Introduction to the Special Issue: Relationships in the Time of COVID-19

This introduction describes the background for the special issue entitled “Relationships in the Time of COVID-19: Examining the Effects of the Global Pandemic on Personal Relationships.” It also examines reasons for conducting interdisciplinary research on COVID-19 and personal relationships, and previews first articles published in the special issue

Preferential, enhanced breast cancer cell migration on biomimetic electrospun nanofiber ‘cell highways’

BACKGROUND: Aggressive metastatic breast cancer cells seemingly evade surgical resection and current therapies, leading to colonization in distant organs and tissues and poor patient prognosis. Therefore, high-throughput in vitro tools allowing rapid, accurate, and novel anti-metastatic drug screening are grossly overdue. Conversely, aligned nanofiber constitutes a prominent component of the late-stage breast tumor margin extracellular matrix. This parallel suggests that the use of a synthetic ECM in the form of a nanoscale model could provide a convenient means of testing the migration potentials of cancer cells to achieve a long-term goal of providing clinicians an in vitro platform technology to test the efficacy of novel experimental anti-metastatic compounds. METHODS: Electrospinning produces highly aligned, cell-adhesive nanofiber matrices by applying a strong electric field to a polymer-containing solution. The resulting fibrous microstructure and morphology closely resembles in vivo tumor microenvironments suggesting their use in analysis of migratory potentials of metastatic cancer cells. Additionally, a novel interface with a gel-based delivery system creates CXCL12 chemotactic gradients to enhance CXCR4-expressing cell migration. RESULTS: Cellular dispersions of MCF-10A normal mammary epithelial cells or human breast cancer cells (MCF-7 and MDA-MB-231) seeded on randomly-oriented nanofiber exhibited no significant differences in total or net distance traveled as a result of the underlying topography. Cells traveled ~2-5 fold greater distances on aligned fiber. Highly-sensitive MDA-MB-231 cells displayed an 82% increase in net distance traversed in the presence of a CXCL12 gradient. In contrast, MCF-7 cells exhibited only 31% increase and MCF-10A cells showed no statistical difference versus control or vehicle conditions. MCF-10A cells displayed little sensitivity to CXCL12 gradients, while MCF-7 cells displayed early sensitivity when CXCL12 concentrations were higher. MDA-MB-231 cells displayed low relative expression levels of CXCR4, but high sensitivity resulting in 55-fold increase at late time points due to CXCL12 gradient dissipation. CONCLUSIONS: This model could create clinical impact as an in vitro diagnostic tool for rapid assessment of tumor needle biopsies to confirm metastatic tumors, their invasiveness, and allow high-throughput drug screening providing rapid development of personalized therapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2407-14-825) contains supplementary material, which is available to authorized users

Hydrogel–Electrospun Fiber Mat Composite Coatings for Neural Prostheses

Achieving stable, long-term performance of implanted neural prosthetic devices has been challenging because of implantation related neuron loss and a foreign body response that results in encapsulating glial scar formation. To improve neuron–prosthesis integration and form chronic, stable interfaces, we investigated the potential of neurotrophin-eluting hydrogel–electrospun fiber mat (EFM) composite coatings. In particular, poly(ethylene glycol)-poly(ε-caprolactone) (PEGPCL) hydrogel–poly(ε-caprolactone) EFM composites were applied as coatings for multielectrode arrays. Coatings were stable and persisted on electrode surfaces for over 1 month under an agarose gel tissue phantom and over 9 months in a PBS immersion bath. To demonstrate drug release, a neurotrophin, nerve growth factor (NGF), was loaded in the PEGPCL hydrogel layer, and coating cytotoxicity and sustained NGF release were evaluated using a PC12 cell culture model. Quantitative MTT assays showed that these coatings had no significant toxicity toward PC12 cells, and neurite extension at day 7 and 14 confirmed sustained release of NGF at biologically significant concentrations for at least 2 weeks. Our results demonstrate that hydrogel–EFM composite materials can be applied to neural prostheses to improve neuron–electrode proximity and enhance long-term device performance and function

Interactions between endothelial cells and electrospun methacrylic terpolymer fibers for engineered vascular replacements

A compliant terpolymer made of hexylmethacrylate (HMA), methylmethacrylate (MMA), and methacrylic acid (MAA) intended for use in small diameter vascular graft applications has been developed. The mechanical properties and in vitro biostability of this terpolymer have been previously characterized. The goal of this investigation was to examine the interactions between endothelial cells and the new terpolymer and to evaluate endothelial cell function. Electrospinning was used to produce both oriented and random terpolymer fiber scaffolds. Smooth solution cast films and tissue culture polystyrene were used as negative and positive controls, respectively. Human blood outgrowth endothelial cells and human umbilical vein endothelial cells were incubated with the test and control samples and characterized with respect to initial cell attachment, proliferation, viability, and maintenance of the endothelial cell phenotype. It was found that the terpolymer is cytocompatible allowing endothelial cell growth, with random fibers being more effective in promoting enhanced cellular activities than oriented fibers. In addition, endothelial cells cultured on these substrates appeared to maintain their phenotype. The results from this study demonstrate that electrospun HMA:MMA:MAA terpolymer has the potential to be used successfully in fabricating small diameter blood vessel replacements

PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML

Although hyperactivation of the Ras-Erk signaling pathway is known to underlie the pathogenesis of juvenile myelomonocytic leukemia (JMML), a fatal childhood disease, the PI3K-Akt signaling pathway is also dysregulated in this disease. Using genetic models, we demonstrate that inactivation of phosphatidylinositol-3-kinase (PI3K) catalytic subunit p110δ, but not PI3K p110α, corrects gain-of-function (GOF) Shp2-induced granulocyte macrophage-colony-stimulating factor (GM-CSF) hypersensitivity, Akt and Erk hyperactivation, and skewed hematopoietic progenitor distribution. Likewise, potent p110δ-specific inhibitors curtail the proliferation of GOF Shp2-expressing hematopoietic cells and cooperate with mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK) inhibition to reduce proliferation further and maximally block Erk and Akt activation. Furthermore, the PI3K p110δ-specific inhibitor, idelalisib, also demonstrates activity against primary leukemia cells from individuals with JMML. These findings suggest that selective inhibition of the PI3K catalytic subunit p110δ could provide an innovative approach for treatment of JMML, with the potential for limiting toxicity resulting from the hematopoietic-restricted expression of p110δ

Perceived psychosocial impacts of legalized same-sex marriage: A scoping review of sexual minority adults’ experiences

A growing body of literature provides important insights into the meaning and impact of the right to marry a same-sex partner among sexual minority people. We conducted a scoping review to 1) identify and describe the psychosocial impacts of equal marriage rights among sexual minority adults, and 2) explore sexual minority women (SMW) perceptions of equal marriage rights and whether psychosocial impacts differ by sex. Using Arksey and O’Malley’s framework we reviewed peer-reviewed English-language publications from 2000 through 2019. We searched six databases (PubMed, PsycINFO, CINAHL, Web of Science, JSTOR, and Sociological Abstracts) to identify English language, peer-reviewed journal articles reporting findings from empirical studies with an explicit focus on the experiences and perceived impact of equal marriage rights among sexual minority adults. We found 59 studies that met our inclusion criteria. Studies identified positive psychosocial impacts of same-sex marriage (e.g., increased social acceptance, reduced stigma) across individual, interpersonal (dyad, family), community (sexual minority), and broader societal levels. Studies also found that, despite equal marriage rights, sexual minority stigma persists across these levels. Only a few studies examined differences by sex, and findings were mixed. Research to date has several limitations; for example, it disproportionately represents samples from the U.S. and White populations, and rarely examines differences by sexual or gender identity or other demographic characteristics. There is a need for additional research on the impact of equal marriage rights and same-sex marriage on the health and well-being of diverse sexual minorities across the globe

Intimate Pride: a Tri-Nation Study on Associations between Positive Minority Identity Aspects and Relationship Quality in Sexual Minorities from German-Speaking Countries

Investigations into the intimate relationships of sexual minorities are proliferating, but often adopt a deficit-oriented and US-centered perspective. In this tri-nation online study with sexual minority participants from Austria, Germany, and Switzerland (N = 571), we (i) assessed the construct validity of the German version of a well-known measure for positive minority identity aspects (the Lesbian, Gay, Bisexual Positive Identity Measure; LGB-PIM), and (ii) explored associations between these aspects (self-awareness, authenticity, community, capacity for intimacy, and social justice) and self-reported relationship quality. Model fit of the German version of the LGB-PIM was deemed acceptable. Higher levels of positive minority identity aspects showed small to moderate associations with higher levels of relationship quality in bivariate analyses, but only capacity for intimacy was linked to relationship quality in higher-order models (controlling for country, age, sexual orientation, gender identity, relationship length, and psychological distress). Results remained robust in several sensitivity analyses. Our results highlight the differential role of positive identity aspects for relationship functioning, with capacity for intimacy as a fruitful leverage point for therapeutic work

PI3Kγ/δ and NOTCH1 Cross-Regulate Pathways That Define the T-cell Acute Lymphoblastic Leukemia Disease Signature

PI3K/AKT and NOTCH1 signaling pathways are frequently dysregulated in T-cell acute lymphoblastic leukemias (T-ALL). Although we have shown that the combined activities of the class I PI3K isoforms p110γ and p110δ play a major role in the development and progression of PTEN-null T-ALL, it has yet to be determined whether their contribution to leukemogenic programing is unique from that associated with NOTCH1 activation. Using an Lmo2-driven mouse model of T-ALL in which both the PI3K/AKT and NOTCH1 pathways are aberrantly upregulated, we now demonstrate that the combined activities of PI3Kγ/δ have both overlapping and distinct roles from NOTCH1 in generating T-ALL disease signature and in promoting tumor cell growth. Treatment of diseased animals with either a dual PI3Kγ/δ or a γ-secretase inhibitor reduced tumor burden, prolonged survival, and induced proapoptotic pathways. Consistent with their similar biological effects, both inhibitors downregulated genes involved in cMYC-dependent metabolism in gene set enrichment analyses. Furthermore, overexpression of cMYC in mice or T-ALL cell lines conferred resistance to both inhibitors, suggesting a point of pathway convergence. Of note, interrogation of transcriptional regulators and analysis of mitochondrial function showed that PI3Kγ/δ activity played a greater role in supporting the disease signature and critical bioenergetic pathways. Results provide insight into the interrelationship between T-ALL oncogenic networks and the therapeutic efficacy of dual PI3Kγ/δ inhibition in the context of NOTCH1 and cMYC signaling

When one phenotype is not enough: divergent evolutionary trajectories govern venom variation in a widespread rattlesnake species

Artículo 10 páginas, 3 figuras 1 tablaUnderstanding the origin and maintenance of phenotypic variation, particularly across a continuous spatial distribution, represents a key challenge in evolutionary biology. For this, animal venoms represent ideal study systems: they are complex, variable, yet easily quantifiable molecular phenotypes with a clear function. Rattlesnakes display tremendous variation in their venom composition, mostly through strongly dichotomous venom strategies, which may even coexist within a single species. Here, through dense, widespread population-level sampling of the Mojave rattlesnake, Crotalus scutulatus, we show that genomic structural variation at multiple loci underlies extreme geographical variation in venom composition, which is maintained despite extensive gene flow. Unexpectedly, neither diet composition nor neutral population structure explain venom variation. Instead, venom divergence is strongly correlated with environmental conditions. Individual toxin genes correlate with distinct environmental factors, suggesting that different selective pressures can act on individual loci independently of their co-expression patterns or genomic proximity. Our results challenge common assumptions about diet composition as the key selective driver of snake venom evolution and emphasize how the interplay between genomic architecture and local-scale spatial heterogeneity in selective pressures may facilitate the retention of adaptive functional polymorphisms across a continuous space.Funding: Leverhulme Trust Grant RPG 2013-315 to WW, Santander Early Career Research Scholarship to GZ, Ministerio de Economía y Competitividad Grant BFU2013-42833-P to JJC.Peer reviewe

PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment

Phosphoinositide-3-kinase and protein kinase B (PI3K-AKT) is upregulated in multiple myeloma (MM). Using a combination of short hairpin RNA (shRNA) lentivirus-mediated knockdown and pharmacologic isoform-specific inhibition we investigated the role of the PI3K p110γ (PI3Kγ) subunit in regulating MM proliferation and bone marrow microenvironment-induced MM interactions. We compared this with inhibition of the PI3K p110δ (PI3kδ) subunit and with combined PI3kδ/γ dual inhibition. We found that MM cell adhesion and migration were PI3Kγ-specific functions, with PI3kδ inhibition having no effect in MM adhesion or migration assays. At concentration of the dual PI3Kδ/γ inhibitor duvelisib, which can be achieved in vivo we saw a decrease in AKT phosphorylation at s473 after tumour activation by bone marrow stromal cells (BMSC) and interleukin-6. Moreover, after drug treatment of BMSC/tumour co-culture activation assays only dual PI3kδ/γ inhibition was able to induce MM apoptosis. shRNA lentiviral-mediated targeting of either PI3Kδ or PI3Kγ alone, or both in combination, increased survival of NSG mice xeno-transplanted with MM cells. Moreover, treatment with duvelisib reduced MM tumour burden in vivo. We report that PI3Kδ and PI3Kγ isoforms have distinct functions in MM and that combined PI3kδ/γ isoform inhibition has anti-MM activity. Here we provide a scientific rationale for trials of dual PI3kδ/γ inhibition in patients with MM