Intestinal epithelial cells of Japanese flounder (Paralichthys olivaceus) as an in vitro model for studying intestine immune function based on transcriptome analysis.

Japanese flounder (Paralichthys olivaceus) is an economically crucial marine species, but diseases like hemorrhagic septicemia caused by Edwardsiella tarda have resulted in significant economic losses. E. tarda infects various hosts, and its pathogenicity in fish is not fully understood. Lipopolysaccharides (LPS) are components of the outer membrane of Gram-negative bacteria and are representative of typical PAMP molecules that cause activation of the immune system. The PoIEC cell line is a newly established intestinal epithelial cell line from P. olivaceus. In order to investigate whether it can be used as an in vitro model for studying the pathogenesis of E. tarda and LPS stimulation, we conducted RNA-seq experiments for the PoIECs model of E. tarda infection and LPS stimulation. In this study, transcriptome sequencing was carried out in the PoIEC cell line after treatment with LPS and E. tarda. A total of 62.52G of high-quality data from transcriptome sequencing results were obtained in nine libraries, of which an average of 87.96% data could be aligned to the P. olivaceus genome. Data analysis showed that 283 and 414 differentially expressed genes (DEGs) in the LPS versus Control (LPS-vs-Con) and E. tarda versus Control groups (Et-vs-Con), respectively, of which 60 DEGs were shared in two comparation groups. The GO terms were predominantly enriched in the extracellular space, inflammatory response, and cytokine activity in the LPS-vs-Con group, whereas GO terms were predominantly enriched in nucleus and positive regulation of transcription by RNA polymerase II in the Et-vs-Con group. KEGG analysis revealed that three immune-related pathways were co-enriched in both comparison groups, including the Toll-like receptor signaling pathway, C-type lectin receptor signaling pathway, and Cytokine-cytokine receptor interaction. Five genes were randomly screened to confirm the validity and accuracy of the transcriptome data. These results suggest that PoIEC cell line can be an ideal in vitro model for studies of marine fish gut immunity and pathogenesis of Edwardsiellosis.

An analytical method for the identification of cell type-specific disease gene modules.

BACKGROUND: Genome-wide association studies have identified genetic variants associated with the risk of brain-related diseases, such as neurological and psychiatric disorders, while the causal variants and the specific vulnerable cell types are often needed to be studied. Many disease-associated genes are expressed in multiple cell types of human brains, while the pathologic variants affect primarily specific cell types. We hypothesize a model in which what determines the manifestation of a disease in a cell type is the presence of disease module comprised of disease-associated genes, instead of individual genes. Therefore, it is essential to identify the presence/absence of disease gene modules in cells. METHODS: To characterize the cell type-specificity of brain-related diseases, we construct human brain cell type-specific gene interaction networks integrating human brain nucleus gene expression data with a referenced tissue-specific gene interaction network. Then from the cell type-specific gene interaction networks, we identify significant cell type-specific disease gene modules by performing statistical tests. RESULTS: Between neurons and glia cells, the constructed cell type-specific gene networks and their gene functions are distinct. Then we identify cell type-specific disease gene modules associated with autism spectrum disorder and find that different gene modules are formed and distinct gene functions may be dysregulated in different cells. We also study the similarity and dissimilarity in cell type-specific disease gene modules among autism spectrum disorder, schizophrenia and bipolar disorder. The functions of neurons-specific disease gene modules are associated with synapse for all three diseases, while those in glia cells are different. To facilitate the use of our method, we develop an R package, CtsDGM, for the identification of cell type-specific disease gene modules. CONCLUSIONS: The results support our hypothesis that a disease manifests itself in a cell type through forming a statistically significant disease gene module. The identification of cell type-specific disease gene modules can promote the development of more targeted biomarkers and treatments for the disease. Our method can be applied for depicting the cell type heterogeneity of a given disease, and also for studying the similarity and dissimilarity between different disorders, providing new insights into the molecular mechanisms underlying the pathogenesis and progression of diseases.

Diffusion radiomics analysis of intratumoral heterogeneity in a murine prostate cancer model following radiotherapy: Pixelwise correlation with histology.

PURPOSE: To investigate the biological meaning of apparent diffusion coefficient (ADC) values in tumors following radiotherapy. MATERIALS AND METHODS: Five mice bearing TRAMP-C1 tumor were half-irradiated with a dose of 15 Gy. Diffusion-weighted images, using multiple b-values from 0 to 3000 s/mm2 , were acquired at 7T on day 6. ADC values calculated by a two-point estimate and monoexponential fitting of signal decay were compared between the irradiated and nonirradiated regions of the tumor. Pixelwise ADC maps were correlated with histological metrics including nuclear counts, nuclear sizes, nuclear spaces, cytoplasmic spaces, and extracellular spaces. RESULTS: As compared with the nonirradiated region, the irradiated region exhibited significant increases in ADC, extracellular space, and nuclear size, and a significant decrease in nuclear counts (P < 0.001 for all). Optimal ADC to differentiate the irradiated from nonirradiated regions was achieved at a b-value of 800 s/mm2 by the two-point method and monoexponential curve fitting. ADC positively correlated with extracellular spaces (r = 0.74) and nuclear sizes (r = 0.72), and negatively correlated with nuclear counts (r = -0.82, P < 0.001 for all). CONCLUSION: As a radiomic biomarker, ADC maps correlating with histological metrics pixelwise could be a means of evaluating tumor heterogeneity and responses to radiotherapy. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:483-489.

Mode Dependency of Quantum Decoherence Studied via an Aharonov-Bohm Interferometer.

We investigate the dependence of decoherence on the mode number M in a multiple-mode Aharonov-Bohm (AB) interferometer. The design of the AB interferometer allows us to precisely determine M by the additivity rule of ballistic conductors; meanwhile, the decoherence rate is simultaneously deduced by the variance of the AB oscillation amplitude. The AB amplitude decreases and fluctuates with depopulating M. Moreover, the normalized amplitude exhibits a maximum at a specific M (∼9). Data analysis reveals that the charge-fluctuation-induced dephasing, which depends on the geometry and the charge relaxation resistance of the system, could play an essential role in the decoherence process. Our results suggest that the phase coherence, in principle, can be optimized using a deliberated design and pave one of the ways toward the engineering of quantum coherence.

Magneto-optical properties of ABC-stacked trilayer graphene.

The generalized tight-binding model is developed to investigate the magneto-optical absorption spectra of ABC-stacked trilayer graphene. The absorption peaks can be classified into nine categories of inter-Landau-level optical excitations, including three intra-group and six inter-group ones. Most of them belong to the twin-peak structures because of the asymmetric Landau level spectrum. The threshold absorption peak alone comes from a certain excitation channel, and its frequency is associated with a specific interlayer atomic interaction. The Landau-level anticrossings cause extra absorption peaks. Moreover, a simple relationship between the absorption frequency and the field strength is absent. The magneto-optical properties of ABC-stacked trilayer graphene are totally different from those of AAA- and ABA-stacked ones, such as the number, intensity and frequency of absorption peaks.

A simple method to improve the quality of diffusion-weighted magnetic resonance imaging with rapid histologic correlation in a murine model.

Diffusion-weighted magnetic resonance imaging (DW-MRI) has been used extensively in biomedical research. However, this technique has often suffered from distortion artifacts because of the magnetic field inhomogeneity surrounding the tissues. Histology is important for validating MRI interpretations, but correlating MRIs with tissue samples is challenging. Here we propose a method to improve DW-MRI and facilitate the matching between MRIs and tissue samples. A cryostat embedding medium, optimal cutting temperature (OCT) compound, was used to cover the examined target during the MRI studies. Frozen OCT compound could aid the examined target to be sectioned in parallel with the imaging plane. Phantom experiments demonstrated that embedding in OCT compound improved the magnetic field inhomogeneity while maintaining the apparent diffusion coefficient. Animal experiments revealed significantly reduced distortions in DW images in both the axial and coronal planes. The in vivo MRIs were easily matched with histologic specimens in a slice-to-slice fashion to examine the corresponding tissue microenvironment. This simple method might improve the quality of DW-MRI and provide histologic information for MRI to serve as an image biomarker.

Ku70 Binding to YAP Alters PARP1 Ubiquitination to Regulate Genome Stability and Tumorigenesis.

YAP is a central player in cancer development with functions extending beyond its recognized role in cell growth regulation. Recent work has identified a link between YAP/TAZ and the DNA damage response. Here, we investigated the mechanistic underpinnings of the crosstalk between DNA damage repair and YAP activity. Ku70, a key component of the non-homologous end joining pathway to repair DNA damage, engaged in a dynamic competition with TEAD4 for binding to YAP, limiting the transcriptional activity of YAP. Depletion of Ku70 enhanced interaction between YAP and TEAD4 and boosted YAP transcriptional capacity. Consequently, Ku70 loss enhanced tumorigenesis in colon cancer and hepatocellular carcinoma (HCC) in vivo. YAP impeded DNA damage repair and elevated genome instability by inducing PARP1 degradation through the SMURF2-mediated ubiquitin-proteasome pathway. Analysis of HCC patient samples substantiated the link between Ku70 expression, YAP activity, PARP1 levels, and genome instability. In conclusion, this research provides insight into the mechanistic interactions between YAP and key regulators of DNA damage repair, highlighting the role of a Ku70-YAP-PARP1 axis in preserving genome stability.

Risks perception of electromagnetic fields in Taiwan: the influence of psychopathology and the degree of sensitivity to electromagnetic fields.

Little is known about the perceived health risks of electromagnetic fields (EMFs) and factors associated with risk perception in non-Western countries. Psychological conditions and risk perception have been postulated as factors that facilitate the attribution of health complaints to environmental factors. This study investigated people's perceived risks of EMFs and other environmental sources, as well as the relationships between risk perception, psychopathology, and the degree of self-reported sensitivity to EMFs. A total of 1,251 adults selected from a nationwide telephone interviewing system database responded to a telephone survey about the relationships between environmental sources and human health. The interview included questions assessing participants' psychiatric conditions and the presence and degree of sensitivity to EMFs. One hundred and seventy participants were self-identified as having sensitivity to EMFs, and 141 met the criteria for psychiatric conditions without EMF sensitivity. More than half of the survey respondents considered power lines and mobile phone base stations to affect people's health to a big extent. Higher sensitivity to EMFs, psychopathology, being female, being married, more years of education, and having a catastrophic illness had positive associations with perceived risks of EMF-related environmental sources as well as for all environmental sources combined. We observed no moderating effect of psychopathology on the association between degree of sensitivity to EMF and risk perception. Thus, psychopathology had influence on general people's risk perception without having influence on the relationship between people's degree of sensitivity to EMF and risk perception. The plausible explanations are discussed in the text.

Precipitating factors of bradycardia after remdesivir administration: ICU admission and cutoff value for declining heart rate.

BACKGROUND: Despite increasing concerns about the association between remdesivir and bradycardia in severe coronavirus disease 2019 (COVID-19) patients receiving remdesivir, information on its clinical course and precipitating factors is limited. Our aim was to investigate possible triggers of bradycardia after remdesivir administration. METHODS: We retrieved the medical records of hospitalized severe and critical COVID-19 patients who received remdesivir from May 1, 2021 to June 30, 2021. Bradycardia was defined as two episodes of a heart rate (HR) < 60 bpm in 24 h. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the discriminability of heart rate pattern on the occurrence of bradycardia. The precipitating factors of bradycardia were examined by a logistic regression model. RESULTS: Regardless of bradycardia status, the median heart rate dropped during remdesivir treatment (from 85 to 72 bpm, p < 0.001), with the heart rate dropping considerably within the first two days of remdesivir treatment. Among various heart rate descriptors, HR ratiomin (d2-d1) had the best discrimination (AUC = 0.7336), and a reduction in HR ratiomin (d2-d1) by 14.65% was associated with bradycardia. Intensive care unit (ICU) admission was associated with an increased risk of bradycardia (odds ratio: 3.41; 95% CI: 1.12-10.41). CONCLUSIONS: In severe COVID-19 patients receiving remdesivir, the risks of bradycardia were influenced by a substantial reduction in heart rate during the first two days of remdesivir treatment and ICU admission. These findings suggest that clinical practitioners should intensively monitor heart rates during remdesivir treatment.

Emotional disturbance and risk factors among COVID-19 confirmed cases in isolation hotels.

Patients with coronavirus disease 2019 (COVID-19) has been isolated in hospital-managed isolation hotels under a policy of the Taiwan government. Centrally isolation patients are more likely to experience psychological symptoms. The purpose of the study was to investigate emotional disturbance during their isolation period and then pinpoint the factors during their isolation period associated with the emotional disturbance. We retrospectively analysed the medical charts of the patients confined to a Banqiao isolation hotel between May 28 and July 3, 2021. The 5-item brief symptom rating scale (BSRS-5) was used to evaluate emotional disturbance levels. Descriptive and logistic regression was used for the data analysis. In total, 197 complete medical records were reviewed, and of these 84 (42.6%) showed emotional disturbance. The majority of them reported only minor disturbance (n = 49, 58.3%). After controlling for confounding factors, being satisfied about medical information was the only protective factor associated with emotional disturbance (OR = 0.2, P = 0.018). Being a male patient (OR = 3.0, P = 0.005), worrying about stigmatization (OR = 2.2, P = 0.041) and being unable to contact family members (OR = 2.9, P = 0.018) increased the risk of experiencing emotional disturbance. Patients with clinical symptoms, namely sore throat (OR = 3.4, P = 0.013) and muscle aches (OR = 6.3, P = 0.005), were also found to be more likely to report emotional disturbance. Mental disturbance commonly occurs among patient with COVID-19 who are isolated in a hospital-managed hotel. Being a male patient, having symptoms, namely a sore throat and muscle pain, being unable to contact family and/or a failure to receive sufficient medical information were found to be associated with emotional disturbance. In order to help isolated patients, government officials should provide a clear rationale for isolation and recognize the patients' efforts to follow the government's policy, which will help to minimize social stigma.

The presence of vacuoles in blastocysts is negatively associated with euploidy and live birth rates.

OBJECTIVE: To investigate whether the presence of vacuoles in biopsied blastocysts is associated with the likelihood of aneuploidy and clinical outcomes. DESIGN: Retrospective observational study. SETTING: A single reproductive center. INTERVENTION(S): None. PATIENT(S): This study retrospectively analyzed data obtained through preimplantation genetic testing for aneuploidy performed on 3351 blastocysts from 826 patients at a single reproductive center between August 2018 and July 2020. Ultimately, 167 single euploid blastocyst transfers were performed in these patients. Vacuoles existing in the trophectoderm or inner cell mass were observed using blastocyst biopsy. After the biopsy, all blastocysts were vitrified, and embryo transfer was performed in a subsequent treatment cycle. MAIN OUTCOME MEASURE(S): The associations between vacuoles and euploidy or live birth rates were assessed using logistic regression models and estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULT(S): Of the 3351 blastocysts from 826 patients, 903 (26.9%) were discovered to have vacuoles. The vacuole-positive group had a significantly lower percentage of euploid blastocysts after TE biopsy than the vacuole-negative group (28.8% vs. 35.5%). Embryos with vacuoles were significantly more likely to be poor quality (30.6% vs. 18.2%). Logistic regression analyses revealed that euploid blastocysts were positively associated with the absence of vacuoles, maternal age, and good embryo quality (vacuole-negative group: adjusted OR 1.291; 95% CI: 1.089-1.530; age <38 years: adjusted OR 1.989; 95% CI: 1.692-2.337; good embryo quality: adjusted OR 1.703; 95% CI: 1.405-2.064). The implantation and live birth rates were significantly lower for the transferred single euploid blastocysts with vacuoles than those without (35.5% vs. 56.6%; 29.0% vs. 52.2%, respectively). The live birth rate was positively associated with the absence of vacuoles (adjusted OR 2.792; 95% CI: 1.180-6.608). CONCLUSION(S): The formation of vacuoles in blastocysts is associated with lower rates of euploidy and live birth. Blastocysts without vacuoles should thus be prioritized for embryo transfer in vitro fertilization cycles.

Significantly shortened telomere length and altered androgen receptor level in cumulus cells from women with polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to investigate the correlation between hormone receptor levels and telomere length (TL) in infertile women with and without polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: This prospective cohort study recruited a total of 431 cumulus oocyte complex (COC) from 88 infertile women between July 2012 and June 2014. The participants were divided into three groups: young age (<38 years, n = 42 and 227 COC), advanced age (≥38 years, n = 33 and 107 COC) and PCOS patients (n = 13 and 97 COC). Cumulus cells were collected from individual follicle during oocyte pick-up, and the mRNA levels of hormone receptors and TL were measured using real-time PCR. RESULTS: The cumulus cells of PCOS patients demonstrated lower mRNA levels of LH receptor (75.57 ± 138.10 vs. 171.07 ± 317.68; p < 0.01) and androgen receptor (1.13 ± 1.52 vs. 4.08 ± 9.57; p < 0.01), as well as a shorter TL (2.39 ± 2.58 vs. 3.96 ± 4.72; p < 0.01) compared to those of the young age group. In the young age group, only androgen receptor mRNA level showed a significant association with TL (rho = 0.148, p = 0.026), while FSH receptor mRNA level was the only factor associated with TL (rho = 0.247, p = 0.015) in PCOS patients. For advanced-aged patients, no significant relationship was observed between hormone receptor mRNA levels and TL. Alternative splicing of androgen receptors was identified in some PCOS patients but not in young age controls. CONCLUSION: The findings suggest that the androgen receptor level and function may be altered in the cumulus cells of PCOS patients, leading to a shorter TL in cumulus cells in PCOS patients.

The development of a novel cancer immunotherapeutic platform using tumor-targeting mesenchymal stem cells and a protein vaccine.

An ideal anticancer strategy should target only the malignant cells but spare the normal ones. In this regard, we established a platform, consisting of an antigen-delivering vehicle and a protein vaccine, for developing an immunotherapeutic approach with the potential for eliminating various cancer types. Mesenchymal stem cells (MSCs) have been demonstrated capable of targeting tumors and integrating into the stroma. Moreover, we have developed a protein vaccine PE(ΔIII)-E7-KDEL3 which specifically recognized E7 antigen and elicited immunity against cervical cancer. Taking advantage of tumor-homing property of MSCs and PE(ΔIII)-E7-KDEL3, we used E6/E7-immortalized human MSCs (KP-hMSCs) as an E7 antigen-delivering vehicle to test if this protein vaccine could effectively eliminate non-E7-expressing tumor cells. Animals which received combined treatment of KP-hMSCs and PE(ΔIII)-E7-KDEL3 demonstrated a significant inhibition of tumor growth and lung-metastasis when compared to PE(ΔIII)-E7-KDEL3 only and KP-hMSCs only groups. The efficiency of tumor suppression correlated positively to the specific immune response induced by PE(ΔIII)-E7-KDEL3. In addition, this combined treatment inhibited tumor growth via inducing apoptosis. Our findings indicated that KP-hMSCs could be used as a tumor-targeting device and mediate antitumor effect of PE(ΔIII)-E7-KDEL3. We believe this strategy could serve as a platform for developing a universal vaccine for different cancer types.

Stabilization of AURKA by the E3 ubiquitin ligase CBLC in lung adenocarcinoma.

CBL family proteins (CBL, CBLB and CBLC in mammals) are E3 ubiquitin ligases of protein tyrosine kinases. CBL mediates the lysosomal degradation of activated EGFR through K63-linked ubiquitination, while CBLC has an oncogenic function by positively regulating EGFR activation through K6 and K11-linked ubiquitination in EGFR mutant lung adenocarcinoma (LAD). Here, we used immunoprecipitation and mass spectrometry to study the CBLC interactome, and found that CBLC is also involved in cell cycle regulation by stabilizing Aurora kinase A (AURKA). CBLC interacted with the kinase domain of AURKA and positively regulated the stability of AURKA by conjugating monoubiquitination and K11/K63-linked polyubiquitination, which are protective from degrading K11/K48 polyubiquitination. CBLC depletion markedly decreased the half-life of AURKA in cycloheximide-treated LAD cells. When LAD cells were synchronized with double thymidine block at the G1/S boundary and then released into mitotic arrest, CBLC depletion delayed the accumulation and activation of AURKA and prevented cancer cells from entering mitosis. CBLC deficiency significantly delayed cell cycle progression, reduced the mitotic population, and increased apoptosis of LAD cells. Targeting CBLC inhibited tumor growth of LAD cells and enhanced their sensitivity to paclitaxel in xenograft models. Immunohistochemical staining of the tissue microarray also revealed a positive correlation between the expression of CBLC and AURKA in normal and LAD tissues, further supporting the positive regulation of AURKA expression by CBLC. In summary, these findings indicate that the oncogenic E3 ligase CBLC plays a role in mitotic entry by stabilizing AURKA via ubiquitination in LAD. This work demonstrates that targeting CBLC combined with paclitaxel might be a potential option for the treatment of LAD patients who have no available targeted therapies.

Discharge and photo-luminance properties of a parallel plates electron emission lighting device.

The gas discharge and photo-luminance properties of a planar lighting source featuring highly uniform light emission and mercury-free design were studied. The current density-voltage characteristics and the associated gas discharge of the devices operating with the values of the ratio of electric field to gas pressure (E/p) between 4.3 kV/Torr-cm and 35.7 kV/Torr-cm indicate that the width of the cathode fall extends over the entire gap between the two electrodes and the device is mostly in the obstructed discharge regime. The optical emission analysis confirmed the electron collision-induced gas emissions and strong effect of gas pressure on the phosphor emission when operated at constant current density, both are indicative of the primary roles played by the electron energy.

Prevalence and psychiatric comorbidity of self-reported electromagnetic field sensitivity in Taiwan: a population-based study.

BACKGROUND/PURPOSE: Psychological factors have been implicated in the etiology of idiopathic environmental illness in many studies. Few studies have ever reported psychiatric morbidity among individuals with electromagnetic hypersensitivity. We aimed to estimate the prevalence and identify the associated factors of self-reported electromagnetic field sensitivity (SREMFS) in adults of Taiwan. METHODS: A total of 1251 adults selected from a nationwide Computer-Assisted Telephone Interviewing system received a telephone survey about the perception of risk from various environmental agents and their effects on health and well-being. RESULTS: The estimated prevalence of people with SREMFS was 13.3 % (95% confidence interval: 11.2-15.3). People aged >65 years were associated with a lower risk of reporting sensitivity to electromagnetic fields, whereas people with a very poor self-reported health status, those who were unable to work, and those who had psychiatric morbidity were associated with a higher risk of having SREMFS. CONCLUSION: The prevalence of SREMFS in the general population of Taiwan is higher than that reported in western countries. People with psychiatric morbidity are more likely to report sensitivity to electromagnetic fields. The cross-sectional design precludes the causal inference of all identified correlates and electromagnetic field sensitivity.

Pharmacology, Toxicity, Bioavailability, and Formulation of Magnolol: An Update.

Magnolol (MG) is one of the primary active components of Magnoliae officinalis cortex, which has been widely used in traditional Chinese and Japanese herbal medicine and possesses a wide range of pharmacological activities. In recent years, attention has been drawn to this component due to its potential as an anti-inflammatory and antitumor drug. To summarize the new biological and pharmacological data on MG, we screened the literature from January 2011 to October 2020. In this review, we provide an actualization of already known anti-inflammatory, cardiovascular protection, antiangiogenesis, antidiabetes, hypoglycemic, antioxidation, neuroprotection, gastrointestinal protection, and antibacterial activities of MG. Besides, results from studies on antitumor activity are presented. We also summarized the molecular mechanisms, toxicity, bioavailability, and formulations of MG. Therefore, we provide a valid cognition of MG.

Azelnidipine and amlodipine: a comparison of their effects and safety in a randomized double-blinded clinical trial in Chinese essential hypertensive patients.

The purpose of this study is to compare the effects and safety of azelnidipine and amlodipine in Chinese essential hypertensive patients. Patients were randomized to receive administration of azelnidipine 8-16 mg/day or amlodipine 2.5-5 mg/day for 8 weeks. The blood pressure and pulse rate were evaluated in an outpatient clinic and by ambulatory blood pressure monitoring. There were 220 patients enrolled to the study. The blood pressure in both groups was decreased significantly (P < 0.001). Compared with amlodipine, the patients received azelnidipine had better response in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (P < 0.01). No significant changes of pulse rate were observed in either group. For the ambulatory blood pressure monitoring, both drugs had stable anti-hypertensive effects over 24 h. The trough/peak ratios of DBP for the azelnidipine and amlodipine groups were, respectively, 46% and 40%. Adverse events occurred at 7.3% and 10.0%, respectively in the azelnidipine and amlodipine groups (P = 0.485). Headache and dizziness were observed at an incidence of more than 1% in both groups. Once-daily administration of azelnidipine effectively controlled blood pressure and had a stable action over 24 h. Azelnidipine had good safety and compliance similar to amlodipine.

Cell Type-Specific Gene Network-Based Analysis Depicts the Heterogeneity of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neuropsychiatric disorder characterized by substantial heterogeneity. To identify the convergence of disease pathology on common pathways, it is essential to understand the correlations among ASD candidate genes and study shared molecular pathways between them. Investigating functional interactions between ASD candidate genes in different cell types of normal human brains may shed new light on the genetic heterogeneity of ASD. Here we apply cell type-specific gene network-based analysis to analyze human brain nucleus gene expression data and identify cell type-specific ASD-associated gene modules. ASD-associated modules specific to different cell types are relevant to different gene functions, for instance, the astrocytes-specific module is involved in functions of axon and neuron projection guidance, GABAergic interneuron-specific modules are involved in functions of postsynaptic membrane, extracellular matrix structural constituent, and ion transmembrane transporter activity. Our findings can promote the study of cell type heterogeneity of ASD, providing new insights into the pathogenesis of ASD. Our method has been shown to be effective in discovering cell type-specific disease-associated gene expression patterns and can be applied to other complex diseases.

Cell Type-Specific Predictive Models Perform Prioritization of Genes and Gene Sets Associated With Autism.

Bulk transcriptomic analyses of autism spectrum disorder (ASD) have revealed dysregulated pathways, while the brain cell type-specific molecular pathology of ASD still needs to be studied. Machine learning-based studies can be conducted for ASD, prioritizing high-confidence gene candidates and promoting the design of effective interventions. Using human brain nucleus gene expression of ASD and controls, we construct cell type-specific predictive models for ASD based on individual genes and gene sets, respectively, to screen cell type-specific ASD-associated genes and gene sets. These two kinds of predictive models can predict the diagnosis of a nucleus with known cell type. Then, we construct a multi-label predictive model for predicting the cell type and diagnosis of a nucleus at the same time. Our findings suggest that layer 2/3 and layer 4 excitatory neurons, layer 5/6 cortico-cortical projection neurons, parvalbumin interneurons, and protoplasmic astrocytes are preferentially affected in ASD. The functions of genes with predictive power for ASD are different and the top important genes are distinct across different cells, highlighting the cell-type heterogeneity of ASD. The constructed predictive models can promote the diagnosis of ASD, and the prioritized cell type-specific ASD-associated genes and gene sets may be used as potential biomarkers of ASD.