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Made available in DSpace on 2018-11-26T16:33:10Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-05-11 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Recent studies have reported incipient morphological caste dimorphism in the Van der Vecht organ size of some temperate Polistes paper wasps. Whether species other than the temperate ones show a similar pattern remains elusive. Here, we have studied some Neotropical Polistes species. By comparing females collected through the year, we showed caste related differences in the size of the Van der Vecht organ in P. ferreri (body size corrected Van der Vech organ size of queens = 0.45 +/- 0.06, workers = 0.38 +/- 0.07 mm(2), p = 0.0021), P. versicolor (body size corrected Van der Vech organ size of queens = 0.54 +/- 0.11, workers = 0.46 +/- 0.09 mm(2), p = 0.010), but not P. simillimus (body size corrected Van der Vech organ size of queens = 0.52 +/- 0.05, workers = 0.49 +/- 0.06 mm(2), p = 0.238). Therefore, it seems that queens and workers of some Neotropical Polistes have diverged in their ontogenic trajectory of the Van der Vecht organ size, providing clear evidence for incipient morphological caste dimorphism. As Polistes are distributed mostly in the tropics, we propose that physical caste differences may be widespread in the genus. Also, we highlight that morphological divergence in the queen-worker phenotypes may have started through differential selection of body structures, like the Van der Vecht organ. Univ Fed Vicosa, Dept Entomol, BR-36570000 Vicosa, MG, Brazil Univ Florence, Dipartimento Biol Evoluzionist Leo Pardi, Via Romana 17, I-50125 Florence, Italy Univ Fed Vicosa, Dept Biol Geral, BR-36570000 Vicosa, MG, Brazil Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas, Dept Zool & Bot, BR-15054000 Sao Paulo, Brazil Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas, Dept Zool & Bot, BR-15054000 Sao Paulo, Brazil CNPq: 143246/2011-9

Background Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1) variant/null (i.e. fully deleterious) acid α-glucosidase (GAA) genotype. This splicing variant occurs in 90% of Caucasian late onset patients, and is associated with a broad range of symptom onset. Methods We analyzed a cohort of 143 compound heterozygous and 10 homozygous IVS1 patients, and we assessed ages at symptom onset, the presence of cis-acting single nucleotide variants (SNVs), and performed splicing analysis and enzyme activity assays. Findings In compound heterozygous IVS1 patients, the synonymous variant c.510C>T was uniquely present on the IVS1 allele in 9/33 (27%) patients with childhood onset, but was absent from 110 patients with onset in adulthood. GAA enzyme activity was lower in fibroblasts from patients who contained c.510C>T than it was in patients without c.510C>T. By reducing the extent of leaky wild-type splicing, c.510C>T modulated aberrant splicing caused by the IVS1 variant. The deleterious effect of c.510C>T was also found in muscle cells, the main target cells in Pompe disease. In homozygous IVS1 patients, the c.510C>T variant was absent in 4/4 (100%) asymptomatic individuals and present in 3/6 (50%) symptomatic patients. In cells from homozygous IVS1 patients, c.510C>T caused reduced leaky wild-type splicing. Interpretation c.510C>T is a genetic modifier in compound heterozygous and homozygous IVS1 patients. This finding is important for neonatal screening programs for Pompe disease. Fund This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17–32) and Metakids (2016–063).

The lack of engineering systems able to faithfully reproduce complex kidney structures in vitro has made it difficult to efficiently model kidney diseases and development. Using polydimethylsiloxane (PDMS) scaffolds and a kidney-derived cell line we developed a system to rapidly engineer custom-made 3D tubules with typical renal epithelial properties. This system was successfully employed to engineer patient-specific tubules, to model polycystic kidney disease (PKD) and test drug efficacy, and to identify a potential new pharmacological treatment. By optimizing our system we constructed functional ureteric bud (UB)-like tubules from human induced pluripotent stem cells (iPSCs), and identified a combination of growth factors that induces budding morphogenesis like embryonic kidneys do. Finally, we applied this assay to investigate budding defects in UB-like tubules derived from a patient with a PAX2 mutation. Our system enables the modeling of human kidney disease and development, drug testing and discovery, and lays the groundwork for engineering anatomically correct kidney tissues in vitro and developing personalized medicine applications., Highlights • Using PDMS scaffolds and kidney cells we developed a system for rapidly engineering complex and functional kidney tubules • Engineered tubules from patient cells were used to model PKD and test drug efficacy, and identify a potential treatment • Engineered human iPSC-derived UB tubules were used to study normal UB developmental processes and patient specific defects

Background Even though liver kinase B1 (LKB1) is usually described as a tumor suppressor in a wide variety of tissues, it has been shown that LKB1 aberrant expression is associated with bad prognosis in Hepatocellular Carcinoma (HCC). Methods Herein we have overexpressed LKB1 in human hepatoma cells and by using histidine pull-down assay we have investigated the role of the hypoxia-related post-translational modification of Small Ubiquitin-related Modifier (SUMO)ylation in the regulation of LKB1 oncogenic role. Molecular modelling between LKB1 and its interactors, involved in regulation of LKB1 nucleocytoplasmic shuttling and LKB1 activity, was performed. Finally, high affinity SUMO binding entities-based technology were used to validate our findings in a pre-clinical mouse model and in clinical HCC. Findings We found that in human hepatoma cells under hypoxic stress, LKB1 overexpression increases cell viability and aggressiveness in association with changes in LKB1 cellular localization. Moreover, by using site-directed mutagenesis, we have shown that LKB1 is SUMOylated by SUMO-2 at Lys178 hampering LKB1 nucleocytoplasmic shuttling and fueling hepatoma cell growth. Molecular modelling of SUMO modified LKB1 further confirmed steric impedance between SUMOylated LKB1 and the STe20-Related ADaptor cofactor (STRADα), involved in LKB1 export from the nucleus. Finally, we provide evidence that endogenous LKB1 is modified by SUMO in pre-clinical mouse models of HCC and clinical HCC, where LKB1 SUMOylation is higher in fast growing tumors. Interpretation Overall, SUMO-2 modification of LKB1 at Lys178 mediates LKB1 cellular localization and its oncogenic role in liver cancer. Fund This work was supported by grants from NIH (US Department of Health and Human services)-R01AR001576-11A1 (J.M.M and M.L.M-C.), Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C), ELKARTEK 2016, Departamento de Industria del Gobierno Vasco (to M.L.M.-C), MINECO: SAF2017–87301-R and SAF2014–52097-R integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovación 2013–2016 cofinanciado con Fondos FEDER (to M.L.M.-C and J.M.M., respectively), BFU2015–71017/BMC MINECO/FEDER, EU (to A.D.Q. and I.D.M.), BIOEF (Basque Foundation for Innovation and Health Research): EITB Maratoia BIO15/CA/014; Instituto de Salud Carlos III:PIE14/00031, integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovacion 2013–2016 cofinanciado con Fondos FEDER (to M.L.M.-C and J.M.M), Asociación Española contra el Cáncer (T.C.D, P·F-T and M.L.M-C), Daniel Alagille award from EASL (to T.C.D), Fundación Científica de la Asociación Española Contra el Cancer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M and M.A), La Caixa Foundation Program (to M.L.M), Programma di Ricerca Regione-Università 2007–2009 and 2011–2012, Regione Emilia-Romagna (to E.V.), Ramón Areces Foundation and the Andalusian Government (BIO-198) (A.D.Q. and I.D.M.), ayudas para apoyar grupos de investigación del sistema Universitario Vasco IT971–16 (P.A.), MINECO:SAF2015–64352-R (P.A.), Institut National du Cancer, FRANCE, INCa grant PLBIO16–251 (M.S.R.), MINECO - BFU2016–76872-R to (E.B.). Work produced with the support of a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (M.V-R). Finally, Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644). Funding sources had no involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication., Highlights • Overexpression of LKB1 in human hepatoma cells during hypoxic stress induces deregulated cell growth and survival. • SUMO-2 modifications of LKB1 at Lys178 occur in human hepatoma cells hampering its nucleocytoplasmic shuttling. • LKB1 SUMOylation is augmented in pre-clinical mouse models and clinical HCC, being a hallmark of more aggressive HCC tumors.

Background Carfilzomib (CFZ) is a new proteasome inhibitor used for the treatment of multiple myeloma. Besides heart failure, angina and myocardial ischemia occurred following administration of CFZ, which is not contraindicated in patients with recent myocardial infarction/unstable angina excluded from the safety trials. Aim of Study To test the effects of CFZ (10− 9 to 10− 7 mol/L) on vascular tone and reactivity in the isolated rabbit heart and aorta. Methods and Results CFZ administered by bolus injection to the isolated heart increased coronary perfusion pressure (CPP) at all tested concentrations and mildly raised left ventricular pressure and heart rate, only at the highest concentration. Addition of CFZ directly into the organ bath increased the basal tone of isolated aortic strips with contraction plateau reached after 10 min. This spasmogenic effect doubled following ablation of the endothelium. Pretreatment with CFZ amplified the vasospastic action exerted by KCl, noradrenaline (NA) and angiotensin II (A) on aortic strips, and impaired vasodilation following administration of nitroglycerin (NTG) and nifedipine (NFP) on the contraction plateau induced by KCl, NA and A. Aortic strips pretreated with CFZ exhibited impaired relaxation, as compared to untreated strips, following administration of acetylcholine (Ach), an endothelium-dependent vasodilating agent, on the plateau of NA contraction (p, Highlights • In the isolated aorta, carfilzomib increased basal tone and vasospastic action of KCl, noradrenaline and angiotensin II. • In the isolated aorta, carfilzomib impaired the anti-spasmogenic activity of nitroglycerin, nifedipine and acetylcholine. • In the isolated heart, carfilzomib increased coronary perfusion pressure, and mildly left ventricular pressure and heart rate. Carfilzomib is a new chemotherapeutic agent used for the treatment of multiple myeloma. Our study shows that carfilzomib increases coronary perfusion pressure, resting vasoconstricting tone, and the spasmogenic effect of noradrenaline and angiotensin II, while it curbs the vasodilatory action of nitroglycerine and nifedipine. Our findings are relevant to human health as they warrant caution in the use of carfilzomib in elderly patients with cardiovascular risk factors and, even more importantly, in those with preexisting heart conditions, who are also eligible to receive carfilzomib, even though they were excluded from the safety trials, based on which carfilzomib use was approved.

8-Oxoguanine, a common mutagenic DNA lesion, generates G:C > T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C > T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs., Graphical Abstract Image 1, Highlights • A modest mutator phenotype in MUTYH-defective colorectal cancer • Novel mutational signature of G>T mutations from persisting 8-oxoguanine:A mispair • This mutational signature is present in oncogenes/tumor suppressor associated with colorectal cancer • The mutational signature allows identifying a role for 8-oxoguanine-related mutations in other types of human cancer. Viel et al. identifies by exome-sequencing a mutational signature in colorectal cancer defective in the MUTYH DNA glycosylase, a DNA repair gene preventing 8-oxoguanine-related mutagenesis. A strong sequence dependence of G > T transversions characterizes this mutational fingerprint and unveils the contribution of persistent 8-oxoG:A mismatches in human cancer.

Circulating tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays almost universal inactivation of TP53. We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. We identified mutations using a pipeline specifically designed to accurately detect variants at very low fractions. We detected TP53 mutations in the cfDNA of 49% SCLC patients and 11.4% of non-cancer controls. When stratifying the 51 initial SCLC cases by stage, TP53 mutations were detected in the cfDNA of 35.7% early-stage and 54.1% late-stage SCLC patients. The results in the controls were further replicated in 10.8% of an independent series of 102 non-cancer controls. The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests., Highlights • CtDNA may play a crucial role in the detection of pre-clinical cancer. • TP53 mutations are detectable in the cfDNA of SCLC patients with early-stage tumors. • Detection of TP53 mutations in non-cancer controls poses serious challenges for the development of ctDNA screening tests. Cell-free DNA (cfDNA) has potential for monitoring response to treatment and relapse, but also for early detection. This is the first study reporting the detection of circulating-tumor DNA (ctDNA) in cases diagnosed with small-cell lung cancer (SCLC). Our results show that TP53 mutations are detectable in the cfDNA of SCLC patients including those with early-stage tumors. Importantly, we also provide evidence that cancer-like TP53 mutations are present in non-cancer controls, which poses serious challenges for the development of ctDNA screening tests.

An endogenous molecular clockwork drives various cellular pathways including metabolism and the cell cycle. Its dysregulation is able to prompt pathological phenotypes including cancer. Besides dramatic metabolic alterations, cancer cells display severe changes in the clock phenotype with likely consequences in tumor progression and treatment response. In this study, we use a comprehensive systems-driven approach to investigate the effect of clock disruption on metabolic pathways and its impact on drug response in a cellular model of colon cancer progression. We identified distinctive time-related transcriptomic and metabolic features of a primary tumor and its metastatic counterpart. A mapping of the expression data to a comprehensive genome-scale reconstruction of human metabolism allowed for the in-depth functional characterization of 24 h-oscillating transcripts and pointed to a clock-driven metabolic reprogramming in tumorigenesis. In particular, we identified a set of five clock–regulated glycolysis genes, ALDH3A2, ALDOC, HKDC1, PCK2, and PDHB with differential temporal expression patterns. These findings were validated in organoids and in primary fibroblasts isolated from normal colon and colon adenocarcinoma from the same patient. We further identified a reciprocal connection of HKDC1 to the clock in the primary tumor, which is lost in the metastatic cells. Interestingly, a disruption of the core-clock gene BMAL1 impacts on HKDC1 and leads to a time-dependent rewiring of metabolism, namely an increase in glycolytic activity, as well as changes in treatment response. This work provides novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and identifies new connections between both systems with pivotal roles in cancer progression and response to therapy., Highlights • Primary and metastatic colon cancer cells from the same patient show differential time-dependent metabolic profiles. • Perturbations of the circadian clock induce differential alterations at the transcriptome level including metabolic pathways. • Core-clock gene (BMAL1) knockdown affects metabolic activity of cancer cells and impinges on treatment response. An evolutionary conserved molecular clockwork allows organisms to adapt physiology and biological processes to the geophysical time by driving various cellular pathways including metabolism and the cell cycle. In addition to dramatic metabolic alterations, cancer cells show severe changes in the biological clock likely to affect tumor progression and treatment response. Increasing efforts have been made to elucidate the connection between the circadian clock circuitry, tumor progression and cancer-associated metabolic alterations, yet a more detailed knowledge of this interplay is still missing. In this study, we investigated distinctive time-related transcriptomic and metabolic features in a cellular model of colon cancer progression and patient samples. We show that a disrupted biological clock leads to altered temporal profiles of gene expression, metabolic reprogramming and changes in drug response, and identify the hexokinase HKDC1 as a crucial element in this connection. Our results provide novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and pave the way to a possible optimization of cancer treatment.

Background Glioblastoma (GBM) is the most frequent and malignant primary brain tumor in adults and despite the progress in surgical procedures and therapy options, the overall survival remains very poor. Glutamate and α-KG are fundamental elements necessary to support the growth and proliferation of GBM cells. Glutamate oxidative deamination, catalyzed by GLUD2, is the predominant pathway for the production of α-KG. Methods GLUD2 emerged from the RNA-seq analysis of 13 GBM patients, performed in our laboratory and a microarray analysis of 77 high-grade gliomas available on the Geo database. Thereafter, we investigated GLUD2 relevance in cancer cell behavior by GLUD2 overexpression and silencing in two different human GBM cell lines. Finally, we overexpressed GLUD2 in-vivo by using zebrafish embryos and monitored the developing central nervous system. Findings GLUD2 expression was found associated to the histopathological classification, prognosis and survival of GBM patients. Moreover, through in-vitro functional studies, we showed that differences in GLUD2 expression level affected cell proliferation, migration, invasion, colony formation abilities, cell cycle phases, mitochondrial function and ROS production. In support of these findings, we also demonstrated, with in-vivo studies, that GLUD2 overexpression affects glial cell proliferation without affecting neuronal development in zebrafish embryos. Interpretation We concluded that GLUD2 overexpression inhibited GBM cell growth suggesting a novel potential drug target for control of GBM progression. The possibility to enhance GLUD2 activity in GBM could result in a blocked/reduced proliferation of GBM cells without affecting the survival of the surrounding neurons.

The World Health Organization has recently introduced molecular prognostic-diagnostic biomarkers in the classification of Central Nervous System (CNS) tumors. In order to characterize subclasses of tumors that cannot find a precise location in the current classification, and, or cannot be tested because of scant material, it is important to find new molecular biomarkers in tissue and, or biological fluid samples. In this study, we identified serum microRNAs that could serve as biomarkers for the diagnosis and prognosis of patients with tumors of glial origin. We retrospectively analyzed microRNA expression in the serum extracellular vesicles of patients with tumors of glial origin. Extracellular vesicles RNA was analyzed by Nanostring. qRT-PCR confirmed 6 overexpressed microRNAs: hsa-miR-4443, hsa-miR-422a, hsa-miR-494-3p, hsa-miR-502-5p, hsa-miR-520f-3p, and hsa-miR-549a. Hsa-miR-4443 was the only microRNA that showed significant differences in most comparisons. In situ hybridization (ISH), confirmed that our signature was mostly expressed in cancer cells. Importantly, hsa-miR-549a and hsa-miR-502-5p expression predicted prognosis in patients with tumors of glial origin. Although more studies are needed, we demonstrated that serum vesicles microRNA profiles are promising diagnostic and prognostic molecular biomarkers that will find an actual application in the clinical practice of CNS tumors., Highlights • We identified a microRNA signature in the serum extracellular vesicles of patients with glial tumors. • The signature was differentially expressed among tumors and controls, showing potentials in the diagnosis of Gliomas. • Hsa-miR-549a and hsa-miR-502-5p expression predicted prognosis in patients with tumors of glial origin. Research in context To find targeted therapies and patients sensitive to specific treatments, we need to better classify different groups of brain tumors identifying novel molecular biomarkers. The most common brain tumors are Gliomas. In this article, we identified a group of very short genes (microRNAs) in the extra-cellular vesicles of the serum of 8 normal and of 28 patients with gliomas. The expression of such genes differs among the different groups of tumors and normal patients, and can help in the diagnosis of gliomas. Interestingly, two microRNAs could predict the outcome of the disease and might find future clinical applications.

Antibodies targeting PD-1 and its ligand PDL1 are used in cancer immunotherapy but may lead to autoimmune diseases, including type 1 diabetes (T1D). It remains unclear whether PDL1 is expressed in pancreatic islets of people with T1D and how is it regulated., “Innovative Medicines Initiative 2”;“European Union(EU)”“Horizon2020”; and EFPIA”,“JDRF International” and The Leona M.and Harry B.Helmsley Charitable Trust”, SCOPUS: ar.j, info:eu-repo/semantics/published

Preoperative lymph node (LN) status is important for the treatment of bladder cancer (BCa). Here, we report a genomic-clinicopathologic nomogram for preoperatively predicting LN metastasis in BCa. In the discovery stage, 325 BCa patients from TCGA were involved and LN-status-related mRNAs were selected. In the training stage, multivariate logistic regression analysis was used to developed a genomic-clinicopathologic nomogram for preoperative LN metastasis prediction in the training set (SYSMH set, n = 178). In the validation stage, we validated the nomogram using two independent sample sets (SYSUCC set, n = 142; RJH set, n = 104) with respect to its discrimination, calibration and clinical usefulness. As results, we identified five LN-status-related mRNAs, including ADRA1D, COL10A1, DKK2, HIST2H3D and MMP11. Then, a genomic classifier was developed to classify patients into high- and low-risk groups in the training set. Furthermore, a nomogram incorporating the five-mRNA-based classifier, image-based LN status, transurethral resection (TUR) T stage, and TUR lymphovascular invasion (LVI) was constructed in the training set, which performed well in the training and validation sets. Decision curve analysis demonstrated the clinical value of our nomogram. Thus, our genomic-clinicopathologic nomogram shows favorable discriminatory ability and may aid in clinical decision-making, especially for cN-patients., Highlights • A genomic classifier was built to classify bladder cancer patients into high- and low-risk groups of lymph node metastasis. • A genomic-clinicopathologic nomogram was developed for predicting lymph node metastasis in bladder cancer patients. • The nomogram shows favorable discrimination and calibration which may aid in clinical decision-making. Preoperative lymph node status is critical for guiding the management of bladder cancer patients. However, current preoperative nodal staging methods are inaccurate. Here, we proposed a user-friendly tool (nomogram) for the preoperative prediction of lymph node metastasis in bladder cancer, which showed good calibration and discrimination. The favorable predictive accuracy was validated in two external institutes. Thus, our nomogram could be an efficient and valuable tool for individual lymph node metastasis prediction and bladder cancer treatment decision making.

Aim To review non-hormonal therapy options for menopausal vasomotor symptoms. The current EMAS position paper aims to provide to provide guidance for managing peri- and postmenopausal women who cannot or do not wish to take menopausal hormone therapy (MHT). Material and methods Literature review and consensus of expert opinion. Results Non-hormonal management of menopausal symptoms includes lifestyle modifications, diet and food supplements, non-hormonal medications and application of behavioral and alternative medicine therapies. There is insufficient or conflicting evidence to suggest that exercise, supplements or a diet rich in phytoestrogens are effective for vasomotor menopausal symptoms. Selective serotonin-reuptake inhibitors (SSRIs), serotonin norepinephrine-reuptake inhibitors (SNRIs) and gabapentin could be proposed as alternatives to MHT for menopausal symptoms, mainly hot flushes. Behavioral therapies and alternative medicine interventions have been tried, but the available evidence is still limited. Conclusions A number of interventions for non-hormonal management of menopausal vasomotor symptoms are now available. For women who cannot or do not wish to take estrogens, non-hormonal management is now a realistic option.

Organic acids are broadly distributed in nature, and humans used them in their natural sources since the early ages, essentially for food and drink preparations. Organic acids are low-molecular-weight organic compounds with one or more acidic groups such as carboxyl, sulfonic, alcohol and thiol groups. These functional groups make organic acids key building block chemicals, which have huge markets and are still commonly refined from petroleum. Indeed, during the first half of the twentieth century, advances in chemical synthesis offered competitive manufacturing processes. This scenario changed starting from the 1990s when development of the industrial biotechnology field, environmental issues and the integration of biomasses processing industries, fermentation and downstream procedures, yielded improved economics for the biological pathways. In this chapter, we mainly review the aspects of current or piloting large-scale successful industrial processes for yeast or fungal organic acid productions. Perspectives are also reported.

Non-native bark and ambrosia beetles represent a threat to forests worldwide. Their invasion patterns are, however, still unclear. Here we investigated first, if the spread of non-native bark and ambrosia beetles is a gradual or a discontinuous process; second, which are the main correlates of their community structure; third, whether those correlates correspond to those of native species. We used data on species distribution of non-native and native scolytines in the continental 48 USA states. These data were analyzed through a beta-diversity index, partitioned into species richness differences and species replacement, using Mantel correlograms and non-metric multidimensional scaling (NMDS) ordination for identifying spatial patterns, and regression on distance matrices to test the association of climate (temperature, rainfall), forest (cover area, composition), geographical (distance), and human-related (import) variables with β-diversity components. For both non-native bark and ambrosia beetles, β-diversity was mainly composed of species richness difference than species replacement. For non-native bark beetles, a discontinuous invasion process composed of long distance jumps or multiple introduction events was apparent. Species richness differences were primarily correlated with differences in import values while temperature was the main correlate of species replacement. For non-native ambrosia beetles, a more continuous invasion process was apparent, with the pool of non-native species arriving in the coastal areas that tended to be filtered as they spread to interior portions of the continental USA. Species richness differences were mainly correlated with differences in rainfall among states, while rainfall and temperature were the main correlates of species replacement. Our study suggests that the different ecology of bark and ambrosia beetles influences their invasion process in new environments. The lower dependency that bark beetles have on climate allowed them to potentially colonize more areas within the USA, while non-native ambrosia beetles, being dependent on rainfall, are typically filtered by the environment.

Background Fatty liver (hepatic steatosis) is one of the most common diseases globally, with increasing prevalence. The role of alcohol consumption in the development of hepatic steatosis has not been systematically examined. Methods We searched Medline, Embase, and ProQuest Dissertations & Theses Global for original data on the relationship between alcohol consumption and hepatic steatosis measured by non-invasive imagery, excluding studies conducted in participants, Highlights • The relationship between low alcohol consumption (

Microbial Fuel cells (MFCs) have been proposed for nutrient removal and energy recovery from different wastes. In this study the anaerobic digestate was used to feed H-type MFC reactors, one with a graphite anode preconditioned withGeobacter sulfurreducensand the other with an unconditioned graphite anode. The data demonstrate that the digestate acts as a carbon source, and even in the absence of anode preconditioning, electroactive bacteria colonise the anodic chamber, producing a maximum power density of 172.2 mW/m2. The carbon content was also reduced by up to 60%, while anaerobic ammonium oxidation (anammox) bacteria, which were found in the anodic compartment of the reactors, contributed to nitrogen removal from the digestate. Overall, these results demonstrate that MFCs can be used to recover anammox bacteria from natural sources, and it may represent a promising bioremediation unit in anaerobic digestor plants for the simultaneous nitrogen removal and electricity generation using digestate as substrate.

Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health.Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n= 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP).Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. Fund: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH. (c) 2018 The Authors. Published by Elsevier B.V.

Background Cytomegalovirus (CMV) is the leading infectious agent causing congenital sensorineural hearing loss and psychomotor retardation. CMV vaccine is currently unavailable and treatment options in pregnancy are limited. Susceptible pregnant women caring for children are at high risk for primary infection. CMV educational and hygienic measures have the potential to prevent primary maternal infection. Methods A mixed interventional and observational controlled study was conducted to investigate the effectiveness of hygiene information among pregnant women at risk for primary CMV infection for personal/occupational reasons. In the intervention arm, CMV-seronegative women, identified at the time of maternal serum screening for fetal aneuploidy at 11–12 weeks of gestation, were given hygiene information and prospectively tested for CMV until delivery. The comparison arm consisted of women enrolled at delivery who were neither tested for nor informed about CMV during pregnancy, and who had a serum sample stored at the screening for fetal aneuploidy. By design, groups were homogeneous for age, parity, education, and exposure to at least one risk factor. The primary outcome was CMV seroconversion. Acceptance of hygiene recommendations was a secondary objective and was measured by a self-report. Findings Four out of 331 (1.2%) women seroconverted in the intervention group compared to 24/315 (7.6%) in the comparison group (delta = 6.4%; 95% CI 3.2–9.6; P, Highlights • The rate of CMV seroconversion was 4/331 (1.2%) in the intervention group vs 24/315 (7.6%) in the comparison group • This study shows that hygiene information of CMV-seronegative pregnant women significantly prevents maternal infection. • 93% participants in the study found hygiene recommendations worth suggesting to all pregnant women. Cytomegalovirus is the leading infectious agent causing congenital sensorineural hearing loss and psychomotor retardation. Contacts with young children have been identified as the main source of virus transmission to mothers. While waiting for a CMV vaccine to become available, this study documents that an intervention based on the identification and hygiene counseling of pregnant women susceptible to be infected by CMV for the first time during pregnancy, significantly prevents maternal infection.

Background Identifying migraineurs by triptan utilization we studied risk for stroke in migraineurs compared to the general population. Methods A cohort study including all citizens 25–80 years of age in Denmark 2003–2011 was conducted. All persons prescribed triptans, and all those hospitalized for a first stroke were identified in the Danish Registries. Information on stroke severity/subtype and cardiovascular risk factors was available for stroke patients. Findings Of the 49,711 patients hospitalized for a first stroke, 1084 were migraineurs using triptans. Adjusting for age, sex, income, and educational level, risk for stroke was higher among migraineurs in respect to all strokes (RR 1.07; CI 1.01–1.14) and ischemic strokes (RR 1.07; CI 1.00–1.14). Risk for hemorrhagic stroke was increased but only in women (RR 1.41; CI 1.11–1.79). Risk was for mild strokes (RR 1.31; CI 1.16–1.48) while risk for severe strokes was lower among migraineurs (RR 0.77; CI 0.65–0.91). Risk was age-related; highest among women 25–45 years (RR ≈ 1.7). Risk was unrelated to numbers of dispensations. Interpretation Migraineurs identified by triptan utilization had higher risk for stroke. Strokes were minor and cardiovascular risk factors were less prevalent pointing to a migraine-specific etiology of stroke different from that of thromboembolism., Highlights • Migraineurs (identified by triptan utilization) are at higher risk for stroke. • The risk is not related to use of triptans as such. Rather the risk seems to be a consequence of the underlying migraine disease. • In migraineurs strokes are minor and less often associated classical stroke risk factors. Major strokes are uncommon. • The study points to an etiology of stroke in migraine different from thromboembolism, probably at the microvascular level. We used triptan utilization as an alternative way of identifying migraine. In this study of the entire Danish population aged 25–80 years migraineurs identified in this way were at higher risk for stroke. The increased risk was not related to use of triptans as such: Rather the risk seems to be a consequence of the underlying migraine disease. Characteristically, strokes in migraineurs are minor strokes and less often associated with classical stroke risk factors. Major strokes are uncommon. The study points to an etiology of stroke in migraineurs different from that of atherosclerotic thromboembolism, probably at the microvascular level.

Considerable ambiguity remains over the extent and nature of millennial/centennial-scale climate instability during the Last Interglacial (LIG). Here we analyse marine and terrestrial proxies from a deep-sea sediment sequence on the Portuguese Margin and combine results with an intensively dated Italian speleothem record and climate-model experiments. The strongest expression of climate variability occurred during the transitions into and out of the LIG. Our records also document a series of multi-centennial intra-interglacial arid events in southern Europe, coherent with cold water-mass expansions in the North Atlantic. The spatial and temporal fingerprints of these changes indicate a reorganization of ocean surface circulation, consistent with low-intensity disruptions of the Atlantic meridional overturning circulation (AMOC). The amplitude of this LIG variability is greater than that observed in Holocene records. Episodic Greenland ice melt and runoff as a result of excess warmth may have contributed to AMOC weakening and increased climate instability throughout the LIG. © 2018, The Author(s)., We thank A. Scrivner and C. Walmsley for assistance with foraminifer sample preparation and J. Rolfe and I. Mather for technical assistance with stable isotope measurements, M. Maslin and D. Thornalley for comments on an earlier version of the manuscript, A. Carlson and E. Galaasen for discussions and E. Galaasen and N. Irvali for providing the MD03-2664 data. V.M., K.R., L.C.S. and P.C.T. acknowledge support for the MD01-2444 study from UK-NERC project NE/G00756X/1 (to P.C.T. and L.C.S.). R.N.D., L.C.S., E.R., G.Z. and P.C.T. acknowledge support from Australian Research Council grant DP160102969 (to R.N.D.). L.M. acknowledges support from the Australian Research Council grant DE150100107. A.S.T. and J.H. are supported by the Australian Research Council (ARC). The numerical experiments were undertaken on the NCI National Facility at the ANU, Australia. B.M. acknowledges support from the CSIC-Ramón y Cajal postdoctoral programme RYC-2013-14073. We wish to acknowledge use of the Ferret program for generating the maps in Fig. 6 and Supplementary Figure 6 in this paper. Ferret is a product of NOAA’s Pacific Marine Environmental Laboratory (information is available at http://ferret.pmel.noaa.gov/Ferret/). This paper is a contribution to the PAGES Working Group on Quaternary Interglacials (QUIGS).

In this paper we investigate the changes in the functional connectivity intensity, and some related properties, in healthy people, across the life span and at resting state. For the explicit computation of the functional connectivity we exploit a recently proposed model, that bases not only on the correlations data provided by the acquisition equipment, but also on different parameters, such as the anatomical distances between nodes and their degrees. The leading purpose of the paper is to show that the proposed approach is able to recover the main aspects of resting state condition known from the available literature, as well as to suggest new insights, perspectives and speculations from a neurobiological point of view. Our study involves 133 subjects, both males and females of different ages, with no evidence of neurological diseases or systemic disorders. First, we show how the model applies to the sample, where the subjects are grouped into 28 different groups (14 of males and 14 of females), according to their age. This leads to the construction of two graphs (one for males and one for females), that can be realistically interpreted as representative of the neural network during the resting state. Second, following the idea that the brain network is better understood by focusing on specific nodes having a kind of centrality, we refine the two output graphs by introducing a new metric that favours the selection of nodes having higher degrees. As a third step, we extensively comment and discuss the obtained results. In particular, it is remarkable that, despite a great overlapping exists between the outcomes concerning males and females, some intriguing differences appear. This motivates a deeper local investigation, which represents the fourth part of the paper, carried out through a thorough statistical analysis. As a result, we are enabled to support that, for two special age groups, a few links contribute in differentiating the behaviour of males and females. In addition, we performed an average-based comparison between the proposed model and the traditional statistical correlation-based approach, then discussing and commenting the main outlined discrepancies.

IntroductionAutoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting.MethodsThe ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an ‘observer-nested-within-subject’ design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach’s alpha.ResultsThe ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items.ConclusionThe ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies.

(1) Background: Non-melanoma skin cancer is the most frequently diagnosed cancer in humans. The process of skin carcinogenesis is still not fully understood. However, several studies have been conducted to better explain the mechanisms that lead to malignancy; (2) Methods: We reviewed the more recent literature about the pathogenesis of non-melanoma skin cancer focusing on basal cell carcinomas, squamous cell carcinoma and actinic keratosis; (3) Results: Several papers reported genetic and molecular alterations leading to non-melanoma skin cancer. Plenty of risk factors are involved in non-melanoma skin cancer pathogenesis, including genetic and molecular alterations, immunosuppression, and ultraviolet radiation; (4) Conclusion: Although skin carcinogenesis is still not fully understood, several papers demonstrated that genetic and molecular alterations are involved in this process. In addition, plenty of non-melanoma skin cancer risk factors are now known, allowing for an effective prevention of non-melanoma skin cancer development. Compared to other papers on the same topic, our review focused on molecular and genetic factors and analyzed in detail several factors involved in non-melanoma skin cancer.

This Correspondence article is a comment which directly relates to the paper “A study of problems encountered in Granger causality analysis from a neuroscience perspective” (Stokes and Purdon, 2017). We agree that interpretation issues of Granger causality (GC) in neuroscience exist, partially due to the historically unfortunate use of the name “causality”, as described in previous literature. On the other hand, we think that Stokes and Purdon use a formulation of GC which is outdated (albeit still used) and do not fully account for the potential of the different frequency-domain versions of GC; in doing so, their paper dismisses GC measures based on a suboptimal use of them. Furthermore, since data from simulated systems are used, the pitfalls that are found with the used formulation are intended to be general, and not limited to neuroscience. It would be a pity if this paper, even if written in good faith, became a wildcard against all possible applications of GC, regardless of the large body of work recently published which aims to address faults in methodology and interpretation. In order to provide a balanced view, we replicate the simulations of Stokes and Purdon, using an updated GC implementation and exploiting the combination of spectral and causal information, showing that in this way the pitfalls are mitigated or directly solved.

This paper reviews what we know about prediction in relation to mood disorders from the perspective of clinical, biological, and physiological markers. It then also presents how information and communication technologies have developed in the field of mood disorders, from the first steps, for example, the transition from paper and pencil to more sophisticated methods, to the development of ecological momentary assessment methods and, more recently, wearable systems. These recent developments have paved the way for the use of integrative approaches capable of assessing multiple variables. The PSYCHE project stands for Personalised monitoring SYstems for Care in mental HEalth.

This special issue focuses on the recent advances on in vivo confocal microscopy (IVCM), a technique used to investigate eye structures at the cellular level without tissue damage. In 1985 Lemp and coworkers were the first to study ex vivo corneas by confocal microscopy and to suggest a possible in vivo use [1]. In the early 1990s, the groups directed by Cavanagh and Kaufman published the first IVCM in humans; thereafter the scientific interest in ocular IVCM rapidly increased. In the last decade, IVCM progressively gained a relevant role in the clinical setting, being of help in the diagnosis and management of a number of conditions such as toxicity induced by preservatives [2, 3] and different eye treatments [4, 5], iatrogenic damage [6], infections [7], and dystrophies [8], pathology of the conjunctiva [9–11] and limbus [12], ocular surface tumors [13], and corneal deposits [14, 15]. IVCM is a valuable tool for enhancing our understanding of anterior segment physiology and pathology, as pointed out by Dr. V. Fasanella et al. in their paper investigating meibomian gland changes occurring with aging and a number of ocular surface diseases. Examples of the usefulness of IVCM in detecting early corneal changes can be found in the paper by Dr. D. Wang et al., who highlighted that a higher-than-normal immune activity may be observed in a subgroup of patients with clear corneal grafts in the absence of any other clinical signs. Dr. P. Song et al. studied the confocal and histopathological features of the stromal scar in keratoconus and suggested that IVCM is capable of detecting subtle keratocyte activation associated with fibrosis. In recent years, IVCM has become increasingly useful in evaluating corneal innervation (which is of key importance in regulating ocular surface homeostasis) [16] and corneal immune and inflammatory responses [17]. In this special issue, three papers explored the changes occurring in corneal innervation in both local and systemic diseases. The paper by Dr. E. F. Wang et al. reviewed the impact of various systemic diseases on corneal innervation and discussed the potential use of IVCM as a noninvasive marker of peripheral neuropathy. The reports by Dr. R. Shetty et al. and Dr. N. K. Pahuja et al. investigated nerve changes occurring, respectively, in dry eye disease and keratoconus. Finally, IVCM plays a role in studying the therapeutic effects of topical eye treatments, as shown in this issue by the paper of Dr. A. M. Fea et al. This special issue provides a useful update on the advances in the rapidly evolving field of IVCM and highlights the contribution of this technology to our understanding of the anterior segment in health and disease. Paolo Fogagnolo Michele Iester Hong Liang Dipika V. Patel

After 60 years from the first report of an enzymatic phosphorylation of proteins, protein kinases are well-established key signaling molecules that impact all major biological processes (reviewed in [1, 2]). Protein and lipid kinases fulfill essential roles in many signaling pathways that regulate normal cell functions [1–5]. Deregulation of kinase activities leads to a variety of pathologies ranging from cancer to inflammatory diseases, diabetes, infectious diseases, cardiovascular disorders, and cell growth and survival [1, 2, 5–11]. A much larger proportion of additional kinases are present in parasites and bacterial, fungal, and viral genomes that are susceptible to exploitation as drug targets [12]. Since many human diseases result from overactivation of protein and lipid kinases due to mutations and/or overexpression, this enzyme class represents an important target for the pharmaceutical industry [6]. Approximately one-third of all protein targets under investigation in the pharmaceutical industry are protein or lipid kinases and to date 33 small molecular weight kinase inhibitors (SMWKIs) and a handful of therapeutic antibodies have been approved for various indications mainly in oncology and many more in various stages of clinical and preclinical development [5]. Kinase inhibitor drugs, which are in clinical trials, target all stages of signal transduction from the receptor protein tyrosine kinases that initiate intracellular signaling, through second-messenger dependent lipid and protein kinases and protein kinases that regulate the cell cycle [10, 13]. While treating chronic phase CML (an almost monogenic disease) with imatinib has been very successful, the treatment of more advanced cancers with kinase inhibitors has proven more difficult due to the heterogeneity of these cancer types as well as due to kinase inhibitor resistance resulting from selection for mutant alleles and/or upregulation of alternative signaling pathways [5, 10]. In addition, powerful broad-scale protein pathway activation mapping and phosphoprofiling of protein kinases and of their specific substrates are contributing to driving the new concept of precision medicine [14–16]. Notable advances have been made in the rational design of small-molecule inhibitors that target unique kinase conformational forms and binding sites and have specific kinase selectivity profiles [5, 17–19]. This special issue provides a selection of original articles focused on kinase targets and therapeutic approaches based on kinase targeting in different cell systems and pathological conditions. Resistance is a major drawback of conventional chemotherapy. The understanding of the mechanisms by which some cancer cells are resistant to ATRA (all-trans-retinoic acid) is crucial in anticancer drug development and requires detailed knowledge of the signaling pathways affected by ATRA. In the paper by R. S. Q. Barceinas et al., the authors show that, in lung cancer cells, ERK pathway activation is involved in the transcription-independent effects of ATRA. They also found that ERK targeting restores the beneficial effects of ATRA, suggesting that combined treatments with ATRA and ERK inhibitors could represent a promising strategy in lung cancer therapy. Targeting of pathways aberrantly activated in cancer is a very powerful approach that has provided promising results, with several drugs already in clinical trials for a number of diseases. The work by M. Civallero et al. provides an excellent example of preclinical testing and comparison of the cytotoxicity of two different kinase inhibitors, namely, the pan-PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitor BEZ235, on mantle, follicular, and T-cell lymphomas, in which the PI3K pathway is known to be hyperactive. They demonstrated that BKM120 and BEZ235 show high effectiveness against lymphoma cells in vitro both as monotherapy and in combination. Because the outcome of lymphoma patients is still very poor, in spite of the great advances following the introduction of monoclonal antibodies based therapy of lymphoma, the results of this work open a new therapeutic window for these malignancies. Along the same lines, the original work by C. Frasson et al. shows the pivotal role played by the PI3K/Akt pathway in promoting survival of primary medulloblastoma cells, the most frequent primitive neuroectodermal tumor in children, with a dismal prognosis in more than one-third of patients. In particular, the authors demonstrate that specific targeting PI3K impairs medulloblastoma primary cells growth and survival through the activation of the mitochondrial cell death program. Remarkably, PI3K signaling suppression seems to selectively hit the cancer stem cell population, sparing the most differentiated cellular counterpart. Since cancer stem cells have been reported to be one of the driving forces of tumor progression and resistance to therapy, these results may guide the development of new combinatorial therapeutic strategies aimed at impairing the survival machinery of both cancer stem cells and tumor bulk cells. The acidophilic kinase CK2 has been shown to play prominent roles in carcinogenesis. In the paper by C. Girardi et al., the authors analyze two inhibitors of CK2, namely, TDB and CX-4945. In particular, they compare their efficacy in terms of persistence of inhibitory effects after their removal. They find a superiority of TDB compared to CX-4945, and they conclude that this property is an added value to be considered when planning new therapies based on CK2 targeting. Inhibition of CK2 is also the focus of the paper by G. Cozza et al., where the authors analyze the properties of quinalizarin, extending its selectivity profile to 140 protein kinases. Consistent with in silico and in vitro analyses, they conclude that quinalizarin not only is one of the most selective inhibitors of CK2 but is also able to discriminate between the isolated CK2 catalytic subunit and CK2 holoenzyme. A different aspect of the Akt kinase functions has been explored by G. Vallejo-Flores and coauthors. Based on the observation that H. pylori infection is the most important environmental risk to developing gastric cancer, mainly, through its virulence factor CagA, they evaluated the capacity of H. pylori CagA positive and negative strains to alter nontransformed glandular acini formation. They found that the Akt and BIM signaling pathway is activated in CagA positive strains and might thus contribute to its oncogenic activity through evasion of anoikis. Overall, this special issue highlights the contribution of targeting signaling pathways in tumorigenesis and describes which compounds are more promising in the future for chemoprevention and anticancer therapy on the basis of their ability to inhibit specific signaling targets. Sandra Marmiroli Doriano Fabbro Yoshihiko Miyata Mariaelena Pierobon Maria Ruzzene

Background and Purpose: During the preparation of a coenological paper concerning the tall-herb vegetation of the Balkans, it emerged that some syntaxa were invalidly described in their original papers, while some other synataxa had been forgotten or considered invalid according to the current phytosociological literature even if they had been validly published in their original papers. The present study deals with the nomenclatural problems of the Rumicetalia balcanici Lakušić 1973, a neglected order of the montane tall-herb vegetation, and those of all its related lower-rank syntaxa.Materials and Methods: All published papers that treated the nomenclatural issues regarding the tall-herb vegetation in the Balkans were analysed. The nomenclature adjustments were made in accordance with the rules of the Code of Phytosociological Nomenclature (ICPN). The original relevés presented in this paper were carried out using the Braun-Blanquet phytosociological approach.Results and Conclusions: The nomenclature adjustments made in the paper result in the validation of the order Rumicetalia balcanicae and of four alliances: Rumicion balcanici, Ranunculion serbici, Cicerbition pancici and Petasition doerfleri. The validity of the alliance Cirsion appendiculati Horvat, Pawlowski et Walas 1937 was here confirmed while the name citation Geion coccinei Horvat in Quezel 1969 was here given for the first time. Finally several tall-herbs association were here validated and some others were proposed as new.

Background In Public Health, a thorough review of abstract quality evaluations and the publication history of studies presented at scientific meetings has never been conducted. To analyse the long-term outcome of quality abstracts submitted to conferences of Italian Society of Hygiene and Public Health (SItI) from 2005 to 2007, we conducted a second analysis of previously published material aiming to estimate full-text publication rate of high quality abstract presented at Italian public health meetings, and to identify predictors of full-text publication. Methods The search was undertaken through scientific databases and search engines and through the web sites of the major Italian journals of Public Health. For each publication confirmed as a full text paper, the journal name, impact factor, year of publication, gender of the first author, type of study design, characteristics of the results and sample size were collected. Results The overall publication rate of the abstracts presented is 23.5 %; most of the papers were published in Public Health journals (average impact factor: 3.007). Non universitary affiliation had resulted in a lower probability of publication, while some of the Conference topics had predisposed the studies to an increased likelihood of publication as well as poster form presentation. Conclusions The method presented in this study provides a good framework for the evaluation of the scientific evidence. The findings achieved should be taken into consideration by the Scientific Societies during the contributions selection phase, with the aim of achieving a continuous improvement of work quality. In the future, it would be interesting to survey the abstract authors to identify reasons for unpublished data.

BACKGROUND: Infectious diseases elimination and eradication have become important areas of focus for global health and countries. Due to the substantial up-front investments required to eliminate and eradicate, and the overall shortage of resources for health, economic analysis can inform decision making on whether elimination/eradication makes economic sense and on the costs and benefits of alternative strategies. In order to draw lessons for current and future initiatives, we review the economic literature that has addressed questions related to the elimination and eradication of infectious diseases focusing on: why, how and for whom? METHODS: A systematic review was performed by searching economic literature (cost-benefit, cost-effectiveness and economic impact analyses) on elimination/eradication of infectious diseases published from 1980 to 2013 from three large bibliographic databases: one general (SCOPUS), one bio-medical (MEDLINE/PUBMED) and one economic (IDEAS/REPEC). RESULTS: A total of 690 non-duplicate papers were identified from which only 43 met the inclusion criteria. In addition, only one paper focusing on equity issues, the "for whom?" question, was found. The literature relating to "why?" is the largest, much of it focusing on how much it would cost. A more limited literature estimates the benefits in terms of impact on economic growth with mixed results. The question of how to eradicate or eliminate was informed by an economic literature highlighting that there will be opportunities for individuals and countries to free-ride and that forms of incentives and/or disincentives will be needed. This requires government involvement at country level and global coordination. While there is little doubt that eliminating infectious diseases will eventually improve equity, it will only happen if active steps to promote equity are followed on the path to elimination and eradication. CONCLUSION: The largest part of the literature has focused on costs and economic benefits of elimination/eradication. To a lesser extent, challenges associated with achieving elimination/eradication and ensuring equity have also been explored. Although elimination and eradication are, for some diseases, good investments compared with control, countries' incentives to eliminate do not always align with the global good and the most efficient elimination strategies may not prioritize the poorest populations. For any infectious disease, policy-makers will need to consider realigning contrasting incentives between the individual countries and the global community and to assure that the process towards elimination/eradication considers equity.

Nowadays, several screening strategies are available to prevent cervical cancer, but inadequate resources, sociocultural barriers, and sampling issues impede their success in low-income countries. To overcome these issues, this study aimed to evaluate the performance of human papillomavirus (HPV) testing from dried urine spots (DUS). Eighty-eight urine samples (including 56 HPV DNA positive specimens) were spotted on filter paper, dried, and stored in paper-bags. HPV DNA was detected from the DUS after 1 week and 4 weeks of storage using a polymerase chain reaction (PCR) assay. The sensitivity, specificity, and concordance of the DUS-based HPV test were evaluated by comparing the results with those of HPV testing on fresh urine samples as the gold standard. The sensitivity of the test was 98.21% (95% CI: 90.56–99.68) for DUS stored for 1 week and 96.42% (95% CI: 87.88–99.01) for DUS stored for 4 weeks. The specificity was 100% (95% CI: 89.28–100) at both time points. The concordance between DUS and fresh urine HPV testing was “almost perfect” using theκstatistic. These preliminary data suggest that a DUS-based assay could bypass sociocultural barriers and sampling issues and therefore could be a suitable, effective tool for epidemiological surveillance and screening programs, especially in low-income countries.

Behavioral differences among age classes, together with the natural tendency of individuals to prefer contacts with individuals of similar age, naturally point to the existence of a community structure in the population network, in which each community can be identified with a different age class. Data on age-dependent contact patterns also reveal how relevant is the role of the population age structure in shaping the spreading of an infectious disease. In the present paper we propose a simple model for epidemic spreading, in which a contact network with an intrinsic community structure is coupled with a simple stochastic SIR model for the epidemic spreading. The population is divided in 4 different age-communities and hosted on a multiple lattice, each community occupying a specific age-lattice. Individuals are allowed to move freely to nearest neighbor empty sites on the age-lattice. Different communities are connected with each other by means of inter-lattices edges, with a different number of external links connecting different age class populations. The parameters of the contact network model are fixed by requiring the simulated data to fully reproduce the contact patterns matrices of the Polymod survey. The paper shows that adopting a topology which better implements the age-class community structure of the population, one gets a better agreement between experimental contact patterns and simulated data, and this also improves the accordance between simulated and experimental data on the epidemic spreading.

Checklists, the result of time-consuming exploration and painstaking bibliographic research, can be easily converted into online databases, which have the advantage of being updatable online in real time, and of reaching a much wider audience. However, thousands of local checklists (Natural Parks, protected areas, etc.) are still available on paper only, and most of those published online appear as dry lists of latin names, which strongly reduces their outreach for a wider audience. The University of Trieste has recently started the publication of several local checklists in a way that may be more appealing for the general public, by linking species' names to archives of digital resources, and especially to digital identification tools produced by software FRIDA (FRiendly IDentificAtion). The query interfaces were developed on the basis of feedback from a wide range of users. The result is no longer a simple list of names accessible on the Web, but a veritable multimedial, interactive portal to the biodiversity of a given area. This paper provides an example of how relevant added value can be given to local lists of taxa by embedding them in a complex system of biodiversity-related resources, making them usable for a much wider audience than a restricted circle of specialists, as testified by the almost 1.000.000 unique visitors reached in 2014. A critical mass of digital resources is also put at disposal of the scientific community by releasing them under a Creative Commons license.

Genetic diseases are a wide group of diseases in which the etiopathogenesis is caused by or related to genetic factors. The role of genetics in the disease development can be more or less relevant depending on the specific characteristics of the disease, and a wide spectrum of complexity exists. Monogenic diseases, for example, are directly caused by defects in a specific gene whereas complex and polygenic diseases are generally caused by the interactions between multiple genes or between genetic and environmental factors. To the last category belong many forms of cancer, an uncontrolled growth of cells with alterations of the genetic materials. In the last decade, a large amount of experimental data has become available, so the identification of strategies to process and, most importantly, interpret them is crucial. The massive volume of data, both in terms of quantity and of dimensionality, and their heterogeneity and low signal-to-noise ratio are just some of the most obvious challenges that they present. To give an example, single nucleotide DNA mutations are one of the most common factors analysed in relation to the development of a genetic disease. However, this sometimes translates into dealing with millions of variants measured across thousands of individuals, where only a handful are informative. In fact, other more complex factors, such as gene expression, could play a significant role. The aim of this special issue is to review the recent advances in computational methods concerned with genetic diseases. The issue received sixteen submissions; each one was referred by at least two international reviewers that we warmly thank for their time. Six papers have been accepted for the publication. “A New Approach for Mining Order-Preserving Submatrices Based on all Common Subsequences” by Y. Xue et al. proposes, in the context of gene expression data, a pattern-based subspace clustering or OPSM (order-preserving submatrix model), based on frequent sequential pattern. The approach has been experimentally proven to be able to discover the biological significant OPSMs and deep OPSMs exhaustively. “Evolutionary Influenced Interaction Pattern as Indicator for the Investigation of Natural Variants Causing Nephrogenic Diabetes Insipidus” by S. Grunert and D. Labudde is devoted to the application of a high-throughput analysis method based on motif conservation among proteins of the same protein family for analysis of interacting sequences. This investigation can help to analyze the pathogenic impact of mutations causing alterations in interacting regions of a protein. This analysis has been applied on membrane proteins, in particular to the aquaporin 2 whose mutants are involved in nephrogenic diabetes insipidus. “Unified Modeling of Familial Mediterranean Fever and Cryopyrin Associated Periodic Syndromes” by Y. Bozkurt et al. describes a unifying dynamical model for Familial Mediterranean Fever (FMF) and Cryopyrin Associated Periodic Syndromes (CAPS) in the form of coupled nonlinear ordinary differential equations. The authors perform a comprehensive bifurcation analysis of the model and show that it exhibits three modes, capturing the healthy, FMF, and CAPS cases. They present extensive simulation results for the model that match clinical observations. “Enhancing the Lasso Approach for Developing a Survival Prediction Model Based on Gene Expression Data” by S. Kaneko et al. presents a novel improvement to the lasso approach, one of the most widely used method to correlate gene expression data with cancer patients' survival. This new algorithm significantly increases the ability to identify “true positives” and its validity is shown on both simulated and real data. “Statistical and Computational Methods for Genetic Diseases: An Overview” by Francesco Camastra, Maria Donata Di Taranto, and Antonino Staiano gives a survey of statistical and computational methods used to analyse the pathogenic role of sequence variants as well as to identify genetic markers of complex diseases by association studies, meta-analysis, and expression studies. “Optimization and Corroboration of the Regulatory Pathway of p42.3 Protein in the Pathogenesis of Gastric Carcinoma” by Y. Hao et al. provides important research directions for exploring the mechanism of action of p42.3 protein in gastric cancer. Through a Bayesian network model, the potential important role of p42.3 is verified by both theoretical analysis and preliminary test. We hope that the readers of this journal will find in the issue interesting papers and that this can encourage and foster further research on computational methods for genetic diseases. Francesco Camastra Roberto Amato Maria Donata Di Taranto Antonino Staiano

Unquestionably, business and industrial information can be considered an extremely important asset to any organization. Some would even go as far as claiming that organization's information resources are the lifeblood of that organization. However, recently other competitors such as countries and enterprises are doing their best to have advanced technology of certain corporation. This business and industrial information leakage tend to halt the ordinary business process of enterprise, causing tremendous economical property loss as well as damage to the competitiveness of enterprise due to the leakage of technology which needs to be effort- and time-consuming. Only security technology cannot directly protect against the underlying security incidents (business and industrial information leakage) that, in practice, lead to loss. Recent surveys suggest up to 60% of security breaches are related to human problem; yet few companies focus on human aspects in their security strategies. Hence to take preventive measures against security breaches, it is necessary to manage and converge three security areas (managerial, physical, and technical management) in the perspective of corporate and business security strategy. The main motivation for this special issue is to bring together researchers and practitioners working on related fields in human centric security management and its services to present current research issues and advances. Papers on practical as well as on theoretical topics and problems are invited. More specifically, the paper entitled “A Comprehensive Availability Modeling and Analysis of a Virtualized Servers System Using Stochastic Reward Nets” by T. A. Nguyen et al. proposed a virtualized servers system with multiple VMs via SRN. This paper encapsulated four VMs running on two VMMs into two hosts, and it also incorporated diverse failure modes and corresponding recovery behaviors regarding hardware and software aspects including host failure, SAN failure, aging-related failure, and Mandelbugs related failure in SRN models. The paper entitled “Software Authority Transition through Multiple Distributors” by K. Han and T. Shon discussed possible issues from using multiple OASs and proposed an improved PAS model that reduces management overheads without any additional entity, while still allowing users to obtain support from multiple OASs. This paper refined our model to support a temporary roaming situation, as well as a permanent OAS change. And it described the security of the proposed model. The paper entitled “The Study on Stage Financing Model of IT Project Investment” by S. Chen et al. applies the real option pricing model to measure the value brought by the stage financing strategy. The paper entitled “Advanced Approach to Information Security Management System Model for Industrial Control System” by S. Park and K. Lee presented two methodologies to prove that a new information security management system based on confidentiality, integrity, availability, and safety is required in the industrial control system. The paper entitled “An Integrative Behavioral Model of Information Security Policy Compliance” by S. H. Kim et al. tried to find the factors of information security policy compliance and suggest the information security policy based upon the founded factors. The paper entitled “The Strategic Measures for the Industrial Security of Small and Medium Business” by C.-M. Lee presented that online security control services and technology deposit system are suggested for such measures. These measures could enhance to a certain extent the industrial security of SMB. The low security awareness and financial difficulties seem to be the main obstacles to equip the SMB with such measures. The paper entitled “AVQS: Attack Route-Based Vulnerability Quantification Scheme for Smart Grid” by J. Ko et al. proposed a novel AVQS to accurately measure the security level in a smart grid. The proposed approach includes NVS and end-to-end security functions. The paper entitled “The Need for Specific Penalties for Hacking in Criminal Law” by S. Oh and K. Lee analyzed the definitions and the penalties for hacking for each country and compared with the national law; then it made suggestions through more specific legislation. This paper expects it will reduce legal controversy and prevent excessive punishment. The paper entitled “Empirical Analysis of Retirement Pension and IFRS Adoption Effects on Accounting Information: Glance at IT Industry” by J. Kim reviewed new pension accounting with K-IFRS and provided empirical changes in liability for retirement allowances with adoption of K-IFRS. It will help to understand the effect of pension accounting on individual firm's financial report and the importance of public announcement of actuarial assumptions. The paper entitled “Security Techniques for Prevention of Rank Manipulation in Social Tagging Services including Robotic Domains” by O. Choi et al. proposed a detection method for tag-ranking manipulation to solve the problem of the existing methods which cannot guarantee the reliability of tagging. The paper entitled “Effects of Corporate Social Responsibility and Governance on Its Credit Ratings” by D. Kim and J. Kim showed nonfinancial information also may have effects on corporate credit rating. The investment on personal data protection could be an example of CSR/CGI activities which have positive effects on corporate credit ratings. Eventually, we firmly believe that the accepted papers would be a meaningful contribution to researchers, students, and practitioners studying this field of strategic management advanced service for sustainable computing environment.

This special issue was focused on the current approaches in the medical and surgical treatment of the most diffuse and important corneal and ocular surface diseases. In addition, the role of current available technologies in the diagnosis and follow-up of patients with ocular surface diseases was also included. We have invited many experts on this topic to highlight the understanding of corneal diseases. Different topics were exhaustively treated. This allows improving the readers' knowledge on each theme, which is nowadays essential in the correct management of patients. In detail, M. De Bernardo and coworkers described and discussed the different formulas to overcome the problem of calculating the intraocular lens power in patients that underwent corneal refractive surgery. L. Mastropasqua and coworkers, focusing on glaucoma surgery, summarized the applications of time and spectral domain anterior segment-OCT in the conjunctival bleb assessment after filtrating surgery. The authors showed the utility of this technology in guiding the clinicians' decisions in the bleb management. F. Semeraro and coworkers analyzed the potential etiopathogenetic mechanisms involved in the epithelial in growth after Descemet's stripping automated endothelial keratoplasty, reviewing the literature, and discussing the most appropriate therapeutic approaches. T. Liu and coworkers proposed a relatively safe designed stromal bed thickness to avoid the endothelial damage following lamellar keratoplasty using an Allegretto WaveLight 3 FS200 femtosecond laser. L. Ambrosone and coworkers evaluated the efficacy of topical verbascoside-based liposomal eye drops in the healing of alkali corneal wound. The authors reported that this approach reduced significantly the first stage of the process of wound healing of the corneal epithelium. P. Vinciguerra and coworkers compared the biomechanical effect, the riboflavin penetration and distribution in 2 transepithelial corneal collagen cross-linking with iontophoresis (I-CXL), with standard cross-linking (S-CXL) and current transepithelial protocol (TE-CXL), in rabbits. The authors found that I-CXL induced a significant increase in corneal stiffness as well as better riboflavin penetration when compared to controls and TE-CXL, but not to S-CXL. M. Lanza and coworkers evaluated the correlation between corneal biomechanical and morphological data in healthy eyes, eyes that underwent myopic photorefractive keratectomy (PRK), keratoconus affected eyes, and keratoconus affected eyes that underwent corneal collagen cross-linking (CCC). The authors suggested suggest that corneal curvature would have a greater influence on corneal deformation than corneal thickness. L. Mastropasqua and coworkers quantified the effect of small incision lenticule extraction (SMILE) on the corneal biomechanics using Scheimpflug noncontact tonometer (CORVIS ST). The authors did not find significant modifications in biomechanical properties after SMILE, suggesting that this procedure could induce only minimal transient alterations of corneal biomechanics. F. Semeraro and coworkers evaluated the efficacy of 50% autologous serum eye drops in ocular surface diseases not improved by conventional therapy reporting that this treatment effectively stabilized and improved signs and symptoms in patients' affected chemical burns, recurrent corneal erosion, neurotropic keratitis, and keratoconjunctivitis sicca. A. Hill-Bator and coworkers reported a high cytoprotective ability of trehalose-based eye drops both in viable epithelial corneal cell number after the desiccation and in preservation of cellular functions. Finally, D. Viswanathan and coworkers evaluated the efficacy of corneal collagen cross-linking for progressive keratoconus in pediatric patients, reporting the treatment as an effective option in stabilizing the condition and reducing the need for corneal grafting. In summary, the papers published in this special issue confirm the progress in both research and treatment of corneal and ocular surface disease. The guest editors wish to thank all the authors of this special issue for contributing the high quality papers. We would also like to thank the referees who have critically evaluated the papers. Ciro Costagliola Mark Batterbury Harminder Singh Dua Leonardo Mastropasqua

It is well recognised that regular exercise is cardioprotective. On the other hand, sedentariety is an established risk factor for cardiovascular diseases. Furthermore, several clues suggest that exercise capacity is a strong predictor of risk of death from any cause in both healthy subjects and in those with cardiovascular diseases. However, the exact mechanisms through which regular physical activity confers cardiovascular protection are not yet well understood. Exercise probably acts at multiple levels. One possibility is that regular exercise modifies genes expression, thereby changing the production of bioactive molecules such as proteins and enzymes; another potential site of action is on the mechanisms of cardiovascular regulation during effort, which are improved after periods of training; finally, exercise can affect endothelial and platelet functions, thus reducing the risks of atherosclerosis and consequently the risk of infarction and stroke. This special issue focuses on potential beneficial mechanisms by which exercise operates to confer protection against cardiovascular diseases. The interesting paper by S. Heber and I. Volf reviews the effects of inactivity and training on platelet functions. In their literature review, they conclude that regular physical activity diminishes or prevents platelet activation in response to acute exercise and that habitual physical activity also positively modulates platelet functions. They also conclude that these effects support the well-recognised relation between exercise and the risk for cardiovascular events, as a physically active lifestyle dramatically reduces cardiovascular mortality. In another intriguing review, C.-Y. Hsu et al. focus on the important topic of the effects of exercise training on autonomic function in chronic heart failure (CHF). Exercise intolerance is one of the major and disturbing symptoms in these patients. Increased sympathetic tone and decreased parasympathetic activity have been often reported in CHF and these phenomena are associated with a poor survival. Data from this review indicate that participation in exercise training programs induces beneficial effects on autonomic function in CHF patients. They also point out that further research could examine additional aspects of the effects of exercise training in this population, such as the impact on the responses to exercise training in different levels of CHF severity, the possibility that a threshold intensity may be needed to affect cardiac autonomic function, and the type of exercise that should be recommended to achieve the highest positive effects on sympathovagal balance. In a third review by A. Crisafulli et al., the complex issue of cardiovascular reflexes during exercise is addressed. During exercise, the neural mechanisms controlling the cardiovascular apparatus regulate cardiac output and arteriolar tone in order to counteract the exercise-induced vasodilation due to functional sympatholysis in the working muscle. These cardiovascular adjustments guarantee adequate perfusion to vital organs (the brain and the heart) and to the working muscles as well as adequate washout of exercise-induced by-products. Moreover, these mechanisms prevent excessive increments in blood pressure. In this review, authors summarise neural reflexes operating during dynamic exercise, particularly their interaction. They point out that cardiovascular regulation during exercise is achieved through the contemporary integration and interaction of input arising from motor cortex (central command), skeletal muscle receptors (exercise pressor reflex), and arterial baroreceptors. They also conclude that further research is warranted to better understand how these reflexes interact during effort. The last interesting review by R. B. Batacan Jr. et al. is about the effects of light intensity activity on cardiovascular risk factors. These authors claim that there is little support for the role of light intensity activity to reduce cardiovascular disease risk factors and that further studies are needed to establish the value of light intensity physical activity in reducing cardiovascular risk factors. Finally, the research paper by N. G. Rocha et al. aims at evaluating the acute effects of exercise on endothelial functions in early metabolic syndrome. They find that these subjects, despite being free of symptoms, present with an early impairment of endothelial function. Moreover, they put forward the hypothesis that the analysis of some biomarkers changes could be potentially useful to develop preventive measures before the onset of overt metabolic syndrome. Collectively, these manuscripts confirm that sedentariety is harmful for the cardiovascular system. Moreover, exercise not only exerts positive effect on cardiovascular functions and reduces the risks of cardiovascular diseases (primary prevention), but could also revert cardiovascular disease and play a preventive role in the progression of pathological conditions (secondary/tertiary prevention).

The aim of this paper is to understand whether the probability of receiving positive peer reviews is influenced by having published in an independently assessed, high-ranking journal: we eventually interpret a positive relationship among peer evaluation and journal ranking as evidence that journal ratings are good predictors of article quality. The analysis is based on a large dataset of over 11,500 research articles published in Italy in the period 2004-2010 in the areas of architecture, arts and humanities, history and philosophy, law, sociology and political sciences. These articles received a score by a large number of externally appointed referees in the context of the Italian research assessment exercise (VQR); similarly, journal scores were assigned in a panel-based independent assessment, which involved all academic journals in which Italian scholars have published, carried out under a different procedure. The score of an article is compared with that of the journal it is published in: more specifically, we first estimate an ordered probit model, assessing the probability for a paper of receiving a higher score, the higher the score of the journal; in a second step, we concentrate on the top papers, evaluating the probability of a paper receiving an excellent score having been published in a top-rated journal. In doing so, we control for a number of characteristics of the paper and its author, including the language of publication, the scientific field and its size, the age of the author and the academic status. We add to the literature on journal classification by providing for the first time a large scale test of the robustness of expert-based classification.

We consider the classical problem of scheduling jobs in a multiprocessor setting in order to minimize the flow time (total time in the system). The performance of the algorithm, both in offline and online settings, can be significantly improved if we allow preemption: i.e., interrupt a job and later continue its execution. Preemption is inherent to make a scheduling algorithm efficient [7,8]. Minimizing the total flow time on parallel machines with preemption is known to be NP-hard on m ≥ 2 machines. Leonardi and Raz [8] showed that the well known heuristic shortest remaining processing time (SRPT) performs within a logarithmic factor of the optimal offline algorithm on parallel machines. It is not known if better approximation factors can be reached and thus SRPT, although it is an online algorithm, becomes the best known algorithm in the off-line setting. In fact, in the on-line setting, Leonardi and Raz showed that no algorithm can achieve a better bound. In this work we present a nicer and simpler proof of the approximation ratio of SRPT. The proof presented in this paper combines techniques from the original paper of Leonardi and Raz [8] with those presented in a later paper on approximating total flow time when job preemption but not job migration is allowed [2] and on approximating total flow time non-clairvoyantly [3], that is when the processing time of a job is only known at time of completion.

The objective of the present paper was the assessment of the chemical composition of the essential oils from four Asteraceae species with a considerable food, medicinal, and agricultural value, collected in Egypt, together with their in vitro inhibitory activity against molds and yeasts. The essential oil of Launaea cornuta flowers was also evaluated for the first time, but because of its very low yield (

Antiphospholipid antibody syndrome (APS) is an autoimmune acquired thrombophilia characterized by recurrent thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). APS can be primary, if it occurs in the absence of any underlying disease, or secondary, if it is associated with another autoimmune disorder, most commonly systemic lupus erythematosus. The exact pathogenetic mechanism of APS is unknown, but different, not mutually exclusive, models have been proposed to explain how anti-PL autoantibodies might lead to thrombosis and pregnancy morbidity. Diagnosis of APS requires that a patient has both a clinical manifestation (arterial or venous thrombosis and/or pregnancy morbidity) and persistently positive aPL, but the clinical spectrum of the disease encompasses additional manifestations which may affect every organ and cannot be explained exclusively by a prothrombotic state. Treatment for aPL-positive patients is based on the patient's clinical status, presence of an underlying autoimmune disease, and history of thrombotic events. In case of aPL positivity without previous thrombotic events, the treatment is mainly focused on reduction of additional vascular risk factors, while treatment of patients with definite APS is based on long-term anticoagulation. Pregnancy complications are usually managed with low-dose aspirin in association with low molecular weight heparin. Refractory forms of APS could benefit from adding hydroxychloroquine and/or intravenous immunoglobulin to anticoagulation therapy. Promising novel treatments include anti-B cell monoclonal antibodies, new-generation anticoagulants, and complement cascade inhibitors. The objective of this review paper is to summarize the recent literature on APS from pathogenesis to current therapeutic options.

Neurons are specialized, electrically excitable cells which use electrical to chemical signals to transmit and elaborate information. Understanding how the cooperation of a great many of neurons in a grid may modify and perhaps improve the information quality, in contrast to few neurons in isolation, is critical for the rational design of cell-materials interfaces for applications in regenerative medicine, tissue engineering, and personalized lab-on-a-chips. In the present paper, we couple an integrate-and-fire model with information theory variables to analyse the extent of information in a network of nerve cells. We provide an estimate of the information in the network in bits as a function of cell density and short-term depression time. In the model, neurons are connected through a Delaunay triangulation of not-intersecting edges; in doing so, the number of connecting synapses per neuron is approximately constant to reproduce the early time of network development in planar neural cell cultures. In simulations where the number of nodes is varied, we observe an optimal value of cell density for which information in the grid is maximized. In simulations in which the posttransmission latency time is varied, we observe that information increases as the latency time decreases and, for specific configurations of the grid, it is largely enhanced in a resonance effect.

Extending the functionality of ubiquitous Si-based microelectronic devices often requires combining materials with different lattice parameters and thermal expansion coefficients. In this paper, scanning X-ray nanodiffraction is used to map the lattice bending produced by thermal strain relaxation in heteroepitaxial Ge microcrystals of various heights grown on high aspect ratio Si pillars. The local crystal lattice tilt and curvature are obtained from experimental three-dimensional reciprocal space maps and compared with diffraction patterns simulated by means of the finite element method. The simulations are in good agreement with the experimental data for various positions of the focused X-ray beam inside a Ge microcrystal. Both experiment and simulations reveal that the crystal lattice bending induced by thermal strain relaxation vanishes with increasing Ge crystal height.

In Saccharomyces cerevisiae the Lysine-acetyltransferase Gcn5 (KAT2) is part of the SAGA complex and is responsible for histone acetylation widely or at specific lysines. In this paper we report that GCN5 deletion differently affects the growth of two strains. The defective mitochondrial phenotype is related to a marked decrease in mtDNA content, which also involves the deletion of specific regions of the molecule. We also show that in wild-type mitochondria the Gcn5 protein is present in the mitoplasts, suggesting a new mitochondrial function independent from the SAGA complex and possibly a new function for this protein connecting epigenetics and metabolism., Summary: In yeast mitochondria the Gcn5 protein is present in the mitoplasts and is localized in the inner mitochondrial membrane. Its deletion affects the mitochondrial phenotype and is related to a marked decrease of mitochondrial DNA content.

Whereas development of mathematical models describing the endocrine system as a whole remains a challenging problem, visible progress has been demonstrated in modeling its subsystems, or axes. Models of hormonal axes portray only the most essential interactions between the hormones and can be described by low-order systems of differential equations. This paper analyzes the properties of a novel model of a hypothalamic-pituitary axis, portraying the interactions in a chain of a release hormone (secreted by the hypothalamus), a tropic hormone (produced by the pituitary gland) and an effector hormone (secreted by a target gland). This model, unlike previously published ones, captures two prominent features of neurohormonal regulation systems, namely, the pulsatile (episodic) production of the release hormone and a complex non-cyclic feedback mechanism that maintains the involved hormone concentrations within certain biological limits. At the same time, the discussed model is analytically tractable; in particular, the existence of a so-called 1-cycle featured by a single pulse over one period is proven mathematically.

The human body is naturally colonized by a huge number of different commensal microbial species, in a relatively stable equilibrium. When this microbial community undergoes dysbiosis at any part of the body, it interacts with the innate immune system and results in a poor health status, locally or systemically. Research studies show that bacteria are capable of significantly influencing specific cells of the immune system, resulting in many diseases, including a neoplastic response. Amongst the multiple different types of diseases, pancreatic cancer and liver cirrhosis were significantly considered in this paper, as they are major fatal diseases. Recently, these two diseases were shown to be associated with increased or decreased numbers of certain oral bacterial species. These findings open the way for a broader perception and more specific investigative studies, to better understand the possible future treatment and prevention. This review aims to describe the correlation between oral dysbiosis and both pancreatic cancer and liver cirrhotic diseases, as well as demonstrating the possible diagnostic and treatment modalities, relying on the oral microbiota, itself, as prospective, simple, applicable non-invasive approaches to patients, by focusing on the state of the art. PubMed was electronically searched, using the following key words: “oral microbiota„ and “pancreatic cancer„ (PC), “liver cirrhosis„, “systemic involvement„, and “inflammatory mediators„. Oral dysbiosis is a common problem related to poor oral or systemic health conditions. Oral pathogens can disseminate to distant body organs via the local, oral blood circulation, or pass through the gastrointestinal tract and enter the systemic circulation. Once oral pathogens reach an organ, they modify the immune response and stimulate the release of the inflammatory mediators, this results in a disease. Recent studies have reported a correlation between oral dysbiosis and the increased risk of pancreatic and liver diseases and provided evidence of the presence of oral pathogens in diseased organs. The profound impact that microbial communities have on human health, provides a wide domain towards precisely investigating and clearly understanding the mechanism of many diseases, including cancer. Oral microbiota is an essential contributor to health status and imbalance in this community was correlated to oral and systemic diseases. The presence of elevated numbers of certain oral bacteria, particularly P. gingivalis, as well as elevated levels of blood serum antibodies, against this bacterial species, was associated with a higher risk of pancreatic cancer and liver cirrhosis incidence. Attempts are increasingly directed towards investigating the composition of oral microbiome as a simple diagnostic approach in multiple diseases, including pancreatic and liver pathosis. Moreover, treatment efforts are concerned in the recruitment of microbiota, for remedial purposes of the aforementioned and other different diseases. Further investigation is required to confirm and clarify the role of oral microbiota in enhancing pancreatic and liver diseases. Improving the treatment modalities requires an exertion of more effort, especially, concerning the microbiome engineering and oral microbiota transplantation.

Correctly recognizing emotions is an essential skill to manage interpersonal relationships in everyday life. Facial expression represents the most powerful mean to convey important information on emotional and cognitive states during interactions with others. In this paper, we analyze physiological responses triggered by an emotion recognition test, which requires the processing of facial cues. In particular, we evaluate the modulation of several Heart Rate Variability indices, collected during the Reading the Mind in the Eyes Test, accounting for test difficulty (derived from a Rasch analysis), test performances, demographic and psychological characteristics of the participants. The main idea is that emotion recognition is associated with the Autonomic Nervous System and, as a consequence, with the Heart Rate Variability. The principal goal of our study was to explore the complexity of the collected measures and their possible interactions by applying a class of flexible models, i.e., the latent class mixed models. Actually, this modelling strategy allows for the identification of clusters of subjects characterized by similar longitudinal trajectories. Both univariate and multivariate latent class mixed models were used. In fact, while the interpretation of the Heart Rate Variability indices is very difficult when considered individually, a joint evaluation provides a better description of the Autonomic Nervous System state.

Background Most carabid beetles are particularly sensitive to local habitat characteristics. Although in China grasslands account for more than 40% of the national land, their biodiversity is still poorly known. The aim of this paper is to identify the main environmental characteristics influencing carabid diversity in different types of grassland in northern China. Methods We investigated the influence of vegetation (plant biomass, cover, density, height and species richness), soil (bulk density, above ground litter, moisture and temperature) and climate (humidity, precipitation and temperature) on carabid community structure (species richness, species composition and functional diversity—measured as body size, movement and total diversity) in three types of grasslands: desert, typical and meadow steppes. We used Canonical correspondence analysis to investigate the role of habitat characteristics on species composition and eigenvector spatial filtering to investigate the responses of species richness and functional diversities. Results We found that carabid community structure was strongly influenced by local habitat characteristics and particularly by climatic factors. Carabids in the desert steppe showed the lowest richness and functional diversities. Climate predictors (temperature, precipitation and humidity) had positive effects on carabid species richness at both regional and ecosystem levels, with difference among ecosystems. Plant diversity had a positive influence on carabid richness at the regional level. Soil compaction and temperature were negatively related to species richness at regional level. Climatic factors positively influenced functional diversities, whereas soil temperature had negative effects. Soil moisture and temperature were the most important drivers of species composition at regional level, whereas the relative importance of the various environmental parameters varied among ecosystems. Discussion Carabid responses to environmental characteristics varied among grassland types, which warns against generalizations and indicates that management programs should be considered at grassland scale. Carabid community structure is strongly influenced by climatic factors, and can therefore be particularly sensitive to ongoing climate change.

This paper describes the production and chemical separation of the 163Ho isotope that will be used in several nuclear physics experiments aiming at measuring the neutrino mass as well as the neutron cross section of the 163Ho isotope. For this purpose, several batches of enriched 162Er have been irradiated at the Institut Laue-Langevin high flux reactor to finally produce 6 mg or 100 MBq of the desired 163Ho isotope. A portion of the Er/Ho mixture is then subjected to a sophisticated chemical separation involving ion exchange chromatography to isolate the Ho product from the Er target material. Before irradiation, a thorough analysis of the impurity content was performed and its implication on the produced nuclide inventory will be discussed.