Efferocytosis is an innate antibacterial mechanism

Mycobacterium tuberculosis persists within macrophages in an arrested phagosome and depends upon necrosis to elude immunity and disseminate. Although apoptosis of M. tuberculosis-infected macrophages is associated with reduced bacterial growth, the bacteria are relatively resistant to other forms of death, leaving the mechanism underlying this observation unresolved. We find that after apoptosis, M. tuberculosis-infected macrophages are rapidly taken up by uninfected macrophages through efferocytosis, a dedicated apoptotic cell engulfment process. Efferocytosis of M. tuberculosis sequestered within an apoptotic macrophage further compartmentalizes the bacterium and delivers it along with the apoptotic cell debris to the lysosomal compartment. M. tuberculosis is killed only after efferocytosis, indicating that apoptosis itself is not intrinsically bactericidal but requires subsequent phagocytic uptake and lysosomal fusion of the apoptotic body harboring the bacterium. While efferocytosis is recognized as a constitutive housekeeping function of macrophages, these data indicate that it can also function as an antimicrobial effector mechanism.Behar, Fortune, and Remold labs for reagents, helpful discussion, and insights. TIM4-blocking antibodies were a generous gift of Vijay Kuchroo. Members of the Harvard Electron Microscopy Core Facility helped in the preparation, staining, and operation of the electron microscope. The Small Animal Biocontainment (ABC) Suite is supported by CFAR 5P30AI060354. T.R.R and S.M.F were supported by CFAR 5P30AI060354, DP2-0d001378, and T32-AI07387. C.N.A. is the recipient of a fellowship from FCT. S.M.B and H.G.R. were supported by R56AI084161 and R01AI072143

Genome-wide signatures of complex introgression and adaptive evolution in the big cats.

The great cats of the genus Panthera comprise a recent radiation whose evolutionary history is poorly understood. Their rapid diversification poses challenges to resolving their phylogeny while offering opportunities to investigate the historical dynamics of adaptive divergence. We report the sequence, de novo assembly, and annotation of the jaguar (Panthera onca) genome, a novel genome sequence for the leopard (Panthera pardus), and comparative analyses encompassing all living Panthera species. Demographic reconstructions indicated that all of these species have experienced variable episodes of population decline during the Pleistocene, ultimately leading to small effective sizes in present-day genomes. We observed pervasive genealogical discordance across Panthera genomes, caused by both incomplete lineage sorting and complex patterns of historical interspecific hybridization. We identified multiple signatures of species-specific positive selection, affecting genes involved in craniofacial and limb development, protein metabolism, hypoxia, reproduction, pigmentation, and sensory perception. There was remarkable concordance in pathways enriched in genomic segments implicated in interspecies introgression and in positive selection, suggesting that these processes were connected. We tested this hypothesis by developing exome capture probes targeting ~19,000 Panthera genes and applying them to 30 wild-caught jaguars. We found at least two genes (DOCK3 and COL4A5, both related to optic nerve development) bearing significant signatures of interspecies introgression and within-species positive selection. These findings indicate that post-speciation admixture has contributed genetic material that facilitated the adaptive evolution of big cat lineages

DNM1 encephalopathy: A new disease of vesicle fission.

ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention

Cultural Psychology and Deconstructing Developmental Psychology

This paper looks at points of convergence and divergence between the different branches of cultural psychology and Burman's ideas in Deconstructing Developmental Psychology (DDP). The paper discusses the relationship between the developing ideas in cultural psychology over time and some of the shared theoretical and conceptual criticisms put forward in DDP. This takes into account some of the differences between symbolic approach, activity theory and an individualistic approach to cultural psychology. In turn, some of the bigger themes within the book are discussed such as the role of 'normalisation' and demarcation of age, and studying the child in context and how these relate to the different account of cultural psychology and the influence these themes have had on the author's own work. Since this paper details a personal research journey, examples are taken from work on home-school mathematics education, child language brokering and young caring. Using these examples, the paper examines how cultural psychology is interested in the mediation between culture and the person, whilst DDP asks us to question the stories and assumptions embedded within developmental psychology

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results:A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance:In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies

Developing consensus-based policy solutions for medicines adherence for Europe: a Delphi study

<p>Abstract</p> <p>Background</p> <p>Non-adherence to prescribed medication is a pervasive problem that can incur serious effects on patients’ health outcomes and well-being, and the availability of resources in healthcare systems. This study aimed to develop practical consensus-based policy solutions to address medicines non-adherence for Europe.</p> <p>Methods</p> <p>A four-round Delphi study was conducted. The Delphi Expert Panel comprised 50 participants from 14 countries and was representative of: patient/carers organisations; healthcare providers and professionals; commissioners and policy makers; academics; and industry representatives. Participants engaged in the study remotely, anonymously and electronically. Participants were invited to respond to open questions about the causes, consequences and solutions to medicines non-adherence. Subsequent rounds refined responses, and sought ratings of the relative importance, and operational and political feasibility of each potential solution to medicines non-adherence. Feedback of individual and group responses was provided to participants after each round. Members of the Delphi Expert Panel and members of the research group participated in a consensus meeting upon completion of the Delphi study to discuss and further refine the proposed policy solutions.</p> <p>Results</p> <p>43 separate policy solutions to medication non-adherence were agreed by the Panel. 25 policy solutions were prioritised based on composite scores for importance, and operational and political feasibility. Prioritised policy solutions focused on interventions for patients, training for healthcare professionals, and actions to support partnership between patients and healthcare professionals. Few solutions concerned actions by governments, healthcare commissioners, or interventions at the system level.</p> <p>Conclusions</p> <p>Consensus about practical actions necessary to address non-adherence to medicines has been developed for Europe. These actions are also applicable to other regions. Prioritised policy solutions for medicines non-adherence offer a benefit to policymakers and healthcare providers seeking to address this multifaceted, complex problem.</p

The Relevance of Maintaining Standing Forests for Global Climate Balance: A Case Study in Brazilian Forests

Estimate Net Ecosystem Exchange (NEE) is important to better understand carbon exchanges between terrestrial ecosystems and the atmosphere. Comprehend these dynamics is essential to better understand the responses of environments to ongoing climatic changes. This study aims to analyze, with AMERIFLUX and LBA network measurements, the variability of NEE and climate variables in four different tropical coverages: Pantanal, Amazonia, Caatinga and Cerrado (savanna). Furthermore, was estimate the Gross Primary Productivity (GPP). We found a distinct seasonality of meteorological variables and CO2 fluxes in each site. Despite acting mostly as a CO2 sink, some environments already show worrying source data in certain periods, pointed out as a direct effect of the reduction of photosynthesis caused by land use changes. The preserved forest plays an important role in maintaining rainfall at a regional and global level, and its maintenance makes it possible, by the way, an important tool in combating global warming via carbon sequestration by trees, which requires commitment and public policies of environmental preservation and recovery of degraded areas

Whole number thinking, learning and development: neuro-cognitive, cognitive and developmental approaches

The participants of working group 2 presented a broad range of studies, 11 papers in total, related to whole number learning representing research groups from 11 countries as follows. Two large cross-sectional studies focused on developmental aspects of young children’s number learning provide a lens for re-examining ‘traditional’ features of number acquisition. van den Heuvel-Panhuizen (the Netherlands) presented a co-authored paper with Elia (Cyprus; Elia and van den Heuvel-Panhuizen 2015) on a cross-cultural study of kindergartners’ number competence focused on counting, additive and multiplicative thinking. Second, Milinković (2015) examined the development of young Serbian children’s initial understanding of representations of whole numbers and counting strategies in a large study of 3- to 7-year-olds. Children’s invented (formal) representations such as set representation and the number line were found to be limited in their recordings. In a South African study focused on early counting and addition, Roberts (2015) directs attention to the role of teachers by providing a framework to support teachers’ interpretation of young disadvantaged learners’ representations of number when engaging with whole number additive tasks. Some papers reflected the increasing role of neuroscientific concepts and methodologies utilised in research on WNA learning and development. Sinclair and Coles (2015) drew upon neuroscientific research to highlight the significant role of symbol-to-symbol connections and the use of fingers and touch counting exempli- fied by the TouchCounts iPad app. Gould (2015) reported aspects of a large Australian large study of children in the first years of schooling aimed at improving numeracy and literacy in disadvantaged communities. A case study exemplified how numerals were identified by relying on a mental number line by using location to retrieve number names. This raised the question addressed in the neuroscientific work of Dehaene and other papers focused on individual differences in how the brain processes numbers. The Italian PerContare1 project (Baccaglini-Frank 2015) built upon the collaboration between cognitive psychologists and mathematics educators, aimed at developing teaching strategies for preventing and addressing early low achievement in arithmetic. It takes an innovative approach to the development of number sense that is grounded upon a kinaesthetic and visual-spatial approach to part-whole relationships. Mulligan and Woolcott (2015) provided a discussion paper on the underlying nature of number. They presented a broader view of mathematics learning (including WNA) as linked to spatial interaction with the environment; the concept of connectivity across concepts and the development of underlying pattern and structural relationships are central to their approach