P4‐154: The Protein Quality Control Protein, Ubiquilin‐2, Regulates Tau Accumulation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152960/1/alzjjalz2019063816.pd

Maternal health care-seeking behaviour of married adolescent girls: A prospective qualitative study in Banke District, Nepal

Background: Nepal has one of the highest rates of maternal mortality in the South Asia region, partly due to the underutilization of maternal health services and the high number of adolescent pregnancies. This study explores married Nepali adolescent girls’ healthcare-seeking behaviour throughout their pregnancies, during their delivery and postpartum. Methods: We conducted a prospective qualitative study in Banke district, Nepal. In-depth interviews were conducted with 27 married adolescent girls before and after delivery. In addition, a focus group discussion was conducted with community health works and key-informant interviews were conducted with family members of adolescent girls, representatives from the government and health care providers. We applied the Social-Ecological Model (SEM) as a framework to guide thematic content analysis and presentation of our qualitative data. Results: Several factors in the SEM influenced maternal health care-seeking behaviour of adolescents. At the individual level, girls’ perceptions, their lack of knowledge about maternal and reproductive health, certain traditional practices, their sole dependency on their husbands and mothers-in-laws and their low decision-making autonomy towards their own health care negatively influenced their utilization of skilled maternal health services. Mothers-in-law and other family members played a critical role in either encouraging or discouraging the use of skilled maternal health services. At the health systems level, lack of adolescent-friendly maternal health services, difficulties in accessing quality maternal health services, and the fixed operating hours of public health facilities restricted their ability to obtain services. The existence of the Safe Motherhood Programme, knowledge sharing platforms such as “women’s groups” and the active role of Female Community Health Volunteers (FCHVs) positively influenced utilization of skilled maternal health services among these girls. Conclusion: Influences on married adolescent girls’ use of skilled maternal health services in Banke District, Nepal were multi-factoral. Ensuring easy access and availability of adolescent-friendly maternal health services are important to encourage adolescent girls to use skilled maternal health services. Moreover, interventions are needed to improve adolescent girls’ knowledge of maternal health, keep them in school, involve family members (mainly mothers-in-law) in health interventions, as well as overcome negative traditional beliefs within the community that discourage care-seeking for skilled maternal health services

Incidence of Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease

Background & aimsType 2 diabetes (T2D) is a growing problem in children. Children with NAFLD are at potentially high risk for developing T2D; however, the incidence of T2D in this population is unknown. This study aimed to determine the incidence of T2D in children with NAFLD and identify associated risk factors.MethodsChildren with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network were followed longitudinally. Incidence of T2D was determined by using clinical history and fasting laboratory values. Cumulative incidence curves were developed for time to T2D. A Cox regression multivariable model was constructed using best subsets Akaike's Information Criteria selection.ResultsThis study included 892 children with NAFLD and with a mean age of 12.8 years (2.7) followed for 3.8 years (2.3) with a total 3234 person-years at risk. The incidence rate of T2D was 3000 new cases per 100,000 person-years at risk. At baseline, 63 children had T2D, and during follow-up, an additional 97 children developed incident T2D, resulting in a period prevalence of 16.8%. Incident T2D was significantly higher in females versus males (hazard ratio [HR], 1.8 [1.0-2.8]), associated with BMI z-score (HR, 1.8 [1.0-3.0]), and more severe liver histology including steatosis grade (HR, 1.3 [1.0-1.7]), and fibrosis stage (HR, 1.3 [1.0-1.5]).ConclusionsChildren with NAFLD are at high risk for existing and incident T2D. In addition to known risk factors for T2D (female and BMI z-score), severity of liver histology at the time of NAFLD diagnosis was independently associated with T2D development. Targeted strategies to prevent T2D in children with NAFLD are needed

P3‐188: Ubiquilin‐2 Regulation Of Tau And Α‐Synuclein In Neurodegenerative Disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152733/1/alzjjalz2018061546.pd

Ubiquilin‐2 exacerbates tau toxicity in vivo

BackgroundUbiquilin‐2 (UBQLN2) is a protein quality control protein involved primarily in shuttling ubiquitinated substrates to the proteasome for degradation and by modulating autophagy. UBQLN2 has been implicated in neurodegenerative disease due to its accumulation in neuropathological deposits and its potential role in regulating protein dyshomeostasis common across different neurodegenerative disorders. The relationship of UBQLN2 to one of the most common aggregating proteins in disease, tau, is unknown.MethodTo evaluate whether UBQLN2 regulates tau clearance, we assessed levels of tau in human embryonic kidney‐293 cells with and without UBQLN2. To determine whether UBQLN2 acts on tau in vivo, P301S tau transgenic mice were crossed with UBQLN2 transgenic and knockout mice and brain levels of tau were assessed at 3, 6 and 9 months of age. To define changes in UBQLN2 in human disease, we measured levels of soluble and insoluble UBQLN2 in human tauopathy brain tissue.ResultCo‐expressed UBQLN2 markedly lowered levels of tau in a cellular model. Conversely, siRNA knockdown of UBQLN2 significantly elevated levels of tau. Surprisingly, a UBQLN2 mutant incapable of binding ubiquitin was more effective at lowering tau than wildtype UBQLN2, suggesting that ubiquitin‐independent pathways may allow UBQLN2 to “handle” tau. In contrast, wildtype UBQLN2 overexpression in vivo did not alter total levels of tau at 3, 6 or 9 months of age. However, UBQLN2 overexpression specifically increased phosphorylated tau while UBQLN2 knockout decreased phosphorylated tau at 9 months. Furthermore, UBQLN2 overexpression increased premature hindlimb paralysis and fatality. The possibility that UBQLN2 also undergoes alterations in disease was evidenced by the fact that UBQLN2 solubility is decreased in human brains with tau pathology.ConclusionOur findings highlight a new role for UBQLN2 in altering tau in the brain. Collectively, our results suggest that while on a rapid time scale UBQLN2 can decrease tau levels, long‐term expression of UBQLN2 in vivo exacerbates tau toxicity. Ongoing research will determine how changing UBQLN2 levels alters components of proteostasis pathways to affect tau toxicity and whether ubiquitin‐independent processes may compete with UBQLN2’s function as a ubiquitin‐proteasome shuttle factor to yield differential effects on tau toxicity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163894/1/alz046096.pd

Maternal health care-seeking behaviour of married adolescent girls: A prospective qualitative study in Banke District, Nepal

Background: Nepal has one of the highest rates of maternal mortality in the South Asia region, partly due to the underutilization of maternal health services and the high number of adolescent pregnancies. This study explores married Nepali adolescent girls’ healthcare-seeking behaviour throughout their pregnancies, during their delivery and postpartum. Methods: We conducted a prospective qualitative study in Banke district, Nepal. In-depth interviews were conducted with 27 married adolescent girls before and after delivery. In addition, a focus group discussion was conducted with community health works and key-informant interviews were conducted with family members of adolescent girls, representatives from the government and health care providers. We applied the Social-Ecological Model (SEM) as a framework to guide thematic content analysis and presentation of our qualitative data. Results: Several factors in the SEM influenced maternal health care-seeking behaviour of adolescents. At the individual level, girls’ perceptions, their lack of knowledge about maternal and reproductive health, certain traditional practices, their sole dependency on their husbands and mothers-in-laws and their low decision-making autonomy towards their own health care negatively influenced their utilization of skilled maternal health services. Mothers-in-law and other family members played a critical role in either encouraging or discouraging the use of skilled maternal health services. At the health systems level, lack of adolescent-friendly maternal health services, difficulties in accessing quality maternal health services, and the fixed operating hours of public health facilities restricted their ability to obtain services. The existence of the Safe Motherhood Programme, knowledge sharing platforms such as “women’s groups” and the active role of Female Community Health Volunteers (FCHVs) positively influenced utilization of skilled maternal health services among these girls. Conclusion: Influences on married adolescent girls’ use of skilled maternal health services in Banke District, Nepal were multi-factoral. Ensuring easy access and availability of adolescent-friendly maternal health services are important to encourage adolescent girls to use skilled maternal health services. Moreover, interventions are needed to improve adolescent girls’ knowledge of maternal health, keep them in school, involve family members (mainly mothers-in-law) in health interventions, as well as overcome negative traditional beliefs within the community that discourage care-seeking for skilled maternal health services

A metagenomic prospective cohort study on gut microbiome composition and clinical infection in small bowel transplantation

ABSTRACTTwo-thirds of small-bowel transplantation (SBT) recipients develop bacteremia, with the majority of infections occurring within 3 months post-transplant. Sepsis-related mortality occurs in 31% of patients and is commonly caused by bacteria of gut origin, which are thought to translocate across the implanted organ. Serial post-transplant surveillance endoscopies provide an opportunity to study whether the composition of the ileal and colonic microbiota can predict the emergence as well as the pathogen of subsequent clinical infections in the SBT patient population. Five participants serially underwent aspiration of ileal and colonic bowel effluents at transplantation and during follow-up endoscopy either until death or for up to 3 months post-SBT. We performed whole-metagenome sequencing (WMS) of 40 bowel effluent samples and compared the results with clinical infection episodes. Microbiome composition was concordant between participants and timepoint-matched ileal and colonic samples. Four out of five (4/5) participants had clinically significant infections thought to be of gut origin. Bacterial translocation from the gut was observed in 3/5 patients with bacterial infectious etiologies. In all three cases, the pathogens had demonstrably colonized the gut between 1–10 days prior to invasive clinical infection. Recipients with better outcomes received donor grafts with higher alpha diversity. There was an increase in the number of antimicrobial resistance genes associated with longer hospital stay for all participants. This metagenomic study provides preliminary evidence to support the pathogen translocation hypothesis of gut-origin sepsis in the SBT cohort. Ileal and colonic microbiome compositions were concordant; therefore, fecal metagenomic analysis could be a useful surveillance tool for impeding infection with specific gut-residing pathogens

Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus

WalKR (YycFG) is the only essential two-component regulator in the human pathogen Staphylococcus aureus. WalKR regulates peptidoglycan synthesis, but this function alone does not explain its essentiality. Here, to further understand WalKR function, we investigate a suppressor mutant that arose when WalKR activity was impaired; a histidine to tyrosine substitution (H271Y) in the cytoplasmic Per-Arnt-Sim (PAS) domain of the histidine kinase WalK. Introducing the WalK mutation into wild-type S. aureus activates the WalKR regulon. Structural analyses of the WalK PAS domain reveal a metal-binding site, in which a zinc ion (Zn) is tetrahedrally-coordinated by four amino acids including H271. The WalK mutation abrogates metal binding, increasing WalK kinase activity and WalR phosphorylation. Thus, Zn-binding negatively regulates WalKR. Promoter-reporter experiments using S. aureus confirm Zn sensing by this system. Identification of a metal ligand recognized by the WalKR system broadens our understanding of this critical S. aureus regulon