Novel or unusual magnetism is a subject of considerable interest, particularly in metals and degenerate semiconductors. In such materials the interplay of magnetism, transport and other Fermi liquid properties can lead to fascinating physical behavior. One example is in magnetic semiconductors, where spin polarized currents may be controlled and used. We report density functional calculations predicting magnetism in doped semiconducting β-FeSi2 and CrSi2 at relatively low doping levels particularly for n-type. In this case, there is a rapid cross-over to a half-metallic state as a function of doping level. The results are discussed in relation to the electronic structure and other properties of these compounds.
We present an analysis of the thermoelectric properties of of n-type GeTe and SnTe in relation to the lead chalcogenides PbTe and PbSe. We find that the singly degenerate conduction bands of semiconducting GeTe and SnTe are highly non-ellipsoidal, even very close to the band edges. This leads to isoenergy surfaces with a strongly corrugated shape that is clearly evident at carrier concentrations well below 0.005 e per formula unit (7–9 × 1019 cm−3 depending on material). Analysis within Boltzmann theory suggests that this corrugation may be favorable for the thermoelectric transport. Our calculations also indicate that values of the power factor for these two materials may well exceed those of PbTe and PbSe. As a result these materials may exhibit n-type performance exceeding that of the lead chalcogenides.
The position of the femoral component in a TKA in the axial plane influences patellar tracking and flexion gap symmetry. Errors in femoral component rotation have been implicated in the need for early revision surgery. Methods of guiding femoral component rotation at the time of implantation typically are derived from the mean position of the flexion-extension axis across experimental subjects. The functional flexion axis (FFA) of the knee is kinematically derived and therefore a patient-specific reference axis that can be determined intraoperatively by a computer navigation system as an alternative method of guiding femoral component rotation. However, it is unclear whether the FFA is reliable and how it compares with traditional methods.
We asked if the FFA could be measured reproducibly at different stages of the operative procedure; (2) where it lies in relation to a CT-derived gold standard; and (3) how it compares with more traditional methods of judging femoral component rotation.
Thirty-seven patients undergoing elective TKAs were recruited to the study. Preoperative CT scans were obtained and the transepicondylar axis (TEA) was identified. The TKA then was performed using computer navigation. The FFA was derived before incision and again after the surgical approach and osseous registration. The navigation system was used to register the surgical TEA. The FFA and surgical TEA then were compared with the CT-derived TEA.
The mean preincision FFA was similar to the intraoperative FFA and therefore deemed reproducible. We observed no differences in variability between surgical TEA and preincision FFA. The FFA was different from the CT-TEA and judged similar in accuracy to the surgical TEA.
The reliability and accuracy of the FFA were similar to those of other intraoperative methods. Further evaluation is required to ascertain whether the FFA improves on currently available methods for determining the ideal rotation of the femoral component during TKA.
Flexion contracture has been shown to impair function and reduce satisfaction following total knee arthroplasty (TKA). The aim of this study was to identify modifiable intra-operative variables that predict post-TKA knee extension.
Data was collected prospectively on 95 patients undergoing total knee arthroplasty, including pre-operative assessment, intra-operative computer assisted surgery (CAS) measurements and functional outcome including range of motion at one year. Patients were divided into two groups: those with mild flexion contracture (> 5°) at the one-year follow-up and those achieving full extension.
The sagittal orientation of the distal femoral cut differed significantly between groups at the one-year follow-up (p = 0.014). Sagittal alignment of greater than 3.5° from the mechanical axis was shown to increase the relative risk of a mild flexion contracture at one-year follow-up by 2.9 times, independent of other variables.
Increasing the sagittal alignment of the distal femoral cut more than 3.5° from the mechanical axis is an independent risk factor for clinically detectable flexion contracture one year from index procedure.
Ratiometric methods of analysis have been developed for the selective determination of lactate or citrate in microlitre samples of human serum, urine or prostate fluids following comparison of anion binding affinities for a family of nine luminescent europium(III) complexes.
The movement of energy and nutrients from aquatic to terrestrial ecosystems can be substantial, and emergent aquatic insects can serve as biovectors not only for nutrients, but also for contaminants present in the aquatic environment. The terrestrial predators Tenodera aridifolia sinensis (Mantodea: Mantidae) and Tidarren haemorrhoidale (Araneae: Theridiidae) and the aquatic predator Buenoa scimitra (Hemiptera: Notonectidae) were chosen to evaluate the efficacy of arsenic transfer between aquatic and terrestrial environments. Culex tarsalis larvae were reared in either control water or water containing 1000 µg l−1 arsenic. Adults that emerged from the control and arsenic treatments were fed to the terrestrial predators, and fourth instar larvae were fed to the aquatic predator reared in control or arsenic contaminated water. Tenodera a. sinensis fed arsenic-treated Cx. tarsalis accumulated 658±130 ng g−1 of arsenic. There was no significant difference between control and arsenic-fed T. haemorrhoidale (range 142–290 ng g−1). Buenoa scimitra accumulated 5120±406 ng g−1 of arsenic when exposed to arsenic-fed Cx. tarsalis and reared in water containing 1000 µg l−1 arsenic. There was no significant difference between controls or arsenic-fed B. scimitra that were not exposed to water-borne arsenic, indicating that for this species environmental exposure was more important in accumulation than strictly dietary arsenic. These results indicate that transfer to terrestrial predators may play an important role in arsenic cycling, which would be particularly true during periods of mass emergence of potential insect biovectors. Trophic transfer within the aquatic environment may still occur with secondary predation, or in predators with different feeding strategies.
The classes and concentrations of volatile organic compounds (VOC) released from fresh and decaying strawberries were investigated and compared. In this study, a total of 147 strawberry volatiles were quantified before and after nine days of storage to explore differences in the aroma profile between fresh strawberries (storage days (SRD) of 0, 1, and 3) and those that had started to decay (SRD = 6 and 9). In terms of concentration, seven compounds dominated the aroma profile of fresh strawberries (relative composition (RC) up to 97.4% by mass, sum concentration): (1) ethyl acetate = 518 mg·m−3, (2) methyl acetate = 239 mg·m−3, (3) ethyl butyrate = 13.5 mg·m−3, (4) methyl butyrate = 11.1 mg·m−3, (5) acetaldehyde = 24.9 mg·m−3, (6) acetic acid = 15.2 mg·m−3, and (7) acetone = 13.9 mg·m−3. In contrast, two alcohols dominated the aroma profile of decayed samples (RC up to 98.6%): (1) ethyl alcohol = 94.2 mg·m−3 and (2) isobutyl alcohol = 289 mg·m−3. Alternatively; if the aroma profiles are re-evaluated by summing odor activity values (ΣOAV); four ester compounds ((1) ethyl butyrate (6,160); (2) ethyl hexanoate (3,608); (3) ethyl isovalerate (1,592); and (4) ethyl 2-methylbutyrate (942)) were identified as the key constituents of fresh strawberry aroma (SRD-0). As the strawberries began to decay; isobutyl alcohol recorded the maximum OAV of 114 (relative proportion (RP) (SRD = 6) = 58.3%). However, as the decay process continued, the total OAV dropped further by 3 to 4 orders of magnitude—decreasing to 196 on SRD = 6 to 7.37 on SRD = 9. The overall results of this study confirm dramatic changes in the aroma profile of strawberries over time, especially with the onset of decay.
fresh and decaying strawberry; strawberry fragrances; mass concentration; threshold; odor activity value (OAV)
Various analyses are applied to physiological signals. While epistemological diversity is necessary to address effects at different levels, there is often a sense of competition between analyses rather than integration. This is evidenced by the differences in the criteria needed to claim understanding in different approaches. In the nervous system, neuronal analyses that attempt to explain network outputs in cellular and synaptic terms are rightly criticized as being insufficient to explain global effects, emergent or otherwise, while higher-level statistical and mathematical analyses can provide quantitative descriptions of outputs but can only hypothesize on their underlying mechanisms. The major gap in neuroscience is arguably our inability to translate what should be seen as complementary effects between levels. We thus ultimately need approaches that allow us to bridge between different spatial and temporal levels. Analytical approaches derived from critical phenomena in the physical sciences are increasingly being applied to physiological systems, including the nervous system, and claim to provide novel insight into physiological mechanisms and opportunities for their control. Analyses of criticality have suggested several important insights that should be considered in cellular analyses. However, there is a mismatch between lower-level neurophysiological approaches and statistical phenomenological analyses that assume that lower-level effects can be abstracted away, which means that these effects are unknown or inaccessible to experimentalists. As a result experimental designs often generate data that is insufficient for analyses of criticality. This review considers the relevance of insights from analyses of criticality to neuronal network analyses, and highlights that to move the analyses forward and close the gap between the theoretical and neurobiological levels, it is necessary to consider that effects at each level are complementary rather than in competition.
neuronal network; criticality; spinal cord
Cytoskeletal motors drive the transport of organelles and molecular cargoes within cells1, and have potential applications in molecular detection and diagnostic devices2,3. Engineering molecular motors with dynamically controllable properties will allow selective perturbation of mechanical processes in living cells, and yield optimized device components for complex tasks such as molecular sorting and directed assembly3. Biological motors have previously been modified by introducing activation/deactivation switches that respond to metal ions4,5 and other signals6. Here we show that myosin motors can be engineered to reversibly change their direction of motion in response to a calcium signal. Building on previous protein engineering studies7–11 and guided by a structural model12 for the redirected power stroke of myosin VI, we constructed bidirectional myosins through the rigid recombination of structural modules. The performance of the motors was confirmed using gliding filament assays and single fluorophore tracking. Our general strategy, in which external signals trigger changes in the geometry and mechanics of myosin lever arms, should enable spatiotemporal control over a range of motor properties including processivity, stride size13, and branchpoint turning14.
CD40L is critically important for the initiation and maintenance of adaptive immune responses. It is generally thought that CD40L expression in CD4+ T cells is regulated transcriptionally and made from new mRNA following antigen recognition. However, recent studies with two-photon microscopy revealed that the majority of cognate interactions between effector CD4+ T cells and APCs are too short for de novo synthesis of CD40L. Given that effector and memory CD4+ T cells store preformed CD40L (pCD40L) in lysosomal compartments and that pCD40L comes to the cell surface within minutes of antigenic stimulation, we and others have proposed that pCD40L might mediate T cell-dependent activation of cognate APCs during brief encounters in vivo. However, it has not been shown that this relatively small amount of pCD40L is sufficient to activate APCs, owing to the difficulty of separating the effects of pCD40L from those of de novo CD40L and other cytokines in vitro. Here we show that pCD40L surface mobilization is resistant to cyclosporine or FK506 treatment, while de novo CD40L and cytokine expression are completely inhibited. These drugs thus provide a tool to dissect the role of pCD40L in APC activation. We find that pCD40L mediates selective activation of cognate but not bystander APCs in vitro and that mobilization of pCD40L does not depend on Rab27a, which is required for mobilization of lytic granules. Therefore, effector CD4+ T cells deliver pCD40L specifically to APCs on the same time scale as the lethal hit of CTLs but with distinct molecular machinery.
CD40L is essential for the development of adaptive immune responses. It is generally thought that CD40L expression in CD4+ T cells is regulated transcriptionally and made from new mRNA following antigen recognition. However, imaging studies show that the majority of cognate interactions between effector CD4+ T cells and APCs in vivo are too short to allow de novo CD40L synthesis. We previously showed that Th1 effector and memory cells store preformed CD40L (pCD40L) in lysosomal compartments and mobilize it onto the plasma membrane immediately after antigenic stimulation, suggesting that primed CD4+ T cells may use pCD40L to activate APCs during brief encounters. Indeed, our recent study showed that pCD40L is sufficient to mediate selective activation of cognate B cells and trigger DC activation in vitro. In this study, we show that pCD40L is present in Th1 and follicular helper T cells developed during infection with lymphocytic choriomeningitis virus, Th2 cells in the airway of asthmatic mice, and Th17 cells from the CNS of animals with experimental autoimmune encephalitis (EAE). pCD40L is nearly absent in both natural and induced Treg cells, even in the presence of intense inflammation such as occurs in EAE. We also found pCD40L expression in CD4 single positive thymocytes and invariant NKT cells. Together, these results suggest that pCD40L may function in T cell development as well as an unexpectedly broad spectrum of innate and adaptive immune responses, while its expression in Treg cells is repressed to avoid compromising their suppressive activity.
Designing correct, robust DNA devices is difficult because of the many possibilities for unwanted interference between molecules in the system. DNA strand displacement has been proposed as a design paradigm for DNA devices, and the DNA strand displacement (DSD) programming language has been developed as a means of formally programming and analysing these devices to check for unwanted interference. We demonstrate, for the first time, the use of probabilistic verification techniques to analyse the correctness, reliability and performance of DNA devices during the design phase. We use the probabilistic model checker prism, in combination with the DSD language, to design and debug DNA strand displacement components and to investigate their kinetics. We show how our techniques can be used to identify design flaws and to evaluate the merits of contrasting design decisions, even on devices comprising relatively few inputs. We then demonstrate the use of these components to construct a DNA strand displacement device for approximate majority voting. Finally, we discuss some of the challenges and possible directions for applying these methods to more complex designs.
DNA computing; formal verification; probabilistic model checking; DNA strand displacement
Commercial standard gas generators are often complex and expensive devices. The objective of this research was to assess the performance of a simplified glass impinger system for standard gas generation from a permeation tube (PT) device. The performance of the impinger standard gas generation system was assessed for four aromatic VOCs (benzene, toluene, ethylbenzene, and m-xylene; BTEX) at varying flow rates (FR) of 50 to 800 mL·min−1. Because actual permeation rate (APR) values deviated from those computed by the manufacturer's formula (MPR), new empirical relationships were developed to derive the predicted PR (PPR) of the target components. Experimental results corrected by such a formula indicate that the compatibility between the APR and MPR generally increased with low FR, while the reproducibility was generally reduced with decreasing flow rate. Although compatibility between different PRs is at a relatively small and narrow FR range, the use of correction formula is recommendable for the accurate use of PT.
impinge; permeation; benzene; toluene; ethylbenzene; xylene
Gradients of diffusible signaling proteins control precise spatial patterns of gene expression in the developing embryo. Here, we use quantitative expression measurements and thermodynamic modeling to uncover the cis-regulatory logic underlying spatially restricted gene expression in a Hedgehog (Hh) gradient in Drosophila. When Hh signaling is low, the Hh effector Gli, known as Cubitus interruptus (Ci) in Drosophila, acts as a transcriptional repressor; when Hh signaling is high, Gli acts as a transcriptional activator. Counterintuitively and in contrast to previous models of Gli-regulated gene expression, we found that low-affinity binding sites for Ci were required for proper spatial expression of the Hh target gene decapentaplegic (dpp) in regions of low Hh signal. Three low-affinity Ci sites enabled expression of dpp in response to low signal; increasing the affinity of these sites restricted dpp expression to regions of maximal signaling. A model incorporating cooperative repression by Ci correctly predicted the in vivo expression of a reporter gene controlled by a single Ci site. Our work clarifies how transcriptional activators and repressors, competing for common binding sites, can transmit positional information to the genome. It also provides an explanation for the widespread presence of conserved, nonconsensus Gli binding sites in Hh target genes.
A study examining demographics and hospital utilization for chronically homeless persons with disabilities was conducted at pre-housing enrollment and at 6 months post-housing. Of the 20 participants, 70% (n = 14) were Black American and 30% (n = 6) were White; 100% (n = 20) were non-Hispanic; 90% (n = 18) were men; 40% (n = 8) were veterans; Median years since last permanent housing and total homelessness were 7 and 10.5 respectively. The following increases were observed: employment (0 to 1); income (20%, n = 4 to 35%, n = 7); primary care (25%, n = 5 to 95%, n = 19); and mental health service use (25%, n = 5 to 60%, n = 12). Known disabilities included HIV (15%, n = 3); hepatitis C (45%, n = 9); mental illness (60%, n = 12) and substance abuse (80%, n = 16) with 45% (n = 9) dually diagnosed. Over the course of the study, Emergency department visits and inpatient hospitalization use decreased. While these differences were not statistically significant (p = 0.14 and p = 0.31, respectively), they translate to an estimated $250,208 savings.
Disability; Housing first; Chronic homeless
NF-κB–inducing kinase (NIK) is an essential upstream kinase
in noncanonical NF-κB signaling. NIK-dependent NF-κB
activation downstream of several TNF receptor family members mediates lymphoid organ
development and B cell homeostasis. Peripheral T cell populations are normal in the
absence of NIK, but the role of NIK during in vivo T cell responses to antigen has
been obscured by other developmental defects in NIK-deficient mice. Here, we have
identified a T cell–intrinsic requirement for NIK in graft-versus-host
disease (GVHD), wherein NIK-deficient mouse T cells transferred into MHC class II
mismatched recipients failed to cause GVHD. Although NIK was not necessary for
antigen receptor signaling, it was absolutely required for costimulation through the
TNF receptor family member OX40 (also known as CD134). When we conditionally
overexpressed NIK in T cells, mice suffered rapid and fatal autoimmunity
characterized by hyperactive effector T cells and poorly suppressive
Foxp3+ Tregs. Together, these data illuminate a critical T
cell–intrinsic role for NIK during immune responses and suggest that its
tight regulation is critical for avoiding autoimmunity.
Traditionally, clinical research studies rely on collecting data with case report forms, which are subsequently entered into a database to create electronic records. Although well established, this method is time-consuming and error-prone. This study compares four electronic data capture (EDC) methods with the conventional approach with respect to duration of data capture and accuracy. It was performed in a West African setting, where clinical trials involve data collection from urban, rural and often remote locations.
Three types of commonly available EDC tools were assessed in face-to-face interviews; netbook, PDA, and tablet PC. EDC performance during telephone interviews via mobile phone was evaluated as a fourth method. The Graeco Latin square study design allowed comparison of all four methods to standard paper-based recording followed by data double entry while controlling simultaneously for possible confounding factors such as interview order, interviewer and interviewee. Over a study period of three weeks the error rates decreased considerably for all EDC methods. In the last week of the study the data accuracy for the netbook (5.1%, CI95%: 3.5–7.2%) and the tablet PC (5.2%, CI95%: 3.7–7.4%) was not significantly different from the accuracy of the conventional paper-based method (3.6%, CI95%: 2.2–5.5%), but error rates for the PDA (7.9%, CI95%: 6.0–10.5%) and telephone (6.3%, CI95% 4.6–8.6%) remained significantly higher. While EDC-interviews take slightly longer, data become readily available after download, making EDC more time effective. Free text and date fields were associated with higher error rates than numerical, single select and skip fields.
EDC solutions have the potential to produce similar data accuracy compared to paper-based methods. Given the considerable reduction in the time from data collection to database lock, EDC holds the promise to reduce research-associated costs. However, the successful implementation of EDC requires adjustment of work processes and reallocation of resources.
Neuronal networks assemble the cellular components needed for sensory, motor and cognitive functions. Any rational intervention in the nervous system will thus require an understanding of network function. Obtaining this understanding is widely considered to be one of the major tasks facing neuroscience today. Network analyses have been performed for some years in relatively simple systems. In addition to the direct insights these systems have provided, they also illustrate some of the difficulties of understanding network function. Nevertheless, in more complex systems (including human), claims are made that the cellular bases of behaviour are, or will shortly be, understood. While the discussion is necessarily limited, this issue will examine these claims and highlight some traditional and novel aspects of network analyses and their difficulties. This introduction discusses the criteria that need to be satisfied for network understanding, and how they relate to traditional and novel approaches being applied to addressing network function.
neuronal network; network; microcircuit; brain; neural circuit; behaviour
Recently, there has been mounting interest in scaling-up vector control against malaria in Africa. It needs to be determined if indoor residual spraying (IRS with DDT) will provide significant marginal protection against malaria over current best practice of long-lasting insecticidal nets (LLINs) and prompt treatment in a controlled trial, given that DDT is currently the most persistent insecticide for IRS.
A 2 armed cluster-randomised controlled trial will be conducted to assess whether DDT IRS and LLINs combined provide better protection against clinical malaria in children than LLINs alone in rural Gambia. Each cluster will be a village, or a group of small adjacent villages; all clusters will receive LLINs and half will receive IRS in addition. Study children, aged 6 months to 13 years, will be enrolled from all clusters and followed for clinical malaria using passive case detection to estimate malaria incidence for 2 malaria transmission seasons in 2010 and 2011. This will be the primary endpoint. Exposure to malaria parasites will be assessed using light and exit traps followed by detection of Anopheles gambiae species and sporozoite infection. Study children will be surveyed at the end of each transmission season to estimate the prevalence of Plasmodium falciparum infection and the prevalence of anaemia.
Practical issues concerning intervention implementation, as well as the potential benefits and risks of the study, are discussed.
ISRCTN01738840 - Spraying And Nets Towards malaria Elimination (SANTE)
CD4+ T cell recognition of MHC:peptide complexes in the context of a costimulatory signal results in the large-scale redistribution of molecules at the T-APC interface to form the immunological synapse. The immunological synapse is the location of sustained TCR signaling and delivery of a subset of effector functions. T cells activated in the absence of costimulation are rendered anergic and are hyporesponsive when presented with antigen in the presence of optimal costimulation. Several previous studies have looked at aspects of immunological synapses formed by anergic T cells, but it remains unclear whether there are differences in the formation or composition of anergic immunological synapses. In this study we anergized primary murine CD4+ T cells by incubation of costimulation-deficient, transfected fibroblast APC. Using a combination of TCR, MHC:peptide, and ICAM-1 staining, we found that anergic T cells make mature immunological synapses with characteristic cSMAC and pSMAC domains that were indistinguishable from control synapses. There were small increases in total phosphotyrosine at the anergic synapse along with significant decreases in phosphorylated ERK 1/2 accumulation. Most striking, there was specific accumulation of c-Cbl and Cbl-b to the anergic synapses. Cbl-b, previously shown to be essential in anergy induction, was found in both the pSMAC and the cSMAC of the anergic synapse. This Cbl-b (and c-Cbl) accumulation at the anergic synapse may play an important role in anergy maintenance and/or induction.
Metal fabrication employs an estimated 3.1 million workers in the United States. The absence of machine guarding and related programs such as lockout/tagout may result in serious injury or death. The purpose of this study was to improve machine-related safety in small metal-fabrication businesses.
We used a randomized trial with two groups: management only and management-employee. We evaluated businesses for the adequacy of machine guarding (machine scorecard) and related safety programs (safety audit). We provided all businesses with a report outlining deficiencies and prioritizing their remediation. In addition, the management-employee group received four one-hour interactive training sessions from a peer educator.
We evaluated 40 metal-fabrication businesses at baseline and 37 (93%) one year later. Of the three nonparticipants, two had gone out of business. More than 40% of devices required for adequate guarding were missing or inadequate, and 35% of required safety programs and practices were absent at baseline. Both measures improved significantly during the course of the intervention. No significant differences in changes occurred between the two intervention groups. Machine-guarding practices and programs improved by up to 13% and safety audit scores by up to 23%. Businesses that added safety committees or those that started with the lowest baseline measures showed the greatest improvements.
Simple and easy-to-use assessment tools allowed businesses to significantly improve their safety practices, and safety committees facilitated this process.
The Nationwide Health Information Network allow for the secure exchange of Electronic Health Records over the Internet. The Department of Veterans Affairs, Department of Defense, and Kaiser Permanente, participated in an implementation of the NwHIN specifications in San Diego, California. This paper focuses primarily on patient involvement. Specifically, it describes how the shared patients were identified, were invited to participate and to provide consent for disclosing parts of their medical record, and were matched across organizations. A total 1,144 were identified as shared patients. Invitation letters containing consent forms were mailed and resulted in 42% participation. Invalid consent forms were a significant issue (25%). Initially, the identity matching algorithms yielded low success rate (5%). However, elimination of certain traits and abbreviations and probabilistic algorithms have significantly increased matching rate. Access to information from external sources better informs providers, improves decisions and efficiency, and helps meet the meaningful use criteria.
Experimental and computational approaches are needed to uncover the mechanisms by which molecular motors convert chemical energy into mechanical work. In this article, we describe methods and software to generate structurally realistic models of molecular motor conformations compatible with experimental data from different sources. Coarse-grained models of molecular structures are constructed by combining groups of atoms into a system of rigid bodies connected by joints. Contacts between rigid bodies enforce excluded volume constraints, and spring potentials model system elasticity. This simplified representation allows the conformations of complex molecular motors to be simulated interactively, providing a tool for hypothesis building and quantitative comparisons between models and experiments. In an example calculation, we have used the software to construct atomically detailed models of the myosin V molecular motor bound to its actin track. The software is available at www.simtk.org.
Molecular simulation; Myosin V; Protein kinematics; Open-source software