Efficacy of REACH Forgiveness across Cultures

Across cultures, most people agree that forgiveness is a virtue. However, culture may influence how willing one should be to forgive and how one might express forgiveness. At a university in the United States, we recruited both foreign-extraction students and domestic students (N = 102) to participate in a six-hour REACH Forgiveness intervention. We investigated the efficacy of the intervention overall as well as whether foreign-extraction and domestic students responded differently to treatment. Forgiveness was assessed using two measures—decisional forgiveness and emotional forgiveness. The six-hour REACH Forgiveness intervention improved participants’ ratings of emotional forgiveness, but not decisional forgiveness, regardless of their culture. Thus, the REACH Forgiveness intervention appears equally efficacious for participants from different cultural backgrounds when conducted in the United States with college students

Overcoming the roadblocks to cardiac cell therapy using tissue engineering

Transplantations of various stem cells or their progeny have repeatedly improved cardiac performance in animal models of myocardial injury; however, the benefits observed in clinical trials have been generally less consistent. Some of the recognized challenges are poor engraftment of implanted cells and, in the case of human cardiomyocytes, functional immaturity and lack of electrical integration, leading to limited contribution to the heart’s contractile activity and increased arrhythmogenic risks. Advances in tissue and genetic engineering techniques are expected to improve the survival and integration of transplanted cells, and to support structural, functional, and bioenergetic recovery of the recipient hearts. Specifically, application of a prefabricated cardiac tissue patch to prevent dilation and to improve pumping efficiency of the infarcted heart offers a promising strategy for making stem cell therapy a clinical reality. [Display omitted

Multiple myeloma causes clonal T-cell immunosenescence: Identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade

© 2016 Macmillan Publishers Limited. Tumour-induced dysfunction of cytotoxic T cells in patients with multiple myeloma (MM) may contribute to immune escape and be responsible for the lack of therapeutic efficacy of immune checkpoint blockade. We therefore investigated dysfunctional clonal T cells in MM and demonstrated immunosenescence but not exhaustion as a predominant feature. T-cell clones were detected in 75% of MM patients and their prognostic significance was revalidated in a new post-immunomodulatory drug cohort. The cells exhibited a senescent secretory effector phenotype: KLRG-1+/CD57+/CD160+/CD28-. Normal-for-age telomere lengths indicate that senescence is telomere independent and potentially reversible. p38-mitogen-activated protein kinase, p16 and p21 signalling pathways known to induce senescence were not elevated. Telomerase activity was found to be elevated and this may explain how normal telomere lengths are maintained in senescent cells. T-cell receptor signalling checkpoints were normal but elevated SMAD levels associated with T-cell inactivation were detected and may provide a potential target for the reversal of clonal T-cell dysfunction in MM. Low programmed death 1 and cytotoxic T-lymphocyte-associated antigen 4 expression detected on T-cell clones infers that these cells are not exhausted but suggests that there would be a suboptimal response to immune checkpoint blockade in MM. Our data suggest that other immunostimulatory strategies are required in MM

Beyond the Red, Purple, and Blue: Election Law Issues in 2012

The Symposium Welcome was given by Clint A. Nichols, the Allen Chair Editor for the University of Richmond Law Review, and Wendy C. Perdue, Dean & Professor of Law at the University of Richmond School of Law. The “Get out the vote?” session was presented by Keesha M. Gaskins, Senior Counsel with the Brennan Center for Justice at New York University; Steven F. Huefner, Professor of Law and Director of Clinical Programs at The Ohio State University Moritz College of Law; Joshua N. Lief, Senior Assistant Attorney General for the Commonwealth of Virginia; and Michael J. Pitts, Professor of Law and Dean’s Fellow at Indiana University’s Robert H. McKinney School of Law. The “Third Parties to the Process” session was presented by Jocelyn F. Benson, Associate Professor of Law at Wayne State University Law School; Joshua A. Douglas, Assistant Professor of Law at the University of Kentucky College of Law; and Rebecca Green, Professor of the Practice of Law and Co-Director of the Election Law Program at the William & Mary Law School. The “Drawing the Lines” session was presented by Keesha M. Gaskins, Senior Counsel with the Brennan Center for Justice at New York University; Dale Ho, Assistant Counsel with the NAACP Legal Defense and Educational Fund; Dr. Michael P. McDonald, Associate Professor of Government and Politics at George Mason University; Donald Palmer, Secretary of the Virginia State Board of Elections; and Rob Richie, Executive Director of FairVote

Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance

Despite improved outcomes in multiple myeloma (MM), a cure remains elusive. However, even before the current therapeutic era, 5% of patients survived >10 years and we propose that immune factors contribute to this longer survival. We identified patient

Dorsomorphin, a Selective Small Molecule Inhibitor of BMP Signaling, Promotes Cardiomyogenesis in Embryonic Stem Cells

Background: Pluripotent embryonic stem (ES) cells, which have the capacity to give rise to all tissue types in the body, show great promise as a versatile source of cells for regenerative therapy. However, the basic mechanisms of lineage specification of pluripotent stem cells are largely unknown, and generating sufficient quantities of desired cell types remains a formidable challenge. Small molecules, particularly those that modulate key developmental pathways like the bone morphogenetic protein (BMP) signaling cascade, hold promise as tools to study in vitro lineage specification and to direct differentiation of stem cells toward particular cell types. Methodology/Principal Findings: We describe the use of dorsomorphin, a selective small molecule inhibitor of BMP signaling, to induce myocardial differentiation in mouse ES cells. Cardiac induction is very robust, increasing the yield of spontaneously beating cardiomyocytes by at least 20 fold. Dorsomorphin, unlike the endogenous BMP antagonist Noggin, robustly induces cardiomyogenesis when treatment is limited to the initial 24-hours of ES cell differentiation. Quantitative-PCR analyses of differentiating ES cells indicate that pharmacological inhibition of BMP signaling during the early critical stage promotes the development of the cardiomyocyte lineage, but reduces the differentiation of endothelial, smooth muscle, and hematopoietic cells. Conclusions/Significance: Administration of a selective small molecule BMP inhibitor during the initial stages of ES cell differentiation substantially promotes the differentiation of primitive pluripotent cells toward the cardiomyocytic lineage, apparently at the expense of other mesodermal lineages. Small molecule modulators of developmental pathways like dorsomorphin could become versatile pharmacological tools for stem cell research and regenerative medicine

A quantitative approach for measuring the reservoir of latent HIV-1 proviruses.

A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1-3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7-9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection

Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A

Charcot-Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation of endogenous normal mitofusins overcame dominant inhibitory effects of CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark mitochondrial stasis and fragmentation independent of causa