cssi/SciSciGPT-SciSciNet huggingface dataset:
Evidence for neuroprotection by the fenamate NSAID, mefenamic acid

Fenamate NSAIDs are inhibitors of cyclooxygenases, antagonists of non-selective cation channels, subtype-selective modulators of GABA(A) receptors, weak inhibitors of glutamate receptors and activators of some potassium channels. These pharmacological actions are all implicated in the pathogenesis of ischemic stroke. The aim of this study was to investigate the hypothesis that the fenamate, mefenamic acid, is neuroprotective in an in vitro and in vivo model of stroke. Embryonic rat hippocampal neurons were cultured and maintained for up to 14 days in vitro. At 9 or 14 days, cells were exposed to glutamate (5microM) or glutamate (5microM) plus mefenamic acid (10-100microM) or the control agent, MK-801 (10microM) for 10min. 24h later, cell death was determined by measuring lactate dehydrogenase (LDH) levels in the culture media. In vivo, male Wistar rats (300-350g) were subjected to 2h middle cerebral artery occlusion (MCAO) followed by 24h reperfusion. Animals received either a single i.v. dose of MFA (10mg/kg or 30mg/kg), or MK-801 (2mg/kg) or saline prior to MCAO or, four equal doses of MFA (20mg/kg) at 1h intervals beginning 1h prior to MCAO. Ischemic damage was then assessed 24h after MCAO. In vitro, mefenamic acid (10-100microM) and MK-801 (10microM) significantly reduced glutamate-evoked cell death compared with control cultures. In vivo, MFA (20mg/kgx4) significantly reduced infarct volume, total ischemic brain damage and edema by 53% (p< or =0.02), 41% (p< or =0.002) and 45% (p< or =0.002) respectively. Furthermore, mefenamic acid reduced cerebral edema when measured as a function of brain water content. MK-801 was also neuroprotective against MCAO brain injury. This study demonstrates a significant neuroprotective effect by a fenamate NSAID against glutamate-induced cell toxicity, in vitro and against ischemic stroke in vivo. Further experiments are currently addressing the mechanism(s) of this neuroprotection.
B7-H1 Signaling is Integrated During CD8+ T Cell Priming and Restrains Effector Differentiation

A promising strategy in tumor immunotherapy is the use of activated dendritic cells as vehicles for tumor vaccines with the goal of activating anti-tumor T cell responses. Current formulations for dendritic cell-based immunotherapies have limited effects on patient survival, providing motivation for further investigation of ways to enhance dendritic cell priming of anti-tumor T cell responses. Using a brief in vitro priming model, we have found that B7-H1 expressed by activated dendritic cells is integrated during priming of naive CD8+ T cells and functions to limit the differentiation of effector T cell responses. CD8+ T cells primed by B7-H1-deficient dendritic cells exhibit increased production of IFN-γ, enhanced target cell killing, and improved anti-tumor activity. Additionally, enhanced memory populations arise from CD8+ T cells primed by B7-H1-deficient dendritic cells. Based on these findings, we suggest that early blockade of B7-H1 signaling should be investigated as a strategy to improve dendritic cell-based anti-tumor immunotherapy.
Toward Highly Sintering-Resistant Nanostructured ZrO2-7wt.%Y2O3 Coatings for TBC Applications by Employing Differential Sintering

There are still concerns in the scientific community about the stability of nanostructured YSZ coatings at high temperatures. Questions have been raised about the possibility of accelerated sintering of these ultrafine materials and the associated changes in properties that could accompany this sintering. In this work, nanostructured YSZ coatings were engineered to counteract sintering effects by tailoring the coatings to exhibit a bimodal microstructure formed by (i) a matrix of dense YSZ zones (produced from molten YSZ particles) and (ii) large porous nanostructured YSZ zones (produced from semimolten nanostructured YSZ particles) that were embedded in the coating microstructure during thermal spraying. These coatings were subjected to heat treatment in air at 1400 °C for 1, 5, and 20 h. The superior driving force for sintering exhibited by the porous nanozones, when compared to that of the dense zones, caused the nanozones to shrink at much faster rates than those exhibited by the denser matrix zones (i.e., differential sintering), thereby creating a significant network of voids in the coating microstructure. Due to these effects, after 20 h exposure at 1400 °C, the thermal conductivity and elastic modulus values of the conventional coatings were approximately two times higher than those of the nanostructured ones.
Photoluminescence Characterization of Defects Introduced in 4H-SiC During High Energy Proton Irradiation and Their Annealing Behavior

We report on the optical properties of defects introduced in epitaxial 4H-SiC by 2 MeV protons using photoluminescence spectroscopy. The near band edge characteristics of nitrogen-doped n-type 4H-SiC are present in the optical spectrum of the as-grown samples. Following a proton irradiation, the material is altered and the luminescence of the shallow centers is attenuated almost entirely with the emergence of deeper shallow traps at energies greater than 300 meV below the conduction band. Subsequent hightemperature thermal annealing of the material results in an increase in the emission spectrum at both the near band edge region (E g = 3.25 eV) and between 2.65 and 2.95 eV. Recovery of the characteristic nitrogen-related peaks at the near band edge following high-temperature annealing is identified, but is not complete even at 1500 °C. In the deep trap region below 2.95 eV, activation of trap centers with annealing results in a sharp increase in the signal intensity of an irradiation-induced defect trap (2.90 eV) as well as the associated phonon replicas. Based on previous ion-implantation and other radiation studies in 4H-SiC, the emergence of the 2.90 eV defect complex and associated phonon replicas after high temperature anneal is the well known D1 photoluminescence. The observed lines in the D1 spectrum are due to exciton recombination at isoelectronic defect centers.
An ultra-high vacuum double axis goniometer for use with an electron spectrometer

Abstract We describe a double axis goniometer designed for moving and indexing an electron spectrometer for angle resolved photoemission studies. A feature of the design is that the two rotations operate independently and either can be carried out with the analyzer at any position. The goniometer is designed to be installed in a 14″ spool piece which makes it possible to add it to an existing 14″ UHV system.
Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior

A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We generated a variant BDNF mouse (BDNFMet/Met) that reproduces the phenotypic hallmarks in humans with the variant allele. BDNFMet was expressed in brain at normal levels, but its secretion from neurons was defective. When placed in stressful settings, BDNFMet/Met mice exhibited increased anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.
Release of chromatin template restriction in rabbit spermatozoa

Abstract The addition of the acidic polymers heparin or polyxanthylic acid to rabbit spermatozoa or sperm heads previously exposed to disulfide reducing agents released sperm DNA template restriction and stimulated high levels of incorporation of DNA precursor into DNA, as assayed with exogenous DNA polymerase. Incorporation did not occur in the presence of DNAase, or in the absence of magnesium ion, any of the four deoxyribonucleotides, or E. coli DNA polymerase. This represents the first report that spermatozoa can synthesize DNA in vitro .
Mechanisms of desorption due to electrons or photons

Abstract It is well established that both electrons and photons can, by quantum processes, cause the desorption of atoms or molecules from suitable solid surfaces. Many research papers and detailed reviews exist in the literature. The basic processes involved are described and some examples given. The review literature is cited.
Women and the future of education

Abstract Statistics show an inexorable trend towards equality between men and women. In education, US figures concur with this, although senior positions do still tend to be held by men, and certain lines of study are almost exclusively pursued by them. The challenge for educational services in the future is to meet the requirements of equal proportions of males and females, yet to take account of their different abilities and expectations. Women's goals in the future society are likely to involve the achievement of success both in their careers and in their family lives.
Qualitative methods and the pursuit of economic understanding

In this paper, I describe the qualitative methods deployed in a series of investigations examining post-disaster recovery following Hurricane Katrina. I argue that qualitative methods, particularly ethnographic field interviews, are essential tools in contexts that the interpretive frameworks (mental models) of the research subjects play a dominant role in shaping broader patterns of social coordination. Given the importance, Austrian economists attribute to non-deterministic learning as the source of endogenous change and discovery in contexts of genuine uncertainty; I argue that this underutilized set of tools ought to be considered particularly valuable.
Accurate diagnosis of nonalcoholic fatty liver disease in human participants via quantitative ultrasound

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States, affects 30% of adult Americans, may progress to nonalcoholic steatohepatitis (NASH) and end-stage liver disease, and is a risk factor for diabetes and cardiovascular disease. The diagnosis, grading, and staging of NAFLD currently is based on liver biopsy examination with histologic assessment. Noninvasive image-based methods to evaluate the liver in adults with NAFLD are urgently needed. We developed a quantitative ultrasound (QUS) method that in animal studies shows promise for detection and quantification of liver fat content. The current study's contribution is to extend the work to human participants by assessing the accuracy of backscatter coefficient and attenuation coefficient for detection of hepatic steatosis in a cohort of adult participants with NAFLD and non-NAFLD controls. QUS parameters measured using routine clinical US scanners show promise for detecting and perhaps grading NAFLD.
Children’s Theory of Mind: Understanding of Desire, Belief and Emotion with Social Referents

Preschooler’s understanding of belief, desire, and emotion was assessed in a new false belief task that explored childen’s mental state reasoning about social situations. The social analog task presented a change in a partner’s play activity rather than a change in the location of a physical object. Two main differences from the usual pattern of theory of mind results were obtained. Five-year-olds had more difficulty understanding a false belief about another’s current social activity compared to a false belief about a physical situation. The understanding of desire exhibited a 3- to 5-year age change that may have been shown because the social situation involved conflicting desires. When there was a conflict, the younger children tended to disregard the stated desire and exhibited ‘social opportunism’ by misattributing desires to permit a social interaction. The new results give a more varied picture of the development of theory of mind, and argue for expanding its study into social frames of reference.
Test ideals in local rings

It is shown that certain aspects of the theory of tight closure are well behaved under localization. Let J be the parameter test ideal for R, a complete local Cohen-Macaulay ring of positive prime characteristic. For any multiplicative system U c R, it is shown that JU -1R is the parameter test ideal for U-1 R. This is proved by proving more general localization results for the here-introduced classes of "F-ideals" of R and "F-submodules of the canonical module" of R, which are annihilators of R modules with an action of Frobenius. It also follows that the parameter test ideal cannot be contained in any parameter ideal of R. Tight closure has produced surprising new results (for instance, that the absolute integral closure of a complete local domain R of prime characteristic is a Cohen-Macaulay algebra for R) as well as tremendously simple proofs for otherwise difficult theorems (such as the fact that the ring of invariants of a linearly reductive group acting on a regular ring is Cohen-Macaulay). The definition of tight closure is recalled in Section 1, but we refer the reader to the papers of Hochster and Huneke listed in the bibliography for more about its applications. While primarily a prime characteristic notion, tight closure offers insight into arbitrary commutative rings containing Q by fairly standard "reduction to characteristic p" techniques. Despite its successes, the tight closure operation, which in its principal setting is a closure operation performed on ideals in a commutative Noetherian ring of prime characteristic, remains poorly understood. For example, tight closure is not known to behave well under localization; given an ideal I of a ring R, letting I* denote the tight closure of I, it is not known whether or not
Nucleologenesis: composition and fate of prenucleolar bodies.

A time course study was conducted on nucleologenesis after release from a mitotic block in the presence and absence of actinomycin D to determine the composition and fate of prenucleolar bodies (PNBs). Prenucleolar bodies, whether naturally occurring or induced by actinomycin D treatment, stain with silver and contain phosphoproteins B23 and C23, two of the major proteins of the interphase nucleolus as determined by double label immunofluorescence with specific antibodies. The nucleolus is formed by fusion of PNBs, which subsequently “reorganize” and form internal fibrillar and peripheral granular regions. Actinomycin D prevents fusion of PNBs, which are then randomly dispersed throughout the nucleus but they still contain proteins B23 and C23. These results demonstrate that the nucleolus is formed by fusion of prenucleolar structures whose biochemical composition resembles the mature nucleolus, since PNBs contain at least two of the major nucleolar proteins.
Thirty-six years in the clinic without an MMP inhibitor. What hath collagenase wrought?

: Vertebrate collagenase was discovered in 1962, and within a few short years, several inhibitors had been identified. At one time or another, virtually every major drug company has had an MMP inhibitor program, but in 1999, there is only one such product on the market. With a potential market for lifelong therapy in rheumatoid arthritis, osteoarthritis, periodontal disease, osteoporosis, and cancer, this is certainly puzzling. The problem is that the chemistry appears to have outstripped the biology. In vitro, there are many inhibitors with nanomolar or picomolar efficacy, but in vivo efficacy in animal models does not always follow. There is also a conceptual problem regarding broad-spectrum vs. highly specific inhibitors. Designing human trials to demonstrate MMP inhibition and clinical efficacy is a daunting problem, especially if one seeks to distinguish anti-MMP activity from anti-inflammatory effect. Adult periodontal disease may be the best available human disease model for development of an MMPI.
Growth of Chlamydia psittaci strain meningopneumonitis in mouse L cells cultivated in a defined medium in spinner cultures.

L cells were grown in spinner cultures in a defined medium consisting of Waymouth medium MB752/1 (19) supplemented with 2 mg of fatty acid-free bovine serum albumin (BSA) per ml and 5 μg of oleate per ml (WO5 medium). Growth in WO5 medium was comparable to spinner L cell growth in two serum-containing media. The optimal concentration of oleate in the WO medium was 5 to 10 μg per ml. The use of 20 to 80 μg of oleate per ml of medium resulted in lower peak populations and earlier declines in viable cell counts. Cell death occurred rapidly in WO160 medium. Cell growth in WO medium containing 5 to 80 μg of oleate per ml was well above the level of growth observed when no oleate was present in the medium. Since the total lipid and fatty acid compositions of the BSA used in this study have been characterized by the authors, the WO medium may be considered a defined medium. L cells have been continuously maintained in spinner cultures in WO5 medium for over 50 passages with no major variation in the growth pattern. A 1000-fold increase inChlamydia psittaci strain meningopneumonitis, with a peak titer of 9.3×107 plaque-forming units per ml, was observed when the chlamydial agents were grown in spinner L cells in WO5 medium.
Muscarinic preferential M1 receptor antagonists enhance the discriminative-stimulus effects of cocaine in rats

Abstract Previous studies of benztropine analogues have found them to inhibit dopamine uptake like cocaine, but with less effectiveness than cocaine in producing behavioral effects related to drug abuse. Studies have assessed whether nonselective muscarinic antagonists decrease the effects of cocaine because many of the benztropine analogues are also muscarinic antagonists. As previous studies were conducted with nonselective muscarinic antagonists and the benztropine analogues show preferential affinity for the M 1 muscarinic receptor subtype, the present study examined interactions of cocaine and the preferential M 1 antagonists, telenzepine (TZP) and trihexyphenidyl (TXP) on subjective effects in rats trained to discriminate cocaine (10 mg/kg, i.p.) from saline injections. Cocaine dose-dependently increased the percentage of responses on the cocaine-appropriate lever, with full substitution at the training dose. In contrast neither TZP nor TXP produced more than 25% cocaine-appropriate responding at any dose. Both M 1 antagonists produced significant leftward shifts in the cocaine dose–effect curve, TZP at 3.0 and TXP at 0.3 and 1.0 mg/kg. The present results indicate that preferential antagonist actions at muscarinic M 1 receptors enhance rather than attenuate the discriminative-stimulus effects of cocaine, and thus those actions unlikely contribute to the reduced cocaine-like effects of BZT analogues.
Experimental and observational studies of seasonal interactions between overlapping life history stages in a migratory bird

Prior to reproduction, migratory animals are at the juxtaposition of three life history stages in which they must finish the non-breeding stage, initiate and complete migration, and prepare for the onset of breeding. However, how these stages interact with one another is not fully understood. We provide evidence that, for migratory birds that begin breeding development prior to departure from non-breeding sites, the level of breeding preparation can drive migration phenology, a critical behavioral determinant of reproductive success. Specifically, male American redstart (Setophaga ruticilla) plasma androgen levels, which increase in males during the period leading into migration, were positively correlated with energetic condition. We empirically tested the hypothesis that elevated androgen simultaneously supports migratory and breeding preparation in a hormone manipulation field experiment. Males with testosterone implants showed advanced preparation for migration and breeding, and ultimately departed on migration earlier than controls. It is assumed that early departure leads to early arrival at breeding areas, which increases breeding success. Collectively, our observational and experimental results demonstrate how overlapping life history stages can interact to influence important components of an individual's fitness. This highlights the critical need for understanding population processes across the full life cycle of an organism to better understand the ecological and evolutionary origins of complex life history events.
A statistical method for test sequence evaluation

A method for test sequence evaluation based on random sampling of detectable faults is presented. This method can be incorporated into most logic simulation codes which use the parallel machine method of fault detection.
Influence of pH and NaCl on growth and survival of Propionibacterium freudenreichii subsp. shermanii, Bacillus pumilus, and Saccharomyces cerevisiae in broth media

The influence of NaCl and pH on growth and survival of Propionibacterium freudenreichii subsp. shermanii , Bacillus pumilus , and Saccharomyces cerevisiae was investigated in terms of prevention of ropiness in bread. Microorganisms were cultured in broth media containing 0–100 g/L NaCl and pH-adjusted to mimic bread pH of 5.6 or the optimum of P. shermanii , pH 6.8–7.0. P. shermanii achieved higher numbers in media containing 10–60 g/L NaCl than in media without salt. The bacterium grew poorly in 80g/L NaCl and did not grow in 90 and 100 g/L NaCl. B. pumilus grew well between 0–30 g/L NaCl, poorly between 40–80 g/L NaCl, and did not grow between 90–100 g/L NaCl. S. cerevisiae grew to higher numbers of 10 g/L NaCl than in the control, but to lower numbers in media containing 20–60 g/L. Concentrations of NaCl greater than 60 g/L prevented growth. The two bacteria reached lower numbers at the pH of bread, while the opposite was true for the yeast. These results suggest that P. shermanii may possibly be used in bread to inhibit ropy spoilage by B. pumilus .
Pregnancy and Lactation Increase Vitamin D-Dependent Intestinal Membrane Calcium Adenosine Triphosphatase and Calcium Binding Protein Messenger Ribonucleic Acid Expression

The calcium demands of pregnancy and lactation are known to up-regulate intestinal calcium absorption. Intestinal epithelial cells contain calcium ATPases and calcium binding proteins, which are believed to play important roles in intestinal calcium transport. However, the possible role of these two proteins in the up-regulation of intestinal calcium absorption observed in pregnancy and lactation is unknown. In this study, intestinal calcium ATPase (PMCA1), calcium binding protein (9K) (CaBP-9K), and vitamin D receptor (VDR) messenger RNA (mRNA) levels were determined by Northern analysis at different stages of pregnancy and early lactation in rats. Intestinal calcium ATPase and calcium binding protein mRNA levels did not differ significantly among nonpregnant rats and rats pregnant for 7 or 14 days. However, at 21 days gestation both calcium ATPase and calcium binding protein mRNA levels increased 2- to 3-fold. Calcium ATPase and calcium binding protein mRNA remained elevated at 7 days of lactation. Plasma 1,25-dihydroxyvitamin D3 (1,25-D3) concentration exhibited a similar pattern, rising markedly at 21 days gestation and remaining elevated in lactation. VDR mRNA levels did not change during the entire experiment. However, intestinal VDR content increased 2-fold in late pregnancy and lactation. These data suggest that transcription of calcium absorption factors is increased in late gestation and early lactation, perhaps mediated by increased plasma 1,25-dihydroxyvitamin D3 concentrations, and that the effects of gestation and lactation on VDR concentrations are probably posttranscriptional.
Deconstructing Craving: Dissociable Cortical Control of Cue Reactivity in Nicotine Addiction

Background Cue reactivity, the ability of cues associated with addictive substances to induce seeking and withdrawal, is a major contributor to addiction. Although human imaging studies show that cigarette-associated cues simultaneously activate the insula and the orbitofrontal cortex and evoke craving, how these activities functionally contribute to distinct elements of cue reactivity remains unclear. Moreover, it remains unclear whether the simultaneous activation of these cortical regions reflects coordinated functional connectivity or parallel processing. Methods We selectively lesioned the insula or orbitofrontal cortex with the excitotoxin ibotenic acid in mice, and their approach to nicotine-associated cues ( n = 6–13/group) and avoidance of withdrawal-associated cues ( n = 5–12/group) were separately examined in place conditioning paradigms. We additionally tested the role of these two cortical structures in approach to food-associated cues ( n = 6–7/group) and avoidance of lithium chloride-associated cues ( n = 6–7/group). Results Our data show a double dissociation in which excitotoxic lesions of the insula and orbitofrontal cortex selectively disrupted nicotine-induced cue approach and withdrawal-induced cue avoidance, respectively. These effects were not entirely generalized to approach to food-associated cues or avoidance of lithium chloride-associated cues. Conclusions Our data provide functional evidence that cue reactivity seen in addiction includes unique neuroanatomically dissociable elements and suggest that the simultaneous activation of these two cortical regions in response to smoking-related cues does not necessarily indicate functional connectivity.
Review finds better endodontic surgery outcomes with microscope use.

DATA SOURCES Medline, Embase and PubMed databases were searched together with hand-searches of a range of journals (Journal of Endodontics, International Endodontic Journal, Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics, Journal of Oral and Maxillofacial Surgery, International Journal of Oral and Maxillofacial Surgery). STUDY SELECTION Clinical studies in several languages (English, French, German, Italian and Spanish) with a minimum follow-up of six months, evaluated using clinical and radiographic examination were included. DATA EXTRACTION AND SYNTHESIS Assessment and data abstraction were carried out independently. Weighted pooled success rates and relative risk assessment between TRS and EMS were calculated and a meta-analysis carried out using a random effects model. RESULTS Twenty-one studies were included. Weighted pooled success rates calculated from extracted raw data showed a 59% positive outcome for TRS (95% confidence interval, 0.55-0.6308) and 94% for EMS (95% confidence interval, 0.8889-0.9816). This difference was statistically significant (P < .0005). The relative risk ratio showed that the probability of success for EMS was 1.58 times the probability of success for TRS. CONCLUSIONS On the basis of the meta-analysis presented, the probability of success for EMS proved significantly greater than the probability of success for TRS.
Burned! the Impact of Work Aspects, Injury, and Job Satisfaction On Unionized Cooks’ Intentions To Leave the Cooking Occupation:

The hospitality industry is marked by chronic labor shortages and high turnover in the cooking occupation, yet research on occupational (as opposed to job or organizational) turnover antecedents in...
Prostate-specific antigen: establishment of the reference range for the clinically normal prostate gland and the effect of digital rectal examination, ejaculation, and time on serum concentrations.

This study investigated the serum prostate-specific antigen concentration in 100 healthy men (mean age, 26.3 years; range, 20–29 years) with a clinically normal prostate gland. The effect of digital rectal examination and ejaculation on the serum concentration, and the variability of the serum concentration over 1-week and 1-month periods were examined. In the 100 subjects, the serum prostate-specific antigen concentration ranged from less than 0.1–2.6 ng/ml. The mean, median, and mode were 0.68 ng/ml, 0.6 ng/ml, and 0.4 ng/ml, respectively. The 97.5th percentile value was 2.1 ng/ml. The mean and median changes in the serum concentration after digital rectal examination were −0.013 ±0.11 ng/ml and 0.0 ng/ml, respectively (P = 0.59 compared with control group). The mean change after ejaculation was 0.05 ±0.12 ng/ml, and the median change was 0.0 ng/ml (P = 0.14 compared with control group). Diurnal variation showed minimal change in 16 patients over a 1-week period. The mean change (p.m. value - a.m. value) was 0.003 ng/ml (range, −0.2–0.06 ng/ml). In addition, the serum concentration showed minimal intrapatient variability in 20 patients throughout a 1-month period; the average coefficient of variation (standard deviation/mean) in these subjects was 16.5% (range, 6.4–45.2%). These results indicate that the range in the serum concentration of prostate-specific antigen for healthy men with a clinically normal prostate gland is significantly lower (0.0–2.6 ng/ml) than the currently employed range (0.0–4.0 ng/ml; Tandem-R PSA assay); in addition, digital rectal examination and ejaculation have no significant effect on the serum concentration. Finally, the time of day has little effect, and the variability in the serum concentration of prostate-specific antigen over a 1-week and 1-month interval is minimal.
Challenges and opportunities in bringing new medications to market for pediatric patients.

The discovery and development of new chemical entities (NCEs) is a risky and costly proposition that proceeds in a highly regulated global environment. Only one or two of every 10,000 compounds generated will display safety and efficacy profiles to enable approval. Because of the large number of preclinical and clinical studies required for registration of an NCE, the average time from synthesis to market exceeds 10 years, and average cost per drug is approaching $1 billion (Fig. 1). In addition, the period that a drug is on the market before similar medication becomes available has been reduced from 10 years to approximately 1.2 years. Bringing a new drug to market often involves thousands of people with different areas of expertise who synthesize the NCE, investigate its putative mechanisms of action and toxicology, evaluate its pharmacokinetics and clinical pharmacology, develop formulations and manufacturing processes, and finally, demonstrate its efficacy and safety in humans (Fig. 1). Each of the steps in this process is complex and requires extensive documentation. Of equal importance to a demonstration of efficacy is the focus on the safety of the compound. In fact, the effort devoted to acquisition and analysis of safety data by the sponsors (the pharmaceutical companies) is usually greater than the effort devoted to demonstrate efficacy.
A comparison of self-perceived clinical competencies in primary care residency graduates

ABSTRACT: One hundred seventy-eight graduates from four primary care residency training programs with common hospital sites (medicine/pediatrics, 72; family medicine, 29; pediatrics, 35; and internal medicine, 42) responded to a mailed survey questionnaire regarding distribution of professional time and self-perceived clinical competencies. Most of the internists, family physicians, and internist/pediatricians (MED/PED) were in primary care, and 57% of the pediatricians were subspecialists. Respondents rated each of 24 clinical vignettes as to their level of comfort in managing the patient problems presented. MED/PED and pediatricians responded similarly to all the infant, child, and adolescent cases. Family physicians were less comfortable in managing the complicated neonatal situations but more comfortable with adolescent health care than the MED/PED or pediatricians. MED/ PED reported greater comfort than family physicians in complex internal medicine issues, but less than internists in intensive care and geriatric consultation. Significant differences in reported competency existed among these primary care practitioners despite substantially overlapping training backgrounds.
Are “Least Publishable Unit” Brief Communications Articles Still Appearing Sooner After Acceptance in this Era of E-Publishing Ahead of Print? Evidence from Three Bellwether Pairs of Life Science Journals that Feature Separate Editions for Full-Length Articles and Letters Papers

Journals devoted exclusively to brief communications or letters papers are common outlets for scientific authors, and many such serials have become famous in their fields. However, a pattern of making these “least publishable units” one's favorite form of publication is often regarded as an attempt to inflate artificially one's CV, by critics who consider longer, comprehensive published studies a more appropriate genre for serious science. Letters papers in letters journals have nonetheless historically been defended on grounds that they appear far more quickly in print after acceptance than do regular full-length articles, giving them a greater chance to be noticed and cited by the scientific community sooner. This article demonstrates that with the advent of e-publishing upon manuscript acceptance and ahead of print, the lag time between the appearance of a letters paper and a corresponding full-length article is diminishing to a matter of days, and arguments for or against letters papers and letters jo...
Evidence of a role for cell death in the disappearance of the embryonic human tail

The development and disappearance of the human tail between stages 14 and 22 were studied using scanning and transmission electron microscopy, supravital staining and light microscopy. The tail is a prominent feature of the human embryo during stage 14 and is composed of paired somites, mesenchyme and extensions of the neural tube, notochord and gut. The tail grows with the embryo through early stage 17 when it extends more than a millimeter from the trunk. Overgrowth by the trunk at the base of the tail may account for the loss of part of its length during late stage 17 and stage 18. However, during stage 17 cells begin to die in all structures throughout the tail. Cell death continues in the succeeding stages reaching massive numbers by stages 18 and 19, and the tail becomes less and less prominent with developmental time. Most of the dead cells are phagocytosed. The debris-laden macrophages appear to migrate from the tail to the body. By late stage 21 or early stage 22 there is no free tail. We conclude that cell death has a major role in the destruction of tail structures and the concurrent loss of the human tail.
Stochastic approximation for neural network weight estimation in the control of uncertain nonlinear systems

The use of neural networks for controlling a nonlinear system with unknown process equations is considered. To make such an approach practical, it is necessary that connection weights in the neural network be estimated. The use of a new stochastic approximation algorithm for this weight estimation that is based on a simultaneous perturbation gradient approximation is considered. It is shown that this algorithm can greatly improve on the efficiency of more standard stochastic approximation algorithms based on finite-difference gradient approximations. >
School Extracurricular Activity Participation and Early School Dropout: A Mixed-Method Study of the Role of Peer Social Networks

This longitudinal study employs a mixed-method design to study associations between participation in school-based extracurricular activities, as measured using school yearbooks, and rates of early school dropout. The role of peer social networks that surround activity participation is of particular interest. Results show that the peer social networks of adolescents overlap significantly with the particular types of extracurricular activities in which they participate over time. Processes of selection and socialization that include the use of social aggression appear to regulate changes in activity membership. When both the individual and his/her social network participate in extracurricular activities the risk of early school dropout is diminished significantly. This activity-associated reduction in dropout is pronounced for youth previously identified as highly aggressive by school personnel.
Rapid cloning and purification of proteins: gateway vectors for protein purification by self-cleaving tags.

ABSTRACT: We have combined Invitrogen’s Gateway 1 cloning technology with self-cleaving puriﬁcation tags togenerate a new system for rapid production of recombinantprotein products. To accomplish this, we engineered ourpreviously reported DI-CM cleaving intein to include aGateway cloning recognition sequence, and demonstratedthat the resulting Gateway-competent intein is unaffected.This intein can therefore be used in several previouslyreported puriﬁcation methods, while at the same time beingcompatible with Gateway cloning. We have incorporatedthis intein into a set of Gateway vectors, which include self-cleaving elastin-like polypeptide (ELP), chitin bindingdomain (CBD), phasin (polyhydroxybutyrate-binding), ormaltose binding domain (MBD) tags. These vectors wereveriﬁed by Gateway cloning of TEM-1 b-lactamase andEscherichia coli catalase genes, and the expressed targetproteins were puriﬁed using the four methods encodedon the vectors. The puriﬁcation methods were unaffectedby replacing the DI-CM intein with the Gateway intein. Itwas observed that some puriﬁcation methods were moreappropriate for each target than others, suggesting utility ofthis technology for rapid process identiﬁcation and optimi-zation. The modular design of the Gateway system andintein puriﬁcation method suggests that any tag and pro-moter can be trivially added to this system for the devel-opment of additional expression vectors. This technologycould greatly facilitate process optimization, allowing severaltargets and methods to be tested in a high-throughputmanner.Biotechnol. Bioeng. 2008;101: 229–240. 2008 Wiley Periodicals, Inc.KEYWORDS: intein-based puriﬁcation; bioprocess optimi-zation; high-throughput screening; gateway cloning
On the equivalence of logical databases

We suggest a new approach to database updates, in which a database is treated as a collection of theories. We investigate two issues: a) equivalence of databases under update operations, b) simultaneous multiple update operations.
Expression and function of clift in the development of somatic gonadal precursors within the Drosophila mesoderm

The gonad forms from cells of two lineages: the germline and soma. The somatic gonadal cells generate the various cell types within the testis or ovary that support gametogenesis. These cells derive from embryonic mesoderm, but how they are specified is unknown. Here, we describe a novel regulator of Drosophila gonadogenesis, clift, mutations in which abolish gonad formation. clift is expressed within somatic gonadal precursors as these cells first form, demonstrating that 9–12 cells are selected as somatic gonadal precursors within each of three posterior parasegments at early stages in gonadogenesis. Despite this early expression, somatic gonadal precursors are specified in the absence of clift function. However, they fail to maintain their fate and, as a consequence, germ cells do not coalesce into a gonad. In addition, using clift as a marker, we show that the anteroposterior and dorsoventral position of the somatic gonadal precursor cells within a parasegment are established by the secreted growth factor Wg, coupled with a gene regulatory hierarchy within the mesoderm. While loss of wg abolishes gonadal precursors, ectopic expression expands the population such that most cells within lateral mesoderm adopt gonadal precursor fates. Initial dorsoventral positioning of somatic gonadal precursors relies on a regulatory cascade that establishes dorsal fates within the mesoderm and is subsequently refined through negative regulation by bagpipe, a gene that specifies nearby visceral mesoderm. Thus, these studies identify essential regulators of gonadal precursor specification and differentiation and reveal novel aspects of the general mechanism whereby distinct fates are allocated within the mesoderm.
Flow visualization and spectral measurements in a simulated rigid disk drive

An experimental simulation of the fluid mechanics of a rigid disk drive has been performed matching the geometry and Ekman number of a full-size (14 in.) disk drive. Three different flow configurations have been studied. The first was a simplified geometry used to determine the basic structure of the flow. The second case explored the effect of the introduction of cooling flow into the basic geometry, and the third considered the separate effect of the blockage due to the presence of the supports for the read heads. All three cases exhibited flow regimes near the rotating hub which were distinct from the flow farther from the hub. In addition, each of the flow configurations contained features not found in the other cases. The implications of these flow features with respect to disk drive performance are discussed. >
The First Year Inventory: a longitudinal follow-up of 12-month-old to 3-year-old children

The First Year Inventory is a parent-report measure designed to identify 12-month-old infants at risk for autism spectrum disorder. First Year Inventory taps behaviors that indicate risk in the developmental domains of sensory-regulatory and social-communication functioning. This longitudinal study is a follow-up of 699 children at 3 years of age from a community sample whose parents completed the First Year Inventory when their children were 12 months old. Parents of all 699 children completed the Social Responsiveness Scale-Preschool version and the Developmental Concerns Questionnaire to determine age 3 developmental outcomes. In addition, children deemed at risk for autism spectrum disorder based on liberal cut points on the First Year Inventory, Social Responsiveness Scale-Preschool, and/or Developmental Concerns Questionnaire were invited for in-person diagnostic evaluations. We found 9 children who had a confirmed diagnosis of autism spectrum disorder from the sample of 699. Receiver operating characteristic analyses determined that a two-domain cutoff score yielded optimal classification of children: 31% of those meeting algorithm cutoffs had autism spectrum disorder and 85% had a developmental disability or concern by age 3. These results suggest that the First Year Inventory is a promising tool for identifying 12-month-old infants who are at risk for an eventual diagnosis of autism spectrum disorder.
Bias associated with using the estimated propensity score as a regression covariate

The use of propensity score methods to adjust for selection bias in observational studies has become increasingly popular in public health and medical research. A substantial portion of studies using propensity score adjustment treat the propensity score as a conventional regression predictor. Through a Monte Carlo simulation study, Austin and colleagues. investigated the bias associated with treatment effect estimation when the propensity score is used as a covariate in nonlinear regression models, such as logistic regression and Cox proportional hazards models. We show that the bias exists even in a linear regression model when the estimated propensity score is used and derive the explicit form of the bias. We also conduct an extensive simulation study to compare the performance of such covariate adjustment with propensity score stratification, propensity score matching, inverse probability of treatment weighted method, and nonparametric functional estimation using splines. The simulation scenarios are designed to reflect real data analysis practice. Instead of specifying a known parametric propensity score model, we generate the data by considering various degrees of overlap of the covariate distributions between treated and control groups. Propensity score matching excels when the treated group is contained within a larger control pool, while the model-based adjustment may have an edge when treated and control groups do not have too much overlap. Overall, adjusting for the propensity score through stratification or matching followed by regression or using splines, appears to be a good practical strategy.
THE LATE AND TERMINAL CLASSIC CERAMIC SEQUENCE AT LA MILPA, BELIZE: IMPLICATIONS FOR ITS OCCUPATION HISTORY

Previous interpretations of the occupation history of La Milpa, Belize, which were based on preliminary ceramic data, suggested that occupation of the site fluctuated dramatically from the Late Preclassic to the Terminal Classic (400 b.c.–a.d. 850). It was determined that the modest Late Preclassic village became a large Early Classic city with regal-ritual architecture and carved monuments. In Late Classic I, it appeared the site was nearly abandoned. Its reoccupation and exponential growth in Late Classic II was followed by rapid abandonment before the end of the Late Classic III/Terminal Classic. New ceramic analyses utilizing attribute analysis with an emphasis on formal modes has clarified the sequence and, in turn, softened the occupation curves. This article provides descriptions of the Late Classic I, II, and III ceramics, along with revised percentage frequency graphs of La Milpa's occupation history based primarily on the work of the La Milpa Archaeological Project (1992–2002).
Interannual and seasonal variability in atmospheric N2O

[1] The increase in atmospheric N2O observed over the last century reflects large-scale human perturbations to the global nitrogen cycle. High-precision measurements of atmospheric N2O over the last decade reveal subtle signals of interannual variability (IAV) superimposed upon the more prominent growth trend. Anthropogenic sources drive the underlying growth in N2O, but are probably too monotonic to explain most of the observed IAV. The causes of both seasonal and interannual variability in atmospheric N2O are explored on the basis of comparisons of a 1993–2004 atmospheric transport simulation to observations of N2O at five stations of the Advanced Global Atmospheric Gases Experiment (AGAGE). The complementary tracers chlorofluorocarbons (CFCs) 11 and 12 and SF6 also are examined. The model simulation does not include a stratospheric sink and thus isolates the effects of surface sources and tropospheric transport. Both model and observations yield correlations in seasonal and interannual variability among species, but only in a few cases are model and observed variability correlated to each other. The results suggest that tropospheric transport contributes substantially to observed variability, especially at Samoa station. However, some features of observed variability are not explained by the model simulation and appear more consistent with a stratospheric influence. At Mace Head, Ireland, N2O and CFC growth rate anomalies are weakly correlated to IAV in polar winter lower stratospheric temperature, a proxy for the strength of the mean meridional stratospheric circulation. Seasonal and interannual variability in the natural sources of N2O may also contribute to observed variability in atmospheric N2O.
RIG-1 receptor expression in the pathology of Alzheimer's disease.

Neuroinflammation plays a critical role in the pathogenesis of Alzheimer’s disease (AD) and involves activation of the innate immune response via recognition of diverse stimuli by pattern recognition receptors (PRRs). The inflammatory inducers and precise innate signaling pathway contributing to AD pathology remain largely undefined. In the present study we analyzed expression levels of innate immune proteins in temporal and occipital cortices from preclinical (no cognitive impairment, NCI, N = 22) to mild cognitive impairment (MCI, N = 20) associated with AD pathology (N = 20) and AD patients (N = 23). We found that retinoic acid-inducible gene-I (RIG-1) is significantly elevated in the temporal cortex and plasma in patients with MCI. In addition, primary human astrocytes stimulated with the RIG-1 ligand 5′ppp RNA showed increased expression of amyloid precursor protein (APP) and amyloid-β (Aβ), supporting the idea that RIG-1 is involved in the pathology of MCI associated with early progression to AD. These findings suggest that RIG-1 may play a critical role in incipient AD.