Examining the Effects of Couples’ Real-Time Stress and Coping Processes on Interaction Quality: Language Use as a Mediator

Stress in romantic relationships is an all-too-common phenomenon that has detrimental effects on relationship well-being. Specifically, stress can lead to negative interactions between partners and ultimately decrease relationship functioning. The systemic-transactional model of dyadic coping posits that by effectively communicating stress and coping with one’s romantic partner, couples can mitigate the deleterious effects of stress. Specifically, partners can engage in positive dyadic coping, which may foster couples’ sense of “we-ness,” strengthen their emotional connection, and facilitate their understanding of each other’s stressful experiences. However, these associations have not yet been examined during partners’ real-time stress conversations. When assessing dyadic coping, a particular aspect of interest is partners’ language use (i.e., pronouns, emotion words, and cognition words), as it may reflect the types of support they communicate to one another. Using real-time interaction data from 41 heterosexual couples, this study examined how couples’ stress and coping processes affect perceived interaction quality following discussions of stress. Specifically, language use (i.e., pronouns, emotion words, and cognition words) was assessed as a mediator on the association between observed stress communication and perceived interaction quality. Overall, results supported our hypotheses; when one partner communicated stress, the other partner responded with language use indicative of different types of dyadic coping (i.e., more you-talk and use of emotion words, less we-talk, I-talk, and use of cognition words), which were in turn associated with interaction quality in mixed directions. Implications of these findings for romantic couples are discussed

Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice

Metabolic syndrome describes a set of obesity-related disorders that increase diabetes, cardiovascular, and mortality risk. Studies of liver-specific protein-tyrosine phosphatase 1b (PTP1b) deletion mice (L-PTP1b[superscript −/−]) suggest that hepatic PTP1b inhibition would mitigate metabolic-syndrome through amelioration of hepatic insulin resistance, endoplasmic-reticulum stress, and whole-body lipid metabolism. However, the altered molecular-network states underlying these phenotypes are poorly understood. We used mass spectrometry to quantify protein-phosphotyrosine network changes in L-PTP1b[superscript −/−] mouse livers relative to control mice on normal and high-fat diets. We applied a phosphosite-set-enrichment analysis to identify known and novel pathways exhibiting PTP1b- and diet-dependent phosphotyrosine regulation. Detection of a PTP1b-dependent, but functionally uncharacterized, set of phosphosites on lipid-metabolic proteins motivated global lipidomic analyses that revealed altered polyunsaturated-fatty-acid (PUFA) and triglyceride metabolism in L-PTP1b[superscript −/−] mice. To connect phosphosites and lipid measurements in a unified model, we developed a multivariate-regression framework, which accounts for measurement noise and systematically missing proteomics data. This analysis resulted in quantitative models that predict roles for phosphoproteins involved in oxidation–reduction in altered PUFA and triglyceride metabolism.Pfizer Inc. (grant)National Institutes of Health (U.S.) (grant 5R24DK090963)National Institutes of Health (U.S.) (grant U54-CA112967)National Institutes of Health (U.S.) (grant CA49152 R37)National Institutes of Health (U.S.) (grant R01-DK080756)National Mouse Metabolic Phenotyping Center at UMASS (Grant (U24-DK093000))National Science Foundation (U.S.) (Graduate Research Fellowship

Disease Detection by Ultrasensitive Quantification of Microdosed Synthetic Urinary Biomarkers

The delivery of exogenous agents can enable noninvasive disease monitoring, but existing low-dose approaches require complex infrastructure. In this paper, we describe a microdose-scale injectable formulation of nanoparticles that interrogate the activity of thrombin, a key regulator of clotting, and produce urinary reporters of disease state. We establish a customized single molecule detection assay that enables urinary discrimination of thromboembolic disease in mice using doses of the nanoparticulate diagnostic agents that fall under regulatory guidelines for “microdosing.”National Science Foundation (U.S.). Graduate Research FellowshipNational Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award F32CA159496-02)Burroughs Wellcome Fund (Career Award at the Scientific Interface)National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)David H. Koch Institute for Integrative Cancer Research at MIT (Frontier Research Program

The WiggleZ Dark Energy Survey: the growth rate of cosmic structure since redshift z=0.9

We present precise measurements of the growth rate of cosmic structure for the redshift range 0.1 < z < 0.9, using redshift-space distortions in the galaxy power spectrum of the WiggleZ Dark Energy Survey. Our results, which have a precision of around 10% in four independent redshift bins, are well-fit by a flat LCDM cosmological model with matter density parameter Omega_m = 0.27. Our analysis hence indicates that this model provides a self-consistent description of the growth of cosmic structure through large-scale perturbations and the homogeneous cosmic expansion mapped by supernovae and baryon acoustic oscillations. We achieve robust results by systematically comparing our data with several different models of the quasi-linear growth of structure including empirical models, fitting formulae calibrated to N-body simulations, and perturbation theory techniques. We extract the first measurements of the power spectrum of the velocity divergence field, P_vv(k), as a function of redshift (under the assumption that P_gv(k) = -sqrt[P_gg(k) P_vv(k)] where g is the galaxy overdensity field), and demonstrate that the WiggleZ galaxy-mass cross-correlation is consistent with a deterministic (rather than stochastic) scale-independent bias model for WiggleZ galaxies for scales k < 0.3 h/Mpc. Measurements of the cosmic growth rate from the WiggleZ Survey and other current and future observations offer a powerful test of the physical nature of dark energy that is complementary to distance-redshift measures such as supernovae and baryon acoustic oscillations.Comment: 17 pages, 11 figures, accepted for publication by MNRA

Reconstructing the three-dimensional GABAergic microcircuit of the striatum

A system's wiring constrains its dynamics, yet modelling of neural structures often overlooks the specific networks formed by their neurons. We developed an approach for constructing anatomically realistic networks and reconstructed the GABAergic microcircuit formed by the medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) of the adult rat striatum. We grew dendrite and axon models for these neurons and extracted probabilities for the presence of these neurites as a function of distance from the soma. From these, we found the probabilities of intersection between the neurites of two neurons given their inter-somatic distance, and used these to construct three-dimensional striatal networks. The MSN dendrite models predicted that half of all dendritic spines are within 100 mu m of the soma. The constructed networks predict distributions of gap junctions between FSI dendrites, synaptic contacts between MSNs, and synaptic inputs from FSIs to MSNs that are consistent with current estimates. The models predict that to achieve this, FSIs should be at most 1% of the striatal population. They also show that the striatum is sparsely connected: FSI-MSN and MSN-MSN contacts respectively form 7% and 1.7% of all possible connections. The models predict two striking network properties: the dominant GABAergic input to a MSN arises from neurons with somas at the edge of its dendritic field; and FSIs are interconnected on two different spatial scales: locally by gap junctions and distally by synapses. We show that both properties influence striatal dynamics: the most potent inhibition of a MSN arises from a region of striatum at the edge of its dendritic field; and the combination of local gap junction and distal synaptic networks between FSIs sets a robust input-output regime for the MSN population. Our models thus intimately link striatal micro-anatomy to its dynamics, providing a biologically grounded platform for further study

BAY61-3606 Affects the Viability of Colon Cancer Cells in a Genotype-Directed Manner

Background: K-RAS mutation poses a particularly difficult problem for cancer therapy. Activating mutations in K-RAS are common in cancers of the lung, pancreas, and colon and are associated with poor response to therapy. As such, targeted therapies that abrogate K-RAS-induced oncogenicity would be of tremendous value. Methods: We searched for small molecule kinase inhibitors that preferentially affect the growth of colorectal cancer cells expressing mutant K-RAS. The mechanism of action of one inhibitor was explored using chemical and genetic approaches. Results: We identified BAY61-3606 as an inhibitor of proliferation in colorectal cancer cells expressing mutant forms of K-RAS, but not in isogenic cells expressing wild-type K-RAS. In addition to its anti-proliferative effects in mutant cells, BAY61-3606 exhibited a distinct biological property in wild-type cells in that it conferred sensitivity to inhibition of RAF. In this context, BAY61-3606 acted by inhibiting MAP4K2 (GCK), which normally activates NFκβ signaling in wild-type cells in response to inhibition of RAF. As a result of MAP4K2 inhibition, wild-type cells became sensitive to AZ-628, a RAF inhibitor, when also treated with BAY61-3606. Conclusions: These studies indicate that BAY61-3606 exerts distinct biological activities in different genetic contexts

Phase II Trial of Concurrent Sunitinib and Image-Guided Radiotherapy for Oligometastases

BACKGROUND: Preclinical data suggest that sunitinib enhances the efficacy of radiotherapy. We tested the combination of sunitinib and hypofractionated image-guided radiotherapy (IGRT) in a cohort of patients with historically incurable distant metastases. METHODS: Twenty five patients with oligometastases, defined as 1-5 sites of active disease on whole body imaging, were enrolled in a phase II trial from 2/08 to 9/10. The most common tumor types treated were head and neck, liver, lung, kidney and prostate cancers. Patients were treated with the recommended phase II dose of 37.5 mg daily sunitinib (days 1-28) and IGRT 50 Gy (days 8-12 and 15-19). Maintenance sunitinib was used in 33% of patients. Median follow up was 17.5 months (range, 0.7 to 37.4 months). RESULTS: The 18-month local control, distant control, progression-free survival (PFS) and overall survival (OS) were 75%, 52%, 56% and 71%, respectively. At last follow-up, 11 (44%) patients were alive without evidence of disease, 7 (28%) were alive with distant metastases, 3 (12%) were dead from distant metastases, 3 (12%) were dead from comorbid illness, and 1 (4%) was dead from treatment-related toxicities. The incidence of acute grade ≥ 3 toxicities was 28%, most commonly myelosuppression, bleeding and abnormal liver function tests. CONCLUSIONS: Concurrent sunitinib and IGRT achieves major clinical responses in a subset of patients with oligometastases. TRIAL REGISTRATION: ClinicalTrials.gov NCT00463060

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts