cssi/SciSciGPT-SciSciNet huggingface dataset:
Comparative Analysis and Refinement of Human PSC-Derived Kidney Organoid Differentiation with Single-Cell Transcriptomics

Summary Kidney organoids derived from human pluripotent stem cells have great utility for investigating organogenesis and disease mechanisms and, potentially, as a replacement tissue source, but how closely organoids derived from current protocols replicate adult human kidney is undefined. We compared two directed differentiation protocols by single-cell transcriptomics of 83,130 cells from 65 organoids with single-cell transcriptomes of fetal and adult kidney cells. Both protocols generate a diverse range of kidney cells with differing ratios, but organoid-derived cell types are immature, and 10%–20% of cells are non-renal. Reconstructing lineage relationships by pseudotemporal ordering identified ligands, receptors, and transcription factor networks associated with fate decisions. Brain-derived neurotrophic factor (BDNF) and its cognate receptor NTRK2 were expressed in the neuronal lineage during organoid differentiation. Inhibiting this pathway improved organoid formation by reducing neurons by 90% without affecting kidney differentiation, highlighting the power of single-cell technologies to characterize and improve organoid differentiation.
Transitions in Poiseuille flow of nematic liquid crystal

Abstract Recent experiments by Sengupta et al. (Phys. Rev. Lett. 2013) [9] revealed interesting transitions that can occur in flow of nematic liquid crystal under carefully controlled conditions within a long microfluidic channel of width much larger than height, and homeotropic anchoring at the walls. At low flow rates the director field of the nematic adopts a configuration that is dominated by the surface anchoring, being nearly parallel to the channel height direction over most of the cross-section; but at high flow rates there is a transition to a flow-dominated state, where the director configuration at the channel centerline is aligned with the flow (perpendicular to the channel height direction). We analyze simple channel-flow solutions to the Leslie–Ericksen model for nematics. We demonstrate that two solutions exist, at all flow rates, but that there is a transition between the elastic free energies of these solutions: the anchoring-dominated solution has the lowest energy at low flow rates, and the flow-dominated solution has lowest energy at high flow rates.
Fluorescent Imaging and Microscopy for Dynamic Processes in Rats

The rat is a favored model organism to study physiological function in vivo. This is largely due to the fact that it has been used for decades and is often more comparable to corresponding human conditions (both normal and pathologic) than mice. Although the development of genetic manipulations in rats has been slower than in mice, recent advances of new genomic editing tools allow for the generation of targeted global and specific cell type mutations in different rat strains. The rat is an ideal model for advancing imaging techniques like intravital multi-photon microscopy or IVMPM. Multi-photon excitation microscopy can be applied to visualize real-time physiologic events in multiple organs including the kidney. This imaging modality can generate four-dimensional high resolution images that are inherently confocal due to the fact that the photon density needed to excite fluorescence only occurs at the objective focal plane, not above or below. Additionally, longer excitation wavelengths allow for deeper penetration into tissue, improved excitation, and are inherently less phototoxic than shorter excitation wavelengths. Applying imaging tools to study physiology in rats has become a valuable scientific technique due to the relatively simple surgical procedures, improved quality of reagents, and reproducibility of established assays. In this chapter, the authors provide an example of the application of fluorescent techniques to study cardio-renal functions in rat models. Use of experimental procedures described here, together with multiple available genetically modified animal models, provide new prospective for the further application of multi-photon microscopy in basic and translational research.
The Use of Multiple Neurotransmitters at Synapses

Abstract Early neurophysiologists believed that each neuron releases only one type of neurotransmitter, and that this phenotype is maintained throughout the life of the neuron. However, later experiments revealed that most neurons release more than one type of neurotransmitter. These multiple neurotransmitters may all be released together from one neuron at the same synapse, or they may be released separately from different axon branches of that neuron, or they may be released in response to different patterns of electrical activity. Many neurons also have the potential to change the types of neurotransmitters they release. Some neurons release one set of neurotransmitters in early development, and a different set after they mature. Other neurons can change the type of neurotransmitter they release in response to electrical activity or environmental changes. The capacity of neurons to synthesize, store, and release more than one type of neurotransmitter enhances the complexity of their signaling and provides opportunities for synaptic plasticity.
Variation in Serious Illness Communication among Surgical Patients Receiving Palliative Care

Background: Natural language processing (NLP), a form of computer-assisted data abstraction, rapidly identifies serious illness communication domains such as code-status confirmation and goals of c...
The Foundations of the Entrepreneurial Society

Just as the entrepreneurial economy is one in which entrepreneurial activity serves as a driving force underlying economic performance, the entrepreneurial society provides the institutional, policy and cultural context conducive to entrepreneurship, which in turn, shapes economic performance. By providing the foundations of the entrepreneurial society, this addresses an inherent paradox – the impact of entrepreneurship on economic performance is embedded in a considerably broader range of influences. This suggests that a focus solely restricted to institutions, policies and culture promoting entrepreneurship is too narrow and may not necessarily generate the public policy goal of a stronger economic performance. This paper concludes that rather than a simple and singular focus on entrepreneurship, effective entrepreneurship policy needs to be compatible with the other main forces shaping and influencing spatial economic performance.
EFFECTS OF INDOMETHACIN AND IBUPROFEN ON LUNG MORPHOMETRY AND BIOMARKERS FOR OXIDATIVE STRESS, DNA DAMAGE AND PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN IN NEONATAL RATS

Background: Indomethacin has been the drug of choice for the treatment of symptomatic patent ductus arteriosus; however, its use is associated with renal and gastrointestinal adverse effects. Although ibuprofen lysine has been shown to be a safer alternative to indomethacin, it was demonstrated to result in persistent pulmonary hypertension of the newborn (PPHN). Objective: To compare the effects of indomethacin and ibuprofen on morphology and biomarkers for oxidative stress, DNA damage and PPHN in normoxic and hyperoxic rat lungs. Methods: Newborn rats were treated with room air (RA) or hyperoxia (50% O2) from the first day of life (P1). The rat pups received intraperitoneal injections of either indomethacin (0.2 mg/kg) on P1 and 0.1 mg/kg on P2 and P3; ibuprofen (10 mg/kg) on P1 and 5 mg/kg on P2 and P3; or saline on P1, P2 and P3, then were killed on P4. Lung morphometry and biomarkers for oxidative stress (8-epi-PGF2α), DNA damage (8-hydroxy-2′-deoxyguanosine) and PPHN (endothelin 1 (ET-1), big ET-1 and total nitric oxide (NO)) were assessed. Results: Both drugs produced oversimplified alveoli with dilated alveolar ducts, but the effect was more severe and widespread with indomethacin. Changes in lung morphometry with indomethacin were associated with higher 8-epi-PGF2α (reflecting oxidative stress) and total NO during hyperoxia; and higher ET-1 during RA. Both drugs suppressed 8-hydroxy-2′-deoxyguanosine (reflecting DNA damage) during hyperoxia. Conclusions: These data demonstrate that both drugs adversely affect lung morphometry. Although the effects were less severe with ibuprofen than indomethacin, treatment with both drugs may lead to PPHN and impaired alveolar and pulmonary vascular development.
Glycemic control in critically 111: A review

Dysglycemia is frequently encountered in critically ill patients in the intensive care units (ICU) and is associated with increased morbidity and mortality. Glycemic control in ICU has three important aspects - hyperglycemia, hypoglyce- mia and glucose variability. All three aspects carry equal importance in the management of critically ill patients and need to be understood. In this review, we will discuss about glucose metabolism in relation to glycemic control in critically ill patients- epidemiology, pathophysiology and management of hyperglycemia, hypoglycemia and glucose variability in critically ill patients.
Cost and Cost-Effectiveness of Large-Scale Screening for Type 1 Diabetes in Colorado

OBJECTIVE To assess the costs and project the potential lifetime cost-effectiveness of the ongoing Autoimmunity Screening for Kids (ASK) program, a large-scale, presymptomatic type 1 diabetes screening program for children and adolescents in the metropolitan Denver region. RESEARCH DESIGN AND METHODS We report the resource utilization, costs, and effectiveness measures from the ongoing ASK program compared with usual care (i.e., no screening). Additionally, we report a practical screening scenario by including utilization and costs relevant to routine screening in clinical practice. Finally, we project the potential cost-effectiveness of ASK and routine screening by identifying clinical benchmarks (i.e., diabetic ketoacidosis [DKA] events avoided, HbA1c improvements vs. no screening) needed to meet value thresholds of $50,000–$150,000 per quality-adjusted life-year (QALY) gained over a lifetime horizon. RESULTS Cost per case detected was $4,700 for ASK screening and $14,000 for routine screening. To achieve value thresholds of $50,000–$150,000 per QALY gained, screening costs would need to be offset by cost savings through 20% reductions in DKA events at diagnosis in addition to 0.1% (1.1 mmol/mol) improvements in HbA1c over a lifetime compared with no screening for patients who develop type 1 diabetes. Value thresholds were not met from avoiding DKA events alone in either scenario. CONCLUSIONS Presymptomatic type 1 diabetes screening may be cost-effective in areas with a high prevalence of DKA and an infrastructure facilitating screening and monitoring if the benefits of avoiding DKA events and improved HbA1c persist over long-run time horizons. As more data are collected from ASK, the model will be updated with direct evidence on screening effects.
The Irvingtonian Avifauna of Cumberland Bone Cave, Maryland.

The early and mid-Pleistocene avian communities of North America are best known from the Rocky Mountain region and peninsular Florida. In the Appalachian Mountain region, only a small number of avian bones from mid-latitude cave deposits have been attributed to this time period. Here, I enlarge this record by reporting on bird bones from Cumberland Bone Cave in western Maryland, a well-known locality for large and small Irvingtonian mammals and other vertebrates. The taxa identified encompass ground birds, waterfowl, a hawk, two eagles, a vulture, an owl, a jay, a flycatcher, a junco or sparrow, and a finch. No purely boreal elements are confirmed as part of the avian assemblage, and all of the extant species that are positively or tentatively identified in the assemblage still occur in the region today. An immature bone referred to the Black Vulture (Coragyps atratus (Bechstein)) represents an Irvingtonian breeding record for the species in Maryland. This record occurs at the northern limit of the current breeding range for the genus. Extinct species in the assemblage include the Passenger Pigeon (Ectopistes migratorius (Linnaeus)), a large screech owl (Megascops guildayi (Brodkorb & Mourer-Chauvire 1984)), and the large goose, Branta dickeyi Miller 1924. It can be argued that none of these represent the extinction of a phyletic lineage during the Irvingtonian. Based on the broad habitat preferences of modern counterparts of the birds in the assemblage, we can expect that Irvingtonian habitats near the site included mixed forest with mast-producing hardwoods and both early and later successional stages represented. There must have been fluvial, wetland, or lacustrine habitat suitable for waterbirds nearby, and probably also open woodland or grassy savannah areas, suitable for vulture foraging, turkey nesting, and booming by Ruffed Grouse.
Effect of culture medium and cell size on functional heterogeneity of canine adipose-derived mesenchymal stromal cells

Background & Aim Introduction Mesenchymal stromal cells (MSCs) are being investigated in clinical trials for treatment of a variety of veterinary conditions based on their anti-inflammatory actions and potential to induce functional tissue repair. However, outcomes of clinical trials have often fallen short of pre-clinical expectations. Heterogeneity of MSC preparations and lack of adequate characterization may be partial contributors to the variability in clinical outcomes. Purpose Identification of subpopulations within heterogenous MSC cultures may improve selection of cells with the desired functionality. Therefore, the functional heterogeneity of different subpopulations of MSCs that vary in size was evaluated, as size is hypothesized to relate to function. Methods, Results & Conclusion Methods A high-throughput, biophysical, label-free microfluidic sorting approach was used to separate subpopulations of canine adipose-derived MSCs (Ad-MSCs) based on size. Size sorted MSCs were then characterized and evaluated for the impact of culture conditions on functional heterogeneity. Results We found that larger subpopulations of MSCs with a mean diameter of ∼18 μm proliferate more slowly, senesce at earlier passages, and are inclined to form adipocytes compared to smaller MSC subpopulations (mean diameter of ∼15 μm). Most importantly, size-dependent functions are affected by culture conditions as well as time in culture. Cell surface staining for MSC-specific CD44 & CD90 antigens showed different sized subpopulations of MSCs had comparable expression levels suggesting that this criterion is not relevant to defining subpopulations of MSCs. However, transcriptome analysis showed that differently sized subpopulations of canine Ad-MSCs have distinct gene expression profiles, and culture medium and time in culture further affect gene expression. Conclusion This work provides a strategy for identifying functional subpopulations of canine MSCs based on size that could facilitate the development of quality cellular therapies through a better understanding of functional heterogeneity.
Upending the status quo: Power-sharing and community building in Schitt’s Creek:

In the CBC sitcom Schitt’s Creek, a family adjusts to living in a small, rural town after losing their fortune. While Schitt’s Creek embraces the ‘fish out of water’ trope, the series explores a co...
Fine-scale spatial structuring of genotypes and phenotypes in natural populations of Asclepias syriaca

Abstract The majority of plants have the ability to reproduce asexually. Despite the importance of asexual reproduction, we still have a limited understanding of how clonality impacts phenotypic and genetic variation within natural populations. Here, we collected phenotypic and genetic data on spatially mapped ramets of common milkweed (Asclepias syriaca) from 10 belt transects from three populations to determine the average size and extent of milkweed clones, whether genotypes and phenotypes were spatially clustered, and whether ramets from the same clone were more similar to each other phenotypically than ramets from different clones. Only 14 % of the 141 ramets that were genotyped belonged to the same clone as another genotyped ramet. Although ramets from the same clone were, on average, closer together than ramets from different clones, we found that the minimum distance between ramets from the same clone was significantly larger than the minimum distance observed between non-clone ramets. Ramets within half a meter of each other had less than a 7% probability of being the same genotype. The high degree of unique genotypes within a single belt transect indicates that sexual reproduction is much more common in milkweed populations than previously thought. Ramets from the same clone were not more similar to each other in height, reproductive allocation, herbivory severity, or leaf traits than ramets from different clones. Our data support the conclusion that even small patches of milkweed that are phenotypically similar are unlikely to be a single clone.
Exploring the Mechanism of Covalent Inhibition: Simulating the Binding Free Energy of α-Ketoamide Inhibitors of the Main Protease of SARS-CoV-2.

The development of reliable ways of predicting the binding free energies of covalent inhibitors is a challenge for computer-aided drug design. Such development is important, for example, in the fight against the SARS-CoV-2 virus, in which covalent inhibitors can provide a promising tool for blocking Mpro, the main protease of the virus. This work develops a reliable and practical protocol for evaluating the binding free energy of covalent inhibitors. Our protocol presents a major advance over other approaches that do not consider the chemical contribution of the binding free energy. Our strategy combines the empirical valence bond method for evaluating the reaction energy profile and the PDLD/S-LRA/s method for evaluating the noncovalent part of the binding process. This protocol has been used in the calculations of the binding free energy of an α-ketoamide inhibitor of Mpro. Encouragingly, our approach reproduces the observed binding free energy. Our study of covalent inhibitors of cysteine proteases indicates that in the choice of an effective warhead it is crucial to focus on the exothermicity of the point on the free energy surface of a peptide cleavage that connects the acylation and deacylation steps. Overall, we believe that our approach should provide a powerful and effective method for in silico design of covalent drugs.
Extended control systems: A theory and its implications

Philosophers and cognitive scientists alike have recently been interested in whether cognition extends beyond the boundaries of skin and skull and into the environment. However, the extended cognit...
A surface mesh deformation method near component intersections for high-fidelity design optimization

Aerodynamic shape optimization based on computational fluid dynamics (CFD) requires three steps: updating the geometry based on the design variables, updating the CFD surface mesh for the new geometry, and updating the CFD volume mesh based on the new surface mesh. While there are many tools available for the first and third steps, the methods available for the second step are insufficient for geometries that have intersecting components. For these geometries, the CFD surface mesh needs to be updated near component intersections to conform to the component geometries and the updated intersection curves. To address this need, we introduce a method that can deform the CFD surface mesh nodes near component intersections. The method can handle arbitrary design changes for each intersecting component as long as the geometric topology is unchanged. Furthermore, the method is suitable for gradient-based optimization because it smoothly deforms every CFD surface node without introducing topological changes in the CFD surface mesh. In this paper, we detail each step of the proposed method and visualize the range of design changes that can be achieved with this approach. Finally, we use the proposed method in an aerodynamic shape optimization problem to optimize the wing-body intersection of the DLR-F6 configuration. These results demonstrate the effectiveness of the proposed method in a high-fidelity design optimization framework. The method applies to both structured and unstructured CFD meshes and makes it possible to use computer-aided design and conceptual design geometry tools within high-fidelity design optimization.
Age-related effects on thymic output and homeostatic T cell expansion following depletional induction in renal transplant recipients

Thymic output and homeostatic mature cell proliferation both influence T cell repopulation following depletional induction, though the relative contribution of each and their association with recipient age have not been well studied. We investigated the repopulating T cell kinetics in kidney transplant recipients who underwent alemtuzumab induction followed by belatacept/rapamycin-based immunosuppression over 36-month posttransplantation. We focused specifically on the correlation between repopulating T cell subsets and the age of patients. Substantial homeostatic Ki67-expressing T cell proliferation was seen posttransplantation. A repertoire enriched for naive T (TNaive ) cells emerged posttransplantation. Analysis by generalized estimating equation linear models revealed a strong negative linear association between reconstituting TNaive cells and advancing age. A relationship between age and persistence of effector memory cells was shown. We assessed thymic output and found an increase in the frequency of recent thymic emigrants (RTEs, CD4+ CD31+ ) at 12-month posttransplantation. Patients under 30 years of age showed significantly higher levels of CD4+ CD31+ cells than patients over 55 years of age pre- and posttransplantation. IL-7 and autologous mature dendritic cells (mDCs) induced CD57- cell proliferation. In contrast, mDCs, but not IL-7, induced CD57+ cell proliferation. This study establishes the relationship between age and thymic output during T cell homeostatic repopulation after alemtuzumab induction. Trial Registration: ClinicalTrials.gov - NCT00565773.
Association between Food Insecurity, Mental Health, and Intentions to Leave the US Army in a Cross-Sectional Sample of US Soldiers.

Background Previous research has demonstrated that certain groups in the United States are at a greater risk for food insecurity. However, food insecurity has not been sufficiently characterized in active duty military populations. Objectives The primary objective of this study was to determine the prevalence of marginal food insecurity at a large US Army installation. The secondary objective was to determine how marginal food insecurity may be associated with intentions to leave the US Army after the current service period ("intentions to leave"). Methods A cross-sectional, online survey was administered by the US Army Public Health Center at an Army installation in 2019 (n = 5677). The main predictor was the 2-item food insecurity screener (Hunger Vital Signs), and the main outcome was a 5-point Likert question, "How likely are you to leave the army after your current enlistment/service period?" that was dichotomized for this analysis. Multiple logistic regression was used to assess the association between marginal food insecurity and intentions to leave. Mental health covariates were analyzed as a potential mediator. Results The sample was primarily male (83%), age >25 y (49%), and White (56%). One-third of respondents were classified as marginally food insecure using the Hunger Vital Signs, and 52% had intentions to leave. There was no significant association between marginal food insecurity and intentions to leave in the composite multivariable model, but mediation analyses revealed that food insecurity was significantly and independently associated with anxiety, depression, and suicidal ideation, which was in turn associated with intentions to leave. Conclusions The association between marginal food insecurity and mental health showed that addressing food insecurity could improve mental health and subsequently reduce intentions to leave. Solutions to reduce military food hardship include expanding Supplemental Nutrition Assistance Program eligibility requirements, improving food resources communication, and expanding healthy food choices on-post.
Are There Cognitive Profiles Unique to Students With Learning Disabilities? A Latent Profile Analysis of Wechsler Intelligence Scale for Children–Fourth Edition Scores

It is often assumed that children with learning disabilities (LD) exhibit unique profiles of ability scores that reflect idiosyncratic cognitive strengths and weaknesses. Interpretation of cognitiv...
Evolutionary expansion of poly-aspartate motif in the activation peptide of mouse cationic trypsinogen limits autoactivation and protects against pancreatitis.

The activation peptide of mammalian trypsinogens typically contains a tetra-aspartate motif (positions P2-P5 in Schechter-Berger numbering) that inhibits autoactivation and facilitates activation b...
National Implementation and Evaluation of a Virtual Subinternship in Urology

Objectives To conduct a nationwide evaluation of student and program director (PD) perspectives of virtual subinternships that took place during the COVID-19 pandemic. Methods In December 2020, we distributed anonymous surveys to all 534 urology residency applicants and 161 urology PDs at academic medical centers across the United States to evaluate virtual subinternships. Surveys assessed curriculum composition, goals, satisfaction, barriers, and future reusability. The primary outcome was overall satisfaction with the subinternship, evaluated on a 5-point Likert scale. Results The survey was completed by 174 students (33%) and 82 PDs (51%), including 81 students (47%) and 32 PDs (41%) who participated in virtual subinternships at 29 institutions. Overall, 77% of students and 78% of PDs rated the electives "excellent" or "very good." On ordinal logistic regression, higher student ratings were associated with duration ≥3 weeks (OR 4.64, p=0.003) and class size ≤4 students (OR 3.33, p=0.015). Higher PD ratings were associated with full-time electives (OR 11.18, p=0.019), class size ≤4 students (OR 13.99, p=0.042), and utilization of the standardized Guidebook from the Society of Academic Urologists (OR 11.89, p=0.038). The most commonly reported challenge to the subinternship's efficacy was lack of hands-on learning (87% of students and 81% of PDs). Looking forward, 45% of students and 66% of PDs recommended incorporating virtual components into future electives. Conclusions The virtual subinternship was a coordinated nationwide initiative to provide urologic education to medical students during a pandemic. The most successful courses were structured with longer duration, full-time commitment, and small class size.
Representing Place in British Literature and Culture, 1660-1830: From Local to Global

Contents: Introduction, Evan Gottlieb and Juliet Shields Part 1 From Local to National: 'Really a sweet town': laying the scene locally in Restoration drama, Bridget Orr What's British about The British Recluse? The political geography of early 18th-century fiction, Juliet Shields Local languages: obscurity and open secrets in Scots vernacular poetry, Janet Sorensen At home in the churchyard: graves, localism, and literary heritage in the prose pastoral, Paul Westover. Part 2 From National to Global: No place like home: from local to global (and back again) in the Gothic novel, Evan Gottlieb Resisting the 'democratic spirit': English Catholicism and the Cisalpine movement, Scott M. Cleary Connecting 18th-century India: orientalism, Della Cruscanism and the translocal poetics of William and Anna Maria Jones, James Mulholland. Part 3 Romanticism and the Return to the Local: 'Usurpt by Cyclops': rivers, industry, and environment in 18th-century poetry, Penny Fielding Local poetry in the Midlands: Francis Mundy's Needwood Forest and Anna Seward's Lichfield poems, JoEllen DeLucia Homes and haunts: Austen's and Mitford's English idylls, Deidre Lynch Coda: knowing your place, Dafydd Moore Works cited Index.
How Agile is Agile Enough? Toward a Theory of Agility in Software Development

This paper outlines a theory of software development agility that draws upon a model of IT innovations. We examine how both exploration and exploitation impact software development agility. We propose a sequential model of learning in which agility is driven by exploration versus exploitation needs and development agility is influenced by learning focus. Organizations need to balance multiple conflicting goals including speed, quality, cost, risk and innovative content. The value of the model is illustrated by probing how software organizations controlled their agility in Internet computing between the years 1997 and 2003.
Methods for simulating string collisions with rigid spatial obstacles

In certain musical instruments, the collisions of a vibrating string with rigid spatial obstacles, such as frets or a curved bridge, are crucial to the tonal quality of the sounds produced. For realistic physical modeling of these instruments, such nonlinearity-inducing interactions need to be examined and simulated accurately. In pursuit of this ultimate goal, we present approaches based on digital waveguides and finite-difference schemes to simulate an ideal string colliding inelastically with rigid obstacles.
Non‐stationary Cross‐Covariance Models for Multivariate Processes on a Globe

. In geophysical and environmental problems, it is common to have multiple variables of interest measured at the same location and time. These multiple variables typically have dependence over space (and/or time). As a consequence, there is a growing interest in developing models for multivariate spatial processes, in particular, the cross-covariance models. On the other hand, many data sets these days cover a large portion of the Earth such as satellite data, which require valid covariance models on a globe. We present a class of parametric covariance models for multivariate processes on a globe. The covariance models are flexible in capturing non-stationarity in the data yet computationally feasible and require moderate numbers of parameters. We apply our covariance model to surface temperature and precipitation data from an NCAR climate model output. We compare our model to the multivariate version of the Matern cross-covariance function and models based on coregionalization and demonstrate the superior performance of our model in terms of AIC (and/or maximum loglikelihood values) and predictive skill. We also present some challenges in modelling the cross-covariance structure of the temperature and precipitation data. Based on the fitted results using full data, we give the estimated cross-correlation structure between the two variables.
Chemical modification of adenylosuccinate synthetase from Escherichia coli by pyridoxal 5'-phosphate. Identification of an active site lysyl residue.

Incubation of adenylosuccinate synthetase from Escherichia coli with low concentrations of pyridoxal 5'-phosphate (PLP) resulted in a rapid loss of activity (92%), concomitant with the formation of a Schiff base. The inactivation of the enzyme by PLP is apparently first order with respect to PLP. The pseudo-first order rate constant, Kapp, showed a hyperbolic dependence on the concentration of PLP, indicating that a kinetically significant PLP.enzyme intermediate is formed during the inactivation process. Stoichiometry and peptide isolation studies showed that 2 lysine residues were modified during reaction of the enzyme with PLP. The three substrates of adenylosuccinate synthetase (GTP, IMP, and aspartate) showed different effects in their ability to protect the enzyme against PLP inactivation. Complete protection of the enzyme against inactivation can be observed only in the presence of high concentrations of GTP. One lysine residue was protected under these conditions. In contrast to GTP, addition of the other two substrates either alone or together to reaction mixtures did not render protection. Peptide mapping by digesting the enzyme with trypsin revealed that the lysine shielded by GTP is Lys140. Replacing the Lys140 with Ile140 by site-directed mutagenesis resulted in total loss of the activity. These results suggest that Lys140 may play an important role in enzymatic activity.
The effect of mitotic checkpoint defects on chromosome stability in mammals

Proc Amer Assoc Cancer Res, Volume 46, 2005 SY23-4 Our group has been studying the consequence of mitotic checkpoint defects on the acquisition of aneuploidy and tumor initiation in mammals. The mitotic checkpoint apparatus monitors faithful attachment of the mitotic spindle to kinetochores and blocks the metaphase-to-anaphase transition if failures occur. Reduced expression of one component of the mitotic checkpoint apparatus, Mad2, leads to an increase in chromosome instability which can be traced to the premature liberation of separase, a protease which cleaves the cohesin protein which bind sister chromatids together. In mice, such chromosome instability has been shown to lead to lung adenocarcinomas with long latencies. Human tumors with reduced Mad2 expression have been reported, consistent with Mad2 being a bona fide tumor suppressor gene. Complete loss of Mad2 expression in human carcinoma cells and primary cells in culture leads to rapid cell death due to premature degradation of cyclin B and failures in mitotic spindle assembly. Thus complete Mad2 loss of function both acutely challenges the mitotic checkpoint (by prevent kinetochore attachment) and incapacitates it thereby leading to mitotic catastrophe. Mad2 is the first example therefore of a tumor suppressor gene which is essential for somatic cell viability. Recent experiments also indicate that overexpression of Mad2 in tumor cells, as a consequence of Rb loss and E2F activation, can also lead to the acquisition of aneuploidy by delaying the separation of sister chromatids as cells attempt to escape the mitotic block imposed by Mad2 overexpression. Preliminary analysis of animals overexpressing a Mad2 transgene will also be discussed.
The Effective Cross Section of Pu240 in Long-Term Reactivity Calculations

The presence of a large, sharp resonance at 1 ev in Pu/sup 240/ results in the effective pile cross section for this isotope being very much larger than the true thermal cross section. Furthermore, the narrowness of this resonance causes the absorption of epithermal neutrons in Pu/sup 240/ to be strongly self- shielded. Consequently, the effective cross section of Pu/sup 210/ will be a junction of reactor spectrum and of the Pu/sup 210/ concentration at any given time. The significance of this effect can be appreciated by noting that the effective cross section of this isotope is frequently more than twice the effective thermal value. An approximate method of calculation was applied to long term reactivity problems. The importance of the resonance augmentation and concentration dependence of the Ar/sup 210/ cross section is particularly evident in the first few thousand Mwd/t and causes significant changes in the reactivity required to reach any longer burnout. Sample calculations are presented and comparisons with the Canadian experimental determinations of the effective Pu/sup 210/ cross section are made. An effective constant Pu/sup 210/ cross section is presented which will yield approximately correct burnout results when used in conventional irradiation studies. (auth)
Aggregations of Sea Otters (Enhydra lutris kenyoni) Feeding on Fish Eggs and Kelp in Prince William Sound, Alaska

Abstract Dietary studies of sea otters often focus on the ecological implications of foraging on large, energy rich prey. Although fish eggs and kelp have been documented as part of sea otter diets in the past, their relative importance and ecological implications have often been overlooked. Evidence of a relatively large aggregation of sea otters foraging on fish eggs and kelp is presented in this study with the potential implications for local herring fishery recovery. A gradual increase in the number of individuals using this resource over time also indicated that sea otters were attracted to large feeding aggregations which may increase exploitation of previously under utilized resources.
Shameless Women: The Anthropological Mirror as Speculum

Woman: An Intimate Geography. Natalie Angier. Boston: Houghton Mifflin, 1999. 398 pp. After Silence: Rape and My Journey Back. Nancy Venable Raine. New York: Crown, 1998. 278 pp. Cunt:. Declaration of Independence. Inga Muscio. Seattle: Seal, 1998. 277 pp.
The negative transfer problem in neural networks: a solution

The authors introduce a modified BP (backpropagation) model that can be used in sequential learning to overcome the NET (negative transfer) effect. Simulations were conducted to contrast the performance of the original BP model with the modified one. The results of the simulations showed that effect of the NT can be completely eliminated, and in some cases reversed, by using the modified BP model. The behavior and interactions of the weight matrices are studied over successive training sessions. This work confirms the need to have an overall cognitive architecture that goes beyond the basic application of the learning model. >
In memoriam: Celso-Ramon Garcia, M.D. (1922–2004), reproductive medicine visionary

This article traces the career of Celso-Ramon Garcia (1922–2004), noted physician, educator, and internationally renowned pioneer in the field of reproductive endocrinology. His work helped to formulate oral contraceptives used by millions of women throughout the world. Garcia's research collaborators included Gregory Pincus and John Rock, who together finalized the landmark clinical data needed to secure initial FDA approval for "the pill" in 1960. In addition to Garcia's monumental work in contraceptive endocrinology, his scholarly interests encompassed physiology of the menopause, minimally invasive reproductive surgery, as well as psychological aspects of infertility. Closely identified with the University of Pennsylvania, Garcia was instrumental in establishing the first formal clinical program in reproductive biology and influenced countless young scientists whose training he supervised and mentored. His distinguished career was emblematic of the best of the medical profession, characterized by compassion, intellect, and a sincere desire to help others. Our manuscript outlines Garcia's wide range of interests, acknowledges his superior fund of knowledge, and honors his humanitarian spirit – all of which contributed to an impressive legacy of medical discoveries. The impact of Prof. Garcia's work will continue to be felt for many years.
Effects of chronic ethanol ingestion upon acyl-CoA: Carnitine acyltransferase in liver and heart

Chronic alcohol ingestion has been shown to cause a profound decrease in the activity of acyl-coenzymeA:carnitine acyltransferase in the liver. Twelve diferent acyl-coenzymes were used as substrates, and the decrease in acyltranser rates ranged from 22–60% of the control. This enzyme was not affected as drastically in the heart. Of 11 acyl-coenzymes tested, only two resulted in significantly lower rates of acyltransfer, even though the rates were decreased with all substrates tested. The specificities of this enzyme showed that increasing the chain length of the acyl group resulted in a decreased acyltransfer when the acyl groups were either saturated, monoenoic, dienoic, or trienoic. Also, increasing the number of ethylenic bonds present in the acyl group of fatty acyl-coenzymes of the same chain length resulted in increased rates of acyltransfer. One exception to this ethylenic bond effect was noted in the heart. Linolenate resulted in an acyl-transfer rate lower than linoleate. Ethanol had little or no effect upon these specificities.
Compensation in the jobless organization

Abstract The job has traditionally played a central role in the design and structure of organizations. Recently, however, the jobless organization has emerged in response to a number of economic and technological developments. As the design and structure of organizations has changed, efforts have increasingly been made to move from the traditional job-based compensation system to a person-based approach. This paper reviews the changes that have been observed in compensation programs as efforts are made to respond to the jobless organization. This paper then highlights possible directions for future research by developing research propositions relating to the impact of person-based pay and the conditions likely to affect the nature of that impact.
Spike communication of dynamic stimuli: rate decoding versus temporal decoding

Abstract We compare two methods for extracting information about a dynamic analog stimulus from a spike train: a rate decoder, which is based on the number of spikes in a counting window, and a temporal decoder, which is based on interspike intervals. We derive analytical expressions for the distortion between a stimulus current that drives an integrate-and-fire spike generator and a reconstruction of that current based on the spike train. We consider intrinsic distortion, which arises due to the limitations of spike coding, and extrinsic distortion, which is due to explicit alterations of the spike train. We find that in the absence of extrinsic distortion, the temporal decoder is superior to the rate decoder. In the presence of extrinsic distortion, the temporal decoder is preferred when low latency is required, but the rate decoder is preferred when the latency requirement is relaxed.
Spontaneous closure of fenestrations in an interatrial Gore-Tex patch: Application to the Fontan procedure

The concept of the partial Fontan procedure, first described with the adjustable atrial septal defect (ASD) and more recently with the fenestrated technique, has become an accepted approach for the management of high-risk patients undergoing the Fontan procedure. Experience with both techniques has shown that a patent ASD placed in a prosthetic interatrial baffle may close spontaneously over a period of weeks to months. The mechanism and timing of spontaneous closure, as well as the effect of antiplatelet therapy on this process, are poorly understood. To better define this process, the interatrial septum of 15 mongrel dogs was excised and replaced with a fenestrated Gore-Tex (W.L. Gore, Flagstaff, AZ) patch. Postoperative echocardiography confirmed the patency of the ASD and left-to-right shunting. Animals were sacrificed 4 to 6 weeks postoperatively, or sooner if infection or other postoperative complications developed. Eight animals underwent no antiplatelet or anticoagulation therapy postoperatively, and 7 received antiplatelet therapy with aspirin. Patches were removed at the end of the study period and analyzed. By 6 weeks, all 2.7-mm and 4-mm holes had closed spontaneously in all animals that had not received antiplatelet therapy. The earliest closure occurred at 1 week. With antiplatelet therapy, hole closure was found to be delayed but not prevented, and was complete by 6 weeks in all but 1 animal. Histologic examination of the explanted patches revealed that closure was accomplished primarily through the ingrowth of fibrous tissue, accompanied by an inflammatory cell infiltrate.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood pressure components and decline in kidney function in community-living older adults: the Cardiovascular Health Study.

Chronic kidney disease is very common in the US population, and it is present in >30% of adults over age 65.1 High blood pressure (BP) is a well-established risk factor for chronic kidney disease and end stage renal disease in youth and middle age.2,3 Elevated pressure in the renal vasculature and consequent elevated intraglomerular pressure lead to failure of autoregulation and endothelial dysfunction and eventually to progressive glomerular and interstitial fibrosis. In contrast, data on the association of high BP with kidney function decline in the elderly, in whom hypertension is highly prevalent,4 are less clear.5,6 In particular, neither randomized trial data nor genome-wide association study data provide clear supporting data for associations between lower BP and reduced risk for kidney function decline. For example, in the placebo arm of the Systolic Hypertension in the Elderly Program, elevated systolic pressure was associated with kidney function decline. Because this arm only included individuals with systolic hypertension, it cannot be easily generalized to a community-dwelling older population.7 The Hypertension in the Very Elderly Trial has not reported kidney function outcomes. In the large International Consortium for Blood Pressure Genome-Wide Association studies, which provide analysis of associations between BP variants and cardiovascular disease, no association was seen between these variants and chronic kidney disease.8 In addition, the relative associations of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) with kidney function decline in the elderly are uncertain. This is of particular clinical importance because hypertension in the elderly is primarily characterized by high SBP and normal to low DBP (isolated systolic hypertension [ISH]).9 In the Cardiovascular Health Study, SBP was the best predictor of cardiovascular events, not PP or DBP.10 In the Framingham Heart Study, however, the association of each BP component with cardiovascular risk varied by age; contrary to associations in young and middle age, PP was the strongest predictor of coronary heart disease in the elderly and DBP was negatively associated with risk.11 The associations of each BP component with kidney function decline are not well known. Recently, the American Heart Association consensus statement on treatment of hypertension in older adults highlighted this large knowledge gap.12 Therefore, we designed this study to examine the associations of SBP, DBP, and PP with kidney function decline using data from the Cardiovascular Health Study.
Serum opacity factor (SOF) of Streptococcus pyogenes evokes antibodies that opsonize homologous and heterologous SOF-positive serotypes of group A streptococci.

Serum opacity factor (SOF) is a protein expressed by Streptococcus pyogenes that opacifies mammalian serum. SOF is also a virulence factor of S. pyogenes, but it has not been previously shown to elicit a protective immune response. Herein, we report that SOF evokes bactericidal antibodies against S. pyogenes in humans, rabbits, and mice. Rabbit antiserum against purified recombinant SOF2 opsonized SOF-positive M type 2, 4, and 28 S. pyogenes in human blood but had no effect on SOF-negative M type 5 S. pyogenes. Furthermore, affinity-purified human antibodies against SOF2 also opsonized SOF-positive streptococci. A combination of antisera against M2 and SOF2 proteins was dramatically more effective in killing streptococci than either antiserum alone, indicating that antibodies against SOF2 enhance the opsonic efficiency of M protein antibodies. Mice tolerated an intravenous injection of 100 μg of SOF without overt signs of toxicity, and immunization with SOF protected mice against challenge infections with M type 2 S. pyogenes. These data indicate that SOF evokes opsonic antibodies that may protect against infections by SOF-positive serotypes of group A streptococci and suggest that different serotypes of SOF have common epitopes that may be useful vaccine candidates to protect against group A streptococcal infections.