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The structure of the title compound, C 11 H 15 N 3 OS, shows the flexibility due to the methyl-ene group at the thio-amide N atom in the side chain, resulting in the mol-ecule being non-planar. The dihedral angle between the plane of the benzene ring and that defined by the atoms of the thio-semicarbazide arm is 79.847 (4)°. In the crystal, the donor-acceptor hydrogen-bond character of the -OH group dominates the inter-molecular associations, acting as a donor in an O-H⋯S hydrogen bond, as well as being a double acceptor in a centrosymmetric cyclic bridging N-H⋯O,O' inter-action [graph set R (4)]. The result is a one-dimensional duplex chain structure, extending along [111]. The usual N-H⋯S hydrogen-bonding association common in thio-semicarbazone crystal structures is not observed.2 2 (4)]. The result is a one-dimensional duplex chain structure, extending along [111]. The usual N-H⋯S hydrogen-bonding association common in thio-semicarbazone crystal structures is not observed.

Cancer related deaths are primarily due to tumor metastasis. To facilitate their dissemination to distant sites, cancer cells develop invadopodia, actin-rich protrusions capable of degrading the surrounding extracellular matrix (ECM). We aimed to determine whether β3 integrin participates in invadopodia formed by lung carcinoma cells, based on our previous findings of specific TGF-β induction of β3 integrin dependent metastasis in animal models of lung carcinoma. In this study, we demonstrate that lung carcinoma cells form invadopodia in response to TGF-β exposure. Invadopodia formation and degradation activity is dependent on β3 integrin expression since β3 integrin deficient cells are not able to degrade gelatin-coated surfaces. Even more, transient over-expression of SRC did not restore invadopodia formation in β3 integrin deficient cells. Finally, we observed that blockade of PLC-dependent signaling leads to more intense labeling for β3 integrin in invadopodia. Our results suggest that β3 integrin function, and location, in lung cancer cells are essential for invadopodia formation, and this integrin regulates the activation of different signal pathways necessary for the invasive structure. β3 integrin has been associated with poor prognosis and increased metastasis in several carcinoma types, including lung cancer. Our findings provide new evidence to support the use of targeted therapies against this integrin to combat the onset of metastases.

Introduction: Lysyl oxidase (LOX) participates in the assembly of collagen and elastin fibres. The impact of vascular LOX over-expression on extracellular matrix (ECM) structure and its contribution to oxidative stress has been analysed., Methods: Studies were conducted on mice over-expressing LOX (Tg), specifically in smooth muscle cells (VSMC). Gene expression was assessed by real-time PCR analysis. Sirius Red staining, H 2 O 2 production and NADPH oxidase activity were analysed in different vascular beds. The size and number of fenestra of the internal elastic lamina were determined by confocal microscopy., Results: LOX activity was up-regulated in VSMC of transgenic mice compared with cells from control animals. At the same time, transgenic cells deposited more organised elastin fibres and their supernatants induced a stronger collagen assembly in in vitro assays. Vascular collagen cross-linking was also higher in Tg mice, which showed a decrease in the size of fenestrae and an enhanced expression of Fibulin-5. Interestingly, higher H 2 O 2 production and NADPH oxidase activity was detected in the vascular wall from transgenic mice. The H 2 O 2 scavenger catalase attenuated the stronger deposition of mature elastin fibres induced by LOX transgenesis., Conclusions: LOX over-expression in VSMC was associated with a change in the structure of collagen and elastin fibres. LOX could constitute a novel source of oxidative stress that might participate in elastin changes and contribute to vascular remodelling., (Copyright © 2017 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: The colonization of the surfaces of dental prostheses by Candida albicans is associated with the development of denture stomatitis. In this context, the use of fluconazole has been proposed, but its disadvantage is microbial resistance. Meanwhile, the oil of Allium sativum has shown an effect in controlling biofilm formation by C. albicans., Aims: The objective of this study was to determine the antifungal activities of the essential oil of A. sativum and fluconazole against clinical isolates of Candida species obtained from rigid, acrylic-based partial or total dentures and to compare these agents' effects on both biofilm and planktonic cells., Methods: A total of 48 clinical isolates obtained from the acrylic surface of partial or complete dentures were examined, and the following species were identified: C. albicans, Candida glabrata, Candida tropicalis, and Candida krusei. For each isolate, the antifungal activities of the essential oil of A. sativum and fluconazole against both biofilm and planktonic cells were evaluated using the Clinical & Laboratory Standards Institute (CLSI) M27-A3 method. The isolates were also evaluated by semiquantitative XTT reduction., Results: All planktonic Candida isolates were susceptible to the essential oil of A. sativum, whereas 4.2% were resistant to fluconazole. Regarding susceptibilities in biofilms, 43.8% of biofilms were resistant to A. sativum oil, and 91.7% were resistant to fluconazole., Conclusions: All planktonic cells of the different Candida species tested are susceptible to <1mg/ml A. sativum oil, and the majority are susceptible to fluconazole. Susceptibility decreases in biofilm cells, with increased resistance to fluconazole compared with A. sativum oil. The essential oil of A. sativum is thus active against clinical isolates of Candida species obtained from dentures, with effects on both biofilm and planktonic cells in vitro., (Copyright © 2017 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: The aim of our study was to analyze the miRNome of pancreatic ductal adenocarcinoma (PDAC) and its preneoplastic lesion intraductal papillary mucinous neoplasm (IPMN), to find new microRNA (miRNA)-based biomarkers for early detection of pancreatic neoplasia., Objective: Effective early detection methods for PDAC are needed. miRNAs are good biomarker candidates., Methods: Pancreatic tissues (n = 165) were obtained from patients with PDAC, IPMN, or from control individuals (C), from Hospital Clínic of Barcelona. Biomarker discovery was done using next-generation sequencing in a discovery set of 18 surgical samples (11 PDAC, 4 IPMN, 3 C). MiRNA validation was carried out by quantitative reverse transcriptase PCR in 2 different set of samples. Set 1-52 surgical samples (24 PDAC, 7 IPMN, 6 chronic pancreatitis, 15 C), and set 2-95 endoscopic ultrasound-guided fine-needle aspirations (60 PDAC, 9 IPMN, 26 C)., Results: In all, 607 and 396 miRNAs were significantly deregulated in PDAC and IPMN versus C. Of them, 40 miRNAs commonly overexpressed in both PDAC and IPMN were selected for further validation. Among them, significant up-regulation of 31 and 30 miRNAs was confirmed by quantitative reverse transcriptase PCR in samples from set 1 and set 2, respectively., Conclusions: miRNome analysis shows that PDAC and IPMN have differential miRNA profiles with respect to C, with a large number of deregulated miRNAs shared by both neoplastic lesions. Indeed, we have identified and validated 30 miRNAs whose expression is significantly increased in PDAC and IPMN lesions. The feasibility of detecting these miRNAs in endoscopic ultrasound-guided fine-needle aspiration samples makes them good biomarker candidates for early detection of pancreatic cancer.

Antibody-dependent cellular cytotoxicity (ADCC) is a set of mechanisms that target cells coated with IgG antibodies of the proper subclasses (IgG1 in the human) to be the prey of cell-to-cell cytolysis executed by immune cells expressing FcRIIIA (CD16A). These effectors include not only natural killer (NK) cells but also other CD16 + subsets such as monocyte/macrophages, NKT cells or γδ T cells. In cancer therapy, ADCC is exploited by antibodies that selectively recognize proteins on the surface of malignant cells. An approach to enhance antitumor activity is to act on effector cells so they are increased in their numbers or enhanced in their individual (on a cell per cell basis) ADCC performance. This enhancement can be therapeutically attained by cytokines (that is, interleukin (IL)-15, IL-21, IL-18, IL-2); immunostimulatory monoclonal antibodies (that is, anti-CD137, anti-CD96, anti-TIGIT, anti-KIR, anti-PD-1); TLR agonists or by adoptive infusions of ex vivo expanded NK cells which can be genetically engineered to become more efficient effectors. In conjunction with approaches optimizing IgG1 Fc affinity to CD16, acting on effector cells offers hope to achieve synergistic immunotherapy strategies.

The importance of juvenile hormone regulating insect oogenesis suggests looking for genes whose expression is regulated by this hormone. SPARC is a calcium-binding glycoprotein that forms part of the extracellular membranes, which in vertebrates participates in bones mineralization or regulating cell proliferation in some cancer types. This large number of functions described for SPARC in different species might be related to the significant differences in its structure observed when comparing different species-groups. Indeed, these structural differences allow characterizing the different clades. In the cockroach Blattella germanica, a SPARC homolog emerged from ovarian transcriptomes that were constructed to find genes responding to juvenile hormone. In insects, SPARC functions have been studied in oogenesis and in embryo development of Drosophila melanogaster. In the present work, using RNAi approaches, novel functions for SPARC in the B. germanica panoistic ovaries are described. We found that depletion of SPARC does not allow to the follicular cells to complete mitosis, resulting in giant follicular cells nuclei and in a great alteration of the ovarian follicle cytoskeleton. The SPARC contribution to B. germanica oogenesis occurs stabilizing the follicular cell program and helping to maintain the nuclear divisions. Moreover, SPARC is necessary to maintain the cytoskeleton of the follicular cells. Any modification of these key processes disables females for oviposition., (Copyright © 2017 Elsevier Inc. All rights reserved.)

During intracellular infections, autophagy significantly contributes to the elimination of pathogens, regulation of pro-inflammatory signaling, secretion of immune mediators and in coordinating the adaptive immune system. Intracellular pathogens such as S. Typhimurium have evolved mechanisms to circumvent autophagy. However, the regulatory mechanisms targeted by S. Typhimurium to modulate autophagy have not been fully resolved. Here we report that cytosolic energy loss during S. Typhimurium infection triggers transient activation of AMPK, an important checkpoint of mTOR activity and autophagy. The activation of AMPK is regulated by LKB1 in a cytosolic complex containing Sirt1 and LKB1, where Sirt1 is required for deacetylation and subsequent activation of LKB1. S. Typhimurium infection targets Sirt1, LKB1 and AMPK to lysosomes for rapid degradation resulting in the disruption of the AMPK-mediated regulation of mTOR and autophagy. The degradation of cytosolic Sirt1/LKB1/AMPK complex was not observed with two mutant strains of S. Typhimurium, ΔssrB and ΔssaV, both compromising the pathogenicity island 2 (SPI2). The results highlight virulence factor-dependent degradation of host cell proteins as a previously unrecognized strategy of S. Typhimurium to evade autophagy.

Purpose: To investigate the effect of virgin olive oil phenolic compounds (PC) alone or in combination with thyme PC on blood lipid profile from hypercholesterolemic humans, and whether the changes generated are related with changes in gut microbiota populations and activities., Methods: A randomized, controlled, double-blind, crossover human trial (n = 12) was carried out. Participants ingested 25 mL/day for 3 weeks, preceded by 2-week washout periods, three raw virgin olive oils differing in the concentration and origin of PC: (1) a virgin olive oil (OO) naturally containing 80 mg PC/kg, (VOO), (2) a PC-enriched virgin olive oil containing 500 mg PC/kg, from OO (FVOO), and (3) a PC-enriched virgin olive oil containing a mixture of 500 mg PC/kg from OO and thyme, 1:1 (FVOOT). Blood lipid values and faecal quantitative changes in microbial populations, short chain fatty acids, cholesterol microbial metabolites, bile acids, and phenolic metabolites were analysed., Results: FVOOT decreased seric ox-LDL concentrations compared with pre-FVOOT, and increased numbers of bifidobacteria and the levels of the phenolic metabolite protocatechuic acid compared to VOO (P < 0.05). FVOO did not lead to changes in blood lipid profile nor quantitative changes in the microbial populations analysed, but increased the coprostanone compared to FVOOT (P < 0.05), and the levels of the faecal hydroxytyrosol and dihydroxyphenylacetic acids, compared with pre-intervention values and to VOO, respectively (P < 0.05)., Conclusion: The ingestion of a PC-enriched virgin olive oil, containing a mixture of olive oil and thyme PC for 3 weeks, decreases blood ox-LDL in hypercholesterolemic humans. This cardio-protective effect could be mediated by the increases in populations of bifidobacteria together with increases in PC microbial metabolites with antioxidant activities.

Purpose/objectives: The goal of this study was to assess the effects of ionizing radiation on the expression of the integrin ligands ICAM-1 and VCAM that control leucocyte transit by lymphatic endothelial cells., Materials/methods: Confluent monolayers of primary human lymphatic endothelial cells (LEC) were irradiated with single dose of 2, 5, 10 or 20 Gy, with 6 MeV-x-rays using a Linear-Accelerator. ICAM-1 and VCAM expression was determined by flow cytometry. Human tissue specimens received a single dose of 20 Gy with 15 MeV-x-rays. MC38, B16-OVA or B16-VEGF-C tumors grown in C57BL/6 mice were irradiated with single dose of 20Gy using a Linear-Accelerator fitted with a 10mm Radiosurgery collimator. Clinical samples were obtained from patients previous and 4 weeks after complete standard radiotherapy. ICAM-1 and VCAM expression was detected in all tissue specimens by confocal microscopy. To understand the role of TGFβ in this process anti-TGFβ blocking mAb were injected i.p. 30min before radiotherapy. Cell adhesion to irradiated LEC was analyzed in adhesion experiments performed in the presence or in the absence of anti- TGFβ and /or anti-ICAM1 blocking mAb., Results: We demonstrate that lymphatic endothelial cells in tumor samples experience induction of surface ICAM-1 and VCAM when exposed to ionizing radiation in a dose- and time-dependent manner. These effects can be recapitulated in cultured LEC, and are in part mediated by TGFβ. These data are consistent with increases in ICAM-1 and VCAM expression on LYVE-1+ endothelial cells in freshly explanted human tumor tissue and in mouse transplanted tumors after radiotherapy. Finally, ICAM-1 and VCAM expression accounts for enhanced adherence of human T lymphocytes to irradiated LEC., Conclusion: Our results show induction of ICAM-1 and VCAM on LVs in irradiated lesions and offer a starting point for elucidating the biological and therapeutic implications of targeting leukocyte traffic in combination to immunotherapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

CD69 is an early activation marker on the surface of T lymphocytes undergoing activation by cognate antigen. We observed intense expression of CD69 on tumor-infiltrating T-lymphocytes that reside in the hypoxic tumor microenvironment and hypothesized that CD69 could be, at least partially, under the control of the transcriptional hypoxia response. In line with this, human and mouse CD3-stimulated lymphocytes cultured under hypoxia (1% O 2 ) showed increased expression of CD69 at the protein and mRNA level. Consistent with these findings, mouse T lymphocytes that had recently undergone hypoxia in vivo , as denoted by pimonidazole staining, were more frequently CD69 + in the tumor and bone marrow hypoxic tissue compartments. We found evidence for HIF-1α involvement both when using T-lymphocytes from inducible HIF-1α -/- mice and when observing tumor-infiltrating T-lymphocytes in mice whose T cells are HIF-1α -/- . Direct pro-transcriptional activity of HIF-1α on a newly identified hypoxia response element (HRE) found in the human CD69 locus was demonstrated by ChIP experiments. These results uncover a connection between the HIF-1α oxygen-sensing pathway and CD69 immunobiology.

Objectives: Levofloxacin monitoring is recommended to obtain clinical cure and low incidence of antimicrobial resistance. During the monitoring procedure, levofloxacin should be measured in plasma samples and several assays are reported for this purpose. However, those methods do not have all of the characteristics for an accessible and reliable drug monitoring. For this reason, we develop a method that has all of the essential characteristics for levofloxacin monitoring., Design and Methods: The procedure of validation was done in terms of Food and Drug Administration guidelines. Subsequently, our assay was applied in plasma samples obtained from healthy volunteers with a single oral administration of levofloxacin as well as patients with respiratory diseases under levofloxacin therapy., Results: Levofloxacin was extracted from samples using only two precipitation steps. Our assay had a rapid run time (5min), adequate sensitivity (0.05μg/ml of lower limit of quantification), and acceptable parameters of validation. Moreover, compound identities were supported using three dimensional spectra and purities were confirmed employing similarity factors (values>900). Variable concentrations of levofloxacin in samples were observed during the application., Conclusions: Levofloxacin is successfully quantified using our method that shows reliable results, appropriate range, rapid analyses, and cost-effective measurements under a simple and easy technique while all prior methods did not have it all together. Consequently, our method is a valuable tool for routine drug monitoring. Moreover, a complete evaluation of specificity was done for levofloxacin in plasma samples for the first time. Meanwhile, the application data supported the necessity of levofloxacin monitoring., (Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Odontogenic tumors constitute a group of heterogeneous lesions of benign and malignant neoplasms with variable aggressiveness. Ameloblastomas are a group of benign but locally invasive neoplasms that occur in the jaws and are derived from epithelial elements of the tooth-forming apparatus. We previously described orosomucoid-1 protein expression in odontogenic myxomas. However, whether orosomucoid-1 is expressed in other odontogenic tumors remains unknown. Since orosomucoid-1 belongs to a group of acute-phase proteins and has many functions in health and disease, we identified and analyzed orosomucoid-1 expression in ameloblastoma variants and ameloblastic carcinoma using western blot and immunohistochemical techniques. Thirty cases of ameloblastoma were analyzed for orsomucoid-1; five specimens were fresh for western blot study (four benign ameloblastomas and one ameloblastic carcinoma), and 25 cases of benign ameloblastoma for immunohistochemical assays. Orosomucoid-1 was widely expressed in each tumor variant analyzed in this study, and differential orosomucoid-1 expression was observed between benign and malignant tumor. Orosomucoid-1 may play an important role in the behavior of ameloblastomas and influence the biology and development of the variants of this tumor.

Efficient induction of defined lineages in pluripotent stem cells constitutes the determinant step for the generation of therapeutically relevant replacement cells to potentially treat a wide range of diseases, including diabetes. Pancreatic differentiation has remained an important challenge in large part because of the need to differentiate uncommitted pluripotent stem cells into highly specialized hormone-secreting cells, which has been shown to require a developmentally informed step-by-step induction procedure. Here, in the framework of using induced pluripotent stem cells (iPSCs) to generate pancreatic cells for pancreatic diseases, we have generated and characterized iPSCs from Pdx1-GFP transgenic mice. The use of a GFP reporter knocked into the endogenous Pdx1 promoter allowed us to monitor pancreatic induction based on the expression of Pdx1, a pancreatic master transcription factor, and to isolate a pure Pdx1-GFP + population for downstream applications. Differentiated cultures timely expressed markers specific to each stage and end-stage progenies acquired a rather immature beta-cell phenotype, characterized by polyhormonal expression even among cells highly expressing the Pdx1-GFP reporter. Our findings highlight the utility of employing a fluorescent protein reporter under the control of a master developmental gene in order to devise novel differentiation protocols for relevant cell types for degenerative diseases such as pancreatic beta cells for diabetes., (Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)

Introduction: Fibulin-5 (FBLN5) is an elastogenic protein critically involved in extracellular matrix (ECM) remodelling, a key process in abdominal aortic aneurysm (AAA). However, the possible contribution of FBLN5 to AAA development has not been addressed., Methods: Expression levels were determined by real-time PCR and Western blot in human abdominal aorta from patients with AAA or healthy donors, as well as in human aortic vascular smooth muscle cells (VSMC). Lentiviral transduction, transient transfections, and chromatin immunoprecipitation (ChIP) assays were also performed., Results: The expression of FBLN5 in human AAA was significantly lower than in healthy donors. FBLN5 mRNA and protein levels and their secretion to the extracellular environment were down-regulated in VSMC exposed to inflammatory stimuli. Interestingly, FBLN5 transcriptional activity was inhibited by TNFα and lipopolysaccharide (LPS), and depends on a SOX response element. In fact, SOX9 expression was reduced in VMSC induced by inflammatory mediators and in human AAA, and correlated with that of FBLN5. Furthermore, SOX9 over-expression limited the reduction of FBLN5 expression induced by cytokines in VSMC. Finally, it was observed that SOX9 interacts with FBLN5 promoter, and that this binding was reduced upon TNFα exposure., Conclusions: FBLN5 downregulation in human AAA could contribute to extracellular matrix remodelling induced by the inflammatory component of the disease., (Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory mAbs to act both on irradiated tumor lesions and on distant, nonirradiated tumor sites. The combination of radiotherapy with immunostimulatory anti-PD1 and anti-CD137 mAbs was conducive to favorable effects on distant nonirradiated tumor lesions as observed in transplanted MC38 (colorectal cancer), B16OVA (melanoma), and 4T1 (breast cancer) models. The therapeutic activity was crucially performed by CD8 T cells, as found in selective depletion experiments. Moreover, the integrities of BATF-3-dependent dendritic cells specialized in crosspresentation/crosspriming of antigens to CD8 + T cells and of the type I IFN system were absolute requirements for the antitumor effects to occur. The irradiation regimen induced immune infiltrate changes in the irradiated and nonirradiated lesions featured by reductions in the total content of effector T cells, Tregs, and myeloid-derived suppressor cells, while effector T cells expressed more intracellular IFNγ in both the irradiated and contralateral tumors. Importantly, 48 hours after irradiation, CD8 + TILs showed brighter expression of CD137 and PD1, thereby displaying more target molecules for the corresponding mAbs. Likewise, PD1 and CD137 were induced on tumor-infiltrating lymphocytes from surgically excised human carcinomas that were irradiated ex vivo These mechanisms involving crosspriming and CD8 T cells advocate clinical development of immunotherapy combinations with anti-PD1 plus anti-CD137 mAbs that can be synergistically accompanied by radiotherapy strategies, even if the disease is left outside the field of irradiation. Cancer Res; 76(20); 5994-6005. ©2016 AACR., (©2016 American Association for Cancer Research.)

Residential wood combustion emissions are one of the major global sources of particulate and gaseous organic pollutants. However, the detailed chemical compositions of these emissions are poorly characterized due to their highly complex molecular compositions, nonideal combustion conditions, and sample preparation steps. In this study, the particulate organic emissions from a masonry heater using three types of wood logs, namely, beech, birch, and spruce, were chemically characterized using thermal desorption in situ derivatization coupled to a GCxGC-ToF/MS system. Untargeted data analyses were performed using the comprehensive measurements. Univariate and multivariate chemometric tools, such as analysis of variance (ANOVA), principal component analysis (PCA), and ANOVA simultaneous component analysis (ASCA), were used to reduce the data to highly significant and wood type-specific features. This study reveals substances not previously considered in the literature as meaningful markers for differentiation among wood types.

Ubiquitination of the TrkA neurotrophin receptor in response to NGF is critical in the regulation of TrkA activation and functions. TrkA is ubiquitinated, among other E3 ubiquitin ligases, by Nedd4-2. To understand mechanistically how TrkA ubiquitination is regulated, we performed a siRNA screening to identify deubiquitinating enzymes and found that USP36 acts as an important regulator of TrkA activation kinetics and ubiquitination. However, USP36 action on TrkA was indirect because it does not deubiquitinate TrkA. Instead, USP36 binds to Nedd4-2 and regulates the association of TrkA and Nedd4-2. In addition, depletion of USP36 increases TrkA·Nedd4-2 complex formation, whereas USP36 expression disrupts the complex, resulting in an enhancement or impairment of Nedd4-2-dependent TrkA ubiquitination, respectively. Moreover, USP36 depletion leads to enhanced total and surface TrkA expression that results in increased NGF-mediated TrkA activation and signaling that augments PC12 cell differentiation. USP36 actions extend beyond TrkA because the presence of USP36 interferes with Nedd4-2-dependent Kv7.2/3 channel regulation. Our results demonstrate that USP36 binds to and regulates the actions of Nedd4-2 over different substrates affecting their expression and functions., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background: Late-life repartnering among functionally independent adults, resulting in complex stepfamilies, has emerged with increased life expectancy, and is likely to develop further. It is perceived as a chance for renewal and autonomy, enabling a release from dependency on offspring, whereas caregiving is associated with dependency and becoming a burden on family members. Thus, the experiences of late-life repartnering and caregiving are opposites. Using a life course perspective, we explore partner caregiving expectations in late-life repartnering from the viewpoints of three generations in complex stepfamilies in Israel, a society characterized by collectivist alongside individualist familial norms., Methods: Using criterion sampling, we recruited 19 stepfamily units (38 families) of functionally independent persons who repartnered at the official retirement age or older and had offspring from a lifelong marriage that ended in widowhood or divorce. One-hundred-seven semi-structured qualitative interviews with older partners, their adult children, and grandchildren were audio-recorded and transcribed verbatim. Analysis was based on grounded theory principles and dyadic analysis adapted to families., Results: Two themes emerged: caregiving commitment and decision making. Issues included: influences of partner-caregiving history; chronic versus temporary caregiving situations; caregiving strengthening partner relationships and influencing stepfamily relationships, and moral dilemmas, such as what happens when fun - a motive for repartnering - is no longer possible. Could abandonment become an option?, Conclusions: From a life course perspective, caregiving, as "on-time," and late-life repartnering, as "off-time," highlight the lack of norms and the need to establish normative behavior for caregiving in late-life repartnering in diverse cultural contexts along with its reservations.

Background: Mechanically assisted coughing with mechanical in-exsufflation (MI-E) is recommended for noninvasive management of respiratory secretions in amyotrophic lateral sclerosis (ALS). To improve the effectiveness of the technique, a new device combining MI-E with high-frequency oscillations (HFO) has been developed. This work aimed to assess the effect of HFO on the cough peak flow generated by MI-E in medically stable subjects with ALS., Methods: This was a prospective study that included subjects with ALS in a medically stable condition. Cough peak flow generated by MI-E was measured in 4 situations: without HFO, with HFO during insufflation, with HFO during exsufflation, and with HFO in both cycles. The parameters used were: insufflation pressure of +40 cm H2O, exsufflation pressure of -40 cm H2O, insufflation time 2 s, exsufflation time 3 s, amplitude of oscillations 10 cm H2O, and frequency of oscillations 15 Hz., Results: Forty-seven subjects with ALS were included: 66% males, 68.2 ± 9.2 y, 40% with bulbar onset, FVC = 1.7 ± 1.1 L, percent-of-predicted FVC = 54.4 ± 26.6%, cough peak flow = 3.8 ± 2.2 L/s, PImax = -39.4 ± 26.4 cm H2O, revised ALS scale = 28.5 ± 9.3, Norris bulbar subscore = 26.1 ± 10.4. No statistical differences were found in cough peak flow generated by MI-E in the 4 situations (without HFO = 4.0 ± 1.2 L/s, with insufflation HFO = 3.9 ± 1.2 L/s, with exsufflation HFO = 4.1 ± 1.2 L/s, with in-exsufflation HFO = 3.9 ± 1.1 L/s)., Conclusions: The addition of HFO to mechanically assisted coughing with MI-E does not have an effect on the cough peak flow of medically stable subjects with ALS., (Copyright © 2016 by Daedalus Enterprises.)

Purpose: Myeloid-derived suppressor cells (MDSC) are considered an important T-cell immunosuppressive component in cancer-bearing hosts. The factors that attract these cells to the tumor microenvironment are poorly understood. IL8 (CXCL8) is a potent chemotactic factor for neutrophils and monocytes., Experimental Design: MDSC were characterized and sorted by multicolor flow cytometry on ficoll-gradient isolated blood leucokytes from healthy volunteers (n = 10) and advanced cancer patients (n = 28). In chemotaxis assays, sorted granulocytic and monocytic MDSC were tested in response to recombinant IL8, IL8 derived from cancer cell lines, and patient sera. Neutrophil extracellular traps (NETs) formation was assessed by confocal microscopy, fluorimetry, and time-lapse fluorescence confocal microscopy on short-term MDSC cultures., Results: IL8 chemoattracts both granulocytic (GrMDSC) and monocytic (MoMDSC) human MDSC. Monocytic but not granulocytic MDSC exerted a suppressor activity on the proliferation of autologous T cells isolated from the circulation of cancer patients. IL8 did not modify the T-cell suppressor activity of human MDSC. However, IL8 induced the formation of NETs in the GrMDSC subset., Conclusions: IL8 derived from tumors contributes to the chemotactic recruitment of MDSC and to their functional control. Clin Cancer Res; 22(15); 3924-36. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Children with Autism spectrum disorders (ASD) frequently present a deficit in interpersonal and social problem solving skills. The Interpersonal Problem-Solving Skills Programme for Children (SCI-Children) comprises 10 weekly, one hour sessions working on interpersonal abilities from a mediation strategy for training purposes., Method: The first study explores the effectiveness of training through pre- and post-treatment evaluations of a sample of 22 children with ASD (7-13 years of age). The second study replicates the programme with 15 children who were assessed three times (three months before the programme starts, at the beginning of the training and at the end of it)., Results: In the first study, significant differences were found in outcome measures (a parent-report subscale of a socialisation measure and child performance on one subscale and total scores of an interpersonal problem-solving skills task). Results in the second study showed no significant changes in absence of the treatment during the waiting period and significant changes after the treatment in the socialisation measure., Conclusions: These findings suggest that the SCI-Children program causes positive impact on the participants. Further evaluation is warranted.

Objectives: To assess the epidemiologic and microbiologic profile and in vitro fluconazole susceptibility of yeasts isolated from the oral mucosa colonization/infection of elderly patients., Background: It has been reported that in older adults increases the oral colonization by Candida particularly C. non-albicans, showing a decreased response to fluconazole, which increases the risk of recalcitrant local and disseminated candidiasis., Materials and Methods: This was a prospective cross-sectional study conducted in 120 elderly patients. Oral samples were obtained of mucosal Candida colonization or infection by swabbing. Each sample was plated on CHROMagar(®)Candida and incubated (36±1.5°C) for two days. The yeast species were identified using the API(®)ID32-C-AUX. Fluconazole susceptibility was tested using a broth microdilution assay according to the CLSI methods., Results: The yeast colonization/infection frequency in the total population was 65.8%. The frequency of the highest Candida carriers was 67.4% in the 70-79-year-old-group. Oral candidiasis was present in 20%, with a tendency to increase with age (33.3% of adults aged>80years), it was determined that the use of prosthesis is associated with a higher colonization rate (Chi2, p=0.011). The frequency of colonization/infection cases with more than one species showed a tendency to increase with age; 18.9% in the 60-69 year-old-group, 20.9% in the 70-79-year-old-group and 29.2% in the ≥80 year-old-group. About fluconazole susceptibility: for C. albicans, 20.3%, about Candida non-albicans species 15.3% were dose dependently susceptible (DDS) and 17.9% were resistant., Conclusions: After 80 years of age, there is a considerable increase in Candida non-albicans species and a reduced susceptibility to fluconazole., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The study aims to explore the way civilians living in the line of fire experience the impact of exposure to warfare on their couple relationships. Semistructured interviews were conducted with 14 couples living on the Israeli side of the border with the Gaza Strip. Four themes emerged: Overall perception of the security situation's impact on the dyadic relationships, dyadic intimacy, role division and decision-making, and Couple's emotional coping: partnership versus separateness. The findings were organized along a continuum between impacted and not-impacted relationships. Couple's position on this continuum was not fixed and could change as a result of to the security situation or marital therapy. The findings were framed in concepts from Dialectic Theory and from the Family Adaptation Models. Implications for couple therapy in these situations were specified., (© 2016 American Association for Marriage and Family Therapy.)

Many systems are naturally represented by a multilayer network in which edges exist in multiple layers that encode different, but potentially related, types of interactions, and it is important to understand limitations on the detectability of community structure in these networks. Using random matrix theory, we analyze detectability limitations for multilayer (specifically, multiplex) stochastic block models (SBMs) in which L layers are derived from a common SBM. We study the effect of layer aggregation on detectability for several aggregation methods, including summation of the layers' adjacency matrices for which we show the detectability limit vanishes as O(L^{-1/2}) with increasing number of layers, L. Importantly, we find a similar scaling behavior when the summation is thresholded at an optimal value, providing insight into the common-but not well understood-practice of thresholding pairwise-interaction data to obtain sparse network representations.

Aims: Destructive remodelling of extracellular matrix (ECM) and inflammation lead to dilation and ultimately abdominal aortic aneurysm (AAA). Fibulin-5 (FBLN5) mediates cell-ECM interactions and elastic fibre assembly and is critical for ECM remodelling. We aimed to characterize FBLN5 regulation in human AAA and analyse the underlying mechanisms., Methods and Results: FBLN5 expression was significantly decreased in human aneurysmatic aortas compared with healthy vessels. Local FBLN5 knockdown promoted aortic dilation and enhanced vascular expression of inflammatory markers in Ang II-infused C57BL/6J mice. Inflammatory stimuli down-regulated FBLN5 expression and transcriptional activity in human aortic vascular smooth muscle cells (VSMC). Further, aortic FBLN5 expression was reduced in LPS-challenged mice. A SOX response element was critical for FBLN5 promoter activity. The SOX9 expression pattern in human AAA parallels that of FBLN5, and like FBLN5, it was reduced in TNFα-stimulated VSMC. Interestingly, SOX9 over-expression prevented the cytokine-mediated reduction of FBLN5 expression and transcription. The inhibition of Class I histone deacetylases (HDACs) by MS-275 or gene silencing attenuated the inflammation-mediated decrease of FBLN5 expression in VSMC and in the vascular wall. Consistently, HDAC inhibition counteracted the reduction of SOX9 expression induced by inflammatory stimuli and prevented the TNFα-mediated decrease in the binding of SOX9 to FBLN5 promoter normalizing FBLN5 expression., Conclusion: We evidence the deregulation of FBLN5 in human AAA and identify a SOX9/HDAC-dependent mechanism involved in the down-regulation of FBLN5 by inflammation. HDAC inhibitors or pharmacological approaches that aimed to preserve FBLN5 could be useful to prevent the disorganization of ECM induced by inflammation in AAA., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: Morphine is one of the first-line therapies for the treatment of pain despite its secondary effects. It modifies the expression of epigenetic factors like miRNAs. In the present study, we analyzed miR-212 and miR-132 and their implication in morphine effects in the zebrafish Central Nervous System (CNS) through the regulation of Bdnf expression., Methods: We used control and knock-down zebrafish embryos to assess the effects of morphine in miRNAs 212/132 and mitotic or apoptotic cells by qPCR, immunohistochemistry and TUNEL assay, respectively. Bdnf and TrkB were studied by western blot and through a primary neuron culture. A luciferase assay was performed to confirm the binding of miRNAs 212/132 to mecp2., Results: Morphine exposure decreases miR-212 but upregulates miR-132, as wells as Bdnf and TrkB, and changes the localization of proliferative cells. However, Bdnf expression was downregulated when miRNAs 212/132 and oprm1 were knocked-down. Furthermore, we proved that these miRNAs inhibit mecp2 expression by binding to its mRNA sequence. The described effects were corroborated in a primary neuron culture from zebrafish embryos., Conclusions: We propose a mechanism in which morphine alters the levels of miRNAs 212/132 increasing Bdnf expression through mecp2 inhibition. oprm1 is also directly involved in this regulation. The present work confirms a relationship between the opioid system and neurotrophins and shows a key role of miR-212 and miR-132 on morphine effects through the regulation of Bdnf pathway., General Significance: miRNAs 212/132 are novel regulators of morphine effects on CNS. Oprm1 controls the normal expression of Bdnf., (Copyright © 2016. Published by Elsevier B.V.)

We report the development procedure for a Spanish version of the CORE measure for subtyping melancholic depression and its psychometric properties. The sample comprised two subsets of depressive patients: 117 in-patients clinically assessed after admission and before discharge; and 34 in- and out-patients who were video-recorded, with each recording being rated by independent raters and re-rated six months later. The internal consistency of the Spanish version of the CORE was high, with Cronbach's alpha coefficient of 0.93 for the total CORE score. High intra-class correlation coefficient for the total score (0.96) and the three subscales (around 0.8) indicate high inter-rater reliability. Baseline and six-month ratings of video-recordings showed high test-retest reliability. Regarding construct validity, the correlation between the CORE and the Newcastle endogeneity scale scores was 0.64. A ROC curve generated an optimal cut-off of 10 to predict the definition of endogeneity/melancholia based on the Newcastle score >=6 and the DSM-IV-TR definition of melancholia. The comparison between the CORE scores at admission and at discharge revealed large differences, indicating demonstrable sensitivity to change. The Spanish version of the CORE system is a reliable and valid instrument for sub-typing depression in terms of melancholic versus non-melancholic sub-types., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Thailand uses cause of death records in civil registration to summarize maternal mortality statistics. A report by the Department of Health using the Reproductive Age Mortality Studies (RAMOS) reported that the maternal mortality ratio (MMR) in 1997 was approximately three to four times higher than MMR based on the civil registration cause of death records. Here, we used multiple data sources to systematically measure maternal mortality in Thailand and showed a disparity between age groups and regions., Methods: We calculated the number of maternal deaths using a two-stage method. In the first stage, we counted the number of deceased mothers who successfully gave live births. In the second stage, we counted the number of women who died during the pregnancy, delivery, or the postpartum period without a live birth., Results: The number of maternal deaths dropped from 268 in 2007 to 226 in 2014. Nearly 50 % of the deaths occurred in Stage 1. The maternal mortality ratio in 2007 was 33.6 per 100,000 live births; the rate fell to 31.8 in 2014. The age ranges of women observed were 15-19, 20-24, 25-29, 30-34, 35-39, 40-44, and 45-49, and the MMR averages were 21.5, 23.8, 27.0, 42.1, 67.7, 115.4, and 423.4 per 100,000 live births, respectively. The Southern region consistently exhibited the highest MMR compared to other regions for every year analyzed, except 2012. Women in Bangkok had a lower risk of dying during pregnancy, delivery, and the postpartum period than women from other regions., Conclusions: We demonstrated that using multiple administrative data sources in the two-stage method was an efficient method that provided systematic measurement and timely reporting on the maternal mortality ratio. An additional benefit of the method was that information provided from the combined data sources, (e.g., the number of maternal deaths by age group and region) was relevant to the safe motherhood policy.

Proper development of the nervous system requires a temporally and spatially orchestrated set of events including differentiation, synapse formation and neurotransmission. Nerve growth factor (NGF) acting through the TrkA neurotrophin receptor (also known as NTRK1) regulates many of these events. However, the molecular mechanisms responsible for NGF-regulated secretion are not completely understood. Here, we describe a new signaling pathway involving TrkA, ARMS (also known as Kidins220), synembryn-B and Rac1 in NGF-mediated secretion in PC12 cells. Whereas overexpression of ARMS blocked NGF-mediated secretion, without affecting basal secretion, a decrease in ARMS resulted in potentiation. Similar effects were observed with synembryn-B, a protein that interacts directly with ARMS. Downstream of ARMS and synembryn-B are Gαq and Trio proteins, which modulate the activity of Rac1 in response to NGF. Expression of dominant-negative Rac1 rescued the secretion defects of cells overexpressing ARMS or synembryn-B. Thus, this neurotrophin pathway represents a new mechanism responsible for NGF-regulated secretion., (© 2016. Published by The Company of Biologists Ltd.)

Clinical management of abdominal aortic aneurysm (AAA) is currently limited to elective surgical repair because an effective pharmacotherapy is still awaited. Inhibition of histone deacetylase (HDAC) activity could be a promising therapeutic option in cardiovascular diseases. We aimed to characterise HDAC expression in human AAA and to evaluate the therapeutic potential of class I and IIa HDAC inhibitors in the AAA model of angiotensin II (Ang II)-infused apolipoprotein-E-deficient (ApoE(-/-)) mice. Real-time PCR, western blot and immunohistochemistry evidenced an increased expression of HDACs 1, 2 (both class I), 4 and 7 (both class IIa) in abdominal aorta samples from patients undergoing AAA open repair (n=22) compared with those from donors (n=14). Aortic aneurysms from Ang-II-infused ApoE(-/-) mice exhibited a similar HDAC expression profile. In these animals, treatment with a class I HDAC inhibitor (MS-275) or a class IIa inhibitor (MC-1568) improved survival, reduced the incidence and severity of AAA and limited aneurysmal expansion evaluated by Doppler ultrasonography. These beneficial effects were more potent in MC-1568-treated mice. The disorganisation of elastin and collagen fibres and lymphocyte and macrophage infiltration were effectively reduced by both inhibitors. Additionally, HDAC inhibition attenuated the exacerbated expression of pro-inflammatory markers and the increase in metalloproteinase-2 and -9 activity induced by Ang II in this model. Therefore, our data evidence that HDAC expression is deregulated in human AAA and that class-selective HDAC inhibitors limit aneurysm expansion in an AAA mouse model. New-generation HDAC inhibitors represent a promising therapeutic approach to overcome human aneurysm progression., (© 2016. Published by The Company of Biologists Ltd.)

Multilayer networks are a useful data structure for simultaneously capturing multiple types of relationships between a set of nodes. In such networks, each relational definition gives rise to a layer. While each layer provides its own set of information, community structure across layers can be collectively utilized to discover and quantify underlying relational patterns between nodes. To concisely extract information from a multilayer network, we propose to identify and combine sets of layers with meaningful similarities in community structure. In this paper, we describe the "strata multilayer stochastic block model" (sMLSBM), a probabilistic model for multilayer community structure. The central extension of the model is that there exist groups of layers, called "strata", which are defined such that all layers in a given stratum have community structure described by a common stochastic block model (SBM). That is, layers in a stratum exhibit similar node-to-community assignments and SBM probability parameters. Fitting the sMLSBM to a multilayer network provides a joint clustering that yields node-to-community and layer-to-stratum assignments, which cooperatively aid one another during inference. We describe an algorithm for separating layers into their appropriate strata and an inference technique for estimating the SBM parameters for each stratum. We demonstrate our method using synthetic networks and a multilayer network inferred from data collected in the Human Microbiome Project.

The activity analysis of a scientific journal is relevant to know the evolution of its characteristics over time. In this paper, results of a bibliometric study of the Revista de Biología Tropical/International Journal of Tropical Biology and Conservation (Costa Rica) are presented. The goal of this study was to describe the main characteristics of its scientific production, and analyze its level of collaboration and its impact between the years 2003-2012. Data was derived from the Web of Science (Thomson-Reuters), and the relationship among authors and coauthors, institutions and countries, and their links with the citations received were analyzed for that period. Descriptive statistics about production (number of documents per year, institution and country), collaboration (authorship index, collaboration among institutions and countries) and impact (IF, position in JCR and number of citations received) were collected. Results showed that the journal has published 1 473 papers in this period, in similar proportions English and Spanish. Mexico, Costa Rica, Venezuela and Colombia are the most common countries of origin, with the Universidad of Costa Rica, Universidad Autónoma de Mexico and the University of Puerto Rico as the most common leader institutions. Collaboration between authors, institutions and countries has shown an increasing trend over the last decade. The co-author index was 3.07 per document, 63 % of publications included 2 or more institutions, and 22 % of the papers were product of international collaboration. The most common collaboration link was between Costa Rica and the United States of America. The impact factor has been oscillating during this last decade, reaching a maximum in 2012 (IF JCR = 0.553). Besides, 10 % of the most cited papers concentrated half of the citations received by the journal, and have a very high number of citations, compared with the journal mean. The main countries that cite the journal were USA, Brazil, Mexico, Argentina and Costa Rica. Data showed an increasing collaboration between authors, institutions and countries, and a direct relationship between the increase of this collaboration and the received impact.

Numerous studies have documented declines in the abundance of reef-building corals over the last several decades and in some but not all cases, phase shifts to dominance by macroalgae have occurred. These assessments, however, often ignore the remainder of the benthos and thus provide limited information on the present-day structure and function of coral reef communities. Here, using an unprecedentedly large dataset collected within the last 10 years across 56 islands spanning five archipelagos in the central Pacific, we examine how benthic reef communities differ in the presence and absence of human populations. Using islands as replicates, we examine whether benthic community structure is associated with human habitation within and among archipelagos and across latitude. While there was no evidence for coral to macroalgal phase shifts across our dataset we did find that the majority of reefs on inhabited islands were dominated by fleshy non-reef-building organisms (turf algae, fleshy macroalgae and non-calcifying invertebrates). By contrast, benthic communities from uninhabited islands were more variable but in general supported more calcifiers and active reef builders (stony corals and crustose coralline algae). Our results suggest that cumulative human impacts across the central Pacific may be causing a reduction in the abundance of reef builders resulting in island scale phase shifts to dominance by fleshy organisms., (© 2016 The Author(s).)

Objective: To describe incidence patterns and trends in children (0-14 years) and adolescents (15-19 age-range) with solid tumours, except those of central nervous system (CNS), in Spain., Methods: Cases were drawn from eleven Spanish population-based cancer registries. Incidence was estimated for the period 1983-2007 and trends were evaluated using Joinpoint regression analysis., Results: The studied tumour groups accounted for 36% of total childhood cancers and 47.6% of those diagnosed in adolescence with annual rates per million of 53.5 and 89.3 respectively. In children 0 to 14 years of age, Neuroblastoma (NB) was the commonest (7.8%) followed by Soft-tissue sarcomas (STS) (6.3%), bone tumours (BT) (6.2%) and renal tumours (RT) (4.5%). NB was the most frequently diagnosed tumour before the 5th birthday, while STS and BT were the commonest at 5-9 years of age, and BT and Carcinoma and other epithelial tumours (COET) at 10-14. COET presented the highest incidence in adolescents, followed by germ-cell tumours (GCT), BT and STS. These four diagnostic groups accounted for 94% of total non-CNS solid tumours, in adolescents. Overall incidence rates increased significantly in children up to 1996 with an annual percentage change (APC) of 2.6% (95%CI: 1.7; 3.6). NB and COET showed significant time trend (APCs: 1.4% and 3.8% respectively) while other tumour groups such as RT, STS, BT or GCT had no significant changes over time. A significant increase was present in NB under the age of 5 and in BT and STS in children aged 10-14 years. In adolescents there were significant increases for all tumours combined (APC=2.7; 95%CI: 1.8-3.6) and for STS, GCT and COET (APCs: 3.2%, 4.4% and 3.5% respectively), while other tumour groups such as hepatic tumours, BT or thyroid carcinomas showed a decreasing trend or no increase., Conclusions: Overall, the incidence of the studied cancers in children increased along the period 1983-1996 with no posterior significant rise, while the incidence in adolescents increased significantly over the whole period 1983-2007. Several specific tumour groups showed significant rises or decrements in childhood or adolescence, although the small number of cases precludes showing significant trends or inflexion points.

Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS) that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1- like (D1R and D5R) and D2- like receptors (D2R, D3R, and D4R). The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS), there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers.

In this work we describe for the first time the generation and characterization of human induced pluripotent stem cells (hiPSCs) from peripheral blood mononuclear cells (PBMCs) and dermal fibroblasts of a Primary Hyperoxaluria Type I (PH1)-diagnosed patient with p.I244T mutation, which is highly prevalent in Canary Islands due to founder effect. Cell reprogramming was performed using non-integrative Sendai viruses containing the Yamanaka factors and the generated PH1-hiPSC lines (PH1-PBMCs-hiPSC4F1 and PH1-Fib-hiPSC4F1) showed normal karyotypes, silencing of the exogenous reprogramming factors, induction of the typical pluripotency-associated markers and in vivo differentiation ability to the three germ layers., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

In this work, mesenchymal stem cells derived from adipose tissue (ADSCs) were used for the generation of the human-induced pluripotent stem cell line G15.AO. Cell reprogramming was performed using retroviral vectors containing the Yamanaka factors, and the generated G15.AO hiPSC line showed normal karyotype, silencing of the exogenous reprogramming factors, induction of the typical pluripotency-associated markers, alkaline phosphatase enzymatic activity, and in vivo and in vitro differentiation ability to the three germ layers., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Modularity is a key organizing principle in real-world large-scale complex networks. The relatively sparse interactions between modules are critical to the functionality of the system and are often the first to fail. We model such failures as site percolation targeting interconnected nodes, those connecting between modules. We find, using percolation theory and simulations, that they lead to a "tipping point" between two distinct regimes. In one regime, removal of interconnected nodes fragments the modules internally and causes the system to collapse. In contrast, in the other regime, while only attacking a small fraction of nodes, the modules remain but become disconnected, breaking the entire system. We show that networks with broader degree distribution might be highly vulnerable to such attacks since only few nodes are needed to interconnect the modules, consequently putting the entire system at high risk. Our model has the potential to shed light on many real-world phenomena, and we briefly consider its implications on recent advances in the understanding of several neurocognitive processes and diseases.

Background: Late-onset neutropenia (LON) is a known adverse effect to rituximab therapy. Information about its real incidence and clinical implications comes from case reports and few retrospective studies specifically designed to study LON. However, large prospective studies of LON are lacking in the literature. We aimed to determine the incidence of LON in a group of non-Hodgkin lymphoma patients treated with rituximab and to analyze the clinical course, complications, and risk factors associated with LON., Patients and Methods: We retrospectively reviewed 183 patients with a diagnosis of non-Hodgkin lymphoma consecutively treated with rituximab alone or in combination with chemotherapy., Results: We identified 11 patients with grade 3/4 LON (13 episodes) out of 183 patients (6%). The median time to onset of LON was 75 days, and the median time to recovery from neutropenia was 100 days. The median neutrophil count nadir was 0.55 × 10(9)/L (range, 0.06-0.9 × 10(9)/L). Two patients presented infectious complications, one with fatal outcome., Conclusion: In our experience, the incidence of recognized LON is low (6%), although its real incidence may be greater because of the asymptomatic course and quick recovery in most cases. Infectious complications are unusual, but life-threatening complications can emerge. A careful evaluation of all cases of LON is warranted., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cognitive impairment is a core symptom of depressive disorders associated with poor social function. New research is needed to analyze depression-related symptoms in cognitive impairment and to observe if they are reversible or not during clinical remission in patients with or without previous episodes. None of the previous studies has analyzed the differences between first and recurrent episodes in a long-term follow-up study related with remission state. The aim of our study was to compare cognitive performance and assess the impact of previous depressive episodes in a sample of patients in acute phase and in remission six month later. 79 depressive patients were assessed at baseline. The instruments used for clinical and cognitive assessment were: Hamilton Depression Rating Scale, Mini-Mental State Examination and the Clinical Global Impression Rating Scales, Trail Making Test parts A and B, Digital Span subtest of WAIS, Stroop Colour Word Test, Tower of London, Controlled Verbal Fluency Task, Semantic Verbal Fluency and Finger Tapping Test. A repeated measures MANCOVA with education as covariate was used. No differences were found at baseline between first episode and recurrent depressive patients. At six month, remitted patients scored significant better in TMT-A, TMT-B, Animals and Tower of London total time. Remitted first depressive patients scored significant worse than remitted recurrent depressive patients. The main finding of the study is the effect of remission on cognitive function despite previous episodes. However first episode remitted patients seemed to have poor access to long term memory than recurrent remitted patients., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Background: demonstrate the importance of considering limb-shaking syndrome in the differential diagnosis of patients who present to the emergency department (ED) with hyperkinetic movements., Methods: In this article, we describe a diagnostic challenge in the ED in which a patient presents with hyperkinetic movements that are initially diagnosed as hemichorea-hemiballismus (HCHB) but are subsequently found to be limb-shaking syndrome with important therapeutic opportunities., Results: Following a diagnosis of left carotid obstruction, the patient underwent left carotid endarterectomy 5 days after admission. Six months after surgery, the patient had no further symptoms, and an ultrasound scan and magnetic resonance angiography have confirmed no restenosis., Conclusion: Limb shaking is an uncommon form of transient ischemic attack that should be recognized and differentiated from conditions such as focal motor seizures. Recognition will almost invariably indicate carotid artery occlusion, and timely treatment may not only abolish the attacks in patients but also reduce their risk of stroke. HCHB represents a spectrum of hyperkinetic movement disorders varying in the severity of choreic and/or ballistic movements. The presented case includes limb-shaking syndrome in the differential diagnosis and prompts for further investigations to complete the assessment., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Rituximab is an IgG1, chimeric monoclonal antibody specifically designed to recognize the CD20 antigen expressed on the surface of normal and malignant B-lymphocytes, from the B-cell precursor to the mature B-cells of the germinal center, and by most neoplasms derived from B-cells. After 2 decades of use, rituximab is firmly positioned in the treatment of follicular lymphoma (FL), both in the front line and in the relapsing disease, improving previous results by including it in classical chemotherapy regimens. However, the pharmacology of rituximab continues to generate controversial issues especially regarding the mechanisms of action in vivo. The contribution of rituximab as a maintenance treatment in FL has been significant progress in the management of this disease without an increase in side effects or a decrease in the quality of life of patients. With the widespread use of rituximab, there are new security alerts and side effects not previously detected in the pivotal trials that clinicians should learn to recognize and manage. In this article, we will review the pharmacokinetics and pharmacodynamics of rituximab, the management issues in the treatment of advanced FL focusing on maintenance rituximab, its long-term efficacy and safety profile, and its effect on the quality of life.

Most large cities are spanned by more than one transportation system. These different modes of transport have usually been studied separately: it is however important to understand the impact on urban systems of coupling different modes and we report in this paper an empirical analysis of the coupling between the street network and the subway for the two large metropolitan areas of London and New York. We observe a similar behaviour for network quantities related to quickest paths suggesting the existence of generic mechanisms operating beyond the local peculiarities of the specific cities studied. An analysis of the betweenness centrality distribution shows that the introduction of underground networks operate as a decentralizing force creating congestion in places located at the end of underground lines. Also, we find that increasing the speed of subways is not always beneficial and may lead to unwanted uneven spatial distributions of accessibility. In fact, for London—but not for New York—there is an optimal subway speed in terms of global congestion. These results show that it is crucial to consider the full, multimodal, multilayer network aspects of transportation systems in order to understand the behaviour of cities and to avoid possible negative side-effects of urban planning decisions., (© 2015 The Author(s).)

The CRB proteins CRB1, CRB2 and CRB3 are members of the cell polarity complex Crumbs in mammals that together with Scribble and Par complexes stablish the polarity of a variety of cell types. Although many members of the Crumbs complex proteins are expressed in the retinal pigment epithelium (RPE), and even though the mRNA of CRB2 has been detected in ARPE-19 cells and in the RPE/Choroid, to date no CRB protein has yet been found in this tissue. To investigate this possibility, we generated an antibody that specifically recognize the mouse CRB2 protein, and we demonstrate the expression of CRB2 in mouse RPE. Confocal analysis shows that CRB2 is restricted to the apicolateral membrane of RPE cells, and more precisely, in the tight junctions. Our study identified CRB2 as the member of the CRB protein family that is present together with the rest of the components of the Crumbs complex in the RPE apico-lateral cell membrane. Considering that the functions of CRB proteins are decisive in the establishment and maintenance of cell-cell junctions in several epithelial-derived cell types, we believe that these findings are a relevant starting point for unraveling the functions that CRB2 might perform in the RPE.

Association of messenger RNAs with large complexes such as processing bodies (PBs) plays a pivotal role in regulating their translation and decay. Little is known about other possible functions of these assemblies. Exposure of haploid yeast cells, carrying mating type "a," to "α pheromone" stimulates polarized growth resulting in a "shmoo" projection; it also induces synthesis of "a pheromone," encoded by MFA2. In this paper, we show that, in response to α pheromone, MFA2 mRNA is assembled with two types of granules; both contain some canonical PB proteins, yet they differ in size, localization, motility, and sensitivity to cycloheximide. Remarkably, one type is involved in mRNA transport to the tip of the shmoo, whereas the other-in local translation in the shmoo. Normal assembly of these granules is critical for their movement, localization, and for mating. Thus, MFA2 mRNAs are transported to the shmoo tip, in complex with PB-like particles, where they are locally translated., (© 2015 Aronov et al.)