A small viral potassium ion channel with an inherent inward rectification

Some algal viruses have coding sequences for proteins with structural and functional characteristics of pore modules of complex K+ channels. Here we exploit the structural diversity among these channel orthologs to discover new basic principles of structure/function correlates in K+ channels. The analysis of three similar K+ channels with ≤ 86 amino acids (AA) shows that one channel (Kmpv1) generates an ohmic conductance in HEK293 cells while the other two (KmpvSP1, KmpvPL1) exhibit typical features of canonical Kir channels. Like Kir channels, the rectification of the viral channels is a function of the K+ driving force. Reconstitution of KmpvSP1 and KmpvPL1 in planar lipid bilayers showed rapid channel fluctuations only at voltages negative of the K+ reversal voltage. This rectification was maintained in KCl buffer with 1 mM EDTA, which excludes blocking cations as the source of rectification. This means that rectification of the viral channels must be an inherent property of the channel. The structural basis for rectification was investigated by a chimera between rectifying and non-rectifying channels as well as point mutations making the rectifier similar to the ohmic conducting channel. The results of these experiments exclude the pore with pore helix and selectivity filter as playing a role in rectification. The insensitivity of the rectifier to point mutations suggests that tertiary or quaternary structural interactions between the transmembrane domains are responsible for this type of gating

Transferrin-Decorated Niosomes with Integrated InP/ZnS Quantum Dots and Magnetic Iron Oxide Nanoparticles: Dual Targeting and Imaging of Glioma

The development of multifunctional nanoscale systems that can mediate efficient tumor targeting, together with high cellular internalization, is crucial for the diagnosis of glioma. The combination of imaging agents into one platform provides dual imaging and allows further surface modification with targeting ligands for specific glioma detection. Herein, transferrin (Tf)-decorated niosomes with integrated magnetic iron oxide nanoparticles (MIONs) and quantum dots (QDs) were formulated (PEGNIO/QDs/MIONs/Tf) for efficient imaging of glioma, supported by magnetic and active targeting. Transmission electron microscopy confirmed the complete co-encapsulation of MIONs and QDs in the niosomes. Flow cytometry analysis demonstrated enhanced cellular uptake of the niosomal formulation by glioma cells. In vitro imaging studies showed that PEGNIO/QDs/MIONs/Tf produces an obvious negative-contrast enhancement effect on glioma cells by magnetic resonance imaging (MRI) and also improved fluorescence intensity under fluorescence microscopy. This novel platform represents the first niosome-based system which combines magnetic nanoparticles and QDs, and has application potential in dual-targeted imaging of glioma

Carbon on the Northwest European Shelf: Contemporary Budget and Future Influences

A carbon budget for the northwest European continental shelf seas (NWES) was synthesized using available estimates for coastal, pelagic and benthic carbon stocks and flows. Key uncertainties were identified and the effect of future impacts on the carbon budget were assessed. The water of the shelf seas contains between 210 and 230 Tmol of carbon and absorbs between 1.3 and 3.3 Tmol from the atmosphere annually. Off-shelf transport and burial in the sediments account for 60–100 and 0–40% of carbon outputs from the NWES, respectively. Both of these fluxes remain poorly constrained by observations and resolving their magnitudes and relative importance is a key research priority. Pelagic and benthic carbon stocks are dominated by inorganic carbon. Shelf sediments contain the largest stock of carbon, with between 520 and 1600 Tmol stored in the top 0.1 m of the sea bed. Coastal habitats such as salt marshes and mud flats contain large amounts of carbon per unit area but their total carbon stocks are small compared to pelagic and benthic stocks due to their smaller spatial extent. The large pelagic stock of carbon will continue to increase due to the rising concentration of atmospheric CO2, with associated pH decrease. Pelagic carbon stocks and flows are also likely to be significantly affected by increasing acidity and temperature, and circulation changes but the net impact is uncertain. Benthic carbon stocks will be affected by increasing temperature and acidity, and decreasing oxygen concentrations, although the net impact of these interrelated changes on carbon stocks is uncertain and a major knowledge gap. The impact of bottom trawling on benthic carbon stocks is unique amongst the impacts we consider in that it is widespread and also directly manageable, although its net effect on the carbon budget is uncertain. Coastal habitats are vulnerable to sea level rise and are strongly impacted by management decisions. Local, national and regional actions have the potential to protect or enhance carbon storage, but ultimately global governance, via controls on emissions, has the greatest potential to influence the long-term fate of carbon stocks in the northwestern European continental shelf

Effects of lumacaftor—ivacaftor therapy on cystic fibrosis transmembrane conductance regulator function in F508del homozygous patients with cystic fibrosis aged 2–11 years

Rationale: Lumacaftor/ivacaftor was approved for the treatment of patients with cystic fibrosis who are homozygous for F508del aged 2 years and older following positive results from phase three trials. However, the improvement in CFTR function associated with lumacaftor/ivacaftor has only been studied in patients over 12 years of age, while the rescue potential in younger children is unknown.Methods: In a prospective study, we aimed to evaluate the effect of lumacaftor/ivacaftor on the CFTR biomarkers sweat chloride concentration and intestinal current measurement as well as clinical outcome parameters in F508del homozygous CF patients 2–11 years before and 8–16 weeks after treatment initiation.Results: A total of 13 children with CF homozygous for F508del aged 2–11 years were enrolled and 12 patients were analyzed. Lumacaftor/ivacaftor treatment reduced sweat chloride concentration by 26.8 mmol/L (p = 0.0006) and showed a mean improvement in CFTR activity, as assessed by intestinal current measurement in the rectal epithelium, of 30.5% compared to normal (p = 0.0015), exceeding previous findings of 17.7% of normal in CF patients homozygous for F508del aged 12 years and older.Conclusion: Lumacaftor/ivacaftor partially restores F508del CFTR function in children with CF who are homozygous for F508del, aged 2–11 years, to a level of CFTR activity seen in patients with CFTR variants with residual function. These results are consistent with the partial short-term improvement in clinical parameters

Drought in the Anthropocene

Drought management is inefficient because feedbacks between drought and people are not fully understood. In this human-influenced era, we need to rethink the concept of drought to include the human role in mitigating and enhancing drought

Drought in a human-modified world: reframing drought definitions, understanding, and analysis approaches

In the current human-modified world, or Anthropocene, the state of water stores and fluxes has become dependent on human as well as natural processes. Water deficits (or droughts) are the result of a complex interaction between meteorological anomalies, land surface processes, and human inflows, outflows, and storage changes. Our current inability to adequately analyse and manage drought in many places points to gaps in our understanding and to inadequate data and tools. The Anthropocene requires a new framework for drought definitions and research. Drought definitions need to be revisited to explicitly include human processes driving and modifying soil moisture drought and hydrological drought development. We give recommendations for robust drought definitions to clarify timescales of drought and prevent confusion with related terms such as water scarcity and overexploitation. Additionally, our understanding and analysis of drought need to move from single driver to multiple drivers and from uni-directional to multi-directional. We identify research gaps and propose analysis approaches on (1) drivers, (2) modifiers, (3) impacts, (4) feedbacks, and (5) changing the baseline of drought in the Anthropocene. The most pressing research questions are related to the attribution of drought to its causes, to linking drought impacts to drought characteristics, and to societal adaptation and responses to drought. Example questions include: (i) What are the dominant drivers of drought in different parts of the world? (ii) How do human modifications of drought enhance or alleviate drought severity? (iii) How do impacts of drought depend on the physical characteristics of drought vs. the vulnerability of people or the environment? (iv) To what extent are physical and human drought processes coupled, and can feedback loops be identified and altered to lessen or mitigate drought? (v) How should we adapt our drought analysis to accommodate changes in the normal situation (i.e. what are considered normal or reference conditions) over time? Answering these questions requires exploration of qualitative and quantitative data as well as mixed modelling approaches. The challenges related to drought research and management in the Anthropocene are not unique to drought, but do require urgent attention. We give recommendations drawn from the fields of flood research, ecology, water management, and water resources studies. The framework presented here provides a holistic view on drought in the Anthropocene, which will help improve management strategies for mitigating the severity and reducing the impacts of droughts in future

Drought in a human-modified world: reframing drought definitions, understanding, and analysis approaches

In the current human-modified world, or Anthropocene, the state of water stores and fluxes has become dependent on human as well as natural processes.Water deficits (or droughts) are the result of a complex interaction between meteorological anomalies, land surface processes, and human inflows, outflows, and storage changes. Our current inability to adequately analyse and manage drought in many places points to gaps in our understanding and to inadequate data and tools. The Anthropocene requires a new framework for drought definitions and research. Drought definitions need to be revisited to explicitly include human processes driving and modifying soil moisture drought and hydrological drought development. We give recommendations for robust drought definitions to clarify timescales of drought and prevent confusion with related terms such as water scarcity and overexploitation. Additionally, our understanding and analysis of drought need to move from single driver to multiple drivers and from uni-directional to multi-directional. We identify research gaps and propose analysis approaches on (1) drivers, (2) modifiers, (3) impacts, (4) feedbacks, and (5) changing the baseline of drought in the Anthropocene. The most pressing research questions are related to the attribution of drought to its causes, to linking drought impacts to drought characteristics, and to societal adaptation and responses to drought. Example questions include (i) What are the dominant drivers of drought in different parts of the world? (ii) How do human modifications of drought enhance or alleviate drought severity? (iii) How do impacts of drought depend on the physical characteristics of drought vs. the vulnerability of people or the environment? (iv) To what extent are physical and human drought processes coupled, and can feedback loops be identified and altered to lessen or mitigate drought? (v) How should we adapt our drought analysis to accommodate changes in the normal situation (i.e. what are considered normal or reference conditions) over time

Welfare of pigs at slaughter

The killing of pigs for human consumption (slaughtering) can take place in a slaughterhouse or on farm. The processes of slaughtering that were assessed for welfare, from the arrival of pigs until their death, were grouped into three main phases: pre-stunning (including arrival, unloading from the truck, lairage, handling and moving of pigs); stunning (including restraint); and bleeding. Stunning methods were grouped into three categories: electrical, controlled atmosphere and mechanical. Twelve welfare consequences the pigs can be exposed to during slaughter were identified: heat stress, cold stress, fatigue, prolonged thirst, prolonged hunger, impeded movement, restriction of movements, resting problem, negative social behaviour, pain, fear and respiratory distress. Welfare consequences and relevant animal-based measures were described. In total, 30 welfare hazards that could occur during slaughter were identified and characterised, most of them related to stunning and bleeding. Staff were identified as the origin of 29 hazards, which were attributed to the lack of appropriate skill sets needed to perform tasks or to fatigue. Corrective and preventive measures for these hazards were assessed: measures to correct hazards were identified, and management was shown to have a crucial role in prevention. Outcome tables linking hazards, welfare consequences, animal-based measures, origins and preventive and corrective measures were developed for each process. Mitigation measures to minimise welfare consequences are proposed.info:eu-repo/semantics/publishedVersio

Welfare of pigs during killing for purposes other than slaughter

Pigs at different stages of the production cycle may have to be killed on-farm for purposes other thanslaughter (where slaughter is dened as killing for human consumption) either individually (e.g.severely injured pigs) or on a large scale (e.g. unproductive animals or for disease control reasons).This opinion assessed the risks associated with the on-farm killing of pigs and included two phases: 1)handling and moving of pigs and 2) killing methods (including restraint). The killing methods weresubdivided into four categories: electrical methods, mechanical methods, gas mixture methods andlethal injec tion. Four welfare consequences to which pigs can be exposed to during on-farm killingwere identied: pain, fear, impeded movement and respiratory distress. Welfare consequences andrelevant animal-based measures were described. In total, 28 hazards were associated with the welfareconsequences; majority of the hazards (24) are related to Phase 2 (killing). The main hazards areassociated with lack of staff skills and training, and poor-designed and constructed facilities. Staff wasidentied as an origin of all hazards, either due to lack of skills needed to perform appropriate killing ordue to fatigue. Corrective measures were identied for 25 hazards. Outcome tables linking hazards,welfare consequences, animal-based measures, hazard origins, prevent ive and corrective measureswere developed and mitigation measures proposed.info:eu-repo/semantics/publishedVersio

Welfare of cattle at slaughter

The killing of cattle for human consumption (slaughtering) can take place in a slaughterhouse or on farm. The processes of slaughtering that were assessed for welfare, from the arrival of cattle until their death (including slaughtering without stunning), were grouped into three main phases: pre‐stunning (including arrival, unloading from the truck, lairage, handling and moving of cattle); stunning (including restraint); and bleeding. Stunning methods were grouped into two categories: mechanical and electrical. Twelve welfare consequences that cattle may be exposed to during slaughter were identified: heat stress, cold stress, fatigue, prolonged thirst, prolonged hunger, impeded movement, restriction of movements, resting problems (inability to rest or discomfort during resting), social stress, pain, fear and distress. Welfare consequences and their relevant animal‐based measures are described. In total, 40 welfare hazards that could occur during slaughter were identified and characterised, most of them related to stunning and bleeding. Staff were identified as the origin of 39 hazards, which were attributed to the lack of appropriate skill sets needed to perform tasks or to fatigue. Measures to prevent and correct hazards were identified, and structural and managerial measures were identified as those with a crucial role in prevention. Outcome tables linking hazards, welfare consequences, animal‐based measures, origin of hazards, and preventive and corrective measures were developed for each process. Mitigation measures to minimise welfare consequences are proposed.info:eu-repo/semantics/publishedVersio