CSF H3F3A K27M circulating tumor DNA copy number quantifies tumor growth and in vitro treatment response

https://deepblue.lib.umich.edu/bitstream/2027.42/145434/1/40478_2018_Article_580.pd

Emerging metabolite-based methods of aspergillosis detection: Advantages and disadvantages of metabolite-based methods of aspergillosis detection at the research stage of development.

<p>Emerging metabolite-based methods of aspergillosis detection: Advantages and disadvantages of metabolite-based methods of aspergillosis detection at the research stage of development.</p

The ongoing search for small molecules to study metal-Associated amyloid-?? species in alzheimers disease

ConspectusThe development of a cure for Alzheimers disease (AD) has been impeded by an inability to pinpoint the root cause of this disorder. Although numerous potential pathological factors have been indicated, acting either individually or mutually, the molecular mechanisms leading to disease onset and progression have not been clear. Amyloid-?? (A??), generated from proteolytic processing of the amyloid precursor protein (APP), and its aggregated forms, particularly oligomers, are suggested as key pathological features in AD-Affected brains. Historically, highly concentrated metals are found colocalized within A?? plaques. Metal binding to A?? (metal-A??) generates/stabilizes potentially toxic A?? oligomers, and produces reactive oxygen species (ROS) in vitro (redox active metal ions; plausible contribution to oxidative stress). Consequently, clarification of the relationship between A??, metal ions, and toxicity, including oxidative stress via metal-A??, can lead to a deeper understanding of AD development.To probe the involvement of metal-A?? in AD pathogenesis, rationally designed and naturally occurring molecules have been examined as chemical tools to target metal-A?? species, modulate the interaction between the metal and A??, and subsequently redirect their aggregation into nontoxic, off-pathway unstructured aggregates. These ligands are also capable of attenuating the generation of redox active metal-A??-induced ROS to mitigate oxidative stress. One rational design concept, the incorporation approach, installs a metal binding site into a framework known to interact with A??. This approach affords compounds with the simultaneous ability to chelate metal ions and interact with A??. Natural products capable of A?? interaction have been investigated for their influence on metal-induced A?? aggregation and have inspired the construction of synthetic analogues. Systematic studies of these synthetic or natural molecules could uncover relationships between chemical structures, metal/A??/metal-A?? interactions, and inhibition of A??/metal-A?? reactivity (i.e., aggregation modes of A??/metal-A??; associated ROS production), suggesting mechanisms to refine the design strategy.Interdisciplinary investigations have demonstrated that the designed molecules and natural products control the aggregation pathways of metal-A?? species transforming their size/conformation distribution. The aptitude of these molecules to impact metal-A?? aggregation pathways, either via inhibition of A?? aggregate formation, most importantly of oligomers, or disaggregation of preformed fibrils, could originate from their formation of complexes with metal-A??. Potentially, these molecules could direct metal-A?? size/conformational states into alternative nontoxic unstructured oligomers, and control the geometry at the A??-ligated metal center for limited ROS formation to lessen the overall toxicity induced by metal-A??. Complexation between small molecules and A??/metal-A?? has been observed by nuclear magnetic resonance spectroscopy (NMR) and ion mobility-mass spectrometry (IM-MS) pointing to molecular level interactions, validating the design strategy. In addition, these molecules exhibit other attractive properties, such as antioxidant capacity, prevention of ROS production, potential blood-brain barrier (BBB) permeability, and reduction of A??-/metal-A??-induced cytotoxicity, making them desirable tools for unraveling AD complexity. In this Account, we summarize the recent development of small molecules, via both rational design and the selection and modification of natural products, as tools for investigating metal-A?? complexes, to advance our understanding of their relation to AD pathology.close5

Diabetic neuropathy in children and youth: New and emerging risk factors

Pediatric neuropathy attributed to metabolic dysfunction is a well‐known complication in children and youth with type 1 diabetes. Moreover, the rise of obesity and in particular of type 2 diabetes may cause an uptick in pediatric neuropathy incidence. However, despite the anticipated increase in neuropathy incidence, pathogenic insights and strategies to prevent or manage neuropathy in the setting of diabetes and obesity in children and youth remain unknown. Data from adult studies and available youth cohort studies are providing an initial understanding of potential diagnostic, management, and preventative measures in early life. This review discusses the current state of knowledge emanating from these efforts, with particular emphasis on the prevalence, clinical presentation, diagnostic approaches and considerations, and risk factors of neuropathy in type 1 and type 2 diabetes in children and youth. Also highlighted are current management strategies and recommendations for neuropathy in children and youth with diabetes. This knowledge, along with continued and sustained emphasis on identifying and eliminating modifiable risk factors, completing randomized controlled trials to assess effectiveness of strategies like weight loss and exercise, and enhancing awareness to support early detection and prevention, are pertinent to addressing the rising incidence of neuropathy associated with diabetes and obesity in children and youth.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/166414/1/pedi13153_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/166414/2/pedi13153.pd

Towards an understanding of amyloid-beta oligomers: characterization, toxicity mechanisms, and inhibitors

Alzheimer&apos;s disease (AD) is characterized by an imbalance between production and clearance of amyloid-?? (A??) species. A?? peptides can transform structurally from monomers into ??-stranded fibrils via multiple oligomeric states. Among the various A?? species, structured oligomers are proposed to be more toxic than fibrils; however, the identification of A?? oligomers has been challenging due to their heterogeneous and metastable nature. Multiple techniques have recently helped us gain a better understanding of oligomers&apos; assembly details and structural properties. Moreover, some progress on elucidating the mechanisms of oligomer-triggered toxicity has been made. Based on the collection of current findings, there is growing consensus that control of toxic A?? oligomers could be a valid approach to regulate A??-associated toxicity, which could advance development of new diagnostics and therapeutics for amyloid-related diseases. In this review, we summarize the recent understanding of A?? oligomers&apos; assembly, structural properties, and toxicity, along with inhibitors against A?? aggregation, including oligomerization.clos

Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer???s Disease, Parkinson???s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade

Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a negative outlook. Although a large amount of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathological features shared across multiple neurodegenerative disorders. In addition, these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compounds capable of simultaneously interacting with several pathological components has been suggested as a solution to undertake the complex pathologies of neurodegenerative diseases. In this review, we outline and discuss possible therapeutic targets in Alzheimer&apos;s disease, Parkinson&apos;s disease, and amyotrophic lateral sclerosis and molecules, previously designed or discovered as potential drug candidates for these disorders with emphasis on multifunctionality. In addition, underrepresented areas of research are discussed to indicate new directions

Palmitate and glucose increase amyloid precursor protein in extracellular vesicles: Missing link between metabolic syndrome and Alzheimer's disease

Abstract The metabolic syndrome (MetS) and Alzheimer's disease share several pathological features, including insulin resistance, abnormal protein processing, mitochondrial dysfunction and elevated inflammation and oxidative stress. The MetS constitutes elevated fasting glucose, obesity, dyslipidaemia and hypertension and increases the risk of developing Alzheimer's disease, but the precise mechanism remains elusive. Insulin resistance, which develops from a diet rich in sugars and saturated fatty acids, such as palmitate, is shared by the MetS and Alzheimer's disease. Extracellular vesicles (EVs) are also a point of convergence, with altered dynamics in both the MetS and Alzheimer's disease. However, the role of palmitate‐ and glucose‐induced insulin resistance in the brain and its potential link through EVs to Alzheimer's disease is unknown. We demonstrate that palmitate and high glucose induce insulin resistance and amyloid precursor protein phosphorylation in primary rat embryonic cortical neurons and human cortical stem cells. Palmitate also triggers insulin resistance in oligodendrocytes, the supportive glia of the brain. Palmitate and glucose enhance amyloid precursor protein secretion from cortical neurons via EVs, which induce tau phosphorylation when added to naïve neurons. Additionally, EVs from palmitate‐treated oligodendrocytes enhance insulin resistance in recipient neurons. Overall, our findings suggest a novel theory underlying the increased risk of Alzheimer's disease in MetS mediated by EVs, which spread Alzheimer's pathology and insulin resistance

A small molecule that displays marked reactivity toward copper-versus zinc-amyloid-?? implicated in Alzheimer&apos;s disease

Alzheimer&apos;s disease (AD) is a complex, multifactorial, neurodegenerative disease that poses tremendous difficulties in pinpointing its precise etiology. A toolkit, which specifically targets and modulates suggested key players, may elucidate their roles in disease onset and progression. We report high-resolution insights on the activity of a small molecule (L2-NO) which exhibits reactivity toward Cu(II)-amyloid-?? (A??) over Zn(II)-A??.close3