“Your Brain Isn’t All Backwards”: Asexual Young Women’s Narratives of Sexual Healthism

Scholarship on asexuality is a growing but underexplored area in the social sciences. In the U.S., asexual people (i.e., individuals who do not experience sexual attraction) navigate a society in which being a sexual person is regarded as a normal and even compulsory aspect of human health and subjectivity. Utilizing an asexual subsample from a broader study of queer young women, this article integrates Foucault’s theorizing around sexuality and repression with scholarship on healthism to examine how discourses of sexual healthism operate among asexual young women in the U.S. South. We argue that in rejecting theories of sexual repression and compulsory “healthy” sexuality, asexual young women both confirm and resist the moral authority and power of religious and health discourses to affirm their identities and find language and communities to make their experiences more intelligible to themselves and others. Our analysis advances emerging scholarship on sexual healthism and its discursive and material effects on marginalized groups

Applications of machine learning to solve biological puzzles

The era of “big data” has led to the generation of more biological data than any human could hope to process. This flood of data has necessitated the development of computational methods to assist in analysis, and has made it possible to begin to model complex biological systems. Machine learning methods represent one avenue for modeling, and allow for the identification of intricate and often cryptic sequence signals underlying many biological processes. In this dissertation, I present two machine learning models, RPIDisorder and MEDJED, which were developed to predict RNA-protein interaction partners (RPIPs) and DNA double-strand break (DSB) repair by the microhomology-mediated end joining (MMEJ) pathway, respectively. I also present the Gene Sculpt Suite, a set of freely available web-based software tools for precision gene editing. RPIDisorder uses signals from protein and RNA sequences (some of which have been previously utilized in published RNA-protein partner prediction methods), but it additionally exploits signal from disordered protein regions to predict interactions with greater specificity than has been possible before. RPIDisorder allows for the prediction of biologically relevant RNA-protein interaction networks, which in turn can assist in the development of clinical interventions for the numerous cancers and neurological and metabolic disorders associated with disruptions in RNA-protein interactions. RPIDisorder is freely available at www.rpidisorder.org. MEDJED (Microhomology-Evoked Deletion Judication EluciDation) uses signal within and surrounding short stretches of homologous DNA sequence (microhomologies) on either side of an introduced DSB to predict the extent to which a targeted genomic site will be repaired using the MMEJ pathway. MEDJED is freely available at www.genesculpt.org/medjed/. The advent of gene editing nucleases including CRISPR/Cas systems, TALENs, and zinc finger nucleases has made it possible to insert, delete, and precisely edit DNA. A great deal of recent research has focused on improving the efficiency and precision of these nucleases by leveraging endogenous DSB repair pathways including non-homologous end joining (NHEJ) and homologous recombination (HR). However, homology-mediated end joining pathways (HMEJ), including MMEJ and single-strand annealing (SSA), provide many advantages over NHEJ and HR. The Gene Sculpt Suite is a set of three web-based tools (GTagHD, MEDJED, and MENTHU) that leverage HMEJ pathways to enhance exogenous DNA knock-in (GTagHD) and produce more efficient and precise gene knock-outs (MEDJED and MENTHU). The Gene Sculpt Suite is freely available at www.genesculpt.org. Taken together, the results of these studies demonstrate that machine learning models can be valuable for identifying sequence signals that regulate macromolecular recognition, with numerous potential applications in both basic and applied research

Repetitive myocardial ischemia promotes coronary growth in the adult mammalian heart

BACKGROUND: Coronary artery disease and ischemic cardiomyopathy represent the leading cause of heart failure and continue to grow at exponential rates. Despite widespread availability of coronary bypass surgery and percutaneous coronary intervention, subsequent ischemic events and progression to heart failure continue to be common occurrences. Previous studies have shown that a subgroup of patients develop collateral blood vessels that serve to connect patent and occluded arteries and restore perfusion to ischemic territories. The presence of coronary collaterals has been correlated with improved clinical outcomes; however, the molecular mechanisms governing this process remain largely unknown. METHODS AND RESULTS: To date, no mouse models of coronary arterial growth have been described. Using a closed‐chest model of myocardial ischemia, we have demonstrated that brief episodes of repetitive ischemia are sufficient to promote the growth of both large coronary arteries and the microvasculature. Induction of large coronary artery and microvascular growth resulted in improvements in myocardial perfusion after prolonged ischemia and protected from subsequent myocardial infarction. We further show that repetitive ischemia did not lead to increased expression of classic proangiogenic factors but instead resulted in activation of the innate immune system and recruitment of macrophages to growing blood vessels. CONCLUSIONS: These studies describe a novel model of coronary angiogenesis and implicate the cardiac macrophage as a potential mediator of ischemia‐driven coronary growth

A motif-based method for predicting interfacial residues in both the RNA and protein components of protein-RNA complexes

Efforts to predict interfacial residues in protein-RNA complexes have largely focused on predicting RNA-binding residues in proteins. Computational methods for predicting protein-binding residues in RNA sequences, however, are a problem that has received relatively little attention to date. Although the value of sequence motifs for classifying and annotating protein sequences is well established, sequence motifs have not been widely applied to predicting interfacial residues in macromolecular complexes. Here, we propose a novel sequence motif-based method for “partner-specific” interfacial residue prediction. Given a specific protein-RNA pair, the goal is to simultaneously predict RNA binding residues in the protein sequence and protein-binding residues in the RNA sequence. In 5-fold cross validation experiments, our method, PS-PRIP, achieved 92% Specificity and 61% Sensitivity, with a Matthews correlation coefficient (MCC) of 0.58 in predicting RNA-binding sites in proteins. The method achieved 69% Specificity and 75% Sensitivity, but with a low MCC of 0.13 in predicting protein binding sites in RNAs. Similar performance results were obtained when PS-PRIP was tested on two independent “blind” datasets of experimentally validated protein- RNA interactions, suggesting the method should be widely applicable and valuable for identifying potential interfacial residues in protein-RNA complexes for which structural information is not available. The PS-PRIP webserver and datasets are available at: http://pridb.gdcb.iastate.edu/PSPRIP/

Loop bounds on non-standard neutrino interactions

We reconsider the bounds on non-standard neutrino interactions with matter which can be derived by constraining the four-charged-lepton operators induced at the loop level. We find that these bounds are model dependent. Naturalness arguments can lead to much stronger constraints than those presented in previous studies, while no completely model-independent bounds can be derived. We will illustrate how large loop-contributions to four-charged-lepton operators are induced within a particular model that realizes gauge invariant non-standard interactions and discuss conditions to avoid these bounds. These considerations mainly affect the $\mathcal O(10^{-4})$ constraint on the non-standard coupling strength \eps_{e\mu}, which is lost. The only model-independent constraints that can be derived are $\mathcal O(10^{-1})$. However, significant cancellations are required in order to saturate this bound.Comment: Minor changes, version to be published in JHEP. 17 pages, 3 Axodraw figures, REVTeX

Psychometric Evaluation and Design of Patient-Centered Communication Measures for Cancer Care Settings

Objective To evaluate the psychometric properties of questions that assess patient perceptions of patient-provider communication and design measures of patient-centered communication (PCC). Methods Participants (adults with colon or rectal cancer living in North Carolina) completed a survey at 2 to 3 months post-diagnosis. The survey included 87 questions in six PCC Functions: Exchanging Information, Fostering Health Relationships, Making Decisions, Responding to Emotions, Enabling Patient Self-Management, and Managing Uncertainty. For each Function we conducted factor analyses, item response theory modeling, and tests for differential item functioning, and assessed reliability and construct validity. Results Participants included 501 respondents; 46% had a high school education or less. Reliability within each Function ranged from 0.90 to 0.96. The PCC-Ca-36 (36-question survey; reliability=0.94) and PCC-Ca-6 (6-question survey; reliability=0.92) measures differentiated between individuals with poor and good health (i.e., known-groups validity) and were highly correlated with the HINTS communication scale (i.e., convergent validity). Conclusion This study provides theory-grounded PCC measures found to be reliable and valid in colorectal cancer patients in North Carolina. Future work should evaluate measure validity over time and in other cancer populations. Practice implications The PCC-Ca-36 and PCC-Ca-6 measures may be used for surveillance, intervention research, and quality improvement initiatives

Synthesis of kainoids via a highly stereoselective hydroformylation of kainic acid.

An efficient prepn. of a series of secondary amines, structurally related to the kainic acid scaffold, is described.  Naturally occurring (-)-α-kainic acid was hydroformylated with complete terminal selectivity and high stereoselectivity.  The stereochem. of the product was investigated through the ROESY and HETLOC spectra of the corresponding 2,4-dinitrophenylhydrazone, showing the presence of a single diastereoisomer with rotamers related to the presence of the Boc group.  The aldehyde was used as a platform to prep. amines by reductive amination in ionic liqs

Hydro­thermally synthesized α-Ba2P2O7

Single crystals of α-Ba2P2O7, dibarium diphosphate, were obtained under hydro­thermal conditions. The structure belongs to the diphosphate A 2P2O7 series with A being an alkaline earth cation. α-Ba2P2O7 crystallizes isotypically with α-Sr2P2O7. All atomic sites have site symmetry m with the exception of two O atoms which reside on general positions. Both Ba2+ cations are coordinated by nine terminal O atoms from eclipsed diphosphate P2O7 anions to form a three-dimensional network throughout the structure

Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo

BACKGROUND: Tissue injury triggers inflammatory responses that promote tissue fibrosis; however, the mechanisms that couple tissue injury, inflammation, and fibroblast activation are not known. Given that dying cells release proinflammatory “damage-associated molecular patterns” (DAMPs), we asked whether proteins released by necrotic myocardial cells (NMCs) were sufficient to activate fibroblasts in vitro by examining fibroblast activation after stimulation with proteins released by necrotic myocardial tissue, as well as in vivo by injecting proteins released by necrotic myocardial tissue into the hearts of mice and determining the extent of myocardial inflammation and fibrosis at 72 hours. METHODS AND RESULTS: The freeze–thaw technique was used to induce myocardial necrosis in freshly excised mouse hearts. Supernatants from NMCs contained multiple DAMPs, including high mobility group box-1 (HMGB1), galectin-3, S100β, S100A8, S100A9, and interleukin-1α. NMCs provoked a significant increase in fibroblast proliferation, α–smooth muscle actin activation, and collagen 1A1 and 3A1 mRNA expression and significantly increased fibroblast motility in a cell-wounding assay in a Toll-like receptor 4 (TLR4)- and receptor for advanced glycation end products–dependent manner. NMC stimulation resulted in a significant 3- to 4-fold activation of Akt and Erk, whereas pretreatment with Akt (A6730) and Erk (U0126) inhibitors decreased NMC-induced fibroblast proliferation dose-dependently. The effects of NMCs on cell proliferation and collagen gene expression were mimicked by several recombinant DAMPs, including HMGB1 and galectin-3. Moreover, immunodepletion of HMGB1 in NMC supernatants abrogated NMC-induced cell proliferation. Finally, injection of NMC supernatants or recombinant HMGB1 into the heart provoked increased myocardial inflammation and fibrosis in wild-type mice but not in TLR4-deficient mice. CONCLUSIONS: These studies constitute the initial demonstration that DAMPs released by NMCs induce fibroblast activation in vitro, as well as myocardial inflammation and fibrosis in vivo, at least in part, through TLR4-dependent signaling

TNF receptor-activated factor 2 mediates cardiac protection through noncanonical NF-κB signaling

To elucidate the mechanisms responsible for cytoprotective effects of TNF receptor-activated factor 2 (TRAF2) in the heart, we employed genetic gain- and loss-of-function studies ex vivo and in vivo in mice with cardiac-restricted overexpression of TRAF2 (Myh6-TRAF2LC). Crossing Myh6-TRAF2LC mice with mice lacking canonical signaling (Myh6-TRAF2LC/Myh6-IκBαΔN) abrogated the cytoprotective effects of TRAF2 ex vivo. In contrast, inhibiting the JAK/STAT pathway did not abrogate the cytoprotective effects of TRAF2. Transcriptional profiling of WT, Myh6-TRAF2LC, and Myh6-TRAF2LC/Myh6-IκBαΔN mouse hearts suggested that the noncanonical NF-κB signaling pathway was upregulated in the Myh6-TRAF2LC mouse hearts. Western blotting and ELISA for the NF-κB family proteins p50, p65, p52, and RelB on nuclear and cytoplasmic extracts from naive 12-week-old WT, Myh6-TRAF2LC, and Myh6-TRAF2LC/Myh6-IκBαΔN mouse hearts showed increased expression levels and increased DNA binding of p52 and RelB, whereas there was no increase in expression or DNA binding of the p50 and p65 subunits. Crossing Myh6-TRAF2LC mice with RelB-/+ mice (Myh6-TRAF2LC/RelB-/+) attenuated the cytoprotective effects of TRAF2 ex vivo and in vivo. Viewed together, these results suggest that crosstalk between the canonical and noncanonical NF-κB signaling pathways is required for mediating the cytoprotective effects of TRAF2