This volume examines the relationship between privacy, surveillance and security, and the alleged privacy–security trade-off, focusing on the citizen’s perspective.
Recent revelations of mass ...surveillance programmes clearly demonstrate the ever-increasing capabilities of surveillance technologies. The lack of serious reactions to these activities shows that the political will to implement them appears to be an unbroken trend. The resulting move into a surveillance society is, however, contested for many reasons. Are the resulting infringements of privacy and other human rights compatible with democratic societies? Is security necessarily depending on surveillance? Are there alternative ways to frame security? Is it possible to gain in security by giving up civil liberties, or is it even necessary to do so, and do citizens adopt this trade-off? This volume contributes to a better and deeper understanding of the relation between privacy, surveillance and security, comprising in-depth investigations and studies of the common narrative that more security can only come at the expense of sacrifice of privacy. The book combines theoretical research with a wide range of empirical studies focusing on the citizen’s perspective. It presents empirical research exploring factors and criteria relevant for the assessment of surveillance technologies. The book also deals with the governance of surveillance technologies. New approaches and instruments for the regulation of security technologies and measures are presented, and recommendations for security policies in line with ethics and fundamental rights are discussed.
This book will be of much interest to students of surveillance studies, critical security studies, intelligence studies, EU politics and IR in general.
ObjectiveInfliximab (IFX) has an established role in Crohn’s disease (CD), with serum trough levels of IFX (TLI) increasingly used to optimise dosing. We report the utility of routine, proactive TLI ...in children on combination therapy with immunosuppression (IS) from a single paediatric centre.MethodsThis is a retrospective chart review of all children with CD receiving IFX therapy conducted betweenJanuary 2014–May 2017. Clinical phenotype, duration of therapy, TLI (µg/mL), drug antibodies, type of IS, biomarkers and changes in management were recorded.Results60 children (8–17 years; median 14.1 years) had 206 TLIs recorded. 56/60 (93%) were on IS, with 5/60 (8%) developing antidrug antibodies (ADAs). 63/206 TLIs were recorded duringan episode of relapse (median 3.0 µg/mL) vs 143/206 TLIs recorded in remission (median 5.2 µg/mL). For children with TLI <3 µg/mL, 31/63 (49%) were in relapse vs 30/143 (21%) in remission. For children with TLI >7 µg/mL, 7/63 (11%) were in relapse vs 46/143 (32%) in remission. Change in management resulted from 43/206 (21%) TLIs in 31/60 (52%) children: 21 dose escalations, 12 de-escalations and 10 changed to adalimumab. Of 31 postinduction TLIs, 15/17 (88%) children with TLI >7 µg/mL achieved clinical and biochemical remission for the duration of therapy (median 14 months), while 4/5 (80%) children with TLI <3 µg/mL required early dose escalation. Combination therapy with thiopurines (TP) (median TLI 4.9 µg/mL) versus methotrexate (MTX) (median TLI 5.2 µg/mL) achieved comparable levels with no difference in relapse frequency.ConclusionsRoutine, proactive TLIs guide optimal management in children with CD. Postinduction and during maintenance, levels <3 µg/mL were associated with relapse and levels >7 µg/mL with sustained remission. Combination IS with TP and MTX appears to offer comparable TLI and ADA rates.
We show that negative-stain electron microscopy and image processing of nucleotide-free (apo) striated muscle myosin-2 subfragment-1 (S1), possessing one light chain or both light chains, is capable ...of resolving significant amounts of structural detail. The overall appearance of the motor and the lever is similar in rabbit, scallop and chicken S1. Projection matching of class averages of the different S1 types to projection views of two different crystal structures of apo S1 shows that all types most commonly closely resemble the appearance of the scallop S1 structure rather than the methylated chicken S1 structure. Methylation of chicken S1 has no effect on the structure of the molecule at this resolution: it too resembles the scallop S1 crystal structure. The lever is found to vary in its angle of attachment to the motor domain, with a hinge point located in the so-called pliant region between the converter and the essential light chain. The chicken S1 crystal structure lies near one end of the range of flexion observed. The Gaussian spread of angles of flexion suggests that flexibility is driven thermally, from which a torsional spring constant of ~23pN·nm/rad2 is estimated on average for all S1 types, similar to myosin-5. This translates to apparent cantilever-type stiffness at the tip of the lever of 0.37pN/nm. Because this stiffness is lower than recent estimates from myosin-2 heads attached to actin, we suggest that binding to actin leads to an allosteric stiffening of the motor–lever junction.
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•Elasticity of muscle crossbridges is important, but its structural basis is obscure.•Muscle myosin heads from rabbit, scallop and chicken share a common structure.•The lever domain hinges about its connection with the motor domain.•The stiffness of the motor–lever hinge is lower than estimates for crossbridges.•Flexibility within the myosin head can be the basis of crossbridge stiffness.
The mitotic kinase Aurora-A and its partner protein TPX2 (Targeting Protein for Xenopus kinesin-like protein 2) are overexpressed in cancers, and it has been proposed that they work together as an ...oncogenic holoenzyme. TPX2 is responsible for activating Aurora-A during mitosis, ensuring proper cell division. Disruption of the interface with TPX2 is therefore a potential target for novel anticancer drugs that exploit the increased sensitivity of cancer cells to mitotic stress. Here, we investigate the interface using coprecipitation assays and isothermal titration calorimetry to quantify the energetic contribution of individual residues of TPX2. Residues Tyr8, Tyr10, Phe16, and Trp34 of TPX2 are shown to be crucial for robust complex formation, suggesting that the interaction could be abrogated through blocking any of the three pockets on Aurora-A that complement these residues. Phosphorylation of Aurora-A on Thr288 is also necessary for high-affinity binding, and here we identify arginine residues that communicate the phosphorylation of Thr288 to the TPX2 binding site. With these findings in mind, we conducted a high-throughput X-ray crystallography-based screen of 1255 fragments against Aurora-A and identified 59 hits. Over three-quarters of these hits bound to the pockets described above, both validating our identification of hotspots and demonstrating the druggability of this protein–protein interaction. Our study exemplifies the potential of high-throughput crystallography facilities such as XChem to aid drug discovery. These results will accelerate the development of chemical inhibitors of the Aurora-A/TPX2 interaction.
Kunzea (Myrtaceae) trees and shrubs, generally called kānuka, grow across most of Aotearoa/New Zealand (NZ). With the exception of K. sinclairii, an offshore island endemic, kānuka had been treated ...as an Australasian species K. ericoides. However, a 2014 taxonomic revision recognized ten species, all endemic to NZ. Kānuka chemistry is less studied than that of its closest relative in NZ, mānuka (Leptospermum scoparium), which shows very distinct regional foliage chemotypes. We have used a miniaturized method with GC and 1H NMR to analyze foliage chemistry of voucher specimens from across the geographic ranges of the ten NZ Kunzea species. We found common mono- and sesquiterpenes, with α-pinene dominant in all samples, but only traces of antimicrobial triketones. Two unusual flavanones, with unsubstituted B-rings and known bioactivity against Phytophthora, did distinguish some of the samples. 5,7-Dihydroxy-6,8-dimethyl flavanone was only found at high concentrations in the three K. sinclairii samples in this study's sample set, but this compound has separately been reported in K. robusta samples from a nearby region. Therefore none of the NZ Kunzea species was distinguished by the chemistry analyzed in this study, but there is a possibility of regional flavonoid chemotypes cutting across the species boundaries.
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•Kunzea (Myrtaceae) trees and shrubs, kānuka, grow across most of Aotearoa/New Zealand (NZ).•Foliage chemistry of voucher specimens of ten species was analyzed by GC and 1H NMR.•Two rare bioactive flavanones were found in some of the samples.•None of the NZ Kunzea species was distinguished by the chemistry analyzed in this study.•There may be regional flavonoid chemotypes cutting across the species boundaries.
The establishment of a functional cerebral cortex depends on the proper execution of multiple developmental steps, culminating in dendritic and axonal outgrowth and the formation and maturation of ...synaptic connections. Dysregulation of these processes can result in improper neuronal connectivity, including that associated with various neurodevelopmental disorders. The γ-Protocadherins (γ-Pcdhs), a family of 22 distinct cell adhesion molecules that share a C-terminal cytoplasmic domain, are involved in multiple aspects of neurodevelopment including neuronal survival, dendrite arborization, and synapse development. The extent to which individual γ-Pcdh family members play unique versus common roles remains unclear. We demonstrated previously that the γ-Pcdh-C3 isoform (γC3), via its unique "variable" cytoplasmic domain (VCD), interacts in cultured cells with Axin1, a Wnt-pathway scaffold protein that regulates the differentiation and morphology of neurons. Here, we confirm that γC3 and Axin1 interact in the cortex
and show that both male and female mice specifically lacking γC3 exhibit disrupted Axin1 localization to synaptic fractions, without obvious changes in dendritic spine density or morphology. However, both male and female γC3 knock-out mice exhibit severely decreased dendritic complexity of cortical pyramidal neurons that is not observed in mouse lines lacking several other γ-Pcdh isoforms. Combining knock-out with rescue constructs in cultured cortical neurons pooled from both male and female mice, we show that γC3 promotes dendritic arborization through an Axin1-dependent mechanism mediated through its VCD. Together, these data identify a novel mechanism through which γC3 uniquely regulates the formation of cortical circuitry.
The complexity of a neuron's dendritic arbor is critical for its function. We showed previously that the γ-Protocadherin (γ-Pcdh) family of 22 cell adhesion molecules promotes arborization during development; it remained unclear whether individual family members played unique roles. Here, we show that one γ-Pcdh isoform, γC3, interacts in the brain with Axin1, a scaffolding protein known to influence dendrite development. A CRISPR/Cas9-generated mutant mouse line lacking γC3 (but not lines lacking other γ-Pcdhs) exhibits severely reduced dendritic complexity of cerebral cortex neurons. Using cultured γC3 knock-out neurons and a variety of rescue constructs, we confirm that the γC3 cytoplasmic domain promotes arborization through an Axin1-dependent mechanism. Thus, γ-Pcdh isoforms are not interchangeable, but rather can play unique neurodevelopmental roles.
Oral sildenafil and intravenous epoprostenol have independently been shown to be effective in patients with pulmonary arterial hypertension.
To investigate the effect of adding oral sildenafil to ...long-term intravenous epoprostenol in patients with pulmonary arterial hypertension.
A 16-week, double-blind, placebo-controlled, parallel-group study.
Multinational study at 41 centers in 11 countries from 3 July 2003 to 27 January 2006.
267 patients with pulmonary arterial hypertension (idiopathic, associated anorexigen use or connective tissue disease, or corrected congenital heart disease) who were receiving long-term intravenous epoprostenol therapy.
Patients were randomly assigned to receive placebo or sildenafil, 20 mg three times daily, titrated to 40 mg and 80 mg three times daily, as tolerated, at 4-week intervals. Of 265 patients who received treatment, 256 (97%) patients (123 in the placebo group and 133 in the sildenafil group) completed the study.
Change from baseline in exercise capacity measured by 6-minute walk distance (primary end point) and hemodynamic measurements, time to clinical worsening, and Borg dyspnea score (secondary end points).
A placebo-adjusted increase of 28.8 meters (95% CI, 13.9 to 43.8 meters) in the 6-minute walk distance occurred in patients in the sildenafil group; these improvements were most prominent among patients with baseline distances of 325 meters or more. Relative to epoprostenol monotherapy, addition of sildenafil resulted in a greater change in mean pulmonary arterial pressure by -3.8 mm Hg (CI, -5.6 to -2.1 mm Hg); cardiac output by 0.9 L/min (CI, 0.5 to 1.2 L/min); and longer time to clinical worsening, with a smaller proportion of patients experiencing a worsening event in the sildenafil group (0.062) than in the placebo group (0.195) by week 16 (P = 0.002). Health-related quality of life also improved in patients who received combined therapy compared with those who received epoprostenol monotherapy. There was no effect on the Borg dyspnea score. Of the side effects generally associated with sildenafil treatment, the most commonly reported in the placebo and sildenafil groups, respectively, were headache (34% and 57%; difference, 23 percentage points CI, 12 to 35 percentage points), dyspepsia (2% and 16%; difference, 13 percentage points CI, 7 to 20 percentage points), pain in extremity (18% and 25%; difference, 8 percentage points CI, -2 to 18 percentage points), and nausea (18% and 25%; difference, 8 percentage points CI, -2 to 18 percentage points).
The study excluded patients with pulmonary arterial hypertension associated with other causes. There was an imbalance in missing data between groups, with 8 placebo recipients having no postbaseline walk assessment compared with 1 sildenafil recipient. These patients were excluded from the analysis.
In some patients with pulmonary arterial hypertension, the addition of sildenafil to long-term intravenous epoprostenol therapy improves exercise capacity, hemodynamic measurements, time to clinical worsening, and quality of life, but not Borg dyspnea score. Increased rates of headache and dyspepsia occurred with the addition of sildenafil.
Mutations in TREM2, a receptor expressed by microglia in the brain, are associated with an increased risk of neurodegeneration, including Alzheimer's disease. Numerous studies support a role for ...TREM2 in sensing damaging stimuli and triggering signaling cascades necessary for neuroprotection. Despite its significant role, ligands and regulators of TREM2 activation, and the mechanisms governing TREM2-dependent responses and its cleavage from the membrane, remain poorly characterized. Here, we present phage display generated antibody single-chain variable fragments (scFvs) to human TREM2 immunoglobulin-like domain. Co-crystal structures revealed the binding of two scFvs to an epitope on the TREM2 domain distal to the putative ligand-binding site. Enhanced functional activity was observed for oligomeric scFv species, which inhibited the production of soluble TREM2 in a HEK293 cell model. We hope that detailed characterization of their epitopes and properties will facilitate the use of these renewable binders as structural and functional biology tools for TREM2 research.
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•scFvs were generated against the immunoglobulin-like domain of the receptor TREM2•Crystal structures revealed scFv binding to epitopes outside the TREM2 CDRs•Oligomeric scFv species reduced levels of shed TREM2 ectodomain in a HEK293 model•The scFvs form renewable structural and functional biology tools for TREM2 research
TREM2 variants are associated with an increased risk of dementia. Szykowska et al. generated scFv antibody fragments to TREM2 immunoglobulin-like domain and solved crystal structures of scFv-TREM2 complexes to reveal their binding modes. Oligomeric scFv species showed enhanced functional activity reducing levels of shed TREM2 ectodomain in a HEK293 model.
The JmjC oxygenases catalyze the N-demethylation of N ε-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified ...assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups.
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