The iminosugar AMP-DNM improves satiety and activates brown adipose tissue through GLP1

Obesity is taking worldwide epidemic proportions, yet effective pharmacological agents with long-term efficacy remain unavailable. Previously, we designed the iminosugar AMP-DNM which potently improves glucose homeostasis by lowering excessive glycosphingolipids. Here we show that AMP-DNM promotes satiety and activates brown adipose tissue (BAT) in obese rodents. Moreover, we demonstrate that the mechanism mediating these favorable actions depends on oral, but not central, administration of AMP-DNM, which ultimately stimulates systemic glucagon-like peptide-1 (GLP1) secretion. We evidence an essential role of brain GLP1 receptors (GLP1r) as AMP-DNM fails to promote satiety and activate BAT in mice lacking the brain GLP1r as well as in mice treated intracerebroventricularly with GLP1r antagonist exendin-9. In conclusion, AMP-DNM markedly ameliorates metabolic abnormalities in obese rodents by restoring satiety and activating BAT through central GLP1r, while improving glucose homeostasis by mechanisms independent of central GLP1r.Bio-organic SynthesisMedical Biochemistr

Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism

Performance of maize single-crosses developed from populations improved by a modified reciprocal recurrent selection Performance de híbridos simples de milho desenvolvidos de populações melhoradas por seleção recorrente recíproca modificada

Maize (Zea mays L.) elite inbred lines developed from pedigree programs tend to be genetically related. Therefore, it is necessary to incorporate unrelated inbreds to those programs to allow the continued release of outstanding single-crosses. The objectives of this research were to compare the usefulness of a modified reciprocal recurrent selection procedure (MRRS) to improve populations to be used as sources of elite inbreds and outstanding single-crosses to integrate pedigree programs, and to investigate the effects of selection on the relative contribution of general (GCA) and specific combining (SCA) abilities to the single-crosses variation. Eight and six S3 lines from populations IG-3-C1 and IG-4-C1, respectively, selected from the first cycle of the MRRS program were crossed in a partial-diallel mating design, and the 48 experimental and five commercial single-crosses were evaluated in six environments. Grain yield mean of the experimental single-crosses (9.57 t ha¹) did not differ from the commercial single-crosses (9.86 t ha¹), and ten of the 48 experimental single-crosses could be released as cultivars because they compared favorably to the currently used single-crosses. Thus, one cycle of the MRRS procedure improved efficiently the populations allowing the development of outstanding single-cross, but additional cycles of selection should be carried out since none of the experimental single-crosses outperformed the highest yielding commercial single-cross. The relative contribution of the GCA over SCA may have been affected by the MRRS, since the SCA was more important than GCA for some of the traits assessed.<br>Linhagens elites de milho (Zea mays L.) desenvolvidas em programas genealógicos tendem a ser geneticamente relacionadas. Portanto, é necessário incorporar linhagens não relacionadas a estes programas para permitir a liberação contínua de híbridos simples superiores. Comparou-se a utilidade de um procedimento modificado de seleção recorrente recíproca (SRRM) em melhorar populações a serem utilizadas como fontes de linhagens elites e híbridos simples superiores para integrar os programas de melhoramento, e investigar os efeitos da seleção na contribuição relativa da capacidade geral (CGC) e da capacidade específica (CEC) de combinação para a variabilidade dos híbridos simples. Oito e seis linhagens S3 obtidas das populações IG-3-C1 e IG-4-C1, respectivamente, selecionadas do primeiro ciclo de SRRM, foram cruzadas no delineamento dialelo parcial e os 48 híbridos simples experimentais (HSE) e cinco híbridos simples comerciais (HSC) foram avaliados em seis ambientes. A média geral de produção de grãos dos HSE (9.57 t ha¹) não diferiu significativamente dos HSC (9.86 t ha¹), e dez dos 48 HSE poderiam ser liberados como cultivares, pois são comparáveis aos híbridos simples comerciais. Portanto, um ciclo de SRRM foi eficiente em melhorar as populações permitindo a produção de híbridos simples superiores, mas ciclos adicionais de seleção deverão ser conduzidos, pois nenhum dos HSE superou o híbrido simples comercial mais produtivo. As contribuições relativas da CGC e da CEC podem ter sido afetadas pela SRRM, uma vez que a CEC foi mais importante que a CGC para alguns caracteres avaliados

General discussion

SCOPUS: cp.jinfo:eu-repo/semantics/publishe