In situ observation on temperature dependence of martensitic transformation and plastic deformation in superelastic NiTi shape memory alloy

Publication date: 15 November 2017
Source:Materials & Design, Volume 134
Author(s): Yao Xiao, Pan Zeng, Liping Lei, Yanzhi Zhang
In situ digital image correlation (DIC) and in situ X-ray diffraction (XRD) are applied to investigate the effect of temperature on martensitic transformation and plastic deformation in superelastic NiTi shape memory alloy. Via in situ DIC, two well-known deformation modes of NiTi are identified at various temperatures: (A) localized forward and reverse transformations with little residual strain (<1%); (B) localized forward transformation and homogenous reverse transformation with considerable residual strain (>1%). As temperature increases from 25°C to 120°C, the mechanical response of NiTi gradually transits from Type A to Type B. We verify that plastic strain accumulates concurrently as the traverse of the front of localized deformation band. Via in situ XRD observation, we conclude that it is material plasticity rather than retained martensite that plays a dominant role in the irreversibility of NiTi. The experimental results provide both macroscopic and lattice level scenarios to understand the temperature dependence of complicated thermomechanical coupling and plasticity in superelastic NiTi.

Graphical abstract

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Fabrication of poly (vinyl alcohol)/graphene nanocomposite foam based on solid state shearing milling and supercritical fluid technology

Publication date: 15 November 2017
Source:Materials & Design, Volume 134
Author(s): Pengju Liu, Wenhua Chen, Yingbin Jia, Shibing Bai, Qi Wang
Combining the nanocomposite and supercritical fluid (SCF) foaming technology develops an effective preparation method for new class of microcellular polymer nanocomposite foam, which has received much attention in both research and practice. In this paper, the poly (vinyl alcohol) (PVA)/graphene nanocomposites were successfully prepared at ambient temperature through the solid state shear milling technique, and made into foam material by using supercritical carbon dioxide as the physical blowing agent. The results indicated that graphene sheets were uniformly incorporated into the PVA matrix after milling, and graphene sheets did not reaggregate in the subsequent melting process. These well-dispersed PVA/graphene nanocomposites presented significant increases in tensile strength and thermal behavior compared to pure PVA. In the SCF foaming procedure, graphene sheets acted as the heterogeneous sites to facilitate the bubble nucleation process. More importantly, the embedded graphene sheets played an effective role of reinforcing the cell walls to stabilize the cellular structure during the cell growth stage, thus compressive properties of the nanocomposite foams were significantly enhanced. The bubbles tended to be elongated along the direction of CO2 decompression at a relatively high foaming temperature and with fast depressurization rate.

Graphical abstract

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Structure and properties of silkworm cocoon (Bombyx mori) treated by hot pressing

Publication date: 15 November 2017
Source:Materials & Design, Volume 134
Author(s): Tao Wang, Lanlan Chen, Lingmei Du, Tingting Shen, Fei Li, Lan Huang, Zhi Li, Dayang Wu
The silkworm cocoon has outstanding mechanical properties due to the specific composite structure. However, the individual cocoon is small and irregular in shape which dramatically hinders its application in artificial composites. Here, rectangular pieces of silkworm cocoons were cut and combined into large sheets by means of hot pressing. The structure and properties of compressed cocoon pieces were investigated. The thickness and porosity of pieces are significantly decreased at the high pressure, besides silk fibers are more deformed and bonded at high temperature cause of sericin's softening and fusion. Tensile strength and modulus are remarkably increased compared to those of the raw cocoon, and so do the interlayer bonding. The stable thermal property of the compressed cocoons demonstrates that compression at a high temperature has little harm to cocoons. Therefore, hot pressing is a practical way to build artificial cocoon composites for engineering applications.

Graphical abstract

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Effect of hatch length on the development of microstructure, texture and residual stresses in selective laser melted superalloy Inconel 718

Publication date: 15 November 2017
Source:Materials & Design, Volume 134
Author(s): Naresh Nadammal, Sandra Cabeza, Tatiana Mishurova, Tobias Thiede, Arne Kromm, Christoph Seyfert, Lena Farahbod, Christoph Haberland, Judith Ann Schneider, Pedro Dolabella Portella, Giovanni Bruno
In the present study, samples fabricated by varying the deposition hatch length during selective laser melting of nickel based superalloy Inconel 718 were investigated. Microstructure and texture of these samples was characterized using scanning electron microscopy, combined with electron back-scattered diffraction, and residual stress assessment, using neutron diffraction method. Textured columnar grains oriented along the sample building direction were observed in the shorter hatch length processed sample. A ten-fold increase in the hatch length reduced the texture intensity by a factor of two attributed to the formation of finer grains in the longer hatch length sample. Larger gradients of transverse residual stress in the longer hatch length sample were also observed. Along the build direction, compressive stresses in the shorter hatch length and negligible stresses for the longer hatch length specimen were observed. Changes to the temperature gradient (G) in response to the hatch length variation, influenced the G to growth rate (R) ratio and the product G×R, in agreement with the microstructures and textures formed. For the residual stress development, geometry of the part also played an important role. In summary, tailored isotropy could be induced in Inconel 718 by a careful selection of parameters during selective laser melting.

Graphical abstract

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Factors associated with routine childhood vaccine uptake and reasons for non-vaccination in India: 1998–2008

Publication date: Available online 24 August 2017
Source:Vaccine
Author(s): Mark Rohit Francis, Hanna Nohynek, Heidi Larson, Vinohar Balraj, Venkata Raghava Mohan, Gagandeep Kang, J. Pekka Nuorti
BackgroundDespite almost three decades of the Universal Immunization Program in India, a little more than half the children aged 12–23months receive the full schedule of routine vaccinations. We examined socio-demographic factors associated with partial-vaccination and non-vaccination and the reasons for non-vaccination among Indian children during 1998 and 2008.MethodsData from three consecutive, nationally-representative, District Level Household and Facility Surveys (1998–99, 2002–04 and 2007–08) were pooled. Multinomial logistic regression was used to identify individual and household level socio-demographic variables associated with the child's vaccination status. The mother's reported reasons for non-vaccination were analyzed qualitatively, adapting from a previously published framework.ResultsThe pooled dataset contained information on 178,473 children 12–23months of age; 53%, 32% and 15% were fully vaccinated, partially vaccinated and unvaccinated respectively. Compared with the 1998–1999 survey, children in the 2007–2008 survey were less likely to be unvaccinated (Adjusted Prevalence Odds Ratio (aPOR): 0.92, 95%CI=0.86–0.98) but more likely to be partially vaccinated (aPOR: 1.58, 95%CI=1.52–1.65). Vaccination status was inversely associated with female gender, Muslim religion, lower caste, urban residence and maternal characteristics such as lower educational attainment, non-institutional delivery, fewer antenatal care visits and non-receipt of maternal tetanus vaccination. The mother's reported reasons for non-vaccination indicated gaps in awareness, acceptance and affordability (financial and non-financial costs) related to routine vaccinations.ConclusionsPersisting socio-demographic disparities related to partial-vaccination and non-vaccination were associated with important childhood, maternal and household characteristics. Further research investigating the causal pathways through which maternal and social characteristics influence decision-making for childhood vaccinations is needed to improve uptake of routine vaccination in India. Also, efforts to increase uptake should address parental fears related to vaccination to improve trust in government health services as part of ongoing social mobilization and communication strategies.



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Vaccine exemptions and the kindergarten vaccination coverage gap

Publication date: Available online 24 August 2017
Source:Vaccine
Author(s): Philip J. Smith, Jana Shaw, Ranee Seither, Adriana Lopez, Holly A. Hill, Mike Underwood, Cynthia Knighton, Zhen Zhao, Megha Shah Ravanam, Stacie Greby, Walter A. Orenstein
BackgroundVaccination requirements for kindergarten entry vary by state, but all states require 2 doses of measles containing vaccine (MCV) at kindergarten entry.ObjectiveTo assess (i) national MCV vaccination coverage for children who had attended kindergarten; (ii) the extent to which undervaccination after kindergarten entry is attributable to parents' requests for an exemption; (iii) the extent to which undervaccinated children had missed opportunities to be administered missing vaccine doses among children whose parent did not request an exemption; and (iv) the vaccination coverage gap between the "highest achievable" MCV coverage and actual MCV coverage among children who had attended kindergarten.MethodsA national survey of 1465 parents of 5–7year-old children was conducted during October 2013 through March 2014. Vaccination coverage estimates are based provider-reported vaccination histories. Children have a "missed opportunity" for MCV if they were not up-to-date and if there were dates on which other vaccines were administered but not MCV. The "highest achievable" MCV vaccination coverage rate is 100% minus the sum of the percentages of (i) undervaccinated children with parents who requested an exemption; and (ii) undervaccinated children with parents who did not request an exemption and whose vaccination statuses were assessed during a kindergarten grace period or period when they were provisionally enrolled in kindergarten.ResultsAmong all children undervaccinated for MCV, 2.7% were attributable to having a parent who requested an exemption. Among children who were undervaccinated for MCV and whose parent did not request an exemption, 41.6% had a missed opportunity for MCV. The highest achievable MCV coverage was 98.6%, actual MCV coverage was 90.9%, and the kindergarten vaccination gap was 7.7%.ConclusionVaccination coverage may be increased by schools fully implementing state kindergarten vaccination laws, and by providers assessing children's vaccination status at every clinic visit, and administering missed vaccine doses.



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Evaluation of the RumiWatchSystem for measuring grazing behaviour of cows

Publication date: Available online 24 August 2017
Source:Journal of Neuroscience Methods
Author(s): J. Werner, L. Leso, C. Umstatter, J. Niederhauser, E. Kennedy, A. Geoghegan, L. Shalloo, M. Schick, B. O'Brien
Feeding behaviour is an important parameter of animal performance, health and welfare, as well as reflecting levels and quality of feed available. Previously, sensors were only used for measuring animal feeding behaviour in indoor housing systems. However, sensors such as the RumiWatchSystem can also monitor such behaviour continuously in pasture-based environments. Therefore, the aim of this study was to validate the RumiWatchSystem to record cow activity and feeding behaviour in a pasture-based system. The RumiWatchSystem was evaluated against visual observation across two different experiments. The time duration per hour at grazing, rumination, walking, standing and lying recorded by the RumiWatchSystem was compared to the visual observation data in Experiment 1. Concordance Correlation Coefficient (CCC) values of CCC=0.96 for grazing, CCC=0.99 for rumination, CCC=1.00 for standing and lying and CCC=0.92 for walking were obtained. The number of grazing and rumination bouts within one hour were also analysed resulting in Cohen's Kappa (κ)=0.62 and κ=0.86 for grazing and rumination bouts, respectively. Experiment 2 focused on the validation of grazing bites and rumination chews. The accordance between visual observation and automated measurement by the RumiWatchSystem was high with CCC=0.78 and CCC=0.94 for grazing bites and rumination chews, respectively. These results indicate that the RumiWatchSystem is a reliable sensor technology for observing cow activity and feeding behaviour in a pasture based milk production system, and may be used for research purposes in a grazing environment.



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Effects of a combination of 3,4-methylenedioxymeth amphetamine and caffeine on real time stimulated dopamine release in the rat striatum: studies using fast cyclic voltammetry

Publication date: Available online 24 August 2017
Source:Journal of Neuroscience Methods
Author(s): J.J. O'Connor, K.M. O'Boyle, J.P. Lowry
It is well documented that caffeine exacerbates the hyperthermia associated with acute exposure to 3,4-methylenedioxymethamphetamine (MDMA) in rats. Previous reports have also indicated that MDMA-related enhancement of dopamine release is exacerbated in the presence of caffeine. In the present study we have examined whether the effects of MDMA on real-time stimulated dopamine release in the absence of uptake inhibition are accentuated in the presence of caffeine. Isolated striatal slices from adult male Wistar rats were treated acutely with MDMA, caffeine, or a combination, and their effects on single and 5pulse stimulated dopamine release monitored using the technique of fast cyclic voltammetry. Caffeine at 10 or 100μM had no significant effect on single pulse stimulated dopamine release. However 100μM caffeine caused a significant peak increase in 5pulse stimulated dopamine release. Both 1 and 30μM MDMA gave rise to a significant increase in both single and 5-pulse dopamine release and reuptake. A combination of 100μM caffeine and 1 or 30μM MDMA did not significantly enhance the effects of MDMA on single or 5pulse dopamine release and reuptake when compared to that applied alone. Utilizing single action potential dependent dopamine release, these results do not demonstrate a caffeine-enhanced MDMA-induced dopamine release.



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Development of a head-mounted wireless microstimulator for deep brain stimulation in rats

Publication date: Available online 24 August 2017
Source:Journal of Neuroscience Methods
Author(s): Felix Fluri, Thomas Mützel, Michael K. Schuhmanna, Miloš Krstić, Heinz Endres, Jens Volkmann
BackgroundCommercial neurostimulators for clinical use are effective in patients; however they are too large and prohibitively expensive for preclinical studies. Thus, there is an urgent need of a small inexpensive and wireless microstimulator which is fully programmable in frequency, pulse width and amplitude for rodent experiments.New methodsRats were subjected to a photothrombotic stroke of the right sensorimotor cortex and a microelectrode was implanted in the right mesencephalic locomotor region. The microstimulator was connected with the head plug of the rat. Three different stimulation frequencies were applied and different stimulating amplitudes were chosen. Under these conditions, gait velocity and locomotor behavior of six rats were examined on a beam.ResultsThe head-mounted microstimulator allowed freedom in all motor activities performed spontaneously by the tested rats. Increasing either the frequency or the stimulating amplitude increased gait velocity and ameliorated locomotor behavior after stroke.Comparison with existing methodsOther devices for DBS in rodents must be implanted under the skin or worn in an animal jacket on the back by the tested rat. Some available systems require even a tethering of the tested animal via a cable to an external stimulation system, which limits the freedom of movement.ConclusionHere, we present a freely programmable microstimulator including DBS-typical stimulating parameters. The lightweight device is connected by a simple plug to the head allowing full freedom of movement and exchange of batteries for long-term experiments. The design of this stimulator is suitable for sophisticated behavior tests requiring balance and skilled walking.



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Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption

Publication date: Available online 24 August 2017
Source:Cell Host & Microbe
Author(s): Kymberleigh A. Romano, Ana Martinez-del Campo, Kazuyuki Kasahara, Carina L. Chittim, Eugenio I. Vivas, Daniel Amador-Noguez, Emily P. Balskus, Federico E. Rey
Choline is an essential nutrient and methyl donor required for epigenetic regulation. Here, we assessed the impact of gut microbial choline metabolism on bacterial fitness and host biology by engineering a microbial community that lacks a single choline-utilizing enzyme. Our results indicate that choline-utilizing bacteria compete with the host for this nutrient, significantly impacting plasma and hepatic levels of methyl-donor metabolites and recapitulating biochemical signatures of choline deficiency. Mice harboring high levels of choline-consuming bacteria showed increased susceptibility to metabolic disease in the context of a high-fat diet. Furthermore, bacterially induced reduction of methyl-donor availability influenced global DNA methylation patterns in both adult mice and their offspring and engendered behavioral alterations. Our results reveal an underappreciated effect of bacterial choline metabolism on host metabolism, epigenetics, and behavior. This work suggests that interpersonal differences in microbial metabolism should be considered when determining optimal nutrient intake requirements.

Graphical abstract

Teaser

The gut microbiota is a dynamic metabolic organ associated with host health and disease phenotypes. Romano, Martinez-del Campo et al. report that choline-consuming gut bacteria reduce the bioavailability of this essential nutrient and deplete methyl-donor metabolites, resulting in alterations to host epigenetic programming and increased susceptibility to metabolic disease.


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An Oxidative Central Metabolism Enables Salmonella to Utilize Microbiota-Derived Succinate

Publication date: Available online 24 August 2017
Source:Cell Host & Microbe
Author(s): Luisella Spiga, Maria G. Winter, Tatiane Furtado de Carvalho, Wenhan Zhu, Elizabeth R. Hughes, Caroline C. Gillis, Cassie L. Behrendt, Jiwoong Kim, Daniela Chessa, Helene L. Andrews-Polymenis, Daniel P. Beiting, Renato L. Santos, Lora V. Hooper, Sebastian E. Winter
The mucosal inflammatory response induced by Salmonella serovar Typhimurium creates a favorable niche for this gut pathogen. Conventional wisdom holds that S. Typhimurium undergoes an incomplete tricarboxylic acid (TCA) cycle in the anaerobic mammalian gut. One change during S. Typhimurium-induced inflammation is the production of oxidized compounds by infiltrating neutrophils. We show that inflammation-derived electron acceptors induce a complete, oxidative TCA cycle in S. Typhimurium, allowing the bacteria to compete with the microbiota for colonization. A complete TCA cycle facilitates utilization of the microbiota-derived fermentation product succinate as a carbon source. S. Typhimurium succinate utilization genes contribute to efficient colonization in conventionally raised mice, but provide no growth advantage in germ-free mice. Mono-association of gnotobiotic mice with Bacteroides, a major succinate producer, restores succinate utilization in S. Typhimurium. Thus, oxidative central metabolism enables S. Typhimurium to utilize a variety of carbon sources, including microbiota-derived succinate.

Graphical abstract

Teaser

Spiga et al. show that during colonization of the intestinal lumen, the enteric pathogen S. Typhimurium performs a complete TCA cycle. This oxidative central metabolism enables S. Typhimurium to utilize the microbiota-derived fermentation product succinate as a nutrient and to compete with the microbiota for colonization of the intestinal tract.


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A Brucella Type IV Effector Targets the COG Tethering Complex to Remodel Host Secretory Traffic and Promote Intracellular Replication

Publication date: Available online 24 August 2017
Source:Cell Host & Microbe
Author(s): Cheryl N. Miller, Erin P. Smith, Jennifer A. Cundiff, Leigh A. Knodler, Jessica Bailey Blackburn, Vladimir Lupashin, Jean Celli
Many intracellular pathogens exploit host secretory trafficking to support their intracellular cycle, but knowledge of these pathogenic processes is limited. The bacterium Brucella abortus uses a type IV secretion system (VirB T4SS) to generate a replication-permissive Brucella-containing vacuole (rBCV) derived from the host ER, a process that requires host early secretory trafficking. Here we show that the VirB T4SS effector BspB contributes to rBCV biogenesis and Brucella replication by interacting with the conserved oligomeric Golgi (COG) tethering complex, a major coordinator of Golgi vesicular trafficking, thus remodeling Golgi membrane traffic and redirecting Golgi-derived vesicles to the BCV. Altogether, these findings demonstrate that Brucella modulates COG-dependent trafficking via delivery of a T4SS effector to promote rBCV biogenesis and intracellular proliferation, providing mechanistic insight into how bacterial exploitation of host secretory functions promotes pathogenesis.

Graphical abstract

Teaser

How bacterial pathogens exploit host secretory functions to achieve their intracellular cycle remains poorly understood. Miller et al. show here that Brucella abortus delivers into macrophages a type IV-secretion effector that remodels Golgi-associated membrane traffic to promote biogenesis of the Brucella replicative vacuole and bacterial proliferation.


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Striatal synapses, circuits, and Parkinson's disease

Publication date: February 2018
Source:Current Opinion in Neurobiology, Volume 48
Author(s): Shenyu Zhai, Asami Tanimura, Steven M Graves, Weixing Shen, D James Surmeier
The striatum is a hub in the basal ganglia circuitry controlling goal directed actions and habits. The loss of its dopaminergic (DAergic) innervation in Parkinson's disease (PD) disrupts the ability of the two principal striatal projection systems to respond appropriately to cortical and thalamic signals, resulting in the hypokinetic features of the disease. New tools to study brain circuitry have led to significant advances in our understanding of striatal circuits and how they adapt in PD models. This short review summarizes some of these recent studies and the gaps that remain to be filled.



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Parsing learning in networks using brain–machine interfaces

Publication date: October 2017
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Amy L Orsborn, Bijan Pesaran
Brain–machine interfaces (BMIs) define new ways to interact with our environment and hold great promise for clinical therapies. Motor BMIs, for instance, re-route neural activity to control movements of a new effector and could restore movement to people with paralysis. Increasing experience shows that interfacing with the brain inevitably changes the brain. BMIs engage and depend on a wide array of innate learning mechanisms to produce meaningful behavior. BMIs precisely define the information streams into and out of the brain, but engage wide-spread learning. We take a network perspective and review existing observations of learning in motor BMIs to show that BMIs engage multiple learning mechanisms distributed across neural networks. Recent studies demonstrate the advantages of BMI for parsing this learning and its underlying neural mechanisms. BMIs therefore provide a powerful tool for studying the neural mechanisms of learning that highlights the critical role of learning in engineered neural therapies.



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Mechanically dynamic PDMS substrates to investigate changing cell environments

Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Yi-Cheun Yeh, Elise A. Corbin, Steven R. Caliari, Liu Ouyang, Sebastián L. Vega, Rachel Truitt, Lin Han, Kenneth B. Margulies, Jason A. Burdick
Mechanics of the extracellular matrix (ECM) play a pivotal role in governing cell behavior, such as cell spreading and differentiation. ECM mechanics have been recapitulated primarily in elastic hydrogels, including with dynamic properties to mimic complex behaviors (e.g., fibrosis); however, these dynamic hydrogels fail to introduce the viscoelastic nature of many tissues. Here, we developed a two-step crosslinking strategy to first form (via platinum-catalyzed crosslinking) networks of polydimethylsiloxane (PDMS) and then to increase PDMS crosslinking (via thiol-ene click reaction) in a temporally-controlled manner. This photoinitiated reaction increased the compressive modulus of PDMS up to 10-fold within minutes and was conducted under cytocompatible conditions. With stiffening, cells displayed increased spreading, changing from ∼1300 to 1900 μm² and from ∼2700 to 4600 μm² for fibroblasts and mesenchymal stem cells, respectively. In addition, higher myofibroblast activation (from ∼2 to 20%) for cardiac fibroblasts was observed with increasing PDMS substrate stiffness. These results indicate a cellular response to changes in PDMS substrate mechanics, along with a demonstration of a mechanically dynamic and photoresponsive PDMS substrate platform to model the dynamic behavior of ECM.



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Self-assembled N-cadherin mimetic peptide hydrogels promote the chondrogenesis of mesenchymal stem cells through inhibition of canonical Wnt/β-catenin signaling

Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Rui Li, Jianbin Xu, Dexter Siu Hong Wong, Jinming Li, Pengchao Zhao, Liming Bian
N-cadherin, a transmembrane protein and major component of adherens junction, mediates cell-cell interactions and intracellular signaling that are important to the regulation of cell behaviors and organ development. Previous studies have identified mimetic peptides that possess similar bioactivity as that of N-cadherin, which promotes chondrogenesis of human mesenchymal stem cells (hMSCs); however, the molecular mechanism remains unknown. In this study, we combined the N-cadherin mimetic peptide (HAVDI) with the self-assembling KLD-12 peptide: the resultant peptide is capable of self-assembling into hydrogels functionalized with N-cadherin peptide in phosphate-buffered saline (PBS) at 37 °C. Encapsulation of hMSCs in these hydrogels showed enhanced expression of chondrogenic marker genes and deposition of cartilage specific extracellular matrix rich in proteoglycan and Type II Collagen compared to control hydrogels, with a scrambled-sequence peptide after 14 days of chondrogenic culture. Furthermore, western blot showed a significantly higher expression of active glycogen synthase kinase-3β (GSK-3β), which phosphorylates β-catenin and facilitates ubiquitin-mediated degradation, as well as a lower expression of β-catenin and LEF1 in the N-cadherin peptide hydrogels versus controls. Immunofluorescence staining revealed significantly less nuclear localization of β-catenin in N-cadherin mimetic peptide hydrogels. Our findings suggest that N-cadherin peptide hydrogels suppress canonical Wnt signaling in hMSCs by reducing β-catenin nuclear translocation and the associated transcriptional activity of β-catenin/LEF-1/TCF complex, thereby enhancing the chondrogenesis of hMSCs. Our biomimetic self-assembled peptide hydrogels can serve as a tailorable and versatile three-dimensional culture platform to investigate the effect of biofunctionalization on stem cell behavior.



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Multiscale design and synthesis of biomimetic gradient protein/biosilica composites for interfacial tissue engineering

Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Jin Guo, Chunmei Li, Shengjie Ling, Wenwen Huang, Ying Chen, David L. Kaplan
Continuous gradients present at tissue interfaces such as osteochondral systems, reflect complex tissue functions and involve changes in extracellular matrix compositions, cell types and mechanical properties. New and versatile biomaterial strategies are needed to create suitable biomimetic engineered grafts for interfacial tissue engineering. Silk protein-based composites, coupled with selective peptides with mineralization domains, were utilized to mimic the soft-to-hard transition in osteochondral interfaces. The gradient composites supported tunable mineralization and mechanical properties corresponding to the spatial concentration gradient of the mineralization domains (R5 peptide). The composite system exhibited continuous transitions in terms of composition, structure and mechanical properties, as well as cytocompatibility and biodegradability. The gradient silicified silk/R5 composites promoted and regulated osteogenic differentiation of human mesenchymal stem cells in an osteoinductive environment in vitro. The cells differentiated along the composites in a manner consistent with the R5-gradient profile. This novel biomimetic gradient biomaterial design offers a useful approach to meet a broad range of needs in regenerative medicine.



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In situ depot comprising phase-change materials that can sustainably release a gasotransmitter H2S to treat diabetic wounds

Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Wei-Chih Lin, Chieh-Cheng Huang, Shu-Jyuan Lin, Meng-Ju Li, Yen Chang, Yu-Jung Lin, Wei-Lin Wan, Po-Chien Shih, Hsing-Wen Sung
Patients with diabetes mellitus are prone to develop refractory wounds. They exhibit reduced synthesis and levels of circulating hydrogen sulfide (H2S), which is an ephemeral gaseous molecule. Physiologically, H2S is an endogenous gasotransmitter with multiple biological functions. An emulsion method is utilized to prepare a microparticle system that comprises phase-change materials with a nearly constant temperature of phase transitions to encapsulate sodium hydrosulfide (NaHS), a highly water-labile H2S donor. An emulsion technique that can minimize the loss of water-labile active compounds during emulsification must be developed. The as-prepared microparticles (NaHS@MPs) provide an in situ depot for the sustained release of exogenous H2S under physiological conditions. The sustained release of H2S promotes several cell behaviors, including epidermal/endothelial cell proliferation and migration, as well as angiogenesis, by extending the activation of cellular ERK1/2 and p38, accelerating the healing of full-thickness wounds in diabetic mice. These experimental results reveal the strong potential of NaHS@MPs for the sustained release of H2S for the treatment of diabetic wounds.



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Deriving vascular smooth muscle cells from mesenchymal stromal cells: Evolving differentiation strategies and current understanding of their mechanisms

Publication date: November 2017
Source:Biomaterials, Volume 145
Author(s): Xiaoqing Zhang, Michelle P. Bendeck, Craig A. Simmons, J. Paul Santerre
Vascular smooth muscle cells (VSMCs) play essential roles in regulating blood vessel form and function. Regeneration of functional vascular smooth muscle tissue to repair vascular diseases is an area of intense research in tissue engineering and regenerative medicine. For functional vascular smooth muscle tissue regeneration to become a practical therapy over the next decade, the field will need to have access to VSMC sources that are effective, robust and safe. While pluripotent stem cells hold good future promise to this end, more immediate translation is expected to come from approaches that generate functional VSMCs from adult sources of multipotent adipose-derived and bone marrow-derived mesenchymal stromal cells (ASCs and BMSCs). The research to this end is extensive and is dominated by studies relating to classical biochemical signalling molecules used to induce differentiation of ASCs and BMSCs. However, prolonged use of the biochemical induction factors is costly and can cause potential endotoxin contamination in the culture. Over recent years several non-traditional differentiation approaches have been devised to mimic defined aspects of the native micro-environment in which VSMCs reside to contribute to the differentiation of VSMC-like cells from ASCs and BMSCs. In this review, the promises and limitations of several non-traditional culture approaches (e.g., co-culture, biomechanical, and biomaterial stimuli) targeting VSMC differentiation are discussed. The extensive crosstalk between the underlying signalling cascades are delineated and put into a translational context. It is expected that this review will not only provide significant insight into VSMC differentiation strategies for vascular smooth muscle tissue engineering applications, but will also highlight the fundamental importance of engineering the cellular microenvironment on multiple scales (with consideration of different combinatorial pathways) in order to direct cell differentiation fate and obtain cells of a desired and stable phenotype. These strategies may ultimately be applied to different sources of stem cells in the future for a range of biomaterial and tissue engineering disciplines.



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The stigma of clean dieting and orthorexia nervosa

Abstract

Background

Although the stigma of eating disorders such as anorexia has been well established, little is known about the social consequences of "clean dieting" and orthorexia nervosa. In two studies, we examined the social stigma of clean dieting and orthorexia.

Method

In Study 1, participants read a vignette describing a woman following a "clean" diet, a woman with anorexia, or a control target (minimal information about the individual). In Study 2, participants read a vignette describing a woman with orthorexia, a woman displaying identical orthorexic behaviors but without the orthorexia label, a woman with anorexia, or a control target. Participants then rated the target individual on a range of measures assessing stereotypes, emotions, and behavioral intentions toward the target.

Results

Study 1 found that the clean-dieting target was evaluated more negatively than the control target on some dimensions, but less negatively than the target with anorexia nervosa. Study 2 found that evaluations of the targets with orthorexia nervosa were more negative than evaluations of a control target, but did not differ from evaluations of the target with anorexia nervosa. Perceptions of the target's control over her behavior were associated with more positive evaluations (Studies 1 and 2), whereas perceptions of blame and responsibility for the condition were associated with more negative evaluations (Study 2).

Conclusions

Overall, these findings highlight the potential negative social consequences of clean dieting and orthorexia nervosa, and point to perceptions of control and blame as potential mechanisms underlying the stigma of these conditions.

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Welcoming the Class of 2021: Prepare for Uncharted Waters.

Author: Kennedy, Maureen Shawn MA, RN, FAAN

Page: 7

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The Human Microbiome.

Author: Clark, Angela P. PhD, RN, ACNS-BC, FAAN, FAHA

Page: 13

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Critical Thinking During Time-Out Protocols.

Author: Lott, Charles

Page: 13

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Critical Thinking During Time-Out Protocols.

Author: S., Sharon via ajnoffthecharts.com

Page: 13

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Natural Disasters and Resilience Training.

Author: Gasparrelli, Sharilyn M. RN, CNOR

Page: 13

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Keeping Assessment Skills Sharp.

Author: Valenzuela, Joshua

Page: 13

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Gun Violence and Children.

Author: Sofer, Dalia

Page: 14

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How Long Should Routine Health Screening Continue?.

Author: Stockwell, Serena

Page: 15

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NewsCAP: Survey outlines the current characteristics of CNSs.

Author:

Page: 15

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Two Studies Suggest Fewer Opioids Could Be Prescribed After Cesarean Sections.

Author: Potera, Carol

Page: 16

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NewsCAP: New app may streamline breast milk management in the NICU.

Author:

Page: 16

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Trends in U.S. Health Care.

Author:

Page: 17

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NewsCAP: Even moderate alcohol use affects cognitive function.

Author:

Page: 17

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NewsCAP: Support services for older adults, caregivers, and those with disabilities have improved, but progress is too slow.

Author:

Page: 17

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NewsCAP: One of every 200 people in Yemen suspected of having cholera.

Author:

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Will Rural Community Hospitals Survive?.

Author: Nelson, Roxanne

Page: 18-19

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AJN On the Cover.

Author: Szulecki, Diane Editor

Page: 20

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AJN On the Web.

Author:

Page: 20

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Delayed Onset Cranial Nerve Palsies After Endovascular Coil Embolization of Direct Carotid-Cavernous Fistulas.

Background: Late recurrence of visual symptoms associated with carotid-cavernous fistula (CCF), including diplopia, is uncommon and raises concern for new or recurrent fistula formation. Methods: We report 2 patients with traumatic CCFs, where cranial nerve paresis resolved after endovascular CCF treatment only to reappear years later. Results: No evidence of recurrent or new fistula formation was found. Both were treated successfully with strabismus surgery. Conclusions: Although the cause of delayed onset diplopia after successful treatment is still unknown, theories include late compression of cranial nerves within the cavernous sinus due to coil mass that can cause chronic ischemia, delayed inflammation due to a thrombophilic nidus created by the coil mass, or injury to the cranial nerves that manifests later due to decompensated strabismus. (C) 2017 by North American Neuro-Ophthalmology Society

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Gorham-Stout Disease Presenting as Acute Unilateral Proptosis.

Gorham-Stout disease (GSD) is a rare angiomatous disorder characterized by osteolysis. We report the case of a 66-year-old woman who developed sudden left eye proptosis and facial pain. Neuroimaging demonstrated a destructive mass involving the roof and lateral wall of the left orbit with adjacent abnormal orbital soft tissue. An initial biopsy of the soft tissue was nondiagnostic; however, transcranial biopsy of the orbital roof revealed an intraosseous cavernous angioma, with infiltration of orbital fat by angiomatous tissue. Despite resection of the orbital roof and lateral wall, the orbital lesion continued to expand, leading to signs of a compressive optic neuropathy. The patient then reported severe back pain, prompting imaging that demonstrated disseminated bony involvement of the axial skeleton, eventually leading to the diagnosis of GSD. The patient was treated with a bisphosphonate and a vascular endothelial growth factor inhibitor with stabilization of disease. (C) 2017 by North American Neuro-Ophthalmology Society

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Co-Trained Convolutional Neural Networks for Automated Detection of Prostate Cancer in Multi-parametric MRI

Publication date: Available online 24 August 2017
Source:Medical Image Analysis
Author(s): Xin Yang, Chaoyue Liu, Zhiwei Wang, Jun Yang, Hung Le Min, Liang Wang, Kwang-Ting (Tim) Cheng
Multi-parameter magnetic resonance imaging (mp-MRI) is increasingly popular for prostate cancer (PCa) detection and diagnosis. However, interpreting mp-MRI data which typically contains multiple unregistered 3D sequences, e.g. apparent diffusion coefficient (ADC) and T2-weighted (T2w) images, is time-consuming and demands special expertise, limiting its usage for large-scale PCa screening. Therefore, solutions to computer-aided detection of PCa in mp-MRI images are highly desirable. Most recent advances in automated methods for PCa detection employ a handcrafted feature based two-stage classification flow, i.e. voxel-level classification followed by a region-level classification. This work presents an automated PCa detection system which can concurrently identify the presence of PCa in an image and localize lesions based on deep convolutional neural network (CNN) features and a single-stage SVM classifier. Specifically, the developed co-trained CNNs consist of two parallel convolutional networks for ADC and T2w images respectively. Each network is trained using images of a single modality in a weakly-supervised manner by providing a set of prostate images with image-level labels indicating only the presence of PCa without priors of lesions' locations. Discriminative visual patterns of lesions can be learned effectively from clutters of prostate and surrounding tissues. A cancer response map with each pixel indicating the likelihood to be cancerous is explicitly generated at the last convolutional layer of the network for each modality. A new back-propagated error E is defined to enforce both optimized classification results and consistent cancer response maps for different modalities, which help capture highly representative PCa-relevant features during the CNN feature learning process. The CNN features of each modality are concatenated and fed into a SVM classifier. For images which are classified to contain cancers, non-maximum suppression and adaptive thresholding are applied to the corresponding cancer response maps for PCa foci localization. Evaluation based on 160 patient data with 12-core systematic TRUS-guided prostate biopsy as the reference standard demonstrates that our system achieves a sensitivity of 0.46, 0.92 and 0.97 at 0.1, 1 and 10 false positives per normal/benign patient which is significantly superior to two state-of-the-art CNN-based methods (Oquab et al., 2015; Zhou et al., 2015) and 6-core systematic prostate biopsies.

Graphical abstract

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Impact of microRNAs on ischemic stroke: From pre- to post-disease

Publication date: Available online 24 August 2017
Source:Progress in Neurobiology
Author(s): Guangwen Li, Kahlilia C. Morris-Blanco, Mary S. Lopez, Tuo Yang, Haiping Zhao, Raghu Vemuganti, Yumin Luo
Stroke is the number one cause of neurological dysfunction in adults and has a heavy socioeconomic burden worldwide. The etiological origins of ischemic stroke and resulting pathological processes are mediated by a multifaceted cascade of molecular mechanisms that are in part modulated by posttranscriptional activity. Accumulating evidence has revealed a role for microRNAs (miRNAs) as essential mediators of posttranscriptional gene silencing in both the physiology of brain development and pathology of ischemic stroke. In this review, we compile miRNAs that have been reported to regulate various stroke risk factors and pre-disease mechanisms, including hypertension, atherosclerosis, and diabetes, followed by an in-depth analysis of miRNAs in ischemic stroke pathogenesis, such as excitotoxicity, oxidative stress, inflammation, apoptosis, angiogenesis and neurogenesis. Since promoting or suppressing expression of miRNAs by specific pharmaceutical and non-pharmaceutical therapies may be beneficial to post-stroke recovery, we also highlight the potential therapeutic value of miRNAs in clinical settings.



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Mitteilungen der DGKFO

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Contrast Enhanced Spectral Mammography: A Review

Publication date: Available online 24 August 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Bhavika K. Patel, M.B.I. Lobbes, John Lewin
Contrast-enhanced spectral mammography (CESM) provides low-energy 2D mammographic images comparable to standard digital mammography and a post-contrast recombined image to assess tumor neovascularity similar to MRI. The utilization of CESM in the United States is currently low but could increase rapidly given many potential indications for clinical use. This article discusses historical background and literature review of indications and diagnostic accuracy of CESM to date. CESM is a growing technique for breast cancer detection and diagnosis that has levels of sensitivity and specificity on par with contrast-enhanced breast MRI. Because of its similar performance and ease of implementation, CESM is being adopted for multiple indications previously reserved for MRI, such as problem-solving, disease-extent in newly diagnosed patients and evaluating the treatment response of neoadjuvant chemotherapy.



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Thoracolithiasis – CT findings of intrapleural loose bodies

Publication date: Available online 24 August 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Gabriela Gayer
Thoracoliths are rare benign intrapleural loose bodies, often containing calcification, that are mobile in the pleural cavity. The presence of these intrapleural nodules is referred to as thoracolithiasis. The exact etiology of thoracoliths is unknown, but they presumably result from a prior episode of mediastinal (epipericardial) fat necrosis. Thoracoliths are usually asymptomatic and incidentally encountered on CT.However, they sometimes pose diagnostic challenges, as a thoracolith may be located within a pleural fissure, and is then indistinguishable from a pulmonary nodule. In addition, migration and rotation of thoracoliths within the pleural space observed on serial CT studies has been reported to raise concern that these might be neoplastic lesions, leading to their surgical removal. Awareness of this benign condition is important in order to avoid unnecessary invasive procedures.



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Optimizing success and avoiding mishaps in the most difficult image guided breast biopsies

Publication date: Available online 24 August 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Sughra Raza, Sona A. Chikarmane, Eva C. Gombos, Dianne Georgian-Smith, Elisabeth P. Frost
Breast cancer is an increasing challenge in developed and limited resource areas of the world. Early detection of breast cancer offers the best chance for optimal care and best outcomes. A critical step in early detection is to obtain efficient and accurate tissue diagnoses. While image-guided core needle breast biopsies are usually straightforward for experienced breast imagers, there are some not uncommon scenarios which present particular challenges. In this review article we will discuss these difficult situations and offer our tried and true methods to ensure safe and successful biopsies, while using stereotactic, ultrasound, and MRI guidance.



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The molecular mechanism and post-transcriptional regulation characteristic of Tetragenococcus halophilus acclimation to osmotic stress revealed by quantitative proteomics

Publication date: Available online 24 August 2017
Source:Journal of Proteomics
Author(s): Jieting Lin, Hebin Liang, Junwei Yan, Lixin Luo
Tetragenococcus halophilus is a moderate halophilic bacterium which was widely used in fermentation processes, growing in a broad range of salinity conditions, and can survive a saturated 26.47% w/w NaCl concentration. However, the mechanism of this outstanding ability to acclimate to extracellular osmotic stress still remains unknown. The current study firstly conducted a quantitative proteomic analysis to identify alterations of the cellular proteome under both hypo-osmotic and hyper-osmotic stress conditions. A total of 1405 proteins were identified and differentially accumulated proteins were analyzed, further functional annotations were performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The results revealed that both hypo- and hyper-osmotic stresses have prominent impacts on the synthesis of proteins involving in multiple cellular functions. Further analyses of the differentially accumulated proteins suggested that the adaptation strategies T. halophilus applies to deal with hypo- and hyper-osmotic stress conditions may be distinct. Comparison of the differentially accumulated proteins in both transcriptomic and proteomic study indicated the existence of post-transcriptional modification during salinity adaptation of T. halophilus. The current study generated a proteomic atlas of differentially accumulated proteins under both hypo- and hyper-osmotic stress conditions, provided an overview of the molecular mechanism of osmotic acclimation of T. halophilus.SignificanceThe current study aimed to reveal how the moderately halophilic Tetragenococcus halophilus adapt to extracellular salinity stress, which is the first proteomic study analyzing the differences in proteome of Tetragenococcus halophilus between hypo- and hyper-osmotic stress to our knowledge. By analyzing the differences in the accumulating levels of the proteome via isobaric labeling-based quantitative proteomic study, we identified proteins with significantly different accumulation levels which may play important roles in the adaptation process to extracellular salinity stress. Examining the cellular functions of these proteins according to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, a draft view of how the bacterium act to acclimate to osmotic stress has been drawn. Further analysis revealing the differences between the transcriptome and proteome suggested that some proteins may undergo post-transcriptional regulation during acclimation process, which still remains unstudied and needs further investigations. The results of the current study can help researchers to gain insights and further reveal the halophilic mechanism of halophiles.

Graphical abstract

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Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib

Publication date: Available online 24 August 2017
Source:Journal of Proteomics
Author(s): Simon Vyse, Frank McCarthy, Malgorzata Broncel, Angela Paul, Jocelyn P. Wong, Amandeep Bhamra, Paul H. Huang
Acquired drug resistance impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapies to overcome resistance represents an unmet need. Understanding the signalling that drives drug resistance will facilitate the development of new salvage therapies to treat patients with secondary TKI resistance. In this study, we utilise mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only 6% and 9.7% of the quantified phosphoproteome is altered upon the acquisition of pazopanib and dasatinib resistance respectively. Pazopanib resistant cells display elevated phosphorylation in cytoskeletal regulatory pathways while dasatinib resistant cells show an upregulation of the insulin receptor/IGF-1R signalling pathway. Drug response profiling rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance.SignificancePazopanib and dasatinib are tyrosine kinase inhibitors (TKIs) approved for the treatment of multiple cancer types. Patients who are treated with these drugs are prone to the development of drug resistance and consequently tumour relapse. Here we use quantitative phosphoproteomics to characterise the signalling pathways which are enriched in cells that have acquired resistance to these two drugs. Furthermore, targeted drug screens were used to identify salvage therapies capable of overcoming pazopanib and dasatinib resistance. This data advances our understanding of the mechanisms of TKI resistance and highlights candidate targets for cancer therapy.



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The medical threat of mamba envenoming in sub-Saharan Africa revealed by genus-wide analysis of venom composition, toxicity and antivenomics profiling of available antivenoms

Publication date: Available online 24 August 2017
Source:Journal of Proteomics
Author(s): Stuart Ainsworth, Daniel Petras, Mikael Engmark, Roderich D. Süssmuth, Gareth Whiteley, Laura-Oana Albulescu, Taline D. Kazandjian, Simon C. Wagstaff, Paul Rowley, Wolfgang Wüster, Pieter C. Dorrestein, Ana Silvia Arias, José M. Gutiérrez, Robert A. Harrison, Nicholas R. Casewell, Juan J. Calvete
Mambas (genus Dendroaspis) are among the most feared of the medically important elapid snakes found in sub-Saharan Africa, but many facets of their biology, including the diversity of venom composition, remain relatively understudied. Here, we present a reconstruction of mamba phylogeny, alongside genus-wide venom gland transcriptomic and high-resolution top-down venomic analyses. Whereas the green mambas, D. viridis, D. angusticeps, D. j. jamesoni and D. j. kaimosae, express 3FTx-predominant venoms, black mamba (D. polylepis) venom is dominated by dendrotoxins I and K. The divergent terrestrial ecology of D. polylepis compared to the arboreal niche occupied by all other mambas makes it plausible that this major difference in venom composition is due to dietary variation. The pattern of intrageneric venom variability across Dendroaspis represented a valuable opportunity to investigate, in a genus-wide context, the variant toxicity of the venom, and the degree of paraspecific cross-reactivity between antivenoms and mamba venoms. To this end, the immunological profiles of the five mamba venoms were assessed against a panel of commercial antivenoms generated for the sub-Saharan Africa market. This study provides a genus-wide overview of which available antivenoms may be more efficacious in neutralising human envenomings caused by mambas, irrespective of the species responsible. The information gathered in this study lays the foundations for rationalising the notably different potency and pharmacological profiles of Dendroaspis venoms at locus resolution. This understanding will allow selection and design of toxin immunogens with a view to generating a safer and more efficacious pan-specific antivenom against any mamba envenomation.Biological significanceThe mambas (genus Dendroaspis) comprise five especially notorious medically important venomous snakes endemic to sub-Saharan Africa. Their highly potent venoms comprise a high diversity of pharmacologically active peptides, including extremely rapid-acting neurotoxins. Previous studies on mamba venoms have focused on the biochemical and pharmacological characterisation of their most relevant toxins to rationalize the common neurological and neuromuscular symptoms of envenomings caused by these species, but there has been little work on overall venom composition or comparisons between them. Only very recently an overview of the composition of the venom of two Dendroaspis species, D. angusticeps and D. polylepis, has been unveiled through venomics approaches. Here we present the first genus-wide transcriptomic-proteomic analysis of mamba venom composition. The transcriptomic analyses described in this paper have contributed 29 (D. polylepis), 23 (D. angusticeps), 40 (D. viridis), 25 (D. j. jamesoni) and 21 (D. j. kaimosae), novel full-length toxin sequences to the non-redundant Dendroaspis sequence database. The mamba genus-wide venomic analysis demonstrated that major D. polylepis venom components are Kunitz-fold family toxins. This feature is unique in relation to the relatively conserved three-finger toxin (3FTx)-dominated venom compositions of the green mambas. Venom variation was interpreted in the context of dietary variation due to the divergent terrestrial ecology of D. polylepis compared to the arboreal niche occupied by all other mambas. Additionally, the degree of cross-reactivity conservation of mamba venoms was assessed by antivenomics against a panel of commercial antivenoms generated for the sub-Saharan Africa market. This study provides a genus-wide overview to infer which available antivenoms may be capable of neutralising human envenomings caused by mambas, irrespective of the species responsible. The information gathered in this study lays the foundations for rationalising the pharmacological profiles of mamba venoms at locus resolution. This understanding will contribute to the generation of a safer and more efficacious pan-Dendroaspis therapeutic antivenom against any mamba envenomation.

Graphical abstract

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Structural identification of N-linked carbohydrates using the GUcal application: A tutorial

Publication date: Available online 24 August 2017
Source:Journal of Proteomics
Author(s): Gabor Jarvas, Marton Szigeti, Andras Guttman
In recent years, analytical glycomics gained a significant role due to the rapidly increasing number of glycoproteins introduced as biopharmaceuticals. One of the frequently used methods for the analysis of complex carbohydrates is capillary electrophoresis with laser induced fluorescent detection (CE-LIF). CE-LIF is a high resolution separation technique with excellent sensitivity capable of discriminating between closely related positional and linkage carbohydrate isomers. Individual glycan structures corresponding to the separated peaks in an electropherogram are identified according to their glucose unit (GU) values by mining the built in database. This tutorial introduces the practical use of the GUcal application, a recently developed glycoinformatics tool, which automatically calculates GU values for all sample components of interest in an electropherogram using either the bracketing standard approach or the recently published triple internal standard method. Furthermore, a worked example demonstrates the way glycan structural elucidation of human immunoglobulin G is processed with the help of this simple and rapid GU value calculation application.SignificanceBiopharmaceuticals have seen something of tremendous development in recent years, which governs the parallel blooming of analytical glycomics. One of the frequently used methods for the analysis of complex carbohydrates is capillary electrophoresis with laser induced fluorescent detection (CE-LIF). CE-LIF is a high resolution separation technique with excellent sensitivity capable of discriminating between closely related positional and linkage carbohydrate isomers. While CE instrumentation is well developed, the related bioinformatics tools are lagging behind. According to our best knowledge, this is the first tutorial paper on the recently disseminated GUcal application, which automatically calculates GU values for all sample components of interest in an electropherogram using either the bracketing standard approach or the new triple internal standard method. On the top the step-by-step instruction how to use the application, the paper includes a worked example demonstrates the way glycan structure elucidation of human immunoglobulin G is processed with the help of the simple and rapid GU value calculation of this new application. After very short training period, the software can be used readily for cutting-edge glycomics of exploratory research or high-throughput routine analysis.

Graphical abstract

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Rooted in the Community: Assessing the Reintegration Impacts of Agriculture on Rural Veterans

Publication date: Available online 24 August 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Karen Besterman-Dahan, Margeaux Chavez, Eni Njoh
ObjectiveTo assess the impact of a Veteran-oriented community agricultural initiative (CAI) on transitioning rural Veterans.DesignConvergent mixed-method program evaluation.SettingA Veteran-oriented farm-to-market CAI in rural Washington State.ParticipantsVeterans who were members of the CAI.Main Outcome MeasuresHealth, well-being, and reintegration were assessed by self-reported data from interview, demographic survey, validated health quality of life measure (Veterans RAND-12 -VR-12), validated reintegration measure (Military to Civilian Questionnaire -M2C-Q), and general satisfaction survey.ResultsVeteran participants were primarily Caucasian (88.4%, n=38) and male (74.4%, n=32) and most had a service-connected disability rating (58.2%, n=25). Qualitative and quantitative data revealed that the veterans participating in this CAI experienced health and reintegration benefits. Results on the M2C-Q, VR-12, and the satisfaction survey suggest that participating in this CAI contributed to improved mental, physical, and emotional health and vocational skills, community connectedness, and interpersonal communication. Qualitative interviews supported quantitative findings and revealed that participating in the CAI provided Veterans with a sense of satisfaction, belonging, and helped decrease the stigma surrounding their Veteran status.ConclusionsVeterans who participate in this CAI reported general improvements in physical and mental health, including improvements in sleep, nutrition, exercise, and decreases in anxiety, pain, depression and medication and substance use, all known factors which impact Veteran reintegration.



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Low-dose-rate prostate brachytherapy: 4–8 week postimplant prostate-specific antigen a novel predictor of biochemical failure-free survival

Publication date: Available online 24 August 2017
Source:Brachytherapy
Author(s): Cameron M. Callaghan, Lin Wang, Abhishek Alluri, Andrew Lauve, Cynthia Boyer, William Russell
PurposeThe purpose of this study was to determine the relationship between patient, disease, and treatment variables and biochemical failure-free survival (bFFS) following low-dose-rate prostate brachytherapy (LDR-BT).Methods and MaterialsData from 624 consecutive patients who received LDR-BT for localized prostate cancer between 2002 and 2012 at a single institution were collected for various patient, disease, and treatment characteristics including a 4–8 week postimplant PSA (4–8wkPSA). Subgroup analysis was stratified by risk category and treatment regimen. Analysis was performed using Kaplan–Meier survival curves, Cox proportional hazard ratios (HRs), and receiver-operator characteristic curves.ResultsA total of 624 consecutive patients were included with followup time of 4.0 ± 3.1 years. Predictors of bFFS included PSA nadir and 4–8wkPSA (HR = 2.48, p = 0.000 and HR = 1.24, p = 0.000, respectively) for total population. Diabetes mellitus (p = 0.026), chronic obstructive pulmonary disease (p = 0.000), alcohol use (p = 0.024), and age (p = 0.002) were predictors for specific subgroups. Receiver-operator characteristic curves 4–8wkPSA were found to be significant (p = 0.036).Conclusion4–8wkPSA is a novel predictor of bFFS for patients receiving LDR-BT across several risk categories and treatment regimens with potential clinical utility as a prognostic indicator. Certain comorbidities and exposure histories also demonstrated significant relationships with bFFS including chronic obstructive pulmonary disease, diabetes mellitus, age, alcohol history, proton pump inhibitor use, PSA nadir, and PSA density.



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Clinical implementation of a novel Double-Balloon single-entry breast brachytherapy applicator

Publication date: Available online 24 August 2017
Source:Brachytherapy
Author(s): Bethany M. Anderson, Charles R. Wallace, Anna-Maria A. De Costa, Rupak K. Das
PurposeThe purpose of the study was to describe the clinical utilization of a novel Double-Balloon applicator for accelerated partial breast irradiation (APBI).Methods and MaterialsThe Double-Balloon single-entry breast applicator contains a single central treatment catheter, as well as four peripheral catheters that can be differentially loaded to customize radiation dose coverage. An inner balloon is filled with up to 7–30 cm³ of saline to increase separation between the peripheral catheters, and an outer balloon is filled with up to 37–115 cm³ of saline to displace breast tissue from the peripheral catheters. Treatment planning objectives include coverage of the breast planning target volume to a minimum of V90 > 90%, limiting dose heterogeneity such that V200 < 10 cm³ and V150 < 50 cm³, and limiting maximum dose to skin (<100% of prescription dose) and ribs (<145% of prescription dose).ResultsHigh-dose-rate APBI was delivered to 11 women using this device (34 Gy in 10 twice daily fractions). The mean V90 was 98.2% (range 94.2–99.4%). The mean skin Dmax with the Double-Balloon applicator was 83.3% (range 75.6–99.5%). The mean breast V200 was 5.8 cm³ (range 2.3–10.2 cm³), and the mean breast V150 was 32.9 cm³ (range 25.0–41.7 cm³). Pretreatment quality assurance was performed using CT prior to each morning fraction and ultrasound prior to each afternoon fraction.ConclusionsThe Double-Balloon applicator can be easily introduced into a previously existing brachytherapy program. APBI plans created with this applicator achieve excellent planning target volume coverage, while limiting skin dose and maintaining breast V200 < 10 cm³.



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Performance, emission, and combustion characteristics of twin-cylinder common rail diesel engine fuelled with butanol-diesel blends

Abstract

Nitrogen oxides and smoke are the substantial emissions for the diesel engines. Fuels comprising high-level oxygen content can have low smoke emission due to better oxidation of soot. The objective of the paper is to assess the potential to employ oxygenated fuel, i.e., n-butanol and its blends with the neat diesel from 0 to 30% by volume. The experimental and computational fluid dynamic (CFD) simulation is carried out to estimate the performance, combustion, and exhaust emission characteristics of n-butanol-diesel blends for various injection timings (9°, 12°, 15°, and 18°) using modern twin-cylinder, four-stroke, common rail direct injection (CRDI) engine. Experimental results reveal the increase in brake thermal efficiency (BTE) by ~ 4.5, 6, and 8% for butanol-diesel blends of 10% (Bu10), 20% (Bu20), and 30% (Bu30), respectively, compared to neat diesel (Bu0). Maximum BTE for Bu0 is 38.4%, which is obtained at 12° BTDC; however, for Bu10, Bu20 and Bu30 are 40.19, 40.9, and 41.7%, which are obtained at 15° BTDC, respectively. Higher flame speed of n-butanol-diesel blends burn a large amount of fuel in the premixed phase, which improves the combustion as well as emission characteristics. CFD and experimental results are compared and validated for all fuel blends for in-cylinder pressure and nitrogen oxides (NO_x), and found to be in good agreement. Both experimental and simulation results witnessed in reduction of smoke opacity, NO_x, and carbon monoxide emissions with the increasing n-butanol percentage in diesel fuel.

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Mortality and its Causes in a German Cohort with Diabetes Mellitus Type 1 after 20 Years of Follow-Up: The JEVIN Trial

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0043-113452

Background The JEVIN trial started as a cross-sectional study in 1989/90 in Jena. After a follow-up of more than 20 years, the mortality incidence of JEVIN participants with type 1 diabetes was surveyed. Methods 103 (78.6%) of the 131 JEVIN patients participating at baseline could be examined. 38 persons (36.9%) had deceased. All JEVIN survey data and routine examinations documented in the electronic patient record EMIL® of surviving and deceased participants were used for analyses. We compared the data of the surviving with the deceased participants (follow-up time: 2,166 person-years). Results The incidence rate of death was 1.75/100 person-years. Median observation time for all patients was 23.1 years (range 0.61–26.6 years). Mean age at death was 58.5 years (34.2–78.4 years), and diabetes duration 35 years (3.5–68.5 years). Most frequent causes of death were: cardiovascular diseases (48.2%, n=13) and infections (25.9%, n=7). There were no differences in age (p=0.302), diabetes duration (p=0.371), BMI (p=0.535), blood pressure (p=0.622/0.820), gender (p=0.566), and smoking status (p=0.709) between surviving and deceased persons. The mean HbA1c of the last year before death or last visit was higher in the deceased than surviving persons (7.5% vs. 7.0%; p=0.010). 57.4% of the surviving and 87.0% of the deceased participants had nephropathy (p=0.012), 79.7% vs. 89.7% retinopathy (p=0.241) and 61.4% vs. 63.3% neuropathy (p=0.860), but only nephropathy was significantly associated with increased mortality risk (HR=4.208, CI:1.226-14.440; HR=2.360, CI:0.696-8.004; HR=0.944, CI:0.436-2.043). Conclusions In the JEVIN population with diabetes mellitus type 1 only, diabetic nephropathy was associated with higher mortality risk.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Creatine Fuels the Thermic Effect of Feeding

Publication date: Available online 24 August 2017
Source:Cell Metabolism
Author(s): Alan R. Saltiel
The current obesity epidemic has focused a great deal of attention on cellular pathways of energy expenditure. While a crucial part of this process is diet-induced thermogenesis, the underlying mechanisms have remained unexplained. In this issue of Cell Metabolism, Kazak et al. (2017) describe a new thermogenic pathway in adipocytes that responds to diet overload, involving creatine cycling. These data suggest that this pathway might limit weight gain during overnutrition.

Teaser

The current obesity epidemic has focused a great deal of attention on cellular pathways of energy expenditure. While a crucial part of this process is diet-induced thermogenesis, the underlying mechanisms have remained unexplained. In this issue of Cell Metabolism, Kazak et al. (2017) describe a new thermogenic pathway in adipocytes that responds to diet overload, involving creatine cycling. These data suggest that this pathway might limit weight gain during overnutrition.


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Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity

Publication date: Available online 24 August 2017
Source:Cell Metabolism
Author(s): Lawrence Kazak, Edward T. Chouchani, Gina Z. Lu, Mark P. Jedrychowski, Curtis J. Bare, Amir I. Mina, Manju Kumari, Song Zhang, Ivan Vuckovic, Dina Laznik-Bogoslavski, Petras Dzeja, Alexander S. Banks, Evan D. Rosen, Bruce M. Spiegelman
Diet-induced thermogenesis is an important homeostatic mechanism that limits weight gain in response to caloric excess and contributes to the relative stability of body weight in most individuals. We previously demonstrated that creatine enhances energy expenditure through stimulation of mitochondrial ATP turnover, but the physiological role and importance of creatine energetics in adipose tissue have not been explored. Here, we have inactivated the first and rate-limiting enzyme of creatine biosynthesis, glycine amidinotransferase (GATM), selectively in fat (Adipo-Gatm KO). Adipo-Gatm KO mice are prone to diet-induced obesity due to the suppression of elevated energy expenditure that occurs in response to high-calorie feeding. This is paralleled by a blunted capacity for β3-adrenergic activation of metabolic rate, which is rescued by dietary creatine supplementation. These results provide strong in vivo genetic support for a role of GATM and creatine metabolism in energy expenditure, diet-induced thermogenesis, and defense against diet-induced obesity.

Graphical abstract

Teaser

Kazak et al. investigate the physiological effects of creatine energetics through loss of function of the rate-limiting enzyme glycine amidinotransferase (GATM) in adipose tissue. Adipo-Gatm KO mice cannot counteract increased calories with energy expenditure and gain weight. Their lower metabolic rate can be rescued by dietary creatine supplementation.


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The FGF21-CCL11 Axis Mediates Beiging of White Adipose Tissues by Coupling Sympathetic Nervous System to Type 2 Immunity

Publication date: Available online 24 August 2017
Source:Cell Metabolism
Author(s): Zhe Huang, Ling Zhong, Jimmy Tsz Hang Lee, Jialiang Zhang, Donghai Wu, Leiluo Geng, Yu Wang, Chi-Ming Wong, Aimin Xu
Type 2 cytokines are important signals triggering biogenesis of thermogenic beige adipocytes in white adipose tissue (WAT) during cold acclimation. However, how cold activates type 2 immunity in WAT remains obscure. Here we show that cold-induced type 2 immune responses and beiging in subcutaneous WAT (scWAT) are abrogated in mice with adipose-selective ablation of FGF21 or its co-receptor β-Klotho, whereas such impairments are reversed by replenishment with chemokine CCL11. Mechanistically, FGF21 acts on adipocytes in an autocrine manner to promote the expression and secretion of CCL11 via activation of ERK1/2, which drives recruitment of eosinophils into scWAT, leading to increases in accumulation of M2 macrophages, and proliferation and commitment of adipocyte precursors into beige adipocytes. These FGF21-elicited type 2 immune responses and beiging are blocked by CCL11 neutralization. Thus, the adipose-derived FGF21-CCL11 axis triggers cold-induced beiging and thermogenesis by coupling sympathetic nervous system to activation of type 2 immunity in scWAT.

Graphical abstract

Teaser

Zhe Huang et al. show that cold activates type 2 immune responses and beiging in subcutaneous WAT through an FGF21-CCL11 axis which drives eosinophil recruitment, M2 macrophage accumulation and proliferation and commitment of beige adipocyte precursors. These findings explain how the immune system communicates with sympathetic nerves to control adaptive thermogenesis.


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The Lymphatic Vasculature: Its Role in Adipose Metabolism and Obesity

Publication date: Available online 24 August 2017
Source:Cell Metabolism
Author(s): Noelia Escobedo, Guillermo Oliver
Obesity is a key risk factor for metabolic and cardiovascular diseases, and although we understand the mechanisms regulating weight and energy balance, the causes of some forms of obesity remain enigmatic. Despite the well-established connections between lymphatics and lipids, and the fact that intestinal lacteals play key roles in dietary fat absorption, the function of the lymphatic vasculature in adipose metabolism has only recently been recognized. It is well established that angiogenesis is tightly associated with the outgrowth of adipose tissue, as expanding adipose tissue requires increased nutrient supply from blood vessels. Results supporting a crosstalk between lymphatic vessels and adipose tissue, and linking lymphatic function with metabolic diseases, obesity, and adipose tissue, also started to accumulate in the last years. Here we review our current knowledge of the mechanisms by which defective lymphatics contribute to obesity and fat accumulation in mouse models, as well as our understanding of the lymphatic-adipose tissue relationship.

Teaser

Obesity and cardiovascular diseases are leading causes of death and disability. In this Review, Oliver and Escobedo expose the relationships between lymphatics, metabolism, and obesity and discuss how this knowledge will provide us with better tools to diagnose and treat some of these pathological conditions.


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Pulmonary fluorosis: a review

Abstract

The increased industrialization and improvised human lifestyle lead to a surge in environmental pollution nowadays. Even the chemicals which are known as prophylactic agents were currently liable to be toxic. One among them is inorganic fluoride whose wider application in numerous processes makes it as an inevitable environmental contaminant and industrial pollutant. Although the systemic toxicity of fluoride has been extensively studied, still there is lacuna in the field of pulmonary fluoride toxicity. Hence, we have focused on the molecular mechanism of action of fluoride compounds on pulmonary system. A study of literatures that focused on the potential physiological and toxicological consequences of fluoride on pulmonary system was carried out. The goal of this review is to present an overview of the research carried out till date on the molecular aspects of fluoride exposure with emphasis on pulmonary system and their possible mechanisms.

http://ift.tt/2xh4UP6

Internship Match and Entry Level Exam Performance of Undergraduate versus Graduate Level Didactic Students

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): B. Leonberg




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Teaching Multiculturalism in an Undergraduate Dietetics Course

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): H. Thornton




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Table of Contents

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9





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Registered Dietitians Facilitate Diabetes Training and Care within a Patient Centered Medical Home Care Delivery Model

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): M. McClarney, M. Timmerman, G. Woscyna, C. Hanson




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Disclosure Page

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement





http://ift.tt/2vtveDB

What's New Online

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9





http://ift.tt/2vb5FMg

Outstanding Dietetics Student Awards, 2017

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9





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Table of Contents

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement





http://ift.tt/2vb4jAT

2017-2018 Officers List and Committee Members

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9





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Sports Dietetics: Impact Beyond Playing Fields

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9
Author(s): Donna S. Martin




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Acknowledgements

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement





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Increased Malnutrition Diagnosis and Reimbursement Indicates Success of Academy of Nutrition and Dietetics Nutrition Focused Physical Exam (NFPE) Hands-on Training Workshop

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): B. Mordarski, R. Hand, J. Wolff, A. Steiber




http://ift.tt/2vtPMvL

Breastfeeding after Gestational Diabetes: GIS Analysis of Maternal-Infant Health Interventions

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): E. MacQuillan, A. Curtis




http://ift.tt/2vb6sfY

Middle East Dietetics Needs Assessment: Identifying Opportunities for Future Collaborative Activities

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): E. Myers, R. Hakeem, N. Bdour, T. Kour, F. Atayata, S. Tashtoush, N. Cakir Bicer, S. Sakar, C. Erginbas, R. Kahill, M. Herrera, M. Boyd




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Back to Basics: All About MyPlate Food Groups

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9
Author(s): Sarah Chang, Kristin Koegel




http://ift.tt/2vaGyZH

Prevalence of Food Insecurity among Hospitalized Patients

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): D. Sowa, C. Hartney, A. Asthana, S. Peterson




http://ift.tt/2vtHTX4

Deepening the Commitment to Interprofessional Education and Practice: Updates from the Global Forum on Innovation in Health Professional Education and the Interprofessional Education Collaborative

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): K. Eliot, K. Kolasa




http://ift.tt/2vbaB3I

Role of Nutrition Focused Physical Exam (NFPE) in the Identification of Malnutrition in Pediatric Patients

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): R. Pipkorn, C. Leon, J. Crouse, N. Fabus, M.B. Feuling, C. Karls, E. Polzin, A. Smith, M. Froh




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Carbohydrate Intake Estimates Do Not Differ by Nursing or Nutrition Discipline or by Two Methods of Evaluation in Acute Care Diabetic Patients at an Academic Medical Center

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): B. Atkinson, M. Perrigue, S. Singh, D. Cuddeback, S. Roesor-Loken, A. Lillie, L. Suhr, D. Corl, W. Brent




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State Dietetic Practice Group Gets Involved in State Regulation Revisions: Relevant, Vital and Never Dull

Publication date: September 2017
Source:Journal of the Academy of Nutrition and Dietetics, Volume 117, Issue 9, Supplement
Author(s): P. Fatzinger McShane, J. Geer, J. Rowley




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Design and Synthesis of Benzoacridines as Estrogenic and Anti-Estrogenic Agents

Publication date: Available online 24 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Kohei Torikai, Rintaro Koga, Xiaohui Liu, Kaoru Umehara, Tatsuya Kitano, Kenji Watanabe, Tohru Oishi, Hiroshi Noguchi, Yasuyuki Shimohigashi
Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERβ (IC50 < μM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).

Graphical abstract

http://ift.tt/2xwLZPC

Pyrrolizines: design, synthesis, anticancer evaluation and investigation of the potential mechanism of action

Publication date: Available online 24 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ahmed M. Gouda, Ahmed H. Abdelazeem, Hany A. Omar, Ashraf N. Abdalla, Mohammed A.S. Abourehab, Hamed I. Ali
A novel set of pyrrolizine-5-carboxamides has been synthesized and evaluated for their anticancer potential against human breast MCF-7, lung carcinoma A549 and hepatoma Hep3B cancer cell lines. Compound 10c was the most active against MCF-7 with IC50 value of 4.72 µM, while compound 12b was the most active against A549 and Hep3B cell lines. Moreover, kinases/COXs inhibition and apoptosis induction were suggested as potential molecular mechanisms for the anticancer activity of the novel pyrrolizines based on their structural features. The new compounds significantly inhibited COX-1 and COX-2 with IC50 values in the ranges of 5.78-11.96 µM and 0.1-0.78 µM, respectively with high COX-2 selectivity over COX-1. Interestingly, the most potent compound in MTT assay, compound 12b, exhibited high inhibitory activity against COX-2 with selectivity index (COX-1/COX-2) > 100. Meanwhile, compound 12b displayed weak to moderate inhibition of six kinases with inhibition% (7-20%) compared to imatinib (inhibition% = 1-38%). The results of cell cycle analysis, annexin V PI/FITC apoptosis assay and caspase-3/7 assay revealed that compound 12b has the ability to induce apoptosis. The docking results of compound 12b into the active sites of COXs, ALK1 and Aurora A indicated that it fits nicely inside their active sites. Overall, the current study highlighted the significant anticancer activity of the newly synthesized pyrrolizines with a potential multi-targeted mechanism which could serve as a base for future studies and further structural optimization into potential anticancer agents.

Graphical abstract

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β-Arrestin biased dopamine D2 receptor partial agonists: synthesis and pharmacological evaluation

Publication date: Available online 24 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Barbara Männel, Harald Hübner, Dorothée Möller, Peter Gmeiner
β-Arrestin biased G protein-coupled receptor ligands represent important molecular probes and may increase favorable drug action and safety as novel therapeutics. Starting from recently discovered hydroxy-substituted heterocyclic piperazine scaffolds, we have developed a series of dopamine D2 receptor ligands with a pyrazolo[1,5-a]pyridine as secondary pharmacophore that is functionalized in position 3 by a formyl or hydroxyiminomethyl substituent. The ligands, especially the benzoxazinone 9d, were found to display substantial β-arrestin-2 recruitment, while being nearly devoid of activity in a GTPγS binding assay. Investigating a new series of truncated analogs lacking a secondary pharmacophore, considerable β-arrestin-2 recruitment in the absence of G protein activation was found, when a 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one was combined with an N-propyl-substituted 1,4-diazepane (15c). Although 15c displayed reduced potency compared to 9d, the dose-response curves indicate that a hydroxy-substituted heterocyclic primary pharmacophore is sufficient for the functionally selective activation of D2R.

Graphical abstract

http://ift.tt/2xwTuWH

Microcystins: Synthesis and structure–activity relationship studies toward PP1 and PP2A

Publication date: Available online 24 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Miriam Fontanillo, Maja Köhn
Microcystins are highly toxic cyanotoxins responsible for plant, animal and human poisoning. Exposure to microcystins, mainly through drinkable water and contaminated food, is a current world health concern. Although it is quite challenging, the synthesis of these potent cyanotoxins, analogs and derivatives helps to detect them, to evaluate their toxicological properties, and to elucidate their binding mechanisms to their main targets Protein Phosphatase-1 (PP1) and -2A (PP2A). This review focuses on synthetic approaches to prepare microcystins and analogs and compiles structure–activity relationship (SAR) studies that describe the unique features of microcystins that make them so potent.

Graphical abstract

http://ift.tt/2xwUH0a