The Biochemical Pathways of Nicotinamide-Derived Pyridones.

As catabolites of nicotinamide possess physiological relevance, pyridones are often included in metabolomics measurements and associated with pathological outcomes in acute kidney injury (AKI). Pyridones are oxidation products of nicotinamide, its methylated form, and its ribosylated form. While they are viewed as markers of over-oxidation, they are often wrongly reported or mislabeled. To address this, we provide a comprehensive characterization of these catabolites of vitamin B3, justify their nomenclature, and differentiate between the biochemical pathways that lead to their generation. Furthermore, we identify an enzymatic and a chemical process that accounts for the formation of the ribosylated form of these pyridones, known to be cytotoxic. Finally, we demonstrate that the ribosylated form of one of the pyridones, the 4-pyridone-3-carboxamide riboside (4PYR), causes HepG3 cells to die by autophagy; a process that occurs at concentrations that are comparable to physiological concentrations of this species in the plasma in AKI patients.

Factors Associated with Successful Completion of Juvenile Mental Health Court.

Justice-involved youth experience a high number of mental health symptoms. There has been an increased effort to address the mental health needs of these youth through specialized juvenile mental health courts (JMHC). To date, there have been few studies that examined characteristics related to successful completion of a JMHC program. This study is a retrospective case file review of 99 individuals ages 10 to 18 years who were involved in a JMHC program. Information collected included educational history, parental factors, psychiatric and abuse history, legal history, risk of removal from home, and risk and protective factors from the Structured Assessment of Violence Risk in Youth (SAVRY) measure. The primary outcome was successful completion of the program. Forty-eight participants (48.5%) successfully completed the program. Neglect, removal from the home, new charges, probation violation, and number of previous charges were negatively associated with successful completion. Positive attitude toward intervention was positively associated with successful completion. Measures that juvenile justice systems may use, such as the SAVRY risk factors and abuse and neglect screens, were not associated with completion. More studies are needed to identify factors associated with successful completion of a JMHC program and to develop interventions to improve outcomes.

Catalytic Reaction Model of Suicide.

Suicide is a devastating outcome of unresolved issues that affect mental health, general wellbeing and socioeconomic stress. The biology of suicidal behavior is still poorly understood, although progress has been made. Suicidal behavior runs in families and genetic studies have provided initial glimpses into potential genes that contribute to suicide risk. Here, we attempt to unify the biology and behavioral dimensions into a model that can guide research in this area. The proposed model envisions suicidal behavior as a catalytic reaction that may result in suicide depending on the conditions, analogously to enzyme catalysis of chemical reactions. A wide array of substrates or reactants, such as hopelessness, depression, debilitating illnesses and diminished motivation can mobilize suicidal thoughts and behaviors (STBs), which can then catalyze the final step/act of suicide. Here, we focus on three biological substrates in particular: threat assessment, motivation to engage in life and impulsivity. Genetic risk factors can affect each of these processes and tilt the balance toward suicidal behavior when existential crises (real or perceived) emerge such as loss of a loved one, sudden changes in social status or serious health issues. Although suicide is a uniquely human behavior, many of the fundamental biological processes are evolutionarily conserved. Insights from animal models may help to shape our understanding of suicidal behavior in man. By examining counterparts of the major biological processes in other organisms, new ideas about the role of genetic risk factors may emerge along with possible therapeutic interventions or preventive measures.

Social media use and body image issues among adolescents in a vulnerable Louisiana community.

Widespread concern has been expressed regarding unrealistic body image and adolescent eating disorder promoting content on social media (SM) platforms. Numerous research studies have examined the impact of SM on body image as well as social vulnerability on negative mental health outcomes. Despite this, few previous studies have examined the impact of SM on body image specifically in vulnerable, underserved, or predominantly minority communities. This study examines the impact of SM on body image issues (BII) in adolescents in a public school system where greater than 50% of the students live in impoverished households. In late 2019, high school student leaders in Northwest Louisiana developed a survey alongside Step Forward, a collective impact initiative. Questions investigated adolescent SM use and mental health in Caddo Parish, namely BII. Teachers within Caddo Parish Public School System administered the survey. Out of the 11,248 total high school students in the school system, nearly 50% were sampled for a sample size of 5,070. Hypotheses included: (1) females were more likely to use SM than males, (2) increasing time spent on SM would correlate with females reporting BII, with males remaining largely unaffected, and (3) highly visual social media (HVSM) platforms would be associated with greater reports of BII than non-HVSM platforms. Results showed females were more likely to use SM (p < 0.001) and report BII (p < 0.001) compared to males, while both sexes reported BII with increasing time spent on SM (p < 0.001). A diversity of platforms were associated with increased BII among SM users compared to non-users (p < 0.001): Pinterest, Reddit, Snapchat, TikTok, Twitter, and YouTube. This conclusion is tempered by the omission of race as a variable in the study design, the use of self-report, and the use of an unvalidated instrument. These findings suggest that the harmful association between SM use and BII may transcend culture and socioeconomic status for a broadly deleterious effect on adolescent mental wellbeing.

Teen Advisory Council Survey's Factors Associated With Self-Harming Thoughts.

Background: The evaluation of teens with self-harming thoughts (SHT) is a high-stakes task for physicians in community and emergency department (ED) settings. The lived experience of adolescents with stress and SHT provides an important source of insight for mental health professionals who evaluate and treat teens A snapshot of the lived experience of teens in northwest Louisiana was captured by the Step Forward Teen Advisory Council (TAC) in 2019. The TAC surveyed peers with the goal of identifying common stressors experienced by local teens in order to inform policy and practices in the local school system. The identification of stressors is a critical step in addressing SHT as adolescents who experience life stressors are at increased risk for self-harming thoughts (SHT), a known precursor to self-harm and suicide. Assessing youth for life stressors is a critical element of suicide prevention. Methods: Local teens queried 5,070 peers attending Caddo Parish schools to better understand the stressors faced by high school students in Northwest Louisiana using a student developed survey. Results were presented to peers at a virtual summit where teens developed action items to reduce stress and presented findings to local leaders. Their efforts ultimately lead to increased supports for students in local schools. Results: Over half of the teens surveyed reported stressors that negatively impacted their physical or emotional well-being. Students endorsing self-harming thoughts reported an average of 7.82 stressors as compared to 3.47 in peers without SHT. Teens with stressors at both home and school were more likely to experience SHT than teens with stressors in a single location. Conclusion: The Gen Z students who developed the TAC Survey identified stress as a major concern for teens in Northwest Louisiana. The TAC Survey data aligns local experience with established data regarding the association between stress, depression and SHT. Second, the results highlight the importance of diving deep to identify all stressors when assessing the risk of self-harm. Finally, the lived experience of local teens with SHT provides critical information for professionals to better understand risk for SHT and suicide in our region and beyond.

Comparative in vivo study of gp96 adjuvanticity in the frog Xenopus laevis.

We have developed in the amphibian Xenopus laevis a unique non-mammalian model to study the ability of certain heat shock proteins (hsps) such as gp96 to facilitate cross-presentation of chaperoned antigens and elicit innate and adaptive T cell responses. Xenopus skin graft rejection provides an excellent platform to study the ability of gp96 to elicit classical MHC class Ia (class Ia) restricted T cell responses. Additionally, the Xenopus model system also provides an attractive alternative to mice for exploring the ability of gp96 to generate responses against tumors that have down-regulated their class Ia molecules thereby escaping immune surveillance. Recently, we have developed an adoptive cell transfer assay in Xenopus clones using peritoneal leukocytes as antigen presenting cells (APCs), and shown that gp96 can prime CD8 T cell responses in vivo against minor histocompatibility skin antigens as well as against the Xenopus thymic tumor 15/0 that does not express class Ia molecules. We describe here the methodology involved to perform these assays including the elicitation, pulsing and adoptive transfer of peritoneal leukocytes, as well as the skin graft and tumor transplantation assays. Additionally we are also describing the harvesting and separation of peripheral blood leukocytes used for flow cytometry and proliferation assays which allow for further characterization of the effector populations involved in skin rejection and anti-tumor responses.

Identification of a dominant CD4 T cell epitope in the membrane lipoprotein Tul4 from Francisella tularensis LVS.

Francisella tularensis is a gram-negative intracellular bacterium that is the causative agent of tularemia. Small mammals such as rodents and rabbits, as well as some biting arthropods, serve as the main vectors for environmental reservoirs of F. tularensis. The low infectious dose, ability to aerosolize the organism, and the possibility of generating antibiotic resistant strains make F. tularensis a prime organism for use in bioterrorism. As a result, some strains of F. tularensis have been placed on the CDC category A select agent list. T cell immune responses are thought to be a critical component in protective immunity to this organism. However, investigation into the immune responses to F. tularensis has been hampered by the lack of molecularly defined epitopes. Here we report the identification of a major CD4(+) T cell epitope in C57Bl/6 (B6) mice. The murine model of F. tularensis infection is relevant as mice are a natural host for F. tularensis LVS and exhibit many of the same features of tularemia seen in humans. Using T cell hybridomas derived from B6 mice that had either been inoculated with F. tularensis and allowed to clear the infection or which had been immunized by conventional means using purified recombinant protein in adjuvant, we have identified amino acids 86-99 of the lipoprotein Tul4 (RLQWQAPEGSKCHD) as an immunodominant CD4 T cell epitope in B6 mice. This epitope is a major component of both the acute and memory responses to F. tularensis infection and can constitute as much as 20% of the responding CD4 T cells in an acute infection. Reactive T cells can also effectively enter the long-term memory T cell pool. The identification of this epitope will greatly aid in monitoring the course of F. tularensis infection and will also aid in the development of effective vaccine strategies for F. tularensis.