cssi/SciSciGPT-SciSciNet huggingface dataset:
Inducing Compliance with Post-Market Studies for Drugs underFDA’s Accelerated Approval Pathway

Problem Definition: In 1992, FDA instituted the accelerated approval pathway (AP) to allow promising drugs to enter the market based on limited evidence of efficacy, thereby permitting manufacturers to verify true clinical benefits through post-market studies. However, most post-market studies have not been completed as promised. We address this non-compliance problem. Academic/Practical Relevance: The prevalence of this non-compliance problem poses considerable public health risk, thus compromising the original purpose of a well-intentioned AP initiative. We provide an internally consistent and implementable solution to the problem through a comprehensive analysis of the myriad complicating factors and trade-offs facing FDA. Methodology: We adopt a Stackelberg framework in which the regulator, which cannot observe the manufacturer’s private cost information or level of effort, leads by imposing a post-market study deadline. The profit-maximizing manufacturer then follows by establishing its level of effort to invest in its post-market study. In establishing its deadline, the regulator optimizes the trade-off between providing public access to potentially effective drugs and mitigating public health risks from ineffective drugs. Results: We develop a deadline-dependent user fee menu as a screening mechanism that establishes an incentive for manufacturer compliance. We show that its effectiveness in inducing compliance depends fundamentally on the enforceability of sanction, a drug-specific measure that indicates how difficult it is to withdraw an unproven drug from the market, and the drug’s success probability: The higher is either, the higher is the probability that the mechanism induces compliance. Managerial Implications: We synthesize and distill the salient trade-offs and nuances facing FDA’s non-compliance problem and provide an implementable solution. We quantify the value of the solution as a function of a drug’s success probability and enforceability. From public policy perspective, we provide guidance for FDA to increase the viability and effectiveness of AP.
Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions

Purpose: Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion–associated colorectal cancer. Experimental Design: We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from the patient charts and molecular testing results. Results: We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in BRAF and RAS wild-type tumors and were enriched in right-sided and mismatch repair–deficient (MMR-D) colorectal cancers. All of the MMR-D colorectal cancers with RTK fusions were found in tumors with acquired MMR-D due to MLH1 promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled BRAF V600E–mutated MMR-D colorectal cancer, rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) colorectal cancer who derived clinical benefit from therapeutic targeting of their translocation. The first harbored an ALK-CAD fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an ALK L1196Q gatekeeper mutation. The second patient, whose tumor contained an ROS1-GOPC fusion, continues to benefit from entrectinib after 9 months of therapy. Conclusions: RTK fusions in colorectal cancer are a rare, but important disease subgroup that occurs in RAS and BRAF wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.
Flexible Regularization Approaches for Fairness in Deep Learning

Artificial Neural Networks (ANN) have been shown to be effective for many predictive tasks, such as system identification and reinforcement learning. However, as they have become more ubiquitous, there have been several examples of models exhibiting anthropomorphic bias (e.g. making predictions correlated with race or gender for unrelated tasks) due to over fitting, amplifying and systematizing bias already inherent in training data. To address this problem, we consider a novel regularization approach for deep learning, inspired by the constrained optimization literature, that directly penalizes unwanted disparities in treatment of populations proportionally to their impact on observed bias. Using this method, we can control bias at training time, as opposed to in a pre- or post-processing step; this results in concurrent out-of-sample improvements in both fairness and accuracy for some data sets. Our methods fit well into existing optimization and training approaches and can be easily generalized across network architectures and notions of fairness. We validate our methods empirically on several real world data sets that contain implicit bias. Namely we consider the impact of race on recidivism prediction, gender on income, and wine color on quality. We also consider fairness in a reinforcement learning setting by controlling the dose of Heparin while being certifiably fair with respect to the patient’s insurance provider.
Voice Analytics of Online Influencers—Soft Selling in Branded Videos

Influencer marketing has been growing rapidly on social media, such that the influencer marketing industry is now worth $15 billion. As more consumers are eager to rely on influencers’ recommendations for shopping, the trustworthiness of influencers’ opinions becomes a key question. Specifically, consumers increasingly question the honesty of influencer opinions when influencers advertise sponsored products from brands. To help consumers make informed shopping decisions, the Federal Trade Commission (FTC)’s endorsement guidelines require influencers to disclose sponsorship. However, little is known about how influencers respond to the FTC’s endorsement guidelines. In this paper, we study how influencers change their content delivery strategies upon sponsorship and how these strategies affect consumer sentiment. Employing both the Instrumental Variable (IV), and Regression Discontinuity (RD) identification strategies, we find that influencers choose a soft selling strategy and tone down their voice loudness significantly in sponsored videos. This voice modulation strategy can help influencers win back favorable consumer sentiment. Above all, influencers who are more popular (have more view counts) are more likely to modulate their voice in their favor. We discuss implications for the four stakeholders: the FTC, brands, influencers, and consumers.
Value Predicate Analysis: A Language‐Based Tool for Diagnosing Behavioral Tendencies of Religious or Value‐Based Groups in Regions of Conflict

This article introduces a language‐based tool for addressing the role of religion in violent conflicts. Value predicate analysis (VPA) is an easily transportable, relatively uncomplicated early warning tool for measuring the probable near‐future behavior of modest‐sized religious groups in settings of potential conflict. We show that it is possible to identify a range of nine types of probable group behavior toward other groups. This approach significantly refines current binary assessments of violent/not‐violent group conduct. The authors (1) provide a warrant for diagnosing religion‐group behavior through performative analysis; (2) present a theoretical overview of VPA; (3) summarize their research, data analysis, and field collection methods; (4) present field test results; and (5) conclude with recommendations for further research.
Development of a specific live-cell assay for native autophagic flux

Autophagy is an evolutionarily conserved pathway mediating the breakdown of cellular proteins and organelles. Emphasizing its pivotal nature, autophagy dysfunction contributes to many diseases; nevertheless, development of effective autophagy modulating drugs is hampered by fundamental deficiencies in available methods for measuring autophagic activity or flux. To overcome these limitations, we introduced the photoconvertible protein Dendra2 into the MAP1LC3B locus of human cells via CRISPR/Cas9 genome editing, enabling accurate and sensitive assessments of autophagy in living cells by optical pulse labeling. We used this assay to perform high-throughput drug screens of four chemical libraries comprising over 30,000 diverse compounds, identifying several clinically relevant drugs and novel autophagy modulators. A select series of candidate compounds also modulated autophagy flux in human motor neurons modified by CRISPR/Cas9 to express GFP-labeled LC3. Using automated microscopy, we tested the therapeutic potential of autophagy induction in several distinct neuronal models of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In doing so, we found that autophagy induction exhibited discordant effects, improving survival in disease models involving the RNA binding protein TDP-43, while exacerbating toxicity in neurons expressing mutant forms of UBQLN2 and C9ORF72 associated with familial ALS/FTD. These studies confirm the utility of the Dendra2-LC3 assay, while illustrating the contradictory effects of autophagy induction in different ALS/FTD subtypes.
The Relationship Between Electronic Health Record System and Performance on Quality Measures in the American College of Rheumatology's Rheumatology Informatics System for Effectiveness (RISE) Registry: Observational Study.

Background: Routine collection of disease activity (DA) and patient-reported outcomes (PROs) in rheumatoid arthritis (RA) are nationally endorsed quality measures and critical components of a treat-to-target approach. However, little is known about the role electronic health record (EHR) systems play in facilitating performance on these measures. Objective: Using the American College Rheumatology’s (ACR’s) RISE registry, we analyzed the relationship between EHR system and performance on DA and functional status (FS) quality measures. Methods: We analyzed data collected in 2018 from practices enrolled in RISE. We assessed practice-level performance on quality measures that require DA and FS documentation. Multivariable linear regression and zero-inflated negative binomial models were used to examine the independent effect of EHR system on practice-level quality measure performance, adjusting for practice characteristics and patient case-mix. Results: In total, 220 included practices cared for 314,793 patients with RA. NextGen was the most commonly used EHR system (34.1%). We found wide variation in performance on DA and FS quality measures by EHR system (median 30.1, IQR 0-74.8, and median 9.0, IQR 0-74.2), respectively). Even after adjustment, NextGen practices performed significantly better than Allscripts on the DA measure (51.4% vs 5.0%; P<.05) and significantly better than eClinicalWorks and eMDs on the FS measure (49.3% vs 29.0% and 10.9%; P<.05). Conclusions: Performance on national RA quality measures was associated with the EHR system, even after adjusting for practice and patient characteristics. These findings suggest that future efforts to improve quality of care in RA should focus not only on provider performance reporting but also on developing and implementing rheumatology-specific standards across EHRs.
The Kingdom of Friends: Reconstructing Fraternity in Kantian Liberalism

Liberalism assumes a number of political values that are central to its popular appeal. Historically, fraternity was an additional value that called on citizens to consider themselves part of a civic community. While contemporary liberalism has placed significant emphasis on the values that promote individualism – liberty and equality – it has rarely referred to fraternity as a value. Yet, a robust version of fraternity is either existent or possible in at least one liberal’s, Kant’s, version of liberalism. Drawing upon Kant’s notions of unity and friendship in his moral and religious writings to show how Kant conceived of fraternity in its private sense, I offer textual evidence of these concepts spilling over into Kant’s theory of right. In so doing, I reconstruct a version of Kantian fraternity that is consistent with Kant’s broader theory of right in an effort to give fraternity a greater role in classical liberalism.
Electrical Power Equipment Maintenance and Testing

The second edition of a bestseller, this definitive text covers all aspects of testing and maintenance of the equipment found in electrical power systems serving industrial, commercial, utility substations, and generating plants. It addresses practical aspects of routing testing and maintenance and presents both the methodologies and engineering basics needed to carry out these tasks. It is an essential reference for engineers and technicians responsible for the operation, maintenance, and testing of power system equipment. Comprehensive coverage includes dielectric theory, dissolved gas analysis, cable fault locating, ground resistance measurements, and power factor, dissipation factor, DC, breaker, and relay testing methods.
Satellite Observation Systems and Environmental Forecasts, Progress and Prospects

One decade has elapsed since the inauguration of the world’s first operational satellite system with the launch of ESSA 1 and ESSA 2 in February 1966. Since then research and development in sensor technology have been incorporated rapidly into improved operational systems. The current operational system consists of satellites in near earth polar orbits (the NOAA series) and in geostationary orbits (the GOES series). The former provide daily visible and twice daily infrared global coverage from medium resolution (4 km visible, 7 km infrared) and high resolution (1 km) radiometers. The NOAA-2 satellite, launched in October 1972, had a multichannel infrared radiometer that provided quantitative data on the vertical profile of atmospheric temperature. An improved version of this vertical temperature profiling radiometer (VTPR) on NOAA-4 currently returns about 1000 profiles per day. Data from the NOAA series in stored form reach central readout and processing facilities, while about 200 ground stations in about 100 countries receive medium resolution local data in real time from the Automatic Picture Transmission (APT) system.
Photoprocesses of Relevance to Supramolecular Chemistry

This contribution focuses exclusively on the application of photophysical methods that can be applied toward signaling a variety of supramolecular chemistry events using examples from the recent literature. It is not intended to be comprehensive but rather to illustrate how specific photo techniques can be used to glean insight into supramolecular phenomena. Given the widespread availability of fluorescence technologies worldwide, the current study reflects its dominant usage in supramolecular chemistry while exemplifying a range of techniques within the discipline. Nondestructive transient absorption spectroscopy is also discussed in light of how it can be utilized in conjunction with supramolecular photochemistry, specifically in the identification of intermediates that cannot be interrogated otherwise. Relevant aspects of molecular photochemistry and photophysics are briefly introduced below and developed further where necessary. Given the number of comprehensive reviews in the general area of supramolecular photochemistry and photophysics, we attempt to highlight only recent examples using a conceptual framework most relevant to the authors of this contribution, largely involving combinations of metal- and organic-based chromophores. Keywords: supramolecular photophysics; supramolecular photochemistry; photoluminescence; fluorescence; quenching; energy transfer; electron transfer; triplet-triplet annihilation; chemical sensing; fluorescence microscopy; transient spectroscopy
Antimicrobials in animal feed: benefits and limitations.

Abstract: Considering that most commercial poultry operations house up to 30,000 birds in one house, additives in feed are the most efficient means for delivering treatments, improving health and treating diseases. Typically, antibiotics used in feed are not specifically for therapeutic purposes but rather for growth promotion and improvement of poultry gut health. There is concern that this practice will ultimately result in an increase in antibiotic-resistant bacteria that may be difficult to treat. This chapter discusses the use of antimicrobials in feed, primarily poultry feed, and the benefits of antibiotic usage. The disadvantages, including the development of antibiotic-resistant bacteria, will also be addressed.
Mechanical tissue resuscitation (MTR): a nonpharmacological approach to treatment of acute myocardial infarction.

Background and Aim Myocardial ischemia-reperfusion injury is known to trigger an inflammatory response involving edema, apoptosis, and neutrophil activation/accumulation. Recently, mechanical tissue resuscitation (MTR) was described as a potent cardioprotective strategy for reduction of myocardial ischemia-reperfusion injury. Here, we further describe the protective actions of MTR and begin to define its therapeutic window. Methods A left ventricular, free-wall ischemic area was created in anesthetized swine for 85 minutes and then reperfused for three hours. Animals were randomized to two groups: (1) untreated controls (Control) and (2) application of MTR that was delayed 90 minutes after the initiation of reperfusion (D90). Hemodynamics and regional myocardial blood flow were assessed at multiple time points. Infarct size and neutrophil accumulation were assessed following the reperfusion period. In separate cohorts, the effect of MTR on myocardial interstitial water (MRI imaging) and blood flow was examined. Results Both groups had similar areas at risk (AAR), hemodynamics, and arterial blood gas values. MTR, even when delayed 90 minutes into reperfusion (D90, 29.2 ± 5.0% of AAR), reduced infarct size significantly compared to Controls (51.9 ± 2.7%, p = 0.006). This protection was associated with a 33% decrease in neutrophil accumulation (p = 0.047). Improvements in blood flow and interstitial water were also observed. Moreover, we demonstrated that the therapeutic window for MTR lasts for at least 90 minutes following reperfusion. Conclusions This study confirms our previous observations that MTR is an effective therapeutic approach to reducing reperfusion injury with a clinically useful treatment window. doi: 10.1111/jocs.12580 (J Card Surg 2015;30:659–667)
Productive Discussion in Science: Gender Equity through Electronic Discourse.

Electronic discussion tools can have several advantages over classroom discussion to support productive learning conversations in science. This paper describes how an electronic collaborative discussion tool called the Multimedia Forum Kiosk (MFK) enabled equitable learning opportunities in scientific discourse: generating explanations, revising ideas of others, and asking questions. Studies compared gender differences in participation between class discussion and MFK discussion, as well as examined three different formats for electronic discussion: anonymous, attributed, and attributed with authority participation. Results indicate that in all discussions, 78% of the students contributed in electronic discussion compared to only 15.3% participation in class discussion. Females participated more than males in electronic discussion, and less than males in classroom discussion. Girls report feeling less stifled when participating in an electronic medium where anonymity is an option. All electronic discussions were characterized by high levels of scientific conceptual content, elaborations, and question-asking. Students generated a repertoire of models for phenomena, asked content-focusing questions, and provided causal explanations using MFK. Implications for future research and design of electronic discussion tools are discussed.
Call for more U.S. renewable energy

“We must explore ways to better capture the Sun's light, the sky's wind, the land's bounty and the Earth's heat to provide energy security for America's families,” U.S. Secretary of the Interior Gail Norton told attendees at the National Conference on Renewable Energy, held on November 28 in Washington, D.C. The conference, co-sponsored by the Interior and Energy departments, focused on the best ways to increase production of renewable energy—wind, solar, and geothermal—on public lands.
Stochastic consistency, and scalable pull-based caching for erratic data stream sources

We introduce the notion of stochastic consistency, and propose a novel approach to achieving it for caches of highly erratic data. Erratic data sources, such as stock prices, sensor data, are common and important in practice. However, their erratic patterns of change make caching hard. Stochastic consistency guarantees that errors in cached values of erratic data remain within a user-specified bound, with a user-specified probability. We use a Brownian motion model to capture the behavior of data changes, and use its underlying theory to predict when caches should initiate pulls to refresh cached copies to maintain stochastic consistency. Our approach allows servers to remain totally stateless, thus achieving excellent scalability and reliability. We also discuss a new real-time scheduling approach for servicing pull requests at the server. Our scheduler delivers prompt response whenever possible, and minimizes the aggregate cache-source deviation due to delays during server overload. We conduct extensive experiments to validate our model on real-life datasets, and show that our scheme outperforms current schemes.
Qualitative and Quantitative Research: How to Choose the Best Design

It is often difficult to choose between quantitative and qualitative research design. At times, a researcher may choose a design because he or she is more familiar with one method or the other or a colleague recommends a particular design. However, our research will be more helpful if we make our decision based on well-considered, suitable design rather than simply choosing a design that is more familiar or comfortable to the researcher. The purpose of this paper is to introduce graduate students and new researchers to quantitative and qualitative research design and to help them choose the best method based on the type of information needed and analytical capability.
Studies on the role of the phi X174 gene A protein in phi X viral strand synthesis. II. Effects of DNA replication of mutations in the 30-nucleotide icosahedral bacteriophage origin.

Abstract phi X174 viral strand circular DNA can be synthesized in vitro from phi X174 replicative form I (RFI) DNA in the presence of the phi X A protein, the Escherichia coli DNA polymerase III elongation system, the E. coli rep helicase, and the E. coli single-stranded DNA binding protein. M13mp9 or pBR322 RFI DNAs containing a 30-base pair sequence found at the phi X origin of replication supported phi X A protein synthesis as well as the phi X template, giving rise to a net molar excess of deoxynucleotide incorporation. In this paper, we show that mutations in positions 1-3 of the 30-nucleotide origin replicated at a lower efficiency than plasmids containing the wild-type origin, because of a deficiency in the reinitiation reaction. Mutations in positions 4-7, upstream of the phi X A protein cleavage site, failed to support replication because of their inability to support nicking. An origin containing a mutation at the residue to which the phi X A protein is covalently linked to the DNA was an active template that supported a net molar excess of incorporation. Mutations at the 3' end of the origin region, retaining only the first 21-25 nucleotides of the 30-base pair origin, failed to support replication because of impaired binding of the phi X A protein to the template and consequently poor nicking. A construct bearing the first 28 nucleotides of the origin supported wild-type replication, as did a plasmid containing a 28-mer origin with a point mutation at position 26, but this latter construct also appeared to be partially deficient in phi X A protein binding activity. These results are consistent with the presence of a phi X A protein binding domain at the 3' end of the origin.
The citrus industries of the United States and Mexico after NAFTA.

The United States and Mexico are two of the largest citrus producing and consuming regions in the world. As such, implementation of the North America Free Trade Agreement (NAFTA) was likely to have major implications for the citrus industries of these two countries. The United States protected its processed orange industry with a sizeable tariff on imported orange juice. The United States used smaller, seasonally adjusted tariffs on imported fresh citrus. Mexico imposed a fiat ad valorem tariff of 20 percent on most fresh and processed citrus products. With the prospect of these tariffs being eliminated under NAFTA, concern was expressed by citrus producers in both countries.
Loss of adenosine-induced negative inotropic effect in hyperexcited rabbit hearts: relationship to PKC

Adenosine produced a negative inotropic effect in hearts isolated from calm rabbits but not from those exhibiting alarm behavior during handling. This study was conducted to determine whether protein kinase C (PKC) activation is responsible for the loss of adenosine-induced negative inotropism in the hearts of hyperexcited rabbits. Adenosine (10 microM) decreased myocardial contractility (dP/dtmax) in the hearts of calm, but not hyperexcited, rabbits but decreased heart rate (HR) and coronary perfusion pressure (PP) in the hearts of both calm and hyperexcited animals. During infusion of calphostin C (200 nM), a PKC inhibitor, adenosine also decreased dP/dtmax in the hearts of hyperexcited rabbits. Calphostin C did not alter the actions of adenosine in the hearts of calm rabbits. Agents that stimulate PKC directly [phorbol 12,13-dibutyrate (PDBu), 1 nM] or indirectly [norepinephrine (NE), 3 nM; angiotensin II (ANG II), 5 nM] abolished the adenosine-induced decrease in dP/dtmax but not HR or PP in the hearts of calm rabbits. During calphostin C, infusion of PDBu, NE, and ANG II failed to prevent the adenosine-induced decrease in dP/dtmax. These data suggest that the lack of a negative inotropic effect of adenosine in hyperexcited rabbits is due to an increase in PKC activity.
Evaluation of the speech intelligibility rating (SIR) test for hearing aid comparisons.

The SIR test was created for use in hearing aid comparisons. The test protocol obtains listener judgments of the intelligibility of connected speech passages. This study was conducted to evaluate t...
Mechanisms of circulatory changes accompanying hypnotic imagination of hyperalgesia and hypoalgesia in causalgic limbs.

1. An analysis was made of the changes of arterial blood pressure, heart rate, and blood flows in forearms, hands, calves and feet accompanying hypnotic imagination of intense hyper- and hypoalgesia in a causalgic limb. The circulatory changes, general and local in limbs, during imagined hyperalgesia, and the blood flow rise in hands and feet accompanying posthypnotic relaxation were studied in 5 patients. 2. The ability to imagine hyperalgesia in a causalgic limb and the accompanying circulatory changes were diminished by nerve block and stellate ganglionic block in the causalgic limb (local anaesthetic) and by general ganglionic block (chlorisondamine), and were usually nearly or completely abolished by general beta-adrenergic block (propranolol). Local cholinergic block (close arterial atropine) had no significant effect on these responses but abolished the blood flow rise in hands and feet during posthypnotic relaxation. 3. Intravenous physiological saline suggested to be identical with previously experienced propranolol also abolished the ability to imagine limb hyperalgesia and the accompanying circulatory changes. Intravenous propranolol suggested to be physiological saline still abolished the ability to imagine limb hyperalgesia and the accompanied circulatory changes. 4. The circulatory changes accompanying imagined limb hyperalgesia were probably secondary to the emotional stimulation made by the experience of hyperalgesia. They were similar to those known from other kinds of unpleasant emotional stimulation. They were in part caused by enhanced sympatho-adrenomedullary activity appearing as a beta-adrenergic effect. Additional causes for the blood flow rise in forearm/calf during imagined hyperalgesia were increase in mean arterial blood pressure and moderate muscle activity in the hyperalgesic limb; cholinergic vasodilatation seemed to be of no significance. However, the posthypnotic rise in hand/foot blood flow appeared to be cholinergic. 5. Intact sympathetic nervous pathways and receptors in a causalgic limb may be necessary for the ability to imagine hyperalgesia in this limb.
Testosterone and personality among college students and military veterans

Abstract Relationships of serum and saliva to personality were examined among 401 college students in four laboratory studies and 5,236 military veterans in one archival study. Among the students, there were few relationships between testosterone and traditional personality measures. Among the veterans, MMPI scores and DSM-III diagnoses showed testosterone related to drug and alcohol abuse, antisocial and generally intemperate behavior, and effective disorders. Consistent with social control theory, correlations were higher among veterans who were lower in socioeconomic status. It appears likely that testosterone has innate effects that are socially undesirable but can be attenuated by bonds between the individual and society. Effect sizes were small, suggesting that testosterone will have noticeable effects only in large populations or individuals who differ markedly from the population mean. Further research should focus upon antisocial correlates of testosterone and conditions that produce marked changes in testosterone levels.
Object-based high-resolution land-cover mapping

There has been a marked increase in availability of high-resolution remotely-sensed datasets over the past eight years. The ability to efficiently extract accurate and meaningful land-cover information from these datasets is crucial if the full potential of these datasets is to be harnessed. Land-cover datasets, particularly high-resolution ones, must be statistically accurate and depict a realistic representation of the landscape if they are to be used by decision makers and trusted by the general public. Furthermore, if such datasets are to be accessible and relevant, mechanisms must exist that facilitate cost-effective and timely production. Object-based image analysis (OBIA) techniques offer the greatest potential for generating accurate and meaningful land-cover datasets in an efficient manner. They overcome the limitations of traditional pixel-based classification methods by incorporating not only spectral data but also spatial and contextual information, and they offer substantial efficiency gains compared to manual interpretation. Drawing on our experience in applying OBIA techniques to high-resolution data, we believe any automated approach to land-cover mapping must: 1) effectively replicate the human image analyst; 2) incorporate datasets from multiple sources; and 3) be capable of processing large datasets. To meet this functionality, an operational OBIA system should: 1) employ expert systems; 2) support vector and raster datasets; and 3) leverage enterprise computing architecture.
Preparation of β-trypsin by affinity chromatography of enterokinase-activated bovine trypsinogen☆☆☆

Abstract The preparation of β-trypsin can be simply accomplished from the activation of bovine trypsinogen with partially purified enterokinase in the presence of STI-Sepharose. Enterokinase catalyzes the specific cleavage of lysine 6-isoleucine 7 and the presence of STI prevents autolysis of β-trypsin by forming a stable inactive complex. The STI immobilized to Sepharose is suitable for the subsequent purification of the activation mixture by affinity chromatography. Inert protein and contaminants are removed with a buffer at pH 4.5. A change to a buffer at pH 2.6 or the introduction of a pH gradient leads to the recovery of highly purified β-trypsin. The procedure produces β-trypsin in a 70–75% yield, which is essentially a theoretical recovery, and all operations can be completed within 6 hr.
Targeting reactive oxygen species in hypertension.

Purpose of reviewHypertension is a major risk factor for vascular diseases such as stroke, myocardial infarction, and renal microvascular disease. The mechanism by which vascular disease develops is complex, and growing evidence suggests that an increase in reactive oxygen species during hypertensio
Gastric mucosal blood flow measurement

1. 1. Pertechnetate clearance (CTc) by the stomach before and after betazole stimulation was compared to regional measurements of gastric blood flow utilizing nuclide (Chromium-51 and Cerium-141) labeled microspheres in five piglets. 2. 2. Pertechnetate clearance closely correlated (correlation coefficient 0.926) with mucosal blood flow in the gastric corpus measured by the microsphere technique. Betazole increased blood flow in the corpus region by 100% but did not alter this relationship. Except in one experiment, microsphere blood flow valves in the antrum and fundus were unchanged by betazole and did not significantly correlate with pertechnetate clearance. 3. 3. Pertechnetate clearance appears to be a reliable method of determining gastric mucosal blood flow in experimental animals and may be considered as a noninvasive method for measuring such flow in humans.
HISTOCHEMICAL COMPARISON OF THE EFFECTS OF A CARCINO‐GENIC AND A NON‐CARCINOGENIC DERIVATIVE OF TRI‐CYCLOQTINAZOLINE

SUMMARY.— Mouse skin is highly sensitive to irritants and to carcinogenic agents. Histochemistry has been used to demonstrate that the pattern in malignant growths is distinctively different from that in hyperplasia produced by irritants. Evidence is given to indicate that the altered pattern of metabolism can be discerned after a single application of the carcinogenic 3-methyl-TCQ (tricycloquinazoline) but that no significant alteration is induced by the non-carcinogenic 2-methyl-TCQ.
Vaginal wall sling for intrinsic sphincter deficiency

Urinary incontinence due to urethral dysfunction can be related to urethral hypermobility (anatomic incontinence), intrinsic sphincter dysfunction (ISD), or both. Correction of ISD requires one of several procedures to increase urethral coaptation and support. Since December 1985, we have used the vaginal wall sling for most of our patients with ISD; we have found it to be a simple and effective method of increasing urethral coaptation with minimal morbidity and complications.
Pharmacokinetics and Pharmacodynamics of the Glutamate Carboxypeptidase II Inhibitor 2-MPPA Show Prolonged Alleviation of Neuropathic Pain through an Indirect Mechanism

Glutamate carboxypeptidase II (GCP II) is a therapeutic target in neurologic disorders associated with excessive activation of glutamatergic systems. The potent, orally bioavailable GCP II inhibitor 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) is effective in preclinical models of diseases where excess glutamate release is implicated, including neuropathic pain, and was the first GCP II inhibitor to be administered to man. The relationships between dosing regimen, pharmacokinetics, and analgesia in a neuropathic pain model were examined in rats to aid development of clinical dosing. The efficacy of oral 2-MPPA in the chronic constrictive injury model was not simply related to plasma concentrations. Even though maximal concentrations were observed within 1 hour of dosing, the analgesic effect took at least 8 days of daily dosing to become significant. The delay was not due to tissue drug accumulation since inhibitory concentrations of the drug were achieved in the nerve within 1 hour of dosing. There was also no accumulation of drug in plasma or tissue after multiple daily dosing. Effects were dependent on reaching a threshold concentration since dividing the daily dose led to a loss of effect. The analgesic effect outlasted plasma exposure and was maintained for days even after daily dosing was halted. The delayed onset, dependence on threshold plasma concentration, and sustained effects after exposure support the hypothesis that an indirect, long-lived mechanism of action exists. Although these longer lasting secondary mechanisms are not yet identified, daily clinical dosing of a GCP II inhibitor seems justified.
Blockade of Estrogen by Hormonal Contraceptives Impairs Fear Extinction in Female Rats and Women

Background Fear extinction is a laboratory model of fear inhibition and is the basis of exposure therapy for anxiety disorders. Emerging evidence from naturally cycling female rodents and women indicates that estrogens are necessary to the consolidation of fear extinction. Hormonal contraceptives (HCs) inhibit estrogen production; yet, their effects on fear extinction are unknown. Methods We used a cross-species translational approach to investigate the impact of HCs and estradiol supplementation on fear extinction in healthy women ( n =76) and female rats ( n = 140). Results Women using HCs exhibited significantly poorer extinction recall compared with naturally cycling women. The extinction impairment was also apparent in HC-treated female rats and was associated with reduced serum estradiol levels. The impairment could be rescued in HC-treated rats either by terminating HC treatment after fear learning or by systemic injection of estrogen-receptor agonists before fear extinction, all of which restored serum estradiol levels. Finally, a single administration of estradiol to naturally cycling women significantly enhanced their ability to recall extinction memories. Conclusions Together, these findings suggest that HCs may impact women's ability to inhibit fear but that this impairment is not permanent and could potentially be alleviated with estrogen treatment.
Hazardous waste and neurobehavioral effects: a developmental perspective.

This paper summarizes the findings gleaned from detailed clinical examinations of three groups of residents who were exposed to trichloroethylene in well water. Also summarized are diagnostic findings for peripheral neuropathy. A detailed description of the neuropsychological test results is included, as well as a summary of domain-specific findings and diagnostic outcomes. A high rate of cognitive deficits of the type seen in patients with central nervous system dysfunction attributable to solvent exposure was seen. In addition, there was a clear developmental trend: subjects who were younger at the time of TCE exposure showed deficits in a larger variety of cognitive realms than did subjects who had already reached adulthood by the time of exposure. In particular, language deficits were seen in the younger, but not older, exposed subjects.
Tightening Monetary Policy Now Is a Bad Mistake

There is no more important policy decision facing the U.S. government than whether it is time to tighten monetary policy after years of economy-rescuing monetary stimulus. This economist look at each and every argument for tightening now and finds them all lacking.
An Alternative Approach to Decisions under Uncertainty Using the Empirical Moment-Generating Function

Objections to mean-variance analysis center on the requirement that the distributions be normal or the resulting inattention to higher-order moments when the solution is viewed as an approximation. A nonparametric approach to decision making under uncertainty is developed in this paper using expected utility maximization, the exponential utility function, and an empirical moment-generating function. A decision rule is obtained for land allocation under uncertainty which is not tied to a particular family of distributions and accounts for all moments of the distribution.
Darwin in Kansas

With respect to the piece “Darwin-free biology” (ScienceScope, 6 Aug., p. 813), where is Erasmus Darwin (grandfather of Charles) when we need him most? As he warned the Kansas State Board of Education in 1794 ([1][1]): > The world itself might have been generated, rather than created; that is, it might have been gradually produced from very small beginnings, increasing by the activity of its inherent principles, rather than by a sudden evolution of the whole by the Almighty fiat. What a magnificent idea of the infinite power of THE GREAT ARCHITECT! THE CAUSE OF CAUSES! PARENT OF PARENTS! ENS ENTIUM! For if we may compare infinities, it would seem to require a greater infinity of power to cause the causes of effects, than to cause the effects themselves. 1. [↵][2]1. E. Darwin , Zoonomia; or The Laws of Organic Life (J. Johnson, London, 1794), vol. 1, p. 509. [OpenUrl][3] [1]: #ref-1 [2]: #xref-ref-1-1 "View reference 1 in text" [3]: {openurl}?query=rft.jtitle%253DZoonomia%253B%2Bor%2BThe%2BLaws%2Bof%2BOrganic%2BLife%26rft.volume%253D1%26rft.spage%253D509%26rft.atitle%253DZOONOMIA%2BOR%2BTHE%2BLAWS%2BOF%2BORGANIC%2BLIFE%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
Elastic Scattering and Reactions of Protons on O 18

The elastic scattering ${\mathrm{O}}^{18}(p, p){\mathrm{O}}^{18}$ and the reactions ${\mathrm{O}}^{18}(p, {p}^{\ensuremath{'}}\ensuremath{\gamma}){\mathrm{O}}^{18}$, ${\mathrm{O}}^{18}(p, {\ensuremath{\alpha}}_{0}){\mathrm{N}}^{15}$, and ${\mathrm{O}}^{18}(p, {\ensuremath{\alpha}}_{1,2}{\ensuremath{\gamma}}_{1,2}){\mathrm{N}}^{15}$ were studied using a thin gas target with the State University of Iowa electrostatic generator. Absolute differential cross sections were measured for the two laboratory angles 86.8\ifmmode^\circ\else\textdegree\fi{} and 159.5\ifmmode^\circ\else\textdegree\fi{} in the incident proton energy range 790 to 3550 kev and angular distributions for ${\ensuremath{\alpha}}_{0}$ and $p$ were measured at several energies. Relative yield curves of gamma rays were obtained in the same energy range as above. The ${\mathrm{F}}^{19}$ levels were observed which have not been previously reported and some new decay modes for previously known levels were observed. From consideration of the detailed shape of the elastic-scattering anomalies and the angular distributions, spin and parity assignments were made to some ${\mathrm{F}}^{19}$ levels.
Engineered RNase P Ribozymes Are Efficient in Cleaving a Human Cytomegalovirus mRNA in Vitro and Are Effective in Inhibiting Viral Gene Expression and Growth in Human Cells

By using an in vitro selection procedure, we have previously isolated RNase P ribozyme variants that efficiently cleave an mRNA sequence in vitro. In this study, a ribozyme variant was used to target the overlapping region of the mRNAs encoding human cytomegalovirus (HCMV) major transcription regulatory proteins IE1 and IE2. The variant is about 90 times more efficient in cleaving the IE1/IE2 mRNA sequence in vitro than the ribozyme derived from the wild type RNase P ribozyme. Our results provide the first direct evidence that a point mutation at nucleotide position 80 of RNase P catalytic RNA from Escherichia coli (U80--> C80) increases the rate of chemical cleavage, and another mutation at nucleotide position 188 (C188--> U188) enhances substrate binding of the ribozyme. Moreover, the variant is more effective in inhibiting viral IE1 and IE2 expression and growth in HCMV-infected cells than the wild type ribozyme. A reduction of about 99% in the expression level of IE1 and IE2 and a reduction of 10,000-fold in viral growth were observed in cells that expressed the variant. In contrast, a reduction of less than 10% in IE1/IE2 expression and viral growth was observed in cells that either did not express the ribozyme or produced a catalytically inactive ribozyme mutant. Thus, engineered RNase P ribozyme variants are highly effective in inhibiting HCMV gene expression and growth. These results also demonstrate the feasibility of engineering highly effective RNase P ribozymes for gene targeting applications, including anti-HCMV gene therapy.
Volcanic ash could mask global CO2 effect

The volcanic ash th at Mount St. Helens spewed into the atmosphere could confound efforts to detect climatic effects of human pollution. The volcanic debris now circling earth could block out some sunlight, causing a slight cooling of the earth's surface that would mask the expected warming effects of increasing carbon dioxide in the atmosphere and delay its detection for more than a decade, according to Kirby Hanson, director of the NOAA Geophysical Monitoring for Climatic Change program. Measurements, some going back to 1958, have shown a 5% increase in atmospheric carbon dioxide over the past two decades. Furthermore, the annual rate of increase is growing, and it is predicted that within 50 years the concentration of carbon dioxide in the atmosphere could be double what it was before the Industrial Revolution. The temperature effect of that doubling, Hanson says, would be a net warming near the earth's surface of about 2° or 3°—averaged over the northern hemisphere.
Limiter probabilistic lifetime analysis

Reliability of tokamak fusion reactors is a key parameter in the successful development of commercial fusion power. In addition, reliability analysis can be used during the design phase of reactor development to perform tradeoff studies. Generation of a set of reliability curves for a particular tokamak in-vessel component, the limiter, is the focus of this paper. The methodology implemented to generate the set of reliability curves consists of the following steps: (1) Identifying those particulars deemed important in characterizing normal and transient operation. This includes enumeration of events initiating transients, referred to as Initiating Events (IE's), via facility level fault tree analysis, of the transients considered. (2) Specifying Failure Modes (FM's) and associated Failure Criteria (FC) to be included in the analysis. Previous lifetime studies, existing design codes and engineering judgment used as guidelines in choosing relevant FM's and FC. (3) Developing and integrating models for normal operation, transient operation and FM's to assess failure times. (4) Assessing probability distributions for state-of-knowledge uncertainties surrounding models and key parameters. These uncertainties are then propagated through a statistical lifetime model to obtain a probabilistic description of limiter reliability. The impact of various parameters on limiter reliability is examined. Results show that the limiter reliability decreases rapidly as a function of time. The occurrence of transients is the main contributor to decreased reliability. The dominant FM's are material loss and cumulative cyclic damage.