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Should teachers have complete autonomy over teaching methods and practices, or should some aspects of their practice be determined by school or government policy? We address this question using repeated (value‐added) maths test scores linked to rich survey data from the TALIS video study. With the possible exception of inexperienced teachers, we generally find no relationship between teacher autonomy and pupil outcomes (test scores, maths self‐efficacy or interest in maths). In partial contrast with our findings for pupil outcomes, teachers with very low levels of autonomy are more likely to report reduced job satisfaction. It may hence be that some level of restriction on teacher autonomy is justified, especially among inexperienced teachers, particularly when it represents only partial control of teachers' approaches in the classroom and is done to introduce evidence‐based methods. [ABSTRACT FROM AUTHOR]

We investigated the effects of two types of competition, races and tournaments (as well as an individual challenge and a do-your-best condition), on two different aspects of performance: effort and strategy. In our experiment, 100 undergraduate participants completed a simple cognitive task under four experimental conditions (in a repeated-measures design) based on different types of competitions and challenges. We used the Linear Ballistic Accumulator to quantify the effects of competition on strategy and effort. The results reveal that competition produced changes in strategy rather than effort, and that trait competitiveness had minimal impact on how people responded to competition. This suggests individuals are more likely to adjust their strategy in competitions, and the uncertainty created by different competition types influences the direction of these strategy adjustments. [ABSTRACT FROM AUTHOR]

We report experimental results on the diffractive imaging of three-dimensionally aligned 2,5-diiodothiophene molecules. The molecules were aligned by chirped near-infrared laser pulses, and their structure was probed at a photon energy of 9.5 keV (λ ≈ 130 pm) provided by the Linac Coherent Light Source. Diffracted photons were recorded on the Cornell–SLAC pixel array detector, and a two-dimensional diffraction pattern of the equilibrium structure of 2,5-diiodothiophene was recorded. The retrieved distance between the two iodine atoms agrees with the quantum-chemically calculated molecular structure to be within 5%. The experimental approach allows for the imaging of intrinsic molecular dynamics in the molecular frame, albeit this requires more experimental data, which should be readily available at upcoming high-repetition-rate facilities. [ABSTRACT FROM AUTHOR]

We examine the underlying cognitive mechanisms that govern how competitions play out over time. We used cognitive modeling to examine the dynamic effects of time remaining and relative performance (whether the person is winning or losing) on effort and strategy. In this experiment, participants completed a competitive decision-making task with varying time limits and starting scores, in a repeated-measures design. Participants were tasked with scoring more points than their computerized opponent during a certain time frame, gaining and losing points for correct and incorrect decisions, respectively. The results showed that as the competition deadline approached and as participants drew ahead of their opponent within a competition, they increased effort and became more cautious. Furthermore, the effect of relative score on effort and caution changed over the course of a competition as the deadline approached. These results highlight the importance of considering dynamics when working to understand how competitions unfold as well as the underlying cognitive mechanisms that give rise to the dynamic behavior. [ABSTRACT FROM AUTHOR]

Cell–cell signaling in microorganisms is still poorly characterized. In this Methods paper, we describe a genetic procedure for detecting cell-nonautonomous genetic effects, and in particular cell–cell signaling, termed the chimeric colony assay (CCA). The CCA measures the effect of a gene on a biological response in a neighboring cell. This assay can measure cell autonomy for range of biological activities including transcript or protein accumulation, subcellular localization, and cell differentiation. To date, the CCA has been used exclusively to investigate colony patterning in the budding yeast Saccharomyces cerevisiae. To demonstrate the wider potential of the assay, we applied this assay to two other systems: the effect of Grr1 on glucose repression of GAL1 transcription in yeast and the effect of rpsL on stop-codon translational readthrough in Escherichia coli. We also describe variations of the standard CCA that address specific aspects of cell–cell signaling, and we delineate essential controls for this assay. Finally, we discuss complementary approaches to the CCA. Taken together, this Methods paper demonstrates how genetic assays can reveal and explore the roles of cell–cell signaling in microbial processes. [ABSTRACT FROM AUTHOR]

Developmental trajectories regarding the age onset of violence and offending have not routinely considered the role of major mental illness (MMI). In parallel, despite several studies investigating the relationship between MMI, violence and offending, fewer have identified motivational processes that may link illness to these outcomes in a more direct and proximal manner. This study investigates whether subtypes of forensic psychiatric patients deemed Not Criminally Responsible on account of Mental Disorder (N = 91) can be identified based on the age onset of mental illness and offending behavior, and whether information on motivational influences for offending—elicited both from the patient directly and detailed collateral information—contributes to the clinical utility of this typology. Results indicated that most patients reported engaging in violence (51%) or antisocial behaviors (72%) prior to the onset of MMI, but that the index offense(s) resulting in forensic admission were predominantly psychotically motivated. In contrast to patients for whom the onset of MMI occurred prior to offending, patients exhibiting premorbid violence had higher levels of risk and criminogenic need; they were more likely to be diagnosed with personality and substance use disorders, and to have conventional (i.e., non-illness-related) motivations ascribed to their index offense. Findings are consistent with the existing literature regarding subgroups of mentally disordered offenders, but provide new information regarding proximal risk factors for violence through better identification of motivational processes. [ABSTRACT FROM AUTHOR]

Learning accurate representations of robot models remains a challenging problem, and is typically approached though large, system-specific feature sets. This method inherently introduces practical shortcomings, as interpretability and transferability of the learned model typically decreases as more features are introduced into the learning framework in order to handle increasing task complexity. In this article, we examine the problem of developing transferable learned models for dexterous manipulation that are able to accurately predict the behavior of physically distinct systems without retraining. We introduce the notion of learning from visually-extracted grasp mechanics-based features, which are formulated by combining geometrically-inspired, analytical representations of the gripper into the feature set to more holistically represent the state of varied systems performing manipulation. We characterize the added utility of using such features through simulation and incorporate them into a classifier to predict specific phenomena, or modes of manipulation, that occur during prehensile within-hand movement. Four modes of manipulation—normal (rolling contact), drop, stuck, and sliding—are defined, collected physically, and trained via a self-supervised learning approach. The classifier is first trained on a single sensorless underactuated hand variant for all four modes. We, then, investigate the transferability of the learned classifier on five different planar gripper variants—analyzing applicability of this approach with both online and offline evaluation. [ABSTRACT FROM AUTHOR]

Dystonia is a chronic and incurable movement disorder. This qualitative study aimed to enhance understanding of the condition by exploring the experience of living with dystonia. Interpretative phenomenological analysis was used to analyse data gathered through semi-structured interviews. Eight participants were recruited via a UK-based dystonia charity. Three superordinate themes emerged from the data: (1) dealing with ignorance and uncertainty: navigating health services with a rare, poorly understood condition; (2) the challenge of social isolation: overcoming barriers to positive social identity; and (3) fear of psychological explanations: the impact of stigmatised attitudes towards psychological explanations for dystonia symptoms. Coping with a rare and chronic condition led to participants feeling isolated and stigmatised by health care services and their communities. Participants were able to overcome this challenge to their identities through the use of social support, particularly from other people with dystonia. Recommendations for reducing the stigmatising experiences of people with dystonia can help to ease the process of adjustment to the illness and enable people to pursue meaningful lives and positive identities. Recommendations for research are aimed at increasing knowledge about these processes. Dystonia has a pervasive, negative impact on the lives of people with the condition. The struggle for diagnosis marks the beginning of a period of psychological adjustment, the difficulty of which is compounded by social isolation and stigma. Support groups and peer interaction help people to integrate dystonia into their concept of a meaningful life and identity. Health professionals should play a pivotal role in assisting patients during the process of adjustment and on-going self-management through sensitive communication and signposting to wider support services. [ABSTRACT FROM AUTHOR]

In recent years, X‐ray speckle‐tracking techniques have emerged as viable tools for wavefront metrology and sample imaging applications. These methods are based on the measurement of near‐field images. Thanks to their simple experimental setup, high angular sensitivity and compatibility with low‐coherence sources, these methods have been actively developed for use with synchrotron and laboratory light sources. Not only do speckle‐tracking techniques give the potential for high‐resolution imaging, but they also provide rapid and robust characterization of aberrations of X‐ray optical elements, focal spot profiles, and sample position and transmission properties. In order to realize these capabilities, software implementations are required that are equally rapid and robust. To address this need, a software suite has been developed for the ptychographic X‐ray speckle‐tracking technique, an X‐ray speckle‐based method suitable for highly divergent wavefields. The software suite is written in Python 3, with an OpenCL back end for GPU and multi‐CPU core processing. It is accessible as a Python module, through the command line or through a graphical user interface, and is available as source code under Version 3 or later of the GNU General Public License. [ABSTRACT FROM AUTHOR]

The ever‐increasing brightness of synchrotron radiation sources demands improved X‐ray optics to utilize their capability for imaging and probing biological cells, nano‐devices and functional matter on the nanometre scale with chemical sensitivity. Hard X‐rays are ideal for high‐resolution imaging and spectroscopic applications owing to their short wavelength, high penetrating power and chemical sensitivity. The penetrating power that makes X‐rays useful for imaging also makes focusing them technologically challenging. Recent developments in layer deposition techniques have enabled the fabrication of a series of highly focusing X‐ray lenses, known as wedged multi‐layer Laue lenses. Improvements to the lens design and fabrication technique demand an accurate, robust, in situ and at‐wavelength characterization method. To this end, a modified form of the speckle tracking wavefront metrology method has been developed. The ptychographic X‐ray speckle tracking method is capable of operating with highly divergent wavefields. A useful by‐product of this method is that it also provides high‐resolution and aberration‐free projection images of extended specimens. Three separate experiments using this method are reported, where the ray path angles have been resolved to within 4 nrad with an imaging resolution of 45 nm (full period). This method does not require a high degree of coherence, making it suitable for laboratory‐based X‐ray sources. Likewise, it is robust to errors in the registered sample positions, making it suitable for X‐ray free‐electron laser facilities, where beam‐pointing fluctuations can be problematic for wavefront metrology. [ABSTRACT FROM AUTHOR]

This paper builds on recent studies of institutional diversity in Australian tertiary education by modifying this model and using it to profile Australian pathway providers. The results offer insight into the role and work of this under-represented part of Australian tertiary education, as well as highlighting key strategic issues for these institutions and encourages a self-reflexive stance towards profiling methodologies. [ABSTRACT FROM AUTHOR]

Background We started a primary care residency program intended to prepare graduates for primary care and increase entry into primary care, using time-limited funds from the Health Resources and Services Administration (HRSA). Objective To compare the graduates of the primary care residency program to their categorical peers, and whether they remained in the state, began primary care careers, and whether they identified as underrepresented in medicine. Methods This is a retrospective study of a cohort of 39 residents who graduated from the University of North Carolina primary care residency program from 2014-2023. In 2016, HRSA grant funding expired and the program continued with ongoing financial support from the 2 institutions. Graduate demographics and career choices were compared to categorical residents (159 total) for graduate years 2014 to 2023. Results The primary care pediatrics residency has graduated 39 residents to date. Job placement data was obtained for all 39 graduates. Graduates of the program have 5.5-fold greater odds (95% CI, 2.5-12.5) of working in primary care roles following graduation than peer categorical residents. Most graduates (33 of 39, 85%) have taken jobs in general pediatrics (including primary care, urgent care, adolescent medicine, or hospital medicine). The program has recruited a large proportion of its residents (12 of 39, 31%) from groups historically underrepresented in medicine. Conclusions We developed an innovative primary care pediatric residency in collaboration with a community partner, spurred by HRSA funds, that has trained a diverse group of new primary care pediatricians. [ABSTRACT FROM AUTHOR]

A method is presented for the measurement of the phase gradient of a wavefront by tracking the relative motion of speckles in projection holograms as a sample is scanned across the wavefront. By removing the need to obtain an undistorted reference image of the sample, this method is suitable for the metrology of highly divergent wavefields. Such wavefields allow for large magnification factors that, according to current imaging capabilities, will allow for nanoradian angular sensitivity and nanoscale sample projection imaging. Both the reconstruction algorithm and the imaging geometry are nearly identical to that of ptychography, except that the sample is placed downstream of the beam focus and that no coherent propagation is explicitly accounted for. Like other X‐ray speckle tracking methods, it is robust to low‐coherence X‐ray sources, making it suitable for laboratory‐based X‐ray sources. Likewise, it is robust to errors in the registered sample positions, making it suitable for X‐ray free‐electron laser facilities, where beam‐pointing fluctuations can be problematic for wavefront metrology. A modified form of the speckle tracking approximation is also presented, based on a second‐order local expansion of the Fresnel integral. This result extends the validity of the speckle tracking approximation and may be useful for similar approaches in the field. [ABSTRACT FROM AUTHOR]

Background: Tanzania's Zanzibar archipelago has made significant gains in malaria control over the last decade and is a target for malaria elimination. Despite consistent implementation of effective tools since 2002, elimination has not been achieved. Importation of parasites from outside of the archipelago is thought to be an important cause of malaria's persistence, but this paradigm has not been studied using modern genetic tools. Methods: Whole-genome sequencing (WGS) was used to investigate the impact of importation, employing population genetic analyses of Plasmodium falciparum isolates from both the archipelago and mainland Tanzania. Ancestry, levels of genetic diversity and differentiation, patterns of relatedness, and patterns of selection between these two populations were assessed by leveraging recent advances in deconvolution of genomes from polyclonal malaria infections. Results: Significant decreases in the effective population sizes were inferred in both populations that coincide with a period of decreasing malaria transmission in Tanzania. Identity by descent analysis showed that parasites in the two populations shared long segments of their genomes, on the order of 5 cM, suggesting shared ancestry within the last 10 generations. Even with limited sampling, two of isolates between the mainland and Zanzibar were identified that are related at the expected level of half-siblings, consistent with recent importation. Conclusions: These findings suggest that importation plays an important role for malaria incidence on Zanzibar and demonstrate the value of genomic approaches for identifying corridors of parasite movement to the island. [ABSTRACT FROM AUTHOR]

Human behavior is dependent on the ability of neuronal circuits to predict the outside world. Neuronal circuits in early visual areas make these predictions based on internal models that are delivered via non-feedforward connections. Despite our extensive knowledge of the feedforward sensory features that drive cortical neurons, we have a limited grasp on the structure of the brain's internal models. Progress in neuroscience therefore depends on our ability to replicate the models that the brain creates internally. Here we record human fMRI data while presenting partially occluded visual scenes. Visual occlusion allows us to experimentally control sensory input to subregions of visual cortex while internal models continue to influence activity in these regions. Because the observed activity is dependent on internal models, but not on sensory input, we have the opportunity to map visual features conveyed by the brain's internal models. Our results show that activity related to internal models in early visual cortex are more related to scene-specific features than to categorical or depth features. We further demonstrate that behavioral line drawings provide a good description of internal model structure representing scene-specific features. These findings extend our understanding of internal models, showing that line drawings provide a window into our brains' internal models of vision. [ABSTRACT FROM AUTHOR]

Bicuspid aortic valve and coarctation of the aorta are risk factors for infective endocarditis and endarteritis. We describe a case of a 4-year-old boy whose severe aortic coarctation was diagnosed only when he presented with endarteritis due to Streptococcus pneumoniae , which evolved into a mycotic pseudoaneurysm requiring urgent repair. • Mycotic (pseudo-)aneurysm of the aorta is very rare in children but is associated with aortic coarctation. • Prompt recognition is important, as surgical repair is usually required. • Sensitivity of transthoracic echocardiography is limited so multimodal imaging is useful for diagnosis. • We describe a case of mycotic pseudoaneurysm due to a non-vaccine strain of Streptococcus pneumoniae in a 4 year old boy. [ABSTRACT FROM AUTHOR]

Faithful segregation of homologous chromosomes at meiosis requires pairing and recombination. In taxa with dimorphic sex chromosomes, pairing between them in the heterogametic sex is limited to a narrow interval of residual sequence homology known as the pseudoautosomal region (PAR). Failure to form the obligate crossover in the PAR is associated with male infertility in house mice (Mus musculus) and humans. Yet despite this apparent functional constraint, the boundary and organization of the PAR is highly variable in mammals, and even between subspecies of mice. Here, we estimate the genetic map in a previously documented expansion of the PAR in the M. musculus castaneus subspecies and show that the local recombination rate is 100-fold higher than the autosomal background. We identify an independent shift in the PAR boundary in the M. musculus musculus subspecies and show that it involves a complex rearrangement, but still recombines in heterozygous males. Finally, we demonstrate pervasive copy-number variation at the PAR boundary in wild populations of M. m. domesticus, M. m. musculus, and M. m. castaneus. Our results suggest that the intensity of recombination activity in the PAR, coupled with relatively weak constraints on its sequence, permit the generation and maintenance of unusual levels of polymorphism in the population of unknown functional significance. [ABSTRACT FROM AUTHOR]

The formation of isonicotinyl-nicotinamide adenine dinucleotide (INH-NAD+) by the mycobacterial catalase-peroxidase enzyme, KatG, was known to be the major component of the mode of action of isoniazid (INH), an anti-tuberculosis drug. However, there are other enzymes that may catalyze this reaction. We have previously reported that neutrophil myeloperoxidase (MPO) is capable of metabolizing INH through the formation of INH-NAD+ adduct, which could be attributed to being a possible mode of action of INH. However, eosinophilic infiltration of the lungs is more pronounced and characteristic of granulomas in Mycobacterium tuberculosis -infected patients. Thus, the aim of the present study is to investigate the role of eosinophil peroxidase (EPO), a key eosinophil enzyme, during INH metabolism and the formation of its active metabolite, INH-NAD+ using purified EPO and eosinophils isolated from asthmatic donors. UV–Vis spectroscopy revealed INH oxidation by EPO led to a new product (λ max = 326 nm) in the presence of NAD+. This adduct was confirmed to be INH-NAD+ using LC-MS analysis where the intact adduct was detected (m / z = 769). Furthermore, EPO catalyzed the oxidation of INH and formed several free radical intermediates as assessed by electron paramagnetic resonance (EPR) spin-trapping; a carbon-centred radical, which is considered to be the reactive metabolite that binds with NAD+, was found when superoxide dismutase was included in the reaction. Our findings suggest that eosinophilic EPO may also play a role in the pharmacological activity of INH through the formation of INH-NAD+ adduct, and supports further evidence that human cells and enzymes are capable of producing the active metabolite involved in tuberculosis treatment. Image 1 • Eosinophil peroxidase (EPO) oxidizes isoniazid (INH). • Purified EPO formed a new product between INH and NAD+. • A carbon radical, formed by catalytic oxidation of INH by EPO, binds with NAD+. • EPO may contribute to the activity of INH by forming INH-NAD+ adduct. [ABSTRACT FROM AUTHOR]

In this article I offer an account of normative thought inspired by Plato's proposal in the Theaetetus that judgement is 'speech spoken ... silently.' After arguing that force conventionalism is the speech act theory best suited for modeling dialogic inner speech, I close the article by sketching the picture of normative thought that results. Though I defend a particular theory of normative speech elsewhere, the core insights of this article can be used by other theorists as well. The arguments offered here also serve as an important step forward for the more general program of using social speech to better understand thought. [ABSTRACT FROM AUTHOR]

To date X‐ray protein crystallography is the most successful technique available for the determination of high‐resolution 3D structures of biological molecules and their complexes. In X‐ray protein crystallography the structure of a protein is refined against the set of observed Bragg reflections from a protein crystal. The resolution of the refined protein structure is limited by the highest angle at which Bragg reflections can be observed. In addition, the Bragg reflections alone are typically insufficient (by a factor of two) to determine the structure ab initio, and so prior information is required. Crystals formed from an imperfect packing of the protein molecules may also exhibit continuous diffraction between and beyond these Bragg reflections. When this is due to random displacements of the molecules from each crystal lattice site, the continuous diffraction provides the necessary information to determine the protein structure without prior knowledge, to a resolution that is not limited by the angular extent of the observed Bragg reflections but instead by that of the diffraction as a whole. This article presents an iterative projection algorithm that simultaneously uses the continuous diffraction as well as the Bragg reflections for the determination of protein structures. The viability of this method is demonstrated on simulated crystal diffraction. This article reports on the combined use of Bragg reflections and diffuse scatter for structure determination in crystallography. [ABSTRACT FROM AUTHOR]

• COVID-19 patients are at increased risk of thromboembolic complications. • Escalated-dose thromboprophylaxis may help reduce the rate of thromboembolic events. • The bleeding risk is highest for patients treated with therapeutic anticoagulation. [ABSTRACT FROM AUTHOR]

Poly(ethylene terephthalate) (PET) was treated with vacuum UV (VUV) (λ= 104.8 and 106.7 nm) photo-oxidation using a microwave (MW) plasma of Ar as the radiation source and the results were compared to treatment with O atoms produced from a remote MW plasma of a gaseous mixture of Ar-O2in the absence of radiation. X-ray photo-electron spectroscopy (XPS) detected a lower saturation level for the atomic % of O with VUV photo-oxidation (32 at%) than with O atom treatment (34 at% O). The C 1s curve fitting results for both treatment methods show a decrease in aromatic sp2carbons and an increase in the amount of carbon-oxygen bonding due to the formation of the carbonyl (C=O) and carbonate-like (O-(C=O)-O) moieties for VUV photo-oxidation; and C-O-C, C=O, and O-C=O moieties for O atom treatment, respectively. Advancing water contact angle measurements showed more of an increase in hydrophilicity with the O atom treated samples than VUV photo-oxidation. Atomic Force Microscopy images displayed smoother surfaces after VUV photo-oxidation while O atom treatment resulted in insignificant changes in surface roughness. Rinsing the treated surfaces with ethanol solvent partially decreased the at% O indicating the formation of a weak boundary during treatment. [ABSTRACT FROM AUTHOR]

Several lines of evidence have pointed towards the potential therapeutic benefit of NSAIDs in cancer therapy. In this study, we have investigated the acute bio-activation of NSAIDs and their metabolites via myeloperoxidase (MPO), a highly-expressed peroxidase enzyme in acute myeloid leukemia. As bio-activation involves the formation of reactive metabolites, we hypothesized that NSAIDs which produced reactive metabolites would be correlated with leukemia cell toxicity. We tested the enzymatic peroxidation of three NSAIDs, namely diclofenac, indomethacin, and naproxen in comparison with their hepatic metabolites, 4′- hydroxydiclofenac (4′-OHD), 5-hydroxydiclofenac (5-OHD), O-desmethyl-N-deschlorobenzoylindomethacin (DMBI), O-desmethylindomethacin (DMI) and O-desmethylnaproxen (ODN). Firstly, we used purified peroxidases in kinetic UV–vis kinetic spectrophotometry, and electron paramagnetic resonance (EPR) experiments to determine oxidation of ascorbic acid and glutathione (GSH), respectively. We then used HL-60 cells, as a model of acute myelogenous leukemia to carry out trypan blue exclusion, cellular ATP analysis, mitochondrial membrane potential (MMP) and cytofluorometric GSH assays. Our results present evidence that diclofenac, 4′-OHD, 5-OHD, DMBI and DMI demonstrated significant cytotoxic effect in the leukemic cells through oxidation by intracellular MPO. In the same vein, only diclofenac and its two metabolites caused a significant drop in the MMP and cellular ATP level; however, the cell death induced by indomethacin metabolites reflected a subtle effect on MMP or GSH content. Interestingly, only diclofenac and 4′-OHD (and not 5- OHD) caused a significant drop in HL-60 cells’ GSH content. Among diclofenac compounds, only 4′-OHD also generated GS radical and caused a significant increase in ascorbate co-oxidation rate. Lastly, even though ODN also generated GS radical and potently cooxidized ascorbate, it showed no significant cytotoxicity. These results provide evidence of a correlation between acute cytotoxicity and MPO-bioactivated NSAIDs, though this was not correlated for all compounds ( e.g. , ODN). Further studies are required to determine both the MPO-dependent and MPO-independent mechanisms of cytotoxicity. [ABSTRACT FROM AUTHOR]

In this essay, I propose a novel hybrid metanormative theory. According to this theory, speakers making normative claims express both cognitive and motivational attitudes in virtue of the constitutive norms of the particular speech acts they perform. This view has four principal virtues: (1) it is consistent with traditional semantic theories, (2) it supports a form of motivational judgment internalism that does justice to externalist intuitions, (3) it illuminates the connection between normative language and normative thought, and (4) it explains how speakers can express different conative states when speaking in different normative domains. In the first section, I discuss the theories of Stephen Finlay and David Copp. I show that they each come very close to having it both ways but ultimately fail. Understanding the shortcomings of these views is instrumental to a clear presentation of my own Hybrid Speech Act theory in section two. In the final section, I demonstrate how my view achieves its four advantages. [ABSTRACT FROM AUTHOR]

Quantitative trait locus (QTL) analyses of intercross populations between widely used mouse inbred strains provide a powerful approach for uncovering genetic factors that influence susceptibility to atherosclerosis. Epistatic interactions are common in complex phenotypes and depend on genetic backgrounds. To dissect genetic architecture of atherosclerosis, we analyzed F2 progeny from a cross between apolipoprotein E-null mice on DBA/2J (DBA-apoE) and C57BL/6J (B6-apoE) genetic backgrounds and compared the results with those from two previous F2 crosses of apolipoprotein E-null mice on 129S6/SvEvTac (129-apoE) and DBA-apoE backgrounds, and B6-apoE and 129-apoE backgrounds. In these round-robin crosses, in which each parental strain was crossed with two others, large-effect QTLs are expected to be detectable at least in two crosses. On the other hand, observation of QTLs in one cross only may indicate epistasis and/or absence of statistical power. For atherosclerosis at the aortic arch, Aath4 on chromosome (Chr)2:66 cM follows the first pattern, with significant QTL peaks in (DBAx129)F2 and (B6xDBA)F2 mice but not in (B6x129)F2 mice. We conclude that genetic variants unique to DBA/2J at Aath4 confer susceptibility to atherosclerosis at the aortic arch. A similar pattern was observed for Aath5 on chr10:35 cM, verifying that the variants unique to DBA/2J at this locus protect against arch plaque development. However, multiple loci, including Aath1 (Chr1:49 cM), and Aath2 (Chr1:70 cM) follow the second type of pattern, showing significant peaks in only one of the three crosses (B6-apoE x 129-apoE). As for atherosclerosis at aortic root, the majority of QTLs, including Ath29 (Chr9:33 cM), Ath44 (Chr1:68 cM) and Ath45 (Chr2:83 cM), was also inconsistent, being significant in only one of the three crosses. Only the QTL on Chr7:37 cM was consistently suggestive in two of the three crosses. Thus QTL analysis of round-robin crosses revealed the genetic architecture of atherosclerosis. [ABSTRACT FROM AUTHOR]

After a functional analysis yielded undifferentiated results, a subsequent assessment suggested self-injury exhibited by a young boy with autism was sensitive to physical restraint. Canvas arm splints with metal stays were initially effective to reduce self-injury. Although we successfully faded the number of stays in each sleeve to 3, self-injury reemerged. We then used a withdrawal design to evaluate a behind-the-back belt connected to the arm splints. When the belt and splints were on, self-injury did not occur. When the belt was removed, self-injury increased, even though the splints remained intact. Finally, we faded the length of the belt to allow increased range of motion, and rates of self-injury remained low. [ABSTRACT FROM AUTHOR]

The Collaborative Cross (CC) is a multiparent panel of recombinant inbred (RI) mouse strains derived from eight founder laboratory strains. RI panels are popular because of their long-term genetic stability, which enhances reproducibility and integration of data collected across time and conditions. Characterization of their genomes can be a community effort, reducing the burden on individual users. Here we present the genomes of the CC strains using two complementary approaches as a resource to improve power and interpretation of genetic experiments. Our study also provides a cautionary tale regarding the limitations imposed by such basic biological processes as mutation and selection. A distinct advantage of inbred panels is that genotyping only needs to be performed on the panel, not on each individual mouse. The initial CC genome data were haplotype reconstructions based on dense genotyping of the most recent common ancestors (MRCAs) of each strain followed by imputation from the genome sequence of the corresponding founder inbred strain. The MRCA resource captured segregating regions in strains that were not fully inbred, but it had limited resolution in the transition regions between founder haplotypes, and there was uncertainty about founder assignment in regions of limited diversity. Here we report the whole genome sequence of 69 CC strains generated by paired-end short reads at 303 coverage of a single male per strain. Sequencing leads to a substantial improvement in the fine structure and completeness of the genomes of the CC. Both MRCAs and sequenced samples show a significant reduction in the genome-wide haplotype frequencies from two wild-derived strains, CAST/EiJ and PWK/PhJ. In addition, analysis of the evolution of the patterns of heterozygosity indicates that selection against three wild-derived founder strains played a significant role in shaping the genomes of the CC. The sequencing resource provides the first description of tens of thousands of new genetic variants introduced by mutation and drift in the CC genomes. We estimate that new SNP mutations are accumulating in each CC strain at a rate of 2.4 6 0.4 per gigabase per generation. The fixation of new mutations by genetic drift has introduced thousands of new variants into the CC strains. The majority of these mutations are novel compared to currently sequenced laboratory stocks and wild mice, and some are predicted to alter gene function. Approximately one-third of the CC inbred strains have acquired large deletions (.10 kb) many of which overlap known coding genes and functional elements. The sequence of these mice is a critical resource to CC users, increases threefold the number of mouse inbred strain genomes available publicly, and provides insight into the effect of mutation and drift on common resources. [ABSTRACT FROM AUTHOR]

Meiotic recombination is an essential feature of sexual reproduction that ensures faithful segregation of chromosomes and redistributes genetic variants in populations. Multiparent populations such as the Diversity Outbred (DO) mouse stock accumulate large numbers of crossover (CO) events between founder haplotypes, and thus present a unique opportunity to study the role of genetic variation in shaping the recombination landscape. We obtained high-density genotype data from 6886 DO mice, and localized 2.2 million CO events to intervals with a median size of 28 kb. The resulting sex-averaged genetic map of the DO population is highly concordant with large-scale (order 10 Mb) features of previously reported genetic maps for mouse. To examine fine-scale (order 10 kb) patterns of recombination in the DO, we overlaid putative recombination hotspots onto our CO intervals. We found that CO intervals are enriched in hotspots compared to the genomic background. However, as many as 26% of CO intervals do not overlap any putative hotspots, suggesting that our understanding of hotspots is incomplete. We also identified coldspots encompassing 329 Mb, or 12% of observable genome, in which there is little or no recombination. In contrast to hotspots, which are a few kilobases in size, and widely scattered throughout the genome, coldspots have a median size of 2.1 Mb and are spatially clustered. Coldspots are strongly associated with copy-number variant (CNV) regions, especially multi-allelic clusters, identified from whole-genome sequencing of 228 DO mice. Genes in these regions have reduced expression, and epigenetic features of closed chromatin in male germ cells, which suggests that CNVs may repress recombination by altering chromatin structure in meiosis. Our findings demonstrate how multiparent populations, by bridging the gap between large-scale and fine-scale genetic mapping, can reveal new features of the recombination landscape. [ABSTRACT FROM AUTHOR]

Wild-derived mouse inbred strains are becoming increasingly popular for complex traits analysis, evolutionary studies, and systems genetics. Here, we report the whole-genome sequencing of two wild-derived mouse inbred strains, LEWES/EiJ and ZALENDE/EiJ, of Mus musculus domesticus origin. These two inbred strains were selected based on their geographic origin, karyotype, and use in ongoing research. We generated 14× and 18× coverage sequence, respectively, and discovered over 1.1 million novel variants, most of which are private to one of these strains. This report expands the number of wild-derived inbred genomes in the Mus genus from six to eight. The sequence variation can be accessed via an online query tool; variant calls (VCF format) and alignments (BAM format) are available for download from a dedicated ftp site. Finally, the sequencing data have also been stored in a lossless, compressed, and indexed format using the multi-string Burrows-Wheeler transform. All data can be used without restriction. [ABSTRACT FROM AUTHOR]

Gene duplication and loss are major sources of genetic polymorphism in populations, and are important forces shaping the evolution of genome content and organization. We have reconstructed the origin and history of a 127-kbp segmental duplication, R2d, in the house mouse (Mus musculus). R2d contains a single protein-coding gene, Cwc22. De novo assembly of both the ancestral (R2d1) and the derived (R2d2) copies reveals that they have been subject to nonallelic gene conversion events spanning tens of kilobases. R2d2 is also a hotspot for structural variation: its diploid copy number ranges from zero in the mouse reference genome to >80 in wild mice sampled from around the globe. Hemizygosity for high copy-number alleles of R2d2 is associated in cis with meiotic drive; suppression of meiotic crossovers; and copy-number instability, with a mutation rate in excess of 1 per 100 transmissions in some laboratory populations. Our results provide a striking example of allelic diversity generated by duplication and demonstrate the value of de novo assembly in a phylogenetic context for understanding the mutational processes affecting duplicate genes. [ABSTRACT FROM AUTHOR]

This article describes a free and open-source data analysis utility designed for fast online feedback during serial X-ray diffraction and scattering experiments: OnDA (online data analysis). Three complete real-time monitors for common types of serial X-ray imaging experiments are presented. These monitors are capable of providing the essential information required for quick decision making in the face of extreme rates of data collection. In addition, a set of modules, functions and algorithms that allow developers to modify the provided monitors or develop new ones are provided. The emphasis here is on simple, modular and scalable code that is based on open-source libraries and protocols. OnDA monitors have already proven to be invaluable tools in several experiments, especially for scoring and monitoring of diffraction data during serial crystallography experiments at both free-electron laser and synchrotron facilities. It is felt that in the future the kind of fast feedback that OnDA monitors provide will help researchers to deal with the expected very high throughput data flow at next-generation facilities such as the European X-ray free-electron laser. [ABSTRACT FROM AUTHOR]

The formation of isonicotinyl-nicotinamide adenine dinucleotide (INH-NAD + ) via the mycobacterial catalase-peroxidase enzyme, KatG, has been described as the major component of the mode of action of isoniazid (INH). However, there are numerous human peroxidases that may catalyze this reaction. The role of neutrophil myeloperoxidase (MPO) in INH-NAD + adduct formation has never been explored; this is important, as neutrophils are recruited at the site of tuberculosis infection (granuloma) through infected macrophages’ cell death signals. In our studies, we showed that neutrophil MPO is capable of INH metabolism using electron paramagnetic resonance (EPR) spin-trapping and UV–Vis spectroscopy. MPO or activated human neutrophils (by phorbol myristate acetate) catalyzed the oxidation of INH and formed several free radical intermediates; the inclusion of superoxide dismutase revealed a carbon-centered radical which is considered to be the reactive metabolite that binds with NAD + . Other human metabolites, including N-acetyl-INH, N-acetylhydrazine, and hydrazine did not show formation of carbon-centered radicals, and either produced no detectable free radicals, N-centered free radicals, or superoxide, respectively. A comparison of these free radical products indicated that only the carbon-centered radical from INH is reducing in nature, based on UV–Vis measurement of nitroblue tetrazolium reduction. Furthermore, only INH oxidation by MPO led to a new product ( λ max = 326 nm) in the presence of NAD + . This adduct was confirmed to be isonicotinyl-NAD + using LC–MS analysis where the intact adduct was detected ( m / z = 769). The findings of this study suggest that neutrophil MPO may also play a role in INH pharmacological activity. [ABSTRACT FROM AUTHOR]

Research on violence perpetrated by individuals with major mental illness (MMI) typically focuses on the presence of specific psychotic symptoms near the time of the violent act. This approach does not distinguish whether symptoms actually motivate the violence or were merely present at the material time. It also does not consider the possibility that non-illness-related factors (e.g., anger, substance use), or multiple motivations, may have been operative in driving violence. The failure to make these distinctions clouds our ability to understand the origins of violence in people with MMI, to accurately assess risk and criminal responsibility, and to appropriately target interventions to reduce and manage risk. This study describes the development of a new coding instrument designed to assess motivations for violence and offending among individuals with MMI, and reports on the scheme's interrater reliability. Using 72 psychiatric reports which had been submitted to the court to assist in determining criminal responsibility, we found that independent raters were able to assess different motivational influences for violence with a satisfactory degree of consistency. More than three-quarters (79.2%) of the sample were judged to have committed an act of violence as a primary result of illness, whereas 20.8% were deemed to have offended as a result of illness in conjunction with other non-illness-based motivating influences. Current findings have relevance for clarifying the rate of illness-driven violence among psychiatric patients, as well as legal and clinical issues related to violence risk and criminal responsibility more broadly. [ABSTRACT FROM AUTHOR]

Genotyping microarrays are an important and widely-used tool in genetics. I present argyle, an R package for analysis of genotyping array data tailored to Illumina arrays. The goal of the argyle package is to provide simple, expressive tools for nonexpert users to perform quality checks and exploratory analyses of genotyping data. To these ends, the package consists of a suite of quality-control functions, normalization procedures, and utilities for visually and statistically summarizing such data. Formatconversion tools allow interoperability with popular software packages for analysis of genetic data including PLINK, R/qtl and DOQTL. Detailed vignettes demonstrating common use cases are included as supporting information. argyle bridges the gap between the low-level tasks of quality control and high-level tasks of genetic analysis. It is freely available at https://github.com/andrewparkermorgan/argyle and has been submitted to Bioconductor. [ABSTRACT FROM AUTHOR]

Genotyping microarrays are an important resource for genetic mapping, population genetics, and monitoring of the genetic integrity of laboratory stocks. We have developed the third generation of the Mouse Universal Genotyping Array (MUGA) series, GigaMUGA, a 143,259-probe Illumina Infinium II array for the house mouse (Mus musculus). The bulk of the content of GigaMUGA is optimized for genetic mapping in the Collaborative Cross and Diversity Outbred populations, and for substrain-level identification of laboratory mice. In addition to 141,090 single nucleotide polymorphism probes, GigaMUGA contains 2006 probes for copy number concentrated in structurally polymorphic regions of the mouse genome. The performance of the array is characterized in a set of 500 high-quality reference samples spanning laboratory inbred strains, recombinant inbred lines, outbred stocks, and wild-caught mice. GigaMUGA is highly informative across a wide range of genetically diverse samples, from laboratory substrains to other Mus species. In addition to describing the content and performance of the array, we provide detailed probe-level annotation and recommendations for quality control. [ABSTRACT FROM AUTHOR]

The article discusses databases, analysis tools, and other informatics resources related to the use of the Collaborative Cross (CC) and complementary Diversity Outbred (DO) population of mice for analyzing genetic and molecular networks underlying complex traits like mouse behavior. It focuses on computational tools used for genetic mapping and analyzing CC and DO genomes. It also focuses on how these tools help in getting a comprehensive view of the polymorphism segregation in CC and DO mice.

The article discusses the 28th International Mammalian Genome Conference (IMGC) that was held from October 26-29, 2014 in Bar Harbor, Maine. Topics include the bioinformatic workshops, the highlights on mammalian models which are useful in human genetics and research on diseases, and the award to travel scholarships which aims to mentor young scientists. It also mentioned the student satellite symposium held at the auditorium of The Jackson Laboratory.

Earthworms are globally distributed and perform essential roles for soil health and microbial structure. We have investigated the effect of an anthropogenic contamination gradient on the bacterial community of the keystone ecological species L umbricus rubellus through utilizing 16 S rRNA pyrosequencing for the first time to establish the microbiome of the host and surrounding soil. The earthworm-associated microbiome differs from the surrounding environment which appears to be a result of both filtering and stimulation likely linked to the altered environment associated with the gut micro-habitat (neutral pH, anoxia and increased carbon substrates). We identified a core earthworm community comprising Proteobacteria (∼50%) and Actinobacteria (∼30%), with lower abundances of Bacteroidetes (∼6%) and Acidobacteria (∼3%). In addition to the known earthworm symbiont ( V erminephrobacter sp.), we identified a potential host-associated Gammaproteobacteria species ( S erratia sp.) that was absent from soil yet observed in most earthworms. Although a distinct bacterial community defines these earthworms, clear family- and species-level modification were observed along an arsenic and iron contamination gradient. Several taxa observed in uncontaminated control microbiomes are suppressed by metal/metalloid field exposure, including eradication of the hereto ubiquitously associated V erminephrobacter symbiont, which raises implications to its functional role in the earthworm microbiome. [ABSTRACT FROM AUTHOR]

Significant departures from expected Mendelian inheritance ratios (transmission ratio distortion, TRD) are frequently observed in both experimental crosses and natural populations. TRD on mouse Chromosome (Chr) 2 has been reported in multiple experimental crosses, including the Collaborative Cross (CC). Among the eight CC founder inbred strains, we found that Chr 2 TRD was exclusive to females that were heterozygous for the WSB/EiJ allele within a 9.3 Mb region (Chr 2 76.9 – 86.2 Mb). A copy number gain of a 127 kb-long DNA segment (designated as responder to drive, R2d) emerged as the strongest candidate for the causative allele. We mapped R2d sequences to two loci within the candidate interval. R2d1 is located near the proximal boundary, and contains a single copy of R2d in all strains tested. R2d2 maps to a 900 kb interval, and the number of R2d copies varies from zero in classical strains (including the mouse reference genome) to more than 30 in wild-derived strains. Using real-time PCR assays for the copy number, we identified a mutation (R2d2WSBdel1) that eliminates the majority of the R2d2WSB copies without apparent alterations of the surrounding WSB/EiJ haplotype. In a three-generation pedigree segregating for R2d2WSBdel1, the mutation is transmitted to the progeny and Mendelian segregation is restored in females heterozygous for R2d2WSBdel1, thus providing direct evidence that the copy number gain is causal for maternal TRD. We found that transmission ratios in R2d2WSB heterozygous females vary between Mendelian segregation and complete distortion depending on the genetic background, and that TRD is under genetic control of unlinked distorter loci. Although the R2d2WSB transmission ratio was inversely correlated with average litter size, several independent lines of evidence support the contention that female meiotic drive is the cause of the distortion. We discuss the implications and potential applications of this novel meiotic drive system. [ABSTRACT FROM AUTHOR]

The second-generation antipsychotic olanzapine is effective in reducing psychotic symptoms but can cause extreme weight gain in human patients. We investigated the role of the gut microbiota in this adverse drug effect using a mouse model. First, we used germ-free C57BL/6J mice to demonstrate that gut bacteria are necessary and sufficient for weight gain caused by oral delivery of olanzapine. Second, we surveyed fecal microbiota before, during, and after treatment and found that olanzapine potentiated a shift towards an “obesogenic” bacterial profile. Finally, we demonstrated that olanzapine has antimicrobial activity in vitro against resident enteric bacterial strains. These results collectively provide strong evidence for a mechanism underlying olanzapine-induced weight gain in mouse and a hypothesis for clinical translation in human patients. [ABSTRACT FROM AUTHOR]

Background: Factors influencing differential responses of prostate tumors to androgen receptor (AR) axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth. Methods: We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy. Results: In LuCaP35 tumors (intra-tumoral T:DHT ratio 2∶1) dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015). In LuCaP96 tumors (T:DHT 10∶1), survival was not improved despite similar DHT reduction (0.02 ng/gm). LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both), reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors), and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively), persistent suppression of intra-tumoral DHT, and 6–8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts. Conclusions: Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and should be validated in additional models. [ABSTRACT FROM AUTHOR]

Estimates of mutational parameters, such as the average fitness effect of a new mutation and the rate at which new genetic variation for fitness is created by mutation, are important for the understanding of many biological processes. However, the causes of interspecific variation in mutational parameters and the extent to which they vary within species remain largely unknown. We maintained multiple strains of the unicellular eukaryote Chlamydomonas reinhardtii, for approximately 1000 generations under relaxed selection by transferring a single cell every ∼10 generations. Mean fitness of the lines tended to decline with generations of mutation accumulation whereas mutational variance increased. We did not find any evidence for differences among strains in any of the mutational parameters estimated. The overall change in mean fitness per cell division and rate of input of mutational variance per cell division were more similar to values observed in multicellular organisms than to those in other single-celled microbes. However, after taking into account differences in genome size among species, estimates from multicellular organisms and microbes, including our new estimates from C. reinhardtii, become substantially more similar. Thus, we suggest that variation in genome size is an important determinant of interspecific variation in mutational parameters. [ABSTRACT FROM AUTHOR]

Understanding the effects of sex and migration on adaptation to novel environments remains a key problem in evolutionary biology. Using a single-cell alga Chlamydomonas reinhardtii, we investigated how sex and migration affected rates of evolutionary rescue in a sink environment, and subsequent changes in fitness following evolutionary rescue. We show that sex and migration affect both the rate of evolutionary rescue and subsequent adaptation. However, their combined effects change as the populations adapt to a sink habitat. Both sex and migration independently increased rates of evolutionary rescue, but the effect of sex on subsequent fitness improvements, following initial rescue, changed with migration, as sex was beneficial in the absence of migration but constraining adaptation when combined with migration. These results suggest that sex and migration are beneficial during the initial stages of adaptation, but can become detrimental as the population adapts to its environment. [ABSTRACT FROM AUTHOR]

A remarkable thing happened in Myanmar in the summer of 2013. A government that, in recent decades, enacted and carried out among the most draconian and repressive policies toward civil society organizations in the world sat down with a large, representative body of such organizations to hear criticisms of a recently passed law. Perhaps more remarkably, the government then revised the law in response to these criticisms, fundamentally altering the people's right to freely associate. This introductory piece to the Pacific Rim Law & Policy Journal's special edition devoted to Myanmar provides context for this seemingly remarkable occurrence. It demonstrates one important and hopeful occurrence in Myanmar's immense and ongoing reform effort. It is the author's hope that this occurrence is merely one example of many systemic reforms underway to address the myriad issues facing Myanmar and its people. [ABSTRACT FROM AUTHOR]

Since the publication of the first comprehensive linkage map for the laboratory mouse, the architecture of recombination as a basic biological process has become amenable to investigation in mammalian model organisms. Here we take advantage of high-density genotyping and the unique pedigree structure of the incipient Collaborative Cross to investigate the roles of sex and genetic background in mammalian recombination. Our results confirm the observation that map length is longer when measured through female meiosis than through male meiosis, but we find that this difference is modified by genotype at loci on both the X chromosome and the autosomes. In addition, we report a striking concentration of crossovers in the distal ends of autosomes in male meiosis that is absent in female meiosis. The presence of this pattern in both single- and double-recombinant chromosomes, combined with the absence of a corresponding asymmetry in the distribution of double-strand breaks, indicates a regulated sequence of events specific to male meiosis that is anchored by chromosome ends. This pattern is consistent with the timing of chromosome pairing and evolutionary constraints on male recombination. Finally, we identify large regions of reduced crossover frequency that together encompass 5% of the genome. Many of these "cold regions" are enriched for segmental duplications, suggesting an inverse local correlation between recombination rate and mutation rate for large copy number variants. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is an immune-mediated condition driven by improper responses to intestinal microflora in the context of environmental and genetic background. GWAS in humans have identified many loci associated with IBD, but animal models are valuable for dissecting the underlying molecular mechanisms, characterizing environmental and genetic contributions and developing treatments. Mouse models rely on interventions such as chemical treatment or introduction of an infectious agent to induce disease. Here, we describe a new model for IBD in which the disease develops spontaneously in 20-week-old mice in the absence of known murine pathogens. The model is part of the Collaborative Cross and came to our attention due to a high incidence of rectal prolapse in an incompletely inbred line. Necropsies revealed a profound proliferative colitis with variable degrees of ulceration and vasculitis, splenomegaly and enlarged mesenteric lymph nodes with no discernible anomalies of other organ systems. Phenotypic characterization of the CC011/Unc mice with homozygosity ranging from 94.1 to 99.8 % suggested that the trait was fixed and acted recessively in crosses to the colitis-resistant C57BL/6J inbred strain. Using a QTL approach, we identified four loci, Ccc1, Ccc2, Ccc3 and Ccc4 on chromosomes 12, 14, 1 and 8 that collectively explain 27.7 % of the phenotypic variation. Surprisingly, we also found that minute levels of residual heterozygosity in CC011/Unc have significant impact on the phenotype. This work demonstrates the utility of the CC as a source of models of human disease that arises through new combinations of alleles at susceptibility loci. [ABSTRACT FROM AUTHOR]

This paper provides a review of the legislative reforms and case law that have impacted the defense of Not Criminally Responsible on Account of Mental Disorder (NCRMD) in Canada over the past three decades. As in other jurisdictions internationally, we observe that legislative reforms of procedural, as opposed to substantive, aspects of the NCRMD defense have impacted the manner in which NCRMD criteria are applied in common practice. More people are being declared NCRMD in recent years, and there is greater heterogeneity in the offending and psychiatric profiles of these individuals, suggesting that NCRMD criteria are being applied more liberally over time. In light of the substantial growth of the forensic mental health system over the past two decades, witnessed both in Canada and abroad, we propose that the study of motivational influences underlying the offending behaviors of persons with serious mental illness (SMI) is necessary to begin disentangling symptom-based offending from violent and antisocial behaviors that may have other motives. This, in turn, can help to determine legal issues, better define the nature of each person's offending and treatment needs, and provide a more fine-grained analysis of the drivers behind the growth experienced by the forensic system. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Self-healing materials science has seen significant advances in the last decade. Recent efforts have demonstrated healing in polymeric materials through chemical reaction, thermal treatment, and ultraviolet irradiation. The existing technology for healing polymeric materials through the aforementioned mechanisms produces an irreversible change in the material and makes it unsuitable for subsequent healing cycles. To overcome these disadvantages, we demonstrate a new composite self-healing material made from an ionomer (Surlyn) and carbon fiber that can sustain damage from medium-velocity impact and heal from the energy of the impact. Furthermore, the carbon fiber embedded in the polymer matrix results in resistive heating of the polymer matrix locally, melts the ionomer matrix around the damage, and heals the material at the damaged location. This paper presents methods to melt-process Surlyn with carbon fiber and demonstrates healing in the material through medium-velocity impact tests, resistive heating, and imaging through electron and optical microscopy. A new metric for quantifying self-healing in the sample, called width-heal ratio, is developed, and we report that the Surlyn-carbon fiber-based material under an optimal rate of heating and at the correct temperature has a width-heal ratio of >0.9, thereby demonstrating complete recovery from the damage. [ABSTRACT FROM AUTHOR]

The nature of spontaneous mutations, including their rate, distribution across the genome, and fitness consequences, is of central importance to biology. However, the low rate of mutation has made it difficult to study spontaneous mutagenesis, and few studies have directly addressed these questions. Here, we present a direct estimate of the mutation rate and a description of the properties of new spontaneous mutations in the unicellular green alga Chlamydomonas reinhardtii. We conducted a mutation accumulation experiment for ~350 generations followed by whole-genome resequencing of two replicate lines. Our analysis identified a total of 14 mutations, including 5 short indels and 9 single base mutations, and no evidence of larger structural mutations. From this, we estimate a total mutation rate of 3.23 x 10210/site/generation (95% C.I. 1.82 x 10-10 to 5.23 x 10-10) and a single base mutation rate of 2.08 x 10-10/site/generation (95% C.I., 1.09 x 10-10 to 3.74 x 10-10). We observed no mutations from A/T → G/C, suggesting a strong mutational bias toward A/T, although paradoxically, the GC content of the C. reinhardtii genome is very high. Our estimate is only the second direct estimate of the mutation rate from plants and among the lowest spontaneous base-substitution rates known in eukaryotes. [ABSTRACT FROM AUTHOR]

Over the past decade, point-of-care ultrasound (US) use by nonphysician providers has grown substan-tially. The purpose of this article is to (1) summarize the literature evaluating military medics' facility at US, (2) more clearly define the potential utility of military prehospital US technology, and (3) lay a pathway for future research of military prehospital US. The authors performed a keyword search using multiple search engines. Each author indepen-dently reviewed the search results and evaluated the literature for inclusion. Of 30 studies identified, five studies met inclusion criteria. The applications included evaluation of cardiac activity, pneumothorax evaluation, and fracture evaluation. Additionally, a descriptive study demonstrated distribution of US exam types during practical use by Army Special Forces Medical Sergeants. No studies evaluated retention of skills over prolonged periods. Multiple studies demonstrate the feasibility of training military medics in US. Even under austere conditions, the majority of studies conclude that medic can perform US with a high degree of accuracy. Lessons learned from these studies tend to support continued use of US in out-of-hospital settings and exploration of the optimal curriculum to introduce this skill. [ABSTRACT FROM AUTHOR]