Crosstalk in the mouse thymus

The development of mature T cells within the thymus is dependent upon intact cortical and medullary microenvironments. In turn, thymic microenvironment themselves are dependent on lymphoid cells to maintain their integrity. Here, Willem van Ewijk and colleagues discuss experiments that have established the phenomenon of ‘crosstalk’ within the mouse thymus and suggest a mechanism whereby lymphoid and stromal cells influence each other in a consecutive manner during T-cell development

Src mediates cytokine-stimulated gene expression in airway myocytes through ERK MAPK

The p38 and extracellular signal-regulated kinases (ERK) mitogen-activated protein kinases (MAPK) participate in cytokine-stimulated inflammatory gene expression in airway smooth muscle cells. The following study was undertaken to determine whether Src tyrosine kinases are signaling intermediaries upstream of cytokine-stimulated MAPK activation and gene expression. Treating human airway myocytes with interleukin (IL)-1β, tumor necrosis factor (TNF) α and interferon (IFN) γ caused a rapid 1.8-fold increase in Src family tyrosine kinase activity within 1 minute that remained 2.3 to 2.7 fold above basal conditions for 15 minutes. This activity was blocked by addition of 30 μM PP1, a pyrimidine inhibitor specific for Src family tyrosine kinases, in immune-complex assays to confirm that this stimulus activates Src tyrosine kinase. Addition of PP1 also blocked cytokine-stimulated expression of IL-1β, IL-6 and IL-8, while decreasing phosphorylation of ERK, but not p38 MAPK. Since this inflammatory stimulus may activate additional inflammatory signaling pathways downstream of Src, we tested the effects of PP1 on phosphorylation of signal transducers and activators of transcription (STAT). PP1 had no effect on cytokine-stimulated STAT 1 or STAT 3 phosphorylation. These results demonstrate that Src tyrosine kinases participate in the regulation of IL-1β, IL-6 and IL-8 expression and that these effects of Src are mediated through activation of ERK MAPK and not p38 MAPK or STAT1/STAT3 phosphorylation

The road to commercialization in Africa: lessons from developing the sickle-cell drug Niprisan

<p>Abstract</p> <p>Background</p> <p>Developing novel drugs from traditional medicinal knowledge can serve as a means to improve public health. Yet countries in sub-Saharan Africa face barriers in translating traditional medicinal knowledge into commercially viable health products. Barriers in moving along the road towards making a new drug available include insufficient manufacturing capacity; knowledge sharing between scientists and medical healers; regulatory hurdles; quality control issues; pricing and distribution; and lack of financing. The case study method was used to illustrate efforts to overcome these barriers during the development in Nigeria of Niprisan – a novel drug for the treatment of sickle cell anemia, a chronic blood disorder with few effective therapies.</p> <p>Discussion</p> <p>Building on the knowledge of a traditional medicine practitioner, Nigeria’s National Institute for Pharmaceutical Research and Development (NIPRD) developed the traditional herbal medicine Niprisan. The commercialization of Niprisan reached a number of commercial milestones, including regulatory approval in Nigeria; securing US-based commercial partner XeChem; demonstrating clinical efficacy and safety; being awarded orphan drug status by the US Food and Drug Administration; and striking important relationships with domestic and international groups. Despite these successes, however, XeChem did not achieve mainstream success for Niprisan in Nigeria or in the United States. A number of reasons, including inconsistent funding and manufacturing and management challenges, have been put forth to explain Niprisan’s commercial demise. As of this writing, NIPRD is considering options for another commercial partner to take the drug forward.</p> <p>Summary</p> <p>Evidence from the Niprisan experience suggests that establishing benefit-sharing agreements, fostering partnerships with established research institutions, improving standardization and quality control, ensuring financial and managerial due diligence, and recruiting entrepreneurial leaders capable of holding dual scientific and business responsibilities should be incorporated into future drug development initiatives based on traditional medicines. Country-level supporting policies and conditions are also important. With more experience and support, and an improved environment for innovation, developing new drugs from traditional medicines may be an attractive approach to addressing diseases in sub-Saharan Africa and other regions.</p

Lessons on Ethical Decision Making from the Bioscience Industry

Mackie and colleagues performed over 100 interviews with managers and executives at 13 bioscience companies to learn about bioindustry ethics from their perspective

Photometry of Kuiper belt object (486958) Arrokoth from New Horizons LORRI

On January 1st 2019, the New Horizons spacecraft flew by the classical Kuiper belt object (486958) Arrokoth (provisionally designated 2014 MU69), possibly the most primitive object ever explored by a spacecraft. The I/F of Arrokoth is analyzed and fit with a photometric function that is a linear combination of the Lommel-Seeliger (lunar) and Lambert photometric functions. Arrokoth has a geometric albedo of p_v = 0.21_(−0.04)^(+0.05) at a wavelength of 550 nm and ≈0.24 at 610 nm. Arrokoth's geometric albedo is greater than the median but consistent with a distribution of cold classical Kuiper belt objects whose geometric albedos were determined by fitting a thermal model to radiometric observations. Thus, Arrokoth's geometric albedo adds to the orbital and spectral evidence that it is a cold classical Kuiper belt object. Maps of the normal reflectance and hemispherical albedo of Arrokoth are presented. The normal reflectance of Arrokoth's surface varies with location, ranging from ≈0.10–0.40 at 610 nm with an approximately Gaussian distribution. Both Arrokoth's extrema dark and extrema bright surfaces are correlated to topographic depressions. Arrokoth has a bilobate shape and the two lobes have similar normal reflectance distributions: both are approximately Gaussian, peak at ≈0.25 at 610 nm, and range from ≈0.10–0.40, which is consistent with co-formation and co-evolution of the two lobes. The hemispherical albedo of Arrokoth varies substantially with both incidence angle and location, the average hemispherical albedo at 610 nm is 0.063 ± 0.015. The Bond albedo of Arrokoth at 610 nm is 0.062 ± 0.015

Altered Hyperlipidemia, Hepatic Steatosis, and Hepatic Peroxisome Proliferator-Activated Receptors in Rats with Intake of Tart Cherry

ABSTRACT Elevated plasma lipids, glucose, insulin, and fatty liver are among components of metabolic syndrome, a phenotypic pattern that typically precedes the development of Type 2 diabetes. Animal studies show that intake of anthocyanins reduces hyperlipidemia, obesity, and atherosclerosis and that anthocyanin-rich extracts may exert these effects in association with altered activity of tissue peroxisome proliferator-activated receptors (PPARs). However, studies are lacking to test this correlation using physiologically relevant, whole food sources of anthocyanins. Tart cherries are a rich source of anthocyanins, and whole cherry fruit intake may also affect hyperlipidemia and/or affect tissue PPARs. This hypothesis was tested in the Dahl Salt-Sensitive rat having insulin resistance and hyperlipidemia. For 90 days, Dahl rats were pair-fed AIN-76a-based diets supplemented with either 1% (wt:wt) freeze-dried whole tart cherry or with 0.85% additional carbohydrate to match macronutrient and calorie provision. After 90 days, the cherry-enriched diet was associated with reduced fasting blood glucose, hyperlipidemia, hyperinsulinemia, and reduced fatty liver. The cherry diet was also associated with significantly enhanced hepatic PPAR-α mRNA, enhanced hepatic PPAR-α target acyl-coenzyme A oxidase mRNA and activity, and increased plasma antioxidant capacity. In conclusion, physiologically relevant tart cherry consumption reduced several phenotypic risk factors that are associated with risk for metabolic syndrome and Type 2 diabetes. Tart cherries may represent a whole food research model of the health effects of anthocyanin-rich foods and may possess nutraceutical value against risk factors for metabolic syndrome and its clinical sequelae.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63187/1/jmf.2007.658.pd

Intra- and inter-pandemic variations of antiviral, antibiotics and decongestants in wastewater treatment plants and receiving rivers

The concentration of eleven antibiotics (trimethoprim, oxytetracycline, ciprofloxacin, azithromycin, cefotaxime, doxycycline, sulfamethoxazole, erythromycin, clarithromycin, ofloxacin, norfloxacin), three decongestants (naphazoline, oxymetazoline, xylometazoline) and the antiviral drug oseltamivir’s active metabolite, oseltamivir carboxylate (OC), were measured weekly at 21 locations within the River Thames catchment in England during the month of November 2009, the autumnal peak of the influenza A[H1N1]pdm09 pandemic. The aim was to quantify the pharmaceutical response to the pandemic and compare this to drug use during the late pandemic (March 2010) and the inter-pandemic periods (May 2011). A large and small wastewater treatment plant (WWTP) were sampled in November 2009 to understand the differential fate of the analytes in the two WWTPs prior to their entry in the receiving river and to estimate drug users using a wastewater epidemiology approach. Mean hourly OC concentrations in the small and large WWTP’s influent were 208 and 350 ng/L (max, 2070 and 550 ng/L, respectively). Erythromycin was the most concentrated antibiotic measured in Benson and Oxford WWTPs influent (max = 6,870 and 2,930 ng/L, respectively). Napthazoline and oxymetazoline were the most frequently detected and concentrated decongestant in the Benson WWTP influent (1650 and 67 ng/L) and effluent (696 and 307 ng/L), respectively, but were below detection in the Oxford WWTP. OC was found in 73% of November 2009’s weekly river samples (max = 193 ng/L), but only in 5% and 0% of the late- and inter-pandemic river samples, respectively. The mean river concentration of each antibiotic during the pandemic largely fell between 17–74 ng/L, with clarithromycin (max = 292 ng/L) and erythromycin (max = 448 ng/L) yielding the highest single measure. In general, the concentration and frequency of detecting antibiotics in the river increased during the pandemic. OC was uniquely well-suited for the wastewater epidemiology approach owing to its nature as a prodrug, recalcitrance and temporally- and spatially-resolved prescription statistics