Engineered Knottin Peptide Enables Noninvasive Optical Imaging of Intracranial Medulloblastoma

Central nervous system tumors carry grave clinical prognoses due to limited effectiveness of surgical resection, radiation, and chemotherapy. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. We demonstrate that mouse cerebellar medulloblastoma (MB) can be targeted and illuminated with a fluorescent, engineered cystine knot (knottin) peptide that binds with high affinity to α β , α β , and α β integrin receptors. This integrin-binding knottin peptide, denoted EETI 2.5F, was evaluated as a molecular imaging probe in both orthotopic and genetic models of MB. Following tail vein injection, fluorescence arising from dye-conjugated EETI 2.5F was localized to the tumor compared with the normal surrounding brain tissue, as measured by optical imaging. The imaging signal intensity correlated with tumor volume. Due to its unique ability to bind to α β integrin, EETI 2.5F showed superior in vivo and ex vivo brain tumor imaging contrast compared with other engineered integrin-binding knottin peptides and with c(RGDfK), a well-studied integrin-binding peptidomimetic. Next, EETI 2.5F was fused to an antibody fragment crystallizable (Fc) domain (EETI 2.5F-Fc) to determine if a larger integrin-binding protein could also target intracranial brain tumors. EETI 2.5F-Fc, conjugated to a fluorescent dye, illuminated MB following i.v. injection and was able to distribute throughout the tumor parenchyma. In contrast, brain tumor imaging signals were not detected in mice injected with EETI 2.5F proteins containing a scrambled integrin-binding sequence, demonstrating the importance of target specificity. These results highlight the potential of using EETI 2.5F and EETI 2.5-Fc as targeted molecular probes for brain tumor imaging

Uncertainty of Forest Biomass Estimates in North Temperate Forests Due to Allometry: Implications for Remote Sensing

Estimates of above ground biomass density in forests are crucial for refining global climate models and understanding climate change. Although data from field studies can be aggregated to estimate carbon stocks on global scales, the sparsity of such field data, temporal heterogeneity and methodological variations introduce large errors. Remote sensing measurements from spaceborne sensors are a realistic alternative for global carbon accounting; however, the uncertainty of such measurements is not well known and remains an active area of research. This article describes an effort to collect field data at the Harvard and Howland Forest sites, set in the temperate forests of the Northeastern United States in an attempt to establish ground truth forest biomass for calibration of remote sensing measurements. We present an assessment of the quality of ground truth biomass estimates derived from three different sets of diameter-based allometric equations over the Harvard and Howland Forests to establish the contribution of errors in ground truth data to the error in biomass estimates from remote sensing measurements

Evidence for the role of EPHX2 gene variants in anorexia nervosa.

Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-ß (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P=0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P=0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus P<0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N=229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (P<0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition

Regenerating zebrafish scales express a subset of evolutionary conserved genes involved in human skeletal disease

BACKGROUND: Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration. RESULTS: We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases (P< 2× 10(−3)). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height (P< 6× 10(−4)), and estimated bone mineral density (eBMD, P< 2× 10(−5)). Zebrafish mutants of two human orthologues that were robustly associated with height (COL11A2, P=6× 10(−24)) or eBMD (SPP1, P=6× 10(−20)) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2(Y228X/Y228X) mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1(P160X/P160X) mutants predominantly showed mineralisation defects. CONCLUSION: We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-021-01209-8

Gender differences in the impact of population-level alcohol policy interventions: evidence synthesis of systematic reviews

Background: Consistent review-level evidence supports the effectiveness of population-level alcohol policies in reducing alcohol-related harms. Such policies interact with well-established social, cultural and biological differences in how men and women perceive, relate to and use alcohol, and with wider inequalities, in ways which may give rise to gender differences in policy effectiveness.  Aims: To examine the extent to which gender-specific data and analyses were considered in, and are available from, systematic reviews of population-level alcohol policy interventions, and where possible, to conduct a narrative synthesis of relevant data.  Methods: A prior systematic ‘review of reviews’ of population level alcohol interventions 2002-2012 was updated to May 2014, all gender-relevant data extracted, and the level and quality of gender reporting assessed. A narrative synthesis of extracted findings was conducted.  Results: Sixty-three systematic reviews, covering ten policy areas, were included. Five reviews (8%) consistently provided information on baseline participation by gender for each individual study in the review and twenty-nine (46%) reported some gender-specific information on the impact of the policies under consideration. Specific findings include evidence of possible gender differences in the impact of and exposure to alcohol marketing, and a failure to consider potential unintended consequences and harm to others in most reviews.  Conclusions: Gender is poorly reported in systematic reviews of population-level interventions to reduce alcohol-related harm, hindering assessment of the intended and unintended effects of such policies on women and men

O FUTURO DA AMAZÔNIA: MODELOS PARA PREVER AS CONSEQÜÊNCIAS DA INFRAESTRUTURA FUTURA NOS PLANOS PLURIANUAIS

Desde 1996 o planejamento de investimentos do governo brasileiro tem sido organizado em planos quadrianuais: Brasil em Ação (1996-1999), Avança Brasil (2000-2003), PPA [Plano Plurianual] (2004-2007), PAC [Programa de Aceleração do Crescimento] (2008-2011), e PAC-2 (2012-2015). Cada plano tem incluído uma longa lista de rodovias, barragens e outros grandes projetos de infraestrutura na Amazônia. Vários desses projetos têm sido incluídos em uma série de planos, pois restrições econômicas não permitiram a realização das obras no ritmo inicialmente imaginado. Este é o caso de obras como a hidrelétrica de Belo Monte e as rodovias BR-163 (Santarém-Cuiabá) e BR-319 (Manaus-Porto Velho). Estes projetos adiados estão hoje sendorealizados ou próximos à realização. Uma série de modelos tem sido elaborada por diferentes grupos para prever as consequências futuras, caso essas obras sejam realizadas. Diferentes modelos captam diferentes aspectos da problemática, e vários deles indicam grandes aumentos de desmatamento e degradação, com graves implicações ambientais e sociais. Um dos modelos parte da premissa de que as estradas teriam efeitos nulos ou até benéficos sobre total de desmatamento, mas essa suposição contradiz o que é observado no mundo real

Rationale, design, and results of the first screening round of a comprehensive, register-based, Chlamydia screening implementation programme in the Netherlands

<p>Abstract</p> <p>Background</p> <p>Implementing <it>Chlamydia trachomatis </it>screening in the Netherlands has been a point of debate for several years. The National Health Council advised against implementing nationwide screening until additional data collected from a pilot project in 2003 suggested that screening by risk profiles could be effective. A continuous increase in infections recorded in the national surveillance database affirmed the need for a more active approach. Here, we describe the rationale, design, and implementation of a <it>Chlamydia </it>screening demonstration programme.</p> <p>Methods</p> <p>A systematic, selective, internet-based <it>Chlamydia </it>screening programme started in April 2008. Letters are sent annually to all 16 to 29-year-old residents of Amsterdam, Rotterdam, and selected municipalities of South Limburg. The letters invite sexually active persons to login to <url>http://www.chlamydiatest.nl</url> with a personal code and to request a test kit. In the lower prevalence area of South Limburg, test kits can only be requested if the internet-based risk assessment exceeds a predefined value.</p> <p>Results</p> <p>We sent invitations to 261,025 people in the first round. One-fifth of the invitees requested a test kit, of whom 80% sent in a sample for testing. The overall positivity rate was 4.2%.</p> <p>Conclusions</p> <p>This programme advances <it>Chlamydia </it>control activities in the Netherlands. Insight into the feasibility, effectiveness, cost-effectiveness, and impact of this large-scale screening programme will determine whether the programme will be implemented nationally.</p

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P &lt; 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P &lt; 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

Medicos, poultice wallahs and comrades in service: masculinity and military medicine in Britain during the First World War

The subject of British military medicine during the First World War has long been a fruitful one for historians of gender. From the bodily inspection of recruits and conscripts through the expanding roles of women as medical care providers to the physical and emotional aftermath of conflict experienced by men suffering from war-related wounds and illness, the medical history of the war has shed important light on how the war shaped British masculinities and femininities as cultural, subjective and embodied identities. Much of this literature has, however, focused on the gendered identities of female nurses and sick and wounded servicemen. Increasingly, however, more complex understandings of the ways in which medical caregiving in wartime shaped the gender identities of male caregivers are starting to emerge. This article explores some of these emerging understandings of the masculinity of male medical caregivers, and their relationship to the wider literature around the complex and sometimes contradictory relationship between warfare and medicine. It examines the ways in which the masculine identity of male medical caregivers from the ranks of the Royal Army Medical Corps, namely stretcher bearers and medical orderlies, was perceived and represented both by the men themselves and those they cared for. In doing so it argues that total war played a crucial role in shaping social and cultural perceptions of caregiving as a gendered practice. It also identifies particular tensions between continuity and change in social understandings of medical care as a gendered practice which would continue to shape twentieth-century British society in the war’s aftermath