Physical activity is associated with grit and resilience in college students: Is intensity the key to success?

Objective: To determine the independent associations among physical activity, sitting, grit, and resilience in college students. Participants: Undergraduate students (n = 244) from a regional university participated in the study in January 2018. Methods: An online survey regarding physical activity, grit, and resilience was distributed via email. Linear regression analyses were used to determine independent associations among grit, resilience, physical activity and sitting. One-way ANCOVAs were used to determine differences in grit and resilience across levels of activity. Results: Vigorous physical activity was positively associated with resilience and the perseverance of effort grit domain, while being negatively associated with the consistency of interest grit domain. Further, grit and resilience scores were significantly higher with increased volumes of vigorous, but not moderate, physical activity. Conclusions: The intensity of physical activity may play an important role in psychosocial determinants related to student success such as grit and resilience.

Glycosylation and oligomeric state of envelope protein might influence HIV-1 virion capture by α4ß7 integrin.

The α4ß7 integrin present on host cells recognizes the V1V2 domain of the HIV-1 envelope protein. This interaction might be involved in virus transmission. Administration of α4ß7-specific antibodies inhibit acquisition of SIV in a macaque challenge model. But the molecular details of V1V2: α4ß7 interaction are unknown and its importance in HIV-1 infection remains controversial. Our biochemical and mutational analyses show that glycosylation is a key modulator of V1V2 conformation and binding to α4ß7. Partially glycosylated, but not fully glycosylated, envelope proteins are preferred substrates for α4ß7 binding. Surprisingly, monomers of the envelope protein bound strongly to α4ß7 whereas trimers bound poorly. Our results suggest that a conformationally flexible V1V2 domain allows binding of the HIV-1 virion to the α4ß7 integrin, which might impart selectivity for the poorly glycosylated HIV-1 envelope containing monomers to be more efficiently captured by α4ß7 integrin present on mucosal cells at the time of HIV-1 transmission.

Adeno-associated viral vectors based on serotype 3b use components of the fibroblast growth factor receptor signaling complex for efficient transduction.

Adeno-associated virus type 3b (AAV3b) has been largely ignored by gene therapists because of the inability of vectors based on this serotype to transduce target tissues efficiently. Here we describe a phenomenon unique to AAV3b in that vectors based on this serotype mediate enhanced transduction in the presence of heparin. Among the many biological functions attributed to heparin, its interaction with, and ability to regulate, several growth factors (GFs) and growth factor receptors (GFRs) has been well characterized. Using GFR-overexpressing cell lines, soluble GFs and heparins, as well as specific GFR inhibitors, we have demonstrated a requirement for fibroblast growth factor receptor-2 (FGFR2) and FGF1 in the heparin-mediated augmentation of AAV3b vector transduction. In contrast to AAV2, we establish that heparin can be used as an adjunct with AAV3b to further increase transduction in a variety of cells and target tissues, additionally suggesting that AAV3b may be an attractive viral vector for clinical use during procedures in which heparin is used. In summary, AAV3b exhibits FGFR2-dependent, markedly enhanced transduction efficiency in the presence of heparin and FGFs, which could make it a useful vector for gene therapy in a variety of human diseases.

Dissection of the role of the stable signal peptide of the arenavirus envelope glycoprotein in membrane fusion.

The arenavirus envelope glycoprotein (GPC) retains a stable signal peptide (SSP) as an essential subunit in the mature complex. The 58-amino-acid residue SSP comprises two membrane-spanning hydrophobic regions separated by a short ectodomain loop that interacts with the G2 fusion subunit to promote pH-dependent membrane fusion. Small-molecule compounds that target this unique SSP-G2 interaction prevent arenavirus entry and infection. The interaction between SSP and G2 is sensitive to the phylogenetic distance between New World (Junín) and Old World (Lassa) arenaviruses. For example, heterotypic GPC complexes are unable to support virion entry. In this report, we demonstrate that the hybrid GPC complexes are properly assembled, proteolytically cleaved, and transported to the cell surface but are specifically defective in their membrane fusion activity. Chimeric SSP constructs reveal that this incompatibility is localized to the first transmembrane segment of SSP (TM1). Genetic changes in TM1 also affect sensitivity to small-molecule fusion inhibitors, generating resistance in some cases and inhibitor dependence in others. Our studies suggest that interactions of SSP TM1 with the transmembrane domain of G2 may be important for GPC-mediated membrane fusion and its inhibition.

X-linked inhibitor of apoptosis protein-mediated attenuation of apoptosis, using a novel cardiac-enhanced adeno-associated viral vector.

Successful amelioration of cardiac dysfunction and heart failure through gene therapy approaches will require a transgene effective at attenuating myocardial injury, and subsequent remodeling, using an efficient and safe delivery vehicle. Our laboratory has established a well-curated, high-quality repository of human myocardial tissues that we use as a discovery engine to identify putative therapeutic transgene targets, as well as to better understand the molecular basis of human heart failure. By using this rare resource we were able to examine age- and sex-matched left ventricular samples from (1) end-stage failing human hearts and (2) nonfailing human hearts and were able to identify the X-linked inhibitor of apoptosis protein (XIAP) as a novel target for treating cardiac dysfunction. We demonstrate that XIAP is diminished in failing human hearts, indicating that this potent inhibitor of apoptosis may be central in protecting the human heart from cellular injury culminating in heart failure. Efforts to ameliorate heart failure through delivery of XIAP compelled the design of a novel adeno-associated viral (AAV) vector, termed SASTG, that achieves highly efficient transduction in mouse heart and in cultured neonatal rat cardiomyocytes. Increased XIAP expression achieved with the SASTG vector inhibits caspase-3/7 activity in neonatal cardiomyocytes after induction of apoptosis through three common cardiac stresses: protein kinase C-γ inhibition, hypoxia, or ß-adrenergic receptor agonist. These studies demonstrate the potential benefit of XIAP to correct heart failure after highly efficient delivery to the heart with the rationally designed SASTG AAV vector.

T-705 (favipiravir) inhibition of arenavirus replication in cell culture.

A number of New World arenaviruses (Junín [JUNV], Machupo [MACV], and Guanarito [GTOV] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. These highly pathogenic viruses and the Old World Lassa fever virus pose a significant threat to public health and national security. The only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associated with significant toxicities. A novel pyrazine derivative currently in clinical trials for the treatment of influenza virus infections, T-705 (favipiravir), has demonstrated broad-spectrum activity against a number of RNA viruses, including arenaviruses. T-705 has also been shown to be effective against Pichinde arenavirus infection in a hamster model. Here, we demonstrate the robust antiviral activity of T-705 against authentic highly pathogenic arenaviruses in cell culture. We show that T-705 disrupts an early or intermediate stage in viral replication, distinct from absorption or release, and that its antiviral activity in cell culture is reversed by the addition of purine bases and nucleosides, but not with pyrimidines. Specific inhibition of viral replication/transcription by T-705 was demonstrated using a lymphocytic choriomeningitis arenavirus replicon system. Our findings indicate that T-705 acts to inhibit arenavirus replication/transcription and may directly target the viral RNA-dependent RNA polymerase.

Internet use and self-injurious behaviors among adolescents and young adults: an interdisciplinary literature review and implications for health professionals.

The ease and accessibility of the Internet has created an environment where individuals can both remain anonymous and interact with others who share their interests. Electronic discussion boards and social-networking sites allow individuals to communicate with others, via public postings, regarding specific topics of interest. These interactions have taken a therapeutic form for adolescents and young adults seeking practical and emotional support on the Internet. Support sites exist for many issues and illnesses, but sites focusing on self-injurious behaviors (SIB) have garnered recent attention because of their potential to either aid in recovery or exacerbate symptoms. SIB are those behaviors in which an individual purposely inflicts harm to his or her body. Based on an interdisciplinary literature review, self-injurious Web sites have been shown to provide anonymous support for individuals experiencing SIB from others who have experienced similar emotions. However, the literature also reveals that some peers who are providing the support are accepting of SIB and guilty of glossing over potentially serious posts. The emotional support received on these sites differs from services those individuals would receive from professionals, such as coping strategies to deal with stressors and a more detailed examination of ominous signs. The use of these Web sites as a help or a hindrance to an individual's recovery from SIB remains highly contested; health professionals should be aware of the pros and cons associated with this phenomenon and should be able to identify safe means of communication for clients suffering from SIB.

Endogenous S-nitrosothiols protect against myocardial injury.

Despite substantial evidence that nitric oxide (NO) and/or endogenous S-nitrosothiols (SNOs) exert protective effects in a variety of cardiovascular diseases, the molecular details are largely unknown. Here we show that following left coronary artery ligation, mice with a targeted deletion of the S-nitrosoglutathione reductase gene (GSNOR(-/-)) have reduced myocardial infarct size, preserved ventricular systolic and diastolic function, and maintained tissue oxygenation. These profound physiological effects are associated with increases in myocardial capillary density and S-nitrosylation of the transcription factor hypoxia inducible factor-1alpha (HIF-1alpha) under normoxic conditions. We further show that S-nitrosylated HIF-1alpha binds to the vascular endothelial growth factor (VEGF) gene, thus identifying a role for GSNO in angiogenesis and myocardial protection. These results suggest innovative approaches to modulate angiogenesis and preserve cardiac function.