Ecstasy: 3,4-Methylenedioxymethamphetamine (MDMA)

This is the published version. Copyright 1998 International Union of CrystallographyThe crystal structure of 3,4-methylenedioxymethamphetamine {systematic name: N-methyl-l-[3,4-(methylenedioxy) phenyl]-2-aminopropane } hydrochloride, C 11H 15 - NO2.HC1, also known as 'ecstasy' or MDMA, has been determined by X-ray diffraction

Systematic Analysis of Gene Expression Differences between Left and Right Atria in Different Mouse Strains and in Human Atrial Tissue

Background: Normal development of the atria requires left-right differentiation during embryonic development. Reduced expression of Pitx2c (paired-like homeodomain transcription factor 2, isoform c), a key regulator of left-right asymmetry, has recently been linked to atrial fibrillation. We therefore systematically studied the molecular composition of left and right atrial tissue in adult murine and human atria. Methods: We compared left and right atrial gene expression in healthy, adult mice of different strains and ages by employing whole genome array analyses on freshly frozen atrial tissue. Selected genes with enriched expression in either atrium were validated by RT-qPCR and Western blot in further animals and in shock-frozen left and right atrial appendages of patients undergoing open heart surgery. Results: We identified 77 genes with preferential expression in one atrium that were common in all strains and age groups analysed. Independent of strain and age, Pitx2c was the gene with the highest enrichment in left atrium, while Bmp10, a member of the TGFb family, showed highest enrichment in right atrium. These differences were validated by RT-qPCR in murine and human tissue. Western blot showed a 2-fold left-right concentration gradient in PITX2 protein in adult human atria. Several of the genes and gene groups enriched in left atria have a known biological role for maintenance of healthy physiology, specifically the prevention of atrial pathologies involved in atrial fibrillation, including membrane electrophysiology, metabolic cellular function, and regulation of inflammatory processes. Comparison of the array datasets with published array analyses in heterozygous Pitx2c+/2 atria suggested that approximately half of the genes with left-sided enrichment are regulated by Pitx2c. Conclusions: Our study reveals systematic differences between left and right atrial gene expression and supports the hypothesis that Pitx2c has a functional role in maintaining ‘‘leftness’’ in the atrium in adult murine and human hearts

Kahr, Charles H. Jr., Vita, Engineer's Council for Professional Development

NPS 1959 Professors in Engineer's Council for Professional DevelopmentNPS 1959 Professors in Engineer's Council for Professional Developmen

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

Fairness als zentrale Herausforderung moderner Aufnahmeverfahren

In der Praxis wird zumeist angenommen, dass die Ergebnisse in einem Aufnahmeverfahren individuelle Unterschiede in den zu erfassenden Fähigkeiten fair messen. Der vorliegende Beitrag gibt einen Überblick über Modelle zur Fairness von Aufnahmeverfahren und deren Überprüfung in der Praxis anhand von Beispielen zum Aufnahmeverfahren für Medizinische Studiengänge in Österreich (MedAT). Der Beitrag arbeitet zudem auch den engen Zusammenhang zwischen Fairness und anderen Gütekriterien heraus und veranschaulicht die Vorteile einer stark theoriegeleiteten automatischen Itemgenerierung (AIG), um auf die erhöhten Qualitätsanforderungen bei modernen Aufnahmeverfahren reagieren zu können

Intracellular trafficking, localization, and mobilization of platelet-borne thiol isomerases

OBJECTIVE: Thiol isomerases facilitate protein folding in the endoplasmic reticulum, and several of these enzymes, including protein disulfide isomerase and ERp57, are mobilized to the surface of activated platelets, where they influence platelet aggregation, blood coagulation, and thrombus formation. In this study, we examined the synthesis and trafficking of thiol isomerases in megakaryocytes, determined their subcellular localization in platelets, and identified the cellular events responsible for their movement to the platelet surface on activation. APPROACH AND RESULTS: Immunofluorescence microscopy imaging was used to localize protein disulfide isomerase and ERp57 in murine and human megakaryocytes at various developmental stages. Immunofluorescence microscopy and subcellular fractionation analysis were used to localize these proteins in platelets to a compartment distinct from known secretory vesicles that overlaps with an inner cell-surface membrane region defined by the endoplasmic/sarcoplasmic reticulum proteins calnexin and sarco/endoplasmic reticulum calcium ATPase 3. Immunofluorescence microscopy and flow cytometry were used to monitor thiol isomerase mobilization in activated platelets in the presence and absence of actin polymerization (inhibited by latrunculin) and in the presence or absence of membrane fusion mediated by Munc13-4 (absent in platelets from Unc13dJinx mice). CONCLUSIONS: Platelet-borne thiol isomerases are trafficked independently of secretory granule contents in megakaryocytes and become concentrated in a subcellular compartment near the inner surface of the platelet outer membrane corresponding to the sarco/endoplasmic reticulum of these cells. Thiol isomerases are mobilized to the surface of activated platelets via a process that requires actin polymerization but not soluble N-ethylmaleimide-sensitive fusion protein attachment receptor/Munc13-4-dependent vesicular-plasma membrane fusion

Steepening of waves at the duskside magnetopause

Surface waves at the magnetopause flanks typically feature steeper, i.e., more inclined leading (antisunward facing) than trailing (sunward facing) edges. This is expected for Kelvin‐Helmholtz instability (KHI) amplified waves. Very rarely, during northward interplanetary magnetic field (IMF) conditions, anomalous/inverse steepening has been observed. The small‐scale tetrahedral configuration of the Magnetospheric Multiscale spacecraft and their high time resolution measurements enable us to routinely ascertain magnetopause boundary inclinations during surface wave passage with high accuracy by four‐spacecraft timing analysis. At the dusk flank magnetopause, 77%/23% of the analyzed wave intervals exhibit regular/inverse steepening. Inverse steepening happens during northward IMF conditions, as previously reported and, in addition, during intervals of dominant equatorial IMF. Inverse steepening observed under the latter conditions may be due to the absence of KHI or due to instabilities arising from the alignment of flow and magnetic fields in the magnetosheath.Key PointsThe MMS spacecraft configuration, orbits, and data resolution enable us to ascertain magnetopause (wave) inclinations with high accuracyInverse wave steepening (steeper trailing edges) occurs also when the IMF is in the GSM x‐y plane, not only during mainly northward IMFInverse steepening may be associated to the absence of KHI or to instabilities from the alignment of flow and magnetic fields in the sheathPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134254/1/grl54723.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134254/2/grl54723_am.pd

A route to high surface area, porosity and inclusion of large molecules in crystals

One of the outstanding challenges in the field of porous materials is the design and synthesis of chemical structures with exceptionally high surface areas(1). Such materials are of critical importance to many applications involving catalysis, separation and gas storage. The claim for the highest surface area of a disordered structure is for carbon, at 2,030 m(2) g(-1) (ref. 2). Until recently, the largest surface area of an ordered structure was that of zeolite Y, recorded at 904 m(2) g(-1) (ref. 3). But with the introduction of metal-organic framework materials, this has been exceeded, with values up to 3,000 m(2) g(-1) (refs 4-7). Despite this, no method of determining the upper limit in surface area for a material has yet been found. Here we present a general strategy that has allowed us to realize a structure having by far the highest surface area reported to date. We report the design, synthesis and properties of crystalline Zn4O(1,3,5-benzenetribenzoate)(2), a new metal-organic framework with a surface area estimated at 4,500 m(2) g(-1). This framework, which we name MOF-177, combines this exceptional level of surface area with an ordered structure that has extra-large pores capable of binding polycyclic organic guest molecules-attributes not previously combined in one material.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62609/1/nature02311.pd

Impact of tunable oligophosphonates on barium sulfate crystallization

Calixarenes can be used as well-defined scaffolds for investigating structure–activity relationships of additives and their impact on crystallization. In this work, we present the crystal growth modification of barium sulfate by p-phosphonic acid calix[n]arenes that vary in size (n = 4, 5, 6, and 8) and thus vary in the size of the internal cavity for the same functionality in the upper rim. The tetrameric, hexameric, and octameric macrocycles induce nanoparticle formation with clear superstructure. In the case of the hexameric calix[6]arene, the initial mesocrystalline superstructure fuses over time to form almost hollow spheres, while the mesocrystals formed in the presence of the tetramer and octamer are stable over an extended period. The pentameric calix[5]arene forms more disordered aggregates of single crystals. Thermogravimetric data shows that a significant proportion of the mass of the barium sulfate-containing solid is the macrocycle, regardless of the choice of macrocycle

Novel Anti-bacterial Activities of β-defensin 1 in Human Platelets: Suppression of Pathogen Growth and Signaling of Neutrophil Extracellular Trap Formation

Human β-defensins (hBD) are antimicrobial peptides that curb microbial activity. Although hBD's are primarily expressed by epithelial cells, we show that human platelets express hBD-1 that has both predicted and novel antibacterial activities. We observed that activated platelets surround Staphylococcus aureus (S. aureus), forcing the pathogens into clusters that have a reduced growth rate compared to S. aureus alone. Given the microbicidal activity of β-defensins, we determined whether hBD family members were present in platelets and found mRNA and protein for hBD-1. We also established that hBD-1 protein resided in extragranular cytoplasmic compartments of platelets. Consistent with this localization pattern, agonists that elicit granular secretion by platelets did not readily induce hBD-1 release. Nevertheless, platelets released hBD-1 when they were stimulated by α-toxin, a S. aureus product that permeabilizes target cells. Platelet-derived hBD-1 significantly impaired the growth of clinical strains of S. aureus. hBD-1 also induced robust neutrophil extracellular trap (NET) formation by target polymorphonuclear leukocytes (PMNs), which is a novel antimicrobial function of β-defensins that was not previously identified. Taken together, these data demonstrate that hBD-1 is a previously-unrecognized component of platelets that displays classic antimicrobial activity and, in addition, signals PMNs to extrude DNA lattices that capture and kill bacteria