Regularized Ordinal Regression and the ordinalNet R Package

Regularization techniques such as the lasso (Tibshirani 1996) and elastic net (Zou and Hastie 2005) can be used to improve regression model coefficient estimation and prediction accuracy, as well as to perform variable selection. Ordinal regression models are widely used in applications where the use of regularization could be beneficial; however, these models are not included in many popular software packages for regularized regression. We propose a coordinate descent algorithm to fit a broad class of ordinal regression models with an elastic net penalty. Furthermore, we demonstrate that each model in this class generalizes to a more flexible form, for instance to accommodate unordered categorical data. We introduce an elastic net penalty class that applies to both model forms. Additionally, this penalty can be used to shrink a non-ordinal model toward its ordinal counterpart. Finally, we introduce the R package ordinalNet, which implements the algorithm for this model class

Regularized Ordinal Regression and the ordinalNet R Package

Regularization techniques such as the lasso (Tibshirani 1996) and elastic net (Zou and Hastie 2005) can be used to improve regression model coefficient estimation and prediction accuracy, as well as to perform variable selection. Ordinal regression models are widely used in applications where the use of regularization could be beneficial; however, these models are not included in many popular software packages for regularized regression. We propose a coordinate descent algorithm to fit a broad class of ordinal regression models with an elastic net penalty. Furthermore, we demonstrate that each model in this class generalizes to a more flexible form, that can be used to model either ordered or unordered categorical response data. We call this the elementwise link multinomial-ordinal class, and it includes widely used models such as multinomial logistic regression (which also has an ordinal form) and ordinal logistic regression (which also has an unordered multinomial form). We introduce an elastic net penalty class that applies to either model form, and additionally, this penalty can be used to shrink a non-ordinal model toward its ordinal counterpart. Finally, we introduce the R package ordinalNet, which implements the algorithm for this model class

Site-Specific Polymer Attachment to HR2 Peptide Fusion Inhibitors against HIV-1 Decreases Binding Association Rates and Dissociation Rates Rather Than Binding Affinity

A popular strategy for overcoming the limited plasma half-life of peptide heptad repeat 2 (HR2) fusion inhibitors against HIV-1 is conjugation with biocompatible polymers such as poly(ethylene glycol) (PEG). However, despite improved resistance to proteolysis and reduced renal elimination, covalent attachment of polymers often causes a loss in therapeutic potency. In this study, we investigated the molecular origins of the loss in potency upon conjugation of linear, midfunctional, and hyperbranched PEG-like polymers to peptides that inhibit HIV-1 host cell membrane fusion. Fluorescence binding assays revealed that polymer conjugation imparted mass transport limitations that manifested as coexistent slower association and dissociation rates from the gp41 target on HIV-1. Furthermore, reduced association kinetics rather than affinity disruption was responsible for the loss in antiviral potency. Finally, the binding assays indicated that the unmodified HR2-derived peptide demonstrated diffusion-limited binding. The observed high potency of the unmodified peptide in HIV-1 inhibition assays was therefore attributed to rapid peptide conformational changes upon binding to the gp41 prehairpin structure. This study emphasizes that the view in which polymer ligation to therapeutic peptides inadvertently leads to loss in potency due to a loss in binding affinity requires scientific verification on a case-by-case basis and that high peptide potency may be due to rapid target binding events

The Genome and Methylome of a Beetle with Complex Social Behavior,Nicrophorus vespilloides(Coleoptera: Silphidae)

Testing for conserved and novelmechanisms underlying phenotypic evolution requires a diversity of genomes available for comparisonspanning multiple independent lineages. For example, complex social behavior in insects has been investigated primarily witheusocial lineages, nearly all of which are Hymenoptera. If conserved genomic influences on sociality do exist, we need data from awider range of taxa that also vary in their levels of sociality. Here,we present the assembled and annotated genome of the subsocialbeetle Nicrophorus vespilloides, a species long used to investigate evolutionary questions of complex social behavior. We used thisgenome to address two questions. First, do aspects of life history, such as using a carcass to breed, predict overlap in gene modelsmore strongly than phylogeny? We found that the overlap in gene models was similar between N. vespilloides and all other insectgroups regardless of life history. Second, like other insects with highly developed social behavior but unlike other beetles, doesN. vespilloides have DNA methylation?We found strong evidence for an active DNA methylation system. The distribution of methylationwassimilar to other insects with exons having themostmethylatedCpGs. Methylation status appears highly conserved; 85%of themethylated genes in N. vespilloides are alsomethylated in the hymentopteran Nasonia vitripennis. The addition of this genomeadds a coleopteran resource to answer questions about the evolution and mechanistic basis of sociality and to address questionsabout the potential role of methylation in social behavior

Masses, radii, and orbits of small Kepler planets : The transition from gaseous to rocky planets

We report on the masses, sizes, and orbits of the planets orbiting 22 Kepler stars. There are 49 planet candidates around these stars, including 42 detected through transits and 7 revealed by precise Doppler measurements of the host stars. Based on an analysis of the Kepler brightness measurements, along with high-resolution imaging and spectroscopy, Doppler spectroscopy, and (for 11 stars) asteroseismology, we establish low false-positive probabilities (FPPs) for all of the transiting planets (41 of 42 have an FPP under 1%), and we constrain their sizes and masses. Most of the transiting planets are smaller than three times the size of Earth. For 16 planets, the Doppler signal was securely detected, providing a direct measurement of the planet's mass. For the other 26 planets we provide either marginal mass measurements or upper limits to their masses and densities; in many cases we can rule out a rocky composition. We identify six planets with densities above 5 g cm-3, suggesting a mostly rocky interior for them. Indeed, the only planets that are compatible with a purely rocky composition are smaller than 2 R ⊕. Larger planets evidently contain a larger fraction of low-density material (H, He, and H2O).Peer reviewedFinal Accepted Versio

A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo

Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Exploiting Nucleotide Composition to Engineer Promoters

The choice of promoter is a critical step in optimizing the efficiency and stability of recombinant protein production in mammalian cell lines. Artificial promoters that provide stable expression across cell lines and can be designed to the desired strength constitute an alternative to the use of viral promoters. Here, we show how the nucleotide characteristics of highly active human promoters can be modelled via the genome-wide frequency distribution of short motifs: by overlapping motifs that occur infrequently in the genome, we constructed contiguous sequence that is rich in GC and CpGs, both features of known promoters, but lacking homology to real promoters. We show that snippets from this sequence, at 100 base pairs or longer, drive gene expression in vitro in a number of mammalian cells, and are thus candidates for use in protein production. We further show that expression is driven by the general transcription factors TFIIB and TFIID, both being ubiquitously present across cell types, which results in less tissue- and species-specific regulation compared to the viral promoter SV40. We lastly found that the strength of a promoter can be tuned up and down by modulating the counts of GC and CpGs in localized regions. These results constitute a “proof-of-concept” for custom-designing promoters that are suitable for biotechnological and medical applications