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The importance of two-way interactions between animals and the physical hydraulic and sedimentological environment are increasingly recognized (e.g., zoogeomorphology). Caddisflies (Trichoptera) are a group of aquatic insects known for their bioconstructions, particularly cases built from fine sediment and silk. Caddisfly cases differ in size, shape and density from the incorporated sediment, and case construction may therefore affect the mobility of these sediments in rivers. However, although communities of caddisfly often use substantial quantities of sediment in case construction, the effect of these bioconstructions on sediment transport in rivers is unknown. We use a flume experiment to compare the bed shear stress required to transport (a) empty caddisfly cases and (b) individual sediment particles, following disaggregation from the case. The cases of three species were considered; two that construct different styles of tubular case (Potamophlax latipennis and Sericostoma personatum) and one that builds a domed case (Agapetus fuscipes). P. latipennis and S. personatum cases were easier to entrain than the sediment grains incorporated into them, whilst A. fuscipes cases were not. Despite their low mass, A. fuscipes cases required the most shear stress to transport them because their domed shape impeded rolling. These findings are important to understand how differences in case design between species, reflect different adaptation strategies to the turbulent hydraulic river habitat. Furthermore, the results suggest that un-attached tubular caddisfly cases may be preferentially transported over other particles on the river bed and thus, where caddisfly occur in high abundance, they may increase fluvial entrainment of sand.

Atypical teratoid rhabdoid tumour (ATRT) is a rare but highly aggressive undifferenti-ated solid tumour arising in the central nervous system and predominantly affecting infants and young children. ATRT is exclusively characterized by the inactivation of SMARCB1, a member of the SWI/SNF chromatin remodelling complex that is essential for the regulation of large sets of genes required for normal development and differentiation. Histone deacetylase inhibitors (HDACi) are a promising anticancer therapy and are able to mimic the normal acetylation functions of SMARCB1 in SMARCB1-deficient cells and drive multilineage differentiation in extracranial rhabdoid tumours. However, the potential efficacy of HDACi in ATRT is unknown. Here, we show that human ATRT cells are highly responsive to the HDACi panobinostat and that sustained treatment leads to growth arrest, increased cell senescence, decreased clonogenicity and induction of a neurogenesis gene-expression profile. Furthermore, in an orthotopic ATRT xenograft model, continuous panobinostat treatment inhibits tumour growth, increases survival and drives neuronal differentiation as shown by the expression of the neuronal marker, TUJ1. Collectively, this preclinical study supports the therapeutic potential of panobinostat-mediated differentiation therapy for ATRT.Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Purpose: This was an open label, phase I (3 + 3 design), multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumors. Method(s): Primary endpoints were to establish MTD, define and describe associated toxicities, including dose limiting toxicities (DLT) and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and its biologic activity, by measuring acetylation of histones in peripheral blood mononuclear cells. Result(s): Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15 mg/m2 which was tolerated. Six were evaluable for adverse events. Two (33%) patients experienced Grade 3-4 thrombocytopenia, 1 (17%) experienced Grade 3 anemia, and 2 (33%) experienced Grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (33%) of the patients studied. Two (33%) patients experienced a Grade 2 QTcF change (0.478 +/- 0.006 ms). One cardiac DLT (T wave changes) was reported. PK values for 15 mg/m2 (n = 9) dosing were: Tmax 0.8 h, Cmax 235.2 ng/mL, AUC0-t 346.8 h ng/mL and t1/2 7.3 h. Panobinostat significantly induced acetylation of histone H3 and H4 at all time points measured when compared to pre-treatment samples (p < 0.05). Pooled quantitative Western blot data confirmed that panobinostat significantly induced acetylation of histone H4 at 6 h (p < 0.01), 24 h (p < 0.01) and 28-70 h (p < 0.01) post dose. Conclusion(s): A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15 mg/m2. PK data and drug tolerability at 15 mg/m2 was similar to that previously published.Copyright © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

Despite the existence of well‐established international environmental and nature conservation policies (e.g., the Ramsar Convention and Convention on Biological Diversity) ponds are largely missing from national and international legislation and policy frameworks. Ponds are among the most biodiverse and ecologically important freshwater habitats, and their value lies not only in individual ponds, but more importantly, in networks of ponds (pondscapes). Ponds make an important contribution to society through the ecosystem services they provide, with effective conservation of pondscapes essential to ensuring that these services are maintained. Implementation of current pond conservation through individual site designations does not function at the landscape scale, where ponds contribute most to biodiversity. Conservation and management of pondscapes should complement current national and international nature conservation and water policy/legislation, as pondscapes can provide species protection in landscapes where large‐scale traditional conservation areas cannot be established (e.g., urban or agricultural landscapes). We propose practical steps for the effective incorporation or enhancement of ponds within five policy areas: through open water sustainable urban drainage systems in urban planning, increased incentives in agrienvironment schemes, curriculum inclusion in education, emphasis on ecological scale in mitigation measures following anthropogenic developments, and the inclusion of pondscapes in conservation policy.

Neuroblastoma is the most common extra-cranial malignancy in childhood and accounts for 15% of childhood cancer deaths. Amplification of MYCN in neuroblastoma is associated with aggressive disease and predicts for poor prognosis. Novel therapeutic approaches are therefore essential to improving patient outcomes in this setting. The histone deacetylases are known to interact with N-Myc and regulate numerous cellular processes via epigenetic modulation, including differentiation. In this study, we used the TH-MYCN mouse model of neuroblastoma to investigate the antitumor activity of the pan-HDAC inhibitor, panobinostat. In particular we sought to explore the impact of long term, continuous panobinostat exposure on the epigenetically driven differentiation process. Continuous treatment of tumor bearing TH-MYCN transgenic mice with panobinostat for nine weeks led to a significant improvement in survival as compared with mice treated with panobinostat for a three-week period. Panobinostat induced rapid tumor regression with no regrowth observed following a nine-week treatment period. Initial tumor response was associated with apoptosis mediated via upregulation of BMF and BIM. The process of terminal differentiation of neuroblastoma into benign ganglioneuroma, with a characteristic increase in S100 expression and reduction of N-Myc expression, occurred following prolonged exposure to the drug. RNA-sequencing analysis of tumors from treated animals confirmed significant upregulation of gene pathways associated with apoptosis and differentiation. Together our data demonstrate the potential of panobinostat as a novel therapeutic strategy for high-risk neuroblastoma patients.Copyright © 2016 UICC.

Background: Deregulated acetylation of histones plays a key role in the pathogenesis of haematological and solid tumors by changing the transcription of genes involved in cell cycle control, differentiation or apoptosis. Thus, there is considerable interest in HDAC inhibition as a potential therapeutic modality in the treatment of hematological and solid tumor malignancies, including pediatric malignancies. Method(s): This is an open label, Phase I, multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumours. Primary endpoints were to define and describe associated toxicities, and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and also to assess its biologic activity by measuring the histone acetylation status in peripheral blood mononuclear cells (PBMNC). Result(s): Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15mg/m2. Three patients were removed from study prior to completion of course one due to tumour progression. A dose of 15mg/m2 was tolerated with one dose limiting toxicity (DLT) observed in the six patients evaluated for DLT. Two (22%) patients experienced grade 3-4 thrombocytopenia, 1 (11%) experienced grade 3 anemia, and 2 (22%) experienced grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (22%) of patients studied. Vomiting (44%), nausea (33%) and hypokalaemia (22%) were also common adverse events. Two (22%) of patients experienced a Grade II QTcF change (0.478 +/- 0.006 msec). One cardiac DLT (T wave changes) was reported. PK values for 15mg/m2 (n=9) dosing were: Tmax 0.8 hours, Cmax 235.2 ng/ml, AUC0-t 346.8h.ng/ml and t1/2 7.3 hours. Pooled flow cytometry results of all nine patient samples confirm that panobinostat significantly induced acetylation of histone H3 and H4 at 6 hours (p< 0.001), 24 hours (P<0.01) and 28-70 hours (p<0.05) post dose. Conclusion(s): A significant, sustained

The term “environmental flows” is now widely used to reflect the hydrological regime required to sustain freshwater and estuarine ecosystems, and the human livelihoods and well-being that depend on them. The definition suggests a central role for ecohydrological science to help determine a required flow regime for a target ecosystem condition. Indeed, many countries have established laws and policies to implement environmental flows with the expectation that science can deliver the answers. This article provides an overview of recent developments and applications of environmental flows on six continents to explore the changing role of ecohydrological sciences, recognizing its limitations and the emerging needs of society, water resource managers and policy makers. Science has responded with new methods to link hydrology to ecosystem status, but these have also raised fundamental questions that go beyond ecohydrology, such as who decides on the target condition of the ecosystem? Some environmental flow methods are based on the natural flow paradigm, which assumes the desired regime is the natural “unmodified” condition. However, this may be unrealistic where flow regimes have been altered for many centuries and are likely to change with future climate change. Ecosystems are dynamic, so the adoption of environmental flows needs to have a similar dynamic basis. Furthermore, methodological developments have been made in two directions: first, broad-scale hydrological analysis of flow regimes (assuming ecological relevance of hydrograph components) and, second, analysis of ecological impacts of more than one stressor (e.g. flow, morphology, water quality). All methods retain a degree of uncertainty, which translates into risks, and raises questions regarding trust between scientists and the public. Communication between scientists, social scientists, practitioners, policy makers and the public is thus becoming as important as the quality of the science.

The importance of flow regime variability for maintaining ecological functioning and integrity of river ecosystems has been firmly established in both natural and anthropogenically modified systems. In this paper we examine river flow regimes across lowland catchments in eastern England using 47 variables, including those derived using the Indicators of Hydrologic Alteration (IHA) software. A Principal Components Analysis (PCA) method was used to identify redundant hydrological variables and those that best characterised the hydrological series (1986-2005). A small number of variables (< 6 variables) characterised up to 95% of the statistical variability in the flow series. The hydrological processes and conditions that the variables represent were found to be significant in structuring the instream macroinvertebrate community LIFE scores at both the family- and species-level. However, hydrological variables only account for a relatively small proportion of the total ecological variability (typically <10%). The research indicates that a range of other factors, including channel morphology and anthropogenic modification of instream habitats, structure riverine macroinvertebrate communities in addition to hydrology. These factors need to be considered in future environmental flow studies to enable the characterisation of baseline/reference conditions for management and restoration purposes.