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Motor neuropathy with conduction block due to pan‐neurofascin antibodies in a patient with chronic lymphocytic leukemia
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Structural characterization of melatonin as an inhibitor of the Wnt deacylase Notum
No full textThe hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/β-catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide that is structurally similar to melatonin came to our attention. We then soaked melatonin and its precursor N-acetylserotonin into Notum crystals and obtained high-resolution structures (≤1.5 Å) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid, and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 µmol/L), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which upregulation of Wnt signalling may be beneficial
Informing the design of privacy-empowering tools for the connected home
No full textConnected devices in the home represent a potentially grave new privacy threat due to their unfettered access to the most personal spaces in people's lives. Prior work has shown that despite concerns about such devices, people often lack sufficient awareness, understanding, or means of taking effective action. To explore the potential for new tools that support such needs directly we developed Aretha, a privacy assistant technology probe that combines a network disaggregator, personal tutor, and firewall, to empower end-users with both the knowledge and mechanisms to control disclosures from their homes. We deployed Aretha in three households over six weeks, with the aim of understanding how this combination of capabilities might enable users to gain awareness of data disclosures by their devices, form educated privacy preferences, and to block unwanted data flows. The probe, with its novel affordances—and its limitations—prompted users to co-adapt, finding new control mechanisms and suggesting new approaches to address the challenge of regaining privacy in the connected home
DNA copy-number measurement of genome replication dynamics by high-throughput sequencing: the sort-seq, sync-seq and MFA-seq family.
No full textGenome replication follows a defined temporal programme that can change during cellular differentiation and disease onset. DNA replication results in an increase in DNA copy number that can be measured by high-throughput sequencing. Here we present a protocol to determine genome replication dynamics using DNA copy-number measurements. Cell populations can be obtained in three variants of the method. First, sort-seq reveals the average replication dynamics across S phase in an unperturbed cell population; FACS is used to isolate replicating and non-replicating subpopulations from asynchronous cells. Second, sync-seq measures absolute replication time at specific points during S phase using a synchronized cell population. Third, marker frequency analysis can be used to reveal the average replication dynamics using copy-number analysis in any proliferating asynchronous cell culture. These approaches have been used to reveal genome replication dynamics in prokaryotes, archaea and a wide range of eukaryotes, including yeasts and mammalian cells. We have found this approach straightforward to apply to other organisms and highlight example studies from across the three domains of life. Here we present a Saccharomyces cerevisiae version of the protocol that can be performed in 7–10 d. It requires basic molecular and cellular biology skills, as well as a basic understanding of Unix and R
Manners cost nothing? Civility on Twitter and political engagement, trust, and affective polarisation in Britain
No full textThis data set was created for the purpose of Harry Gable's 2020 MPhil thesis (Politics, Comparative Government) that has been deposited under the same title. It was created by relation to a Qualtrics online survey, which was completed by participants between 26 November and 1 December 2019. Participants were recruited using the online subject recruitment platform Prolific. The author recommends using the statistical analysis software R to analyse the data contained within the Excel spreadsheet
Genomic detection of a virus lineage replacement event of dengue virus serotype 2 in Brazil, 2019
No full textBACKGROUND: Despite efforts to mitigate the impact of DENV epidemics, the virus remains a public health problem in tropical and subtropical regions around the world. Most DENV cases in the Americas between January and July 2019 were reported in Brazil. São Paulo state in the southeast of Brazil has reported nearly half of all DENV infections in the country.
OBJECTIVES: To understand the origin and dynamics of the 2019 DENV outbreak.
METHODS: Here using portable nanopore sequencing we generated 20 new DENV genome sequences from viremic patients with suspected dengue infection residing in two of the most-affected municipalities of Sao Paulo state, Araraquara and São José do Rio Preto. We conducted a comprehensive phylogenetic analysis with 1,630 global DENV strains to better understand the evolutionary history of the DENV lineages that currently circulate in the region.
FINDINGS: The new outbreak strains were classified as DENV2 genotype III (American/Asian genotype). Our analysis shows that the 2019 outbreak is the result of a novel DENV lineage that was recently introduced to Brazil from the Caribbean region. Dating phylogeographic analysis suggests that DENV2-III BR-4 was introduced to Brazil in or around early 2014, possibly from the Caribbean region.
MAIN CONCLUSIONS: Our study describes the early detection of a newly introduced and rapidly-expanding DENV2 virus lineage in Brazil
Interaction among branched polyethylenimine (PEI), sodium dodecyl sulfate (SDS) and metal cations during copper recovery from water using polymer-surfactant aggregates
No full textThe application of polymer–surfactant aggregates (PSAs) to recover heavy metal ions from water is a novel treatment process for aqueous metallic effluents. To better employ this strategy, branched polyethylenimine (PEI), sodium dodecyl sulfate (SDS) and copper ions were selected to investigate their interaction in water and to improve the recyclable PSAs process for metal removal and recovery. Electrostatic association between PEI and SDS caused the formation of PSAs, and the addition of SDS to a partially protonated PEI solution caused a pH increase; however, re-dispersal of PSAs could be achieved via an increase in pH. Precipitation of PSAs depended on pH, SDS/PEI concentration ratio and the total concentration of PEI; the optimal SDS/PEI ratio decreased as pH increased, and a higher concentration of PEI showed a greater potential to precipitate. PEI formed a strong complex with Cu2+, with the most stable complex at a PEI/Cu chelation ratio of 4. Acidification decreased the chelation capacity of PEI to Cu2+, because of the competition from protons for amino groups. Complexation with Cu2+ in turn reduced the proton buffer capacity of PEI in a non-acid solution. The removal of Cu2+ increased by increasing the total PEI concentration, or by increasing pH from 1 to above 4. Ionic strength and hardness had no marked effect on Cu2+ removal using the PSAs process. Following the initial interaction among PEI, SDS and Cu2+, the Cu2+ could then be released from the PSAs by acidification and the reuse of the PSAs material could be achieved by alkalization. Copper removal and recovery were still up to 98 % and 88 % after three reuse cycles of the PSAs process, respectively
International taxation and environmental protection
No full textBuilding upon the existing literature, this Chapter shows that international tax law might have either positive or negative effects on the protection of the environment. First, this Chapter discusses the positive effects that international tax law could have on environmental protection if global environmental taxes were to be adopted. Second, by means of three concrete examples, this chapter analyzes three types of negative effects that international tax provisions might have on environmental protection. The international tax provisions that apply to the aviation sector are used as a first example to show that international tax law can cause a country’s tax system to be or remain disconnected from or inconsistent with its environmental policy agenda, which is problematic. Then, the case of environmental border tax adjustments is used to show how international tax provisions are sometimes used as an argument against the adoption of innovative domestic or regional tax measures that would allegedly help foster environmental protection. Finally, a third potential negative effect of international tax law on environmental protection is discussed through the example of emissions trading schemes, to highlight how double tax treaties might affect their effectiveness. This Chapter concludes that the interactions between international tax law and environmental protection need to be acknowledged and that coordination is key to ensure that international tax law does not undermine the legislator’s efforts to protect the environment