The Smooth Colonel Meets the Reverend

Kernel smoothing techniques have attracted much attention and some notoriety in recent years. The attention is well deserved as kernel methods free researchers from having to impose rigid parametric structure on their data. The notoriety arises from the fact that the amount of smoothing (i.e., local averaging) that is appropriate for the problem at hand is under the control of the researcher. In this paper we provide a deeper understanding of kernel smoothing methods for discrete data by leveraging the unexplored links between hierarchical Bayesmodels and kernelmethods for discrete processes. A number of potentially useful results are thereby obtained, including bounds on when kernel smoothing can be expected to dominate non-smooth (e.g., parametric) approaches in mean squared error and suggestions for thinking about the appropriate amount of smoothing.

The smooth colonel meets the reverend

Kernel smoothing techniques have attracted much attention and some notoriety in recent years. The attention is well deserved as kernel methods free researchers from having to impose rigid parametric structure on their data. The notoriety arises from the fact that the amount of smoothing (i.e., local averaging) that is appropriate for the problem at hand is under the control of the researcher. In this paper we provide a deeper understanding of kernel smoothing methods for discrete data by leveraging the unexplored links between hierarchical Bayesmodels and kernelmethods for discrete processes. A number of potentially useful results are thereby obtained, including bounds on when kernel smoothing can be expected to dominate non-smooth (e.g., parametric) approaches in mean squared error and suggestions for thinking about the appropriate amount of smoothing

Crystal structure of a thermostable Bacillus DNA polymerase l large fragment at 2.1 Å resolution

AbstractBackground: The study of DNA polymerases in the Pol l family is central to the understanding of DNA replication and repair. DNA polymerases are used in many molecular biology techniques, including PCR, which require a thermostable polymerase. In order to learn about Pol l function and the basis of thermostability, we undertook structural studies of a new thermostable DNA polymerase.Results: A DNA polymerase large, Klenow-like, fragment from a recently identified thermostable strain of Bacillus stearothermophilus (BF) was cloned, sequenced, overexpressed and characterized. Its crystal structure was determined to 2.1 Å resolution by the method of multiple isomorphous replacement.Conclusions: This structure represents the highest resolution view of a Pol l enzyme obtained to date. Comparison of the three Pol l structures reveals no compelling evidence for many of the specific interactions that have been proposed to induce thermostability, but suggests that thermostability arises from innumerable small changes distributed throughout the protein structure. The polymerase domain is highly conserved in all three proteins. The N-terminal domains are highly divergent in sequence, but retain a common fold. When present, the 3′-5′ proofreading exonuclease activity is associated with this domain. Its absence is associated with changes in catalytic residues that coordinate the divalent ions required for activity and in loops connecting homologous secondary structural elements. In BF, these changes result in a blockage of the DNA-binding cleft

Effect of Laparoscopic Adjustable Gastric Banding on Metabolic Syndrome and Its Risk Factors in Morbidly Obese Adolescents

We examined the effect of laparoscopic adjustable gastric banding (LAGB) on weight loss, inflammatory markers, and components of the Metabolic Syndrome (MeS) in morbidly obese adolescents and determined if those with MeS lose less weight post-LAGB than those without. Data from 14–18 yr adolescents were obtained at baseline, 6 and 12 months following LAGB. Significant weight loss and improvements in MeS components were observed 6 months and one year following LAGB. The incidence of MeS declined 56.8% after 6 months and 69.6% after 12 months. There was no significant difference in amount of weight lost post-LAGB between those with and without MeS at either timepoint. Correlations between change in weight parameters and components of MeS in those with and without MeS at baseline were examined and found to vary by diagnostic category. LAGB is effective for short-term improvement in weight, inflammatory markers, and components of MeS in morbidly obese adolescents

Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas.

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations

Gender Dependence for a Subset of the Low-Abundance Signaling Proteome in Human Platelets

The incidence of cardiovascular diseases is ten-times higher in males than females, although the biological basis for this gender disparity is not known. However, based on the fact that antiplatelet drugs are the mainstay for prevention and therapy, we hypothesized that the signaling proteomes in platelets from normal male donors might be more activated than platelets from normal female donors. We report here that platelets from male donors express significantly higher levels of signaling cascade proteins than platelets from female donors. In silico connectivity analysis shows that the 24 major hubs in platelets from male donors focus on pathways associated with megakaryocytic expansion and platelet activation. By contrast, the 11 major hubs in platelets from female donors were found to be either negative or neutral for platelet-relevant processes. The difference may suggest a biological mechanism for gender discrimination in cardiovascular disease

Revised Thickness of the Lunar Crust from GRAIL Data: Implications for Lunar Bulk Composition

High-resolution gravity data from GRAIL have yielded new estimates of the bulk density and thickness of the lunar crust. The bulk density of the highlands crust is 2550 kg m-3. From a comparison with crustal composition measured remotely, this density implies a mean porosity of 12%. With this bulk density and constraints from the Apollo seismic experiment, the average global crustal thickness is found to lie between 34 and 43 km, a value 10 to 20 km less than several previous estimates. Crustal thickness is a central parameter in estimating bulk lunar composition. Estimates of the concentrations of refractory elements in the Moon from heat flow, remote sensing and sample data, and geophysical data fall into two categories: those with refractory element abundances enriched by 50% or more relative to Earth, and those with abundances the same as Earth. Settling this issue has implications for processes operating during lunar formation. The crustal thickness resulting from analysis of GRAIL data is less than several previous estimates. We show here that a refractory-enriched Moon is not require

A frequentist framework of inductive reasoning

Reacting against the limitation of statistics to decision procedures, R. A. Fisher proposed for inductive reasoning the use of the fiducial distribution, a parameter-space distribution of epistemological probability transferred directly from limiting relative frequencies rather than computed according to the Bayes update rule. The proposal is developed as follows using the confidence measure of a scalar parameter of interest. (With the restriction to one-dimensional parameter space, a confidence measure is essentially a fiducial probability distribution free of complications involving ancillary statistics.) A betting game establishes a sense in which confidence measures are the only reliable inferential probability distributions. The equality between the probabilities encoded in a confidence measure and the coverage rates of the corresponding confidence intervals ensures that the measure's rule for assigning confidence levels to hypotheses is uniquely minimax in the game. Although a confidence measure can be computed without any prior distribution, previous knowledge can be incorporated into confidence-based reasoning. To adjust a p-value or confidence interval for prior information, the confidence measure from the observed data can be combined with one or more independent confidence measures representing previous agent opinion. (The former confidence measure may correspond to a posterior distribution with frequentist matching of coverage probabilities.) The representation of subjective knowledge in terms of confidence measures rather than prior probability distributions preserves approximate frequentist validity.Comment: major revisio

Structure and Evolution of the Lunar Procellarum Region as Revealed by GRAIL Gravity Data

The Procellarum region is a broad area on the nearside of the Moon that is characterized by low elevations, thin crust, and high surface concentrations of the heat-producing elements uranium, thorium, and potassium. The Procellarum region has been interpreted as an ancient impact basin approximately 3200 km in diameter, though supporting evidence at the surface would have been largely obscured as a result of the great antiquity and poor preservation of any diagnostic features. Here we use data from the Gravity Recovery and Interior Laboratory (GRAIL) mission to examine the subsurface structure of Procellarum. The Bouguer gravity anomalies and gravity gradients reveal a pattern of narrow linear anomalies that border the Procellarum region and are interpreted to be the frozen remnants of lava-filled rifts and the underlying feeder dikes that served as the magma plumbing system for much of the nearside mare volcanism. The discontinuous surface structures that were earlier interpreted as remnants of an impact basin rim are shown in GRAIL data to be a part of this continuous set of quasi-rectangular border structures with angular intersections, contrary to the expected circular or elliptical shape of an impact basin. The spatial pattern of magmatic-tectonic structures bounding Procellarum is consistent with their formation in response to thermal stresses produced by the differential cooling of the province relative to its surroundings, coupled with magmatic activity driven by the elevated heat flux in the region