A relative entropy rate method for path space sensitivity analysis of stationary complex stochastic dynamics

We propose a new sensitivity analysis methodology for complex stochastic dynamics based on the Relative Entropy Rate. The method becomes computationally feasible at the stationary regime of the process and involves the calculation of suitable observables in path space for the Relative Entropy Rate and the corresponding Fisher Information Matrix. The stationary regime is crucial for stochastic dynamics and here allows us to address the sensitivity analysis of complex systems, including examples of processes with complex landscapes that exhibit metastability, non-reversible systems from a statistical mechanics perspective, and high-dimensional, spatially distributed models. All these systems exhibit, typically non-gaussian stationary probability distributions, while in the case of high-dimensionality, histograms are impossible to construct directly. Our proposed methods bypass these challenges relying on the direct Monte Carlo simulation of rigorously derived observables for the Relative Entropy Rate and Fisher Information in path space rather than on the stationary probability distribution itself. We demonstrate the capabilities of the proposed methodology by focusing here on two classes of problems: (a) Langevin particle systems with either reversible (gradient) or non-reversible (non-gradient) forcing, highlighting the ability of the method to carry out sensitivity analysis in non-equilibrium systems; and, (b) spatially extended Kinetic Monte Carlo models, showing that the method can handle high-dimensional problems

Muscle differentiation in a colonial ascidian: organisation, gene expression and evolutionary considerations

Background: Ascidians are tunicates, the taxon recently proposed as sister group to the vertebrates. They possess a chordate-like swimming larva, which metamorphoses into a sessile adult. Several ascidian species form colonies of clonal individuals by asexual reproduction. During their life cycle, ascidians present three muscle types: striated in larval tail, striated in the heart, and unstriated in the adult body-wall. Results: In the colonial ascidian Botryllus schlosseri, we investigated organisation, differentiation and gene expression of muscle beginning from early buds to adults and during zooid regression. We characterised transcripts for troponin T (BsTnT-c), adult muscle-type (BsMA2) and cytoplasmic-type (BsCA1) actins, followed by in situ hybridisation (ISH) on sections to establish the spatio-temporal expression of BsTnT-c and BsMA2 during asexual reproduction and in the larva. Moreover, we characterised actin genomic sequences, which by comparison with other metazoans revealed conserved intron patterns. Conclusion: Integration of data from ISH, phalloidin staining and TEM allowed us to follow the phases of differentiation of the three muscle kinds, which differ in expression pattern of the two transcripts. Moreover, phylogenetic analyses provided evidence for the close relationship between tunicate and vertebrate muscle genes. The characteristics and plasticity of muscles in tunicates are discussed. </p

Lake surface temperature [in “State of the Climate in 2017”]

Observed lake surface water temperature anomalies in 2017 are placed in the context of the recent warming observed in global surface air temperature by collating long-term in situ lake surface temperature observations from some of the world’s best-studied lakes and a satellite-derived global lake surface water temperature dataset. The period 1996–2015, 20 years for which satellite-derived lake temperatures are available, is used as the base period for all lake temperature anomaly calculations

Challenges in treating patients with inflammatory bowel disease and concurrent viral hepatitis infection

Introduction: Inflammatory bowel diseases (IBD) require long-term administration of immunomodulatory treatments to maintain disease remission. Due to the high worldwide prevalence of hepatitis B (HBV) or C (HCV) virus infections, presence of concurrent hepatitis can be a relevant clinical issue to manage when treating IBD. Areas covered: The paper summarizes epidemiological data about IBD and HBV/HCV infection and reviews current knowledge about the natural history of HBV and HCV in the IBD setting, concentrating on risk of hepatitis reactivation during immunosuppressive treatment. Most updated recommendations for management of HBV and HCV infections in IBD patients are discussed. Expert commentary: The development of new drugs for IBD with different molecular targets and the availability of potent and efficacious antiviral drugs for HBV and HCV will simplify management of hepatitis infection in IBD patients in the near future

Limites e possibilidades da Educação Ambiental em uma escola municipal agrícola de ensino fundamental

Ao compreendermos a educação enquanto formação humana intencional para a vida em sociedade, trazemos seu papel como possibilidade de transformação e pressupomos a transversalidade do tema meio ambiente. A análise do Projeto Político Pedagógico (PPP) de uma Escola Municipal Agrícola de Ensino Fundamental do Estado de São Paulo - Brasil, mediante as três possíveis dimensões da Educação Ambiental (EA), nos permitiu verificar: desafios, como a necessidade de reconhecimento da comunidade local articulada às questões globais, e perspectivas para trabalhos futuros a partir de ligações entre as dimensões da EA no PPP

Integração curricular do tema agropecuária em uma escola municipal agrícola : sentidos construídos

Considerando os desafios da educação ambiental para o enfrentamento da crise ambiental, este recorte de pesquisa, de natureza qualitativa, analisou os enunciados dos professores de uma escola agrícola (Rio Claro, SP, Brasil), buscando compreender como têm integrado o tema Agropecuária em suas práticas. Buscando a construção de sentidos sob uma perspectiva bakhtiniana, a leitura dos enunciados iniciais dos professores indicou que maioria dos professores o considera importante e indicam integrá-lo com frequência em suas atividades. No entanto, este não parece ser problematizado: os sentidos produzidos parecem distantes de romper, por meio da crítica, com o discurso hegemônico sobre a questão agropecuária

Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.

Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors

Limited utility of ITPA deficiency to predict early anemia in HCV patients with advanced fibrosis receiving telaprevir

Background: Severe anemia is a common side effect of Pegylated Interferon + Ribavirin (PR) and Telaprevir (TVR) in hepatitis C virus (HCV) genotype 1 patients with advanced fibrosis or cirrhosis (F3-F4). Inosine triphosphatase (ITPA) genetic variants are associated with RBV- induced anemia and dose reduction. Aim: To test the association of ITPA polymorphisms rs1127354 and rs7270101 with hemoglobin (Hb) decline, need for RBV dose reduction (RBV DR), erythropoietin (EPO) support and blood transfusions during the first 12 weeks of TVR triple therapy. Materials and Methods: 69 consecutive HCV-1 patients (mean age 57 years) with F3-F4 who received PR and TVR were genotyped for ITPA polymorphisms rs1127354 and rs7270101. Estimated ITPA deficiency was graded on severity (0-3, no deficiency/mild/moderate/severe). Results: ITPA deficiency was absent in 48 patients (70%), mild in 12 (17%) and moderate in 9 patients (13%). Mean week 4 Hb decline was higher in non ITPA deficient patients (3,85 g/dL) than in mildly or moderately ITPA deficient patients (3,07 g/dL and 1,67 g/dL, p<0.0001). Grade 3-4 anemia developed in 81% non ITPA deficient patients versus 67% mild deficient and 55% moderate deficient patients (p = ns). Grade of ITPA deficiency was not associated with RbvDR (no deficiency: 60%, mild: 58%, moderate: 67%; p = ns), EPO use (no deficiency: 65%, mild: 58%, moderate:56%; p = ns) or need for blood transfusion (no deficiency: 27%, mild: 17%, moderate: 33%; p = ns). Conclusions: In patients with F3-F4 chronic hepatitis C receiving TVR based therapy, ITPA genotype does not impact on the management of early anemia. \ua9 2014 Aghemo et al

Ancient DNA from domestic animal species remains : preliminary approaches

DNA analysis from ancient and old remains offers new tools to answer archaeozoological questions and investigate the origin of the genetic variability in domestic animal species. Molecular genetics techniques contribute to identify the species supporting classical osteological studies and to establish the relationship to modern species and breeds. Mitochondrial DNA (mtDNA) sequences are useful to reconstruct the history of maternal lineages comparing haplotype variations of present and old DNA samples. Mitochondrial data from modern cattle populations show a high diversity in Anatolia and in the Middle East supporting a near-Eastern matrilineal centre of origin. On the contrary in Europe a single family of mitochondrial haplotypes strongly dominates. A number of recent studies reported the successful recovery of ancient and old nuclear DNA (nuDNA) sequences. Such studies represent an important breakthrough, as nuDNA can be used for the characterisation of genetic loci directly involved in phenotypic traits, answering challenging questions. A bright example is offered by the study on the single nuclear exon of melanocortin type 1 receptor gene from a ca. 43,000 years old mammoth bone from Siberia, showing that mammoth populations were polymorphic with regard to hair colour, harbouring both dark and light haired animals. In contrast, these studies on ancient and old DNA sequences need great caution, due to the analytical problems caused by post-mortem damage of DNA, contamination from exogenous sources of mt- and nuDNA, and the consequent reliability of observed polymorphisms. The present research describes the preliminary analytical approach to DNA study of faunal remains (103 animal bones of different domestic species: Bos taurus 51; Ovis aries/Capra hircus 39; Sus scrofa/Sus domesticus 10; Gallus gallus 1; Equus caballus/Equus sp. 2), collected in seven archaeological sites located within the province of Trento, in the Alpine region of Trentino Alto-Adige (N-E Italy). The chosen sites, dating from the Bronze Age to the late Middle Ages, display different settlement typology and include Iron Age retic houses, votive Bronze Age contexts, a 4th century roman villa and several 13th century medieval buildings. Archaeozoological data will be collected on species, skeletal parts, age of slaughter, method of butchery, evidence of bone working and presence of paleopathologies. We describe the analytical procedure used in preparing and collecting samples and in extracting and analysing DNA from a subset of the bones previously described

From current status to optimization of HCV treatment: Recommendations from an expert panel

Chronic hepatitis C virus (HCV) infection is a major public health problem at a global level, causing an enormous burden of hepatic and extra-hepatic morbidity and mortality. Treatment of chronic HCV (CHC) has been revolutionized in the last few years by the introduction of highly effective and well tolerated direct acting antiviral agents (DAAs) able to achieve >90% rates of sustained virological response (SVR) in many groups of patients, including those previously excluded from interferon-based regimens. For such reason interferon-free regimens are now the treatments of choice for all patients. Successful anti-HCV treatment can stop liver disease progression and can solve the HCV-related extra hepatic manifestations, eventually reducing both liver-related and overall mortality. Together with the rapidly accumulating data about the evolution of treatment landscape, different guidelines from national and international Liver Scientific Societies have been published until today. However, these recommendations may not be applied worldwide as, due to high treatment costs, most of them identify as priority groups only patients with advanced liver disease. Moreover some types of patients pose clinical management problems for which even the guidelines do not always provide useful answers. With the aim of treatment optimization by filling some of the gaps of the current guidelines and addressing the remaining unmet needs in practice, a group of Italian experts, experienced on treatment of HCV infection, met in Stresa in February 2016. The summary of all the considerations arising from this two-day meeting and the final statements are reported in this position paper