Kato square root problem with unbounded leading coefficients

We prove the Kato conjecture for elliptic operators, $L=-\nabla\cdot\left((\mathbf A+\mathbf D)\nabla\ \right)$, with $\mathbf A$ a complex measurable bounded coercive matrix and $\mathbf D$ a measurable real-valued skew-symmetric matrix in $\mathbb{R}^n$ with entries in $BMO(\mathbb{R}^n)$;\, i.e., the domain of $\sqrt{L}\,$ is the Sobolev space $\dot H^1(\mathbb{R}^n)$ in any dimension, with the estimate $\|\sqrt{L}\, f\|_2\lesssim \| \nabla f\|_2$

Cerebellum Transcriptome of Mice Bred for High Voluntary Activity Offers Insights into Locomotor Control and Reward-Dependent Behaviors.

The role of the cerebellum in motivation and addictive behaviors is less understood than that in control and coordination of movements. High running can be a self-rewarding behavior exhibiting addictive properties. Changes in the cerebellum transcriptional networks of mice from a line selectively bred for High voluntary running (H) were profiled relative to an unselected Control (C) line. The environmental modulation of these changes was assessed both in activity environments corresponding to 7 days of Free (F) access to running wheel and to Blocked (B) access on day 7. Overall, 457 genes exhibited a significant (FDR-adjusted P-value < 0.05) genotype-by-environment interaction effect, indicating that activity genotype differences in gene expression depend on environmental access to running. Among these genes, network analysis highlighted 6 genes (Nrgn, Drd2, Rxrg, Gda, Adora2a, and Rab40b) connected by their products that displayed opposite expression patterns in the activity genotype contrast within the B and F environments. The comparison of network expression topologies suggests that selection for high voluntary running is linked to a predominant dysregulation of hub genes in the F environment that enables running whereas a dysregulation of ancillary genes is favored in the B environment that blocks running. Genes associated with locomotor regulation, signaling pathways, reward-processing, goal-focused, and reward-dependent behaviors exhibited significant genotype-by-environment interaction (e.g. Pak6, Adora2a, Drd2, and Arhgap8). Neuropeptide genes including Adcyap1, Cck, Sst, Vgf, Npy, Nts, Penk, and Tac2 and related receptor genes also exhibited significant genotype-by-environment interaction. The majority of the 183 differentially expressed genes between activity genotypes (e.g. Drd1) were under-expressed in C relative to H genotypes and were also under-expressed in B relative to F environments. Our findings indicate that the high voluntary running mouse line studied is a helpful model for understanding the molecular mechanisms in the cerebellum that influence locomotor control and reward-dependent behaviors

COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration

published_or_final_versio

Rational design of biosafe crop resistance to a range of nematodes using RNA interference

Double stranded RNA (dsRNA) molecules targeting two genes have been identified that suppress economically important parasitic nematode species of banana. Proteasomal Alpha Subunit 4 (pas-4) and Actin-4 (act-4) were identified from a survey of sequence databases and cloned sequences for genes conserved across four pests of banana, Radopholus similis, Pratylenchus coffeae, Meloidogyne incognita and Helicotylenchus multicinctus. These four species were targeted with dsRNAs containing exact 21 nucleotide matches to the conserved regions. Potential off-target effects were limited by comparison to Caenorhabditis, Drosophila, rat, rice and Arabidopsis genomes. In vitro act-4 dsRNA treatment of R. similis suppressed target gene expression by 2.3 fold, nematode locomotion by 66 ± 4% and nematode multiplication on carrot discs by 49 ± 5%. The best transgenic carrot hairy root lines expressing act-4 or pas-4 dsRNA reduced transcript message abundance of target genes in R. similis by 7.9 fold and 4 fold and nematode multiplication by 94 ± 2% and 69 ± 3%, respectively. The same act-4 and pas-4 lines reduced P. coffeae target transcripts by 1.7 and 2 fold and multiplication by 50 ± 6% and 73 ± 8%. Multiplication of M. incognita on the pas-4 lines was reduced by 97 ± 1% and 99 ± 1% while target transcript abundance was suppressed 4.9 and 5.6 fold. There was no detectable RNAi effect on non-target nematodes exposed to dsRNAs targeting parasitic nematodes. This work defines a framework for development of a range of non-protein defences to provide broad resistance to pests and pathogens of crops

Should the grading of colorectal adenocarcinoma include microsatellite instability status?

Adenocarcinomas of the colon and rectum are graded using a 2-tiered system into histologic low-grade and high-grade tumors based on the proportion of gland formation. The current grading system does not apply to subtypes of carcinomas associated with a high frequency of microsatellite instability (MSI), such as mucinous and medullary carcinomas. We investigated the combined effect of histologic grade and MSI status on survival for 738 patients with colorectal carcinoma (48% female; mean age at diagnosis 68.2 years). The proportion of high-grade adenocarcinoma was 18%. MSI was observed in 59 adenocarcinomas (9%), with higher frequency in high-grade tumors compared with low-grade tumors (20% versus 6%; P < .001). Using Cox regression models, adjusting for sex and age at diagnosis and stratifying by the American Joint Committee on Cancer stage, microsatellite stable (MSS) high-grade tumors were associated with increased hazard of all-cause and colorectal cancer specific mortality: hazard ratio 2.09 (95% confidence interval [CI], 1.58-2.77) and 2.54 (95% CI, 1.86-3.47), respectively, both P < .001. A new grading system separating adenocarcinoma into low grade (all histologic low grade and MSI high grade) and high grade (MSS histologic high grade) gave a lower Akaike information criterion value when compared with the current grading system and thus represented a better model fit to stratify patients according to survival. We found that patients with a high-grade adenocarcinoma had significantly shorter survival than patients with low-grade adenocarcinoma only if the tumor was MSS, suggesting that the grading of colorectal adenocarcinoma with high-grade histologic features should be made according to the MSI status of the tumor. (C) 2014 Elsevier Inc. All rights reserved

Lifetime alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- but not BRAF+ colorectal cancer.

Ethanol in alcoholic beverages is a causative agent for colorectal cancer. Colorectal cancer is a biologically heterogeneous disease, and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist. We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal cancer. We calculated usual alcohol intake for 10-year periods from age 20 using recalled frequency and quantity of beverage-specific consumption for 38,149 participants aged 40-69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between lifetime alcohol intake and colorectal cancer risk. Heterogeneity in the HRs across subtypes of colorectal cancer was assessed. A positive dose-dependent association between lifetime alcohol intake and overall colorectal cancer risk (mean follow-up = 14.6 years; n = 596 colon and n = 326 rectal cancer) was observed (HR = 1.08, 95% CI: 1.04-1.12 per 10 g/day increment). The risk was greater for rectal than colon cancer (phomogeneity  = 0.02). Alcohol intake was associated with increased risks of KRAS+ (HR = 1.07, 95% CI: 1.00-1.15) and BRAF-/KRAS- (HR = 1.05, 95% CI: 1.00-1.11) but not BRAF+ tumors (HR = 0.89, 95% CI: 0.78-1.01; phomogeneity  = 0.01). Alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- tumors originating via specific molecular pathways including the traditional adenoma-carcinoma pathway but not with BRAF+ tumors originating via the serrated pathway. Therefore, limiting alcohol intake from a young age might reduce colorectal cancer originating via the traditional adenoma-carcinoma pathway

An interdisciplinary cruise dedicated to understanding ocean eddies upstream of the Prince Edward Islands

A detailed hydrographic and biological survey was carried out in the region of the South-West Indian Ridge during April 2004. Altimetry and hydrographic data have identified this region as an area of high flow variability. Hydrographic data revealed that here the Subantarctic Polar Front (SAF) and Antarctic Polar Front (APF) converge to form a highly intense frontal system. Water masses identified during the survey showed a distinct separation in properties between the northwestern and southeastern corners. In the north-west, water masses were distinctly Subantarctic (>8.5°C, salinity >34.2), suggesting that the SAF lay extremely far to the south. In the southeast corner water masses were typical of the Antarctic zone, showing a distinct subsurface temperature minimum of <2.5°C. Total integrated chl-a concentration during the survey ranged from 4.15 to 22.81 mg chl-a m[superscript (-2)], with the highest concentrations recorded at stations occupied in the frontal region. These data suggest that the region of the South-West Indian Ridge represents not only an area of elevated biological activity but also acts as a strong biogeographic barrier to the spatial distribution of zooplankton

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition