Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome

Joubert syndrome-related disorders (JSRD) are a group of syndromes sharing the neuroradiological features of cerebellar vermis hypoplasia and a peculiar brainstem malformation known as the 'molar tooth sign'. We identified mutations in the CEP290 gene in five families with variable neurological, retinal and renal manifestations. CEP290 expression was detected mostly in proliferating cerebellar granule neuron populations and showed centrosome and ciliary localization, linking JSRDs to other human ciliopathies.     

Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors

Aberrant methylation of CpG islands and genomic deletion are two predominant mechanisms of gene inactivation in tumorigenesis, but the extent to which they interact is largely unknown. The lack of an integrated approach to study these mechanisms has limited the understanding of tumor genomes and cancer genes. Restriction landmark genomic scanning (RLGS; ref. 1) is useful for global analysis of aberrant methylation of CpG islands, but has not been amenable to alignment with deletion maps because the identity of most RLGS fragments is unknown. Here, we determined the nucleotide sequence and exact chromosomal position of RLGS fragments throughout the genome using the whole chromosome of origin of the fragments and in silico restriction digestion of the human genome sequence. To study the interaction of these gene-inactivation mechanisms in primary brain tumors, we integrated RLGS-based methylation analysis with high-resolution deletion maps from microarray-based comparative genomic hybridization (array CGH; ref. 3). Certain subsets of gene-associated CpG islands were preferentially affected by convergent methylation and deletion, including genes that exhibit tumor-suppressor activity, such as CISH1 (encoding SOCS1; ref. 4), as well as genes such as COE3 that have been missed by traditional non-integrated approaches. Our results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.     

Enhancement of peritoneal macrophage activity by bovine gamma globulin in mice

Mice treated with bovine gamma globulins showed an increased resistance to Salmonella typhimurium infection. This phenomenon seems to be bound to an increase of peritoneal macrophage phagocytic activity, as shown by the method of chemiluminescence, in experiments performed on peritoneal macrophages from mice treated with bovine gamma globulin.     

热裂解气相色质谱应用于古代壁画中油类黏合剂的分析

采用热裂解气相色质谱分析方法，研究了古代壁画中常见的亚麻油、核桃油、罂粟油和桐油4种天然干性油类黏合剂．通过标准干性油老化膜的分析，建立了一种快速、方便的适合于真正古代壁画中油类样品分析的指纹特征峰图谱，并对采自不同年代及不同地区的古代壁画样品进行分析测试，以评估指纹特征峰图谱的可行性．分析时采用了热裂解与甲基化同时进行的技术．分析结果显示，4种干性油的不饱和脂肪酸在成膜后的甲基化产物均为壬二酸二甲酯，离子质量与离子电荷量比值为217，是干性油的特征检测峰．4种油中不同含量的软脂酸和硬脂酸在干性油成膜前后的比值不变，为干性油的甄别提供了可能性．这一研究为国内古代壁画中干性油及其种类的鉴别提供了一种有效的方法．     

Forecasting interest rates through Vasicek and CIR models: A partitioning approach

The aim of this paper is to propose a new methodology that allows forecasting, through Vasicek and CIR models, of future expected interest rates based on rolling windows from observed financial market data. The novelty, apart from the use of those models not for pricing but for forecasting the expected rates at a given maturity, consists in an appropriate partitioning of the data sample. This allows capturing all the statistically significant time changes in volatility of interest rates, thus giving an account of jumps in market dynamics. The new approach is applied to different term structures and is tested for both models. It is shown how the proposed methodology overcomes both the usual challenges (e.g., simulating regime switching, volatility clustering, skewed tails) as well as the new ones added by the current market environment characterized by low to negative interest rates.     

How Future Depends on Past and Rare Events in Systems of Life

The dependence on history of both present and future dynamics of life is a common intuition in biology and in humanities. Historicity will be understood in terms of changes of the space of possibilities (or of “phase space”) as well as by the role of diversity in life’s structural stability and of rare events in history formation. We hint to a rigorous analysis of “path dependence” in terms of invariants and invariance preserving transformations, as it may be found also in physics, while departing from the physico-mathematical analyses. The idea is that the (relative or historicized) invariant traces of the past under organismal or ecosystemic transformations contribute to the understanding (or the “theoretical determination”) of present and future states of affairs. This yields a peculiar form of unpredictability (or randomness) in biology, at the core of novelty formation: the changes of observables and pertinent parameters may depend also on past events. In particular, in relation to the properties of synchronic measurement in physics, the relevance of diachronic measurement in biology is highlighted. This analysis may a fortiori apply to cognitive and historical human dynamics, while allowing to investigate some general properties of historicity in biology.     

APJ acts as a dual receptor in cardiac hypertrophy

Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues. Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate Gαi and elicits a protective response, stretch signals in an APJ-dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of β-arrestins or by pharmacological doses of apelin acting through Gαi. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.     

Precipitation analysis of as-cast HK40 steel after isothermal aging

As-cast HK40 steel was aged at 700, 800, or 900℃ for times as long as 2000 h. Microstructural characterization showed that the primary M₇C₃ carbide network contained a substantial content of manganese, in agreement with the microsegregation of manganese calculated by Thermo-Calc using the Scheil-Gulliver module. The dissolution of primary carbides caused the solute supersaturation of austenite and subsequent precipitation of fine M₂₃C₆ carbides in the austenite matrix for aged specimens. During prolonged aging, the carbide size increased with increasing time because of the coarsening process. A time-temperature-precipitation diagram for M₂₃C₆ carbides was calculated using the Thermo-Calc PRISMA software; this diagram showed good agreement with the experimental growth kinetics of precipitation. The fine carbide precipitation caused an increase in hardness; however, the coarsening process of carbides promoted a decrease in hardness. Nanoindentation tests of the austenite matrix indicated an increase in ductility with increasing aging time.     

8-oxo-guanine bypass by human DNA polymerases in the presence of auxiliary proteins

Specialized DNA polymerases (DNA pols) are required for lesion bypass in human cells. Auxiliary factors have an important, but so far poorly understood, role. Here we analyse the effects of human proliferating cell nuclear antigen (PCNA) and replication protein A (RP-A) on six different human DNA pols--belonging to the B, Y and X classes--during in vitro bypass of different lesions. The mutagenic lesion 8-oxo-guanine (8-oxo-G) has high miscoding potential. A major and specific effect was found for 8-oxo-G bypass with DNA pols lambda and eta. PCNA and RP-A allowed correct incorporation of dCTP opposite a 8-oxo-G template 1,200-fold more efficiently than the incorrect dATP by DNA pol lambda, and 68-fold by DNA pol eta, respectively. Experiments with DNA-pol-lambda-null cell extracts suggested an important role for DNA pol lambda. On the other hand, DNA pol iota, together with DNA pols alpha, delta and beta, showed a much lower correct bypass efficiency. Our findings show the existence of an accurate mechanism to reduce the deleterious consequences of oxidative damage and, in addition, point to an important role for PCNA and RP-A in determining a functional hierarchy among different DNA pols in lesion bypass.