Identification of nesfatin-1 as a satiety molecule in the hypothalamus

The brain hypothalamus contains certain secreted molecules that are important in regulating feeding behaviour. Here we show that nesfatin, corresponding to NEFA/nucleobindin2 (NUCB2), a secreted protein of unknown function, is expressed in the appetite-control hypothalamic nuclei in rats. Intracerebroventricular (i.c.v.) injection of NUCB2 reduces feeding. Rat cerebrospinal fluid contains nesfatin-1, an amino-terminal fragment derived from NUCB2, and its expression is decreased in the hypothalamic paraventricular nucleus under starved conditions. I.c.v. injection of nesfatin-1 decreases food intake in a dose-dependent manner, whereas injection of an antibody neutralizing nesfatin-1 stimulates appetite. In contrast, i.c.v. injection of other possible fragments processed from NUCB2 does not promote satiety, and conversion of NUCB2 to nesfatin-1 is necessary to induce feeding suppression. Chronic i.c.v. injection of nesfatin-1 reduces body weight, whereas rats gain body weight after chronic i.c.v. injection of antisense morpholino oligonucleotide against the gene encoding NUCB2. Nesfatin-1-induced anorexia occurs in Zucker rats with a leptin receptor mutation, and an anti-nesfatin-1 antibody does not block leptin-induced anorexia. In contrast, central injection of alpha-melanocyte-stimulating hormone elevates NUCB2 gene expression in the paraventricular nucleus, and satiety by nesfatin-1 is abolished by an antagonist of the melanocortin-3/4 receptor. We identify nesfatin-1 as a satiety molecule that is associated with melanocortin signalling in the hypothalamus.     

Dampening of death pathways by schnurri-2 is essential for T-cell development

Generation of a diverse and self-tolerant T-cell repertoire requires appropriate interpretation of T-cell antigen receptor (TCR) signals by CD4(+?) CD8(+) double-positive thymocytes. Thymocyte cell fate is dictated by the nature of TCR-major-histocompatibility-complex (MHC)-peptide interactions, with signals of higher strength leading to death (negative selection) and signals of intermediate strength leading to differentiation (positive selection). Molecules that regulate T-cell development by modulating TCR signal strength have been described but components that specifically define the boundaries between positive and negative selection remain unknown. Here we show in mice that repression of TCR-induced death pathways is critical for proper interpretation of positive selecting signals in vivo, and identify schnurri-2 (Shn2; also known as Hivep2) as a crucial death dampener. Our results indicate that Shn2(-/-) double-positive thymocytes inappropriately undergo negative selection in response to positive selecting signals, thus leading to disrupted T-cell development. Shn2(-/-) double-positive thymocytes are more sensitive to TCR-induced death in vitro and die in response to positive selection interactions in vivo. However, Shn2-deficient thymocytes can be positively selected when TCR-induced death is genetically ablated. Shn2 levels increase after TCR stimulation, indicating that integration of multiple TCR-MHC-peptide interactions may fine-tune the death threshold. Mechanistically, Shn2 functions downstream of TCR proximal signalling compenents to dampen Bax activation and the mitochondrial death pathway. Our findings uncover a critical regulator of T-cell development that controls the balance between death and differentiation.     

Permanent El Niño during the Pliocene warm period not supported by coral evidence

The El Ni?o/Southern Oscillation (ENSO) system during the Pliocene warm period (PWP; 3-5 million years ago) may have existed in a permanent El Ni?o state with a sharply reduced zonal sea surface temperature (SST) gradient in the equatorial Pacific Ocean. This suggests that during the PWP, when global mean temperatures and atmospheric carbon dioxide concentrations were similar to those projected for near-term climate change, ENSO variability--and related global climate teleconnections-could have been radically different from that today. Yet, owing to a lack of observational evidence on seasonal and interannual SST variability from crucial low-latitude sites, this fundamental climate characteristic of the PWP remains controversial. Here we show that permanent El Ni?o conditions did not exist during the PWP. Our spectral analysis of the δ(18)O SST and salinity proxy, extracted from two 35-year, monthly resolved PWP Porites corals in the Philippines, reveals variability that is similar to present ENSO variation. Although our fossil corals cannot be directly compared with modern ENSO records, two lines of evidence suggest that Philippine corals are appropriate ENSO proxies. First, δ(18)O anomalies from a nearby live Porites coral are correlated with modern records of ENSO variability. Second, negative-δ(18)O events in the fossil corals closely resemble the decreases in δ(18)O seen in the live coral during El Ni?o events. Prior research advocating a permanent El Ni?o state may have been limited by the coarse resolution of many SST proxies, whereas our coral-based analysis identifies climate variability at the temporal scale required to resolve ENSO structure firmly.     

Common variation in GPC5 is associated with acquired nephrotic syndrome

Severe proteinuria is a defining factor of nephrotic syndrome irrespective of the etiology. Investigation of congenital nephrotic syndrome has shown that dysfunction of glomerular epithelial cells (podocytes) plays a crucial role in this disease. Acquired nephrotic syndrome is also assumed to be associated with podocyte injury. Here we identify an association between variants in GPC5, encoding glypican-5, and acquired nephrotic syndrome through a genome-wide association study and replication analysis (P value under a recessive model (P(rec)) = 6.0 × 10(-11), odds ratio = 2.54). We show that GPC5 is expressed in podocytes and that the risk genotype is associated with higher expression. We further show that podocyte-specific knockdown and systemic short interfering RNA injection confers resistance to podocyte injury in mouse models of nephrosis. This study identifies GPC5 as a new susceptibility gene for nephrotic syndrome and implicates GPC5 as a promising therapeutic target for reducing podocyte vulnerability in glomerular disease.     

Al-Pd-Mn-Mg、Al-Pd-Mn-Zn和Al-Pd-Mn-Mg-Zn系准晶态合金的研究

本文研究了Al-Pd-Mn-Mg、Al-Pd-Mn-Zn和Al-Pd-Mn-Mg-Zn三种多元系合金的准晶形成规律、准晶态合金的成分范围和热稳定性。研究结果表明,Al-Pd-Mn-Mg系准晶态合金的成分范围基本上可按以下范围选择构成,Al:60～80(at％)、Pd:0～20(at％)、Mn:0～10(a％)、Mg:0～10(at％),而Al-Pd-Mn-Zn为Al:60～75(at％)、Pd:0～20(at％)、Mn:0～10(at％)、Zn:0～10(at％),Al-Pd-Mn-Mg-Zn为Al:60～5(at％)、Pd:0～20(at％)、Mg:0～5(at％)、Zn:0～5(at％)。三种系列的准晶态合金均为非热稳定性准晶,其晶化温度约为673～873K左右。     

Al-Cu-Fe-Pd-Mn和Al-Cr-Pd-Mn系准晶态合金的研究

研究了Al-Cu-Fe-Pd-Mn和Al-Cr-Pd-Mn两种多元系合金的准晶形成规律、准晶态合金的成分范围和准晶的热稳定性。研究结果表明,Al-Cu-Fe-Pd-Mn准晶态合金的成分范围基本上可按如下范围选择构成,Al:60～75(at％),Cu:0～20(at％),Fe:0～15(at％),Pd:0～20(at％),Mn:0～10(at％)。这类多元系准晶是一种热稳定性准晶。Al-Cr-Pd-Mn准晶态合金的成分范围可按如下范围选择构成,Al:65～85(at％),Cr:0～15(at％),Pd:0～20(at％),Mn:0～10(at％)。在Al-Cr-Pd-Mn多元系准晶中,当Cr含量较低时为热稳定性准晶;当Cr含量较高时为非热稳定性准晶。