Women’s suffrage societies and the gendering of power: The National Union of Women’s Suffrage Societies (NUWSS) and Women's Social and Political Union (WSPU) as pioneers of women-led organisations

This work challenges the consistent application by historians of the term’s militant to the Women’s Social and Political Union (WSPU) and constitutional to the National Union of Women’s Suffrage Societies (NUWSS). The continuous links with militancy obscures the success of the structures and systems utilised by both societies and this study will concentrate on similarities of the two organisations rather differences. It will provide a focus on a distinctive new approach, an alternative to the previous separation of the societies. This will be accomplished by addressing an important and neglected study of both organisations that were essentially female. This thesis will propose an analytical framework for understanding how both suffrage societies created and ran two very successful organisations. The success of the structures and systems they utilised, provides a new understanding of how they accomplished monster demonstrations. A case study of the South West will detail how they developed new societies nationwide, networked, developed alliances with influential local people and used resident knowledge to recruit women from all sectors of society. This study identifies how the NUWSS and WSPU suffrage movements contributed to social change. More importantly this work identifies how women organisations both utilised and transgressed the separate spheres ideology. A new understanding of how both societies exploited gender and power to accomplish the success of their organisations. They achieved this by identifying male methods and techniques, they utilised and reinterpreted. This study uses the Edwardian shopping experience of large department stores opening women only tea rooms and provided the WSPU an example for their own very successful shops. They seized market opportunities to raise awareness. The structures and systems employed, were often a reinterpretation of male management methods and facilitated the administration of membership, recruitment, people, events, publicity, propaganda, marketing, executive decisions and governed processes and procedures

Modulating functionally-distinct vagus nerve fibers using microelectrodes and kilohertz frequency electrical stimulation

Modulation of functionally distinct nerve fibers with bioelectronic devices provides a therapeutic opportunity for various diseases. In this study, we began by developing a computational model including four major subtypes of myelinated fibers and one unmyelinated fiber. Second, we used an intrafascicular electrode to perform kHz-frequency electric stimulation to preferentially modulate a population of fibers. Our model suggests that fiber physical properties and electrode-to-fascicle distance severely impacts stimulus-response relationships. Large diameter fibers (Aα-and Aβ-) were only minimally influenced by the fascicle size and electrode location, while smaller diameter fibers (Aδ-, B-and C-) indicated a stronger dependency.Clinical Relevance-Our findings support the possibility of selectively modulating functionally-distinct nerve fibers using electrical stimulation in a small, localized region. Our model provides an effective tool to design next-generation implantable devices and therapeutic stimulation strategies toward minimizing off-target effects

The development and assessment of biological treatments for children

The development of biological agents with specific immunological targets has revolutionized the treatment of a wide variety of paediatric diseases where traditional immunosuppressive agents have been partly ineffective or intolerable. The increasing requirement for pharmaceutical companies to undertake paediatric studies has provided impetus for studies of biologics in children. The assessment of biological agents in children to date has largely relied upon randomized controlled trials using a withdrawal design, rather than a parallel study design. This approach has been largely used due to ethical concerns, including use of placebo treatments in children with active chronic disease, and justified on the basis that treatments have usually already undergone robust assessment in related adult conditions. However, this study design limits the reliability of the data and can confuse the interpretation of safety results. Careful ongoing monitoring of safety and efficacy in real-world practice through national and international biologics registries and robust reporting systems is crucial. The most commonly used biological agents in children target tumour necrosis factor-α, interleukin-1, interleukin-6 and cytotoxic lymphocyte-associated antigen-4. These agents are most frequently used in paediatric rheumatic diseases. This review discusses the development and assessment of biologics within paediatric rheumatology with reference to the lessons learned from use in other subspecialties

ProRepeat: an integrated repository for studying amino acid tandem repeats in proteins

ProRepeat (http://prorepeat.bioinformatics.nl/) is an integrated curated repository and analysis platform for in-depth research on the biological characteristics of amino acid tandem repeats. ProRepeat collects repeats from all proteins included in the UniProt knowledgebase, together with 85 completely sequenced eukaryotic proteomes contained within the RefSeq collection. It contains non-redundant perfect tandem repeats, approximate tandem repeats and simple, low-complexity sequences, covering the majority of the amino acid tandem repeat patterns found in proteins. The ProRepeat web interface allows querying the repeat database using repeat characteristics like repeat unit and length, number of repetitions of the repeat unit and position of the repeat in the protein. Users can also search for repeats by the characteristics of repeat containing proteins, such as entry ID, protein description, sequence length, gene name and taxon. ProRepeat offers powerful analysis tools for finding biological interesting properties of repeats, such as the strong position bias of leucine repeats in the N-terminus of eukaryotic protein sequences, the differences of repeat abundance among proteomes, the functional classification of repeat containing proteins and GC content constrains of repeats’ corresponding codons

Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment: Poordad et al.

Although direct‐acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection have demonstrated high rates of sustained virologic response, virologic failure may still occur, potentially leading to the emergence of viral resistance, which can decrease the effectiveness of subsequent treatment. Treatment options for patients who failed previous DAA‐containing regimens, particularly those with nonstructural protein 5A inhibitors, are limited and remain an area of unmet medical need. This phase 2, open‐label study (MAGELLAN‐1) evaluated the efficacy and safety of glecaprevir (GLE) + pibrentasvir (PIB) ± ribavirin (RBV) in HCV genotype 1–infected patients with prior virologic failure to HCV DAA‐containing therapy. A total of 50 patients without cirrhosis were randomized to three arms: 200 mg GLE + 80 mg PIB (arm A), 300 mg GLE + 120 mg PIB with 800 mg once‐daily RBV (arm B), or 300 mg GLE + 120 mg PIB without RBV (arm C). By intent‐to‐treat analysis, sustained virologic response at posttreatment week 12 was achieved in 100% (6/6, 95% confidence interval 61‐100), 95% (21/22, 95% confidence interval 78‐99), and 86% (19/22, 95% confidence interval 67‐95) of patients in arms A, B, and C, respectively. Virologic failure occurred in no patients in arm A and in 1 patient each in arms B and C (two patients were lost to follow‐up in arm C). The majority of adverse events were mild in severity; no serious adverse events related to study drug and no relevant laboratory abnormalities in alanine aminotransferase, total bilirubin, or hemoglobin were observed. Conclusion: The combination of GLE and PIB was highly efficacious and well tolerated in patients with HCV genotype 1 infection and prior failure of DAA‐containing therapy; RBV coadministration did not improve efficacy. (Hepatology 2017;66:389–397)

Palmitoylation and Membrane Association of the Stress Axis Regulated Insert (STREX) Controls BK Channel Regulation by Protein Kinase C

Large-conductance, calcium- and voltage-gated potassium (BK) channels play an important role in cellular excitability by controlling membrane potential and calcium influx. The stress axis regulated exon (STREX) at splice site 2 inverts BK channel regulation by protein kinase A (PKA) from stimulatory to inhibitory. Here we show that palmitoylation of STREX controls BK channel regulation also by protein kinase C (PKC). In contrast to the 50% decrease of maximal channel activity by PKC in the insertless (ZERO) splice variant, STREX channels were completely resistant to PKC. STREX channel mutants in which Ser(700), located between the two regulatory domains of K(+) conductance (RCK) immediately downstream of the STREX insert, was replaced by the phosphomimetic amino acid glutamate (S700E) showed a ∼50% decrease in maximal channel activity, whereas the S700A mutant retained its normal activity. BK channel inhibition by PKC, however, was effectively established when the palmitoylation-mediated membrane-anchor of the STREX insert was removed by either pharmacological inhibition of palmitoyl transferases or site-directed mutagenesis. These findings suggest that STREX confers a conformation on BK channels where PKC fails to phosphorylate and to inhibit channel activity. Importantly, PKA which inhibits channel activity by disassembling the STREX insert from the plasma membrane, allows PKC to further suppress the channel gating independent from voltage and calcium. Our results present an important example for the cross-talk between ion channel palmitoylation and phosphorylation in regulation of cellular excitability

Formation and evolution of the ionospheric plasma density shoulder and its relationship to the superfountain effects investigated during the 6 November 2001 great storm

This study investigates the 6 November 2001 great storm’s impact on the topside ionosphere utilizing data from the onboard TOPEX/Poseidon-NASA altimeter, Defense Meteorological Satellite Program–Special Sensor Ions, Electrons and Scintillation instruments and ACE interplanetary observatory. A set of field-aligned profiles demonstrate the storm evolution, caused by the precursor and promptly penetrating interplanetary eastward electric (E) fields, and strong equatorward winds reducing chemical loss, during the long-duration negative BZ events. At daytime-evening, the forward fountain experienced repeated strengthening, as the net eastward E field suddenly increased. The resultant symmetrical equatorial anomaly exhibited a continuous increase,while the energy inputs at both auroral regions were similar. In both hemispheres, by progressing poleward, a midlatitude shoulder exhibiting increased plasma densities, a plasma-density dropoff (steep gradient) and a plasma depletion appeared. These features were maintained while the reverse fountain operated. At the dropoff, elevated temperatures indicated the plasmapause. Consequently, the plasma depletion was the signature of plasmaspheric erosion. In each hemisphere, an isolated plasma flow, supplying the minimum plasma, was detected at the shoulder. Plasmaspheric compression, due to the enhanced E fields, could trigger this plasma flow. Exhibiting strong longitudinal variation at evening-nighttime, the shoulder increased 306% over the southeastern Pacific, where the nighttime Weddell Sea Anomaly (WSA) appeared before the storm. There, the shoulder indicated the storm-enhanced equatorward section of the quiet time WSA. Owing to the substantial equatorward plasmapause movement, a larger poleward section of the quiet time WSA eroded away, leaving a large depletion behind. This study reports first these (northern, southern) plasma flows and dramatic storm effects on a nighttime WSA