E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia

Acute lung injury (ALI) is linked to mitochondrial injury, resulting in impaired cellular oxygen utilization; however, it is unknown how these events are linked on the molecular level. Cardiolipin, a mitochondrial-specific lipid, is generated by cardiolipin synthase (CLS1). Here, we show that S.aureus activates a ubiquitin E3 ligase component, Fbxo15, that is sufficient to mediate proteasomal degradation of CLS1 in epithelia, resulting in decreased cardiolipin availability and disrupted mitochondrial function. CLS1 is destabilized by the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), which binds CLS1 to phosphorylate and regulates CLS1 disposal. Like Fbxo15, PINK1 interacts with and regulates levels of CLS1 through a mechanism dependent upon Thr219. S.aureus infection upregulates this Fbxo15-PINK1 pathway to impair mitochondrial integrity, and Pink1 knockout mice are less prone to S.aureus-induced ALI. Thus, ALI-associated disruption of cellular bioenergetics involves bioeffectors that utilize a phosphodegron to elicit ubiquitin-mediated disposal of a key mitochondrial enzyme. © 2014 The Authors

The Biochemical and Cellular Basis for Nutraceutical Strategies to Attenuate Neurodegeneration in Parkinson’s Disease

Future therapeutic intervention that could effectively decelerate the rate of degeneration within the substantia nigra pars compacta (SNc) could add years of mobility and reduce morbidity associated with Parkinson’s disease (PD). Neurodegenerative decline associated with PD is distinguished by extensive damage to SNc dopaminergic (DAergic) neurons and decay of the striatal tract. While genetic mutations or environmental toxins can precipitate pathology, progressive degenerative succession involves a gradual decline in DA neurotransmission/synaptic uptake, impaired oxidative glucose consumption, a rise in striatal lactate and chronic inflammation. Nutraceuticals play a fundamental role in energy metabolism and signaling transduction pathways that control neurotransmission and inflammation. However, the use of nutritional supplements to slow the progression of PD has met with considerable challenge and has thus far proven unsuccessful. This review re-examines precipitating factors and insults involved in PD and how nutraceuticals can affect each of these biological targets. Discussed are disease dynamics (Sections 1 and 2) and natural substances, vitamins and minerals that could impact disease processes (Section 3). Topics include nutritional influences on α-synuclein aggregation, ubiquitin proteasome function, mTOR signaling/lysosomal-autophagy, energy failure, faulty catecholamine trafficking, DA oxidation, synthesis of toxic DA-quinones, o-semiquinones, benzothiazolines, hyperhomocyseinemia, methylation, inflammation and irreversible oxidation of neuromelanin. In summary, it is clear that future research will be required to consider the multi-faceted nature of this disease and re-examine how and why the use of nutritional multi-vitamin-mineral and plant-based combinations could be used to slow the progression of PD, if possible

To live with a sibling who suffers from an eating disorder

Utifrån mina tidigare erfarenheter inom barnpsykiatrin tänker jag att syskon till psykiskt sjuka barn och ungdomar varit en exkluderad grupp som inte fått sitt utrymme inom vården. Det är av stor vikt att deras tankar och känslor blir belysta för att hitta sätt att möta upp denna grupp. I hälso- och sjukvårdslagen betonas barns behov av information, råd och stöd. Studiens syfte var att undersöka ungdomars upplevelser av att leva med ett syskon som lider av ätstörning. Tre pojkar och två flickor i ålder 15-20 intervjuades i studien. Som analysmetod användes en kvalitativ innehållsanalys enligt Morse och Field. Denna studie bekräftar tidigare kunskap om syskons erfarenheter av att leva med ett syskon som lider av en ätstörning. Syskonen beskriver en oro för systern och brist på information om syskonets sjukdom och behandling. De påverkas negativt av konflikter vid måltider och flera syskon beskriver att de känner skam över systerns sjukdom. Den här studien visar också på att det fanns skillnader i hur pojkarna och flickorna upplevde sin systers sjukdom. Flickorna upplevdes mer känslomässigt drabbade. Flickorna beskrev att deras vardag blivit starkt påverkad av systerns sjukdom, medan pojkarna beskrev att deras vardagsliv med kompisar och aktiviteter inte påverkades i större utsträckning.Ett resultat som framkommer som något nytt och positivt i studien är att flera ungdomar framhåller att familjens rutiner vid maten blivit något bra för dem, sedan deras syster påbörjat sin ätstörningsbehandling. Flickorna förmedlar att de kommit sin syster mer nära och att de känner mer samhörighet nu än innan systern fick sin ätstörning. Om föräldrarna förmår att skapa en god struktur och ett öppet och stödjande samtalsklimat vid måltider så kan de negativa effekterna för familjen minskas och behandlingen skapa ett tillfälle för hela familjen att hitta bra rutiner för familjens måltider.In my experience siblings of mentally ill children and adolescents have been an excluded group within health care. It is of great importance that their thoughts and feelings are expressed in order to find ways to meet up this group. The health care law emphasizes children´s need for information, advice and support. The study´s purpose was to examine adolescents’ experiences of living with a sibling suffering from an eating disorder. Three boys and two girls in the age 15-20 were interviewed in the study. The interviews were analyzed with a qualitative content analysis. This study confirms prior knowledge of adolescents’ experiences of living with a sibling who is suffering from an eating disorder. The adolescents are concerned about their siblings and lack information about their siblings’ illness and treatment progress. They are negatively affected by conflicts at mealtimes and several siblings are feeling shame about their siblings’ illness. There were differences in how brothers and sisters experienced their sisters´ disease. The girls seemed to be more emotionally affected. The girls described that their everyday life had been heavily influenced of their sisters´ illness, while the boys described that their everyday life with friends and activities weren´t affected to a greater extent. One new result that emerges as something positive was that several informants described that the eating disorder had led to better meal situations in the family. Although the adolescents described initial conflicts around meal times, it appeared that ones the parents took control and organized family meals together the adolescents could see that this was beneficiary for the whole family. The sisters described that they felt more togetherness now than before the sister had her eating disorder. If parents are able to create a good structure and an open and supportive climate at meals the negative effects for the family may be reduced and treatment may create an opportunity for the whole the family to find good meal routines

Evaluation of spirituality as a moderator of risk for suicidal ideation in a community sample of adolescents

Includes bibliographical references (pages [133]-150).Using a path model initially developed and tested with college students, this study evaluated the manner in which negative life events (NLE), hopelessness, and depression served as predictors of suicide ideation in community adolescents. Since spirituality may play an important role in psychological well-being, the moderating effect of spirituality was also evaluated in this sample. High school students (n = 338) completed self-report questionnaires as part of a school-wide mental health screening. The variables were subjected to hierarchical regression analyses to construct two path models of risk for suicide ideation based on diathesis-stress theory. Multiple dimensions of spirituality were then evaluated as moderators of each pathway in the models. As expected, depression and hopelessness predicted suicide ideation, with depression serving as the stronger predictor. These variables also mediated the path between NLE and suicide ideation. Additionally, hopelessness partially mediated the relationship between NLE and depression, while depression fully mediated the path between NLE and hopelessness. These findings highlight the value of evaluating multidirectional pathways in accordance with existing theories. Only two dimensions of spirituality moderated risk. High existential well-being (EWB) buffered the impact of depressive symptoms on suicidal thoughts. Additionally, as NLE increased, the combined factor representing religious and spiritual identification (COS/REL) had a mild buffering effect on suicide ideation. Finally, EWB and COS/REL moderated the path between depression and hopelessness, with high EWB serving as the more substantial buffer of risk. In terms of the protective nature of spirituality, EWB—defined as one's perceived ability to competently cope with life difficulties—may have relevance in reducing psychological distress and enhancing mental well-being in teens. Religious and spiritual identification appear to have a positive, yet limited, effect on reducing risk during this developmental period. These results are tempered by several limitations pertaining to the measurement of spiritual constructs which may be addressed in future research.Ph.D. (Doctor of Philosophy

Living with a sibling who suffers from an eating disorder: a pilot interview study

Carina Callio, Sanna Aila Gustafsson Faculty of Medicine and Health, University Health Care Research Center, Region Örebro County, Örebro University, Örebro, Sweden Background and objective: Having a sibling who suffers from an eating disorder (ED) has a profound effect on healthy siblings’ own health, quality of life and family relationships, yet siblings have been an excluded group within health care, and there is a lack of knowledge regarding healthy siblings’ needs and wishes for information and support. Thus, the aim of this study was to examine adolescents’ experiences of living with a sibling who suffers from an ED. Method: In this small-scale pilot study, three boys and two girls aged 15–20 years were interviewed, and the interviews were analyzed by qualitative content analysis. Results: This study confirms prior knowledge of adolescents’ experiences of living with a sibling who is suffering from an ED. The adolescents were concerned about their siblings and lacked information about their siblings’ illness and treatment progress. The girls described that their everyday life had been heavily influenced by their sisters’ illness, while the boys described that their everyday life with friends and activities were not affected to such a great extent. One new result that emerged as something positive was that some informants described that although the ED was a source of conflict in the family, it had led to greater awareness of the importance of gaining sufficient energy and had contributed to better meal situations in the family. Conclusion: Having a sibling with an ED had a profound and negative effect on family relationships, and was often a source of conflict, especially around mealtime. However, it appeared that if parents were able to organize family meals and create an open and supportive climate, the negative effects for the family could be reduced. The health care professionals need to acknowledge the siblings’ need for information and support, and support parents in their important role of caring for well siblings. Keywords: eating disorders, adolescents, siblings, famil

Spirituality as a moderator of risk for suicide ideation in college students

Includes bibliographical references (pages [98]-108)M.A. (Master of Arts

Generation of three-dimensional human neuronal cultures: application to modeling CNS viral infections

Abstract Background A variety of neurological disorders including neurodegenerative diseases and infection by neurotropic viruses can cause structural and functional changes in the central nervous system (CNS), resulting in long-term neurological sequelae. An improved understanding of the pathogenesis of these disorders is important for developing efficacious interventions. Human induced pluripotent stem cells (hiPSCs) offer an extraordinary window for modeling pathogen-CNS interactions, and other cellular interactions, in three-dimensional (3D) neuronal cultures that can recapitulate several aspects of in vivo brain tissue. Methods Herein, we describe a prototype of scaffold-free hiPSC-based adherent 3D (A-3D) human neuronal cultures in 96-well plates. To test their suitability for drug screening, A-3D neuronal cultures were infected with herpes simplex virus type 1 (HSV-1) with or without acyclovir. Results The half maximal inhibitory concentration (IC50) of acyclovir was 3.14 μM and 3.12 μM determined using flow cytometry and the CX7 High Content Screening platform, respectively. Conclusions Our A-3D neuronal cultures provide an unprecedented opportunity for high-content drug screening programs to treat human CNS infections