A model-based multithreshold method for subgroup identification

Thresholding variable plays a crucial role in subgroup identification for personalizedmedicine. Most existing partitioning methods split the sample basedon one predictor variable. In this paper, we consider setting the splitting rulefrom a combination of multivariate predictors, such as the latent factors, principlecomponents, and weighted sum of predictors. Such a subgrouping methodmay lead to more meaningful partitioning of the population than using a singlevariable. In addition, our method is based on a change point regression modeland thus yields straight forward model-based prediction results. After choosinga particular thresholding variable form, we apply a two-stage multiple changepoint detection method to determine the subgroups and estimate the regressionparameters. We show that our approach can produce two or more subgroupsfrom the multiple change points and identify the true grouping with high probability.In addition, our estimation results enjoy oracle properties. We design asimulation study to compare performances of our proposed and existing methodsand apply them to analyze data sets from a Scleroderma trial and a breastcancer study

Evaluation of the zucker diabetic fatty (ZDF) rat as a model for human disease based on urinary peptidomic profiles

Representative animal models for diabetes-associated vascular complications are extremely relevant in assessing potential therapeutic drugs. While several rodent models for type 2 diabetes (T2D) are available, their relevance in recapitulating renal and cardiovascular features of diabetes in man is not entirely clear. Here we evaluate at the molecular level the similarity between Zucker diabetic fatty (ZDF) rats, as a model of T2D-associated vascular complications, and human disease by urinary proteome analysis. Urine analysis of ZDF rats at early and late stages of disease compared to age- matched LEAN rats identified 180 peptides as potentially associated with diabetes complications. Overlaps with human chronic kidney disease (CKD) and cardiovascular disease (CVD) biomarkers were observed, corresponding to proteins marking kidney damage (eg albumin, alpha-1 antitrypsin) or related to disease development (collagen). Concordance in regulation of these peptides in rats versus humans was more pronounced in the CVD compared to the CKD panels. In addition, disease-associated predicted protease activities in ZDF rats showed higher similarities to the predicted activities in human CVD. Based on urinary peptidomic analysis, the ZDF rat model displays similarity to human CVD but might not be the most appropriate model to display human CKD on a molecular level

Rational F-Theory GUTs without exotics

We construct F-theory GUT models without exotic matter, leading to the MSSM matter spectrum with potential singlet extensions. The interplay of engineering explicit geometric setups, absence of four-dimensional anomalies, and realistic phenomenology of the couplings places severe constraints on the allowed local models in a given geometry. In constructions based on the spectral cover we find no model satisfying all these requirements. We then provide a survey of models with additional U(1) symmetries arising from rational sections of the elliptic fibration in toric constructions and obtain phenomenologically appealing models based on SU(5) tops. Furthermore we perform a bottom-up exploration beyond the toric section constructions discussed in the literature so far and identify benchmark models passing all our criteria, which can serve as a guideline for future geometric engineering.Comment: 27 Pages, 1 Figur

Cognitive appraisal of environmental stimuli induces emotion-like states in fish

The occurrence of emotions in non-human animals has been the focus of debate over the years. Recently, an interest in expanding this debate to non-tetrapod vertebrates and to invertebrates has emerged. Within vertebrates, the study of emotion in teleosts is particularly interesting since they represent a divergent evolutionary radiation from that of tetrapods, and thus they provide an insight into the evolution of the biological mechanisms of emotion. We report that Sea Bream exposed to stimuli that vary according to valence (positive, negative) and salience (predictable, unpredictable) exhibit different behavioural, physiological and neuromolecular states. Since according to the dimensional theory of emotion valence and salience define a two-dimensional affective space, our data can be interpreted as evidence for the occurrence of distinctive affective states in fish corresponding to each the four quadrants of the core affective space. Moreover, the fact that the same stimuli presented in a predictable vs. unpredictable way elicited different behavioural, physiological and neuromolecular states, suggests that stimulus appraisal by the individual, rather than an intrinsic characteristic of the stimulus, has triggered the observed responses. Therefore, our data supports the occurrence of emotion-like states in fish that are regulated by the individual's perception of environmental stimuli.European Commission [265957 Copewell]; Fundacao para a Ciencia e Tecnologia [SFRH/BD/80029/2011, SFRH/BPD/72952/2010]info:eu-repo/semantics/publishedVersio

Effects of habitat and livestock on nest productivity of the Asian houbara Chlamydotis macqueenii in Bukhara Province, Uzbekistan

To inform population support measures for the unsustainably hunted Asian houbara Chlamydotis macqueenii (IUCN Vulnerable) we examined potential habitat and land-use effects on nest productivity in the Kyzylkum Desert, Uzbekistan. We monitored 177 nests across different semi-arid shrub assemblages (clay-sand and salinity gradients) and a range of livestock densities (0–80 km-2). Nest success (mean 51.4%, 95% CI 42.4–60.4%) was similar across four years; predation caused 85% of those failures for which the cause was known, and only three nests were trampled by livestock. Nesting begins within a few weeks of arrival when food appears scarce, but later nests were more likely to fail owing to the emergence of a key predator, suggesting foraging conditions on wintering and passage sites may be important for nest productivity. Nest success was similar across three shrub assemblages and was unrelated to landscape rugosity, shrub frequency or livestock density, but was greater with taller mean shrub height (range 13–67 cm) within 50 m. Clutch size (mean = 3.2 eggs) and per-egg hatchability in successful nests (87.5%) did not differ with laying date, shrub assemblage or livestock density. We therefore found no evidence that livestock density reduced nest productivity across the range examined, while differing shrub assemblages appeared to offer similar habitat quality. Asian houbara appear well-adapted to a range of semi-desert habitats and tolerate moderate disturbance by pastoralism. No obvious in situ mitigation measures arise from these findings, leaving regulation and control as the key requirement to render hunting sustainable

Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations

The Turkey Ig-like receptor family: identification, expression and function.

The chicken leukocyte receptor complex located on microchromosome 31 encodes the chicken Ig-like receptors (CHIR), a vastly expanded gene family which can be further divided into three subgroups: activating CHIR-A, bifunctional CHIR-AB and inhibitory CHIR-B. Here, we investigated the presence of CHIR homologues in other bird species. The available genome databases of turkey, duck and zebra finch were screened with different strategies including BLAST searches employing various CHIR sequences, and keyword searches. We could not identify CHIR homologues in the distantly related zebra finch and duck, however, several partial and complete sequences of CHIR homologues were identified on chromosome 3 of the turkey genome. They were designated as turkey Ig-like receptors (TILR). Using cDNA derived from turkey blood and spleen RNA, six full length TILR could be amplified and further divided according to the typical sequence features into one activating TILR-A, one inhibitory TILR-B and four bifunctional TILR-AB. Since the TILR-AB sequences all displayed the critical residues shown to be involved in binding to IgY, we next confirmed the IgY binding using a soluble TILR-AB1-huIg fusion protein. This fusion protein reacted with IgY derived from various gallinaceous birds, but not with IgY from other bird species. Finally, we tested various mab directed against CHIR for their crossreactivity with either turkey or duck leukocytes. Whereas no staining was detectable with duck cells, the CHIR-AB1 specific mab 8D12 and the CHIR-A2 specific mab 13E2 both reacted with a leukocyte subpopulation that was further identified as thrombocytes by double immunofluorescence employing B-cell, T-cell and thrombocyte specific reagents. In summary, although the turkey harbors similar LRC genes as the chicken, their distribution seems to be distinct with predominance on thrombocytes rather than lymphocytes

Role of the mesoamygdaloid dopamine projection in emotional learning

Amygdala dopamine is crucially involved in the acquisition of Pavlovian associations, as measured via conditioned approach to the location of the unconditioned stimulus (US). However, learning begins before skeletomotor output, so this study assessed whether amygdala dopamine is also involved in earlier 'emotional' learning. A variant of the conditioned reinforcement (CR) procedure was validated where training was restricted to curtail the development of selective conditioned approach to the US location, and effects of amygdala dopamine manipulations before training or later CR testing assessed. Experiment 1a presented a light paired (CS+ group) or unpaired (CS- group) with a US. There were 1, 2 or 10 sessions, 4 trials per session. Then, the US was removed, and two novel levers presented. One lever (CR+) presented the light, and lever pressing was recorded. Experiment 1b also included a tone stimulus. Experiment 2 applied intra-amygdala R(+) 7-OH-DPAT (10 nmol/1.0 A mu l/side) before two training sessions (Experiment 2a) or a CR session (Experiment 2b). For Experiments 1a and 1b, the CS+ group preferred the CR+ lever across all sessions. Conditioned alcove approach during 1 or 2 training sessions or associated CR tests was low and nonspecific. In Experiment 2a, R(+) 7-OH-DPAT before training greatly diminished lever pressing during a subsequent CR test, preferentially on the CR+ lever. For Experiment 2b, R(+) 7-OH-DPAT infusions before the CR test also reduced lever pressing. Manipulations of amygdala dopamine impact the earliest stage of learning in which emotional reactions may be most prevalent

The evolution of methods for establishing evolutionary timescales

The fossil record is well known to be incomplete. Read literally, it provides a distorted view of the history of species divergence and extinction, because different species have different propensities to fossilize, the amount of rock fluctuates over geological timescales, as does the nature of the environments that it preserves. Even so, patterns in the fossil evidence allow us to assess the incompleteness of the fossil record. While the molecular clock can be used to extend the time estimates from fossil species to lineages not represented in the fossil record, fossils are the only source of information concerning absolute (geological) times in molecular dating analysis. We review different ways of incorporating fossil evidence in modern clock dating analyses, including node-calibrations where lineage divergence times are constrained using probability densities and tip-calibrations where fossil species at the tips of the tree are assigned dates from dated rock strata. While node-calibrations are often constructed by a crude assessment of the fossil evidence and thus involves arbitrariness, tip-calibrations may be too sensitive to the prior on divergence times or the branching process and influenced unduly affected by well-known problems of morphological character evolution, such as environmental influence on morphological phenotypes, correlation among traits, and convergent evolution in disparate species. We discuss the utility of time information from fossils in phylogeny estimation and the search for ancestors in the fossil record. This article is part of the themed issue ‘Dating species divergences using rocks and clocks’

Prevalence of Disorders Recorded in Dogs Attending Primary-Care Veterinary Practices in England

Purebred dog health is thought to be compromised by an increasing occurence of inherited diseases but inadequate prevalence data on common disorders have hampered efforts to prioritise health reforms. Analysis of primary veterinary practice clinical data has been proposed for reliable estimation of disorder prevalence in dogs. Electronic patient record (EPR) data were collected on 148,741 dogs attending 93 clinics across central and south-eastern England. Analysis in detail of a random sample of EPRs relating to 3,884 dogs from 89 clinics identified the most frequently recorded disorders as otitis externa (prevalence 10.2%, 95% CI: 9.1-11.3), periodontal disease (9.3%, 95% CI: 8.3-10.3) and anal sac impaction (7.1%, 95% CI: 6.1-8.1). Using syndromic classification, the most prevalent body location affected was the head-and-neck (32.8%, 95% CI: 30.7-34.9), the most prevalent organ system affected was the integument (36.3%, 95% CI: 33.9-38.6) and the most prevalent pathophysiologic process diagnosed was inflammation (32.1%, 95% CI: 29.8-34.3). Among the twenty most-frequently recorded disorders, purebred dogs had a significantly higher prevalence compared with crossbreds for three: otitis externa (P = 0.001), obesity (P = 0.006) and skin mass lesion (P = 0.033), and popular breeds differed significantly from each other in their prevalence for five: periodontal disease (P = 0.002), overgrown nails (P = 0.004), degenerative joint disease (P = 0.005), obesity (P = 0.001) and lipoma (P = 0.003). These results fill a crucial data gap in disorder prevalence information and assist with disorder prioritisation. The results suggest that, for maximal impact, breeding reforms should target commonly-diagnosed complex disorders that are amenable to genetic improvement and should place special focus on at-risk breeds. Future studies evaluating disorder severity and duration will augment the usefulness of the disorder prevalence information reported herein