ALBERT

Description: This paper investigates the forced second-order consensus problem in directed networks with time delays. First, a general forced consensus protocol is studied and some sufficient and necessary conditions on control parameters are obtained to guarantee the forced consensus; based on these conditions, several convenient methods for choosing parameters are provided. Then, by analysing the poles of the closed-loop system, the delay sensitivity of the protocol is investigated. The maximal upper bound of the allowable delays is provided. Simulation examples are presented to illustrate the effectiveness of the theoretical results.

Description: Vitamin B12 (VitB12 or cobalamin) is an essential cofactor in several metabolic pathways. Clinically, VitB12 deficiency is associated with pernicious anemia, neurodegenerative disorder, cardiovascular disease and gastrointestinal disease. Although previous genome-wide association studies (GWAS) identified several genes, including FUT2 , CUBN , TCN1 and MUT , that may influence VitB12 levels in European populations, common genetic determinants of VitB12 remain largely unknown, especially in Asian populations. Here we performed a GWAS in 1999 healthy Chinese men and replicated the top findings in an independent Chinese sample with 1496 subjects. We identified four novel genomic loci that were significantly associated with serum level of VitB12 at a genome-wide significance level of 5.00 x 10 –8 . These four loci were MS4A3 (11q12.1; rs2298585; P = 2.64 x 10 –15 ), CLYBL (13q32; rs41281112; P = 9.23 x 10 –10 ), FUT6 (19p13.3; rs3760776; P = 3.68 x 10 –13 ) and 5q32 region (rs10515552; P = 3.94 x 10 –8 ). In addition, we also confirmed the association with the serum level of VitB12 for the previously reported FUT2 gene and identified one novel non-synonymous single-nucleotide polymorphism in FUT2 gene in this Chinese population (19q13.33; rs1047781; P = 3.62 x 10 –36 ). The new loci identified offer new insights into the biochemical pathways involved in determining the serum level of VitB12 and provide opportunities to better delineate the role of VitB12 in health and disease.

Description: We propose a general framework for dimension reduction in regression to fill the gap between linear and fully nonlinear dimension reduction. The main idea is to first transform each of the raw predictors monotonically and then search for a low-dimensional projection in the space defined by the transformed variables. Both user-specified and data-driven transformations are suggested. In each case, the methodology is first discussed in generality and then a representative method is proposed and evaluated by simulation. The proposed methods are applied to a real dataset.

Description: TDP-43 proteinopathies are clinically and genetically heterogeneous diseases that had been considered distinct from classical amyloid diseases. Here, we provide evidence for the structural similarity between TDP-43 peptides and other amyloid proteins. Atomic force microscopy and electron microscopy examination of peptides spanning a previously defined amyloidogenic fragment revealed a minimal core region that forms amyloid fibrils similar to the TDP-43 fibrils detected in FTLD-TDP brain tissues. An ALS-mutant A315E amyloidogenic TDP-43 peptide is capable of cross-seeding other TDP-43 peptides and an amyloid-β peptide. Sequential Nuclear Overhauser Effects and double-quantum-filtered correlation spectroscopy in nuclear magnetic resonance (NMR) analyses of the A315E-mutant TDP-43 peptide indicate that it adopts an anti-parallel β conformation. When added to cell cultures, the amyloidogenic TDP-43 peptides induce TDP-43 redistribution from the nucleus to the cytoplasm. Neuronal cultures in compartmentalized microfluidic-chambers demonstrate that the TDP-43 peptides can be taken up by axons and induce axonotoxicity and neuronal death, thus recapitulating key neuropathological features of TDP-43 proteinopathies. Importantly, a single amino acid change in the amyloidogenic TDP-43 peptide that disrupts fibril formation also eliminates neurotoxicity, supporting that amyloidogenesis is critical for TDP-43 neurotoxicity.

Description: RNAi technology is taking strong position among the key therapeutic modalities, with dozens of siRNA-based programs entering and successfully progressing through clinical stages of drug development. To further explore potentials of RNAi technology as therapeutics, we engineered and tested VEGFR2 siRNA molecules specifically targeted to tumors through covalently conjugated cyclo(Arg-Gly-Asp- d -Phe-Lys[PEG-MAL]) (cRGD) peptide, known to bind αvβ3 integrin receptors. cRGD-siRNAs were demonstrated to specifically enter and silence targeted genes in cultured αvβ3 positive human cells (HUVEC). Microinjection of zebrafish blastocysts with VEGFR2 cRGD-siRNA resulted in specific inhibition of blood vessel growth. In tumor-bearing mice, intravenously injected cRGD-siRNA molecules generated no innate immune response and bio-distributed to tumor tissues. Continuous systemic delivery of two different VEGFR2 cRGD-siRNAs resulted in down-regulation of corresponding mRNA (55 and 45%) and protein (65 and 45%) in tumors, as well as in overall reduction of tumor volume (90 and 70%). These findings demonstrate strong potential of cRGD-siRNA molecules as anti-tumor therapy.

Description: Although courts have incorporated statistical hypothesis testing into their evaluation of numerical evidence in a variety of cases, they have primarily focused on one aspect of a statistical analysis: whether or not the result is ‘statistically significant’ at the 0.05 or ‘two-standard deviation’ level. The theory underlying hypothesis testing is also concerned with the power of the test to detect a meaningful difference. This article shows that using the insights provided by power calculations should assist courts to better interpret and evaluate the statistical analyses submitted into evidence. In particular, the concept of power should help in assessing whether a sample is too small to provide reliable inferences. On the other hand very large samples can classify minor differences as statistically significant. This occurs when the power of the test at the standard 0.05 level is very high. It will be seen that requiring significance at a more stringent level, e.g. 0.005, which can be determined from a power calculation, often resolves this problem.

Description: Circadian clocks allow organisms to orchestrate the daily rhythms in physiology and behaviors, and disruption of circadian rhythmicity can profoundly affect fitness. The mammalian circadian oscillator consists of a negative primary feedback loop and is associated with some ‘auxiliary’ loops. This raises the questions of how these interlocking loops coordinate to regulate the period and maintain its robustness. Here, we focused on the REV-ERBα/ Cry1 auxiliary loop, consisting of Rev-Erbα/ROR-binding elements (RORE) mediated Cry1 transcription, coordinates with the negative primary feedback loop to modulate the mammalian circadian period. The silicon simulation revealed an unexpected rule: the intensity ratio of the primary loop to the auxiliary loop is inversely related to the period length, even when post-translational feedback is fixed. Then we measured the mRNA levels from two loops in 10-mutant mice and observed the similar monotonic relationship. Additionally, our simulation and the experimental results in human osteosarcoma cells suggest that a coupling effect between the numerator and denominator of this intensity ratio ensures the robustness of circadian period and, therefore, provides an efficient means of correcting circadian disorders. This ratio rule highlights the contribution of the transcriptional architecture to the period dynamics and might be helpful in the construction of synthetic oscillators.

Description: Using Herschel data from the deepest SPIRE and PACS surveys (HerMES and PEP) in COSMOS, GOODS-S and GOODS-N, we examine the dust properties of infrared (IR)-luminous ( L IR  〉 10 10  L ) galaxies at 0.1 〈 z  〈 2 and determine how these evolve with cosmic time. The unique angle of this work is the rigorous analysis of survey selection effects, making this the first study of the star-formation-dominated, IR-luminous population within a framework almost entirely free of selection biases. We find that IR-luminous galaxies have spectral energy distributions (SEDs) with broad far-IR peaks characterized by cool/extended dust emission and average dust temperatures in the 25–45 K range. Hot ( T  〉 45 K) SEDs and cold ( T  〈 25 K), cirrus-dominated SEDs are rare, with most sources being within the range occupied by warm starbursts such as M82 and cool spirals such as M51. We observe a luminosity–temperature ( L - T ) relation, where the average dust temperature of log [ L IR /L ] ~ 12.5 galaxies is about 10 K higher than that of their log [ L IR /L ] ~ 10.5 counterparts. However, although the increased dust heating in more luminous systems is the driving factor behind the L - T relation, the increase in dust mass and/or starburst size with luminosity plays a dominant role in shaping it. Our results show that the dust conditions in IR-luminous sources evolve with cosmic time: at high redshift, dust temperatures are on average up to 10 K lower than what is measured locally ( z 0.1). This is manifested as a flattening of the L - T relation, suggesting that (ultra)luminous infrared galaxies [(U)LIRGs] in the early Universe are typically characterized by a more extended dust distribution and/or higher dust masses than local equivalent sources. Interestingly, the evolution in dust temperature is luminosity dependent, with the fraction of LIRGs with T  〈 35 K showing a two-fold increase from z  ~ 0 to z  ~ 2, whereas that of ULIRGs with T  〈 35 K shows a six-fold increase. Our results suggest a greater diversity in the IR-luminous population at high redshift, particularly for ULIRGs.

Description: The development of economical de novo gene synthesis methods using microchip-synthesized oligonucleotides has been limited by their high error rates. In this study, a low-cost, effective and improved-throughput (up to 32 oligos per run) error-removal method using an immobilized cellulose column containing the mismatch binding protein MutS was produced to generate high-quality DNA from oligos, particularly microchip-synthesized oligonucleotides. Error-containing DNA in the initial material was specifically retained on the MutS-immobilized cellulose column (MICC), and error-depleted DNA in the eluate was collected for downstream gene assembly. Significantly, this method improved a population of synthetic enhanced green fluorescent protein (720 bp) clones from 0.93% to 83.22%, corresponding to a decrease in the error frequency of synthetic gene from 11.44/kb to 0.46/kb. In addition, a parallel multiplex MICC error-removal strategy was also evaluated in assembling 11 genes encoding ~21 kb of DNA from 893 oligos. The error frequency was reduced by 21.59-fold (from 14.25/kb to 0.66/kb), resulting in a 24.48-fold increase in the percentage of error-free assembled fragments (from 3.23% to 79.07%). Furthermore, the standard MICC error-removal process could be completed within 1.5 h at a cost as low as $0.374 per MICC.

Description: Human infertility affects 10–15% of couples, half of which is attributed to the male partner. Abnormal spermatogenesis is a major cause of male infertility. Characterizing the genes involved in spermatogenesis is fundamental to understand the mechanisms underlying this biological process and in developing treatments for male infertility. Although many genes have been implicated in spermatogenesis, no dedicated bioinformatic resource for spermatogenesis is available. We have developed such a database, SpermatogenesisOnline 1.0 ( http://mcg.ustc.edu.cn/sdap1/spermgenes/ ), using manual curation from 30 233 articles published before 1 May 2012. It provides detailed information for 1666 genes reported to participate in spermatogenesis in 37 organisms. Based on the analysis of these genes, we developed an algorithm, Greed AUC Stepwise (GAS) model, which predicted 762 genes to participate in spermatogenesis (GAS probability 〉0.5) based on genome-wide transcriptional data in Mus musculus testis from the ArrayExpress database. These predicted and experimentally verified genes were annotated, with several identical spermatogenesis-related GO terms being enriched for both classes. Furthermore, protein–protein interaction analysis indicates direct interactions of predicted genes with the experimentally verified ones, which supports the reliability of GAS. The strategy (manual curation and data mining) used to develop SpermatogenesisOnline 1.0 can be easily extended to other biological processes.