How do learners and speakers make sense of their language and make their language make sense?
Is it dived or dove? Dwarfs or dwarves? If the best students aced the test, did the pretty good students ...beece it? You've probably often pondered such questions yourself, but did you know that similar questions have inspired some of the most important advances in our understanding not only of how languages change but also of how children acquire grammar and how the human mind works?
This book is designed to help readers make sense of morphological change and, more generally, of the concept of analogy and its role in language and in human cognition. With a critical look at the past 150 years of linguistic work on analogical change, David Fertig brings clarity to a field rife with terminological and theoretical confusion.
Key featuresExplains traditional and modern approaches to analogical changeIllustrates the relevance of analogy to current linguistic and psycholinguistic theoryExplores the many ways that covert reanalysis can reshape grammatical systems
Non-negative matrix factorization (NMF) is an unsupervised learning method well suited to high-throughput biology. However, inferring biological processes from an NMF result still requires additional ...post hoc statistics and annotation for interpretation of learned features. Here, we introduce a suite of computational tools that implement NMF and provide methods for accurate and clear biological interpretation and analysis. A generalized discussion of NMF covering its benefits, limitations and open questions is followed by four procedures for the Bayesian NMF algorithm Coordinated Gene Activity across Pattern Subsets (CoGAPS). Each procedure will demonstrate NMF analysis to quantify cell state transitions in a public domain single-cell RNA-sequencing dataset. The first demonstrates PyCoGAPS, our new Python implementation that enhances runtime for large datasets, and the second allows its deployment in Docker. The third procedure steps through the same single-cell NMF analysis using our R CoGAPS interface. The fourth introduces a beginner-friendly CoGAPS platform using GenePattern Notebook, aimed at users with a working conceptual knowledge of data analysis but without a basic proficiency in the R or Python programming language. We also constructed a user-facing website to serve as a central repository for information and instructional materials about CoGAPS and its application programming interfaces. The expected timing to setup the packages and conduct a test run is around 15 min, and an additional 30 min to conduct analyses on a precomputed result. The expected runtime on the user's desired dataset can vary from hours to days depending on factors such as dataset size or input parameters.
The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological ...differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1-0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes.
Although p16 protein expression, a surrogate marker of oncogenic human papillomavirus (HPV) infection, is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC), its ...prevalence and significance have not been well established in cancer of the oral cavity, hypopharynx, or larynx, collectively referred as non-OPSCC, where HPV infection is less common than in the oropharynx.
p16 expression and high-risk HPV status in non-OPSCCs from RTOG 0129, 0234, and 0522 studies were determined by immunohistochemistry (IHC) and in situ hybridization (ISH). Hazard ratios from Cox models were expressed as positive or negative, stratified by trial, and adjusted for clinical characteristics.
p16 expression was positive in 14.1% (12 of 85), 24.2% (23 of 95), and 19.0% (27 of 142) and HPV ISH was positive in 6.5% (six of 93), 14.6% (15 of 103), and 6.9% (seven of 101) of non-OPSCCs from RTOG 0129, 0234, and 0522 studies, respectively. Hazard ratios for p16 expression were 0.63 (95% CI, 0.42 to 0.95; P = .03) and 0.56 (95% CI, 0.35 to 0.89; P = .01) for progression-free (PFS) and overall survival (OS), respectively. Comparing OPSCC and non-OPSCC, patients with p16-positive OPSCC have better PFS and OS than patients with p16-positive non-OPSCC, but patients with p16-negative OPSCC and non-OPSCC have similar outcomes.
Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement of HPV detection methods are warranted before broad application in the clinical setting.
Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular ...locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased V
max with unchanged K
m), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes.
Alcohol use disorder has been linked to dysregulation of the brain stress systems, producing a negative emotional state leading to chronic relapsing behavior. Vasopressin receptors appear to have a ...regulatory role in stress, anxiety, and alcohol. This study evaluated the novel compound, ABT-436, a V1b receptor antagonist, in alcohol-dependent participants in a 12-week clinical trial. Men and women (n=150) who met criteria for DSM-IV alcohol dependence were recruited across four sites. Participants received double-blind ABT-436 or placebo, and a computerized behavioral intervention. ABT-436 was titrated to 800 mg/day during weeks 2-12. Although the primary outcome, percentage of heavy drinking days, was lower in participants receiving ABT-436 compared with placebo, this difference was not statistically significant (31.3 vs 37.6, respectively; p=0.172; d=0.20). However, participants receiving ABT-436 had significantly greater percentage of days abstinent than those receiving placebo (51.2 vs 41.6, respectively; p=0.037; d=0.31). No significant differences were found between treatment groups on any other measures of drinking, alcohol craving, or alcohol-related consequences. Smokers receiving ABT-436 smoked significantly fewer cigarettes per week than those receiving placebo (p=0.046). ABT-436 was well tolerated, with diarrhea (mild-to-moderate severity) being the most common side effect. In subgroup analyses, participants with relatively higher baseline levels of stress responded better to ABT-436 than placebo on select drinking outcomes, suggesting there may be value in testing medications targeting the vasopressin receptor in high stress, alcohol-dependent patients.
New spectral line observations, obtained with the Jansky Very Large Array (VLA), of a sample of 34 galaxies in 17 close pairs are presented in this paper. The sample of galaxy pairs is selected to ...contain galaxies in close, major interactions (i.e. projected separations <30
$h_{70}^{-1}$
kpc, and mass ratios less extreme than 4:1), while still having a sufficiently large angular separation that the VLA can spatially resolve both galaxies in the pair. Of the 34 galaxies, 17 are detected at >3σ. We compare the H i gas fraction of the galaxies with the triggered star formation present in that galaxy. When compared to the star formation rates (SFRs) of non-pair galaxies matched in mass, redshift, and local environment, we find that the star formation enhancement is weakly positively correlated (∼2.5σ) with H i gas fraction. In order to help understand the physical mechanisms driving this weak correlation, we also present results from a small suite of binary galaxy merger simulations with varying gas fractions. The simulated galaxies indicate that larger initial gas fractions are associated with lower levels of interaction-triggered star formation (relative to an identical galaxy in isolation), but also show that high gas fraction galaxies have higher absolute SFRs prior to an interaction. We show that when interaction-driven SFR enhancements are calculated relative to a galaxy with an average gas fraction for its stellar mass, the relationship between SFR and initial gas fraction dominates over the SFR enhancements driven by the interaction. Simulated galaxy interactions that are matched in stellar mass but not in gas fraction, like our VLA sample, yield the same general positive correlation between SFR enhancement and gas fraction that we observe.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer-associated fibroblasts (CAF). This study used a ...convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid coculture experiments. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing data indicated that CAF density is associated with increased inflammation and epithelial-mesenchymal transition (EMT) in epithelial cells. Transfer learning using transcriptional data from patient-derived organoid and CAF cocultures provided in silico validation of CAF induction of inflammatory and EMT epithelial cell states. Further experimental validation in cocultures demonstrated integrin beta 1 (ITGB1) and vascular endothelial factor A (VEGFA) interactions with neuropilin-1 mediating CAF-epithelial cell cross-talk. Together, this study introduces transfer learning from human single-cell data to organoid coculture analyses for experimental validation of discoveries of cell-cell cross-talk and identifies fibroblast-mediated regulation of EMT and inflammation.
Adaptation of transfer learning to relate human single-cell RNA sequencing data to organoid-CAF cocultures facilitates discovery of human pancreatic cancer intercellular interactions and uncovers cross-talk between CAFs and tumor cells through VEGFA and ITGB1.
Self-employment and mental health Bogan, Vicki L.; Fertig, Angela R.; Just, David R.
Review of economics of the household,
09/2022, Letnik:
20, Številka:
3
Journal Article
Recenzirano
This paper analyzes the role of mental health in self-employment decisions. We find evidence of a relationship between psychological distress and self-employment for men that depends on type of ...self-employment and severity of psychological distress. Specifically, there is suggestive evidence of a causal link from moderate psychological distress to self-employment in an unincorporated business as a main job for men. Additionally, we find evidence that long term mental illness can significantly increase the probability of self-employment in an unincorporated business for both men and women. Our results suggest that individual difficulty in wage-and-salary employment is the likely mechanism for this connection.
The neutral gas content of post-merger galaxies Ellison, Sara L; Fertig, Derek; Rosenberg, Jessica L ...
Monthly notices of the Royal Astronomical Society,
03/2015, Letnik:
448, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Measurements of the neutral hydrogen gas content of a sample of 93 post-merger galaxies are presented, from a combination of matches to the ALFALFA.40 data release and new Arecibo observations. By ...imposing completeness thresholds identical to that of the ALFALFA (Arecibo Legacy Fast ALFA) survey, and by compiling a mass-, redshift- and environment-matched control sample from the public ALFALFA.40 data release, we calculate gas fraction offsets (Δf
gas) for the post-mergers, relative to the control sample. We find that the post-mergers have H i gas fractions that are consistent with undisturbed galaxies. However, due to the relative gas richness of the ALFALFA.40 sample, from which we draw our control sample, our measurements of gas fraction enhancements are likely to be conservative lower limits. Combined with comparable gas fraction measurements by Fertig et al. in a sample of galaxy pairs, who also determine gas fraction offsets consistent with zero, we conclude that there is no evidence for significant neutral gas consumption throughout the merger sequence. From a suite of 75 binary merger simulations we confirm that star formation is expected to decrease the post-merger gas fraction by only 0.06 dex, even several Gyr after the merger. Moreover, in addition to the lack of evidence for gas consumption from gas fraction offsets, the observed H i detection fraction in the complete sample of post-mergers is twice as high as the controls, which suggests that the post-merger gas fractions may actually be enhanced. We demonstrate that a gas fraction enhancement in post-mergers, relative to a stellar mass-matched control sample, would indeed be the natural result of merging randomly drawn pairs from a parent population which exhibits a declining gas fraction with increasing stellar mass.
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