The prevention of experimentally induced reticulo-sarcoma by hypothyroidism

Zusammenfassung Die Entstehung von Reticulosarkom bei Ratten nach mehrmaliger Injektion von Trypanblau kann unterdrückt werden durch Entkräftung, Verabreichung anti-thyreoidaler Mittel und durch alle andern Faktoren, welche den Stoffwechsel herabsetzen.     

A short-term sink for atmospheric CO2 in subtropical mode water of the North Atlantic Ocean

Large-scale features of ocean circulation, such as deep water formation in the northern North Atlantic Ocean, are known to regulate the long-term physical uptake of CO2 from the atmosphere by moving CO2-laden surface waters into the deep ocean. But the importance of CO2 uptake into water masses that ventilate shallower ocean depths, such as subtropical mode waters of the subtropical gyres, are poorly quantified. Here we report that, between 1988 and 2001, dissolved CO2 concentrations in subtropical mode waters of the North Atlantic have increased at a rate twice that expected from these waters keeping in equilibrium with increasing atmospheric CO2. This accounts for an extra 0.4-2.8 Pg C (1 Pg = 10(15) g) over this period (that is, about 0.03-0.24 Pg C yr(-1)), equivalent to 3-10% of the current net annual ocean uptake of CO2 (ref. 3). We suggest that the lack of strong winter mixing events, to greater than 300 m in depth, in recent decades is responsible for this accumulation, which would otherwise disturb the mode water layer and liberate accumulated CO2 back to the atmosphere. However, future climate variability (which influences subtropical mode water formation) and changes in the North Atlantic Oscillation (leading to a return of deep winter mixing events) may reduce CO2 accumulation in subtropical mode waters. We therefore conclude that, although CO2 uptake by subtropical mode waters in the North Atlantic--and possibly elsewhere--does not always represent a long-term CO2 sink, the phenomenon is likely to contribute substantially to interannual variability in oceanic CO2 uptake.     

Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4

Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns, and members of the pro-inflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains called Toll/IL-1R/plant R gene homology (TIR) domains. Intracellular signalling mechanisms mediated by TIRs are similar, with MyD88 (refs 5-8) and TRAF6 (refs 9, 10) having critical roles. Signal transduction between MyD88 and TRAF6 is known to involve the serine-threonine kinase IL-1 receptor-associated kinase 1 (IRAK-1) and two homologous proteins, IRAK-2 (ref. 12) and IRAK-M. However, the physiological functions of the IRAK molecules remain unclear, and gene-targeting studies have shown that IRAK-1 is only partially required for IL-1R and TLR signalling. Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs. IRAK-4-deficient animals are completely resistant to a lethal dose of lipopolysaccharide (LPS). In addition, animals lacking IRAK-4 are severely impaired in their responses to viral and bacterial challenges. Our results indicate that IRAK-4 has an essential role in innate immunity.     

Inactivation of the p53 pathway in retinoblastoma

Most human tumours have genetic mutations in their Rb and p53 pathways, but retinoblastoma is thought to be an exception. Studies suggest that retinoblastomas, which initiate with mutations in the gene retinoblastoma 1 (RB1), bypass the p53 pathway because they arise from intrinsically death-resistant cells during retinal development. In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumour progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Our data provide evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, they support the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma.     

基于字典学习的低剂量X-ray CT图像去噪

介绍了一种基于字典学习的去噪方法,并将其应用于降低低剂量CT图像噪声水平的研究.针对体模图像和病人图像,分别选择低剂量CT图像和正常剂量CT图像作为训练样本,采用K-SVD算法,通过迭代学习构建图像字典;然后,结合正交匹配跟踪算法,实现图像稀疏表示,稀疏成分对应于图像的有用信息,其他成分对应于图像噪声;最后,依据图像的稀疏成分重建图像,达到去除噪声的目的.实验结果表明:字典的大小、稀疏表示的约束条件等参数会显著影响所提算法的去噪结果;相比低剂量CT图像,将正常剂量CT图像作为训练样本可以得到更好的去噪结果;在相同的噪声水平下,所提算法与传统图像去噪算法相比可以更好地去除图像噪声,且保留了图像的细节信息.     

RhoA/Rho-kinase and vascular diseases: what is the link?

RhoA/Rho-kinase pathway plays an important role in many pathological conditions. RhoA participates in the regulation of smooth muscle tone and activates many downstream kinases. The best characterized are the serine/threonine kinase isoforms (Rho-kinase or ROCK), ROCKα/ROCK2 and ROCKβ/ROCK1. ROCK is necessary for diverse functions such as local blood flow, arterial/pulmonary blood pressure, airway resistance and intestinal peristalsis. ROCK activation permits actin/myosin interactions and smooth muscle cells contraction by maintaining the activity of myosin light-chain kinase, independently of the free cytosolic calcium level. The sensitization of smooth muscle myofilaments to calcium has been implicated in many pathological states, such as hypertension, diabetes, heart attack, stroke, pulmonary hypertension, erectile dysfunction, and cancer. The focus of this review is on the involvement of RhoA/Rho-kinase in diseases. We will briefly describe the ROCK isoforms and the role of RhoA/Rho-kinase in the vasculature, before exploring the most recent findings regarding this pathway and various diseases.     

Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.     

The role of Rab5a GTPase in endocytosis and post-endocytic trafficking of the hCG-human luteinizing hormone receptor complex

This study examined the role of Rab5a GTPase in regulating hCG-induced internalization and trafficking of the hCG-LH receptor complex in transfected 293T cells. Coexpression of wild-type Rab5a (WT) or constitutively active Rab5a (Q79L) with LHR significantly increased hCG-induced LHR internalization. Conversely, coexpression of dominant negative Rab5a (S34N) with LHR reduced internalization. Confocal microscopy showed LHR colocalizing with Rab5a (WT) and Rab5a (Q79L) in punctuate structures. Coexpression of Rab5a (WT) and Rab5a (Q79L) with LHR significantly increased colocalization of LHR in early endosomes. Conversely, dominant negative Rab5a (S34N) decreased this colocalization. While Rab5a stimulated internalization of LHR, it significantly decreased LHR recycling to the cell surface and increased degradation. Dominant negative Rab5a (S34N) increased LHR recycling and decreased degradation. These results suggest that Rab5a plays a role in LHR trafficking by facilitating internalization and fusion to early endosomes, increasing the degradation of internalized receptor resulting in a reduction in LHR recycling.