Investigation of serum amyloid a within animal species focusing on the 1-25 amino acid region.

AA amyloidosis, characterized by the misfolding of serum amyloid A (SAA) protein, is the most common amyloid protein disorder across multiple species. SAA is a positive-acute phase protein synthesized by the liver in response to inflammation or stress, and it normally associates with high-density lipoprotein at its N-terminus. In this study, we focused on the 1-25 amino acid (aa) region of the complete 104 aa SAA sequence to examine the aggregation propensity of AA amyloid. A library comprising eight peptides from different species was assembled for analysis. To access the aggregation propensity of each peptide region, a bioinformatic study was conducted using the algorithm TANGO. Congo red (CR) binding assays, Thioflavin T (ThT) assays, and transmission electron microscopy (TEM) were utilized to evaluate whether the synthesized peptides formed amyloid-like fibrils. All synthetic SAA 1-25 congeners resulted in amyloid-like fibrils formation (per CR and/or ThT staining and TEM detection) at the exception of the ferret SAA1-25 fragment, which generated plaque-like materials by TEM. Ten residues were preserved among SAA 1-25 congeners resulting in amyloid-like fibrils, i.e. F6, E9, A10, G13, D16, M17, A20, Y21, D23, and M24. Amino acid residues highlighted by this study may have a role in increasing the propensity for amyloid-like fibril formation. This study put an emphasis on region 1-25 in the mechanism of SAA1 misfolding.

Diabetes mellitus drug discovery: insights into targeting feline and human amylin with small molecules.

BACKGROUND: Type 2 diabetes (T2D) is a health concern for both humans and cats, with cases rising over the past decade. Around 70% of patients from either species exhibit pancreatic aggregates of islet amyloid polypeptide (IAPP), a protein that proves toxic upon misfolding. These misfolded protein aggregates congregate in the islets of Langerhans of the pancreas, diminishing the capability of ß-cells to produce insulin and further perpetuating disease. OBJECTIVE: Our team's drug discovery program is investigating newly synthesized compounds that could diminish aggregates of both human and feline IAPP, potentially disrupting the progression of T2D. MATERIAL AND METHODS: We prepared 24 compounds derived from diaryl urea, as ureas have previously demonstrated great potential at reducing accumulations of misfolded proteins. Biophysical methods were employed to analyze the anti-aggregation activity of these compounds at inhibiting and/or disrupting IAPP fibril formation in vitro. RESULTS: The results demonstrate that compounds 12 and 24 were most effective at reducing the fibrillization and aggregation of both human and feline IAPP. When compared with the control for each experiment, samples treated with either compound 12 or 24 exhibited fewer accumulations of amyloid-like fibrils. CONCLUSION: Urea-based compounds, such as compounds 12 and 24, may prove crucial in future pre-clinical studies in the search for therapeutics for T2D.

The association between inflammatory markers in blood and cerebrospinal fluid: a systematic review and meta-analysis.

BACKGROUND: Neuroinflammatory processes have been hypothesized to play a role in the pathogenesis of psychiatric and neurological diseases. Studies on this topic often rely on analysis of inflammatory biomarkers in peripheral blood. Unfortunately, the extent to which these peripheral markers reflect inflammatory processes in the central nervous system (CNS) is unclear. METHODS: We performed a systematic review and found 29 studies examining the association between inflammatory marker levels in blood and cerebrospinal (CSF) samples. We performed a random effects meta-analysis of 21 studies (pooled n = 1679 paired samples) that reported the correlation of inflammatory markers in paired blood-CSF samples. RESULTS: A qualitative review revealed moderate to high quality of included studies with the majority of studies reporting no significant correlation of inflammatory markers between paired blood-CSF. Meta-analyses revealed a significant low pooled correlation between peripheral and CSF biomarkers (r = 0.21). Meta-analyses of individual cytokines revealed a significant pooled correlation for IL-6 (r = 0.26) and TNFα (r = 0.3) after excluding outlier studies, but not for other cytokines. Sensitivity analyses showed that correlations were highest among participants with a median age above 50 (r = 0.46) and among autoimmune disorder patients (r = 0.35). CONCLUSION: This systematic review and meta-analysis revealed poor correlation between peripheral and central inflammatory markers in paired blood-CSF samples, with increased correlations in certain study populations. Based on the current findings, peripheral inflammatory markers are a poor reflection of the neuroinflammatory profile.

Hyperphosphorylated tau (p-tau) and drug discovery in the context of Alzheimer's disease and related tauopathies.

Alzheimer's disease (AD) is the most common form of dementia, characterized by intracellular neurofibrillary tangles (NFTs) and extracellular ß-amyloid (ßA) plaques. No disease-modifying therapy is currently available to prevent the progression of, or cure, the disease. Misfolded hyperphosphorylated tau (p-tau) is considered a pivotal point in the pathogenesis of AD and other tauopathies. Compelling evidence suggests that it is a key driver of the accumulation of NFTs and can be directly correlated with the extent of dementia in patients with AD. Therefore, inhibiting tau hyperphosphorylation-induced aggregation could be a viable strategy to discover and develop therapeutics for patients with AD.

Spatiotemporal and genetic regulation of A-to-I editing throughout human brain development.

Posttranscriptional RNA modifications by adenosine-to-inosine (A-to-I) editing are abundant in the brain, yet elucidating functional sites remains challenging. To bridge this gap, we investigate spatiotemporal and genetically regulated A-to-I editing sites across prenatal and postnatal stages of human brain development. More than 10,000 spatiotemporally regulated A-to-I sites were identified that occur predominately in 3' UTRs and introns, as well as 37 sites that recode amino acids in protein coding regions with precise changes in editing levels across development. Hyper-edited transcripts are also enriched in the aging brain and stabilize RNA secondary structures. These features are conserved in murine and non-human primate models of neurodevelopment. Finally, thousands of cis-editing quantitative trait loci (edQTLs) were identified with unique regulatory effects during prenatal and postnatal development. Collectively, this work offers a resolved atlas linking spatiotemporal variation in editing levels to genetic regulatory effects throughout distinct stages of brain maturation.

Recent Advances in the Discovery of Therapeutics to Curtail Islet Amyloid Polypeptide Aggregation for Type 2 Diabetes Treatment.

In humans with type 2 diabetes, at least 70% of patients exhibit islet amyloid plaques formed by misfolding islet amyloid polypeptides (IAPP). The oligomeric conformation and accumulation of the IAPP plaques lead to a panoply of cytotoxic effects on the islet ß-cells. Currently, no marketed therapies for the prevention or elimination of these amyloid deposits exist, and therefore significant efforts are required to address this gap. To date, most of the experimental treatments are limited to only in vitro stages of testing. In general, the proposed therapeutics use various targeting strategies, such as binding to the N-terminal region of islet amyloid polypeptide on residues 1-19 or the hydrophobic region of IAPP. Other strategies include targeting the peptide self-assembly through π-stacking. These methods are realized by using several different families of compounds, four of which are highlighted in this review: naturally occurring products, small molecules, organometallic compounds, and nanoparticles. Each of these categories holds immense potential to optimize and develop inhibitor(s) of pancreatic amyloidosis in the near future.

Revisiting misfolding propensity of serum amyloid A1: Special focus on the signal peptide region.

AA amyloidosis is the result of overproduction and aberrant processing of acute-phase serum amyloid A1 (SAA1) by hepatocytes. Proteolytic cleavage of SAA1 is believed to play a central role in AA amyloid formation. The SAA1 protein undergoes a cleavage of 18 residues consisting of the signal peptide at the N-terminal region. To better understand the mechanism behind systemic amyloidosis in the SAA1 protein, we studied the misfolding propensity of the signal peptide region. We first examined the signal peptide amino acid SAA derived from different animal species. A library of 16 peptides was designed to evaluate the propensity of aggregation. The amyloidogenic potential of each SAA1 signal peptide homolog was assessed using in silico Tango program, thioflavin T (ThT) fluorescence, transmission electron microscopy (TEM), and seeding with misfolded human SAA1 signal peptide. After 7 days of incubation, most of the SAA1 signal peptide fragments had the propensity to form fibrils at a concentration of 100 µM in 50 mM Tris buffer at 37 °C by TEM. All peptides were able to generate fibrils at a higher concentration, i.e 500 µM in 25 mM Tris buffer with 50% HFIP, by ThT. All SAA1 signal synthetic peptides designed from the different animal species had the propensity to misfold and form fibrils, particularly in species with low occurrence of systemic amyloidosis. The human SAA1 signal peptide region was capable to seed the SAA1 1-25 and 32-47 peptide regions. Characterizing fibrillar conformations are relevant for seeding intact and/or fragmented SAA, which may contribute, to the mechanism of protein misfolding. This research signifies the importance of the signal peptide region and its possible contribution to the misfolding of aggregation-prone proteins.

Behavioral Health Service Use by Military Children During Afghanistan and Iraq Wars.

Medical claims were analyzed from 2810 military children who visited a civilian emergency department (ED) or hospital from 2000 to 2014 with behavioral health as the primary diagnosis and TRICARE as the primary/secondary payer. Visit prevalence was estimated annually and categorized: 2000-2002 (pre-deployment), 2003-2008 (first post-deployment), 2009-2014 (second post-deployment). Age was categorized: preschoolers (0-4 years), school-aged (5-11 years), adolescents (12-17 years). During Afghanistan and Iraq wars, 2562 military children received 4607 behavioral health visits. School-aged children's mental health visits increased from 61 to 246 from pre-deployment to the second post-deployment period. Adolescents' substance use disorder (SUD) visits increased almost 5-fold from pre-deployment to the first post-deployment period. Mental disorders had increased odds (OR = 2.93, 95% CI 1.86-4.61) of being treated during hospitalizations than in EDs. Adolescents had increased odds of SUD treatment in EDs (OR = 2.92, 95% CI 1.85-4.60) compared to hospitalizations. Implications for integrated behavioral health and school behavioral health interventions are discussed.

Evaluating Behavioral Health Interventions for Military-Connected Youth: A Systematic Review.

INTRODUCTION: Military-connected youth are at increased risk for experiencing distinct psychosocial and behavioral health vulnerabilities. Although behavioral health interventions have been developed to treat vulnerabilities in military-connected youth, little is known about the methodological quality of studies evaluating these interventions. In this study, a systematic review of behavioral health interventions for military-connected youth was conducted to examine methodological quality and treatment outcomes. MATERIALS AND METHODS: Electronic databases were systematically searched for studies evaluating behavioral health interventions for military-connected youth which yielded 3,324 citations. Methodological quality was evaluated by 2 researchers with 3 measures that assessed scientific rigor, transparency, external and internal validity, and power for quantitative, qualitative, and mixed-method trials. Interrater reliability was strong (κ = 0.81). Sample characteristics and treatment outcomes were also assessed. RESULTS: Fourteen studies meeting full inclusion criteria evaluated 10 behavioral health interventions. Methodological quality scores for all studies were poor to fair, with limitations in reporting, external and internal validity, and power. Research designs were predominantly nonexperimental. Treatment effects for both psychosocial and behavioral health outcomes were consistently positive for all studies. In studies reporting effect sizes, treatment effects were small to moderate (d = 0.01-0.42, odds ratio = 0.04-0.47, b = -0.02-0.56). Demographic and military characteristics of samples were inconsistently reported. CONCLUSION: Behavioral health interventions for military-connected youth have noteworthy methodological limitations, indicating a need to employ more rigorous research strategies. Positive treatment outcomes, however, suggest promising interventions for improving psychosocial and behavioral health problems in military-connected youth. Future research directions and implications for clinical-community practice are also discussed.