3-hydroxy-L-kynurenamine is an immunomodulatory biogenic amine

Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-l-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-gamma mediated STAT1/NF-kappa Beta pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1 beta, IFN-gamma, and IL-17 production, and inhibiting generation of effector CD8(+) T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance. 3-hydroxy-L-kynurenamine (3-HKA) is a metabolite deriving from a lateral pathway of tryptophan catabolism. Here the authors identify 3-HKA as a biogenic amine and show it has anti-inflammatory properties that can protect mice against psoriasis and nephrotoxic nephritis.Peer reviewe

Capturing sequence diversity in metagenomes with comprehensive and scalable probe design.

Metagenomic sequencing has the potential to transform microbial detection and characterization, but new tools are needed to improve its sensitivity. Here we present CATCH, a computational method to enhance nucleic acid capture for enrichment of diverse microbial taxa. CATCH designs optimal probe sets, with a specified number of oligonucleotides, that achieve full coverage of, and scale well with, known sequence diversity. We focus on applying CATCH to capture viral genomes in complex metagenomic samples. We design, synthesize, and validate multiple probe sets, including one that targets the whole genomes of the 356 viral species known to infect humans. Capture with these probe sets enriches unique viral content on average 18-fold, allowing us to assemble genomes that could not be recovered without enrichment, and accurately preserves within-sample diversity. We also use these probe sets to recover genomes from the 2018 Lassa fever outbreak in Nigeria and to improve detection of uncharacterized viral infections in human and mosquito samples. The results demonstrate that CATCH enables more sensitive and cost-effective metagenomic sequencing

Genome sequencing reveals Zika virus diversity and spread in the Americas

Although the recent Zika virus (ZIKV) epidemic in the Americas and its link to birth defects have attracted a great deal of attention, much remains unknown about ZIKV disease epidemiology and ZIKV evolution, in part owing to a lack of genomic data. Here we address this gap in knowledge by using multiple sequencing approaches to generate 110 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak. We analysed the timing and patterns of introductions into distinct geographic regions; our phylogenetic evidence suggests rapid expansion of the outbreak in Brazil and multiple introductions of outbreak strains into Puerto Rico, Honduras, Colombia, other Caribbean islands, and the continental United States. We find that ZIKV circulated undetected in multiple regions for many months before the first locally transmitted cases were confirmed, highlighting the importance of surveillance of viral infections. We identify mutations with possible functional implications for ZIKV biology and pathogenesis, as well as those that might be relevant to the effectiveness of diagnostic tests

Improved upper limb function in non-ambulant children with SMA type 2 and 3 during nusinersen treatment: a prospective 3-years SMArtCARE registry study

Background The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months. Methods SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Results Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score. Conclusion Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity

Gripe aviária : entusiasmo ou preocupação?

O objetivo deste caso é avaliar como o aparecimento de uma doença de aves (Gripe Aviária ou Influenza Aviária) em países importadores de carne de frango, desde 2001, está influenciando o comércio internacional de produtos avícolas. Foram analisadas as oportunidades do Brasil e, em especial, de uma empresa exportadora de frangos, a Avesul, de melhorar a penetração em mercados ainda não explorados, e aumentar faturamento de exportação. Também, foi avaliado o risco da Gripe Aviária entrar no Brasil, e como esta doença poderia afetar a produção e exportação de frangos do país e da Avesul. O protagonista do caso, presidente da empresa Avesul, Sr. Paulo Carvalho, ao analisar o cenário mundial relacionado com a Gripe Aviária, que num momento faz com que a demanda internacional por carne de frangos se incremente, e em outro momento agita o mercado mundial, reduzindo o consumo de carne de frangos pela população, se depara com o seguinte dilema: entusiasma-se com a possibilidade de aumentar as exportações de carne de frangos, aumentando a penetração de vendas em mercados mais exigentes, e por conseqüência, de maior lucratividade, projetando então um aumento da produção de carne em sua empresa, alocando para isto recursos para investimentos em novos abatedouros, e para implementação de sistemas de qualidade em toda a cadeia de produção de frangos ou, ao contrário, preocupa-se com a crise no setor produtivo de carne de frangos, causado pela queda no consumo e nos preços, influenciados pelos novos surtos de Gripe Aviária surgidos na Europa, e reduz a produção de carne da empresa, fechando abatedouros? Após avaliar várias estratégias, a empresa optou por dar segmento ao seu processo de expansão e qualificação das exportações, projetando para isto uma série de melhorias em seus processos produtivos, além da estruturação de um departamento de comércio exterior mais agressivo e atuante. O objetivo estratégico da empresa foi definido como: ser uma das maiores e melhores empresas produtoras e exportadoras de carne de frangos do país

Gripe aviária : entusiasmo ou preocupação?

O objetivo deste caso é avaliar como o aparecimento de uma doença de aves (Gripe Aviária ou Influenza Aviária) em países importadores de carne de frango, desde 2001, está influenciando o comércio internacional de produtos avícolas. Foram analisadas as oportunidades do Brasil e, em especial, de uma empresa exportadora de frangos, a Avesul, de melhorar a penetração em mercados ainda não explorados, e aumentar faturamento de exportação. Também, foi avaliado o risco da Gripe Aviária entrar no Brasil, e como esta doença poderia afetar a produção e exportação de frangos do país e da Avesul. O protagonista do caso, presidente da empresa Avesul, Sr. Paulo Carvalho, ao analisar o cenário mundial relacionado com a Gripe Aviária, que num momento faz com que a demanda internacional por carne de frangos se incremente, e em outro momento agita o mercado mundial, reduzindo o consumo de carne de frangos pela população, se depara com o seguinte dilema: entusiasma-se com a possibilidade de aumentar as exportações de carne de frangos, aumentando a penetração de vendas em mercados mais exigentes, e por conseqüência, de maior lucratividade, projetando então um aumento da produção de carne em sua empresa, alocando para isto recursos para investimentos em novos abatedouros, e para implementação de sistemas de qualidade em toda a cadeia de produção de frangos ou, ao contrário, preocupa-se com a crise no setor produtivo de carne de frangos, causado pela queda no consumo e nos preços, influenciados pelos novos surtos de Gripe Aviária surgidos na Europa, e reduz a produção de carne da empresa, fechando abatedouros? Após avaliar várias estratégias, a empresa optou por dar segmento ao seu processo de expansão e qualificação das exportações, projetando para isto uma série de melhorias em seus processos produtivos, além da estruturação de um departamento de comércio exterior mais agressivo e atuante. O objetivo estratégico da empresa foi definido como: ser uma das maiores e melhores empresas produtoras e exportadoras de carne de frangos do país

Integration of mature adipocytes to build up a functional three-layered full-skin equivalent

Large, deep full-thickness skin wounds from high-graded burns or trauma are not able to reepithelialize sufficiently, resulting in scar formation, mobility limitations, and cosmetic deformities. In this study, in vitro-constructed tissue replacements are needed. Furthermore, such full-skin equivalents would be helpful as in vivo-like test systems for toxicity, cosmetic, and pharmaceutical testing. Up to date, no skin equivalent is available containing the underlying subcutaneous fatty tissue. In this study, we composed a full-skin equivalent and evaluated three different media for the coculture of mature adipocytes, fibroblasts, and keratinocytes. Therefore, adipocyte medium was supplemented with ascorbyl-2-phosphate and calcium chloride, which are important for successful epidermal stratification (Air medium). This medium was further supplemented with two commercially available factor combinations often used for the in vitro culture of keratinocytes (Air-HKGS and Air- KGM medium). We showed that in all media, keratinocytes differentiated successfully to build a stratified epidermal layer and expressed cytokeratin 10 and 14. Perilipin A-positive adipocytes could be found in all tissue models for up to 14 days, whereas adipocytes in the Air-HKGS and Air-KGM medium seemed to be smaller. Adipocytes in all tissue models were able to release adipocyte-specific factors, whereas the supplementation of keratinocyte-specific factors had a slightly negative effect on adipocyte functionality. The permeability of the epidermis of all models was comparable since they were able to withstand a deep penetration of cytotoxic Triton X in the same manner. Taken together, we were able to compose functional three-layered fullskin equivalents by using the Air medium