Harnessing cross-species alignment to discover SNPs and generate a draft genome sequence of a bighorn sheep (Ovis canadensis)

Background: Whole genome sequences (WGS) have proliferated as sequencing technology continues to improve and costs decline. While many WGS of model or domestic organisms have been produced, a growing number of non-model species are also being sequenced. In the absence of a reference, construction of a genome sequence necessitates de novo assembly which may be beyond the ability of many labs due to the large volumes of raw sequence data and extensive bioinformatics required. In contrast, the presence of a reference WGS allows for alignment which is more tractable than assembly. Recent work has highlighted that the reference need not come from the same species, potentially enabling a wide array of species WGS to be constructed using cross-species alignment. Here we report on the creation a draft WGS from a single bighorn sheep (Ovis canadensis) using alignment to the closely related domestic sheep (Ovis aries). Results: Two sequencing libraries on SOLiD platforms yielded over 865 million reads, and combined alignment to the domestic sheep reference resulted in a nearly complete sequence (95% coverage of the reference) at an average of 12x read depth (104 SD). From this we discovered over 15 million variants and annotated them relative to the domestic sheep reference. We then conducted an enrichment analysis of those SNPs showing fixed differences between the reference and sequenced individual and found significant differences in a number of gene ontology (GO) terms, including those associated with reproduction, muscle properties, and bone deposition. Conclusion: Our results demonstrate that cross-species alignment enables the creation of novel WGS for non-model organisms. The bighorn sheep WGS will provide a resource for future resequencing studies or comparative genomics

Accounting for the growth of observation stays in the assessment of Medicare\u27s Hospital Readmissions Reduction Program

IMPORTANCE: Decreases in 30-day readmissions following the implementation of the Medicare Hospital Readmissions Reduction Program (HRRP) have occurred against the backdrop of increasing hospital observation stay use, yet observation stays are not captured in readmission measures. OBJECTIVE: To examine whether the HRRP was associated with decreases in 30-day readmissions after accounting for observation stays. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included a 20% sample of inpatient admissions and observation stays among Medicare fee-for-service beneficiaries from January 1, 2009, to December 31, 2015. Data analysis was performed from November 2021 to June 2022. A differences-in-differences analysis assessed changes in 30-day readmissions after the announcement of the HRRP and implementation of penalties for target conditions (heart failure, acute myocardial infarction, and pneumonia) vs nontarget conditions under scenarios that excluded and included observation stays. MAIN OUTCOMES AND MEASURES: Thirty-day inpatient admissions and observation stays. RESULTS: The study included 8 944 295 hospitalizations (mean [SD] age, 78.7 [8.2] years; 58.6% were female; 1.3% Asian; 10.0% Black; 2.0% Hispanic; 0.5% North American Native; 85.0% White; and 1.2% other or unknown). Observation stays increased from 2.3% to 4.4% (91.3% relative increase) of index hospitalizations among target conditions and 14.1% to 21.3% (51.1% relative increase) of index hospitalizations for nontarget conditions. Readmission rates decreased significantly after the announcement of the HRRP and returned to baseline by the time penalties were implemented for both target and nontarget conditions regardless of whether observation stays were included. When only inpatient hospitalizations were counted, decreasing readmissions accrued into a -1.48 percentage point (95% CI, -1.65 to -1.31 percentage points) absolute reduction in readmission rates by the postpenalty period for target conditions and -1.13 percentage point (95% CI, -1.30 to -0.96 percentage points) absolute reduction in readmission rates by the postpenalty period for nontarget conditions. This reduction corresponded to a statistically significant differential change of -0.35 percentage points (95% CI, -0.59 to -0.11 percentage points). Accounting for observation stays more than halved the absolute decrease in readmission rates for target conditions (-0.66 percentage points; 95% CI, -0.83 to -0.49 percentage points). Nontarget conditions showed an overall greater decrease during the same period (-0.76 percentage points; 95% CI, -0.92 to -0.59 percentage points), corresponding to a differential change in readmission rates of 0.10 percentage points (95% CI, -0.14 to 0.33 percentage points) that was not statistically significant. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that the reduction of readmissions associated with the implementation of the HRRP was smaller than originally reported. More than half of the decrease in readmissions for target conditions appears to be attributable to the reclassification of inpatient admission to observation stays

Control of magnetic anisotropy by orbital hybridization in (La0.67Sr0.33MnO3)n/(SrTiO3)n superlattice

The asymmetry of chemical nature at the hetero-structural interface offers an unique opportunity to design desirable electronic structure by controlling charge transfer and orbital hybridization across the interface. However, the control of hetero-interface remains a daunting task. Here, we report the modulation of interfacial coupling of (La0.67Sr0.33MnO3)n/(SrTiO3)n superlattices by manipulating the periodic thickness with n unit cells of SrTiO3 and n unit cells La0.67Sr0.33MnO3. The easy axis of magnetic anisotropy rotates from in-plane (n = 10) to out-of-plane (n = 2) orientation at 150 K. Transmission electron microscopy reveals enlarged tetragonal ratio > 1 with breaking of volume conservation around the (La0.67Sr0.33MnO3)n/(SrTiO3)n interface, and electronic charge transfer from Mn to Ti 3d orbitals across the interface. Orbital hybridization accompanying the charge transfer results in preferred occupancy of 3d3z2-r2 orbital at the interface, which induces a stronger electronic hopping integral along the out-of-plane direction and corresponding out-of-plane magnetic easy axis for n = 2. We demonstrate that interfacial orbital hybridization in superlattices of strongly correlated oxides may be a promising approach to tailor electronic and magnetic properties in device applications

A Bayesian Nonparametric Approach to Modeling Motion Patterns

The most difficult—and often most essential— aspect of many interception and tracking tasks is constructing motion models of the targets to be found. Experts can often provide only partial information, and fitting parameters for complex motion patterns can require large amounts of training data. Specifying how to parameterize complex motion patterns is in itself a difficult task. In contrast, nonparametric models are very flexible and generalize well with relatively little training data. We propose modeling target motion patterns as a mixture of Gaussian processes (GP) with a Dirichlet process (DP) prior over mixture weights. The GP provides a flexible representation for each individual motion pattern, while the DP assigns observed trajectories to particular motion patterns. Both automatically adjust the complexity of the motion model based on the available data. Our approach outperforms several parametric models on a helicopter-based car-tracking task on data collected from the greater Boston area

Modulatory Role for Retinoid-related Orphan Receptor α in Allergen-induced Lung Inflammation

Rationale: Nuclear receptors play a critical role in the regulation of inflammation, thus representing attractive targets for the treatment of asthma

Cten Is Targeted by Kras Signalling to Regulate Cell Motility in the Colon and Pancreas

CTEN/TNS4 is an oncogene in colorectal cancer (CRC) which enhances cell motility although the mechanism of Cten regulation is unknown. We found an association between high Cten expression and KRAS/BRAF mutation in a series of CRC cell lines (p = 0.03) and hypothesised that Kras may regulate Cten. To test this, Kras was knocked-down (using small interfering (si)RNA) in CRC cell lines SW620 and DLD1 (high Cten expressors and mutant for KRAS). In each cell line, Kras knockdown was mirrored by down-regulation of Cten Since Kras signals through Braf, we tested the effect of Kras knockdown in CRC cell line Colo205 (which shows high Cten expression and is mutant for BRAF but wild type for KRAS). Cten levels were unaffected by Kras knockdown whilst Braf knockdown resulted in reduced Cten expression suggesting that Kras signals via Braf to regulate Cten. Quantification of Cten mRNA and protein analysis following proteasome inhibition suggested that regulation was of Cten transcription. Kras knockdown inhibited cell motility. To test whether this could be mediated through Cten, SW620 cells were co-transfected with Kras specific siRNAs and a Cten expression vector. Restoring Cten expression was able to restore cell motility despite Kras knockdown (transwell migration and wounding assay, p<0.001 for both). Since KRAS is mutated in many cancers, we investigated whether this relationship could be demonstrated in other tumour models. The experiments were repeated in the pancreatic cancer cell lines Colo357 & PSN-1(both high Cten expressors and mutant for KRAS). In both cell lines, Kras was shown to regulate Cten and forced expression of Cten was able to rescue loss of cell motility following Kras knockdown in PSN-1 (transwell migration assay, p<0.001). We conclude that, in the colon and pancreas, Cten is a downstream target of Kras and may be a mechanism through which Kras regulates of cell motility