Search

Fathers are a crucial source of support for children following the birth of an infant sibling. This study examined whether fathers were more vulnerable to the effects of interparental conflict than mothers, and whether there was a subsequent spillover cascade from interparental conflict to children's externalizing behavior problems. We followed 241 families after the birth of a second child. Mothers and fathers reported on interparental conflict and parental efficacy at 1 and 4 months postpartum and punitive discipline and firstborn children's externalizing behavior problems across a longitudinal investigation (prenatal and 4, 8, and 12 months postpartum). For both mothers and fathers, interparental conflict prenatally predicted decreased parental efficacy following the birth. Fathers’ lower parental efficacy was significantly associated with increased punitive discipline toward the older sibling at 4 months, whereas mothers’ lower parental efficacy was not. Coercive family processes were present between mothers’ and fathers’ punitive discipline and older siblings’ externalizing behavior problems. Results were inconsistent with the father vulnerability hypothesis in that both mothers and fathers were vulnerable to interparental conflict, which in turn spilled over to create coercive family processes that exacerbated children's externalizing behavior problems in the year following the birth of a second child.

X-ray powder diffraction experiments using resistively heated diamond anvil cells have been conducted in order to establish the phase behavior of antimony up to 31 GPa and 835 K. The dip in the melting curve at 5.7 GPa and 840 K is identified as the triple point between the Sb-I, incommensurate Sb-II, and liquid phases. No evidence of the previously reported simple cubic phase was observed. Determination of the phase boundary between Sb-II and Sb-III suggests the existence of a second triple point in the region of 13 GPa and 1200 K. The incommensurate composite structure of Sb-II was found to remain ordered to the highest temperatures studies-no evidence of disordering of the guest-atom chains was observed. Indeed, the modulation reflections that arise from interactions between the host and guest subsystems were found to be present to the highest temperatures, suggesting such interactions remain relatively strong in Sb even in the presence of increased thermal motion. Finally, we show that the incommensurately modulated structure recently reported as giving an improved fit to diffraction data from incommensurate Ba-IV can be rejected as the structure of Sb-II using a simple density argument.

A working group at the National Institute for Mathematical and Biological Synthesis (NIMBioS) explored the feasibility of integrating 2 complementary approaches relevant to ecological risk assessment. Adverse outcome pathway (AOP) models provide "bottom-up" mechanisms to predict specific toxicological effects that could affect an individual's ability to grow, reproduce, and/or survive from a molecular initiating event. Dynamic energy budget (DEB) models offer a "top-down" approach that reverse engineers stressor effects on growth, reproduction, and/or survival into modular characterizations related to the acquisition and processing of energy resources. Thus, AOP models quantify linkages between measurable molecular, cellular, or organ-level events, but they do not offer an explicit route to integratively characterize stressor effects at higher levels of organization. While DEB models provide the inherent basis to link effects on individuals to those at the population and ecosystem levels, their use of abstract variables obscures mechanistic connections to suborganismal biology. To take advantage of both approaches, we developed a conceptual model to link DEB and AOP models by interpreting AOP key events as measures of damage-inducing processes affecting DEB variables and rates. We report on the type and structure of data that are generated for AOP models that may also be useful for DEB models. We also report on case studies under development that merge information collected for AOPs with DEB models and highlight some of the challenges. Finally, we discuss how the linkage of these 2 approaches can improve ecological risk assessment, with possibilities for progress in predicting population responses to toxicant exposures within realistic environments. Integr Environ Assess Manag 2018;14:615-624. © 2018 SETAC.

Additional file 1: Table 1S. Published Components of Kudzu from China. Figure 1S. Cytotoxicity of the cells used. Figure 2S. Activity of Kudzuâ s vehicles (glycerol and Ethanol) and ARVs in acute infection of HeLa-CD4-LTR-LacZ cells with an X4 tropic virus. Figure 3S. Kudzu does not alter CD4, CXCR4 and CCR5 cell membrane expression. Table 2S. Table of primers/probes used.

Introduction: The reported prevalence of ALK receptor tyrosine kinase gene (ALK) rearrangement in NSCLC ranges from 2% to 7%. The primary standard diagnostic method is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has also proved to be a reproducible and sensitive technique. Reverse-transcriptase polymerase chain reaction (RT-PCR) has also been advocated, and most recently, the advent of targeted next-generation sequencing (NGS) for ALK and other fusions has become possible. This study compares anaplastic lymphoma kinase (ALK) evaluation with all four techniques in resected NSCLC from the large European Thoracic Oncology Platform Lungscape cohort. Methods: A total of 96 cases from the European Thoracic Oncology Platform Lungscape iBiobank, with any ALK immunoreactivity were examined by FISH, central RT-PCR, and NGS. An H-score higher than 120 defines IHC positivity. RNA was extracted from the same formalin-fixed, paraffin-embedded tissues. For RT-PCR, primers covered the most frequent ALK translocations. For NGS, the Oncomine Solid Tumour Fusion Transcript Kit (Thermo Fisher Scientific, Waltham, MA) was used. The concordance was assessed using the Cohen κ coefficient (two-sided α ≤ 5%). Results: NGS provided results for 77 of the 95 cases tested (81.1%), whereas RT-PCR provided results for 77 of 96 (80.2%). Concordance occurred in 55 cases of the 60 cases tested with all four methods (43 ALK negative and 12 ALK positive). Using ALK copositivity for IHC and FISH as the criterion standard, we derived a sensitivity for RT-PCR/NGS of 70.0%/85.0%, with a specificity of 87.1%/79.0%. When either RT-PCR or NGS was combined with IHC, the sensitivity remained the same, whereas the specificity increased to 88.7% and 83.9% respectively. Conclusion: NGS evaluation with the Oncomine Solid Tumour Fusion transcript kit and RT-PCR proved to have high sensitivity and specificity, advocating their use in routine practice. For maximal sensitivity and specificity, ALK status should be assessed by using two techniques and a third one in discordant cases. We therefore propose a customizable testing algorithm. These findings significantly influence existing testing paradigms and have clear clinical and economic impact. © 2017 International Association for the Study of Lung Cancer

Background Anterior cruciate ligament (ACL) reconstruction using hamstring graft or bone-patella-bone graft results in the accumulation of bone debris within the knee joint. This has been identified as a causative factor in post-operative complications, including knee effusion and osteophyte generation. This technical note describes a technique aiming to reduce the accumulation of bone debris within the knee joint following ACL reconstruction. Method Following creation of the femoral tunnel using a retrograde reamer during ACL reconstruction, the reamer is removed and the femoral tunnel guide left in place. In the attempt to reduce the presence of bone debris, a 20 ml syringe of sterile saline is then injected at high pressure through the guide and femoral tunnel from outside to in. Results In our experience, this additional operative step significantly reduced the accumulation of bone debris within the femoral canal during ACL reconstruction. Conclusions We conclude that this simple additional step can reduce bone debris left within the joint during ACL reconstruction.

The intermeniscal ligament is an anatomical structure which is a risk of damage during arthroscopic anterior cruciate ligament reconstruction. We present a simple technique to protect this structure during the procedure.

The transfer of retention times based on thermodynamic models between columns can aid in separation optimization and compound identification in gas chromatography. Although earlier investigations have been reported, this problem remains unsuccessfully addressed. One barrier is poor predictive accuracy when moving from a reference column or system to a new target column or system. This is attributed to challenges associated with the accurate determination of the effective geometric parameters of the columns. To overcome this, we designed least squares-based models that account for geometric parameters of the columns and thermodynamic parameters of compounds as they partition between mobile and stationary phases. Quasi-Newton-based algorithms were then used to perform the numerical optimization. In this first of three parts, the model used to determine the geometric parameters of the reference column and the thermodynamic parameters of compounds subjected to separation is introduced. As will be shown, the overall approach significantly improves the predictive accuracy and transferability of thermodynamic data (and retention times) between columns of the same stationary phase chemistry. The data required for the determination of the thermodynamic parameters and retention time prediction are obtained from fast and simple experiments. The proposed model and optimization algorithms were tested and validated using simulated and experimental data.

The transfer of thermodynamic parameters governing retention of a molecule in gas chromatography from a reference column to a target column is a difficult problem. Successful transfer demands a mechanism whereby the column geometries of both columns can be determined with high accuracy. This is the second part in a series of three papers. In Part I of this work we introduced a new approach to determine the actual effective geometry of a reference column and thermodynamic-based parameters of a suite of compounds on the column. Part II, presented here, illustrates the rapid estimation of the effective inner diameter (or length) and the effective phase ratio of a target column. The estimation model based on the principle of least squares; a fast Quasi-Newton optimization algorithm was developed to provide adequate computational speed. The model and optimization algorithm were tested and validated using simulated and experimental data. This study, together with the work in Parts I and III, demonstrates a method that improves the transferability of thermodynamic models of gas chromatography retention between gas chromatography columns.

Objectives This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype–guided antiplatelet therapy after percutaneous coronary intervention (PCI). Background CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. Methods After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. Results Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). Conclusions These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.

Background Clostridium thermocellum is a promising microorganism for conversion of cellulosic biomass to biofuel, without added enzymes; however, the low ethanol titer produced by strains developed thus far is an obstacle to industrial application. Results Here, we analyzed changes in the relative concentration of intracellular metabolites in response to gradual addition of ethanol to growing cultures. For C. thermocellum, we observed that ethanol tolerance, in experiments with gradual ethanol addition, was twofold higher than previously observed in response to a stepwise increase in the ethanol concentration, and appears to be due to a mechanism other than mutation. As ethanol concentrations increased, we found accumulation of metabolites upstream of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) reaction and depletion of metabolites downstream of that reaction. This pattern was not observed in the more ethanol-tolerant organism Thermoanaerobacterium saccharolyticum. We hypothesize that the Gapdh enzyme may have different properties in the two organisms. Our hypothesis is supported by enzyme assays showing greater sensitivity of the C. thermocellum enzyme to high levels of NADH, and by the increase in ethanol tolerance and production when the T. saccharolyticum gapdh was expressed in C. thermocellum. Conclusions We have demonstrated that a metabolic bottleneck occurs at the GAPDH reaction when the growth of C. thermocellum is inhibited by high levels of ethanol. We then showed that this bottleneck could be relieved by expression of the gapdh gene from T. saccharolyticum. This enzyme is a promising target for future metabolic engineering work. Electronic supplementary material The online version of this article (10.1186/s13068-017-0961-3) contains supplementary material, which is available to authorized users.

The crystal structure of the GH78 family α-rhamnosidase from Klebsiella oxytoca (KoRha) has been determined at 2.7 A resolution with rhamnose bound in the active site of the catalytic domain. Curiously, the putative catalytic acid, Asp 222, is preceded by an unusual non-proline cis-peptide bond which helps to project the carboxyl group into the active centre. This KoRha homodimeric structure is significantly smaller than those of the other previously determined GH78 structures. Nevertheless, the enzyme displays α-rhamnosidase activity when assayed in vitro, suggesting that the additional structural domains found in the related enzymes are dispensible for function. Proteins 2015; 83:1742–1749. © 2015 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.

Testis cancer is the most commonly diagnosed cancer in young men. Most cases represent sporadic occurrences. Most commonly it presents at an early stage (clinical stage I) and is highly curable with radical orchiectomy. Even more advanced stages of testicular cancer are curable with a multimodality treatment approach. There are no widely accepted screening strategies for germ cell tumors. This article discusses the known risk factors and epidemiology of testis cancer, the presentation, and work up for new patients, and the prognosis and cure rates based on the staging and current treatment modalities for testis cancer patients.

The Washington family struggled financially in the years following the untimely death of George's father, Augustine, in 1743. Accordingly, they invested in social strategies that allowed the family to compensate for their economic stress by demonstrating gentility, displays of refined etiquette, and fashionable apparel. A gentleman's hair was a crucial component of these efforts. George and his three brothers each found ways to express their status through their respective hair styles which is reflected by the recovery of 209 wig hair curlers from George's boyhood home (Ferry Farm, Fredericksburg, Virginia). The spatial distribution of these curlers reflects activity areas related to wig hair maintenance. Some of the curlers exhibited preserved residue from this maintenance. Infrared spectroscopy and X-ray fluorescence were used to examine residues on the ceramic curlers. Evidence for two types of hair powder was documented on three different curlers. One consisted of lime plaster and starch and the other of calcium carbonate and kaolin clay. Both of these recipes reflect an effort to economize costs associated with hair dressing and demonstrate the thriftiness of the mid-eighteenth century Washington family hair budget.

Objective: Development of a model for the prediction of δ13Cprotein from δ13Ccollagen and Δ13Cap-co. Model-generated values could, in turn, serve as “consumer” inputs for multisource mixture modeling of paleodiet. Methods: Linear regression analysis of previously published controlled diet data facilitated the development of a mathematical model for predicting δ13Cprotein (and an experimentally generated error term) from isotopic data routinely generated during the analysis of osseous remains (δ13Cco and Δ13Cap-co). Results: Regression analysis resulted in a two-term linear model (δ13Cprotein (%) = (0.78 × δ13Cco) − (0.58× Δ13Cap-co) − 4.7), possessing a high R-value of 0.93 (r2 = 0.86, P < 0.01), and experimentally generated error terms of ±1.9% for any predicted individual value of δ13Cprotein. This model was tested using isotopic data from Formative Period individuals from northern Chile's Atacama Desert. Conclusions: The model presented here appears to hold significant potential for the prediction of the carbon isotope signature of dietary protein using only such data as is routinely generated in the course of stable isotope analysis of human osseous remains. These predicted values are ideal for use in multisource mixture modeling of dietary protein source contribution. Am J Phys Anthropol 157:694–703, 2015. © 2015 Wiley Periodicals, Inc.

New structures of the N-terminal 43 kDa fragment of the E. coli DNA gyrase B subunit reveal two discrete monovalent cation-binding sites that could have functional roles., Four new crystal structures of the ATPase domain of the GyrB subunit of Escherichia coli DNA gyrase have been determined. One of these, solved in the presence of K+, is the highest resolution structure reported so far for this domain and, in conjunction with the three other structures, reveals new insights into the function of this domain. Evidence is provided for the existence of two monovalent cation-binding sites: site 1, which preferentially binds a K+ ion that interacts directly with the α-phosphate of ATP, and site 2, which preferentially binds an Na+ ion and the functional significance of which is not clear. The crystallographic data are corroborated by ATPase data, and the structures are compared with those of homologues to investigate the broader conservation of these sites.

Ceramic-on-metal (CoM) is a relatively new bearing combination for total hip arthroplasty (THA) with few reported outcomes. A total of 287 CoM THAs were carried out in 271 patients (mean age 55.6 years (20 to 77), 150 THAs in female patients, 137 in male) under the care of a single surgeon between October 2007 and October 2009. With the issues surrounding metal-on-metal bearings the decision was taken to review these patients between March and November 2011, at a mean follow-up of 34 months (23 to 45) and to record pain, outcome scores, radiological analysis and blood ion levels. The mean Oxford Hip Score was 19.2 (12 to 53), 254 patients with 268 hips (95%) had mild/very mild/no pain, the mean angle of inclination of the acetabular component was 44.8o (28o to 63o), 82 stems (29%) had evidence of radiolucent lines of > 1 mm in at least one Gruen zone and the median levels of cobalt and chromium ions in the blood were 0.83 μg/L (0.24 μg/L to 27.56 μg/L) and 0.78 μg/L (0.21 μg/L to 8.84 μg/L), respectively. The five-year survival rate is 96.9% (95% confidence interval 94.7% to 99%). Due to the presence of radiolucent lines and the higher than expected levels of metal ions in the blood, we would not recommend the use of CoM THA without further long-term follow-up. We plan to monitor all these patients regularly. Cite this article: Bone Joint J 2015;97-B:300–5.

More than three decades ago the idea of using ambient water diffusion on manufactured glasses as an archeological dating method was proposed for historic period artifacts. In this study, we use infrared spectroscopy (FTIR) and secondary ion mass spectrometry (SIMS) to model water diffusion into the surface of two soda-lime glasses that differ principally in the alumina and magnesium content. Lower temperature hydration experiments (60–140 °C) were conducted and the surface diffused water was measured by infrared absorption, transflectance, and reflectance spectroscopy to establish the diffusion coefficients and activation energies, and to investigate the change in glass surface structure with time at a constant temperature. SIMS was also used to document water diffusion within a sample recovered from a 19th century archeological slave quarters at Thomas Jefferson's Monticello plantation in Virginia, USA.

Load carriage is recognised as a primary occupational factor leading to slip and fall injuries, and therefore assessing balance maintenance during such tasks is critical in assessing injury risk. Ten males completed 55 strides under five carriage conditions: (1) unassisted anterior, (2) unassisted posterior, (3) assisted anterior, (4) assisted posterior and (5) unloaded gait (UG). Kinematic data were recorded from markers affixed to landmarks on the right side of each participant, in order to calculate segment angles for the foot, shank, thigh and pelvis. Continuous relative phase (CRP) variability was calculated for each segment pair and local dynamic stability was calculated for each segment in all three movement planes. In general, irrespective of the assistive device or movement plane, anterior load carriage was most stable (lower CRP variability and maximum finite-time Lyapunov exponents). Moreover, load carriage was less dynamically stable than UG, displaying the importance of objectively investigating safe load carriage practices.Dynamical systems analyses were used to comprehensively evaluate the stability of various handheld load carriage methods. In general, anterior load carriage was significantly more stable than posterior load carriage,Mover's assistive device had small but beneficial effects on stability, and load carriage was less stable than UG.

Objectives To determine the costs of treatment and the duration of survival, adjusted for quality of life, for patients with muscle-invasive bladder cancer treated with immediate radical cystectomy (RC) or with neoadjuvant chemotherapy (NAC) with intent for subsequent RC. Methods and materials A retrospective review of our institutional review board–approved database identified patients with muscle-invasive bladder cancer treated at our institution from 2004 to 2011. Patients were divided into those receiving RC alone and those receiving NAC before planned RC. Patients who refused RC following NAC were included in an intention-to-treat analysis. Survival duration was converted to quality-adjusted life years (QALYs), and costs of treatment per QALY were determined. Results A total of 119 patients (65.4%) received RC alone and 63 (34.6%) received NAC, 38 of whom proceeded to cystectomy as planned. Mean total costs were $42,890 and $52,429 for RC and NAC, respectively (P = 0.005). The 5-year overall survival was 31.7% and 42.5% for the RC-only group and the NAC group, respectively (P = 0.034). The 5-year overall survival measured in QALYs was 21.9% and 42.9% for the RC-only and the NAC groups, respectively (P = 0.021). The increased cost for NAC was $5,840 per additional life year gained (95% CI: $1,772–$9,909) and $6,187 per additional QALY gained (95% CI: $1,877–$10,498). Conclusions The use of NAC is associated with a significant increase in quality-adjusted survival. The additional cost per QALY gained is approximately $6,000. The cost-utility analysis of NAC compares favorably with other cancer-specific therapies.

The carbon skeleton of ecologically and pharmacologically important iridoid monoterpenes is formed in a reductive cyclization reaction unrelated to canonical terpene cyclization. Here we report the crystal structure of the recently discovered iridoid cyclase (from Catharanthus roseus) bound to a mechanism-inspired inhibitor that illuminates substrate binding and catalytic function of the enzyme. Key features that distinguish iridoid synthase from its close homolog progesterone 5 beta-reductase are highlighted.

The GH94 glycoside hydrolase cellodextrin phosphorylase (CDP, EC 2.4.1.49) produces cellodextrin oligomers from short β-1→4-glucans and α-D-glucose 1-phosphate. Compared to cellobiose phosphorylase (CBP), which produces cellobiose from glucose and α-D-glucose 1-phosphate, CDP is biochemically less well characterised. Herein, we investigate the donor and acceptor substrate specificity of recombinant CDP from Ruminiclostridium thermocellum and we isolate and characterise a glucosamine addition product to the cellobiose acceptor with the non-natural donor α-D-glucosamine 1-phosphate. In addition, we report the first X-ray crystal structure of CDP, along with comparison to the available structures from CBPs and other closely related enzymes, which contributes to understanding of the key structural features necessary to discriminate between monosaccharide (CBP) and oligosaccharide (CDP) acceptor substrates., Graphical abstract Image 1, Highlights • Screening of CDP activity against a variety of donors and acceptors. • GlcN-1-P acts as CDP donor and generates a single turnover product. • Xyl-1-P and Man-1-P are poor donors but competitive inhibitors of CDP. • Oligosaccharides with GlcN and Xyl at the non-reducing end are good CDP acceptors. • The apo structure of CDP and its complex with cellotetraose and Pi have been resolved.

The incongruity between the small and apparently impoverished Rapa Nui population that early European travelers encountered and the magnificence of its numerous and massive stone statues has fed a deep fascination with the island. Ethnographic and archaeological evidence suggest that the indigenous population was previously greater than the estimated 1,500–3,000 individuals observed by visitors in the eighteenth century. Our goal was to determine the maximum population that might have lived on the island by estimating its agricultural productivity in the time before European contact. To determine the agricultural potential of the island we sampled soils and established six weather stations in diverse contexts and recorded data over a 2-year period. We find that the island is wetter on average than previously believed. We also find that rainfall and temperature respond linearly to elevation, but a spatial model of precipitation requires correction for a rain shadow effect. We adapted to Rapa Nui an island-wide spatial model designed to identify agriculturally viable zones elsewhere in Polynesia. Based on functions relating climate and substrate age to measurements of soil base saturation, we identified 3,134 ha that were suitable for traditional dryland sweet potato cultivation, or about 19% of the 164 km2 island. We used a nutrient-cycling model to estimate yields. Modeled yields are highly sensitive to nitrogen (N) inputs and reliable estimates of these rates are unavailable, requiring us to bracket the rate of N inputs. In the case of low N availability, yields under continuous cultivation were very small, averaging 1.5 t/ha of wet sweet potato tuber. When the N fixation rate was quadrupled sustainable yields increased to 5.1 t/ha. In each N scenario we used a model of food-limited demography to examine the consequences of altering agricultural practices, the labor supply, the ability of the population to control its fertility, and the presence or absence of surplus production to support social inequalities. In the low-N case viable populations average approximately 3,500 individuals across all parameter combinations, vs. 17,500 in the high-N case, although sustainable populations in excess of 25,000 were possible under some assumptions.

We examined the hypothesis that skilled performance is monitored on the basis of fluency, where fluency is operationally defined as temporal regularity or rhythmicity rather than speed. Since error is often associated with variable timing, we tested the possibility that people use varied timing as a metacognitive cue. Using a sequential counting task, which may be representative of the broader class of skilled, multi-step tasks, we found that shifting between irregular and regular timing led to greater confidence ratings when the timing associated with the task was regular. We argue that regular, consistent timing, when compared directly to irregular timing, produced feelings of fluent task performance, leading to increased confidence. In the first experiment, we demonstrated that both accuracy and confidence were higher when participants completed a task presented with regular timing. In the second experiment, we found a dissociation between accuracy and confidence, strengthening the argument that individuals relied on monitoring of fluency to support their metacognitive judgments. In Study 3 and an assessment of naive beliefs, we ruled out alternative explanations for these findings.

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and are commonly used for pain relief and fever reduction. NSAIDs are used following childhood vaccinations and cancer immunotherapies; however, how NSAIDs influence the development of immunity following these therapies is unknown. We hypothesized that NSAIDs would modulate the development of an immune response to Listeria monocytogenes-based immunotherapy. Treatment of mice with the non-specific COX-inhibitor, indomethacin, impaired the generation of cell-mediated immunity. This phenotype was due to inhibition of the inducible COX-2 enzyme as treatment with the COX-2-selective inhibitor Celecoxib similarly inhibited the development of immunity. In contrast, loss of COX-1 activity improved immunity to L. monocytogenes. Impairments in immunity were independent of bacterial burden, dendritic cell co-stimulation, or innate immune cell infiltrate. Instead, we observed prostaglandin E(2) (PGE(2)) production following L. monocytogenes is critical for the formation of an antigen-specific CD8+ T-cell response. Use of the alternative analgesic acetaminophen did not impair immunity. Taken together, our results suggest that COX-2 is necessary for optimal CD8+ T-cell responses to L. monocytogenes while COX-1 is detrimental. Use of pharmacotherapies that spare COX-2 activity and the production of PGE(2) like acetaminophen will be critical for the generation of optimal anti-tumor responses using L. monocytogenes.

Quantum states superposed across multiple particles or degrees of freedom are of crucial importance for the development of quantum technologies. Creating these states deterministically and with high effciency is an ongoing challenge. A promising approach is the repeated excitation of multi-level quantum emitters, which have been shown to naturally generate light with quantum statistics. Here we describe how to create one class of higher dimensional quantum state, a so called W-state, which is superposed across multiple time bins. We do this by repeated Raman scattering of photons from a charged quantum dot in a pillar microcavity. We show this method can be scaled to larger dimensions with no reduction in coherence or single photon character. We explain how to extend this work to enable the deterministic creation of arbitrary time-bin encoded qudits., 6 pages, 4 figures

To better control gastrointestinal nematode infections in humans and animals, it is important to understand the strategies used by these parasites to modulate the host immune system. In this regard, molecules released by parasites have been attributed crucially important roles in host-parasite negotiations. We characterized the excretory/secretory (E/S) microRNA (miRNA) and protein profiles from the mouse gastrointestinal nematode parasite Trichuris muris. Released miRNAs were subjected to miRNA sequencing and E/S proteins were analysed by mass spectrometry. Fourteen miRNAs were identified in T. muris exosome-like vesicles, as well as 73 proteins of nematode origin, 11 of which were unique to this study. Comparison with published nematode protein secretomes revealed high conservation at the functional level.

Shale development – extraction of oil and gas from shale rock formations using hydraulic fracturing or ‘fracking’ – has become a critical focus for energy debates in the US and UK. In both countries, potential industry expansion into new areas for shale extraction is expected to produce a wide range of environmental and social impacts and to change the configuration of future energy systems. To engage with emergent views on these complex, multi-scale issues, we held a series of day-long deliberation workshops (two in the US and two in the UK) designed and facilitated for diverse groups of people to discuss a range of possible consequences and meanings of shale development. Amid nuanced differences between and within national contexts, notable similarities in views were tracked across all four workshops. Concerns in common were not limited to specific risks such as water contamination. Participants also questioned whether shale development was compatible with their visions for and concerns about the longer-term future – including views on impacts and causes of climate change, societal dependency on fossil fuels, development of alternative energy technologies, the perceived short-term objectives of government and industry agencies, and obligations to act responsibly toward future generations. Extending prior qualitative research on shale development and on energy systems change, this research brings open-ended and cross-national public deliberation inquiry to bear on broader issues of climate change, responsibility, and ideas about how shale development might undermine or reinforce the energy systems that people consider important for the future.

Effective regulation of primary carbon metabolism is critically important for bacteria to successfully adapt to different environments. We have identified an uncharacterised transcriptional regulator; RccR, that controls this process in response to carbon source availability. Disruption of rccR in the plant-associated microbe Pseudomonas fluorescens inhibits growth in defined media, and compromises its ability to colonise the wheat rhizosphere. Structurally, RccR is almost identical to the Entner-Doudoroff (ED) pathway regulator HexR, and both proteins are controlled by the same ED-intermediate; 2-keto-3-deoxy-6-phosphogluconate (KDPG). Despite these similarities, HexR and RccR control entirely different aspects of primary metabolism, with RccR regulating pyruvate metabolism (aceEF), the glyoxylate shunt (aceA, glcB, pntAA) and gluconeogenesis (pckA, gap). RccR displays complex and unusual regulatory behaviour; switching repression between the pyruvate metabolism and glyoxylate shunt/gluconeogenesis loci depending on the available carbon source. This regulatory complexity is enabled by two distinct pseudo-palindromic binding sites, differing only in the length of their linker regions, with KDPG binding increasing affinity for the 28 bp aceA binding site but decreasing affinity for the 15 bp aceE site. Thus, RccR is able to simultaneously suppress and activate gene expression in response to carbon source availability. Together, the RccR and HexR regulators enable the rapid coordination of multiple aspects of primary carbon metabolism, in response to levels of a single key intermediate., Author summary Here we show how Pseudomonas controls multiple different primary carbon metabolism pathways by sensing levels of KDPG, an Entner Doudoroff (ED) pathway intermediate. KDPG binds to two highly similar transcription factors; the ED regulator HexR and the previously uncharacterised protein RccR. RccR inversely controls the glyoxylate shunt, gluconeogenesis and pyruvate metabolism, suppressing the first two pathways as pyruvate metabolism genes are expressed, and vice versa. This complex regulation is enabled by two distinct RccR-binding consensus sequences in the RccR regulon promoters. KDPG binding simultaneously increases RccR affinity for the glyoxylate shunt and gluconeogenesis promoters, and releases repression of pyruvate metabolism. This elegant two-regulator circuit allows Pseudomonas to rapidly respond to carbon source availability by sensing a single key intermediate, KDPG.

Pyruvate kinase (PKLR) deficiency protects mice and humans against blood-stage malaria. Although mouse strain AcB62 carries a malaria-protective PklrI90N genetic mutation, it is phenotypically susceptible to blood stage malaria induced by infection with Plasmodium chabaudi AS, suggesting a genetic modifier of the PklrI90N protective effect. Linkage analysis in a F2 cross between AcB62 (PklrI90N) and another PK deficient strain CBA/Pk (PklrG338D) maps this modifier (designated Char10) to chromosome 9 (LOD = 10.8, 95% Bayesian CI = 50.7–75Mb). To study the mechanistic basis of the Char10 effect, we generated an incipient congenic line (Char10C) that harbors the Char10 chromosome 9 segment from AcB62 fixed on the genetic background of CBA/Pk. The Char10 effect is shown to be highly penetrant as the Char10C line recapitulates the AcB62 phenotype, displaying high parasitemia following P. chabaudi infection, compared to CBA/Pk. Char10C mice also display a reduction in anemia phenotypes associated with the PklrG338D mutation including decreased splenomegaly, decreased circulating reticulocytes, increased density of mature erythrocytes, increased hematocrit, as well as decreased iron overload in kidney and liver and decreased serum iron. Erythroid lineage analyses indicate that the number of total TER119+ cells as well as the numbers of the different CD71+/CD44+ erythroblast sub-populations were all found to be lower in Char10C spleen compared to CBA/Pk. Char10C mice also displayed lower number of CFU-E per spleen compared to CBA/Pk. Taken together, these results indicate that the Char10 locus modulates the severity of pyruvate kinase deficiency by regulating erythroid responses in the presence of PK-deficiency associated haemolytic anemia.

To determine whether rheumatoid arthritis disease activity correlates with changing weather conditions. A longitudinal analysis of 133 patients attending the Department of Rheumatology, Musgrave Park Hospital, Belfast was performed. Participants had a diagnosis of rheumatoid arthritis and were receiving subcutaneous anti-TNF therapy (Adalimumab or Etanercept) for a period of >6 months. Data were collected at five time points. This included tender joint count, swollen joint count, patient visual analogue score (VAS), erythrocyte sedimentation rate, C-reactive protein, VAS, and DAS-28 (Disease Activity Score). Each weather factor (maximum, minimum temperature, pressure, rainfall, sunshine, humidity, and wind-speed) was analysed against each patients' DAS-28 score at five time points, using an analysis of covariance. A significant correlation was noted between low DAS-28 and increased hours of sunshine (p < 0.001). Sunny conditions were associated with a DAS-28 reduction of 0.037 (95 % CI -0.059, -0.016) p < 0.001. A significant correlation between humidity and DAS-28 was also noted (p = 0.016). Increased humidity was associated with an increased DAS-28 of 0.007 (95 % CI 0.001, 0.013) p = 0.016. Higher temperatures were associated with a non-significant decrease in DAS-28 (p = 0.16). In this study, rheumatoid arthritis disease activity (as measured by DAS-28) was significantly lower in both more sunny and less humid conditions.

On Rapa Nui (Easter Island), four geological sources of rhyolitic obsidian were utilised to manufacture obsidian artefacts, including tanged implements known as mata‘a . In the present study, a total of 332 mata‘a from the collections of Bishop Museum were analysed using portable X-ray fluorescence (pXRF). Two analytical methods, Discriminant Function Analysis and Support Vector Machines Classification, were used to assign geographical provenance to these artefacts. These appear to be manufactured using obsidians predominantly from Orito, one of four geological sources on the island. This study demonstrates how non-destructive analyses of museum collections can contribute to our understanding of obsidian procurement and production on Rapa Nui.

Sacred sites and traditional cultural properties are crucial to the preservation of indigenous peoples’ culture and society, and are increasingly recognised by international and state law and non-governmental entities. This article explores the various legal and non-legal documents addressing sacred sites and traditional cultural properties, and the duties and responsibilities imposed on businesses involved in the resource extraction industries: conducting consultation with affected indigenous peoples and obtaining, at times, their free, prior and informed consent for the project. While by no means exhaustive, this broad survey encompasses laws and court decisions from international bodies, the United States and examples from other countries, international guidelines, industry standards and laws of indigenous peoples. It concludes that conducting good faith, socially appropriate and respectful consultation with indigenous peoples prior to conducting extraction activities that will or may affect sacred sit...

Hydration rate development on obsidians within the laboratory has become the preferred calibration procedure for the obsidian dating method. A fundamental assumption of this calibration procedure has been that water concentration within the hydration layer is at equilibrium with regard to the experimental partial pressure. Our analysis of hydration layers from short-term low temperature (110–150 °C) experiments reveal that water densities decrease with higher temperature and have not reached equilibrium. This may result in non-representative activation energies for archaeological samples. Longer experimental periods will be required to obtain hydration layers that can be used for a correct calibration.