SiC-depleted zirconium diboride layer is thermodynamically stable. The SiC-depleted layer developed due to active oxidation of SiC. The oxygen partial pressure in the SiC-depleted layer was calculated to lie between 4.0 × 10−14 and 1.8 × 10−11 Pa. Even though SiC underwent active oxidation, the overall process was consistent with passive oxidation and the formation of a protective surface layer.
Opioid peptide receptor studies. 17. Attenuation of chronic morphine effects after antisense oligodeoxynucleotide knock-down of RGS9 protein in cells expressing the cloned Mu opioid receptor.

RGS proteins are a recently described class of regulators that influence G-protein-mediated signaling pathways. We have shown previously that chronic morphine results in functional uncoupling of the μ opioid receptor from its G protein in CHO cells expressing cloned human μ opioid receptors. In the present study, we examined the effects of morphine treatment (1 μM, 20 h) on DAMGO-stimulated high-affinity [35S]GTP-γ-S binding and DAMGO-mediated inhibition of forskolin-stimulated cAMP accumulation in HN9.10 cells stably expressing the cloned rat μ opioid receptor, in the absence and presence of the RGS9 protein knock-down condition (confirmed by Western blot analysis). RGS9 protein expression was reduced by blocking its mRNA with an antisense oligodeoxynucleotide (AS-114). Binding surface analysis resolved two [35S]GTP-γ-S binding sites (high affinity and low affinity sites). In sense-treated control cells, DAMGO-stimulated [35S]GTP-γ-S binding by increasing the Bmax of the high-affinity site. In sense-treated morphine-treated cells, DAMGO-stimulated [35S]GTP-γ-S binding by decreasing the high-affinity Kd without changing the Bmax. AS-114 significantly inhibited chronic morphine-induced upregulation of adenylate cyclase activity and partially reversed chronic morphine effects as measured by DAMGO-stimulated [35S]GTP-γ-S binding. Morphine treatment increased the EC50 (6.2-fold) for DAMGO-mediated inhibition of forskolin-stimulated cAMP activity in control cells but not in cells treated with AS-114 to knock-down RGS9. These results provide additional evidence for involvement of RGS9 protein in modulating opioid signaling, which may contribute to the development of morphine tolerance and dependence. Synapse 52:209–217, 2004. Published 2004 Wiley-Liss, Inc.
Different phases of afterdischarge during rapid kindling procedure in mice

Summary The basic mechanisms of hippocampal networks in epileptogenesis are not entirely understood. To help achieve a better understanding of these mechanisms, we studied the extra-cellular electrically evoked responses in the hippocampi of mice during rapid kindling. Kindling protocol was achieved by stimulating the dorsal right hippocampus six times daily for four days using bipolar electrodes to produce sub-convulsive electrical discharges. Motor responses and analyzed electroencephalographic recordings showed progression from partial complex seizures to generalized seizures associated with different consecutive patterns within the afterdischarges. A spike-wave pattern appeared immediately after stimulation in combination with a poly-spike complex superimposed over the wave (AD1). AD1 was followed by a poly-spike complex (AD2), which was followed by a progressive modification of repetitive spikes (AD3). An ictal depression event was observed at the end of each AD3. Theta oscillations were observed at stage 1–2 of kindling, while beta/gamma oscillations appeared within AD2, associated with stage 4–5 from Racine's score. Benzodiazepine, a GABA (A) agonist (Diazepam) administered at non-sedative doses and only on days 3 and 4 of kindling, limited beta and gamma frequency bands and the progression of seizure severity, suggesting that the failure of GABA (A) agonism mediates the propagation or generalization of seizures. We conclude that different phases of afterdischarge occur during kindling and that high frequencies mediate generalization of seizures.
Evidence for the identification of lymphocyte activating factor as the adherent cell-derived mediator responsible for enhanced antibody synthesis by nude mouse spleen cells

Abstract Human adherent peripheral blood leukocytes spontaneously elaborate both a thymocyte proliferative factor and a factor which augments the in vitro anti-sheep erythrocyte (SRC) plaque-forming cell (PFC) response of nu/nu mouse spleen cells. Nonadherent leukocytes do not spontaneously elaborate either factor. The adherent cell-derived factors appear to have an identical molecular weight (approximately 14,500 Daltons) as determined by Sephadex gel filtration. The data support the hypothesis that the molecule(s) mediating both enhancing activities is identical to the previously described adherent leukocyte product, LAF.