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The Coronavirus (COVID-19) pandemic has negatively shifted the foundations of human health and the well-being of humanity on a global scale. Its contagiousness and lethal symptoms pose a threat to everyone, especially seniors over 65 years, immunocompromised individuals, and people with preexisting health conditions. The factors of the social determinants of health had great influence on the vaccination status for Black and Brown communities. Access to life-saving treatment and resources was hindered by the poor social determinants and socioeconomic status, which led to slow vaccination numbers. This article examines that equitable vaccination access, distribution, and health literacy in Black and Brown communities are all supported by careful analysis of the notion of dignity.

When leaders at institutions of higher education downplay everyday incivilities directed against racial and other minority groups, it can obscure the magnitude of intergroup antipathy at these schools. At the most prominent university in the only state whose flag contains the Confederate emblem, we wondered whether reports of so-called microaggressions were more common than university leaders sometimes suggest, more frequent in certain campus spaces than in others, and likely to invoke the South and its history. Using online diaries, we collected 1,301 accounts of incidents from 684 students during the 2014–2015 academic year.  Our mixed-method approach revealed widespread incivilities, many of them blatant, both on and off campus. Microaggressions in classrooms were less frequent but as blatant as those in living spaces, and reports of environmental microaggressions seemed particularly likely to invoke students’ references to the history of the region. This research suggests the value of using online diaries as a method for understanding the everyday experiences of vulnerable students at predominantly white institutions of higher learning.

Recent research suggests that meaning in life relates to processes of social judgments and could facilitate relationships between racially diverse individuals. At this time however, there is no study that examines factors that influence the relationship between meaning, racial prejudice, and values. To fill this gap, the present study examined whether (1) self-transcendence and (2) psychological inflexibility mediates the relationship between perceived meaning in life and prejudice. The study was conducted with 253 White students (females, 77.9%; males, 22.1%) from a university located in the southern United States. Standard path-analytic approaches through the macro PROCESS program were used to examine a parallel mediational model. Results evidenced that self-transcendence and psychological inflexibility had a significant indirect effect on the relationship between meaning in life and prejudice, and that reversely, meaning also functioned as a mediator of self-transcendence and prejudice and psychological inflexibility and prejudice. Findings suggest that among White college students the effect of meaning on prejudice changes in the context of self-transcendence and psychological inflexibility, and that without self-transcendence and psychological flexibility, meaning could actually result in greater prejudice.

Proxy estimates of atmospheric CO2are necessary to reconstruct Earth's climate history. Confidence in paleo‐CO2estimates can be increased by comparing results from multiple proxies at a single site, but so far this strategy has been implemented only for marine‐based techniques. Here we present CO2estimates for the well‐studied early Paleocene Castle Rock site in Colorado using four paleobotanical proxies. Median estimates range from 470 to 813 ppm, demonstrating fair correspondence. The synthesis yields a median of 616 ppm (352–1110 ppm at 95% confidence), considerably higher than previous early Paleocene CO2estimates (~300 ppm). Ash bed geochronology by the high‐precision U‐Pb method places the Castle Rock assemblage at 63.844 ± 0.097 Ma (fully propagated 2σ error). When these results are placed into the broader context of other Cenozoic CO2estimates from plant‐gas‐exchange approaches and coeval estimates of global mean surface temperature, a pattern emerges of an Earth system sensitivity around 3 °C per CO2doubling during the Paleocene and Eocene, a time with little land ice, then steepening to >7 °C after the Eocene once land ice was present on Antarctica. As atmospheric CO2continues to increase, we enter a climate state whose analog in terms of CO2concentration is found millions of years ago. Information about climate from such distant times is only available to us via proxy methods (i.e., indicators of climate recorded in ancient rocks and fossils); increasing confidence in proxy results is therefore a high priority. Here we compare four different CO2proxy methods using plant fossils from an exceptionally diverse rainforest that existed near present‐day Denver, Colorado, 63.8 million years ago. Estimates are largely congruent and higher than previously thought (~600 ppm). The higher CO2levels during this warm period are in better agreement with the current understanding of long‐term Earth system climate sensitivity, and results from the newer gas‐exchange proxy methods paint a coherent picture of Earth system sensitivity evolution over the Cenozoic. Multiproxy studies increase confidence in paleoclimate reconstructions; we present the first such study for land‐based CO2proxiesOur study highlights relatively new, more widely applicable proxy methods based on robust models of gas exchange in C3photosynthesisOur CO2estimates are more congruent with the current understanding of Earth system sensitivity than are previous lower estimates

Geological samples must be archived for all if we are to solve the riddles of Earth’s complex history.

ABSTRACTLoss-of-function mutations of the ß-cell ATP-sensitive potassium channels (KATP) cause the most common and severe form of congenital hyperinsulinism (KATPHI), a disorder of ß-cell function characterized by severe hypoglycemia. Children with KATPHI are typically unresponsive to medical therapy and require pancreatectomy for intractable hypoglycemia. We tested the hypothesis that inhibition of insulin receptor signaling may prevent hypoglycemia in KATPHI. To test this hypothesis, we examined the effect of an antibody allosteric inhibitor of the insulin receptor, XMetD, on fasting plasma glucose in a mouse model of KATPHI (SUR-1−/−mice). SUR-1−/−and wild-type mice received twice weekly intraperitoneal injections of either XMetD or control antibody for 8 wks. Treatment with XMetD significantly decreased insulin sensitivity, and increased hepatic glucose output and fasting plasma glucose. These findings support the potential use of insulin receptor antagonists as a therapeutic approach to control the hypoglycemia in congenital hyperinsulinism.

IMPORTANCE: Galcanezumab (LY2951742), a monoclonal antibody against calcitonin gene-related peptide (CGRP), is one of a novel class of new medicines for migraine prevention. OBJECTIVE: To assess whether at least 1 dose of galcanezumab was superior to placebo for episodic migraine prevention. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial was conducted in the United States (July 7, 2014, to August 19, 2015) in clinics of 37 licensed physicians with a specialty including, but not limited to, psychiatry, neurology, internal medicine, and primary care. Subcutaneous injections of galcanezumab, 5, 50, 120, or 300 mg, or placebo were given monthly during the 3-month treatment period. A total of 936 patients were assessed; 526 did not meet study entry or baseline criteria and 410 patients were randomly assigned to receive placebo or galcanezumab. Analyses were conducted on an intent-to-treat population, which included all patients who were randomized and received at least 1 dose of study drug. INTERVENTIONS: Short-term migraine treatments were allowed as needed except for opioids or barbiturates. MAIN OUTCOMES AND MEASURES: To determine if at least 1 of the 4 doses of galcanezumab tested was superior to placebo for migraine prevention measured by the mean change from baseline in the number of migraine headache days 9 weeks to 12 weeks after randomization. RESULTS: Of the 936 patients assessed, 410 met entry criteria (aged 18-65 years with 4-14 migraine headache days per month and migraine onset prior to age 50 years) and were randomized to receive placebo or galcanezumab.For the primary end point, galcanezumab, 120 mg, significantly reduced migraine headache days compared with placebo (99.6% posterior probability −4.8 days; 90% BCI, −5.4 to −4.2 days vs 95% superiority threshold [Bayesian analysis] −3.7 days; 90% BCI, −4.1 to −3.2 days). Adverse events reported by 5% or more of patients in at least 1 galcanezumab dose group and more frequently than placebo included injection-site pain, upper respiratory tract infection, nasopharyngitis, dysmenorrhea, and nausea. CONCLUSIONS AND RELEVANCE: Monthly subcutaneous injections of galcanezumab, both 120 mg and 300 mg, demonstrated efficacy (repeated-measures analysis) for the preventive treatment of migraine and support further development in larger phase 3 studies. All dosages were safe and well tolerated for the preventive treatment of episodic migraine. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02163993

A generic Bayesian framework is presented to track lost-in-space noncooperative maneuvering satellites. The developed framework predicts the reachability set for a lost-in-space satellite given bounds on maneuver parameters such as maneuver time and maneuver magnitude. Reachability sets are represented as a desired order polynomial series as a function of maneuver parameters. Recent advances in non-product quadrature methods are utilized to compute coefficients of this polynomial series in a computationally efficient manner. A major contribution of this work is to develop quadrature methods to generate samples for spherically uniform distribution for bounded magnitude maneuvers. Samples generated from this polynomial series are used for direct particle propagation in a traditional Bayesian filter rather than solving governing equations of motion for each sample point. An important component of the developed framework is a search strategy which exploits the reachability set calculations to task the sensor to increase the detection probability of the satellite. The samples generated from initial reachability sets are updated to systematically reduce the target search region based on actual detection of the target in a Bayesian framework. Numerical simulations are performed to show the efficacy of the developed ideas for tracking a lost-in-space satellite with the help of space based sensor. Performance of the proposed method varies widely based on factors such as the reachability set polynomial order, maneuver uncertainty bounds, sensor parameters (Field of view, measurement frequency, and detection probability), and initial conditions. For numerical experiments performed, the observer gained the custody of the maneuvering target in 100%and 96%of Monte Carlo (MC) simulations for the single maneuver and two maneuver cases, respectively.

XOMA 358 (X358) is a fully human monoclonal antibody to the insulin receptor that acts as a negative allosteric modulator of insulin signaling. It is being developed as a novel treatment of hyperinsulinemic hypoglycemia. This report describes pharmacokinetic (PK) and pharmacodynamic (PD) data from a first-in-human clinical trial.

Ibudilast, a nonselective phosphodiesterase inhibitor, is used clinically in Asia for the treatment of asthma and poststroke dizziness. Recent preclinical studies have suggested that it also inhibits glial cell activation in rodents, and may alter opioid-mediated effects, including analgesia and withdrawal symptoms. The effects of ibudilast on the abuse potential of opioids in humans are largely unknown. The present study was designed to examine the influence of ibudilast on subjective (including drug craving), reinforcing, and analgesic effects of oxycodone in human volunteers diagnosed with opioid dependence (equivalent to moderate–severe opioid use disorder). Non-treatment-seeking opioid-dependent male volunteers (n=11) underwent an in-patient detoxification with morphine, followed by maintenance on placebo (0 mg b.i.d.) and active ibudilast (50 mg b.i.d.). Under each maintenance dose, six experimental sample and choice sessions were completed involving oral oxycodone administration (0, 15, and 30 mg/70 kg, p.o.). Subjective effects of oxycodone and drug craving were measured with visual analog scales (VAS) and a Drug Effects Questionnaire. The cold pressor test was used to produce pain, and a modified progressive-ratio choice procedure was used to measure the reinforcing effects of oxycodone. Under the active ibudilast condition compared with the placebo condition, ratings of drug liking following 15 mg of oxycodone were decreased significantly. The mean drug breakpoint value was also significantly lower in the active vs the placebo ibudilast condition under the 15 mg oxycodone condition, but not significantly lower under the 30 mg oxycodone condition. Heroin craving was significantly reduced under active ibudilast vs placebo, and similar effects were observed for tobacco and cocaine craving. Furthermore, mean subjective ratings of pain were lower in the active ibudilast condition. Our data suggest that ibudilast may be useful for treating opioid use disorders and it may enhance the analgesic effects of oxycodone.

The article discusses on removal of confederate statues with new statues which narrates role that local black men played in fighting for their freedom.

The hanging of a noose on the University of Mississippi’s statue of civil rights pioneer James Meredith in February 2014 was framed by university administrators as the act of a few deviant white students, but our analysis suggests otherwise. A historical review shows the university’s long-standing resistance to meaningful change and a continuing lack of transparency following racist incidents. Visual analysis shows that the university remains saturated with monuments, place names, and other symbols of racial dominance. Narratives of marginalized people on campus, including some of the authors, reveal the corrosive effects of normalized white supremacy. The authors’ analysis suggests that, instead of an aberration, the noosing aligned the statue with the prevailing symbolic environment. This study builds bridges between sociological analysis and critical race theory and demonstrates the importance of group processes in understanding and responding to racist incidents on campuses.

Ibudilast is a small molecular weight, orally administered compound that was originally developed and approved in Japan over 20 years ago for bronchial asthma and poststroke complication (subsequently defined as poststroke dizziness in 2002). Over the last 10 years, there has been substantial progress in better understanding ibudilasts molecular and cellular actions including macrophage migration inhibitory factor inhibition, phosphodiesterase inhibition and attenuation of activated glia. Moreover, its potential safety and efficacy in new neurological indications has been explored via animal models and Phase I and II clinical studies. Phase II clinical trials have now initiated in methamphetamine and other drug addictions, progressive multiple sclerosis and pain. A current model of ibudilast target action and a review of its translational progress and prospects as a new medication in these disorders is described.

Controversy exists around the incidence and cause of hyperlactatemia during asthma exacerbations. We evaluated the incidence, potential causes, and adverse events of hyperlactatemia in patients with acute asthma exacerbation.

AV513 is a select fucoidan, a sulfated polysaccharide of botanical origin. It inhibits tissue factor pathway inhibitor (TFPI) activity and accelerates clotting of human hemophilia A and B plasma. In prior work, subcutaneous administration of AV513 to mice with hemophilia A improved hemostasis. The current studies were designed to evaluate potential efficacy and safety in dogs with hemophilia A (hemophilia A dogs) with minimally increased hemostasis after adenoassociated viral-FVIII gene transfer and in treatment-naive severe hemophilia A dogs. AV513 administered subcutaneously to low-FVIII dogs for multiple weeks improved hemostasis as exhibited in thromboelastography (TEG) and cuticle bleeding time (CBT) tests. Moreover, AV513 administered orally to AAV-FVIII dogs and treatment-naive severe hemophilia A dogs for a multiweek dose-escalating period yielded correction to normal ranges in both TEG and CBT end points at 5 to 15 mg/kg and 15 to 20 mg/kg dose levels, respectively. In all 3 separate studies, throughout their duration, AV513 was well tolerated by the dogs without any adverse events. Additional pharmacologic characterization of AV513 included intravenous pharmacokinetic analysis in rats. In summary, the combination of safety and efficacy in 2 global tests of hemostasis in the hemophilia A dog model indicate that further evaluation of AV513 as a hemostatic agent in hemophilia A patients is warranted.

AV513 is a select fucoidan, a sulfated polysaccharide of botanical origin. It inhibits tissue factor pathway inhibitor (TFPI) activity and accelerates clotting of human hemophilia A and B plasma. In prior work, subcutaneous administration of AV513 to mice with hemophilia A improved hemostasis. The current studies were designed to evaluate potential efficacy and safety in dogs with hemophilia A (hemophilia A dogs) with minimally increased hemostasis after adenoassociated viral-FVIII gene transfer and in treatment-naive severe hemophilia A dogs. AV513 administered subcutaneously to low-FVIII dogs for multiple weeks improved hemostasis as exhibited in thromboelastography (TEG) and cuticle bleeding time (CBT) tests. Moreover, AV513 administered orally to AAV-FVIII dogs and treatment-naive severe hemophilia A dogs for a multiweek dose-escalating period yielded correction to normal ranges in both TEG and CBT end points at 5 to 15 mg/kg and 15 to 20 mg/kg dose levels, respectively. In all 3 separate studies, throughout their duration, AV513 was well tolerated by the dogs without any adverse events. Additional pharmacologic characterization of AV513 included intravenous pharmacokinetic analysis in rats. In summary, the combination of safety and efficacy in 2 global tests of hemostasis in the hemophilia A dog model indicate that further evaluation of AV513 as a hemostatic agent in hemophilia A patients is warranted.

The treatment of neuropathic pain is a major unresolved medical challenge. Present pharmacotherapies only have modest efficacy and numerous side effects. The use of opioid analgesics is additionally coupled with dependence and withdrawal syndromes. Ibudilast (AV-411) is a non-selective phosphodiesterase inhibitor that is also known to suppress glial cell activation. It has been used clinically for other indications with a good safety profile. As glial cell activation is considered to crucially contribute to neuropathic pain as well as opioid dependence and withdrawal, the authors conceived that ibudilast may be useful for treating these conditions. Preclinical data indicate that ibudilast crosses the blood–brain barrier, is well tolerated, is active on oral administration, reduces glial activation and attenuates pain symptoms in diverse rat models of neuropathic pain. In addition, it enhances acute morphine analgesia and attenuates morphine tolerance and withdrawal. Thus ibudilast may improve opioid efficacy and is a promising therapeutic candidate for neuropathic pain, with a novel mechanism of action.

The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLU(K5) in dorsal root ganglia, the dorsal horn, and trigeminal ganglia makes it a target of interest for these indications. We examined the in vitro and in vivo pharmacology of the competitive GLU(K5)-selective kainate receptor antagonist LY466195 [(3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoro-1-pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid)], the most potent GLU(K5) antagonist described to date. Comparisons were made to the competitive GLU(K5)/alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLU(K5) receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 muM)-induced currents with an IC(50) value of 0.045 +/- 0.011 muM. In HEK293 cells transfected with GLU(K5), GLU(K2)/GLU(K5), or GLU(K5)/GLU(K6) receptors, LY466195 produced IC(50) values of 0.08 +/- 0.02, 0.34 +/- 0.17, and 0.07 +/- 0.02 muM, respectively. LY466195 was efficacious in a dural plasma protein extravasation (PPE) model of migraine with an ID(100) value of 100 mug/kg i.v. LY466195 was also efficacious in the c-fos migraine model, with a dose of 1 mug/kg i.v. significantly reducing the number of Fos-positive cells in the rat nucleus caudalis after electrical stimulation of the trigeminal ganglion. Furthermore, LY466195 showed no contractile activity in the rabbit saphenous vein in vitro. The diethyl ester prodrug of LY466195 was also efficacious in the same PPE and c-fos models after oral administration at doses of 10 and 100 mug/kg, respectively while having no N-methyl-d-aspartate antagonist-like behavioral effects at oral doses up to 100 mg/kg.

This article discusses the effect of gold mining on the environment. It is said that large miners are taking 500,000 tons of earth a day to have ounces of gold. Eight U.S. jewelry companies, including Zales and Tiffany & Co., have signed on to a national campaign called No to Dirty Gold promising to comply with gold's ethical issues. Complaints are being reported in Guatemala and also in Yanachoca, Peru where a massive open-pit mine is being operated by Newmont Mining.

ABSTRACTBB-83698, a potent and selective inhibitor of peptide deformylase, was the first compound of this novel antibacterial class to progress to clinical trials. Single- and/or multiple-dose studies with doses ranging from 10 to 50 mg of BB-83698/kg of body weight were done with mice, rats, and dogs. Intravenous pharmacokinetics were characterized by low to moderate clearances and moderate volumes of distribution for all species. In dogs, but not in rodents, central nervous system (CNS) effects were dose limiting for intravenously administered BB-83698 and were suspected to be related to a high maximum concentration of the agent in plasma (Cmax) rather than to total systemic exposure. Controlled infusion studies with dogs demonstrated that CNS effects could be avoided without compromising systemic exposure by reducing the Cmax. A randomized, double-blind, placebo-controlled, five-way-crossover, single-dose-escalation, phase I study to explore the safety, tolerability, and pharmacokinetics of intravenous BB-83698 at doses ranging from 10 to 475 mg was performed with healthy male volunteers. Systemic exposures were generally in linear relationships with administered doses in animals and humans. Pharmacokinetics were consistent, predictable, and exhibited good allometric scaling among all species (r2>0.98). Moreover, BB-83698 dosing in humans proceeded to a predicted efficacious exposure (the area under the concentration-time curve/MIC ratio, up to 184) without any clinically significant adverse effects.

Extant neotropical rainforest biomes are characterized by a high diversity and abundance of angiosperm trees and vines, high proportions of entire–margined leaves, high proportions of large leaves (larger than 4500 mm2), high abundance of drip tips and a suite of characteristic dominant families: Sapotaceae, Lauraceae, Leguminosae (Fabaceae), Melastomataceae and Palmae (Arecaceae). Our aim is to define parameters of extant rainforests that will allow their recognition in the fossil record of South America and to evaluate all known South American plant fossil assemblages for first evidence and continued presence of those parameters. We ask when did these critical rainforest characters arise? When did vegetative parameters reach the level of abundance that we see in neotropical forests? Also, when do specific lineages become common in neotropical forests?Our review indicates that evidence of neotropical rainforest is exceedingly rare and equivocal before the Palaeocene. Even in the Palaeocene, the only evidence for tropical rainforest in South America is the appearance of moderately high pollen diversity. By contrast, North American sites provide evidence that rainforest leaf physiognomy was established early in the Palaeocene. By the Eocene in South America, several lines of evidence suggest that neotropical rainforests were diverse, physiognomically recognizable as rainforest and taxonomically allied to modern neotropical rainforests. A mismatch of evidence regarding the age of origin between sites of palaeobotanical high diversity and sites of predicted tropical climates should be reconciled with intensified collecting efforts in South America. We identify several lines of promising research that will help to coalesce previously disparate approaches to the origin, longevity and maintenance of high diversity floras of South America.

Originally identified as a modulator of glycogen metabolism, glycogen synthase kinase-3 (GSK3) is now understood to play an important regulatory role in a variety of pathways including initiation of protein synthesis, cell proliferation, cell differentiation, apoptosis, and is essential for embryonic development as a component of the Wnt signaling cascade. GSK3 can be considered as a target for both metabolic and neurological disorders. GSK3s association with neuronal apoptosis and hyper-phosphorylation of tau make this kinase an attractive therapeutic target for neurodegenerative conditions such as head trauma, stroke and Alzheimers disease. While noting GSK3s many associated functions, this review will focus on GSK3 as a central negative regulator in the insulin signaling pathway, its role in insulin resistance, and the utility of GSK3 inhibitors for intervention and control of metabolic diseases including type 2 diabetes. Recent crystal structures, including the active (phosphorylated Tyr-216) form of GSK3, provide a wealth of structural information and greater understanding of GSK3s unique regulation and substrate specificity. Many potent and selective small molecule inhibitors of GSK3 have now been identified, and used in vitro to modulate glycogen metabolism and gene transcription, increase glycogen synthase activity and enhance insulin-stimulated glucose transport. The pharmacology of potent and selective GSK3 inhibitors (CT 99021 and CT 20026) is described in a number of in vitro and in vivo models following acute or chronic exposure. The efficacy of clinical candidates in diabetic primates and the implications for clinical development are discussed. The profile of activity is consistent with a unique form of insulin sensitization which is well suited for indications such as metabolic syndrome X and type 2 diabetes.

This article explores the practice of multicultural education within a Pacific Island university with a majority of faculty from Caucasian background and over 90 percent of students from Asian/Pacific Island ethnicities. This article is Phase II of a research project that began in 1999 with the goal to further understand the practice of multicultural pedagogy in higher education. Phase I measured the attitudes of faculty toward diversity and multiculturalism in general while this article attempts to narrow the focus to their perceptions of their actual practice of multicultural pedagogy in the classroom and in curriculum development. Through survey methodology and descriptive analysis, a picture emerges of the link between attitudes and practice. It was found that faculty ranked high on their willingness to engage and incorporate multicultural strategies in their teaching. Many often did not feel, however, that they had the skills or knowledge to do so. Many also felt that they were not well equipped to deal with a multicultural environment. While the data suggest that many are willing and open to diversity and multiculturalism, they struggle with strategies to incorporate those attitudes in their teaching. In comparing some of the data from the two phases of the research we argue that a culture of political correctness seems to mask certain ethnocentric beliefs that may then be reflected in classroom teaching and curriculum development.

We have identified Wnt10b as a potent inhibitor of adipogenesis that must be suppressed for preadipocytes to differentiate in vitro. Here, we demonstrate that a specific inhibitor of glycogen synthase kinase 3, CHIR 99021, mimics Wnt signaling in preadipocytes. CHIR 99021 stabilizes free cytosolic beta-catenin and inhibits adipogenesis by blocking induction of CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. Preadipocyte differentiation is inhibited when 3T3-L1 cells are exposed to CHIR 99021 for any 24 h period during the first 3 days of adipogenesis. Consistent with this time frame of inhibition, expression of Wnt10b mRNA is suppressed upon induction of differentiation, with a 50% decline by 6 h and complete inhibition by 36 h. Of the agents used to induce differentiation, exposure of 3T3-L1 cells to methyl-isobutylxanthine or cAMP is sufficient to suppress expression of Wnt10b mRNA. Inhibition of adipogenesis by Wnt10b is likely mediated by Wnt receptors, Frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 6. These receptors, like Wnt10b, are highly expressed in preadipocytes and stromal vascular cells. Finally, we demonstrate that disruption of extracellular Wnt signaling by expression of secreted Frizzled related proteins causes spontaneous adipocyte conversion.

Analyzes the controversy over United States (U.S.) President George W. Bush's national student testing plan. Role of testing in student's learning; Expenditures of the government on students in the U.S. from 1970-2000; Significance of the policy to the growing incidence of cheating on examinations.

A postorbital bar is one of a suite of derived features which distinguishes basal primates from their putative sister taxon, plesiadapiforms. Two hypotheses have been put forward to explain postorbital bar development and variation in circumorbital form: the facial torsion model and visual predation hypothesis. To test the facial torsion model, we employ strain data on circumorbital and mandibular loading patterns in representative primates with a postorbital bar and masticatory apparatus similar to basal primates. To examine the visual predation hypothesis, we employ metric data on orbit orientation in Paleocene and Eocene primates, as well as several clades of visual predators and foragers that vary interspecifically in postorbital bar formation.

ABSTRACTPeptoids differ from peptides in that peptoids are composed of N-substituted rather than alpha-carbon-substituted glycine units. In this paper we report the in vitro and in vivo antibacterial activities of several antibacterial peptoids discovered by screening combinatorial chemistry libraries for bacterial growth inhibition. In vitro, the peptoid CHIR29498 and some of its analogues were active in the range of 3 to 12 μg/ml against a panel of gram-positive and gram-negative bacteria which included isolates which were resistant to known antibiotics. Peptoid antimicrobial activity againstStaphylococcus aureuswas rapid, bactericidal, and independent of protein synthesis. β-Galactosidase and propidium iodide leakage assays indicated that the membrane is the most likely target of activity. Positional isomers of an active peptoid were also active, consistent with a mode of action, such as membrane disruption, that does not require a specific fit between the molecule and its target. In vivo, CHIR29498 protected S. aureus-infected mice in a simple infection model.

This study tested the hypothesis that tissue factor pathway inhibitor (TFPI) would improve mortality and morbidity evoked by peritonitis-induced bacteremia in pigs. Secondarily, it sought to determine if TFPI treatment would attenuate cardiodynamic abnormalities produced by this septic model. 32 pigs were chronically instrumented with intracardiac transducers to measure left ventricular pressure and diameter, pulmonary and aortic pressures, and cardiac output. At least 5 days after surgery to implant transducers, basal cardiovascular readings and blood samples were obtained. Using a randomized, blinded study design, either purified, reconstituted TFPI (1 mg/kg bolus, 10 mg/kg/min for 48 h), placebo (arginine buffer), or saline was administered to pigs immediately after Escherichia coli 0111.B4 (3.0–11 ± 109colony-forming U/kg)-laden fibrin clots were implanted intraperitoneally, producing peritonitis and bacteremia. Pigs did not receive antibiotics or supportive therapy. No significant differences in primary or secondary endpoints were noted between the arginine and saline groups, so these data were combined into a control group (N = 20). 5 of 12 TFPI pigs survived (42), while 5 of 20 control pigs survived (25); this difference was not significant (p = .714, Fisher's exact test). TFPI treatment augmented cardiac output in surviving pigs, but did not affect any other cardiovascular performance variable (heart rate, diameter shortening, or systemic and pulmonary vascular resistance). In controls, peritonitis induced rapid increase in plasma tumor necrosis factor-± (428 ± 771 to 5,933 ± 559 pg/mL at 2 h) and interleukin-8 (180 ± 153 to 1,393 ± 145 pg/mL at 2 h). TFPI treatment significantly attenuated cytokine responses to sepsis, reducing peak tumor necrosis factor-± to 2,103 ± 813 pg/mL and reducing peak interleukin-8 levels to 534 ± 211 pg/mL at 2 h (p < .05, Tukey test, two-way ANOVA). In conclusion, TFPI treatment attenuated important mediator components of the inflammatory response but did not provide significant survival benefit.

Presents a guide on how women can raise healthy, responsible sons. Extra social challenges faced by black boys while growing up; Providing positive male and female role models; Teaching boys about sex, racism, and respect for females; Fostering discipline and self-confidence; Importance of constant communication; Involving the father in child rearing.

There is considerable support in the ecological literature for the theory that phytoplankton communities experience non-equilibrium conditions. Therefore, it is possible that not all species of an algal community are deficient in the same nutrient, challenging the belief held by some aquatic scientists and lake managers that phosphorus is the universal nutrient limiting phytoplankton growth in lakes. Simultaneous additions of NH4+ and PO43- were necessary to stimulate community photosynthesis - uptake of 14CO2 - during summer stratification in a number of northern Rocky Mountain lakes and reservoirs, whereas adding one nutrient had no significant effect on community photosynthesis. However, size-fractionated bioassays showed that additions of nitrogen alone stimulated photosynthesis of specific size classes of phytoplankton in these systems. The authors' data have the following implications for lake management: (1) phosphorus should not be assumed to be the only nutrient controlling photosynthesis; (2) simultaneous enrichment of nitrogen and phosphorus may be necessary to measurably increase community photosynthesis, especially in nutrient dilute systems; and (3) adding NH4+ may cause changes in phytoplankton community structure without changing community primary production.