Many-Body Superradiance and Dynamical Mirror Symmetry Breaking in Waveguide QED.

The many-body decay of extended collections of two-level systems remains an open problem. Here, we investigate whether an array of emitters coupled to a one-dimensional bath undergoes Dicke superradiance. This is a process whereby a completely inverted system becomes correlated via dissipation, leading to the release of all the energy in the form of a rapid photon burst. We derive the minimal conditions for the burst to happen as a function of the number of emitters, the chirality of the waveguide, and the single-emitter optical depth, both for ordered and disordered ensembles. Many-body superradiance occurs because the initial fluctuation that triggers the emission is amplified throughout the decay process. In one-dimensional baths, this avalanchelike behavior leads to a spontaneous mirror symmetry breaking, with large shot-to-shot fluctuations in the number of photons emitted to the left and right. Superradiant bursts may thus be a smoking gun for the generation of correlated photon states of exotic quantum statistics.

Robust, 3-Dimensional Visualization of Human Colon Enteric Nervous System Without Tissue Sectioning.

BACKGROUND & AIMS: Small, 2-dimensional sections routinely used for human pathology analysis provide limited information about bowel innervation. We developed a technique to image human enteric nervous system (ENS) and other intramural cells in 3 dimensions. METHODS: Using mouse and human colon tissues, we developed a method that combines tissue clearing, immunohistochemistry, confocal microscopy, and quantitative analysis of full-thickness bowel without sectioning to quantify ENS and other intramural cells in 3 dimensions. RESULTS: We provided 280 adult human colon confocal Z-stacks from persons without known bowel motility disorders. Most of our images were of myenteric ganglia, captured using a 20× objective lens. Full-thickness colon images, viewed with a 10× objective lens, were as large as 4 × 5 mm2. Colon from 2 pediatric patients with Hirschsprung disease was used to show distal colon without enteric ganglia, as well as a transition zone and proximal pull-through resection margin where ENS was present. After testing a panel of antibodies with our method, we identified 16 antibodies that bind to molecules in neurons, glia, interstitial cells of Cajal, and muscularis macrophages. Quantitative analyses demonstrated myenteric plexus in 24.5% ± 2.4% of flattened colon Z-stack area. Myenteric ganglia occupied 34% ± 4% of myenteric plexus. Single myenteric ganglion volume averaged 3,527,678 ± 573,832 mm3 with 38,706 ± 5763 neuron/mm3 and 129,321 ± 25,356 glia/mm3. Images of large areas provided insight into why published values of ENS density vary up to 150-fold-ENS density varies greatly, across millimeters, so analyses of small numbers of thin sections from the same bowel region can produce varying results. Neuron subtype analysis revealed that approximately 56% of myenteric neurons stained with neuronal nitric oxide synthase antibody and approximately 33% of neurons produce and store acetylcholine. Transition zone regions from colon tissues of patients with Hirschsprung disease had ganglia in multiple layers and thick nerve fiber bundles without neurons. Submucosal neuron distribution varied among imaged colon regions. CONCLUSIONS: We developed a 3-dimensional imaging method for colon that provides more information about ENS structure than tissue sectioning. This approach could improve diagnosis for human bowel motility disorders and may be useful for other bowel diseases as well.

Notch1 is asymmetrically distributed from the beginning of embryogenesis and controls the ventral center.

Based on functional evidence, we have previously demonstrated that early ventral Notch1 activity restricts dorsoanterior development in Xenopus We found that Notch1 has ventralizing properties and abolishes the dorsalizing activity of ß-catenin by reducing its steady state levels, in a process that does not require ß-catenin phosphorylation by glycogen synthase kinase 3ß. In the present work, we demonstrate that Notch1 mRNA and protein are enriched in the ventral region from the beginning of embryogenesis in Xenopus This is the earliest sign of ventral development, preceding the localized expression of wnt8a, bmp4 and Ventx genes in the ventral center and the dorsal accumulation of nuclear ß-catenin. Knockdown experiments indicate that Notch1 is necessary for the normal expression of genes essential for ventral-posterior development. These results indicate that during early embryogenesis ventrally located Notch1 promotes the development of the ventral center. Together with our previous evidence, these results suggest that ventral enrichment of Notch1 underlies the process by which Notch1 participates in restricting nuclear accumulation of ß-catenin to the dorsal side.

Muscularis macrophage development in the absence of an enteric nervous system.

The nervous system of the bowel regulates the inflammatory phenotype of tissue resident muscularis macrophages (MM), and in adult mice, enteric neurons are the main local source of colony stimulating factor 1 (CSF1), a protein required for MM survival. Surprisingly, we find that during development MM colonize the bowel before enteric neurons. This calls into question the requirement for neuron-derived CSF1 for MM colonization of the bowel. To determine if intestinal innervation is required for MM development, we analyzed MM of neonatal Ret-/- (Ret KO) mice that have no enteric nervous system in small bowel or colon. We found normal numbers of well-patterned MM in Ret KO bowel. Similarly, the abundance and distribution of MM in aganglionic human colon obtained from Hirschsprung disease patients was normal. We also identify endothelial cells and interstitial cells of Cajal as the main sources of CSF1 in the developing bowel. Additionally, MM from neonatal Ret KOs do not differ from controls in baseline activation status or cytokine-production in response to lipopolysaccharide. Unexpectedly, these data demonstrate that the enteric nervous system is dispensable for MM colonization and patterning in the bowel, and suggest that modulatory interactions between MM and the bowel nervous system are established postnatally.

CYLD Inhibits the Development of Skin Squamous Cell Tumors in Immunocompetent Mice.

Cylindromatosis (CYLD) is a deubiquitinase (DUB) enzyme that was initially characterized as a tumor suppressor of adnexal skin tumors in patients with CYLD syndrome. Later, it was also shown that the expression of functionally inactive mutated forms of CYLD promoted tumor development and progression of non-melanoma skin cancer (NMSC). However, the ability of wild-type CYLD to inhibit skin tumorigenesis in vivo in immunocompetent mice has not been proved. Herein, we generated transgenic mice that express the wild type form of CYLD under the control of the keratin 5 (K5) promoter (K5-CYLDwt mice) and analyzed the skin properties of these transgenic mice by WB and immunohistochemistry, studied the survival and proliferating characteristics of primary keratinocytes, and performed chemical skin carcinogenesis experiments. As a result, we found a reduced activation of the nuclear factor kappa B (NF-κB) pathway in the skin of K5-CYLDwt mice in response to tumor necrosis factor-α (TNF-α); accordingly, when subjected to insults, K5-CYLDwt keratinocytes are prone to apoptosis and are protected from excessive hyperproliferation. Skin carcinogenesis assays showed inhibition of tumor development in K5-CYLDwt mice. As a mechanism of this tumor suppressor activity, we found that a moderate increase in CYLD expression levels reduced NF-κB activation, which favored the differentiation of tumor epidermal cells and inhibited its proliferation; moreover, it decreased tumor angiogenesis and inflammation. Altogether, our results suggest that increased levels of CYLD may be useful for anti-skin cancer therapy.

Fungal endophytes in Peperomia obtusifolia and their potential as inhibitors of chickpea fungal pathogens.

Chickpea (Cicer arietinum L., Fabaceae) is the second most important legume after common bean (Phaseolus vulgaris L., Fabaceae) and third in production among the legumes grains worldwide. Ascochyta blight and Fusarium wilt are among the main fungal infections which cause the major losses of chickpea crop. In this work we report the phyto-pathogen controlling properties of 24 endophyte Phomopsis/Diaporthe isolates on the chickpea fungal pathogens Ascochyta rabiei, Fusarium oxysporum and Fusarium solani. The Phomopsis/Diaporthe strains were isolated amongst a total of 62 endophytic fungi from the aerial parts of the herbaceous perennial American plant Peperomia obtusifolia (Piperaceae) along with Fusarium, Septoria, Colletotrichum, Alternaria and Roussoella genera among others. Phomopsis/Diaporthe isolates were identified as Diaporthe infecunda (12 isolates), Diaporthe sackstoni (1 isolate), Diaporthe cf. brasiliensis (4 isolates) and Phomopsis cf. tuberivora (7 isolates). All the Phomopsis/Diaporthe strains antagonized A. rabiei strain AR2 with a mean of inhibition (% I) of 86.59 ± 1.49% in dual cultures. The metabolic characterization of the Phomopsis/Diaporthe strains showed groups in three clusters which were in agreement with the taxonomic identification. Bioautographic evaluation of organic extracts showed that those of D. cf. brasiliensis and D. infecunda were better as inhibitors. Strain Po 45 was one of the most active (cluster 1, 96.87% I), and its ethyl acetate extract inhibited A. rabiei growth in a bioautographic assay until at least 10 µg/mm applied showing a specific chromatographic band as the responsible of the A. rabiei inhibition.

Does the right ventricle experiment morphologic and functional changes similarly to the left ventricle during pregnancy?

OBJECTIVE: Morphological and functional right ventricular (RV) changes during normal pregnancy remain poorly characterized. Similar to left ventricle, RV load and function are expected to change, and establishing reference values for RV during a healthy pregnancy is critical for the evaluation of pregnancy-related heart disease. The aim of the study was to describe RV adaptation in a prospective cohort. METHODS: Serial echocardiographic examinations were performed in second trimester (24 ± 2 weeks), third (32 ± 2 week) trimester, and postpartum (>3 months after delivery). Nulliparous women were evaluated as control group. RV linear dimensions, areas, and function were assessed and compared. RESULTS: Forty-three pregnant women were evaluated and compared with nineteen nulliparous women as control. Function parameters decreased along gestation. RV fractional area fell from second to third trimester (52.01 ± 0.92 vs 48.73 ± 0.97, P < .05), as well as tricuspid annular plane systolic excursion (2.62 ± 0.05 vs 2.41 ± 0.05, P < .05); however, RV longitudinal strain (L) decreased earlier, showing main changes from second trimester (26.17 ± 0.86 vs 22.71 ± 0.57, P < .003, control vs second trimester). S'-wave velocity followed a different pattern without changes during pregnancy. RV diameters significantly increased during pregnancy: basal (3.65 ± 0.06 vs 3.90 ± 0.06, P < .05), mid- (2.70 ± 0.06 vs 3.00 ± 0.07, P < .05), longitudinal (6.90 ± 0.09 vs 7.32 ± 0.11, P < .05), and right ventricle outflow tract proximal diameter (3.20 ± 0.06 vs 3.44 ± 0.06, P < .05). RV areas also suffered early variation during pregnancy. In postpartum evaluation, all these changes were reversed. CONCLUSION: During pregnancy, RV experiments important variations. RV size increases, and its function decreases. Changes in LS were earlier compared with other function measures.

Loss of Tbx3 in murine neural crest reduces enteric glia and causes cleft palate, but does not influence heart development or bowel transit.

Transcription factors that coordinate migration, differentiation or proliferation of enteric nervous system (ENS) precursors are not well defined. To identify novel transcriptional regulators of ENS development, we performed microarray analysis at embryonic day (E) 17.5 and identified many genes that were enriched in the ENS compared to other bowel cells. We decided to investigate the T-box transcription factor Tbx3, which is prominently expressed in developing and mature ENS. Haploinsufficiency for TBX3 causes ulnar-mammary syndrome (UMS) in humans, a multi-organ system disorder. TBX3 also regulates several genes known to be important for ENS development. To test the hypothesis that Tbx3 is important for ENS development or function, we inactivated Tbx3 in all neural crest derivatives, including ENS progenitors using Wnt1-Cre and a floxed Tbx3 allele. Tbx3 fl/fl; Wnt1-Cre conditional mutant mice die shortly after birth with cleft palate and difficulty feeding. The ENS of mutants was well-organized with a normal density of enteric neurons and nerve fiber bundles, but small bowel glial cell density was reduced. Despite this, bowel motility appeared normal. Furthermore, although Tbx3 is expressed in cardiac neural crest, Tbx3 fl/fl; Wnt1-Cre mice had structurally normal hearts. Thus, loss of Tbx3 within neural crest has selective effects on Tbx3-expressing neural crest derivatives.

The Combined Use of Proteomics and Transcriptomics Reveals a Complex Secondary Metabolite Network in Peperomia obtusifolia.

Peperomia obtusifolia, an ornamental plant from the Piperaceae family, accumulates a series of secondary metabolites with interesting biological properties. From a biosynthesis standpoint, this species produces several benzopyrans derived from orsellinic acid, which is a polyketide typically found in fungi. Additionally, the chiral benzopyrans were reported as racemic and/or as diastereomeric mixtures, which raises questions about the level of enzymatic control in the cyclization step for the formation of the 3,4-dihydro-2H-pyran moiety. Therefore, this article describes the use of shotgun proteomic and transcriptome studies as well as phytochemical profiling for the characterization of the main biosynthesis pathways active in P. obtusifolia. This combined approach resulted in the identification of a series of proteins involved in its secondary metabolism, including tocopherol cyclase and prenyltransferases. The activity of these enzymes was supported by the phytochemical profiling performed in different organs of P. obtusifolia. However, the polyketide synthases possibly involved in the production of orsellinic acid could not be identified, suggesting that orsellinic acid may be produced by endophytes intimately associated with the plant.

The role of bone marrow mononuclear cell-conditioned medium in the proliferation and migration of human dermal fibroblasts.

BACKGROUND: Several recent studies have demonstrated the great potential of bone marrow cells in regenerative medicine, not only for their ability to differentiate to match a damaged cell type, but also because they synthesize and release various growth factors and cytokines.We examined the effect of bone marrow cell-conditioned medium in the healing process, especially in terms of fibroblast proliferation and migration. METHODS: These in vitro studies consisted of co-culture (without direct contact) of dermal fibroblasts with mononuclear bone marrow cells and the use of conditioned medium obtained from these cultures in a scratch wound model. RESULTS: Mononuclear cells were found to increase the proliferation of fibroblasts, and the conditioned medium showed a stimulatory effect on the migration of fibroblasts. CONCLUSION: When considered together with the observed increase in growth factor levels in conditioned medium, it appears that these cells act through a paracrine mechanism.

Trypanocidal Activity of Flavokawin B, a Component of Polygonum ferrugineum Wedd.

The trypanocidal potential of the natural chalcone flavokawin B, which was isolated from the hexanic extract of Polygonum ferrugineum Wedd., is reported here. Although flavokawin B is widespread, this is the first report about its trypanocidal properties on both Trypanosoma cruzi (IC50 = 9.5 µM, IC50 = 34.7 µM benznidazol, Y strain) epimastigotes and Trypanosoma brucei (IC50 = 4.8 µM, IC50 = 6.4 µM pentamidine, 29-13 strain) procyclic forms, which was also corroborated on T. brucei strain 427 (IC50 = 6.2 µM). In order to learn more about its properties, unspecific cytotoxicity on Hep G2 cells was investigated as well as the trans-splicing inhibitory potential on T. brucei cells. The results shown here point to flavokawin B as a candidate in the search for new agents. It is also cheaper and less toxic than the available drugs to treat trypanosomiasis with a special focus on sleeping sickness disease.

The first description of the extended-spectrum beta-lactamase blaSHV-12 gene in a Salmonella monophasic Typhimurium strain isolated from acute gastroenteritis in a kidney transplant recipient in Southeast Spain.

Acute gastroenteritis (AGE) is a common disease within the population. Most cases are self-limited. However, intensive treatment is sometimes necessary to ensure patient integrity. This disease is characterized by vomiting and/or diarrhea with blood or mucus, discomfort, fever, and nonspecific abdominal pain. Commonly involved pathogens in the developed world include: viruses, bacteria, and parasites. In this paper we report a rare cause of AGE.

Child and Adolescent Sexual Abuse in Women Seeking Help for Sexual and Reproductive Mental Health Problems: Prevalence, Characteristics, and Disclosure.

This is a multicentric, descriptive, cross-sectional study of child and adolescent sexual abuse in women over 18 years in 24 primary care sexual and reproductive health centers in Catalonia. A total of 1,013 women were recruited; 345 (37.6%, 95% CI: 34.6-40.9) reported exposure to child sexual abuse: 32.4% disclosed being touched in a sexual way, and 9.6% reported completed sexual intercourse. Abuse occured before the age of 13 in 63.4% of respondents. The perpetrator was a relative or an acquaintance in almost 80% of cases. The risk was higher among women of Central or South American origin (OR: 2.86; 95% CI: 1.33-6.12). Only 31.9% of women disclosed the abuse and 17.3% were blamed. Abuse that involved attempted or completed sexual intercourse was significantly associated with recurrence, physical violence, and revictimization in adulthood.

Peripheral Atherosclerosis in Patients With Erectile Dysfunction: A Population-Based Study.

INTRODUCTION: The presence of erectile dysfunction (ED) could be a warning of vascular disease in different arterial territories. AIM: The aim of this study was to investigate the association between ED and the presence of atherosclerosis in 2 different vascular beds: carotid and lower limbs. METHODS: A total of 614 volunteers between 45 and 74 years of age (mean age 61.0 years) were randomly selected from the general population. ED was assessed using the International Index of Erectile Function (IIEF-5). Ankle-brachial index (ABI) measurement and carotid atherosclerosis were evaluated by echo-Doppler. MAIN OUTCOME MEASURES: Mean carotid intima-media thickness (IMT), prevalence of carotid plaques, mean ABI, and prevalence of ABI < 0.9 were the main outcome measures. RESULTS: ED was present in 373 subjects (59.7%). Mean carotid IMT was significantly higher in men with ED (0.762 ± 0.151 mm vs 0.718 ± 0.114 mm, P < .001). Also the global prevalence of carotid plaques was more frequent in men with ED (63.8% vs 44.8%, P < .001), even after adjusting by age, cardiovascular risk factors, and ongoing treatment (P = .039). Both the IMT and the prevalence of carotid plaques increased significantly with ED severity (P trend .004 and <.001, respectively). There were no significant differences between groups neither in mean ABI nor in the prevalence of subjects with ABI < 0.9. However, there was a trend to a lower ABI and a higher prevalence of ABI < 0.9 with increasing ED severity. CONCLUSION: In the general population, the presence of ED identifies subjects with higher atherosclerosis burden in carotid arteries but not in the lower extremities.

Clinical features and survival of 338 multiple myeloma patients treated with hematopoietic stem cell transplantation or conventional chemotherapy.

Therapeutic approaches against multiple myeloma (MM) have largely changed during the past decade. Hematopoietic stem cell transplantation (HSCT) and licensing of immunomodulators and proteasome inhibitors have resulted in better response and increased overall survival rates compared to previous conventional therapies. To assess the impact that these new strategies have had on outcome of patients with symptomatic MM in Spain, we conducted an epidemiological retrospective analysis of 338 newly diagnosed patients with stage II-III MM who started first-line treatment over a 2-yr period (2003-2005) by collecting data from their medical records. Most patients had been diagnosed with secretory MM (94.4%), 41.7% stage II and 58.3% stage III. The presence of bone lesions (72.2%), as well as anemia (79.8%) and elevated beta2-microglobulin levels (62.3%), was a common finding; in contrast, hypercalcemia and elevated serum creatinine were less frequent (25% each). First-line treatment had consisted of either conventional chemotherapy (62%) or induction treatment plus autologous HSCT (38%), as per standard clinical practice. HSCT not only resulted in greater objective response rates (93% vs. 50%), but also contributed to a significant increase in 3-yr survival (85% vs. 49.7%; 95% CI, range 77-91 vs. 41-58; P < 0.001). Overall, 55% of patients presented treatment-related adverse events, mainly hematological. Toxicity rates were higher among patients treated with alkylating-based regimens and in those undergoing transplantation. In conclusion, data analysis shows an adequate balance between increased response rates and safety that supports the use of up-front high-dose HSCT therapy in younger patients. Most importantly, this study provides further confirmation that the introduction of HSCT has significantly prolonged survival of patients with MM.

Preliminary investigation of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives as a novel series of mGlu5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia.

As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.

Extending metabolome coverage for untargeted metabolite profiling of adherent cultured hepatic cells.

MS-based metabolite profiling of adherent mammalian cells comprises several challenging steps such as metabolism quenching, cell detachment, cell disruption, metabolome extraction, and metabolite measurement. In LC-MS, the final metabolome coverage is strongly determined by the separation technique and the MS conditions used. Human liver-derived cell line HepG2 was chosen as adherent mammalian cell model to evaluate the performance of several commonly used procedures in both sample processing and LC-MS analysis. In a first phase, metabolite extraction and sample analysis were optimized in a combined manner. To this end, the extraction abilities of five different solvents (or combinations) were assessed by comparing the number and the levels of the metabolites comprised in each extract. Three different chromatographic methods were selected for metabolites separation. A HILIC-based method which was set to specifically separate polar metabolites and two RP-based methods focused on lipidome and wide-ranging metabolite detection, respectively. With regard to metabolite measurement, a Q-ToF instrument operating in both ESI (+) and ESI (-) was used for unbiased extract analysis. Once metabolite extraction and analysis conditions were set up, the influence of cell harvesting on metabolome coverage was also evaluated. Therefore, different protocols for cell detachment (trypsinization or scraping) and metabolism quenching were compared. This study confirmed the inconvenience of trypsinization as a harvesting technique, and the importance of using complementary extraction solvents to extend metabolome coverage, minimizing interferences and maximizing detection, thanks to the use of dedicated analytical conditions through the combination of HILIC and RP separations. The proposed workflow allowed the detection of over 300 identified metabolites from highly polar compounds to a wide range of lipids.

Antioxidant protection of proteins and lipids in processed pork loin chops through feed supplementation with avocado.

This study was conducted to analyze the impact of dietary avocado on the oxidative stability of lipids and proteins during pork processing. Loins from control (fed basic diet) and treated pigs (fed on avocado-supplemented diet) were roasted (102 °C/20 min) and subsequently packed in trays wrapped with oxygen-permeable films and chilled at 4 °C for 12 days. At each processing stage (raw, cooked and cooked & chilled), pork samples from both groups were analyzed for the concentration of TBARS, the loss of tryptophan and free thiols, and the formation of protein carbonyls, disulphide bonds and Schiff bases. Processing led to a depletion of tryptophan and sulfur-containing amino acids and an increase of lipid and protein oxidation products. Dietary avocado was not able to protect against the oxidation of tryptophan and thiols but cooked & chilled loins from treated pigs had significantly lower concentration of lipid and protein carbonyls than control counterparts. Likewise, dietary avocado alleviated the formation of Schiff bases during cooking. These results illustrate the benefits of dietary avocado on the oxidative stability of processed pork loins.

Effect of pre-cooking methods on the chemical and sensory deterioration of ready-to-eat chicken patties during chilled storage and microwave reheating.

The effects of pre-cooking methods, namely, boiling (BL), roasting (RT) and grilling (GR), refrigerated storage (14 days/+4 °C) and microwave reheating on chicken patties were studied. Physical, chemical and sensory parameters were evaluated in order to correlate the chemical deterioration of ready-to-eat chicken patties with the acceptance of the odor. Chemical deterioration was evaluated through the chemical composition, Maillard compounds, Thiobarbituric acid-reactive substances (TBARS) and volatiles. Sensory deterioration (odor liking) was performed by an acceptance test with hedonic scale. According to the TBARS values and volatile compounds generated in the head space during the examined stages, the pre-cooking method and the storage time had a significant effect on lipid oxidation, whereas reheating in a microwave had a negligible impact. At each succeeding processing stage, panelists gave lower odor scores to all samples and no significant differences were found between treatments at any stage. RT and GR patties showed less intense chemical changes and presented higher acceptation scores by the sensory panel than BL patties. Thus, the choice of pre-cooking method and control of storage conditions plays a key role in the inhibition of oxidative changes in ready-to-eat chicken patties.