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1.
iScience ; 27(6): 110023, 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38957788

ABSTRACT

We delve into the distinctive color gamut characteristics resulting from color dispersion of surface relief grating (SRG) and wavelength degeneracy of volume holographic optical element (VHOE) in a diffractive light guide. While a laser-like spectrum achieves an impressive 194% sRGB color gamut for both cases, it proves unsuitable for VHOE light guides due to limitations in breaking the field of view (FOV) of the display. Conversely, a broad-band light source, such as LEDs, offers continuous FOV but reduces the common color gamut to 50% sRGB. We then present a newly designed VHOE light guide capable of achieving the common color gamut of 130% sRGB using two multiplexed holograms of each color, closely matching the 133% sRGB achieved by an SRG light guide. This article presents the first theoretical methodology to elucidate color performance of diffractive light guides utilizing VHOEs with holographic multiplexing, affirming their suitability for crafting high-quality near-eye display.

2.
Phys Med Biol ; 2024 Jul 02.
Article in English | MEDLINE | ID: mdl-38955331

ABSTRACT

OBJECTIVE: The trend in the medical field is towards intelligent detection-based medical diagnostic systems. However, these methods are often seen as "black boxes" due to their lack of interpretability. This situation presents challenges in identifying reasons for misdiagnoses and improving accuracy, which leads to potential risks of misdiagnosis and delayed treatment. Therefore, how to enhance the interpretability of diagnostic models is crucial for improving patient outcomes and reducing treatment delays. So far, only limited researches exist on deep learning-based prediction of spontaneous pneumothorax, a pulmonary disease that affects lung ventilation and venous return. Approach. This study develops an integrated medical image analysis system using explainable deep learning model for image recognition and visualization to achieve an interpretable automatic diagnosis process. Main results. The system achieves an impressive 95.56% accuracy in pneumothorax classification, which emphasizes the significance of the blood vessel penetration defect in clinical judgment. Significance. This would lead to improve model trustworthiness, reduce uncertainty, and accurate diagnosis of various lung diseases, which results in better medical outcomes for patients and better utilization of medical resources. Future research can focus on implementing new deep learning models to detect and diagnose other lung diseases that can enhance the generalizability of this system. .

3.
ACS Nano ; 18(24): 15545-15556, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38838261

ABSTRACT

Deterministic formation of membrane scission necks by protein machinery with multiplexed functions is critical in biology. A microbial example is M2 viroporin, a proton pump from the influenza A virus that is multiplexed with membrane remodeling activity to induce budding and scission in the host membrane during viral maturation. In comparison, the dynamin family constitutes a class of eukaryotic proteins implicated in mitochondrial fission, as well as various budding and endocytosis pathways. In the case of Dnm1, the mitochondrial fission protein in yeast, the membrane remodeling activity is multiplexed with mechanoenzyme activity to create fission necks. It is not clear why these functions are combined in these scission processes, which occur in drastically different compositions and solution conditions. In general, direct experimental access to changing neck sizes induced by individual proteins or peptide fragments is challenging due to the nanoscale dimensions and influence of thermal fluctuations. Here, we use a mechanical model to estimate the size of scission necks by leveraging small-angle X-ray scattering structural data of protein-lipid systems under different conditions. The influence of interfacial tension, lipid composition, and membrane budding morphology on the size of the induced scission necks is systematically investigated using our data and molecular dynamic simulations. We find that the M2 budding protein from the influenza A virus has robust pH-dependent membrane activity that induces nanoscopic necks within the range of spontaneous hemifission for a broad range of lipid compositions. In contrast, the sizes of scission necks generated by mitochondrial fission proteins strongly depend on lipid composition, which suggests a role for mechanical constriction.


Subject(s)
Cell Membrane , Cell Membrane/metabolism , Cell Membrane/chemistry , Viral Matrix Proteins/metabolism , Viral Matrix Proteins/chemistry , Dynamins/metabolism , Dynamins/chemistry , Influenza A virus/metabolism , Scattering, Small Angle , Viroporin Proteins
4.
Opt Express ; 32(11): 20401-20411, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38859152

ABSTRACT

A FMCW LiDAR system of both the distributed feedback laser and external cavity laser is established in baseband beat notes, rather than up-conversion to an intermediate frequency to exclude flicker noise. Meanwhile, utilizing fast-scanning MEMS mirrors, high-quality real-time (1 fps) 4-D images of the slow-moving object (10 mm/s) can be directly constructed at the baseband with a central frequency as low as 100 kHz and a small Doppler shift. The proposed LiDAR architecture based on such a low-frequency baseband significantly improves the optical power budget on the transmitter side and eliminates the costly high-speed sampling circuits on the receiver side.

5.
Nutrients ; 16(9)2024 May 03.
Article in English | MEDLINE | ID: mdl-38732634

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent pediatric liver disorder, primarily attributed to dietary shifts in recent years. NAFLD is characterized by the accumulation of lipid species in hepatocytes, leading to liver inflammation that can progress to steatohepatitis, fibrosis, and cirrhosis. Risk factors contributing to NAFLD encompass genetic variations and metabolic disorders such as obesity, diabetes, and insulin resistance. Moreover, transgenerational influences, resulting in an imbalance of gut microbial composition, epigenetic modifications, and dysregulated hepatic immune responses in offspring, play a pivotal role in pediatric NAFLD development. Maternal nutrition shapes the profile of microbiota-derived metabolites in offspring, exerting significant influence on immune system regulation and the development of metabolic syndrome in offspring. In this review, we summarize recent evidence elucidating the intricate interplay between gut microbiota, epigenetics, and immunity in fetuses exposed to maternal nutrition, and its impact on the onset of NAFLD in offspring. Furthermore, potential therapeutic strategies targeting this network are also discussed.


Subject(s)
Epigenesis, Genetic , Gastrointestinal Microbiome , Maternal Nutritional Physiological Phenomena , Non-alcoholic Fatty Liver Disease , Prenatal Exposure Delayed Effects , Non-alcoholic Fatty Liver Disease/immunology , Non-alcoholic Fatty Liver Disease/microbiology , Non-alcoholic Fatty Liver Disease/etiology , Humans , Female , Pregnancy , Animals , Risk Factors
6.
ArXiv ; 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38699164

ABSTRACT

Biological sequences do not come at random. Instead, they appear with particular frequencies that reflect properties of the associated system or phenomenon. Knowing how biological sequences are distributed in sequence space is thus a natural first step toward understanding the underlying mechanisms. Here we propose a new method for inferring the probability distribution from which a sample of biological sequences were drawn for the case where the sequences are composed of elements that admit a natural ordering. Our method is based on Bayesian field theory, a physics-based machine learning approach, and can be regarded as a nonparametric extension of the traditional maximum entropy estimate. As an example, we use it to analyze the aneuploidy data pertaining to gliomas from The Cancer Genome Atlas project. In addition, we demonstrate two follow-up analyses that can be performed with the resulting probability distribution. One of them is to investigate the associations among the sequence sites. This provides us a way to infer the governing biological grammar. The other is to study the global geometry of the probability landscape, which allows us to look at the problem from an evolutionary point of view. It can be seen that this methodology enables us to learn from a sample of sequences about how a biological system or phenomenon in the real world works.

7.
Nutrients ; 16(9)2024 Apr 28.
Article in English | MEDLINE | ID: mdl-38732572

ABSTRACT

The effects of gut microbiota on the association between carbohydrate intake during pregnancy and neonatal low birth weight (LBW) were investigated. A prospective cohort study was conducted with 257 singleton-born mother-child pairs in Taiwan, and maternal dietary intake was estimated using a questionnaire, with each macronutrient being classified as low, medium, or high. Maternal fecal samples were collected between 24 and 28 weeks of gestation, and gut microbiota composition and diversity were profiled using 16S rRNA amplicon gene sequencing. Carbohydrates were the major source of total energy (56.61%), followed by fat (27.92%) and protein (15.46%). The rate of infant LBW was 7.8%, which was positively correlated with maternal carbohydrate intake. In the pregnancy gut microbiota, Bacteroides ovatus and Dorea spp. were indirectly and directly negatively associated with fetal growth, respectively; Rosenburia faecis was directly positively associated with neonatal birth weight. Maternal hypertension during pregnancy altered the microbiota features and was associated with poor fetal growth. Microbiota-accessible carbohydrates can modify the composition and function of the pregnancy gut microbiota, thus providing a potential marker to modulate deviations from dietary patterns, particularly in women at risk of hypertension during pregnancy, to prevent neonatal LBW.


Subject(s)
Dietary Carbohydrates , Feces , Gastrointestinal Microbiome , Infant, Low Birth Weight , Humans , Female , Gastrointestinal Microbiome/drug effects , Pregnancy , Infant, Newborn , Adult , Prospective Studies , Feces/microbiology , Maternal Nutritional Physiological Phenomena , Taiwan , RNA, Ribosomal, 16S/genetics , Fetal Development
8.
bioRxiv ; 2024 Mar 27.
Article in English | MEDLINE | ID: mdl-38585764

ABSTRACT

Cohesin is required for chromatin loop formation. However, its precise role in regulating gene transcription remains largely unknown. We investigated the relationship between cohesin and RNA Polymerase II (RNAPII) using single-molecule mapping and live-cell imaging methods in human cells. Cohesin-mediated transcriptional loops were highly correlated with those of RNAPII and followed the direction of gene transcription. Depleting RAD21, a subunit of cohesin, resulted in the loss of long-range (>100 kb) loops between distal (super-)enhancers and promoters of cell-type-specific genes. By contrast, the short-range (<50 kb) loops were insensitive to RAD21 depletion and connected genes that are mostly housekeeping. This result explains why only a small fraction of genes are affected by the loss of long-range chromatin interactions due to cohesin depletion. Remarkably, RAD21 depletion appeared to up-regulate genes located in early initiation zones (EIZ) of DNA replication, and the EIZ signals were amplified drastically without RAD21. Our results revealed new mechanistic insights of cohesin's multifaceted roles in establishing transcriptional loops, preserving long-range chromatin interactions for cell-specific genes, and maintaining timely order of DNA replication.

9.
Int J Mol Sci ; 25(8)2024 Apr 12.
Article in English | MEDLINE | ID: mdl-38673867

ABSTRACT

Sialyltransferase-catalyzed membrane protein and lipid glycosylation plays a vital role as one of the most abundant post-translational modifications and diversification reactions in eukaryotes. However, aberrant sialylation has been associated with cancer malignancy and metastasis. Sialyltransferases thus represent emerging targets for the development of small molecule cancer drugs. Herein, we report the inhibitory effects of a recently discovered lithocholic acid derivative FCW393 on sialyltransferase catalytic activity, integrin sialyation, cancer-associated signal transduction, MDA-MB-231 and B16F10 cell migration and invasion, and in in vivo studies, on tumor growth, metastasis, and angiogenesis. FCW393 showed effective and selective inhibition of the sialyltransferases ST6GAL1 (IC50 = 7.8 µM) and ST3GAL3 (IC50 = 9.45 µM) relative to ST3GAL1 (IC50 > 400 µM) and ST8SIA4 (IC50 > 100 µM). FCW393 reduced integrin sialylation in breast cancer and melanoma cells dose-dependently and downregulated proteins associated with the integrin-regulated FAK/paxillin and GEF/Rho/ROCK pathways, and with the VEGF-regulated Akt/NFκB/HIF-1α pathway. FCW393 inhibited cell migration (IC50 = 2.6 µM) and invasion in in vitro experiments, and in in vivo studies of tumor-bearing mice, FCW393 reduced tumor size, angiogenesis, and metastatic potential. Based on its demonstrated selectivity, cell permeability, relatively low cytotoxicity (IC50 = 55 µM), and high efficacy, FCW393 shows promising potential as a small molecule experimental tool compound and a lead for further development of a novel cancer therapeutic.


Subject(s)
Cell Movement , Sialyltransferases , Sialyltransferases/metabolism , Sialyltransferases/antagonists & inhibitors , Humans , Animals , Mice , Cell Line, Tumor , Cell Movement/drug effects , Neoplasm Metastasis , Female , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemistry , Signal Transduction/drug effects , Cell Proliferation/drug effects , Lithocholic Acid/pharmacology
10.
RMD Open ; 10(2)2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38637112

ABSTRACT

OBJECTIVES: This study aimed to develop a predictive model using polygenic risk score (PRS) to forecast renal outcomes for adult systemic lupus erythematosus (SLE) in a Taiwanese population. METHODS: Patients with SLE (n=2782) and matched non-SLE controls (n=11 128) were genotyped using Genome-Wide TWB 2.0 single-nucleotide polymorphism (SNP) array. PRS models (C+T, LDpred2, Lassosum, PRSice-2, PRS-continuous shrinkage (CS)) were constructed for predicting SLE susceptibility. Logistic regression was assessed for C+T-based PRS association with renal involvement in patients with SLE. RESULTS: In the training set, C+T-based SLE-PRS, only incorporating 27 SNPs, outperformed other models with area under the curve (AUC) values of 0.629, surpassing Lassosum (AUC=0.621), PRSice-2 (AUC=0.615), LDpred2 (AUC=0.609) and PRS-CS (AUC=0.602). Additionally, C+T-based SLE-PRS demonstrated consistent predictive capacity in the testing set (AUC=0.620). Individuals in the highest quartile exhibited earlier SLE onset (39.06 vs 44.22 years, p<0.01), higher Systemic Lupus Erythematosus Disease Activity Index scores (3.00 vs 2.37, p=0.04), elevated risks of renal involvement within the first year of SLE diagnosis, including WHO class III-IV lupus nephritis (OR 2.36, 95% CI 1.47 to 3.80, p<0.01), estimated glomerular filtration rate <60 mL/min/1.73m2 (OR 1.49, 95% CI 1.18 to 1.89, p<0.01) and urine protein-to-creatinine ratio >150 mg/day (OR 2.07, 95% CI 1.49 to 2.89, p<0.01), along with increased seropositivity risks, compared with those in the lowest quartile. Furthermore, among patients with SLE with onset before 50 years, the highest PRS quartile was significantly associated with more serious renal diseases within the first year of SLE diagnosis. CONCLUSIONS: PRS of SLE is associated with earlier onset, renal involvement within the first year of SLE diagnosis and seropositivity in Taiwanese patients. Integrating PRS with clinical decision-making may enhance lupus nephritis screening and early treatment to improve renal outcomes in patients with SLE.


Subject(s)
Lupus Erythematosus, Systemic , Lupus Nephritis , Adult , Humans , Lupus Nephritis/diagnosis , Lupus Nephritis/epidemiology , Lupus Nephritis/genetics , Genetic Risk Score , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/epidemiology , Kidney , Genotype
11.
Telemed J E Health ; 30(6): e1705-e1712, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38512470

ABSTRACT

Background: The scarcity of medical resources and personnel has worsened due to COVID-19. Telemedicine faces challenges in assessing wounds without physical examination. Evaluating pressure injuries is time consuming, energy intensive, and inconsistent. Most of today's telemedicine platforms utilize graphical user interfaces with complex operational procedures and limited channels for information dissemination. The study aims to establish a smart telemedicine diagnosis system based on YOLOv7 and large language model. Methods: The YOLOv7 model is trained using a clinical data set, with data augmentation techniques employed to enhance the data set to identify six types of pressure injury images. The established system features a front-end interface that includes responsive web design and a chatbot with ChatGPT, and it is integrated with a database for personal information management. Results: This research provides a practical pressure injury staging classification model with an average F1 score of 0.9238. The system remotely provides real-time accurate diagnoses and prescriptions, guiding patients to seek various medical help levels based on symptom severity. Conclusions: This study establishes a smart telemedicine auxiliary diagnosis system based on the YOLOv7 model, which possesses capabilities for classification and real-time detection. During teleconsultations, it provides immediate and accurate diagnostic information and prescription recommendations and seeks various medical assistance based on the severity of symptoms. Through the setup of a chatbot with ChatGPT, different users can quickly achieve their respective objectives.


Subject(s)
COVID-19 , Pressure Ulcer , Telemedicine , Humans , Pressure Ulcer/diagnosis , COVID-19/diagnosis , SARS-CoV-2
12.
J Hazard Mater ; 469: 133891, 2024 May 05.
Article in English | MEDLINE | ID: mdl-38457971

ABSTRACT

Per- and polyfluoroalkyl substances (PFAS) is a large compound class (n > 12,000) that is extensively present in food, drinking water, and aquatic environments. Reduced serum triglycerides and hepatosteatosis appear to be the common phenotypes for different PFAS chemicals. However, the hepatosteatosis potential of most PFAS chemicals remains largely unknown. This study aims to investigate PFAS-induced hepatosteatosis using in vitro high-throughput phenotype profiling (HTPP) and high-throughput transcriptomic (HTTr) data. We quantified the in vitro hepatosteatosis effects and mitochondrial damage using high-content imaging, curated the transcriptomic data from the Gene Expression Omnibus (GEO) database, and then calculated the point of departure (POD) values for HTPP phenotypes or HTTr transcripts, using the Bayesian benchmark dose modeling approach. Our results indicated that PFAS compounds with fully saturated C-F bonds, sulfur- and nitrogen-containing functional groups, and a fluorinated carbon chain length greater than 8 have the potential to produce biological effects consistent with hepatosteatosis. PFAS primarily induced hepatosteatosis via disturbance in lipid transport and storage. The potency rankings of PFAS compounds are highly concordant among in vitro HTPP, HTTr, and in vivo hepatosteatosis phenotypes (ρ = 0.60-0.73). In conclusion, integrating the information from in vitro HTPP and HTTr analyses can accurately project in vivo hepatosteatosis effects induced by PFAS compounds.


Subject(s)
Fluorocarbons , Gene Expression Profiling , Bayes Theorem , Transcriptome , Phenotype , Fluorocarbons/toxicity
13.
Adv Mater ; 36(23): e2311157, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38402421

ABSTRACT

Understanding the magnetic and ferroelectric ordering of magnetoelectric multiferroic materials at the nanoscale necessitates a versatile imaging method with high spatial resolution. Here, soft X-ray ptychography is employed to simultaneously image the ferroelectric and antiferromagnetic domains in an 80 nm thin freestanding film of the room-temperature multiferroic BiFeO3 (BFO). The antiferromagnetic spin cycloid of period 64 nm is resolved by reconstructing the corresponding resonant elastic X-ray scattering in real space and visualized together with mosaic-like ferroelectric domains in a linear dichroic contrast image at the Fe L3 edge. The measurements reveal a near perfect coupling between the antiferromagnetic and ferroelectric ordering by which the propagation direction of the spin cycloid is locked orthogonally to the ferroelectric polarization. In addition, the study evinces both a preference for in-plane propagation of the spin cycloid and changes of the ferroelectric polarization by 71° between multiferroic domains in the epitaxial strain-free, freestanding BFO film. The results provide a direct visualization of the strong magnetoelectric coupling in BFO and of its fine multiferroic domain structure, emphasizing the potential of ptychographic imaging for the study of multiferroics and non-collinear magnetic materials with soft X-rays.

14.
Ecotoxicol Environ Saf ; 272: 116085, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38342010

ABSTRACT

Zearalenone (ZEN) is a prevalent mycotoxin that severely impacts human and animal health. However, the possible interactions between ZEN exposure, pathogen infection, immune system, and reactive oxygen species (ROS) were rarely investigated. We studied the effects of early-life ZEN (50 µM) exposure on the immune response of Caenorhabditis elegans against Bacillus thuringiensis infection and the associated mechanisms. The transcriptomic responses of C. elegans after early-life ZEN exposure were investigated using RNA sequencing and followed by verification using quantitative PCR analysis. We also investigated the immune responses of the worms through B. thuringiensis killing assays and by measuring oxidative stress. The transcriptomics result showed that early-life exposure to ZEN resulted in 44 differentially expressed genes, 7 of which were protein-coding genes with unknown functions. The Gene Ontology analysis suggested that metabolic processes and immune response were among the most significantly enriched biological processes, and the KEGG analysis suggested that lysosomes and metabolic pathways were the most significantly enriched pathways. The ZEN-exposed worms exhibited significantly reduced survival after 24-h B. thuringiensis infection, reaching near 100% mortality compared to 60% of the controls. Using qRT-PCR assay, we found that ZEN further enhanced the expression of immunity genes lys-6, spp-1, and clec-60 after B. thuringiensis infection. A concurrently enhanced ROS accumulation was also observed for ZEN-exposed worms after B. thuringiensis infection, which was 1.2-fold compared with the controls. Moreover, ZEN exposure further enhanced mRNA expression of catalases (ctl-1 and ctl-2) and increased catalase protein activity after B. thuringiensis exposure compared with their non-exposed counterparts, suggesting an elevated oxidative stress. This study suggests that early-life exposure to mycotoxin zearalenone overstimulates immune responses involving spp-17, clec-52, and clec-56, resulting in excessive ROS production, enhanced oxidative stress as indicated by aggravated ctl expression and activity, and a decline in host resistance to pathogenic infection which ultimately leads to increased mortality under B. thuringiensis infection. Our findings provide evidence that could improve our understanding on the potential interactions between mycotoxin zearalenone and pathogens.


Subject(s)
Bacillus thuringiensis , Mycotoxins , Zearalenone , Animals , Humans , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Zearalenone/toxicity , Reactive Oxygen Species/metabolism , Bacillus thuringiensis/genetics , Bacillus thuringiensis/metabolism , Mycotoxins/metabolism , Oxidative Stress , Antioxidants/metabolism , Immunity
15.
bioRxiv ; 2024 Jan 07.
Article in English | MEDLINE | ID: mdl-38260291

ABSTRACT

Deterministic formation of membrane scission necks by protein machinery with multiplexed functions is critical in biology. A microbial example is the M2 viroporin, a proton pump from the influenza A virus which is multiplexed with membrane remodeling activity to induce budding and scission in the host membrane during viral maturation. In comparison, the dynamin family constitutes a class of eukaryotic proteins implicated in mitochondrial fission, as well as various budding and endocytosis pathways. In the case of Dnm1, the mitochondrial fission protein in yeast, the membrane remodeling activity is multiplexed with mechanoenzyme activity to create fission necks. It is not clear why these functions are combined in these scission processes, which occur in drastically different compositions and solution conditions. In general, direct experimental access to changing neck sizes induced by individual proteins or peptide fragments is challenging due to the nanoscale dimensions and influence of thermal fluctuations. Here, we use a mechanical model to estimate the size of scission necks by leveraging Small-Angle X-ray Scattering (SAXS) structural data of protein-lipid systems under different conditions. The influence of interfacial tension, lipid composition, and membrane budding morphology on the size of the induced scission necks is systematically investigated using our data and molecular dynamic simulations. We find that the M2 budding protein from the influenza A virus has robust pH-dependent membrane activity that induces nanoscopic necks within the range of spontaneous hemi-fission for a broad range of lipid compositions. In contrast, the sizes of scission necks generated by mitochondrial fission proteins strongly depend on lipid composition, which suggests a role for mechanical constriction.

16.
Circulation ; 149(16): 1285-1297, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38235591

ABSTRACT

BACKGROUND: TTN truncation variants (TTNtvs) are the most common genetic lesion identified in individuals with dilated cardiomyopathy, a disease with high morbidity and mortality rates. TTNtvs reduce normal TTN (titin) protein levels, produce truncated proteins, and impair sarcomere content and function. Therapeutics targeting TTNtvs have been elusive because of the immense size of TTN, the rarity of specific TTNtvs, and incomplete knowledge of TTNtv pathogenicity. METHODS: We adapted CRISPR activation using dCas9-VPR to functionally interrogate TTNtv pathogenicity and develop a therapeutic in human cardiomyocytes and 3-dimensional cardiac microtissues engineered from induced pluripotent stem cell models harboring a dilated cardiomyopathy-associated TTNtv. We performed guide RNA screening with custom TTN reporter assays, agarose gel electrophoresis to quantify TTN protein levels and isoforms, and RNA sequencing to identify molecular consequences of TTN activation. Cardiomyocyte epigenetic assays were also used to nominate DNA regulatory elements to enable cardiomyocyte-specific TTN activation. RESULTS: CRISPR activation of TTN using single guide RNAs targeting either the TTN promoter or regulatory elements in spatial proximity to the TTN promoter through 3-dimensional chromatin interactions rescued TTN protein deficits disturbed by TTNtvs. Increasing TTN protein levels normalized sarcomere content and contractile function despite increasing truncated TTN protein. In addition to TTN transcripts, CRISPR activation also increased levels of myofibril assembly-related and sarcomere-related transcripts. CONCLUSIONS: TTN CRISPR activation rescued TTNtv-related functional deficits despite increasing truncated TTN levels, which provides evidence to support haploinsufficiency as a relevant genetic mechanism underlying heterozygous TTNtvs. CRISPR activation could be developed as a therapeutic to treat a large proportion of TTNtvs.


Subject(s)
Cardiomyopathy, Dilated , Humans , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/therapy , Cardiomyopathy, Dilated/pathology , Connectin/genetics , Haploinsufficiency/genetics , Clustered Regularly Interspaced Short Palindromic Repeats/genetics , RNA, Guide, CRISPR-Cas Systems , Myocytes, Cardiac/metabolism
17.
Psychiatry Clin Neurosci ; 78(1): 69-76, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37812045

ABSTRACT

AIM: No previous studies, to our knowledge, have investigated the association between psychiatrist density and suicide, accounting for individual- and area-level characteristics. METHODS: We investigated all suicide cases in 2007-2017 identified from the national cause-of-death data files, with each suicide case matched to 10 controls by age and sex and each suicide case/control assigned to one of the 355 townships across Taiwan. Our primary outcome was the odds ratio (OR) of suicide and its 95% confidence interval (CI) estimated via multilevel models, which included both individual- and area-level characteristics. Townships with no psychiatrists were compared with the quartiles of townships with psychiatrists (density per 100,000 population): quartile 1 (Q1) (0.01-3.02); quartile 2 (Q2) (3.02-7.20); quartile 3 (Q3) (7.20-13.82); and quartile 4 (Q4) (>13.82). RESULTS: A total of 40,930 suicide cases and 409,300 age- and sex-matched controls were included. We found that increased psychiatrist density was associated with decreased suicide risk (Q1: adjusted OR [aOR], 0.95 [95% CI, 0.90-1.01]; Q2: aOR, 0.90 [95% CI, 0.85-0.96]; Q3: aOR, 0.89 [95% CI, 0.83-0.94]; Q4: aOR, 0.89 [95% CI, 0.83-0.95]) after adjusting for individual-level characteristics (employment state, monthly income, physical comorbidities, and the diagnosis of psychiatric disorders) and area socioeconomic characteristics. CONCLUSIONS: The psychiatrist density-suicide association suggests an effect of increased availability of psychiatric services on preventing suicide. Suicide prevention strategies could usefully focus on enhancing local access to psychiatric services.


Subject(s)
Psychiatrists , Suicide , Humans , Case-Control Studies , Taiwan/epidemiology , Suicide/psychology , Suicide Prevention
18.
Psychol Med ; 54(7): 1452-1460, 2024 May.
Article in English | MEDLINE | ID: mdl-37981870

ABSTRACT

BACKGROUND: Somatic symptom disorders (SSD) and functional somatic syndromes (FSS) are often regarded as similar diagnostic constructs; however, whether they exhibit similar clinical outcomes, medical costs, and medication usage patterns has not been examined in nationwide data. Therefore, this study focused on analyzing SSD and four types of FSS (fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, functional dyspepsia). METHODS: This population-based matched cohort study utilized Taiwan's National Health Insurance (NHI) claims database to investigate the impact of SSD/FSS. The study included 2 615 477 newly diagnosed patients with SSD/FSS and matched comparisons from the NHI beneficiary registry. Healthcare utilization, mortality, medical expenditure, and medication usage were assessed as outcome measures. Statistical analysis involved Cox regression models for hazard ratios, generalized linear models for comparing differences, and adjustment for covariates. RESULTS: All SSD/FSS showed significantly higher adjusted hazard ratios for psychiatric hospitalization and all-cause hospitalization compared to the control group. All SSD/FSS exhibited significantly higher adjusted hazard ratios for suicide, and SSD was particularly high. All-cause mortality was significantly higher in all SSD/FSS. Medical costs were significantly higher for all SSD/FSS compared to controls. The usage duration of all psychiatric medications and analgesics was significantly higher in SSD/FSS compared to the control group. CONCLUSION: All SSD/FSS shared similar clinical outcomes and medical costs. The high hazard ratio for suicide in SSD deserves clinical attention.


Subject(s)
Medically Unexplained Symptoms , Humans , Cohort Studies , Taiwan/epidemiology , Somatoform Disorders/drug therapy , Somatoform Disorders/epidemiology , Somatoform Disorders/psychology , Research Design
19.
J Chin Med Assoc ; 87(2): 196-201, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38132568

ABSTRACT

BACKGROUND: This study aimed to explore the impact of diabetes on overactive bladder (OAB) presentations and related predictors of healthcare-seeking behavior among adults aged ≥ 40 years in China, Taiwan, and South Korea. METHODS: An internet-based survey was conducted to assess the prevalence of diabetes, OAB presentations, and self-perceived urinary symptoms by a multi-national sample of 8284 individuals who completed the survey between June 2, 2015 and July 31, 2015. Independent associations with health-seeking behavior for urinary symptoms were estimated with odds ratio (OR) with 95% confidence interval (95% CI) using multivariate logistic regression. RESULTS: Diabetes was reported in 13.6% of participants and OAB was 20.8%. Diabetic participants were older than non-diabetic participants in both sexes. Participants with diabetes reported a higher rate of OAB (43.1%) and increased bothersome symptoms associated with OAB than those without diabetes. Participants with diabetes (OR, 3.07 [2.39-3.96]], urgent incontinence (OR, 2.38 [1.86-3.03]), frequency (OR, 1.86 [1.45-2.38]), and nocturia (OR, 1.14 [1.05-1.24]) were associated with healthcare-seeking behavior. CONCLUSION: The proportion of diabetic participants with OAB was 2.5-fold higher than those without diabetes. Diabetes, urinary frequency, nocturia, and urgent incontinence are predictors of medical treatment-seeking behavior, but the key symptom of OAB-urgency is not a predictor of treatment-seeking behavior. It is important for clinicians to recognize the interplay between diabetes and OAB and to early identify various bothersome urinary symptoms for better health outcomes in daily practice.


Subject(s)
Diabetes Mellitus , Nocturia , Urinary Bladder, Overactive , Adult , Male , Female , Humans , Urinary Bladder, Overactive/epidemiology , Nocturia/complications , Nocturia/epidemiology , Cross-Sectional Studies , Taiwan/epidemiology , Diabetes Mellitus/epidemiology , Patient Acceptance of Health Care , China/epidemiology , Republic of Korea/epidemiology
20.
Article in English | MEDLINE | ID: mdl-37917527

ABSTRACT

This study investigated the extent that the non-verbal behaviors of virtual humans (VHs) and their socio-demographic attributes altered users' collision avoidance behaviors in Virtual Reality (VR). Users interacted with VHs representing different levels of ethnicities and gender, exhibiting different conditions of physical movement, and gaze behaviors. The VHs were depicted in three major ethnic conditions namely Asian, Caucasian, and Black. The physical movement states of the VHs were either static in the path of the user or walking toward the user in the opposite direction. The non-verbal gaze behavior of the VHs was either direct gaze or averted gaze. We used an HTC Vive tracking system to track users' performing real walking while we collected objective measures (i,e., continuous gaze, fixation gaze, clearance distance, and travel length), and subjective variables (i.e., game experiences and social presence). The results showed that the ethnicity of the VHs significantly impacted the gaze behavior of the users, and the gender of the VHs affected the user avoidance movement and their reciprocal gaze behavior. Our results revealed that users' physical movement, gaze behaviors, and collision avoidance were moderated by the VHs' perceived ethnicity, gender, and gaze behaviors. Understanding the impact of the socio-demographics attributes of VHs and their gaze behavior on users' collision avoidance is critical for applications in which users are navigating through virtual traffic, crowd, and other inter-personal simulations.

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