Biology subjects

Pak, K.

Publications and source records attributed to Pak, K..

7 recordsLinked to original sources

bioRxiv2025

Myositis-specific autoantibodies recognizing Mi2 also target the autoimmune regulator (AIRE) protein at a shared PHD-zinc finger

ObjectivesIn dermatomyositis patients with anti-Mi2 autoantibodies, autoantibodies can enter muscle cells, leading to the aberrant expression of genes normally repressed by the Mi2/nucleosome remodeling and deacetylation (NuRD) complex. However, the mechanism by which autoantibodies interfere with Mi2/NuRD function remains unclear. This study aimed to identify additional autoantibodies in anti-Mi2-positive patients as well as the specific epitopes recognized by anti-Mi2 and any novel autoantibodies. MethodsPhage ImmunoPrecipitation Sequencing (PhIP-Seq) was used to screen serum samples from anti-Mi2-positive myositis patients for autoantibodies. Enzyme-linked immunosorbent assays (ELISA) and luciferase immunoprecipitation system (LIPS) immunoassays were used to detect autoantibodies in serum samples from myositis patients and healthy controls. ResultsPhIP-Seq identified autoantibodies recognizing the autoimmune regulator (AIRE) in sera from anti-Mi2 autoantibody-positive patients. Both anti-AIRE and anti-Mi2 autoantibodies predominantly recognized a homologous region of the plant homeodomain zinc finger type I (PHD1), which is critical for AIRE and Mi2/NuRD function. ELISA and LIPS testing showed that anti-Mi2 autoantibody-positive patients were positive for anti-AIRE autoantibodies, while AIRE reactivity was largely absent in healthy comparators, anti-Mi2 autoantibody-negative-myositis, and other autoimmune diseases. Affinity-purified anti-Mi2 autoantibodies recognized both Mi2 and AIRE by ELISA, whereas anti-Mi2-depleted immunoglobulin fractions did not recognize either protein. ConclusionsAutoantibodies recognizing Mi2 also recognize AIRE at a homologous PHD1 finger. This region is required by the Mi2/NuRD complex to anchor the nucleosome and consequently repress gene expression. Our findings suggest that anti-Mi2 autoantibodies disrupt NuRD complex function by binding to the PHD1 domain. Further studies are needed to determine if anti-Mi2 autoantibodies bind other PHD1-containing proteins and their functional implications.

immunology↗

bioRxiv2024

Photoperiodicity in Glucose Metabolism in the Human Brain

Photoperiodicity in the human brain function, which is a critical factor for social well-being, has been widely debated. In this study, 432 healthy males underwent fasting-state brain [18F]fluorodeoxyglucose positron emission tomography (PET) scanning twice: first at the baseline and then at the 5-year follow-up. We analyzed the effect of day length on brain glucose uptake separately for the baseline and follow-up studies and examined changes in glucose consumption as a function of the day length deviation for each participant between the repeated PET scans. Glucose uptake in the cuneus was consistently predicted by the day length on the day of scanning and by within-participant day length deviations. This longitudinal large-scale PET study provides a landmark evidence for photoperiodicity in glucose metabolism in the human brain. The cuneus may be an essential part of the visual cortex, translating environmental photoperiodic changes into temporal cues that influence cognitive function and social behavior. Significance statementPhotoperiodicity in the human brain function has been widely debated. The current study provides a landmark evidence in this regard by demonstrating how the photoperiod shapes glucose metabolism in the brain of healthy males, highlighting the crucial role of the cuneus in processing visual information related to photoperiodic changes in the environment. Understanding photoperiodicity in the function of the human brain offers insights into how humans adapt to their environments for social well-being and underscores the potential health implications of changes in the exposure of natural light.

neuroscience↗

bioRxiv2022

Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor-induced myositis

ObjectivesInflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICI) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis. MethodsBulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM, and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (7 ICI-myositis, 4 DM, 3 AS, 6 IMNM, and 2 IBM). ResultsUnsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1, and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1{gamma} autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed co-existing myocarditis. ICI-MYO2 was composed of patients with predominant necrotizing pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway. ConclusionsWe identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICIDM and ICI-MYO1, and only ICI-MYO1 patients developed myocarditis.

immunology↗

bioRxiv2022

Brain glucose metabolism and ageing: A 5-year longitudinal study in a large PET cohort

BackgroundAgeing and clinical factors impact brain glucose metabolism. However, there is a substantial variation of the reported effects on brain glucose metabolism across studies due to the limited statistical power and cross-sectional study designs. MethodsWe retrospectively analyzed data from 441 healthy males (mean 42.8, range 38-50 years) who underwent health check-up program twice at baseline and 5-year follow-up. Health check-up program included 1) brain 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET), 2) anthropometric and body composition measurements, 3) blood samples, and 4) questionnaires for stress and depression. After spatial normalization of brain FDG PET scans, standardized uptake value ratio (SUVR) was measured from 12 region-of-interests. We used hierarchical clustering analysis to reduce their dimensionality before the Bayesian hierarchical modelling. Five clusters were established for predicting regional SUVR; 1) metabolic cluster (body mass index, waist-to-hip ratio, fat percentage, muscle percentage, homeostatic model assessment index-insulin resistance), 2) blood pressure (systolic, diastolic), 3) glucose (fasting plasma glucose level, HbA1c), 4): psychological cluster (stress, depression), and 5) heart rate. The effects of clinical variable clusters on regional SUVR were investigated using Bayesian hierarchical modelling with brms that applies the Markov-Chain Monte Carlo sampling tools. ResultsAll the clinical variables except depression changed during the 5-year follow-up. SUVR decreased in caudate, cingulate, frontal lobe and parietal lobe and increased in cerebellum, hippocampus, occipital lobe, pallidum, putamen, temporal lobe and thalamus. SUVRs of thalamus, pallidum, hippocampus, putamen and parietal lobe were negatively associated with metabolic cluster and the effects of glucose on SUVRs varied across regions. SUVRs of thalamus, hippocampus, cingulate, cerebellum increased and those with occipital lobe decreased with heart rate. The effects of blood pressure and psychological cluster markedly overlapped with zero across regions. ConclusionRegionally selective decline in brain glucose utilization begins already in the middle age, while individual differences in brain glucose metabolism remain stable. In addition to ageing, brain glucose utilization is also associated with metabolic cluster, blood glucose levels and heart rate. These effects are also consistent over the studied period of 5 years in the middle adulthood.

neuroscience↗

bioRxiv2022

The predictive power of mRNA mapping for Cannabinoid 1 receptor protein in the human brain

Type 1 cannabinoid (CB1) receptor is expressed in cortex, hippocampus, amygdala, basal ganglia, and cerebellum. With the help of the Allen Human Brain Atlas, genomic maps visualize not only the gene expression across whole brain regions, but also the functional profile of brain structures. Therefore, it is more timely than ever to integrate genomic mapping from brain mRNA atlas with the protein expression from positron emission tomography (PET) scans for better understanding of CB1 receptor of the human brain. F18-FMPEP-d2 PET scans were retrieved from the AIVO neuroinformatics project. Autoradiography data were based on the study with H3-CP55940. mRNA expressions of CNR1 gene (Cannabinoid receptor 1) were downloaded from the Allen Human Brain Atlas. Volume of distribution (VT) from F18-FMPEP-d2 PET scans, CNR1 gene expression, and H3-CP55940 binding were calculated and Spearman correlation analysis was performed. Also, a meta-analysis was done to investigate the association between protein expression from PET and mRNA expression from the Allen Human Brain Atlas. Between VT of F18-FMPEP-d2 PET scans and CNR1 mRNA expression, moderate strength of correlation was observed (rho = 0.5026, p = 0.0354). Strong positive correlation was also found between CNR1 mRNA expression and H3-CP55940 binding (rho = 0.6727, p = 0.0281), validating the finding between F18-FMPEP-d2 PET scans and CNR1 mRNA. From the meta-analysis, the correlation coefficient ranged from -0.46 to 0.99, with a pooled effect of 0.58. In conclusion, the moderate to strong associations between gene and protein expression for CB1 receptor in the human brain were observed that CNR1 mRNA mapping might have the predictive power for in vivo CB1 receptor protein expression. From the meta-analysis, the moderate to strong correlation was observed between mRNA expression and protein expressions across multiple genes, showing the predictive power of genes to estimate protein levels of human brains. HIGHLIGHTSO_LIWe investigated the association between CNR1 gene expression from the Allen Human Brain Atlas and type 1 cannabinoid (CB1) receptor expression from F18-FMPEP-d2 PET scans. C_LIO_LIThe moderate to strong associations between gene and protein expression for CB1 receptor in the human brain were observed that CNR1 mRNA mapping might have the predictive power for in vivo CB1 receptor protein expression. C_LIO_LIFrom the meta-analysis, the moderate to strong correlation was observed between mRNA expression and protein expressions across multiple genes, showing the predictive power of genes to estimate protein levels of human brains. C_LI

neuroscience↗

bioRxiv2020

Dopamine receptors in obesity: a meta-analysis

The brain plays a major role in controlling the desire to eat. This meta-analysis aimed to assess the association between dopamine receptor (DR) availability, measured using positron emission tomography, and obesity. We performed a systematic search of MEDLINE (from inception to June 2019) and EMBASE (from inception to June 2019) for articles published in English using the keywords "dopamine receptor," "obesity," and "neuroimaging." Fitting a locally weighted estimated scatterplot smoothing curve for binding potential (BPND) of the ventral striatum measured by 11C-raclopride was performed. Five studies involving 119 subjects were included in this analysis. 11C-raclopride was used in four studies, regardless of the ROIs included. The curve of BPND of the ventral striatum went up and down at BMI of 20-30 kg/m2 and became flat after a BMI of >40 kg/m2. Linear regression analysis was performed with BPND of the striatum from two studies (n = 20). The BPND of the striatum was negatively associated with BMI. In conclusion, dopamine plays a major role in the reward system with regard to obesity. Compared to normal-weight subjects, overweight and obese subjects had decreased DR availability. However, this tendency should be interpreted carefully with regard to radiopharmaceuticals and ROIs.

neuroscience↗

bioRxiv2018

Altered protein quality control contributes to noise-induced hearing loss

Exposure to damaging levels of noise is the most common cause of hearing loss and impairs high frequency hearing in more than 15 % of adult Americans. Using mice exposed to increasing levels of noise in combination with quantitative proteomics, we tested how noise insults remodel the cochlear proteome both acutely and after a two-week recovery period. We used ABR & DPOAE recordings to define the intensity of noise exposure necessary to produce temporary or permanent threshold shifts (TTS, PTS) in young adult mice and found noise at 94 and 105 dB SPL levels for 30 minutes elicits TTS and PTS, respectively. We quantified thousands of proteins and found that noise insults cause a rapid increase rather than a decrease in the levels of many proteins involved with protein homeostasis, myelin, cytoskeletal structures, and cell junctions such as the synapse. The vast majority of proteins with increased levels immediately after noise exposure showed normal levels after two weeks of recovery. However, several proteins involved in oxidative stress and neuroprotection had significantly increased levels only after the recovery period suggesting they play in important role in regeneration. Interestingly, a small panel of mitochondrial proteins were significantly altered only in PTS conditions suggesting potential discrete protein mechanisms. Our discovery-based proteomic analysis extends the recent description of noise-induced cochlear synaptopathy and shows that noise insults drive a robust proteostasis response. These data provide a new understanding of noise sensitive proteins and may inform the development of effective preventiative strategies or therapies for NIHL.

neuroscience↗