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Ulcerative colitis is a chronic condition in which a dysregulated immune response contributes to the acute intestinal inflammation of the colon. Current clinical therapies often exhibit limited efficacy and undesirable side effects. Here, programmable nanomicelles were designed for colitis treatment and loaded with RU.521, an inhibitor of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. STING-inhibiting micelles (SIMs) comprise hyaluronic acid-stearic acid conjugates and include a reactive oxygen species (ROS)-responsive thioketal linker. SIMs were designed to selectively accumulate at the site of inflammation and trigger drug release in the presence of ROS. Our in vitrostudies in macrophages and in vivostudies in a murine model of colitis demonstrated that SIMs leverage HA-CD44 binding to target sites of inflammation. Oral delivery of SIMs to mice in both preventive and delayed therapeutic models ameliorated colitis’s severity by reducing STING expression, suppressing the secretion of proinflammatory cytokines, enabling bodyweight recovery, protecting mice from colon shortening, and restoring colonic epithelium. In vivoend points combined with metabolomics identified key metabolites with a therapeutic role in reducing intestinal and mucosal inflammation. Our findings highlight the significance of programmable delivery platforms that downregulate inflammatory pathways at the intestinal mucosa for managing inflammatory bowel diseases.

Biological transformation unlocks untapped potential for innovative, high-value products. Bifunctional assemblies enable diverse functionalities through modular combinations of biobased modules and offer the potential for cost-efficient and environmentally friendly functionalization of components. Component functionalization can be applied in industries with high economic and technological potential and societal relevance. In medical technology, for example, bifunctional assemblies have the potential to apply an antimicrobial coating to implants to ward off bacterial contamination of the surface. At present bifunctional assemblies have not yet been used in manufacturing in a scalable manner. Therefore, it is not possible to exploit these potentials because, from a manufacturing technology perspective, bifunctional assemblies are a new class of materials and therefore pose new requirements for manufacturing technology. It is not sufficiently known which manufacturing technologies can apply bifunctional assemblies to components in a scalable manner, i.e. over large areas, homogeneously and in large quantities. To identify biocompatible manufacturing technologies potentially suitable for the application of bifunctional assemblies to components, a description model is needed that provides technology-related manufacturing requirements of bifunctional assemblies. This work contributes to the systematic identification and quantification of these technology-related manufacturing requirements.

Graphical Abstract:

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illus por, Reprinted from Jan-Feb 1969 edition of Armor

(men's) OFFSET: 4mm PRICE; $135 OFFSET: Omm PRICE: $135 PRICE: $140 0 SAUCONY KINVARA 12 FIT; CUSHION; PERFORMANCE; BASICS: A lighter, simplified upper with added ground contact to smooth out the ride PROS Just enough impact protection Neutral barefootlike feel and wide toe box CONS May lull newbies into overdoing it Less cushioning than some WEIGHT: 7.5oz. [Extracted from the article]

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The GenoType Diet: Change Your Genetic Destiny to Live the Longest, Fullest and Healthiest Life Possible by Dr. Peter J. D'Adamo, with Catherine Whitney Broadway Books, 1745 Broadway, New York, [...]

The article reviews bicycles for triathletes by bike manufacturers including Felt IA 2 by Felt Bicycles, Kestrel 4000 Shimano 105 by Kestrel Bicycles, and Specialized Shiv Expert by Specialized Bicycle Components.

The objective of the study was to evaluate incidence of and risk factors for sepsis following peripherally inserted central catheter (PICC) removal. The retrospective cohort study looked at neonatal intensive care unit patients with PICC placement between February 2003 and June 2010 at a single medical center in the United States. Results showed that 14216 patients (6.5) had sepsis within 5 days of PICC removal. PICC removal because of adverse events was significantly associated with sepsis (P= .017). Antibiotic use before PICC removal did not have a significant impact on sepsis. The conclusions of the study are that removal of PICCs because of adverse events is significantly associated with late-onset neonatal sepsis and that antibiotic use at the time of PICC removal is not associated with a decline in sepsis rate.

The article evaluates several bicycles for triathletes, including the Cervélo P2, Cannondale Slice 5 105 and Fuji Norcom Straight 2.3.

Se analizaron las creencias de docentes de educación básica acerca del bullying, para lo cual se seleccionaron las tres escuelas secundarias públicas de Sonora donde se encontró la mayor frecuencia de reportes de bullyingpor los estudiantes en un estudio previo realizado por Valdés et al. (2013). Participaron 45 docentes de estas escuelas, 15 fueron entrevistados y el resto respondió una encuesta con preguntas abiertas. Los docentes definieron el bullyingcomo violencia directa, que involucra a estudiantes u otros actores. Consideran de forma no sistémica la acción de los factores asociados al bullyingy ubican en la familia y el contexto social la explicación del fenómeno. Desplazan la responsabilidad de las intervenciones hacia otros actores y consideran estrategias de intervención aisladas. Se concluye que las creencias de los docentes acerca del bullyingreducen el margen de acción para que este problema reciba atención en el ámbito escolar.

El estudio tuvo como objetivo definir perfiles de estudiantes de posgrado en ciencias e ingenierías con base en su percepción de la importancia y desarrollo de competencias científicas. Utilizando un muestreo aleatorio simple se seleccionaron 146 estudiantes de posgrado de tres instituciones de educación superior de Sonora. Se les administró un cuestionario para medir su percepción acerca de la importancia de las competencias científicas en sus currículos y el desarrollo alcanzado en las mismas. Con una prueba de conglomerados no jerárquicos K-medias se identificaron dos perfiles. El primero, integrado por 112 (76.7%) de los estudiantes, se definió como “Perfil Académico Deseado”, y el segundo al que se denominó “Perfil Académico Mejorable” incluyó a 34 estudiantes (23.3%). El primer perfil se caracterizó por percibir mayor importancia en las competencias científicas de sus currículos y el desarrollo alcanzado en las mismas; además, refirieron mayor participación en proyectos de investigación y productividad académica.

ABSTRACTqnrgenes are plasmid-mediated quinolone resistance genes mainly harbored on large conjugative multiresistant plasmids. The qnrDgene was recently observed in Salmonella entericaon a small nonconjugative plasmid (p2007057). We describe two strains of Providencia rettgeriharboring qnrDon nonconjugative plasmids. The plasmids were 99% identical, with 2,683 bp and four open reading frames, including qnrD, but exhibited only 53% identity with the plasmid found in S. enterica.

This article reports the results of an industrial case study demonstrating the efficacy of a model-based testing process in assuring the quality of highly configurable systems from the automation domain. Escalating demand for flexibility has made modern embedded software systems highly configurable. This configurability is often realized through parameters and a highly configurable system possesses a handful of those. Small changes in parameter values can account for significant changes in the system’s behavior, whereas in other cases, changed parameters may not result in any perceivable reaction. This case study addresses the challenge of applying model-based testing to configurable embedded software systems to reduce development effort. As a result of the case study, a model-based testing process was developed and tailored toward the needs of the automation domain. This process integrates existing model-based testing methods and tools, such as combinatorial design and constraint processing. The testing process was applied as part of the case study and analyzed in terms of its actual saving potentials, which reduced the testing effort by more than a third.

The energy consumption of industrial wireless devices and the resulting requirement for battery changes is one of the limiting factors of this technology. In this paper, an overview over the special requirements of wireless systems with a focus on energy consumption is given. This is then matched against the possibilities provided by energy harvesting in an industrial environment in order to evaluate the feasibility of fully autonomous devices. Experimental results from the deployment of energy harvesting methods in a simulated process as well as results from an integrated autonomous temperature transmitter are given.

The article presents training guides for triathletes. When training alone, athletes can assess their swimming techniques by creating a video and then watching the video to check on mistakes. Gadgets such as multifunctional running computers, training DVDs and music can help athletes avoid boredom. To train running indoors, athletes can use several trainers such as wind trainers and fluid and magnetic resistance trainers.

Academic detailing is a medical education outreach service that typically features in-person individualized discussion of therapeutic decisions. The onset of the SARS-CoV2 (COVID-19) pandemic compelled many existing academic detailing services to switch to providing their services virtually. This format switch brought opportunities and challenges to detailing programs across North America. Technology enabled programs to continue, but adaptations were necessary, including communication style changes enabling automated booking, and optimizing support materials for a virtual environment. Specifically, communication decisions, including when to screen share and strategies to encourage two-way communication must be addressed to maintain the advantage of a discussion format. As pandemic limitations resolve, and academic detailing services move forward, it is important consider advantages and challenges of virtual academic detailing, and how pandemic work will inform future approaches to academic detailing that may blend in person and virtual outreach.

Cryptococcus neoformans is a fungal pathogen that is responsible for life-threatening disease, particularly in the context of compromised immunity. This organism makes extensive use of mannose in constructing its cell wall, glycoproteins, and glycolipids. Mannose also comprises up to two-thirds of the main cryptococcal virulence factor, a polysaccharide capsule that surrounds the cell. The glycosyltransfer reactions that generate cellular carbohydrate structures usually require activated donors such as nucleotide sugars. GDP-mannose, the mannose donor, is produced in the cytosol by the sequential actions of phosphomannose isomerase, phosphomannomutase, and GDP-mannose pyrophosphorylase. However, most mannose-containing glycoconjugates are synthesized within intracellular organelles. This topological separation necessitates a specific transport mechanism to move this key precursor across biological membranes to the appropriate site for biosynthetic reactions. We have discovered two GDP-mannose transporters in C. neoformans, in contrast to the single such protein reported previously for other fungi. Biochemical studies of each protein expressed in Saccharomyces cerevisiae show that both are functional, with similar kinetics and substrate specificities. Microarray experiments indicate that the two proteins Gmt1 and Gmt2 are transcribed with distinct patterns of expression in response to variations in growth conditions. Additionally, deletion of the GMT1 gene yields cells with small capsules and a defect in capsule induction, while deletion of GMT2 does not alter the capsule. We suggest that C. neoformans produces two GDP-mannose transporters to satisfy its enormous need for mannose utilization in glycan synthesis. Furthermore, we propose that the two proteins have distinct biological roles. This is supported by the different expression patterns of GMT1 and GMT2 in response to environmental stimuli and the dissimilar phenotypes that result when each gene is deleted.

ABSTRACTCryptococcus neoformansis a fungal pathogen that is responsible for life-threatening disease, particularly in the context of compromised immunity. This organism makes extensive use of mannose in constructing its cell wall, glycoproteins, and glycolipids. Mannose also comprises up to two-thirds of the main cryptococcal virulence factor, a polysaccharide capsule that surrounds the cell. The glycosyltransfer reactions that generate cellular carbohydrate structures usually require activated donors such as nucleotide sugars. GDP-mannose, the mannose donor, is produced in the cytosol by the sequential actions of phosphomannose isomerase, phosphomannomutase, and GDP-mannose pyrophosphorylase. However, most mannose-containing glycoconjugates are synthesized within intracellular organelles. This topological separation necessitates a specific transport mechanism to move this key precursor across biological membranes to the appropriate site for biosynthetic reactions. We have discovered two GDP-mannose transporters in C. neoformans, in contrast to the single such protein reported previously for other fungi. Biochemical studies of each protein expressed in Saccharomyces cerevisiaeshow that both are functional, with similar kinetics and substrate specificities. Microarray experiments indicate that the two proteins Gmt1 and Gmt2 are transcribed with distinct patterns of expression in response to variations in growth conditions. Additionally, deletion of the GMT1gene yields cells with small capsules and a defect in capsule induction, while deletion of GMT2does not alter the capsule. We suggest that C. neoformansproduces two GDP-mannose transporters to satisfy its enormous need for mannose utilization in glycan synthesis. Furthermore, we propose that the two proteins have distinct biological roles. This is supported by the different expression patterns of GMT1and GMT2in response to environmental stimuli and the dissimilar phenotypes that result when each gene is deleted.

The agaric Crinipellis perniciosa (Tricholomataceae) is a hemibiotrophic pathogen which causes witches' broom disease of cacao and has recently decimated the Brazilian cacao industry. In addition to the pathogenic cacao (C-) biotype, other biotypes are found in association with unrelated plant taxa, notably bignoniaceous lianas (L-biotype), solanaceous hosts (S -biotype), and the shrub Heteropterys acutifolia (H-biotype). The C-and S-biotypes are non-outcrossing and form broom symptoms on hosts, whereas the L-biotype is outcrossing and asymptomatic. Phylogenetic analysis of several regions of the rRNA locus revealed near identity between C- and S-biotype isolates from diverse locations, with the L- and H-biotypes forming separate groupings. Preliminary analysis of sequence data from Moniliophthora roreri, causal agent of frosty pod disease, indicates that this morphologically distinct pathogen may be closely related to C. perniciosa. Similarities in host infection between C. perniciosa and M. roreri have previously been noted but it is difficult to reconcile the gross morphological differences. Pairings between C. perniciosa and M. roreri gave rise to a clamped dikaryotic mycelium suggestive of a hybridisation event.

Macfadyena unguis‐cati(L.) has been widely used in folk medicine as an anti‐inflammatory, antimalarial and antivenereal. The purpose of this study was to chemically characterize the main plant components, and to evaluate the biological properties of some of the fractions derived from leaves (MACb) and liana (MACa) of this plant.

This research study evaluated a new bed utilization program established in the surgical nursing section at a major military medical facility. The study involved four wards with 83 beds before the new system was implemented, and three wards with 71 beds after the implementation. Five variables were identified as having an effect on the bed management program. These variables were time of discharge, escort compliance, bed availability, staff satisfaction, and patient satisfaction. Both a paired t test and an independent t test were applied for statistical analysis at the 0.05 level of significance. Data were collected for 1 month at two different intervals for comparison, using two surveys, patient records, 24-hour nursing reports, and same-day surgical schedules. A sample size of 103 was used as a basis for time of discharge and staff and patient satisfaction. The staff satisfaction survey also included a demographic data sheet. Escort compliance and bed availability were based on a 30-day time frame. The sample subjects included all patients who entered the surgical nursing section and their health care providers. Data analysis revealed significant differences in escort compliance and bed availability between the pre and post data. Findings from this study support the need for a functional, efficient bed management system.

Marchantins and related compounds, isolated from different species of liverworts, were investigated for their inhibitory potential on cyclooxygenase (COX) and 5-lipoxygenase 5-(LOX), the key enzymes of the arachidonic acid cascade, and additionally in a cell-free lipid-peroxidation system. The results were compared with rate constants obtained in pulse-radiolytic studies. All substances tested showed significant inhibitory COX and 5-LOX-activity. Marchantin B with two catechol moieties, as in NDGA, exerted an enhanced inhibitory effect in all test systems. The most active compound in the 5-LOX-test was Perrottetin D (IC50= 0.66 μM), which was also effective in the COX and lipid-peroxidation assay. While the rate constant determined by pulse radiolysis was rather low, EPR studies at elevated temperatures demonstrated for perrottetin D the presence of a pyrogallol-type radical, generated by a furan-ring opening reaction. In conclusion, all compounds from liverworts investigated possess significant antiinflammatory activities. The results let us suggest that all these phenolic compounds can be considered as promising leads due to their strong radical scavenger potential.

Baeomycesic acid (1), a β-orcinol depside isolated from the lichen Thamnolia subuliformis(Ehrh.) W. Culb. was tested for in vitroinhibitory effects on arachidonate metabolism. Results showed that baeomycesic acid has potent dose-dependent inhibitory effects on 5-lipoxygenase isolated from porcine leucocytes, with an IC50value of 8.3 μM. Structure-activity relationships are discussed in comparison to other phenolic lichen constituents. Baeomycesic was inactive when tested for in vitroinhibitory effects against cyclooxygenase isolated from sheep seminal vesicle microsomes.

The presence of an alkamide in lichens is reported for the first time. The alkamide was isolated from Stereocaulon alpinumLaur. and identified through spectroscopic analysis as 9-cis-octa-decenamide (1). With reference to previously known activity of alkamides from both the plant and animal kingdoms on inflammatory processes, 1 was tested for in vitroinhibitory activity against the key enzymes of the major pathways involved in arachidonate metabolism. The compound was shown to exhibit moderate dose-dependent inhibitory activity against cyclooxygenase from sheep seminal vesicle microsomes (IC50= 64.3 μM) whilst showing only slight activity against 5-lipoxygenase from porcine leucocytes.

Five new linear acetylenic compounds, namely, pentadeca-6,8,10-triynoic acid (1), octadeca-8,10,12-triynoic acid (2), trans-pentadec-10-en-6,8-diynoic acid (3), cis-hexadec-11-en-7,9-diynoic acid (4), and cis-octadec-12-en-7,9-diynoic acid (5), were isolated from the bark of Heisteria acuminata by bioassay-guided fractionation, using cyclooxygenase (COX) and 5-lipoxygenase (5-LO) assays as models for antiinflammatory activity. The structures of compounds 1−5 were established by NMR, MS, IR, and Raman spectroscopy. These isolated compounds were found to be potent inhibitors of COX. Compounds 4 and 5 were the most potent inhibitors of 5-LO, whereas the other compounds only showed a weak inhibition at the same concentration.

Abstract:  Various studies over the last 25 years in Man and animal models have revealed many steps in the pathogenesis of myasthenia gravis (MG) which is now considered the classical organ specific, autoantibody mediated and T cell dependent human autoimmune disease. Though not a disease entity, MG is associated with pathological alterations of the thymus in about 80% of cases. These are described here with reference to distinct models of autoimmunization against the acetylcholine receptor (AChR). In MG with thymitis, intrathymic production of AChR-specific autoantibodies is the result of a classical antigen-driven immune reaction that occurs completely inside the thymus and probably involves AChR on myoid cells as the triggering (myasthenogenic) antigen. Genetic factors contribute essentially to the pathogenesis of this form of MG. In thymoma-associated MG genetic factors are probably of marginal significance. Neither intratumour autoantibody production nor T cell activation seem to occur and the AChR is not the myasthenogenic antigen. Instead, abnormal neurofilaments that share epitopes with the AChR and other autoantigen targets in paraneoplastic MG are expressed in thymomas and may trigger autoantigen-specific, non-tolerogenic T cell selection by molecular mimicry. These data support the hypothesis that initial steps in the pathogenesis of most MG cases take place within abnormal thymic microenvironments, be they inflammatory or neoplastic. Where these initial steps occur in MG cases without thymic pathology is not known. Likewise, the factors involved in the initial triggering of MG remain enigmatic in all MG subtypes.

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Zusammenfassung Die Durchbruchsbewegungen des Zahnkeims finden stets im intermediären Stadium seines Wurzelwachstums statt. Nur während dieser Entwicklungsphase besitzt die apikale Pulpa einen ausreichend großen Durchmesser, der es ihr ermöglicht, die für den Durchbruch des Zahnkeims erforderlichen expansiven Schubkräfte zu entwickeln. Biomechanisch gesehen, dienen die Milchzähne den untergeordneten bleibenden Zahnkeimen als Durchbruchszügler. Wenn durch vorzeitigen Milchzahnverlust der Frühdurchbruch des untergeordneten bleibenden Zahnkeims zu stark provoziert wird, muß in extremen Fällen mit Störungen der endogenen Reifung seiner Hartsubstanzen gerechnet werden. Bei vorzeitigem Verlust unvollständig wurzelresorbierter Milchzähne bleiben an den untergeordneten Zahnkeimen oftmals perikoronale Knochentaschen zurück, die besonders bei sagittalem Engstand des Zahnes eine vertikale Unterentwicklung seines Alveolarfortsatzes zur Folge haben können. Auch nach Einstellung des Zahnes in die Okklusion entwickelt der inzwischen stark reduzierte apikale Pulpawulst noch Durchbruchskräfte, die der endgültigen Bewältigung der physiologischen Bißhebung dienen. Selbst im ausgewachsenen Kiefer behalten die pulpavitalen Zähne noch eine permanente Durchbruchstendenz, um die zahn-intrudierende Wirkung des Kaudrucks wieder auszugleichen und dadurch die Bißhöhe zu erhalten. Für den regulären Durchbruch der bleibenden Zähne ist auch die gegenseitige Beeinflussung der Zahnkeime untereinander von Bedeutung. Bei Nichtanlage von Zahnkeimen zeigen die Nachbarzahnkeime eine geringere Eruptionspotenz, was ihren Durchbruch zeitlich beeinträchtigt und sich auf die endgültige physiologische Bißhebung nachteilig auswirken kann. Diese Zusammenhänge werden bei umfangreicher Hypodontie besonders deutlich.

Zusammenfassung Im orthognathen Wechselgebiß stellt sich der Sechsjahrmolar auf einer temporär gekrümmten Kauebene ein, die der Verfasser als primitive Speekurve bezeichnet hat. Erst nach dem Wechsel der Milchseitenzähne bezieht der Sechsjahrmolar gemeinsam mit den Prämolaren eine Position auf dem krümmungsfreien Abschnitt der Kauebene. Die permanente Speekurve wird im orthognathen Gebiß nur von dem zweiten und dem dritten Molaren gebildet. Bei angelegter Kurzkieferbasis stellt sich der Sechsjahrmolar auf einer abnormgekrümmten primitiven Speekurve ein (Frühsymptom einer noch latenten retromolaren sagittalen Kieferenge). In diesem Falle muß mit einem Platzmangel für die reguläre Einstellung des zweiten Molaren auf der permanenten Speekurve gerechnet werden. Prädestiniert für einen sagittalen Platzmangel im Molarenbereich sind alle Fälle mit überwiegend vertikalem Gesichtsschädelwachstum. Der raumbeengte zweite Molar schiebt schon während seines Durchbruches, bzw. nach Absetzen einer kieferorthopädischen Behandlung, die Seitenzähne so weit nach mesial, bis ihm eine funktionsangepaßte Einstellung auf der permanenten Speekurve möglich ist. Entsprechend dem Ausmaß seines sagittalen Platzmangels kommt es sekundär zu mehr oder weniger stark ausgeprägten Engständen oder Protrusionen im Frontzahnbereich, denen man nur mit einer geeigneten Extraktionstherapie erfolgreich begegnen kann. Im Indikationsfalle muß auch an die kieferorthopädische Extraktion des zweiten Molaren gedacht werden. Ein solcher Fall wird beschrieben.

Sera from patients with systemic lupus erythematosus and other autoimmune disorders contain antibodies against nuclear proteins. One such autoantibody system, known as Sm, reacts with antigens associated with small nuclear RNA molecules. In this paper we report the use of Sm autoantibodies to isolate a cDNA clone for the mRNA of one of these nuclear antigens. A HeLa cell cDNA library was screened by message selection followed by autoantibody reaction of cell-free translation products. This led to the identification of a cDNA clone, p281, containing sequences complementary to mRNA for an Sm autoantibody-reactive, 11,000 Mr protein. This cloned Sm antigen comigrated with the small nuclear RNA-associated protein known as "E" and reacted with four out of four Sm autoantibodies that precipitate E protein from total mRNA translation products. RNA gel blot hybridization with clone p281 DNA revealed a poly(A)+ mRNA of approximately equal to 600 nucleotides in human and marmoset (New World primate) cells. Southern blot hybridization of HeLa cell and human lymphocyte DNA indicated the presence of 6-10 copies of p281-homologous sequences. Similar copy numbers were observed with genomic DNA from baboon, cat, and mouse, indicating that the Sm antigen mRNA sequence represented in p281 is conserved across three classes of the Mammalia (primates, carnivores, and rodents). However, no cross-hybridization of p281 was observed with frog or Drosophila DNA. In light of existing evidence that the mammalian Sm antigen E is a weaker autoantigen than other small nuclear RNA-associated proteins, these results suggest a possible correlation between a protein's capacity to serve as an autoantigen during breakdown of the host's immunological tolerance and its extent of evolutionary conservation, whereas the inverse relationship applies to conventional immunity. We suspect, as have others, that this is a clue to the mechanism of autoimmunity.

This study evaluated the performance characteristics of a new research-use-only transcription-mediated amplification (TMA) assay for the detection of rRNA from Treponema pallidum. Analytical sensitivity determined using dark-field microscopy-quantitated T. pallidumwas 1.4 organisms/ml (95% confidence interval [CI], 0.7 to 6.33 organisms/ml).

Delafloxacin is a novel fluoroquinolone with activity against Gram-positive, Gram-negative, and atypical pathogens, including fluoroquinolone-nonsusceptible methicillin-resistant Staphylococcus aureus(MRSA). The microbiological results of a phase 3 clinical trial in adults with community-acquired pneumonia (CAP) comparing delafloxacin (300 mg intravenously [i.v.] with the option to switch to 450 mg orally every 12 h) to moxifloxacin (400 mg i.v.

The article evaluates several cycling shoes, including the Pearl Izumi Tri Fly IV Carbon, Fizik K1 and Louis Garneau Tri X-Lite.