Τρίτη 22 Αυγούστου 2017
Protective efficacy of a hydroxy fatty acid against gastric Helicobacter infections
Abstract
Background
We have previously revealed that omega-3 polyunsaturated fatty acids can prevent Helicobacter pylori infection by blocking the futalosine pathway, an alternative route for menaquinone (MK) biosynthesis.
Materials and Methods
1, Different H. pylori strains were grown in liquid media supplemented with linoleic acid, an omega-6 fatty acid, or its 10-hydroxy derivative, 10-hydroxy-cis-12-octadecenoic acid (HYA), in the presence or absence of MK. The bacterial numbers in the media were estimated by plating; 2, C57BL/6NCrl mice received drinking water supplemented with different fatty acids starting from 1 week before infection with H. pylori or Helicobacter suis until the end of the experiment. The gastric colonization levels of H. pylori or H. suis were determined 2 weeks after infection by plating or quantitative PCR, respectively; 3, Mice were given HYA, starting 1 week before infection with H. suis and continuing until 6 months after infection, for analysis of the gastric conditions.
Results
1, A low concentration (20 μmol/L) of HYA in culture broth suppressed the growth of H. pylori, and this inhibition was reduced by MK supplementation; 2, HYA treatment protected mice against H. pylori or H. suis infection; 3, HYA treatment suppressed the formation of lymphoid follicles in the gastric mucus layer after H. suis infection.
Conclusions
HYA prevents gastric Helicobacter infections by blocking their futalosine pathways. Daily HYA supplementation is effective for the prevention of gastric mucosa-associated lymphoid tissue lymphoma induced by persistent infection with H. suis.
http://ift.tt/2ipOjVS
Efficacy of three-in-one capsule bismuth quadruple therapy for Helicobacter pylori eradication in clinical practice in a multinational patient population
Abstract
Background
Bismuth quadruple therapy (BQT) has been proven superior to standard triple therapy for Helicobacter pylori eradication in randomized clinical trials; however, little is known about the efficacy of BQT in daily routine practice.
Methods
In a single-center cohort study, we analyzed consecutive H. pylori-positive patients in whom three-in-one capsule BQT (Pylera® + omeprazole) has been prescribed. All patients were instructed in a standardized fashion, and a prospective follow-up was planned. PCR on gastric biospies for clarithromycin and levofloxacin resistance was performed before treatment in a subgroup of patients. Treatment outcome was assessed by 13C urea breath test or by histology not earlier than 4 weeks after end of treatment.
Results
Three-in-one capsule BQT has been prescribed in 322 patients. Approximately 70.2% of patients had a migrational background. PCR results were available in 163 patients and identified resistance to clarithromycin and levofloxacin in 29 (17.8%) and 20 (12.3%) of cases, respectively. BQT was prescribed as first-line, second-line, and salvage treatments in 74%, 17%, and 9% of cases, respectively. Five patients discontinued treatment due to side effects (1.8%). By modified intention-to-treat and per-protocol analyzes, the overall H. pylori eradication rates were 95.0% (95% CI 94.92%-95.08%) and 96.7% (95% CI 94.6%-98.8%), respectively. The low number of treatment failures (n = 9) did not allow to identify risk factors for failure.
Conclusion
Three-in-one capsule bismuth quadruple therapy is effective and safe for treatment of H. pylori infection in routine practice, irrespective of the patient's migrational background or the number of previous treatment failures.
http://ift.tt/2g3mJwE
Role of illumination intensity in microcystin development using Microcystis aeruginosa as the model algae
Abstract
Microcystis aeruginosa (M. aeruginosa) is one of the most common genera of cyanobacteria in algal blooms. In the present work, the impact of the illumination intensity on the growth of M. aeruginosa has been studied and a grinding method for the extraction of intracellular microcystins (MCs) was developed. The variations of algal density, pH, total phosphorus (TP), and total nitrogen (TN) have been investigated during MCs' culturing period. Results showed that the extraction efficiency of MC-YR by the grinding method was 275% higher than the sonication method, and the extraction efficiencies of MC-RR and MC-LR by the grinding method were similar to the sonication method. The optimal illumination intensity for M. aeruginosa was found to be 19–38 μmol m−2 s−1 with suitable pH range of 7.5–10.5. Active release of extracellular MCs was not significantly observed when illumination intensities were ≤ 38 μmol m−2 s−1. Furthermore, the intracellular MC yields under different illumination intensities were found to be a relatively stable level. However, excess illumination intensity (≥ 47 μmol m−2 s−1) led to the lysis of algal cell and increased the concentrations of extracellular MCs, with MC-RR as the dominant compound. The calculated intracellular/extracellular MCs ratios for MC-RR, MC-LR, and MC-YR were 2.38 (N = 100, SD = 2.44), 2.68 (N = 64, SD = 3.48), and 1.25 (N = 30, SD = 1.64), respectively. Strong illumination intensity and cell lysis were found to be the two major factors influencing the release of extracellular MCs.
http://ift.tt/2vdn3vR
Comparison of the efficacy and feasibility of laser enucleation of bladder tumor versus transurethral resection of bladder tumor: a meta-analysis
Abstract
The transurethral resection of bladder tumor (TURBT) remains the most widely used method in the surgical treatment of the non-muscle invasive bladder tumor (NMIBT). Despite its popularity, the laser technique has been widely used in urology as an alternative, via the application of transurethral laser enucleation of bladder tumor. The aim of the present study was to compare the efficacy and feasibility between transurethral laser enucleation and transurethral resection of bladder tumor. A systematic search of the following databases was conducted: PubMed, Wed of Science, Cochrane Library, EMBASE, Google scholar, and Medline. The search included studies up to the 1st of January 2017. The outcomes of interest that were used in order to assess the two techniques included operation time, catheterization time, hospitalization time, obturator nerve reflex, bladder perforation, bladder irritation, 24-month-recurrence rate, and the postoperative adjuvant intravesical chemotherapy. A total of 13 trials with 2012 participants were included, of which 975 and 1037 underwent transurethral laser enucleation and transurethral resection of bladder tumor, respectively. No significant difference was noted in the operation time between the two groups, although significant differences were reported for the variables catheterization time, hospitalization time, obturator nerve reflex, bladder perforation, bladder irritation, and 24-month-recurrence rate. In the mitomycin and epirubicin subgroups, no significant differences were observed in the laser enucleation and TURBT methods with regard to the 24-month-recurrence rate. The laser enucleation was superior to TURBT with regard to the parameters obturator nerve reflex, bladder perforation, catheterization time, hospitalization time, and 24-month-recurrence rate. Moreover, laser enucleation can offer a more accurate result of the tumor's pathological stage and grade.
http://ift.tt/2vcNqSw
Rebirth of the Incretin Concept; its conception and early development
Source:Peptides
Author(s): Vincent Marks
This paper describes the resurrection of the Incretin Concept in the early 1960s. It began with the more or less simultaneous discovery by three groups working independently in London. Dupre demonstrated that secretin given intravenously with glucose increased its rate of disappearance from the blood, McIntyre and co-workers established that hyperglycaemia evoked by oral glucose stimulated more insulin secretion than comparable hyperglycaemia produced by intravenous glucose and Marks and Samols established the insulinotropic properties of glucagon. The concept evolved with the discovery by Samols and co-workers that oral glucose stimulated the release of immunoreactive glucagon-like substances from the gut mucosa and the subsequent isolation of glucagon immunoreactive compounds, most notably oxyntomodulin and glicentin, and of gastic inhibitory polypetide (GIP). It concluded with the isolation and characterisation of glucagon-like peptide 1 (7-36) amide.
http://ift.tt/2w1qwyE
Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Alerie Guzman De La Fuente, Simona Lange, Maria Elena Silva, Ginez A. Gonzalez, Herbert Tempfer, Peter van Wijngaarden, Chao Zhao, Ludovica Di Canio, Andrea Trost, Lara Bieler, Pia Zaunmair, Peter Rotheneichner, Anna O'Sullivan, Sebastien Couillard-Despres, Oihana Errea, Maarja A. Mäe, Johanna Andrae, Liqun He, Annika Keller, Luis F. Bátiz, Christer Betsholtz, Ludwig Aigner, Robin J.M. Franklin, Francisco J. Rivera
The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfbret/ret mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.
Graphical abstract
Teaser
Following toxin-induced demyelination in PC-deficient mice and using a number of in vitro approaches, Guzman de la Fuente et al. show that CNS pericytes (PCs) respond to demyelination and, through Lama2 secretion, stimulate oligodendrocyte progenitor cell differentiation during remyelination. These findings extend PC function beyond vascular homeostasis toward regeneration.http://ift.tt/2w1iYfu
Dopamine Encodes Retrospective Temporal Information in a Context-Independent Manner
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Kaitlyn M. Fonzi, Merridee J. Lefner, Paul E.M. Phillips, Matthew J. Wanat
The dopamine system responds to reward-predictive cues to reflect a prospective estimation of reward value, although its role in encoding retrospective reward-related information is unclear. We report that cue-evoked dopamine release in the nucleus accumbens core encodes the time elapsed since the previous reward or rather the wait time. Specifically, a cue that always follows the preceding reward with a short wait time elicits a greater dopamine response relative to a distinct cue that always follows the preceding reward with a long wait time. Differences in the dopamine response between short wait and long wait cues were evident even when these cues were never experienced together within the same context. Conditioned responding updated accordingly with a change in cue-evoked dopamine release but was unrelated to a difference in the dopamine response between cues. Collectively, these findings illustrate that the cue-evoked dopamine response conveys a subjective estimation of the relative reward rate.
Graphical abstract
Teaser
Fonzi et al. demonstrate that cue-evoked dopamine release encodes retrospective time-related information. They find that the dopamine system can discern differences between cues that have never been experienced together in the same context.http://ift.tt/2w1iXbq
The Proprioceptive System Regulates Morphologic Restoration of Fractured Bones
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Ronen Blecher, Sharon Krief, Tal Galili, Eran Assaraf, Tomer Stern, Yoram Anekstein, Gabriel Agar, Elazar Zelzer
Successful fracture repair requires restoration of bone morphology and mechanical integrity. Recent evidence shows that fractured bones of neonatal mice undergo spontaneous realignment, dubbed "natural reduction." Here, we show that natural reduction is regulated by the proprioceptive system and improves with age. Comparison among mice of different ages revealed, surprisingly, that 3-month-old mice exhibited more rapid and effective natural reduction than newborns. Fractured bones of null mutants for transcription factor Runx3, lacking functional proprioceptors, failed to realign properly. Blocking Runx3 expression in the peripheral nervous system, but not in limb mesenchyme, recapitulated the null phenotype, as did inactivation of muscles flanking the fracture site. Egr3 knockout mice, which lack muscle spindles but not Golgi tendon organs, displayed a less severe phenotype, suggesting that both receptor types, as well as muscle contraction, are required for this regulatory mechanism. These findings uncover a physiological role for proprioception in non-autonomous regulation of skeletal integrity.
Graphical abstract
Teaser
Blecher et al. report that natural reduction, the process whereby fractured bones are realigned, fails in mutant mice lacking functional proprioceptive circuitry. Surprisingly, natural reduction was more rapid and effective in 3-month-old mice than in newborns. These findings suggest a physiological role for proprioception in non-autonomous regulation of skeletal integrity.http://ift.tt/2w1iWEo
Constitutive Immune Activity Promotes Tumorigenesis in Drosophila Intestinal Progenitor Cells
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Kristina Petkau, Meghan Ferguson, Silvia Guntermann, Edan Foley
Gut innate immune defenses control bacterial populations and protect the host interior from invasion. Although excess intestinal immune activity frequently promotes inflammatory illnesses, we know little about the consequences of chronic innate immune activity exclusively in endodermal gut cells of an otherwise normal animal. To address this question, we examined the consequences of persistent inflammatory signals in adult fly intestinal progenitor cells. We found that constitutive immune activity disrupts expression of homeostatic regulators such as Notch pathway components and induces hyperplasia throughout the gut. Consistent with these observations, we found that persistent immune signals interfere with progenitor cell differentiation and exacerbate the formation of Notch-dependent intestinal tumors. These findings uncover a link between constitutive immune activity and tumorigenesis in intestinal stem cells.
Graphical abstract
Teaser
Petkau et al. show that persistent immune activity in gut progenitor cells promotes tumorigenesis in adult flies.http://ift.tt/2w1iW7m
Mediator MED23 Links Pigmentation and DNA Repair through the Transcription Factor MITF
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Min Xia, Kun Chen, Xiao Yao, Yichi Xu, Jiaying Yao, Jun Yan, Zhen Shao, Gang Wang
DNA repair is related to many physiological and pathological processes, including pigmentation. Little is known about the role of the transcriptional cofactor Mediator complex in DNA repair and pigmentation. Here, we demonstrate that Mediator MED23 plays an important role in coupling UV-induced DNA repair to pigmentation. The loss of Med23 specifically impairs the pigmentation process in melanocyte-lineage cells and in zebrafish. Med23 deficiency leads to enhanced nucleotide excision repair (NER) and less DNA damage following UV radiation because of the enhanced expression and recruitment of NER factors to chromatin for genomic stability. Integrative analyses of melanoma cells reveal that MED23 controls the expression of a melanocyte master regulator, Mitf, by modulating its distal enhancer activity, leading to opposing effects on pigmentation and DNA repair. Collectively, the Mediator MED23/MITF axis connects DNA repair to pigmentation, thus providing molecular insights into the DNA damage response and skin-related diseases.
Graphical abstract
Teaser
Xia et al. find that MED23 controls Mitf expression by modulating its enhancer function, thus connecting DNA repair to pigmentation.http://ift.tt/2vWQIMl
Coronary Artery Formation Is Driven by Localized Expression of R-spondin3
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Fabio Da Silva, Ana Sofia Rocha, Fariba Jian Motamedi, Filippo Massa, Cem Basboga, Harris Morrison, Kay Dietrich Wagner, Andreas Schedl
Coronary arteries are essential to support the heart with oxygen, and coronary heart disease is one of the leading causes of death worldwide. The coronary arteries form at highly stereotyped locations and are derived from the primitive vascular plexus of the heart. How coronary arteries are remodeled and the signaling molecules that govern this process are poorly understood. Here, we have identified the Wnt-signaling modulator Rspo3 as a crucial regulator of coronary artery formation in the developing heart. Rspo3 is specifically expressed around the coronary stems at critical time points in their development. Temporal ablation of Rspo3 at E11.5 leads to decreased β-catenin signaling and a reduction in arterial-specific proliferation. As a result, the coronary stems are defective and the arterial tree does not form properly. These results identify a mechanism through which localized expression of RSPO3 induces proliferation of the coronary arteries at their stems and permits their formation.
Graphical abstract
Teaser
Coronary arteries supply the heart with blood, and coronary diseases are one of the leading causes of death worldwide. Da Silva et al. find that RSPO3 is specifically expressed around the developing stems of the left and right coronaries, where it promotes their formation by stimulating arterial-specific proliferation through Wnt/β-catenin signaling.http://ift.tt/2vWJAzN
Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Alba Torrents de la Peña, Jean-Philippe Julien, Steven W. de Taeye, Fernando Garces, Miklos Guttman, Gabriel Ozorowski, Laura K. Pritchard, Anna-Janina Behrens, Eden P. Go, Judith A. Burger, Edith E. Schermer, Kwinten Sliepen, Thomas J. Ketas, Pavel Pugach, Anila Yasmeen, Christopher A. Cottrell, Jonathan L. Torres, Charlotte D. Vavourakis, Marit J. van Gils, Celia LaBranche, David C. Montefiori, Heather Desaire, Max Crispin, Per Johan Klasse, Kelly K. Lee, John P. Moore, Andrew B. Ward, Ian A. Wilson, Rogier W. Sanders
The production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 SOSIP.664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp)120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation. The resulting next-generation SOSIP.v5 trimers induce strong autologous tier-2 neutralizing antibody (NAb) responses in rabbits. In addition, the BG505 SOSIP.v6 trimers induced weak heterologous NAb responses against a subset of tier-2 viruses that were not elicited by the prototype BG505 SOSIP.664. These stabilization methods can be applied to trimers from multiple genotypes as components of multivalent vaccines aimed at inducing broadly NAbs (bNAbs).
Graphical abstract
Teaser
Native-like HIV-1 envelope trimers are a platform for efforts to induce broadly neutralizing antibodies. Torrents de la Peña et al. design HIV-1 envelope trimers with enhanced stability and reduced flexibility. These modified trimers improve the induction of neutralizing antibodies and provide new opportunities toward elicitation of broadly neutralizing antibodies.http://ift.tt/2vX5NO3
PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Maria Gato-Cañas, Miren Zuazo, Hugo Arasanz, Maria Ibañez-Vea, Laura Lorenzo, Gonzalo Fernandez-Hinojal, Ruth Vera, Cristian Smerdou, Eva Martisova, Imanol Arozarena, Claudia Wellbrock, Diana Llopiz, Marta Ruiz, Pablo Sarobe, Karine Breckpot, Grazyna Kochan, David Escors
PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity.
Graphical abstract
Teaser
Gato-Cañas et al. find that PDL1 protects cancer cells from interferon toxicity by counteracting interferon signaling through the activities of two non-classical conserved motifs. Human cancers acquire somatic mutations within these motifs that enhance PDL1 anti-interferon activities, favoring tumor progression.http://ift.tt/2vWnugz
Triggering of NOD2 Receptor Converts Inflammatory Ly6Chigh into Ly6Clow Monocytes with Patrolling Properties
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Anne-Julie Lessard, Manon LeBel, Benoit Egarnes, Paul Préfontaine, Peter Thériault, Arnaud Droit, Alexandre Brunet, Serge Rivest, Jean Gosselin
The signals that regulate the fate of circulating monocytes remain unknown. In the present study, we demonstrate that triggering of the NOD2 receptor by muramyl dipeptide (MDP) converts inflammatory Ly6Chigh monocytes into patrolling Ly6Clow monocytes. Administration of MDP to Nr4a1−/− mice, which lack Ly6Clow monocytes, or to Ly6Clow-depleted mice led to the emergence of blood-patrolling monocytes with a profile similar to that of Ly6Clow monocytes, including high expression of CX3CR1 and LFA1. Using intravital microscopy in animal models of inflammatory diseases, we also found that converted Ly6Chigh monocytes patrol the endothelium of blood vessels and that their presence contributes to a reduction in the inflammatory response following MDP injection. Our results demonstrate that NOD2 contributes to the regulation of blood monocytes and suggest that it could be therapeutically targeted to treat inflammatory diseases.
Graphical abstract
Teaser
The signals that regulate the conversion of inflammatory monocytes into patrolling subset(s) remain unknown. Here, Lessard et al. demonstrate that triggering NOD2 transforms inflammatory Ly6Chigh monocytes into Ly6Clow monocytes that look and function like patrolling cells.http://ift.tt/2vWFcAx
Serotonergic Modulation of Sensory Representation in a Central Multisensory Circuit Is Pathway Specific
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Zheng-Quan Tang, Laurence O. Trussell
Many studies have explored how neuromodulators affect synaptic function, yet little is known about how they modify computations at the microcircuit level. In the dorsal cochlear nucleus (DCN), a region that integrates auditory and multisensory inputs from two distinct pathways, serotonin (5-HT) enhances excitability of principal cells, predicting a generalized reduction in sensory thresholds. Surprisingly, we found that when looked at from the circuit level, 5-HT enhances signaling only from the multisensory input, while decreasing input from auditory fibers. This effect is only partially explained by an action on auditory nerve terminals. Rather, 5-HT biases processing for one input pathway by simultaneously enhancing excitability in the principal cell and in a pathway-specific feed-forward inhibitory interneuron. Thus, by acting on multiple targets, 5-HT orchestrates a fundamental shift in representation of convergent auditory and multisensory pathways, enhancing the potency of non-auditory signals in a classical auditory pathway.
Graphical abstract
Teaser
Neuromodulators may alter sensory processing upon changes in behavioral state. Tang and Trussell demonstrate that the neuromodulator serotonin shifts the representation of convergent auditory and multisensory pathways at a microcircuit level, enhancing the potency of non-auditory signals in a classical auditory brain region.http://ift.tt/2vWMHYp
Composition and Control of a Deg/ENaC Channel during Presynaptic Homeostatic Plasticity
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Brian O. Orr, David Gorczyca, Meg A. Younger, Lily Y. Jan, Yuh-Nung Jan, Graeme W. Davis
The homeostatic control of presynaptic neurotransmitter release stabilizes information transfer at synaptic connections in the nervous system of organisms ranging from insect to human. Presynaptic homeostatic signaling centers upon the regulated membrane insertion of an amiloride-sensitive degenerin/epithelial sodium (Deg/ENaC) channel. Elucidating the subunit composition of this channel is an essential step toward defining the underlying mechanisms of presynaptic homeostatic plasticity (PHP). Here, we demonstrate that the ppk1 gene encodes an essential subunit of this Deg/ENaC channel, functioning in motoneurons for the rapid induction and maintenance of PHP. We provide genetic and biochemical evidence that PPK1 functions together with PPK11 and PPK16 as a presynaptic, hetero-trimeric Deg/ENaC channel. Finally, we highlight tight control of Deg/ENaC channel expression and activity, showing increased PPK1 protein expression during PHP and evidence for signaling mechanisms that fine tune the level of Deg/ENaC activity during PHP.
Graphical abstract
Teaser
Orr et al. define the subunit composition of an essential Deg/ENaC channel that controls the rapid induction and sustained expression of presynaptic homeostatic plasticity. The demonstration that PPK1 incorporates into DEG/ENaC channels with diverse physiological activities highlights the potential for tremendous DEG/ENaC channel diversity in Drosophila.http://ift.tt/2vX0BJZ
Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Oliver H. Miller, Andreas Bruns, Imen Ben Ammar, Thomas Mueggler, Benjamin J. Hall
The NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant depression. Understanding how antagonism of NMDARs alters synapse and circuit function is pivotal to developing circuit-based therapies for depression. Using virally induced gene deletion, ex vivo optogenetic-assisted circuit analysis, and in vivo chemogenetics and fMRI, we assessed the role of NMDARs in the medial prefrontal cortex (mPFC) in controlling depression-related behavior in mice. We demonstrate that post-developmental genetic deletion of the NMDAR subunit GluN2B from pyramidal neurons in the mPFC enhances connectivity between the mPFC and limbic thalamus, but not the ventral hippocampus, and reduces depression-like behavior. Using intersectional chemogenetics, we show that activation of this thalamocortical circuit is sufficient to elicit a decrease in despair-like behavior. Our findings reveal that GluN2B exerts input-specific control of pyramidal neuron innervation and identify a medial dorsal thalamus (MDT)→mPFC circuit that controls depression-like behavior.
Graphical abstract
Teaser
In these experiments, Miller et al. show that GluN2B-containing NMDARs are enriched at synapses between the medial dorsal thalamus and medial prefrontal cortex. They also show that post-developmental deletion of these receptors in the mPFC enhances synaptic connectivity and that direct activation of this circuit in vivo drives strong antidepressant-like behavior in mice.http://ift.tt/2vWlEwk
Neurotensin Receptor-1 Identifies a Subset of Ventral Tegmental Dopamine Neurons that Coordinates Energy Balance
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Hillary L. Woodworth, Hannah M. Batchelor, Bethany G. Beekly, Raluca Bugescu, Juliette A. Brown, Gizem Kurt, Patrick M. Fuller, Gina M. Leinninger
Dopamine (DA) neurons in the ventral tegmental area (VTA) are heterogeneous and differentially regulate ingestive and locomotor behaviors that affect energy balance. Identification of which VTA DA neurons mediate behaviors that limit weight gain has been hindered, however, by the lack of molecular markers to distinguish VTA DA populations. Here, we identified a specific subset of VTA DA neurons that express neurotensin receptor-1 (NtsR1) and preferentially comprise mesolimbic, but not mesocortical, DA neurons. Genetically targeted ablation of VTA NtsR1 neurons uncouples motivated feeding and physical activity, biasing behavior toward energy expenditure and protecting mice from age-related and diet-induced weight gain. VTA NtsR1 neurons thus represent a molecularly defined subset of DA neurons that are essential for the coordination of energy balance. Modulation of VTA NtsR1 neurons may therefore be useful to promote behaviors that prevent the development of obesity.
Graphical abstract
Teaser
Woodworth et al. identify a subset of VTA dopamine neurons that express neurotensin receptor-1. Ablation of these neurons leads to enhanced physical activity and energy expenditure that protect mice from diet-induced obesity, revealing an important role for VTA NtR1 neurons in the regulation of body weight.http://ift.tt/2vWPGQw
Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Mikkel Roland Holst, Maite Vidal-Quadras, Elin Larsson, Jie Song, Madlen Hubert, Jeanette Blomberg, Magnus Lundborg, Maréne Landström, Richard Lundmark
Cellular blebbing, caused by local alterations in cell-surface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrin-independent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension-mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol-interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor.
Graphical abstract
Teaser
Holst et al. show that clathrin-independent endocytosis facilitates the rearrangement of the cell surface in response to a decrease in cell volume. This regulation, mediated by the protein GRAF1, suppresses cellular blebbing and the invasiveness of cancer cells, clarifying why GRAF1 acts as a tumor suppressor.http://ift.tt/2vWKpby
Asymmetric Centriole Numbers at Spindle Poles Cause Chromosome Missegregation in Cancer
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Marco R. Cosenza, Anna Cazzola, Annik Rossberg, Nicole L. Schieber, Gleb Konotop, Elena Bausch, Alla Slynko, Tim Holland-Letz, Marc S. Raab, Taronish Dubash, Hanno Glimm, Sven Poppelreuther, Christel Herold-Mende, Yannick Schwab, Alwin Krämer
Chromosomal instability is a hallmark of cancer and correlates with the presence of extra centrosomes, which originate from centriole overduplication. Overduplicated centrioles lead to the formation of centriole rosettes, which mature into supernumerary centrosomes in the subsequent cell cycle. While extra centrosomes promote chromosome missegregation by clustering into pseudo-bipolar spindles, the contribution of centriole rosettes to chromosome missegregation is unknown. We used multi-modal imaging of cells with conditional centriole overduplication to show that mitotic rosettes in bipolar spindles frequently harbor unequal centriole numbers, leading to biased chromosome capture that favors binding to the prominent pole. This results in chromosome missegregation and aneuploidy. Rosette mitoses lead to viable offspring and significantly contribute to progeny production. We further show that centrosome abnormalities in primary human malignancies frequently consist of centriole rosettes. As asymmetric centriole rosettes generate mitotic errors that can be propagated, rosette mitoses are sufficient to cause chromosome missegregation in cancer.
Graphical abstract
Teaser
Extra centrosomes are frequent in human cancers and cause chromosome missegregation via clustering into a pseudo-bipolar mitotic spindle array. Cosenza et al. now demonstrate that centriole rosettes, a transient stage of extra centrosome formation, drive chromosome missegregation in addition to centrosome clustering and are frequently found in primary tumors.http://ift.tt/2vWlzJ2
SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Waaqo Daddacha, Allyson E. Koyen, Amanda J. Bastien, PamelaSara E. Head, Vishal R. Dhere, Geraldine N. Nabeta, Erin C. Connolly, Erica Werner, Matthew Z. Madden, Michele B. Daly, Elizabeth V. Minten, Donna R. Whelan, Ashley J. Schlafstein, Hui Zhang, Roopesh Anand, Christine Doronio, Allison E. Withers, Caitlin Shepard, Ranjini K. Sundaram, Xingming Deng, William S. Dynan, Ya Wang, Ranjit S. Bindra, Petr Cejka, Eli Rothenberg, Paul W. Doetsch, Baek Kim, David S. Yu
DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity.
Graphical abstract
Teaser
SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection and is dysregulated in Aicardi-Goutières syndrome and cancer. Daddacha et al. define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity.http://ift.tt/2vWJtEn
Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Jiameng Dan, Philippe Rousseau, Swanand Hardikar, Nicolas Veland, Jiemin Wong, Chantal Autexier, Taiping Chen
Proper telomere length is essential for embryonic stem cell (ESC) self-renewal and pluripotency. Mouse ESCs (mESCs) sporadically convert to a transient totipotent state similar to that of two-cell (2C) embryos to recover shortened telomeres. Zscan4, which exhibits a burst of expression in 2C-like mESCs, is required for telomere extension in these cells. However, the mechanism by which Zscan4 extends telomeres remains elusive. Here, we show that Zscan4 facilitates telomere elongation by inducing global DNA demethylation through downregulation of Uhrf1 and Dnmt1, major components of the maintenance DNA methylation machinery. Mechanistically, Zscan4 recruits Uhrf1 and Dnmt1 and promotes their degradation, which depends on the E3 ubiquitin ligase activity of Uhrf1. Blocking DNA demethylation prevents telomere elongation associated with Zscan4 expression, suggesting that DNA demethylation mediates the effect of Zscan4. Our results define a molecular pathway that contributes to the maintenance of telomere length homeostasis in mESCs.
Graphical abstract
Teaser
Mouse embryonic stem cells sporadically convert to a transient totipotent (2C-like) state in which shortened telomeres are extended dependent on Zscan4. Dan et al. demonstrate that Zscan4 facilitates telomere elongation by inducing Uhrf1-dependent Uhrf1 and Dnmt1 degradation, leading to global DNA demethylation.http://ift.tt/2vX3k66
Regulation of Peripheral Myelination through Transcriptional Buffering of Egr2 by an Antisense Long Non-coding RNA
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Margot Martinez-Moreno, Timothy Mark O'Shea, John P. Zepecki, Alexander Olaru, Jennifer K. Ness, Robert Langer, Nikos Tapinos
Precise regulation of Egr2 transcription is fundamentally important to the control of peripheral myelination. Here, we describe a long non-coding RNA antisense to the promoter of Egr2 (Egr2-AS-RNA). During peripheral nerve injury, the expression of Egr2-AS-RNA is increased and correlates with decreased Egr2 transcript and protein levels. Ectopic expression of Egr2-AS-RNA in dorsal root ganglion (DRG) cultures inhibits the expression of Egr2 mRNA and induces demyelination. In vivo inhibition of Egr2-AS-RNA using oligonucleotide GapMers released from a biodegradable hydrogel following sciatic nerve injury reverts the EGR2-mediated gene expression profile and significantly delays demyelination. Egr2-AS-RNA gradually recruits H3K27ME3, AGO1, AGO2, and EZH2 on the Egr2 promoter following sciatic nerve injury. Furthermore, expression of Egr2-AS-RNA is regulated through ERK1/2 signaling to YY1, while loss of Ser184 of YY1 regulates binding to Egr2-AS-RNA. In conclusion, we describe functional exploration of an antisense long non-coding RNA in peripheral nervous system (PNS) biology.
Graphical abstract
Teaser
Martinez-Moreno et al. report a role for a long non-coding RNA antisense to the promoter of Egr2, Egr2-AS-RNA, during the response to peripheral nerve injury. Inhibition of Egr2-AS-RNA following sciatic nerve injury reverts EGR2-mediated gene expression and delays demyelination.http://ift.tt/2vWPD7i
Peptide-Based Scaffolds Support Human Cortical Progenitor Graft Integration to Reduce Atrophy and Promote Functional Repair in a Model of Stroke
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Fahad A. Somaa, Ting-Yi Wang, Jonathan C. Niclis, Kiara F. Bruggeman, Jessica A. Kauhausen, Haoyao Guo, Stuart McDougall, Richard J. Williams, David R. Nisbet, Lachlan H. Thompson, Clare L. Parish
Stem cell transplants offer significant hope for brain repair following ischemic damage. Pre-clinical work suggests that therapeutic mechanisms may be multi-faceted, incorporating bone-fide circuit reconstruction by transplanted neurons, but also protection/regeneration of host circuitry. Here, we engineered hydrogel scaffolds to form "bio-bridges" within the necrotic lesion cavity, providing physical and trophic support to transplanted human embryonic stem cell-derived cortical progenitors, as well as residual host neurons. Scaffolds were fabricated by the self-assembly of peptides for a laminin-derived epitope (IKVAV), thereby mimicking the brain's major extracellular protein. Following focal ischemia in rats, scaffold-supported cell transplants induced progressive motor improvements over 9 months, compared to cell- or scaffold-only implants. These grafts were larger, exhibited greater neuronal differentiation, and showed enhanced electrophysiological properties reflective of mature, integrated neurons. Varying graft timing post-injury enabled us to attribute repair to both neuroprotection and circuit replacement. These findings highlight strategies to improve the efficiency of stem cell grafts for brain repair.
Graphical abstract
Teaser
Somaa et al. examine the capacity of peptide-based scaffolds to structurally and functionally support human pluripotent stem cell-derived neural transplants in the stroke-injured brain. Scaffolds promoted graft maturation and integration and reduced host tissue atrophy, resulting in improved motor function over a period of 9 months.http://ift.tt/2vXdIuY
Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics
Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Nigel G. Kooreman, Patricia E. de Almeida, Jonathan P. Stack, Raman V. Nelakanti, Sebastian Diecke, Ning-Yi Shao, Rutger-Jan Swijnenburg, Veronica Sanchez-Freire, Elena Matsa, Chun Liu, Andrew J. Connolly, Jaap F. Hamming, Paul H.A. Quax, Michael A. Brehm, Dale L. Greiner, Leonard D. Shultz, Joseph C. Wu
There is growing interest in using embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) derivatives for tissue regeneration. However, an increased understanding of human immune responses to stem cell-derived allografts is necessary for maintaining long-term graft persistence. To model this alloimmunity, humanized mice engrafted with human hematopoietic and immune cells could prove to be useful. In this study, an in-depth analysis of graft-infiltrating human lymphocytes and splenocytes revealed that humanized mice incompletely model human immune responses toward allogeneic stem cells and their derivatives. Furthermore, using an "allogenized" mouse model, we show the feasibility of reconstituting immunodeficient mice with a functional mouse immune system and describe a key role of innate immune cells in the rejection of mouse stem cell allografts.
Graphical abstract
Teaser
Kooreman et al. use various types of humanized mice for the modeling of pluripotent stem cell alloimmunity. They report the development of a wasting disease-like syndrome within these mice over time, limiting their functionality, and provide ways to address this by using an immune reconstituted "allogenized" mouse model.http://ift.tt/2vWMBjv
Terminating the criminal collaboration in pancreatic cancer: Nanoparticle-based synergistic therapy for overcoming fibroblast-induced drug resistance
Publication date: November 2017
Source:Biomaterials, Volume 144
Author(s): Liying Wang, Xiangrui Liu, Quan Zhou, Meihua Sui, Zipeng Lu, Zhuxian Zhou, Jianbin Tang, Yi Miao, Min Zheng, Weilin Wang, Youqing Shen
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a dismal overall prognosis mainly unchanged over the past decades. PDAC is generally refractory to conventional treatments, and thus novel therapies are urgently needed. Recently, accumulating evidence has indicated that human pancreatic stellate cells (PSCs) facilitate PDAC development and drug resistance through paracrine activation of hedgehog pathway. Here, we report that smart SN38 (active metabolite of irinotecan) polymeric prodrug-based nanoparticles effectively encapsulate the commercial hedgehog pathway inhibitor GDC-0449 for co-delivery. More intriguingly, we obtained size-tunable nanoparticles with increased GDC-0449 loading efficiency by simply extending the chain length of the hydrophobic SN38 block. To better evaluate the efficacy and investigate the synergistic mechanisms, we immortalized human PSCs and established fibroblast-containing models in vitro and in vivo. In PSCs, BxPC-3 cells and MIA PaCa-2 cells, GDC-0449 suppressed the co-culture induced up-regulations of the two drug resistance contributors: sonic hedgehog transcription factor glioma-associated protein1 (GLI-1) and UGT1A glucuronosyltransferase. Importantly, the nanoparticle-mediated co-delivery system exhibited potent antitumor efficacy with enhanced apoptosis and reduced collagen, α-SMA and GLI-1 expression in tumor tissues. These findings reveal a potential strategy to utilize nanoparticle-mediated drug co-delivery platform as an effective combination therapy for fibroblast-enriched PDAC.
http://ift.tt/2w11UWF
Convex Bone Deformity after Closed Reduction of Nasal Bone Fracture
Nasal fractures are the most common type of facial fracture treated by plastic surgeons. Here, we clarify the postoperative deformities that frequently remain after closed reduction of fresh nasal bone fracture by three-dimensional computed tomography (3D-CT).
http://ift.tt/2vcN2TR
Clinical Outcomes for Minimally Invasive Primary and Secondary Orbital Reconstruction using an Advanced Synergistic Combination of Navigation and Endoscopy
Sequelae of inadequate orbital reconstruction include enophthalmos, hypoglobus, and diplopia. Accuracy of orbital reconstruction is largely subjective and especially difficult to achieve due to anatomic distortion in secondary or late reconstruction and in extensive injury. We combined computer navigation and endoscopy to perform accurate, aesthetic, and safe minimal-access primary and secondary orbital reconstruction.
http://ift.tt/2wCP0k7
Sentinel lymph node biopsy for thin melanomas under the American Joint Committee on Cancer 8th edition cancer staging system
The American Joint Committee on Cancer (AJCC) will implement the 8th edition of their cancer staging system on the 1st January 2018, with changes to the way in which thin melanomas are classified. Our understanding of these criteria contrasts with previous correspondence in this journal.1 Tumours with a Breslow thickness <0.8mm will be classified as T1a if they do not exhibit ulceration, and as T1b if they do exhibit ulceration. All tumours measuring 0.8-1.0mm thick will be reclassified as T1b regardless of ulceration.
http://ift.tt/2vcZ8N5
Preventing the Complications of Tissue Expansion Using Fat Grafting Under Expanded Skin
We read with great interest the brief clinical report entitled "Preventing the complications of tissue expansion using fat grafting under expanded skin" by Jiang et al.1 The authors demonstrate for the first time a technique improving the texture of expanded skin and preventing expansion failure by lipofilling into the ischemic region of the expanded flap. We would like to congratulate the authors for their primary work to make the skin expansion can be smoothly completed. Improving expansion efficiency and decreasing complications of expansion are always the subjects that we have thought a great deal about and worked intensively on.
http://ift.tt/2wCmzTq
Motor Nerve to the Masseter: A Pediatric Anatomic Study and the “3:1 Rule”
The motor nerve to the masseter (masseteric nerve) provides a robust local neural source for facial reanimation and nerve transfer. Its intraoperative identification is well-described in adults. The purpose of this study was to determine the location of the motor nerve to the masseter in the pediatric population using surgical landmarks.
http://ift.tt/2vcQBti
Non-living microvascular training models: Face validity of liquid latex and the challenge of structural vs. “physiological” patency assessment
Microvascular anastomosis training increasingly uses assessment tools to objectively evaluate the surgeons' performance and to track progression in this challenging learning curve. The first steps in microvascular skills acquisition are accomplished via a variety of training models in a safe simulation training environment1, with an increasing use of non-living biological models over living animal models, in line with the ethical considerations of replacement, reduction and refinement.
http://ift.tt/2wlo2xO
Development of a Universal Nutritional Screening Platform for Plastic Surgery Patients
Background: Plastic surgeons routinely see patients with complex or chronic wounds of all etiology. In a previous study, we found that up to 1 in 4 of these patients is at risk for malnutrition, which may be influencing their ability to heal. The goal of this study was to develop and validate a universal screening protocol that would be fast and accurate and allow for effective intervention and optimization of nutrition before plastic surgery. Methods: To accomplish these goals, we adopted a 2-part screening algorithm using the Canadian Nutritional Screening Tool (CNST) to triage patients in our outpatient clinics and then further screened those identified as being at risk using the Subjective Global Assessment (SGA) tool and blood work. Results: We screened 111 patients with diagnoses related to breast cancer (n = 10; 9.01%), elective surgery (n = 38; 34.23%), emergency surgery (n = 8; 7.21%), fractures (n = 15; 13.51%), and wounds (n = 40; 36.04%). Of the screened subjects, 15.32% (n = 17) were found to be at nutritional risk using the CNST, and 13 were confirmed to be moderately or severely malnourished using the SGA. Importantly, there were no positive correlations between nutritional status and smoking, diabetes, body mass index, or age, indicating that a universal screening protocol is needed to effectively screen a diverse plastic surgery population for malnutrition. Conclusions: Screening patients with both the CNST and the SGA is an effective way to identify patients before surgery to improve outcomes.http://ift.tt/2g3LyJ0
Effects of river-lake interactions in water and sediment on phosphorus in Dongting Lake, China
Abstract
As a large river connected lake, Dongting Lake is influenced by anthropogenic activities and the discharge from its upstream tributaries in the lake basin and by the water recharge via a connection to the Yangtze River (YR) outside the basin. This makes the lake phosphorous cycle more complex than that in other disconnected lakes. Here, we calculated section fluxes and ran a hydrodynamic model to investigate the phosphorus (P) variations in response to the changing interactions in the water and sediment between the YR, four tributaries, and the lake. Results show that particulate P was the dominant form with a significant linear relationship with suspended sediment (r 2 = 0.906). The sediment input reduction from the YR through three water inlets, which is closely related to the Three Gorges Reservoir operation since 2003, led to a decrease in the total P (TP) concentration in the western Dongting Lake. However, the impact and range of this decrease were fairly limited. Compared with the limited effect of the YR, the raised TP flux from the Yuanjiang tributary controlled the TP concentration at the outlet of the western Dongting Lake. Apart from the influence of the YR and the tributaries, anthropogenic activities (sand dredging) in the eastern Dongting Lake also contributed to a high TP concentration around the S10 area through sediment resuspension. We suggest that, compared with the reduction in TP flux and sediment load from the connected Yangtze River outside the basin, the elements within the basin (increased TP input from tributaries and sand dredging) have a greater effect on the variations of TP in Dongting Lake.
http://ift.tt/2vmrJhY
Microbial diversity in solar greenhouse soils in Round-Bohai Bay-Region, China: The influence of cultivation year and environmental condition
Abstract
Round-Bohai Bay (RBB)-Region is an important crop production area in China, where vegetables are mainly produced in solar greenhouses. However, excessive fertilization and monoculture have caused serious deterioration of soil quality in this region. Soil microbial communities play pivotal roles in many ecosystem processes and are recognized as integrative components of soil quality. Therefore, in this study, we investigated bacterial and fungal diversity in solar greenhouse soils covering a wide range of cultivation year (CY) and sampling site (SS), by using pyrosequencing technology. Surprisingly, CY and SS had little influence on bacterial and fungal relative abundance and diversity. However, environmental factors (EF) and soil available potassium (K) in particular made a significant contribution to the variation of soil bacterial and fungal communities. Specifically, K showed significant (P < 0.05) correlations with dominant bacterial phyla Bacteroidetes, Acidobacteria, Chloroflexi, and Planctomycetes and fungal phyla Ascomycota and Basidiomycota. These results suggested that soil EF appeared more important than CY and SS in shaping the compositions of bacterial and fungal communities. In addition, since fertilizer K has been in the long-term abused in RBB-Region, future vegetable production should pay more attention to K input to reduce the negative effect on soil microbial communities.
http://ift.tt/2v3C3jK
A Comparative Study of the Effects of Sodium Selenite and Glutathione Mono Ethyl Ester on Aged Adipose-Derived Stem Cells: The Telomerase and Cellular Responses
Rejuvenation Research , Vol. 0, No. 0.
http://ift.tt/2vm4AMK
Microbial community composition and electricity generation in cattle manure slurry treatment using microbial fuel cells: effects of inoculum addition
Abstract
Microbial fuel cell (MFC) is a sustainable technology to treat cattle manure slurry (CMS) for converting chemical energy to bioelectricity. In this work, two types of allochthonous inoculum including activated sludge (AS) and domestic sewage (DS) were added into the MFC systems to enhance anode biofilm formation and electricity generation. Results indicated that MFCs (AS + CMS) obtained the maximum electricity output with voltage approaching 577 ± 7 mV (~ 196 h), followed by MFCs (DS + CMS) (520 ± 21 mV, ~ 236 h) and then MFCs with autochthonous inoculum (429 ± 62 mV, ~ 263.5 h). Though the raw cattle manure slurry (RCMS) could facilitate electricity production in MFCs, the addition of allochthonous inoculum (AS/DS) significantly reduced the startup time and enhanced the output voltage. Moreover, the maximum power (1.259 ± 0.015 W/m2) and the highest COD removal (84.72 ± 0.48%) were obtained in MFCs (AS + CMS). With regard to microbial community, Illumina HiSeq of the 16S rRNA gene was employed in this work and the exoelectrogens (Geobacter and Shewanella) were identified as the dominant members on all anode biofilms in MFCs. For anode microbial diversity, the MFCs (AS + CMS) outperformed MFCs (DS + CMS) and MFCs (RCMS), allowing the occurrence of the fermentative (e.g., Bacteroides) and nitrogen fixation bacteria (e.g., Azoarcus and Sterolibacterium) which enabled the efficient degradation of the slurry. This study provided a feasible strategy to analyze the anode biofilm formation by adding allochthonous inoculum and some implications for quick startup of MFC reactors for CMS treatment.
http://ift.tt/2wBhhYr
Distribution of polybrominated diphenyl ethers in breast milk, cord blood and placentas: a systematic review
Abstract
Polybrominated diphenyl ethers (PBDEs) have been extensively used as flame retardants in consumer products. PBDEs rapidly bioaccumulate in the environment, food, wild animals and humans. In this review, we investigated the harmful effects of PBDEs on humans, especially in early life, and summarised the levels of PBDEs in human biological samples (breast milk, cord blood and placentas). In addition, we described the spatiotemporal distribution of PBDEs in this review. PBDE levels in breast milk, cord blood and placentas were generally higher in North America than in other regions, such as Asia, Europe, Oceania and Africa. However, high levels of PBDEs in human biological samples were detected at e-waste recycling sites in South China, East China and South Korea. This finding suggests that newborns living in e-waste regions are exposed to high levels of PBDEs during prenatal and postnatal periods. The time trends of PBDE concentration differed according to the region. Few studies have investigated PBDE levels in humans from 1967 to 2000, but they increased rapidly after 2000. PBDE concentration peaked at approximately 2006 globally. Compared with other PBDE congeners, BDE-47, BDE-153 and BDE-209 were the major components, but the detection rate of BDE-209 was lower than those of others. Future studies should focus on determining the BDE-209 concentration, which requires the implementation of different analytical approaches. Additionally, the levels of PBDEs in human samples and the environment should be monitored, especially in e-waste recycling regions.
Graphical abstract
The figures described the spatial distribution of the lowest (Fig. a1) and highest concentration of ∑PBDE (Fig. a2) in different countries by 2006 and described the spatial distribution of the lowest (Fig. b1) and highest concentration of ∑PBDE (Fig. b2) in different countries from 2007 to 2015. All the figures indicated that the levels of PBDEs in North America were substantially higher than those in many regions of Europe, Asia, Oceania, or Africa. Comparing Fig. a1–b1 or Fig. a2–b2, increasing trends were observed in some countries, especially in some regions in China, Korea and Canada.
http://ift.tt/2wB6bmi
Low-temperature stress: is phytohormones application a remedy?
Abstract
Among the various abiotic stresses, low temperature is one of the major environmental constraints that limit the plant development and crop productivity. Plants are able to adapt to low-temperature stress through the changes in membrane composition and activation of reactive oxygen scavenging systems. The genetic pathway induced due to temperature downshift is based on C-repeat-binding factors (CBF) which activate promoters through the C-repeat (CRT) cis-element. Calcium entry is a major signalling event occurring immediately after a downshift in temperature. The increase in the level of cytosolic calcium activates many enzymes, such as phospholipases and calcium dependent-protein kinases. MAP-kinase module has been shown to be involved in the cold response. Ultimately, the activation of these signalling pathways leads to changes in the transcriptome. Several phytohormones, such as abscisic acid, brassinosteroids, auxin, salicylic acid, gibberellic acid, cytokinins and jasmonic acid, have been shown to play key roles in regulating the plant development under low-temperature stress. These phytohormones modulate important events involved in tolerance to low-temperature stress in plants. Better understanding of these events and genes controlling these could open new strategies for improving tolerance mediated by phytohormones.
http://ift.tt/2im6pIe
UPAR Targeted Molecular Imaging of Cancers with Small Molecule-Based Probes
Publication date: Available online 22 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Feng Ding, Seng Chen, Wanshu Zhang, Yufeng Tu, Yao Sun
Molecular imaging can allow the non-invasive characterization and measurement of biological and biochemical processes at the molecular and cellular levels in living subjects. The imaging of specific molecular targets that are associated with cancers could allow for the earlier diagnosis and better treatment of diseases. Small molecule-based probes play prominent roles in biomedical research and have high clinical translation ability. Here, with an emphasis on small molecule-based probes, we review some recent developments in biomarkers, imaging techniques and multimodal imaging in molecular imaging and highlight the successful applications for molecular imaging of cancers.
Graphical abstract
http://ift.tt/2wuXQBb
Design, Synthesis and Biological Evaluation of 1,3-diphenylbenzo[f][1,7]naphthyrdines
Publication date: Available online 22 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sateesh Kumar Arepalli, Byeongwoo Park, Kiho Lee, Hyunji Jo, Kyu-Yeon Jun, Youngjoo Kwon, Jong-Soon Kang, Jae-Kyung Jung, Heesoon Lee
A novel series of twenty 1,3-diphenylbenzo[f][1,7]benzonaphthyrdine derivatives were designed and synthesized through intermolecular imino Diels-Alder reaction. Their in vitro cytotoxic activities were evaluated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Majority of synthesized compounds exhibited significant cytotoxic activities against all tested human cancer cell lines. Among them 4l, 4m, and 4o derivatives exhibited most promising cytotoxic activities. Furthermore these compounds were evaluated against human Topoisomerase IIα inhibition. Interestingly, the compound 4l exhibited 1.3 and 1.2 times more potent human Topoisomerase IIα inhibition than the reference drug etoposide in both 100 µM and 20 µM concentrations respectively. Molecular docking studies for the compound 4l have also been executed by Sybyl X-2.1 in which it reveals the binding site of the compound 4l with topo IIα DNA cleavage site where etoposide was situated. The benzo[f][1,7]naphthyridine ring was stacked between the DNA bases of the cleavage site.
Graphical abstract
http://ift.tt/2wuXuum
Synthesis and preliminary in vivo evaluation of new [18F]fluoro-inositols as Positron Emission Tomography radiotracers
Publication date: Available online 22 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Charlotte Collet, Sébastien Schmitt, Fatiha Maskali, Alexandra Clément, Françoise Chrétien, Gilles Karcher, Pierre-Yves Marie, Sylvain Poussier, Sandrine Lamandé-Langle
This study describes the synthesis and radiosynthesis of eight new [18F]fluoro-inositol-based radiotracers in myo- and scyllo- inositol configuration. These radiotracers are equipped with a propyl linker bearing fluorine-18. This fluorinated arm is either on a hydroxyl group, i.e. O-alkylated inositols, or on the cyclohexyl backbone, i.e. C-branched derivatives. To modulate lipophilicity, inositols were synthesized in acetylated or hydroxylated form. Automated radiosynthesis was performed on the AllInOne module and the radiotracers were produced in good radiochemical yields (15 to 31.5% dc). Preliminary in vivo preclinical evaluation of these eight [18F]fluoro-inositols as Positron Emission Tomography (PET) imaging agents in a breast tumour-bearing mouse model was performed and compared with [18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG). Amongst the different inositols, [18F]myo-2 showed the highest tumour uptake 2.34 ±0.39%ID/g, revealing the potential of this tracer for monitoring breast cancer.
Graphical abstract
http://ift.tt/2wuTcmE
Analysis of the binding sites of vitamin D 1α-hydroxylase (CYP27B1) and vitamin D 24-hydroxylase (CYP24A1) for the design of selective CYP24A1 inhibitors: homology modelling, molecular dynamics simulations and identification of key binding requirements
Publication date: Available online 22 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ismail M. Taban, Jinge Zhu, Hector F. DeLuca, Claire Simons
A homology model of human CYP27B1 was built using MOE and ith further optimisation by molecular dynamics simulations of the hCYP27B1 homology model and a hCYP27B1-SDZ-88357 complex. Docking results from the hCYP27B1-SDZ-88357 complex showed amino acids Arg107, Asn387 and Asp320 have an important role in binding interaction, with Asp320 part of the important acid - alcohol pair situated in the I-helix with the conserved sequence (A/G) GX (E/D) (T/S), which assumes an essential role in the binding of an oxygen molecule for catalysis. Additional docking experiments with selective hCYP27B1 or hCYP24A1 inhibitors using both the hCYP27B1 model and a triple mutant hCYP24A1 model provided further support for the importance of H-bonding interactions with the three identified active site amino acids. To confirm the role of Arg107, Asn387 and Asp320 in the active site of hCYP27B1 compounds were designed that would form H-bonding interactions, as determined from docking experiments with hCYP27B1 model. Subsequent synthesis and CYP24A1 and CYP27B1 enzyme assays of the designed compounds 1a and 1b showed a ∼ 5-fold selectivity for CYP27B1 confirming the importance of Asp320 in particular and also Asn387 and Arg107 as important amino acids for CYP27B1 inhibitory activity.
Graphical abstract
http://ift.tt/2wv4siT
Psoriasis or not? Review of 51 clinically confirmed cases reveals an expanded histopathologic spectrum of psoriasis
Abstract
Background
Psoriasis is usually diagnosed clinically, so only non-classic or refractory cases tend to be biopsied. Diagnostic uncertainty persists when dermatopathologists encounter features regarded as non-classic for psoriasis.
Objective
Define and document classic and non-classic histologic features in skin biopsies from patients with clinically confirmed psoriasis.
Methods
Minimal clinical diagnostic criteria were informally validated and applied to a consecutive series of biopsies histologically consistent with psoriasis. Clinical confirmation required two of the following criteria: 1. classic morphology, 2. classic distribution, 3. nail pitting, 4. family history, with #1 and/or #2 as one criterion in every case
Results
Fifty-one biopsies from 46 patients were examined. Classic features of psoriasis included hypogranulosis (96%), club-shaped rete ridges (96%), dermal papilla capillary ectasia (90%), Munro microabscess (78%), suprapapillary plate thinning (63%), spongiform pustules (53%), and regular acanthosis (14%). Non-classic features included irregular acanthosis (84%), junctional vacuolar alteration (76%), spongiosis (76%), dermal neutrophils (69%), necrotic keratinocytes (67%), hypergranulosis (65%), neutrophilic spongiosis (61%), dermal eosinophils (49%), compact orthokeratosis (37%), papillary dermal fibrosis (35%), lichenoid infiltrate (25%), plasma cells (16%), and eosinophilic spongiosis (8%).
Conclusions
Psoriasis exhibits a broader histopathologic spectrum. The presence of some non-classic features does not necessarily exclude the possibility of psoriasis.
http://ift.tt/2vUGA6O
Scholar : These new articles for Asia Pacific Translation and Intercultural Studies are available online
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Scholar : These new articles for Advanced Robotics are available online
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Comparative study of the formation of brominated disinfection byproducts in UV/persulfate and UV/H 2 O 2 oxidation processes in the presence of bromide
Abstract
The objective of this research was to compare the transformation of Br− and formation of brominated byproducts in UV/persulfate (PS) and UV/H2O2 processes. It was revealed that Br− was efficiently transformed to free bromine which reacted with humic acid (HA) or dihydroxybenzoic acid resulting in the formation of brominated byproducts such as bromoacetic acids (BAAs) in UV/PS system. In contrast, no free bromine and brominated byproducts could be detected in UV/H2O2 system, although the oxidization of Br− was evident. We presumed that the oxidation of Br− by hydroxyl radicals led to the formation of bromine radicals. However, the bromine radical species could be immediately reduced back to Br− by H2O2 before coupling to each other to form free bromine, which explains the undetection of free bromine and BAAs in UV/H2O2. In addition to free bromine, we found that the phenolic functionalities in HA molecules, which served as the principal reactive sites for free chlorine attack, could be in situ generated when HA was exposed to free radicals. This study demonstrates that UV/H2O2 is more suitable than UV/PS for the treatment of environmental matrices containing Br−.
Graphical abstract
Graphical abstract
http://ift.tt/2vb2n7m
Cytologic features of tubular adenoma of ampulla causing distal common bile duct stricture: A case report and review of the literature
CytoJournal 2017 14(1):19-19
Adenomas of the ampulla of Vater are distinctly rare, representing <10% of periampullary neoplasms. Very few reports of the cytologic features of ampullary adenomas are present in literature, particularly in bile duct brushing samples. A case report and review of the literature is presented. The typical cytologic features of ampullary adenomas on cytologic preparations include tall, thin columnar cells with mildly hyperchromatic elongated nuclei and nuclear pseudostratification, in a relatively clean background. The key differential diagnostic entities include invasive adenocarcinoma, thermal artifact, and reactive atypia.
http://ift.tt/2g0GEN2
Can an inadequate cervical cytology sample in ThinPrep be converted to a satisfactory sample by processing it with a SurePath preparation?
CytoJournal 2017 14(1):20-20
Background: The Norwegian Cervical Cancer Screening Program recommends screening every 3 years for women between 25 and 69 years of age. There is a large difference in the percentage of unsatisfactory samples between laboratories that use different brands of liquid-based cytology. We wished to examine if inadequate ThinPrep samples could be satisfactory by processing them with the SurePath protocol. Materials and Methods: A total of 187 inadequate ThinPrep specimens from the Department of Clinical Pathology at University Hospital of North Norway were sent to Akershus University Hospital for conversion to SurePath medium. Ninety-one (48.7%) were processed through the automated "gynecologic" application for cervix cytology samples, and 96 (51.3%) were processed with the "nongynecological" automatic program. Results: Out of 187 samples that had been unsatisfactory by ThinPrep, 93 (49.7%) were satisfactory after being converted to SurePath. The rate of satisfactory cytology was 36.6% and 62.5% for samples run through the "gynecology" program and "nongynecology" program, respectively. Of the 93 samples that became satisfactory after conversion from ThinPrep to SurePath, 80 (86.0%) were screened as normal while 13 samples (14.0%) were given an abnormal diagnosis, which included 5 atypical squamous cells of undetermined significance, 5 low-grade squamous intraepithelial lesion, 2 atypical glandular cells not otherwise specified, and 1 atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion. A total of 2.1% (4/187) of the women got a diagnosis of cervical intraepithelial neoplasia 2 or higher at a later follow-up. Conclusions: Converting cytology samples from ThinPrep to SurePath processing can reduce the number of unsatisfactory samples. The samples should be run through the "nongynecology" program to ensure an adequate number of cells.
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Macrophages induce EMT to promote invasion of lung cancer cells through the IL-6-mediated COX-2/PGE2/β-catenin signalling pathway
Source:Molecular Immunology, Volume 90
Author(s): Dehai Che, Shuai Zhang, Zihan Jing, Lihua Shang, Shi Jin, Fang Liu, Jing Shen, Yue Li, Jing Hu, Qingwei Meng, Yan Yu
Infiltration of macrophages plays a critical role in the connection between inflammation and cancer invasion; however, the molecular mechanism that enables this crosstalk remains unclear. This paper investigates a molecular link between infiltration of macrophages and metastasis of lung cancer cells.In this study, the macrophage density and cyclooxygenase-2 (COX-2) protein were examined in surgical specimens by immunohistochemistry (IHC), and the prostaglandin E2 (PGE2) levels were determined in the blood of 30 non-small cell lung cancer (NSCLC) patients using enzyme-linked immunosorbent assay (ELISA). We demonstrated that macrophage infiltration was significantly associated with elevated tumour COX-2 expression and serum PGE2 levels in NSCLC patients. Interestingly, the COX-2 and PGE2 levels as well as macrophages were poor predictors of NSCLC patient survival. THP-1-derived macrophages were co-cultured in vitro with A549 and H1299 lung cancer cells. In the co-culture process, interleukin-6 (IL-6) induced the COX-2/PGE2 pathway in lung cancer cells, which subsequently promoted β-catenin translocation from the cytoplasm to the nucleus, resulting in epithelial-mesenchymal transition (EMT) and lung cancer cell invasion.Our findings show that the IL-6-dependent COX-2/PGE2 pathway induces EMT to promote invasion of tumour cells through β-catenin activation during the interaction between macrophages and lung cancer cells, which suggests that inhibition of COX-2/PGE2 or macrophages has the potential to suppress metastasis of lung cancer cells.
http://ift.tt/2wu9Lzf
Utomilumab and ISA101b Vaccination in Patients With HPV-16-Positive Incurable Oropharyngeal Cancer
Conditions: Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites; Malignant Neoplasms of Lip Oral Cavity and Pharynx; Oropharyngeal Cancer
Interventions: Drug: Utomilumab; Biological: ISA101b
Sponsors: M.D. Anderson Cancer Center; ISA Pharmaceuticals B.V.; Pfizer
Not yet recruiting - verified August 2017
http://ift.tt/2vkF3DK
Interventions: Drug: Utomilumab; Biological: ISA101b
Sponsors: M.D. Anderson Cancer Center; ISA Pharmaceuticals B.V.; Pfizer
Not yet recruiting - verified August 2017
http://ift.tt/2vkF3DK
Percutaneous Ethanol Injection for Benign Cystic Thyroid Nodules
Condition: Thyroid Nodule
Intervention: Drug: ethanol injection
Sponsor: hassan harby
Recruiting - verified August 2017
http://ift.tt/2v22rdV
Intervention: Drug: ethanol injection
Sponsor: hassan harby
Recruiting - verified August 2017
http://ift.tt/2v22rdV
Scholar : These new articles for Acta Linguistica Hafniensia are available online
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Scholar : These new articles for Australian Journal of Earth Sciences are available online
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Scholar : These new articles for Acta Agriculturae Scandinavica, Section B — Soil & Plant Science are available online
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