Oncogenic mutations of ALK kinase in neuroblastoma

Neuroblastoma in advanced stages is one of the most intractable paediatric cancers, even with recent therapeutic advances. Neuroblastoma harbours a variety of genetic changes, including a high frequency of MYCN amplification, loss of heterozygosity at 1p36 and 11q, and gain of genetic material from 17q, all of which have been implicated in the pathogenesis of neuroblastoma. However, the scarcity of reliable molecular targets has hampered the development of effective therapeutic agents targeting neuroblastoma. Here we show that the anaplastic lymphoma kinase (ALK), originally identified as a fusion kinase in a subtype of non-Hodgkin's lymphoma (NPM-ALK) and more recently in adenocarcinoma of lung (EML4-ALK), is also a frequent target of genetic alteration in advanced neuroblastoma. According to our genome-wide scans of genetic lesions in 215 primary neuroblastoma samples using high-density single-nucleotide polymorphism genotyping microarrays, the ALK locus, centromeric to the MYCN locus, was identified as a recurrent target of copy number gain and gene amplification. Furthermore, DNA sequencing of ALK revealed eight novel missense mutations in 13 out of 215 (6.1%) fresh tumours and 8 out of 24 (33%) neuroblastoma-derived cell lines. All but one mutation in the primary samples (12 out of 13) were found in stages 3-4 of the disease and were harboured in the kinase domain. The mutated kinases were autophosphorylated and displayed increased kinase activity compared with the wild-type kinase. They were able to transform NIH3T3 fibroblasts as shown by their colony formation ability in soft agar and their capacity to form tumours in nude mice. Furthermore, we demonstrate that downregulation of ALK through RNA interference suppresses proliferation of neuroblastoma cells harbouring mutated ALK. We anticipate that our findings will provide new insights into the pathogenesis of advanced neuroblastoma and that ALK-specific kinase inhibitors might improve its clinical outcome.     

Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.     

Reconstruction of flood events over the last 150 years in the lower reaches of the Changjiang River

The reconstruction of paleofloods in the Holocene has become one research highlight for the present global change study. The core sediments from one newly-emerged bar in the lower Changjiang River (Yangtze River) mainstream were collected for grain size and organic elemental measurements, with aim to reconstruct the flood events over the past 150 years. Major grain size parameters such as mean grain size, probability cumulative curve and C-M diagram of the core sediments clearly indicate the flood event deposition. Furthermore, the TOC/TN ratios in the sediments can indicate flood events considering that during the flash floods, strong surface erosion in the upper and lower reaches of the Changjiang River can transport a large amount of undecomposed plant debris and organic components with relatively low C/N ratios into the lower mainstream. Based on 210Pb dating and sedimentary geochemical results, the research profile recorded several large floods happened from 1850 to 1954, which agrees well with the historical documents and hydrological observations. Interesting to note that the flood events since the 1960s cannot be distinctly recognized on the basis of sediment grain size and organic elemental compositions of the profile, which mainly reflects the intensive human activities over the last fifty years, especially condense dam construction, have significantly changed the characters of suspended sediment into the lower mainstream.     

醇对SDS-CTAB-H2O体系双水相性质的影响

研究了短链一元醇(乙醇、正丁醇)和二元醇(乙二醇、1,4—丁二醇)对正负离子表面活性剂混合溶液(十二烷基硫酸钠—十六烷基三甲基溴化铵—水)双水相的影响。结果表明：一元醇的加入不但缩短了双水相的成相时间、使原水溶液双水相的区域得到扩展而且还会导致新双水相区域的出现,这种影响随着醇类链长的增长而增大。而二元醇的加入对双水相的相图影响不大,只是对形成双水相的表面活性剂最低总浓度稍有影响。实验结果也表明,出现双水相的表面活性剂最低总浓度与混合溶液的临界胶束浓度(CMC)有关,但CMC并不是决定出现双水相表面活性剂最低浓度的唯一因素。     

Time synchronization module for automatic identification system

This paper proposed a design and implementation procedure of the Time Synchronization Module (TSM) for the Automatic Identification System (AIS). The proposed TSM module uses a Temperature Compensated Crystal Oscillator (TCXO) as a local reference clock, and consists of a Digitally Controlled Oscillator (DCO), a divider, a phase discriminator, and register blocks. The TSM measures time difference between the 1 PPS from the Global Navigation Satellite System (GNSS) receiver and the generated transmitter clock. The measured time difference is compensated by controlling the DCO and the transmit clock is synchronized to the Universal Time Coordinated (UTC). The designed TSM can also be synchronized to the reference time derived from the received message. The proposed module is tested using the experimental AIS transponder set. The experimental results show that the proposed module satisfies the functional and timing specification of the AIS technical standard, ITU-R M.1371.     

A physically-based statistical forecast model for the middle-lower reaches of the Yangtze River Valley summer rainfall

A new approach to forecast the middle-lower reaches of the Yangtze River Valley summer rainfall in June-August （JJA） is proposed in this paper. The year-to-year increment of the middle-lower reaches of the Yangtze River Valley is forecasted and hence the summer precipitation could be predicted. In this paper, DY is defined as the difference of a variable between the current year and the preceding year （year-to-year increment）. YR denotes the seasonal mean precipitation rate of the middle-lower reaches of the Yangtze River Valley summer rainfall. After analyzing the atmospheric circulation anomalies in winter and spring that were associated with the DY of YR, six key predictors for the DY of YR have been identified. Then the forecast model for the DY of YR is established by using the multi-linear regression method. The predictors for the DY of YR are Antarctic Oscillation, the meridional wind shear between 850hPa and 200hPa over the Indo-Australian region, and so on. The prediction model shows a high skill for the hindcast during 1997-2006, with the average relative root mean square error is at 18%. The model can even reproduce the upward and downward trends of YR during 1984--1998 and 1998--2006. Considering that the current operational forecast models of the summer precipitation over the China region have the average forecast scores at 60%--70% and that the prediction skill for the middle-lower reaches of Yangtze River Valley summer precipitation remains quite limited up to now, thus this new approach to predict the year-to-year increment of the summer precipitation over the Yangtze River Valley （and hence the summer precipitation itself） has the potential to significantly increase the operational forecast skill of the summer precipitation.     

The kinetic studies of direct methane oxidation to methanol in the plasma process

The research outlined here includes a study of methanol production from direct methane conversion by means of thermal and plasma method. The kinetic study, derived from thermal-based approach, was carried out to investigate thoroughly the possible intermediate species likely to be presented in the process. A set of plasma experiments was undertaken by using dielectric barrier discharge （DBD）, classified as non-thermal plasma, done at atmospheric pressure and room temperature. Plasma process yields more methanol than thermal process at the same methane conversion rates and methane to oxygen feed ratios. Oxidation reaction of thermal process resulted CO and CO2 as the most dominant products and the selectivity reached 19% and 68%, respectively. Moreover, more CO and less CO2 were produced in plasma process than in thermal process. The selectivity of CO and CO2 by plasma was 47% and 20%, respectively. Ethane （C2H6）was detected as the only higher hydrocarbon with a significant concentration. The concentration of ethane reached 9% of the total products in plasma process and 17% in thermal process. The maximum selectivity of methanol, the target material of this research, was 12% obtained by plasma method and less than 5% by thermal process. In some certain points, the kinetic model closely matched with the experimental results.     

Difference in direct charge-parity violation between charged and neutral B meson decays

Equal amounts of matter and antimatter are predicted to have been produced in the Big Bang, but our observable Universe is clearly matter-dominated. One of the prerequisites for understanding this elimination of antimatter is the nonconservation of charge-parity (CP) symmetry. So far, two types of CP violation have been observed in the neutral K meson (K(0)) and B meson (B(0)) systems: CP violation involving the mixing between K(0) and its antiparticle (and likewise for B(0) and ), and direct CP violation in the decay of each meson. The observed effects for both types of CP violation are substantially larger for the B(0) meson system. However, they are still consistent with the standard model of particle physics, which has a unique source of CP violation that is known to be too small to account for the matter-dominated Universe. Here we report that the direct CP violation in charged B(+/-)-->K(+/-)pi(0) decay is different from that in the neutral B(0) counterpart. The direct CP-violating decay rate asymmetry, (that is, the difference between the number of observed B(-)-->K(-)pi(0) event versus B(+)-->K(+) pi(0) events, normalized to the sum of these events) is measured to be about +7%, with an uncertainty that is reduced by a factor of 1.7 from a previous measurement. However, the asymmetry for versus B(0)-->K(+)pi(-) is at the -10% level. Although it is susceptible to strong interaction effects that need further clarification, this large deviation in direct CP violation between charged and neutral B meson decays could be an indication of new sources of CP violation-which would help to explain the dominance of matter in the Universe.