Covariance Assisted Multivariate Penalized Additive Regression (CoMPAdRe)

We propose a new method for the simultaneous selection and estimation of multivariate sparse additive models with correlated errors. Our method called Covariance Assisted Multivariate Penalized Additive Regression (CoMPAdRe) simultaneously selects among null, linear, and smooth non-linear effects for each predictor while incorporating joint estimation of the sparse residual structure among responses, with the motivation that accounting for inter-response correlation structure can lead to improved accuracy in variable selection and estimation efficiency. CoMPAdRe is constructed in a computationally efficient way that allows the selection and estimation of linear and non-linear covariates to be conducted in parallel across responses. Compared to single-response approaches that marginally select linear and non-linear covariate effects, we demonstrate in simulation studies that the joint multivariate modeling leads to gains in both estimation efficiency and selection accuracy, of greater magnitude in settings where signal is moderate relative to the level of noise. We apply our approach to protein-mRNA expression levels from multiple breast cancer pathways obtained from The Cancer Proteome Atlas and characterize both mRNA-protein associations and protein-protein subnetworks for each pathway. We find non-linear mRNA-protein associations for the Core Reactive, EMT, PIK-AKT, and RTK pathways

In Vivo Targeting through Click Chemistry

Targeting small molecules to diseased tissues as therapy or diagnosis is a significant challenge in drug delivery. Drug-eluting devices implanted during invasive surgery allow the controlled presentation of drugs at the disease site, but cannot be modified once the surgery is complete. We demonstrate that bioorthogonal click chemistry can be used to target circulating small molecules to hydrogels resident intramuscularly in diseased tissues. We also demonstrate that small molecules can be repeatedly targeted to the diseased area over the course of at least one month. Finally, two bioorthogonal reactions were used to segregate two small molecules injected as a mixture to two separate locations in a mouse disease model. These results demonstrate that click chemistry can be used for pharmacological drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug-eluting vascular grafts and stents.Engineering and Applied Science

Gender Differences in Presentation, Management, and In-Hospital Outcomes for Patients with AMI in a Lower-Middle Income Country: Evidence from Egypt

BACKGROUND: Many studies in high-income countries have investigated gender differences in the care and outcomes of patients hospitalized with acute myocardial infarction (AMI). However, little evidence exists on gender differences among patients with AMI in lower-middle-income countries, where the proportion deaths stemming from cardiovascular disease is projected to increase dramatically. This study examines gender differences in patients in the lower-middle-income country of Egypt to determine if female patients with AMI have a different presentation, management, or outcome compared with men. METHODS AND FINDINGS: Using registry data collected over 18 months from 5 Egyptian hospitals, we considered 1204 patients (253 females, 951 males) with a confirmed diagnosis of AMI. We examined gender differences in initial presentation, clinical management, and in-hospital outcomes using t-tests and χ(2) tests. Additionally, we explored gender differences in in-hospital death using multivariate logistic regression to adjust for age and other differences in initial presentation. We found that women were older than men, had higher BMI, and were more likely to have hypertension, diabetes mellitus, dyslipidemia, heart failure, and atrial fibrillation. Women were less likely to receive aspirin upon admission (p<0.01) or aspirin or statins at discharge (p = 0.001 and p<0.05, respectively), although the magnitude of these differences was small. While unadjusted in-hospital mortality was significantly higher for women (OR: 2.10; 95% CI: 1.54 to 2.87), this difference did not persist in the fully adjusted model (OR: 1.18; 95% CI: 0.55 to 2.55). CONCLUSIONS: We found that female patients had a different profile than men at the time of presentation. Clinical management of men and women with AMI was similar, though there are small but significant differences in some areas. These gender differences did not translate into differences in in-hospital outcome, but highlight differences in quality of care and represent important opportunities for improvement

Dimerization of Receptor Protein-Tyrosine Phosphatase alpha in living cells

BACKGROUND: Dimerization is an important regulatory mechanism of single membrane-spanning receptors. For instance, activation of receptor protein-tyrosine kinases (RPTKs) involves dimerization. Structural, functional and biochemical studies suggested that the enzymatic counterparts of RPTKs, the receptor protein-tyrosine phosphatases (RPTPs), are inhibited by dimerization, but whether RPTPs actually dimerize in living cells remained to be determined. RESULTS: In order to assess RPTP dimerization, we have assayed Fluorescence Resonance Energy Transfer (FRET) between chimeric proteins of cyan- and yellow-emitting derivatives of green fluorescent protein, fused to RPTPα, using three different techniques: dual wavelength excitation, spectral imaging and fluorescence lifetime imaging. All three techniques suggested that FRET occurred between RPTPα -CFP and -YFP fusion proteins, and thus that RPTPα dimerized in living cells. RPTPα dimerization was constitutive, extensive and specific. RPTPα dimerization was consistent with cross-linking experiments, using a non-cell-permeable chemical cross-linker. Using a panel of deletion mutants, we found that the transmembrane domain was required and sufficient for dimerization. CONCLUSIONS: We demonstrate here that RPTPα dimerized constitutively in living cells, which may be mediated by the transmembrane domain, providing strong support for the model that dimerization is involved in regulation of RPTPs

Versatile click alginate hydrogels crosslinked via tetrazine–norbornene chemistry

Alginate hydrogels are well-characterized, biologically inert materials that are used in many biomedical applications for the delivery of drugs, proteins, and cells. Unfortunately, canonical covalently crosslinked alginate hydrogels are formed using chemical strategies that can be biologically harmful due to their lack of chemoselectivity. In this work we introduce tetrazine and norbornene groups to alginate polymer chains and subsequently form covalently crosslinked click alginate hydrogels capable of encapsulating cells without damaging them. The rapid, bioorthogonal, and specific click reaction is irreversible and allows for easy incorporation of cells with high post-encapsulation viability. The swelling and mechanical properties of the click alginate hydrogel can be tuned via the total polymer concentration and the stoichiometric ratio of the complementary click functional groups. The click alginate hydrogel can be modified after gelation to display cell adhesion peptides for 2D cell culture using thiol-ene chemistry. Furthermore, click alginate hydrogels are minimally inflammatory, maintain structural integrity over several months, and reject cell infiltration when injected subcutaneously in mice. Click alginate hydrogels combine the numerous benefits of alginate hydrogels with powerful bioorthogonal click chemistry for use in tissue engineering applications involving the stable encapsulation or delivery of cells or bioactive molecules.Engineering and Applied Science

Click-Crosslinked Injectable Gelatin Hydrogels

Injectable gelatin hydrogels formed with bioorthogonal click chemistry (ClickGel) are cell-responsive ECM mimics for in vitro and in vivo biomaterials applications. Gelatin polymers with pendant norbornene (GelN) or tetrazine (GelT) groups can quickly and spontaneously crosslink upon mixing, allowing for high viability of encapsulated cells, establishment of 3D elongated cell morphologies, and biodegradation when injected in vivo.Engineering and Applied Science

Gender differences in initial presentation.

a<p>Mean (standard deviation) and p-values from t-test reported for continuous variables.</p