Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling

Obesity is a major public health problem in most developed countries and a major risk factor for diabetes and cardiovascular disease. Emerging evidence indicates that ciliary dysfunction can contribute to human obesity but the underlying molecular and cellular mechanisms are unknown. Bardet-Biedl syndrome (BBS) is a genetically heterogeneous human obesity syndrome associated with ciliary dysfunction. BBS proteins are thought to play a role in cilia function and intracellular protein/vesicle trafficking. Here, we show that BBS proteins are required for leptin receptor (LepR) signaling in the hypothalamus. We found that Bbs2−/−, Bbs4−/− and Bbs6−/− mice are resistant to the action of leptin to reduce body weight and food intake regardless of serum leptin levels and obesity. In addition, activation of hypothalamic STAT3 by leptin is significantly decreased in Bbs2−/−, Bbs4−/− and Bbs6−/− mice. In contrast, downstream melanocortin receptor signaling is unaffected, indicating that LepR signaling is specifically impaired in Bbs2−/−, Bbs4−/− and Bbs6−/− mice. Impaired LepR signaling in BBS mice was associated with decreased Pomc gene expression. Furthermore, we found that BBS1 protein physically interacts with the LepR and that loss of BBS proteins perturbs LepR trafficking. Our data indicate that BBS proteins mediate LepR trafficking and that impaired LepR signaling underlies energy imbalance in BBS. These findings represent a novel mechanism for leptin resistance and obesity

Ronald E. McNair Scholars Program Profiles and Abstracts 2022

This is the complete event program and provides presentation abstracts and biographies of McNair scholars and their mentors

ARH-seq: identification of differential splicing in RNA-seq data

The computational prediction of alternative splicing from high-throughput sequencing data is inherently difficult and necessitates robust statistical measures because the differential splicing signal is overlaid by influencing factors such as gene expression differences and simultaneous expression of multiple isoforms amongst others. In this work we describe ARH-seq, a discovery tool for differential splicing in case-control studies that is based on the information-theoretic concept of entropy. ARH-seq works on high-throughput sequencing data and is an extension of the ARH method that was originally developed for exon microarrays. We show that the method has inherent features, such as independence of transcript exon number and independence of differential expression, what makes it particularly suited for detecting alternative splicing events from sequencing data. In order to test and validate our workflow we challenged it with publicly available sequencing data derived from human tissues and conducted a comparison with eight alternative computational methods. In order to judge the performance of the different methods we constructed a benchmark data set of true positive splicing events across different tissues agglomerated from public databases and show that ARH-seq is an accurate, computationally fast and high-performing method for detecting differential splicing events

Biochem Biophys Res Commun

Polymerase chain reaction (PCR) has become a fundamental technique in molecular biology. Nonetheless, further improvements of the existing protocols are required to broaden the applicability of PCR for routine diagnostic purposes, to enhance the specificity and the yield of PCRs as well as to reduce the costs for high-throughput applications. One known problem typically reported in PCR experiments is the poor amplification of GC-rich DNA sequences. Here we designed and tested a novel effective and low-cost PCR enhancer, a concentration-dependent combination of betaine, dithiothreitol, and dimethyl sulfoxide that broadly enhanced the quantitative and/or qualitative output of PCRs. Additionally, we showed that the performances of this enhancer mix are comparable to those of commercially available PCR additives and highly effective with different DNA polymerases. Thus, we propose the routine application of this PCR enhancer mix for low- and high-throughput experiments

Molecular cloning and characterization of the Fugu rubripes MEST/COPG2 imprinting cluster and chromosomal localization in Fugu and Tetraodon nigroviridis

We isolated Fugu genomic clones using the human MEST (Mesoderm-Specific Transcript) cDNA as probe. Sequence analysis revealed the presence of MEST and three additional genes which show homology to plant DNBP (DNA-Binding Protein), vertebrate COPG2 (Coat Protein Gamma 2), as well as to human and mouse UCN (Urocortin). Structures of Fugu and human MEST, COPG2 and UCN genes are very similar. Since MEST and COPG2 are neighboring genes on human chromosome 7q32, we can conclude that we identified their orthologs and that linkage of these genes is evolutionarily conserved in vertebrates. Unlike human MEST which underlies isoform-specific imprinting and is methylated in a parent-of-origin-specific fashion, the CpG island of the Fugu ortholog is completely methylated. The translation start of Fugu MEST is identical to the non-imprinted human isoform which is in good agreement with the assumption that genomic imprinting is restricted to mammals. Comparative mapping of these genes by fluorescence in-situ hybridization to metaphase chromosomes of Fugu rubripes and Tetraodon nigroviridis showed clear signals on one of the smallest acrocentric chromosomal pairs, which in Fugu, can be easily classified by its unique triangular shape

Nietzsche et la pensée indienne

Dans son œuvre, Nietzsche se réfère sporadiquement à la pensée de l'Inde p attaquer avec violence la pensée chrétienne car les chrétiens d'après lui ont fait de la souffran argument contre la vie, tel ne serait pas le cas des brahmanes et des bouddhistes. Trois idées dominent le rapport de Nietzsche à la pensée indienne. La première est l'oubli de la philosophie indienne dans les recherches universitaires. La deuxième est la philosophie brahmanique vue d'abord sous l'ascétisme comparé entre brahmanes et chrétiens, ensuite sous les Lois de Manou qui exaltent l'inégalitédes droits et des personnes : les brahmanes ont su prendre le pouvoir sur les dieux et les hommes. La troisième idée est la philosophie bouddhique : Nietzsche considèreque dans le bouddhisme la volontéde néant l'emporte sur la volonté de vie; ensuite, il invente, d'une part, un bouddhisme physiologique opposé à la morale chrétienne, d'autre part un bouddhisme européen , synonyme d'un retour des idéaux chrétiens moins le Christ en croixIn his books, Nietzsche reports sporadically on the thought of India in aim to attack with violence christian thought because christians according to him, use suffering like an argument against life, this situation would be different on Brahmans and Buddhists. Three ideas dominate the references of Nietzsche with Indian thought : the first is the forgetting of Indian philosophy in College researches. The second is the brahmanic philosophy seeing, at first on comparative ascetism between brahmans and christians, and, at second on The Laws of Manu with the idea of unequal rights and persons : brahmans have said to bring the power on Gods and men. The third idea is the buddhist philosophy : in buddhism, Nietzsche considers that will of nothing wins on will of life ; and he invents, on one hand a physiologic buddhism against christian morals, and on second hand a European buddhism which sees like a return of the christian moral ideal without Christ on crosswise.PARIS4-BU Serpente (751052129) / SudocSudocFranceF