Variable Selection and Model Averaging in Semiparametric Overdispersed Generalized Linear Models

We express the mean and variance terms in a double exponential regression model as additive functions of the predictors and use Bayesian variable selection to determine which predictors enter the model, and whether they enter linearly or flexibly. When the variance term is null we obtain a generalized additive model, which becomes a generalized linear model if the predictors enter the mean linearly. The model is estimated using Markov chain Monte Carlo simulation and the methodology is illustrated using real and simulated data sets.Comment: 8 graphs 35 page

Придністровський конфлікт: чинники існування напруги

Стаття присвячена аналізу та систематизації чинників, що обумовлюють збереження статус-кво у процесі придністровського врегулювання на глобальному, регіональному та локальному рівні.The article is devoted to the analysis and systematization of factors leading to the preservation of the status-quo in the Transnistrian settlement process on global, regional and local level

Transport of Cytoplasmically Synthesized Proteins into the Mitochondria in a Cell Free System from Neurospora crassa

Synthesis and transport of mitochondrial proteins were followed in a cell-free homogenate of Neurospora crassa in which mitochondrial translation was inhibited. Proteins synthesized on cytoplasmic ribosomes are transferred into the mitochondrial fraction. The relative amounts of proteins which are transferred in vitro are comparable to those transferred in whole cells. Cycloheximide and puromycin inhibit the synthesis of mitochondrial proteins but not their transfer into mitochondria. The transfer of immunoprecipitable mitochondrial proteins was demonstrated for matrix proteins, carboxyatractyloside-binding protein and cytochrome c. Import of proteins into mitochondria exhibits a degree of specificity. The transport mechanism differentiates between newly synthesized proteins and preexistent mitochondrial proteins, at least in the case of matrix proteins. In the cell-free homogenate membrane-bound ribosomes are more active in the synthesis of mitochondrial proteins than are free ribosomes. The finished translation products appear to be released from the membrane-bound ribosomes into the cytosol rather than into the membrane vesicles. The results suggest that the transport of cytoplasmically synthesized mitochondrial proteins is essentially independent of cytoplasmic translation; that cytoplasmically synthesized mitochondrial proteins exist in an extramitochondrial pool prior to import; that the site of this pool is the cytosol for at least some of the mitochondrial proteins; and that the precursors in the extramitochondrial pool differ in structure or conformation from the functional proteins in the mitochondria

A nonlinear mixed-effects modeling approach for ecological data: Using temporal dynamics of vegetation moisture as an example

Increasingly, often ecologist collects data with nonlinear trends, heterogeneous variances, temporal correlation, and hierarchical structure. Nonlinear mixed-effects models offer a flexible approach to such data, but the estimation and interpretation of these models present challenges, partly associated with the lack of worked examples in the ecological literature. We illustrate the nonlinear mixed-effects modeling approach using temporal dynamics of vegetation moisture with field data from northwestern Patagonia. This is a Mediterranean-type climate region where modeling temporal changes in live fuel moisture content are conceptually relevant (ecological theory) and have practical implications (fire management). We used this approach to answer whether moisture dynamics varies among functional groups and aridity conditions, and compared it with other simpler statistical models. The modeling process is set out “step-by-step”: We start translating the ideas about the system dynamics to a statistical model, which is made increasingly complex in order to include different sources of variability and correlation structures. We provide guidelines and R scripts (including a new self-starting function) that make data analyses reproducible. We also explain how to extract the parameter estimates from the R output. Our modeling approach suggests moisture dynamic to vary between grasses and shrubs, and between grasses facing different aridity conditions. Compared to more classical models, the nonlinear mixed-effects model showed greater goodness of fit and met statistical assumptions. While the mixed-effects approach accounts for spatial nesting, temporal dependence, and variance heterogeneity; the nonlinear function allowed to model the seasonal pattern. Parameters of the nonlinear mixed-effects model reflected relevant ecological processes. From an applied perspective, the model could forecast the time when fuel moisture becomes critical to fire occurrence. Due to the lack of worked examples for nonlinear mixed-effects models in the literature, our modeling approach could be useful to diverse ecologists dealing with complex data.Fil: Oddi, Facundo José. Universidad Nacional de Río Negro. Sede Andina. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Miguez, Fernando E.. University of Iowa; Estados UnidosFil: Ghermandi, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Biodiversidad y Medioambiente. Universidad Nacional del Comahue. Centro Regional Universidad Bariloche. Instituto de Investigaciones en Biodiversidad y Medioambiente; ArgentinaFil: Bianchi, Lucas Osvaldo. Universidad Nacional de Río Negro. Sede Andina. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garibaldi, Lucas Alejandro. Universidad Nacional de Río Negro. Sede Andina. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Are ribosomal DNA clusters rearrangement hotspots? A case study in the genus Mus (Rodentia, Muridae)

<p>Abstract</p> <p>Background</p> <p>Recent advances in comparative genomics have considerably improved our knowledge of the evolution of mammalian karyotype architecture. One of the breakthroughs was the preferential localization of evolutionary breakpoints in regions enriched in repetitive sequences (segmental duplications, telomeres and centromeres). In this context, we investigated the contribution of ribosomal genes to genome reshuffling since they are generally located in pericentromeric or subtelomeric regions, and form repeat clusters on different chromosomes. The target model was the genus <it>Mus </it>which exhibits a high rate of karyotypic change, a large fraction of which involves centromeres.</p> <p>Results</p> <p>The chromosomal distribution of rDNA clusters was determined by <it>in situ </it>hybridization of mouse probes in 19 species. Using a molecular-based reference tree, the phylogenetic distribution of clusters within the genus was reconstructed, and the temporal association between rDNA clusters, breakpoints and centromeres was tested by maximum likelihood analyses. Our results highlighted the following features of rDNA cluster dynamics in the genus <it>Mus</it>: i) rDNA clusters showed extensive diversity in number between species and an almost exclusive pericentromeric location, ii) a strong association between rDNA sites and centromeres was retrieved which may be related to their shared constraint of concerted evolution, iii) 24% of the observed breakpoints mapped near an rDNA cluster, and iv) a substantial rate of rDNA cluster change (insertion, deletion) also occurred in the absence of chromosomal rearrangements.</p> <p>Conclusions</p> <p>This study on the dynamics of rDNA clusters within the genus <it>Mus </it>has revealed a strong evolutionary relationship between rDNA clusters and centromeres. Both of these genomic structures coincide with breakpoints in the genus <it>Mus</it>, suggesting that the accumulation of a large number of repeats in the centromeric region may contribute to the high level of chromosome repatterning observed in this group. However, the elevated rate of rDNA change observed in the chromosomally invariant clade indicates that the presence of these sequences is insufficient to lead to genome instability. In agreement with recent studies, these results suggest that additional factors such as modifications of the epigenetic state of DNA may be required to trigger evolutionary plasticity.</p

Genetic Association Studies of Copy-Number Variation: Should Assignment of Copy Number States Precede Testing?

Recently, structural variation in the genome has been implicated in many complex diseases. Using genomewide single nucleotide polymorphism (SNP) arrays, researchers are able to investigate the impact not only of SNP variation, but also of copy-number variants (CNVs) on the phenotype. The most common analytic approach involves estimating, at the level of the individual genome, the underlying number of copies present at each location. Once this is completed, tests are performed to determine the association between copy number state and phenotype. An alternative approach is to carry out association testing first, between phenotype and raw intensities from the SNP array at the level of the individual marker, and then aggregate neighboring test results to identify CNVs associated with the phenotype. Here, we explore the strengths and weaknesses of these two approaches using both simulations and real data from a pharmacogenomic study of the chemotherapeutic agent gemcitabine. Our results indicate that pooled marker-level testing is capable of offering a dramatic increase in power (-fold) over CNV-level testing, particularly for small CNVs. However, CNV-level testing is superior when CNVs are large and rare; understanding these tradeoffs is an important consideration in conducting association studies of structural variation

Dispersal and reproductive careers of male mountain gorillas in Bwindi Impenetrable National Park, Uganda

Dispersal is a key event in the life of an animal and it influences individual reproductive success. Male mountain gorillas exhibit both philopatry and dispersal, resulting in a mixed one-male and multimale social organization. However, little is known about the relationship between male dispersal or philopatry and reproductive careers in Bwindi mountain gorillas. Here we analyze data spanning from 1993 to 2017 on social groups in Bwindi Impenetrable National Park, Uganda to examine the proportion of males that disperse, age of dispersal, pathways to attaining alpha status, fate of dispersing males and philopatric males, and male tenure length as well as make comparisons of these variables to the Virunga mountain gorilla population. We report previously undocumented cases of dispersal by immature males and old males and we also observed the only known case of a fully mature male immigrating into a breeding group. We used genetic tracking of known individuals to estimate that a minimum of 25% of males that disperse to become solitary males eventually form new groups. No differences were found between the Bwindi and Virunga population in the age of male dispersal, the proportion of males that disperse, the age of alpha male acquisition, and dominance tenure length. The lack of differences may be due to small sample sizes or because the observed ecological variability does not lead to life history differences between the populations. Males in both populations follow variable strategies to attain alpha status leading to the variable one-male and multimale social organization, including dispersal to become solitary and eventually form a group, via group fissioning, usurping another alpha male, or inheriting the alpha position when a previous group leader dies

Datopotamab–deruxtecan plus durvalumab in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial

Sequential adaptive trial designs can help accomplish the goals of personalized medicine, optimizing outcomes and avoiding unnecessary toxicity. Here we describe the results of incorporating a promising antibody-drug conjugate, datopotamab-deruxtecan (Dato-DXd) in combination with programmed cell death-ligand 1 inhibitor, durvalumab, as the first sequence of therapy in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomization trial for high-risk stage 2/3 breast cancer. The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed by a taxane-based regimen tailored to tumor subtype (block B), followed by doxorubicin-cyclophosphamide (block C). Subtype-specific algorithms based on magnetic resonance imaging volume change and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathologic complete response, which is the primary endpoint assessed when resection occurs. There are two primary efficacy analyses: after block A and across all blocks for six prespecified HER2-negative subtypes (defined by hormone receptor status and/or response-predictive subtypes). In total, 106 patients were treated with Dato-DXd/durvalumab in block A. In the immune-positive subtype, Dato-DXd/durvalumab exceeded the prespecified threshold for success (graduated) after block A; and across all blocks, pathologic complete response rates were equivalent to the rate expected for the standard of care (79%), but 54% achieved that result after Dato-DXd/durvalumab alone (block A) and 92% without doxorubicin-cyclophosphamide (after blocks A + B). The treatment strategy across all blocks graduated in the hormone-negative/immune-negative subtype. No new toxicities were observed. Stomatitis was the most common side effect in block A. No patients receiving block A treatment alone had adrenal insufficiency. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype.ClinicalTrials.gov registration: NCT01042379