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Current treatments for coronavirus disease 2019 (COVID-19) lung disease have limited efficacy. Low-dose radiation therapy (LDRT) has received both interest and criticism as a potential treatment for this condition. In this qualitative study we explored clinicians’ perspectives to identify barriers to testing LDRT in clinical trials and implementing it in clinical practice.
Phase 1 clinical trials have established low-dose, whole-lung radiation therapy (LD-RT) as safe for patients with coronavirus disease 2019 (COVID-19)-related pneumonia. By focally dampening cytokine hyperactivation, LD-RT may improve disease outcomes through immunomodulation.
Introduction The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. Methods We used standard searches to find publications using ADNI data. Results (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β‐amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white‐matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion‐like spreading of Aβ pathology along WM tracts predict known patterns of cortical Aβ deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by “classic” AD pathology but also by normal biomarkers, accelerated decline, and suspected non‐Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and surrogate outcome measures using longitudinal structural magnetic resonance imaging may further reduce clinical trial cost and duration; (11) Advances in machine learning techniques such as neural networks have improved diagnostic and prognostic accuracy especially in challenges involving MCI subjects; and (12) Network connectivity measures and genetic variants show promise in multimodal classification and some classifiers using single modalities are rivaling multimodal classifiers. Discussion Taken together, these studies fundamentally deepen our understanding of AD progression and its underlying genetic basis, which in turn informs and improves clinical trial design.
Keratins 1 (K1) and 10 (K10) are the primary keratins expressed in differentiated epidermis. Mutations in K1/K10 are associated with human skin diseases. We determined the crystal structure of the complex between the distal (2B) helices of K1 and K10 to better understand how human keratin structure correlates with function. The 3.3 Å resolution structure confirms many features inferred by previous biochemical analyses, but adds unexpected insights. It demonstrates a parallel, coiled-coil heterodimer with a predominantly hydrophobic intermolecular interface; this heterodimer formed a higher order complex with a second K1-K10-2B heterodimer via a Cys401K10 disulfide link, although the bond angle is unanticipated. The molecular surface analysis of K1-K10-2B identified several pockets, one adjacent to the disulfide linkage and conserved in K5-K14. The solvent accessible surface area of the K1-K10 structure is 20–25% hydrophobic. The 2B region contains mixed acidic and basic patches proximally (N-terminal), whereas it is largely acidic distally (C-terminal). Mapping of conserved and nonconserved residues between K1-K10 and K5-K14 onto the structure demonstrated the majority of unique residues align along the outer helical ridge. Finally, the structure permitted a fresh analysis of the deleterious effects caused by K1/K10 missense mutations found in patients with phenotypic skin disease.
Background: Wilson disease (WD) is caused by accumulation of excess copper (Cu) due to a mutation in the gene encoding the liver Cu transporter ATP7B, and is characterized by acute liver failure or cirrhosis and neuronal cell death. We investigated the effect of OSIP108, a plant derived decapeptide that prevents Cu-induced apoptosis in yeast and human cells, on Cu-induced toxicity in various mammalian in vitro models relevant for WD and in a Cu-toxicity zebrafish larvae model applicable to WD. Methods: The effect of OSIP108 was evaluated on viability of various cell lines in the presence of excess Cu, on liver morphology of a Cu-treated zebrafish larvae strain that expresses a fluorescent reporter in hepatocytes, and on oxidative stress levels in wild type AB zebrafish larvae. Results: OSIP108 increased not only viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7B{sup H1069Q}, but also viability of Cu-treated human glioblastoma U87 cells. Aberrancies in liver morphology of Cu-treated zebrafish larvae were observed, which were further confirmed as Cu-induced hepatotoxicity by liver histology. Injections of OSIP108 into Cu-treated zebrafish larvae significantly increased the amount of larvae with normal liver morphology and decreased Cu-induced production of reactive oxygen species. Conclusions: OSIP108 prevents Cu-induced toxicity in in vitro models and in a Cu-toxicity zebrafish larvae model applicable to WD. General significance: All the above data indicate the potential of OSIP108 as a drug lead for further development as a novel WD treatment. - Highlights: • Wilson disease (WD) is characterized by accumulation of toxic copper (Cu). • OSIP108 increases viability of Cu-treated cellular models applicable to WD. • OSIP108 injections preserve liver morphology of Cu-treated zebrafish larvae. • OSIP108 injections into zebrafish larvae abrogates Cu-induced oxidative stress.
Large language models (LLMs) show promise in supporting differential diagnosis, but their performance is challenging to evaluate due to the unstructured nature of their responses, and their accuracy compared to existing diagnostic tools is not well characterized. To assess the current capabilities of LLMs to diagnose genetic diseases, we benchmarked these models on 5213 previously published case reports using the Phenopacket Schema, the Human Phenotype Ontology and Mondo disease ontology. Prompts generated from each phenopacket were sent to seven LLMs, including four generalist models and three LLMs specialized for medical applications. The same phenopackets were used as input to a widely used diagnostic tool, Exomiser, in phenotype-only mode. The best LLM ranked the correct diagnosis first in 23.6% of cases, whereas Exomiser did so in 35.5% of cases. While the performance of LLMs for supporting differential diagnosis has been improving, it has not reached the level of commonly used traditional bioinformatics tools. Future research is needed to determine the best approach to incorporate LLMs into diagnostic pipelines.
Many risk genes for the development of Alzheimer’s disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aβ deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis.
Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein–protein interaction (PPI) networks within human cells. Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy participants from the projects 1000 Genomes and ExAC. Somatic missense mutations are also significantly enriched in PPI interfaces compared to noninterfaces in 10,861 tumor exomes. We computationally identified 470 putative oncoPPIs in a pan-cancer analysis and demonstrate that oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. Further, we experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of these on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritization of alleles with PPI-perturbing mutations to inform pathobiological mechanism- and genotype-based therapeutic discovery.
Recombination of rapidly evolving RNA-viruses provides an important mechanism for diversifcation, spread, and emergence of new variants with enhanced ftness. Foot-and-mouth disease virus (FMDV) causes an important transboundary disease of livestock that is endemic to most countries in Asia and Africa. Maintenance and spread of FMDV are driven by periods of dominance of specifc viral lineages. Current understanding of the molecular epidemiology of FMDV lineages is generally based on the phylogenetic relationship of the capsid-encoding genes, with less attention to the process of recombination and evolution of non-structural proteins. In this study, the putative recombination breakpoints of FMDVs endemic to Southeast Asia were determined using full-open reading frame sequences. Subsequently, the lineages’ divergence times of recombination-free genome regions were estimated. These analyses revealed a close relationship between two of the earliest endemic viral lineages that appear unrelated when only considering the phylogeny of their capsid proteins. Contrastingly, one lineage, named O/CATHAY, known for having a particular host predilection (pigs) has evolved independently. Additionally, intra-lineage recombination occurred at diferent breakpoints compared to the inter-lineage process. These results provide new insights about FMDV recombination patterns and the evolutionary interdependence of FMDV serotypes and lineages.
Metabolites detectible in human biofuids are attractive biomarkers for the diagnosis of early Lyme disease (ELD), a vector-borne infectious disease. Urine represents an easily obtained clinical sample that can be applied for diagnostic purposes. However, few studies have explored urine for biomarkers of ELD. In this study, metabolomics approaches were applied to evaluate small molecule metabolites in urine from patients with ELD (n=14), infectious mononucleosis (n=14) and healthy controls (n=14). Metabolic biosignatures for ELD versus healthy controls and ELD versus infectious mononucleosis were generated using untargeted metabolomics. Pathway analyses and metabolite identifcation revealed the dysregulation of several metabolic processes in ELD as compared to healthy controls or mononucleosis, including metabolism of tryptophan. Linear discriminant analyses demonstrated that individual metabolic biosignatures can correctly discriminate ELD from the other patient groups with accuracies of 71 to 100%. These data provide proof-of-concept for use of urine metabolites as biomarkers for diagnostic classifcation of ELD.
Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been demonstrated to match the efficacy of CB-5083, an ATP-competitive inhibitor, in cellular models. However, the mechanism is not well understood. This study systematically investigates the structures of new triazole inhibitors bound to both wild-type and disease mutant forms of p97 and measures their effects on function. These inhibitors bind at the interface of the D1 and D2 domains of each p97 subunit, shifting surrounding helices and altering the loop structures near the C-terminal α2 G helix to modulate domain-domain communications. A key structural moiety of the inhibitor affects the rotameric conformations of interacting side chains, indirectly modulating the N-terminal domain conformation in p97 R155H mutant. The differential effects of inhibitor binding to wild-type and mutant p97 provide insights into drug design with enhanced specificity, particularly for oncology applications.
Abstract Recently approved anti-amyloid immunotherapies for Alzheimer’s disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the circumstances requiring confirmatory testing are poorly understood. Individual-level interpretation of diagnostic test results requires knowledge of disease prevalence in relation to clinical presentation (clinical pretest probability). Here, in a study of 6,896 individuals evaluated from 11 cohort studies from six countries, we determined the positive and negative predictive value of five plasma biomarkers for amyloid-β pathology in cognitively impaired individuals in relation to clinical pretest probability. We observed that p-tau217 could rule in amyloid-β pathology in individuals with probable AD dementia (positive predictive value above 95%). In mild cognitive impairment, p-tau217 interpretation depended on patient age. Negative p-tau217 results could rule out amyloid-β pathology in individuals with non-AD dementia syndromes (negative predictive value between 90% and 99%). Our findings provide a framework for the individual-level interpretation of plasma biomarkers, suggesting that p-tau217 combined with clinical phenotyping can identify patients where amyloid-β pathology can be ruled in or out without the need for PET or CSF confirmatory testing.
Varicose veins represent a common cause of cardiovascular morbidity, with limited available medical therapies. Although varicose veins are heritable and epidemiologic studies have identified several candidate varicose vein risk factors, the molecular and genetic basis remains uncertain. Here we analyzed the contribution of common genetic variants to varicose veins using data from the Veterans Affairs Million Veteran Program and four other large biobanks. Among 49,765 individuals with varicose veins and 1,334,301 disease-free controls, we identified 139 risk loci. We identified genetic overlap between varicose veins, other vascular diseases and dozens of anthropometric factors. Using Mendelian randomization, we prioritized therapeutic targets via integration of proteomic and transcriptomic data. Finally, topological enrichment analyses confirmed the biologic roles of endothelial shear flow disruption, inflammation, vascular remodeling and angiogenesis. Further, these findings may facilitate future efforts to develop nonsurgical therapies for varicose veins.
Significance Inherited or acquired defects in mitochondria lead to devastating disorders for which we have no effective general therapies. We recently reported that breathing normobaric 11% O 2 prevents neurodegeneration in a mouse model of a pediatric mitochondrial disease, Leigh syndrome. Here we provide updated survival curves of mice treated with varying doses of oxygen and explore eventual causes of death. We explore alternative hypoxia regimens and report that neither intermittent nor moderate hypoxia regimens suffice to prevent neurological disease. Finally, we show that hypoxia can not only prevent, but also reverses the brain lesions in mice with advanced neuropathology. Our preclinical studies will help guide future clinical studies aimed at harnessing hypoxia as a safe and practical therapy.
Chum salmon Oncorhynchus keta alevin developing in gravel habitats downstream of Bonneville Dam on the Columbia River are exposed to elevated levels of total dissolved gas (TDG) when water is spilled at the dam to move migrating salmon smolts downstream to the Pacific Ocean. Current water quality criteria for the management of dissolved gas in dam tailwaters were developed primarily to protect salmonid smolts and are assumed to be protective of alevin if adequate depth compensation is provided. We studied whether chum salmon alevin exposed to six levels of dissolved gas ranging from 100% to 130% TDG at three development periods between hatch and emergence (hereafter early, middle, and late stage) suffered differential mortality, growth, gas bubble disease, or seawater tolerance. Each life stage was exposed for 50 d (early stage), 29 d (middle stage), or 16 d (late stage) beginning at 13, 34, and 37 d post-hatch, respectively, through 50% emergence. The mortality for all stages from exposure to emergence was estimated to be 8% (95% confidence interval (CI) of 4% to 12%) when dissolved gas levels were between 100% and 117% TDG. Mortality significantly increased as dissolved gas levels rose above 117% TDG,; with the lethal concentration that produced 50% mortality (LC50 ) was estimated to be 128.7% TDG (95% CI of 127.2% to 130.2% TDG) in the early and middle stages. By contrast, there was no evidence that dissolved gas level significantly affected growth in any life stage except that the mean wet weight at emergence of early stage fish exposed to 130% TDG was significantly less than the modeled growth of unexposed fish. The proportion of fish afflicted with gas bubble disease increased with increasing gas concentrations and occurred most commonly in the nares and gastrointestinal tract. Early stage fish exhibited higher ratios of filament to lamellar gill chloride cells than late stage fish, and these ratios increased and decreased for early and late stage fish, respectively, as gas levels increased; however, there were no significant differences in mortality between life stages after 96 h in seawater. The study results suggest that current water quality guidelines for the management of dissolved gas appear to offer a conservative level of protection to chum salmon alevin incubating in gravel habitat downstream of Bonneville Dam.
Our hypothesis is that changes in gene and protein expression are crucial to the development of late onset Alzheimer’s disease (LOAD). Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late onset Alzheimer’s diseaseLOAD. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: 1. Predicting expression quantitative trait loci (eQTLs), 2. Determining differential expression, 3. Analyzing networks of transcript and peptide relationships and 4. Validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65-105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairmentMCI; age range 66-107; 63% female; RUSH cohort). Our top target is Heat Shock Protein Family A Member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of Abeta40 and Abeta42 levels in amyloid precursor protein APP mutant cells as well as significant elevation of microtubule associated protein Tau and phospho- Tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late onset Alzheimer’s diseaseLOAD processes.
Abstract Parkinson’s disease (PD) is a multifactorial neurodegenerative disease that is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta and by the anomalous accumulation of α-synuclein aggregates into Lewy bodies and Lewy neurites. Research suggests 2 distinct subtypes of PD: the brain-first subtype if the pathology arises from the brain and then spreads to the peripheral nervous system (PNS) and the body-first subtype, where the pathological process begins in the PNS and then spreads to the central nervous system. This review primarily focuses on the body-first subtype. The influence of the gut microbiota on the development of PD has been the subject of growing interest among researchers. It has been suggested that gut inflammation may be closely associated with pathogenesis in PD, therefore leading to the hypothesis that gut microbiota modulation could play a significant role in this process. Nutrition can influence gut health and alter the risk and progression of PD by altering inflammatory markers. This review provides an overview of recent research that correlates variations in gut microbiota composition between patients with PD and healthy individuals with the impact of certain nutrients and dietary patterns, including the Mediterranean diet, the Western diet, and the ketogenic diet. It explores how these diets influence gut microbiota composition and, consequently, the risk of PD. Last, it examines fecal transplantation and the use of prebiotics, probiotics, or synbiotics as potential therapeutic strategies to balance the gut microbiome, aiming to reduce the risk or delay the progression of PD.
Abstract Nonalcoholic fatty liver disease (NAFLD) is becoming a major etiological risk factor for hepatocellular carcinoma (HCC) in the United States and other Western countries. In this study, we investigated the role of gene-specific promoter cytosine DNA methylation and gene expression alterations in the development of NAFLD-associated HCC in mice using (1) a diet-induced animal model of NAFLD, (2) a Stelic Animal Model of nonalcoholic steatohepatitis-derived HCC, and (3) a choline- and folate-deficient (CFD) diet (CFD model). We found that the development of NAFLD and its progression to HCC was characterized by down-regulation of glycine N-methyltransferase (Gnmt) and this was mediated by progressive Gnmt promoter cytosine DNA hypermethylation. Using a panel of genetically diverse inbred mice, we observed that Gnmt down-regulation was an early event in the pathogenesis of NAFLD and correlated with the extent of the NAFLD-like liver injury. Reduced GNMT expression was also found in human HCC tissue and liver cancer cell lines. In in vitro experiments, we demonstrated that one of the consequences of GNMT inhibition was an increase in genome methylation facilitated by an elevated level of S-adenosyl-L-methionine. Overall, our findings suggest that reduced Gnmt expression caused by promoter hypermethylation is one of the key molecular events in the development of NAFLD-derived HCC and that assessing Gnmt methylation level may be useful for disease stratification.