Towards Metabolic Engineering of Podophyllotoxin Production

The pharmaceutically important anticancer drugs etoposide and teniposide are derived from podophyllotoxin, a natural product isolated from roots of Podophyllum hexandrum growing in the wild. The overexploitation of this endangered plant has led to the search for alternative sources. Metabolic engineering aimed at constructing the pathway in another host cell is very appealing, but for that approach, an in-depth knowledge of the pathway toward podophyllotoxin is necessary. In this chapter, we give an overview of the lignan pathway leading to podophyllotoxin. Subsequently, we will discuss the engineering possibilities to produce podophyllotoxin in a heterologous host. This will require detailed knowledge on the cellular localization of the enzymes of the lignan biosynthesis pathway. Due to the high number of enzymes involved and the scarce information on compartmentalization, the heterologous production of podophyllotoxin still remains a tremendous challenge. At the moment, research is focusing on the last step(s) in the conversion of deoxypodophyllotoxin to (epi)podophyllotoxin and 4′-demethyldesoxypodophyllotoxin by plant cytochromes

A systematic assessment of drought termination in the United Kingdom

Drought termination can be associated with dramatic transitions from drought to flooding. Greater attention may be given to these newsworthy and memorable events, but drought terminations that proceed gradually also pose challenges for water resource managers. This paper defines drought termination as a distinctive phase of the event. Using observed river flow records for 52 UK catchments, a more systematic and objective approach for detecting drought terminations is demonstrated. The parameters of the approach are informed by a sensitivity analysis that ensures a focus on terminations of multi-season to multi-year droughts. The resulting inventory of 467 drought terminations provides an unprecedented historical perspective on this phenomenon in the UK. Nationally and regionally coherent drought termination events are identifiable, although their characteristics vary both between and within major episodes. Contrasting drought termination events in 1995–1998 and 2009–2012 are examined in greater depth. The data are also used to assess potential linkages between metrics of drought termination and catchment properties. The duration of drought termination is moderately negatively correlated with elevation (rs =  −0.47) and catchment average rainfall (rs =  −0.42), suggesting that wetter catchments in upland areas of the UK tend to experience shorter drought terminations. More urbanized catchments tend to have gradual drought terminations (contrary to expectations of flashy hydrological response in such areas), although this may also reflect the type of catchments typical of lowland England. Significant correlations are found between the duration of the drought development phase and both the duration (rs =  −0.29) and rate (rs =  0.28) of drought termination. This suggests that prolonged drought development phases tend to be followed by shorter and more abrupt drought terminations. The inventory helps to place individual events within a long-term context. The drought termination phase in 2009–2012 was, at the time, regarded as exceptional in terms of magnitude and spatial footprint, but the Thames river flow record identifies several comparable events before 1930. The chronology could, in due course, provide a basis for exploring the complex drivers, long-term variability, and impacts of drought termination events

Drought termination: concept and characterisation

There are numerous anecdotal examples of drought terminations documented throughout the historical record on most continents. The end of a drought is the critical time during which water resource managers urgently require information on the replenishment of supplies. Yet this phase has been relatively neglected by the academic community, with much of the existing body of research on drought termination assessing the likelihood of droughts ending rather than its temporal profile. In particular, there has been little effort to characterise drought termination events themselves. This is partly explained by existing definitions of drought termination as a specific point in time when drought is considered to have finished, rather than a more holistic consideration based on approaches developed within biological sciences. There is also a lack of understanding about how drought termination propagates through the hydrological cycle. This paper specifically examines and reviews available research on drought termination, highlighting limitations associated with current definitions and offering suggestions for characterising the temporal stages of drought. An alternative definition of drought termination is proposed: a period between the maximum negative anomaly and a return to above-average conditions. Once this phase has been delineated, the duration, rate and seasonality of drought termination can be derived. The utility of these metrics is illustrated through a case study of the 2010–2012 drought in the UK, and the propagation of drought termination between river flows and groundwater levels

Fusarium on french garlic, etiology and characterization of an emerging disease

Background: Yearly, France produces more than 20000 tons of garlic representing 3500 producersand 3000 ha. Since the mid-2000s and in spite of high demanding production specifications, aphytopathogenic fungus belonging to genus Fusarium, causes damage during storage leading to rootand bulb rots. The annual losses have a major impact on the viability of the French industry.Objectives: Two major objectives were to :• Elucidate the etiology of the disease on garlic• Develop a test to evaluate the aggressiveness of strainsMethods: Strains were isolated from the two major French production areas (South West and SouthEast) during the 2017 and 2018 production campaigns. Eleven garlic varieties on more than 90 plotswere used. All tested cloves were surface-sterilized with NaOCl and fungi were allowed to develop onPDA.To evaluate aggressiveness of each strain, twelve surface-sterilized cloves soaked in 1.0*106spores/mL were used. All cloves were placed separately at 23°C at saturated humidity for 18 days.Symptoms were noted with rating scale from 0 (absence of symptoms) to 5 (clove entirely brown).Every 2 days, Area Under the Disease Progress Curve was calculated for each clove.Results: In total, 1580 strains were successfully isolated, 262 identified (98% F. proliferatum and 2%F. oxysporum) and 48 tested for their aggressiveness. All varieties seemed to be infected equally,some plots more than the others. All tested strains shows aggressiveness on garlic, from 60 to 140%as compared to a reference strain

EpiLPS: A fast and flexible Bayesian tool for estimation of the time-varying reproduction number.

In infectious disease epidemiology, the instantaneous reproduction number [Formula: see text] is a time-varying parameter defined as the average number of secondary infections generated by an infected individual at time t. It is therefore a crucial epidemiological statistic that assists public health decision makers in the management of an epidemic. We present a new Bayesian tool (EpiLPS) for robust estimation of the time-varying reproduction number. The proposed methodology smooths the epidemic curve and allows to obtain (approximate) point estimates and credible intervals of [Formula: see text] by employing the renewal equation, using Bayesian P-splines coupled with Laplace approximations of the conditional posterior of the spline vector. Two alternative approaches for inference are presented: (1) an approach based on a maximum a posteriori argument for the model hyperparameters, delivering estimates of [Formula: see text] in only a few seconds; and (2) an approach based on a Markov chain Monte Carlo (MCMC) scheme with underlying Langevin dynamics for efficient sampling of the posterior target distribution. Case counts per unit of time are assumed to follow a negative binomial distribution to account for potential overdispersion in the data that would not be captured by a classic Poisson model. Furthermore, after smoothing the epidemic curve, a "plug-in'' estimate of the reproduction number can be obtained from the renewal equation yielding a closed form expression of [Formula: see text] as a function of the spline parameters. The approach is extremely fast and free of arbitrary smoothing assumptions. EpiLPS is applied on data of SARS-CoV-1 in Hong-Kong (2003), influenza A H1N1 (2009) in the USA and on the SARS-CoV-2 pandemic (2020-2021) for Belgium, Portugal, Denmark and France

Key stakeholder voices:Investigating student perceptions of teachers’ use of assessment for learning

Many schools aim to implement Assessment for Learning (AfL) to stimulate students to take more ownership of their learning and develop self-regulatory skills. This survey-based study is among the few in the field showing how students experience the extent of implementation of AfL, here in English language and mathematics classes in 12 Dutch secondary schools. Analysis showed no differences between the subjects. Students (N = 685) experienced activities to clarify the learning intentions and success criteria and eliciting evidence on their learning progress regularly (between 50–74% of the lessons). Students hardly ever experienced activities aimed at peer- and self-assessment (less than 25% of the lessons). However, cluster analysis revealed three distinct clusters related to the extent of AfL strategy use students experienced. Overall, we can conclude that AfL is not yet fully integrated into teaching practices. Teachers’ skills, knowledge and attitudes required to increase student engagement in AfL practices and strengthen students’ self-regulated learning need more attention in future teacher professional development trajectories.</p

Galectin-1, an Endogenous Lectin Produced by Thymic Epithelial Cells, Induces Apoptosis of Human Thymocytes

Galectin-1, a β-galactoside binding protein, is produced by thymic epithelial cells and binds to human thymocytes. We have previously reported that galectin-1 induces the apoptosis of activated T lymphocytes. Because the majority of thymocytes die via apoptosis while still within the thymus, we tested whether galectin-1 could induce the apoptosis of these cells. We now report that in vitro exposure to galectin-1 induced apoptosis of two subsets of CD4lo CD8lo thymocytes. The phenotypes of susceptible thymocytes were consistent with that of both negatively selected and nonselected cells. Galectin-1–induced apoptosis was enhanced by preexposure of thymocytes to antibody to CD3, suggesting that galectin-1 may be a participant in T-cell– receptor mediated apoptosis. In contrast, pretreatment of thymocytes with dexamethasone had no effect on galectin-1 susceptibility. We noted that 71% of the cells undergoing apoptosis after galectin-1 treatment had a DNA content greater than 2N, indicating that proliferating thymocytes were most sensitive to galectin-1. We propose that galectin-1 plays a role in the apoptosis of both negatively selected and nonselected thymocytes, and that the susceptibility of thymocytes to galectin-1 is regulated, in part, by entry or exit from the cell cycle

Psychosis and relapse in bipolar disorder are related to GRM3 DAOA and GRIN2B genotype

Objective: Dysfunction in glutamate signalling is thought to play a role in the pathophysiology of bipolar disorder (BD). There is evidence of associations between single nucleotide polymorphisms (SNPs) in GRM3, GRIN2B, and DAOA genes and the diagnosis of BD. In this pilot study, we investigated the frequency of SNP variants in these 3 genes within South African population groups, and assessed interactions between genes and phenotypes of BD disease severity. Method: Multiplex SNaPshotTM PCR was used to genotype 191 case and 188 control samples. Cases comprised of 191 individuals in a South African cohort of mixed ancestry and Caucasians, with BD Type 1. Phenotypes of BD disease severity were: age of onset, number of illness episodes, number of hospitalisations for depression or mania and history of psychotic symptoms. Results: There were no significant difference in SNP allele frequencies between cases and controls. In the case-only analysis, the GRM3 rs6465084 heterozygote was associated with a 4-fold increased risk of lifetime history of psychotic symptoms, and the specific variants within the gene pair, DAOA and GRIN2B, had a significant interaction with the number of hospitalisations for mania, with lowest admission rates associated with both pairs of ancestral alleles.Conclusion: In BD, variations in glutamatergic genes may influence phenotypes related to the severity of illness. Speculatively, newly derived genes associated with various evolutionary advantages, may also increase the risk for more severe BD. These preliminary findings deserve validation in a larger cohort

TGF-β Sustains Tumor Progression through Biochemical and Mechanical Signal Transduction.

Transforming growth factor β (TGF-β) signaling transduces immunosuppressive biochemical and mechanical signals in the tumor microenvironment. In addition to canonical SMAD transcription factor signaling, TGF-β can promote tumor growth and survival by inhibiting proinflammatory signaling and extracellular matrix (ECM) remodeling. In this article, we review how TGF-β activated kinase 1 (TAK1) activation lies at the intersection of proinflammatory signaling by immune receptors and anti-inflammatory signaling by TGF-β receptors. Additionally, we discuss the role of TGF-β in the mechanobiology of cancer. Understanding how TGF-β dampens proinflammatory responses and induces pro-survival mechanical signals throughout cancer development is critical for designing therapeutics that inhibit tumor progression while bolstering the immune response

A Few Considerations on Structural and Logical Composition in Specification Theories

Over the last 20 years a large number of automata-based specification theories have been proposed for modeling of discrete,real-time and probabilistic systems. We have observed a lot of shared algebraic structure between these formalisms. In this short abstract, we collect results of our work in progress on describing and systematizing the algebraic assumptions in specification theories.Comment: In Proceedings FIT 2010, arXiv:1101.426