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Objective: To explore the microstructural damage of white matter in acute diquat (DQ) poisoning patients using diffusion kurtosis imaging (DKI) and Tract-based Spatial Statistics (TBSS)., Methods: This study included 19 DQ poisoning patients and 19 age-matched controls. MRI was performed using a 3.0 T Philips Achieva scanner with sequences including 3D T1WI, T2WI, DWI, 3D T2WI-FLAIR, and DKI (3 b-values, 15 directions). DICOM to NIFTI image form conversion was done using MRIcron's Dcm2niigui, followed by motion and eddy current correction with FSL to create a brain mask. Scalar indicators (MK, AK, RK, FAK) were calculated with DKE software. TBSS was used for spatial normalization, skeletonization, and projection of DKI indices for group analysis with TFCE for multiple comparison correction (P < 0.025)., Results: After the screening and enrollment process, 19 DQ-poisoned patients and 19 healthy volunteers were analyzed. No significant age or sex differences were found between groups. For Mean Kurtosis (MK), the right corticospinal tract showed a significant difference with a mean difference of 0.21 (95 % CI: 0.15-0.27) and P = 0.000503. Axial Kurtosis (AK) in the left superior longitudinal fasciculus had a mean difference of 0.18 (95 % CI: 0.12-0.24) and P = 0.0024. Fractional Anisotropy of Kurtosis (FAK) in the right corticospinal tract showed a mean difference of 0.19 (95 % CI: 0.13-0.25) and P = 0.0000318. Axial Kurtosis (AK) positively correlated with blood drug levels (r = 0.52, P < 0.05). Seven patients developed subcortical leukodystrophy, mainly in the frontal parietal lobe, with possible insular lobe involvement., Conclusions: DQ poisoning primarily damages the right corticospinal tract, right cingulate gyrus, and left superior longitudinal fasciculus, potentially causing movement and visual impairments. The injury involves demyelination and axonal degeneration, with asymmetrical damage between hemispheres. The left superior longitudinal fasciculus injury is dose-dependent, and unlike prior studies, dopaminergic nuclei were unaffected. The frontal parietal lobe is predominantly affected, with some insular lobe involvement in DQ poisoning patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The occurrence of suspended cords of the left atrium (SCLA) is rare and has seldom been described. The purpose of this study was to summarize the cases of SCLA accidentally detected by coronary CT angiography (CCTA), describe their imaging features, conduct a preliminary analysis of their clinical significance, and review relevant literature., Methods: A total of 10,796 patients who underwent CCTA examinations from July 2020 to November 2021 were consecutively selected. The original and three-dimensional reconstruction images were reviewed to identify patients with SCLA. A control group was selected in a 1:2 ratio based on age, BMI, sex, and education level. The imaging characteristics and clinical data of the two groups were collected and compared. The case group was divided into two subgroups based on the starting and ending positions of the SCLA: Group 1 with the SCLA between the free wall and free wall, and Group 2 with the SCLA between the septum wall and free wall. The clinical features of these subgroups were compared. Furthermore, a review of literature on SCLA published in the past fifteen years that includes its clinical and imaging features was conducted., Results: In this study, a total of 35 patients were found to have SCLA, resulting in an incidence rate of approximately 0.32%. After excluding 1 patient for whom clinical features could not be obtained, the case group included a total of 18 males and 16 females, with a male-to-female ratio of 1:1 and a median age of 57.00 (52.00-64.00) years. It was found that 19 (55.88%) cases of SCLA were located near the right superior pulmonary vein ostia, while no SCLA was found near the left lower pulmonary vein orifice. A significant difference in the incidence of atrial arrhythmia between the two groups was observed (p = 0.009). Additionally, 3 patients (8.82%) in the SCLA group had a history of transient cerebral ischemic attack (TIA), which was significantly different from that in the control group (p = 0.035). The anteroposterior and transverse diameters of the left atrium were longer in the case group than in the control group (p < 0.05), but there was no significant change in left atrial volume. Subgroup analyses found no significant difference in the incidence of cerebral infarction, atrial arrhythmia, or other intracardiac structural malformations, although there was a significant difference in cord length (p = 0.013), with the length of SCLA in Group 1 and Group 2 being 2.64 ± 0.99 cm and 3.39 ± 0.68 cm, respectively. Notably, only 1 of these 34 patients was diagnosed based on echocardiography, whereas all cases were perfectly visualized using CCTA., Conclusion: SCLA is rare. CCTA can accurately detect and depict this abnormal structure as compared to echocardiography. SCLA may be linked to a higher incidence of atrial arrhythmias or transient ischemic attacks. It is important for radiologists and cardiovascular experts to recognize this structure, and further investigation is necessary to determine its clinical significance., (© 2024. The Author(s).)

In this work, magnetic molecularly imprinted polymers (MIPs) for specific recognition of Hydroxytyrosol (HT) were designed by vinyl-modified magnetic particles (Fe 3 O 4 @SiO 2 @VTEOs) as carrier, ternary deep eutectic solvent (DES) as functional monomer, while ethylene glycol dimethacrylate (EGDMA) as crosslinker. The optimum amount of DES was obtained by adsorption experiments (molar ratio, caffeic acid: choline chloride: formic acid = 1:6:3) which were 140 μL in total. Under the optimized amount of DES, the maximum adsorption capacity of the MIPs particles was 42.43 mg g -1 , which was superior to non-imprinted polymer (4.64 mg g -1 ) and the imprinting factor (IF) is 9.10. Syringin and Oleuropicrin were used as two reference molecules to test the selectivity of the DES-MIPs particles. The adsorption capacity of HT was 40.11 mg g -1 . Three repeated experiments show that the polymer has high stability and repeatability (RSD = 5.50)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Despite numerous advances in our understanding of zebrafish cardiac regeneration, an aspect that remains less studied is how regenerating cardiomyocytes invade, and eventually replace, the collagen-containing fibrotic tissue following injury. Here, we provide an in-depth analysis of the process of cardiomyocyte invasion using live-imaging and histological approaches. We observed close interactions between protruding cardiomyocytes and macrophages at the wound border zone, and macrophage-deficient irf8 mutant zebrafish exhibited defects in extracellular matrix (ECM) remodeling and cardiomyocyte protrusion into the injured area. Using a resident macrophage ablation model, we show that defects in ECM remodeling at the border zone and subsequent cardiomyocyte protrusion can be partly attributed to a population of resident macrophages. Single-cell RNA-sequencing analysis of cells at the wound border revealed a population of cardiomyocytes and macrophages with fibroblast-like gene expression signatures, including the expression of genes encoding ECM structural proteins and ECM-remodeling proteins. The expression of mmp14b , which encodes a membrane-anchored matrix metalloproteinase, was restricted to cells in the border zone, including cardiomyocytes, macrophages, fibroblasts, and endocardial/endothelial cells. Genetic deletion of mmp14b led to a decrease in 1) macrophage recruitment to the border zone, 2) collagen degradation at the border zone, and 3) subsequent cardiomyocyte invasion. Furthermore, cardiomyocyte-specific overexpression of mmp14b was sufficient to enhance cardiomyocyte invasion into the injured tissue and along the apical surface of the wound. Altogether, our data shed important insights into the process of cardiomyocyte invasion of the collagen-containing injured tissue during cardiac regeneration. They further suggest that cardiomyocytes and resident macrophages contribute to ECM remodeling at the border zone to promote cardiomyocyte replenishment of the fibrotic injured tissue.

The transition from paraquat (PQ) to diquat (DQ), both organic dication herbicides, in China has led to significant increases in the number of acute DQ poisoning cases. Case studies have shown that acute DQ poisoning resulted in injury to the central nervous system (CNS), but the mechanism underlying the injury remains to be explored. The present study aimed to investigate how DQ influenced purinergic signaling between astrocytes and microglia and whether extracellular ATP (eATP) was involved in promoting neuroinflammation induced by acute DQ toxicity through the activation of the P2X4/NLRP3 signaling pathway. We constructed a rat model of acute DQ toxicity to observe the pathological changes in hippocampal tissues after DQ exposure and measure the expression levels of IL-1β and TNF-α in the hippocampal tissue. We also established an in vitro co-culture model of C6 astrocytes and BV-2 microglia using transwell chambers, measured the amount of eATP secreted into C6 astrocytes after DQ treatment, and assessed the inflammatory response and changes in the P2X4/NLRP3 signaling pathway in BV-2 microglia. The results showed that the neurons in the hippocampal tissue of rats exhibited loose arrangement, nuclear consolidation, and necrosis after DQ exposure, and IL-1β and TNF-α levels were signification higher in the hippocampal tissue after DQ exposure. DQ exposure to the co-cultured cells induced an increase in ATP secretion from C6 astrocytes as well as a significant increase of P2X4, NLRP3, IL-1β, and IL-18 expression in BV-2 microglia. In contrast, pretreatment of C6 astrocytes with apyrase (an ATP hydrolase) resulted in a significant decrease of P2X4, NLRP3, IL-1β, and IL-18 expression in BV-2 microglia. Furthermore, inhibition of P2X4 expression in BV-2 microglia by transfection with si-P2X4 effectively reversed the increase of NLRP3, IL-1β, and IL-18 in BV-2 microglia induced by DQ when co-cultured with C6 astrocytes. These results indicate that astrocytes can activate the P2X4/NLRP3 signaling pathway in microglia through the DQ-induced extracellular release of ATP to promote neuroinflammation in rat hippocampal tissue., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ozone pollution has been associated with several adverse effects, including memory impairment, intellectual retardation, emotional disturbances. However, the potential mechanisms remain uncertain. The present study aimed to investigate whether ozone (O 3 ) regulates synaptic plasticity through PI3K/Akt/GSK3β signaling pathway and induces neurobehavioral modifications among the young rats. In vivo, the newborn rats were used to construct the animal model of early postnatal O 3 treatment. In vitro, this study measured the effect of different concentrations of serum from O 3 treated rats on the viability of the PC12 cells, and investigated the modifications of synaptic plasticity and PI3K/Akt/GSK3β signaling pathway in the hippocampus and PC12 cells after O 3 treated. The results revealed significant depression-like behavior and increased hippocampal histopathological damage in the young rats after O 3 treated. Compared with the control group, the expression levels of synaptic related proteins including Drebrin, PSD95, Synaptophysin and PIK3R1, p-Akt, and p-GSK3β were decreased in the O 3 treated group. In vitro assays, a significant reduction in Drebrin, PSD95, Synaptophysin, PIK3R1, p-Akt, and p-GSK3β was found in PC12 cells after O 3 serum treated. While 740Y-P (a specific PI3K activator) administered, the expression levels of Drebrin, PSD95, Synaptophysin, PIK3R1, p-Akt, and p-GSK3β in the 740Y-P + O 3 group were significantly elevated in vivo and vitro compared with the O 3 -only group. In addition, miRNAs modulating PIK3R1 were screened on bioinformatics website, the study found aberrant expression of miR-221-3p in the hippocampus and serum of O 3 treated group. Inhibition of miR-221-3p expression effectively reversed the reduction of Drebrin, PSD95, Synaptophysin, PIK3R1, p-Akt, and p-GSK3β in PC12 cells induced by O 3 treatment. Altogether, these studies indicate that O 3 restrained the expression of PI3K/Akt/GSK3β signaling pathway and impaired synaptic plasticity that resulted in depressive-like behavior in young rats. Moreover, miR-221-3p plays an important role in this procedure by regulating PIK3R1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the effects of acute paraquat (PQ) exposure on the phenotypic polarization of hippocampal microglia and its mechanism., Methods: An acute PQ exposure rat model was established. Male SD rats were exposed to 0, 5, 25, and 50 mg/kg PQ, and brain hippocampal tissue was collected after 1, 3, and 7 days of exposure, respectively. Hippocampal pathological changes were examined by H&E staining, and immunohistochemistry (IHC) was used to detect changes in the number of Iba-1-positive cells, the average number of endpoints, and the average process length. The protein expression of Iba-1 was detected by western blotting. BV-2 microglia were treated with 0, 0.01, 0.025, 0.05, or 0.1 μmol/L PQ for 24 h. ELISA and western blotting assays were performed to detect the expression of TNF-α and IL-1β in vivo and in vitro. The M1 microglia marker iNOS, the M2 microglia marker Arg-1, and the p-JAK2 and p-STAT3 protein were detected by western blotting. JAK2/STAT3 pathway activation role in regulating microglia phenotypic polarization was further validated in vivo and in vitro by JAK2-specific inhibitor AG490 administration., Results: After acute PQ exposure, hippocampal neurons showed pathological changes such as loose arrangement and nuclear pyknosis, the number of Iba-1 positive cells and the expression of Iba-1 protein increased, and the average number of endpoints and average process length of microglia decreased. Histological examination revealed that compared with the control group, in the 50 mg/kg PQ group on the 3rd and 7th day, the expression of TNF-α, IL-1β, and iNOS significantly increased, while that of Arg-1 significantly decreased. p-JAK2 and p-STAT3 expression significantly increased in the 50 mg/kg PQ group on the 1st, 3rd, and 7th day. In vitro, compared with the control group, the expression of TNF-α, IL-1β, iNOS, p-JAK2, and p-STAT3 significantly increased, while Arg-1 expression was significantly reduced in the 0.025, 0.05, and 0.1 μmol/L PQ groups. After AG490 administration, the expression levels of p-JAK2, p-STAT3, iNOS, TNF-α, and IL-1β in the AG490 +PQ group were significantly inhibited in vivo and in vitro compared with the PQ-only group. On the contrary, Arg-1 expression was significantly increased., Conclusion: Our results suggest that acute PQ exposure may induce M1-type polarization of hippocampal microglia by activating the JAK2/STAT3 pathway, which in turn releases pro-inflammatory factors such as TNF-α and IL-1β, leading to hippocampal inflammatory damage., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Inner ear vestibular and spiral ganglion neurons (VGNs and SGNs) are known to play pivotal roles in balance control and sound detection. However, the molecular mechanisms underlying otic neurogenesis at early embryonic ages have remained unclear. Here, we use single-cell RNA sequencing to reveal the transcriptomes of mouse otic tissues at three embryonic ages, embryonic day 9.5 (E9.5), E11.5, and E13.5, covering proliferating and undifferentiated otic neuroblasts and differentiating VGNs and SGNs. We validate the high quality of our studies by using multiple assays, including genetic fate mapping analysis, and we uncover several genes upregulated in neuroblasts or differentiating VGNs and SGNs, such as Shox2, Myt1, Casz1, and Sall3. Notably, our findings suggest a general cascaded differentiation trajectory during early otic neurogenesis. The comprehensive understanding of early otic neurogenesis provided by our study holds critical implications for both basic and translational research., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The toxicity of the bipyridine cationic herbicide paraquat (PQ) to the lung and kidneys has been widely documented, but the acute toxic effects of PQ on the nervous system have received little attention. This study aimed to explore the changes in the phenotypic differentiation of microglia in rats caused by acute PQ exposure. As results, acute PQ exposure induced pyknosis, edema, and apoptosis in substantia nigra neurons. Immunohistochemistry and western blotting showed that, on day 18, with the increase of exposure dose, the number of Iba-1-positive cells presented an increasing trend with no statistically significant difference among the groups (P > 0.05). Compared with the control group, the process length of Iba-1-positive cells decreased of acute 25 mg/kg PQ exposure on day 18 (P < 0.05). Compared with the control group, on day 39, the number of Iba-1-positive cells in the SN decreased of acute 25 mg/kg PQ exposure, while that increased of acute 45 mg/kg PQ exposure (P < 0.05). The number of endpoints decreased of acute 25 mg/kg PQ exposure (P < 0.05). The process length became shorter both of acute 25 mg/kg and 45 mg/kg PQ exposure (P < 0.05). On day 69, compared with the control group, the number of Iba-1-positive cells in the SN significantly increased of acute 45 mg/kg PQ exposure (P < 0.05). The number of endpoints increased and the process length became longer of acute 25 mg/kg PQ exposure (P < 0.05). Then, the mean fluorescence intensity of inducible nitric oxide synthase (iNOS) and arginine 1 (ARG1) was compared. The number of the M1 phenotype of microglia increased during the early stage of acute 25 mg/kg PQ exposure, whereas the number of the M2 phenotype of microglia increased during the early stage of acute 45 mg/kg PQ exposure (P < 0.05). On day 39, compared with the control group, the expression of iNOS in the SN of acute 45 mg/kg PQ exposure increased than of acute 25 mg/kg exposure. The expression of Arg-1 of 25 mg/kg PQ exposure was significantly increased (P < 0.05). On day 69, the expression of iNOS and ARG1 increased in the 25 and 45 mg/kg PQ exposure groups. In summary, changes in microglia phenotypic differentiation were related to exposure dose and exposure time (P < 0.05)., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Backgroud: Present electrocardiogram (ECG) criteria for diagnosing left ventricular hypertrophy (LVH) usually have low sensitivity, while the newly proposed SD + SV4 criterion, namely the deepest S-wave amplitude in any lead (SD) plus SV4 amplitude, has been reported to have higher sensitivity and accuracy compared with other existing criteria. We aimed to further evaluate the diagnostic value of the SD + SV4 criterion in reference to the gold standard cardiac magnetic resonance imaging (CMR) in LVH diagnosis., Methods: This retrospective study enrolled 138 patients who received CMR examination-60 patients with reduced ejection fraction (EF) and 78 patients with preserved EF. The left ventricular mass index (LVMI) measured by CMR was used as the gold standard for diagnosing LVH., Result: The diagnostic value of the SD + SV4 criterion was compared with other 4 commonly used criteria. By CMR, 29 out of 138 people (21%) were diagnosed with LVH in reference to CMR. The SD + SV4 criterion had markedly higher sensitivity in diagnosing LVH compared with other criteria, but no higher specificity. There was no significant difference in area under receiver operating characteristic (ROC) curve among these criteria. The SD + SV4 criterion was not markedly consistent with CMR in diagnosing LVH. Compared to the other criteria, the SD + SV4 criterion had the highest sensitivity in patients with reduced ejection fraction; however, the area under the curve (AUC) of the SD + SV4 criterion in patients with reduced EF was significantly lower than in patients with preserved EF., Conclusion: The newly proposed SD + SV4 criterion did not have a better diagnostic value compared with other existing criteria, and the statistical power of the SD + SV4 criterion was influenced by EF., (© 2020 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)

Background: Transverse myelitis (TM) is due to inflammatory spinal cord injury with bilateral neurologic involvement, which is sensory, motor, or autonomic in nature. It may be associated with autoimmune disease, vaccination, intoxication and infections. The most common infection cause of TM is Coxsackie virus and Mycoplasma pneumoniae. The cryptococcosis is rare. We present the case of disseminated cryptococcosis revealed by transverse myelitis in an immunocompetent 55-year-old male patient. The literature review is also stated., Case Presentation: The 55-year-old man suffered from gradual numbness, weakness in both lower limbs and finally paralyzed in the bed. The thoracic spine Computed tomography (CT) was normal, but multiple nodules in the lung were accidentally discovered. Thoracic Magnetic Resonance Imaging (MRI) showed diffused thoracic spinal cord thickening and extensively intramedullary T2 hyper intensity areas. Gadolinium contrast enhanced T1WI showed an intramedullary circle-enhanced nodule at 9th thoracic level. Diagnosis was made by histological examination of the bilateral lung biopsy. The patient was treated successfully with systemic amphotericin B liposome and fluconazole and intrathecal dexamethasone and amphotericin B liposome., Conclusions: This is a patient with disseminated cryptococcosis involving the lung, spinal cord and adrenal glands, which is rare in the absence of immunodeficiency.

Exfoliation and dispersion of boron nitride nanosheets (BNNSs) is the key to achieving desired reinforcing effects for ordinary Portland cement (OPC). Few studies exist, however, of the dispersion of BNNSs in a cement-induced alkaline environment and their effect on the mechanical properties of normal OPC paste. In this study, protocols were developed to prepare BNNS-reinforced OPC paste. Ultrasonication was used to exfoliate BNNSs from h-BN in water based suspensions. The addition of surfactants in the suspension was found to hinder the exfoliation of the BNNSs. The surfactants were, however, found to be essential for the dispersion of the BNNSs in pore solution. Among the three surfactants used in this study, polycarboxylate based superplasticizer was most suitable as it maintained over 40% of the BNNSs stable in the pore solution for 4 hours and increased the hydration flow peak over 20%. Atomic force microscopy results indicated that the thickness of the BNNSs was mostly under 10 nm. With the addition of 0.003 wt% BNNSs, the compressive and tensile strengths of the cement were increased by 13% and 8%, respectively. Besides the nucleation effect as indicated by hydration heat, pore structure refinement and chemical bonding were also found as the main reinforcing mechanisms of BNNSs in OPC matrix.

Aims: Patients with unexplainable giant T-wave inversion in the precordial leads and apical wall thickness <15 mm have been reported. These patients cannot be diagnosed as apical hypertrophic cardiomyopathy (AHCM) according to the current criteria. The objective of this study was to evaluate the apical morphological features of this type of patients using cardiac magnetic resonance., Methods and Results: Institutional ethics approval and written informed consent were obtained. A total of 60 subjects with unexplainable giant T-wave inversion and 76 healthy volunteers were prospectively enrolled in the study. The segmented left ventricular (LV) wall thickness was measured according to the American Heart Association 17-segmented model. The apical angle (apA) as well as the regional variations in LV wall thickness was analysed. Considerable variation in LV wall thickness in normals was observed with progressive thinning from the base to apex (male and female, P < 0.01). The apical thickness of subjects with giant T-wave inversion was 8.10 ± 1.67 mm in male, which is thicker than that of controls (4.14 ± 1.17 mm, P < 0.01). In female, the apical thickness was also significantly different from controls (5.85 ± 2.16 vs. 2.99 ± 0.65 mm, P < 0.01). Compared with normals, the apA decreased significantly in male (87.44 ± 13.86 vs.115.03 ± 9.90°, P < 0.01) and female (90.69 ± 8.84 vs. 110.07 ± 13.58°, P < 0.01) subjects, respectively., Conclusion: Although the absolute thickness of apical wall was below the current diagnostic criteria of AHCM, the apical morphological features of subjects with unexplainable giant T-wave inversion were significantly different from normals. Whether these subjects should be included into a preclinical scope of AHCM needs further investigations., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: Ventricular septal defects (VSDs) constitute the most prevalent congenital heart disease (CHD), occurs either in isolation (isolated VSD) or in combination with other cardiac defects (complex VSD). Copy number variation (CNV) has been highlighted as a possible contributing factor to the etiology of many congenital diseases. However, little is known concerning the involvement of CNVs in either isolated or complex VSDs., Methods: We analyzed 154 unrelated Chinese individuals with VSD by chromosomal microarray analysis. The subjects were recruited from four hospitals across China. Each case underwent clinical assessment to define the type of VSD, either isolated or complex VSD. CNVs detected were categorized into syndrom related CNVs, recurrent CNVs and rare CNVs. Genes encompassed by the CNVs were analyzed using enrichment and pathway analysis., Results: Among 154 probands, we identified 29 rare CNVs in 26 VSD patients (16.9 %, 26/154) and 8 syndrome-related CNVs in 8 VSD patients (5.2 %, 8/154). 12 of the detected 29 rare CNVs (41.3 %) were recurrently reported in DECIPHER or ISCA database as associated with either VSD or general heart disease. Fifteen genes (5 %, 15/285) within CNVs were associated with a broad spectrum of complicated CHD. Among these15 genes, 7 genes were in "abnormal interventricular septum morphology" derived from the MGI (mouse genome informatics) database, and nine genes were associated with cardiovascular system development (GO:0072538).We also found that these VSD-related candidate genes are enriched in chromatin binding and transcription regulation, which are the biological processes underlying heart development., Conclusions: Our study demonstrates the potential clinical diagnostic utility of genomic imbalance profiling in VSD patients. Additionally, gene enrichment and pathway analysis helped us to implicate VSD related candidate genes.

Primary ovarian insufficiency (POI), also known as premature ovarian failure (POF), is defined as more than six months of cessation of menses before the age of 40 years, with two serum follicle stimulating hormone (FSH) levels (at least 1 month apart) falling in the menopause range. The cause of POI remains undetermined in the majority of cases, although some studies have reported increased levels of reactive oxygen species (ROS) in idiopathic POF. The role of mitochondrial DNA in the pathogenesis of POI has not been studied extensively. This aim of this study was to uncover underlying mitochondrial genetic defects in patients with POI. The entire region of the mitochondrial genome was amplified in subjects with idiopathic POI (n=63) and age-matched healthy female controls (n=63) using nine pair sets of primers, followed by screening of the mitochondrial genome using an Illumina MiSeq. We identified a total of 96 non-synonymous mitochondrial variations in POI patients and 93 non-synonymous variations in control subjects. Of these, 21 (9 in POI and 12 in control) non-synonymous variations had not been reported previously. Eight mitochondrial cytochrome coxidase 1 (MT-CO1) missense variants were identified in POI patients, whereas only four missense mutations were observed in controls. A high incidence of MT-CO1 missense variants were identified in POI patients compared with controls, and the difference between the groups was statistically significant (13/63 vs. 5/63, p=0.042). Our results show that patients with primary ovarian insufficiency exhibit an increased incidence of mitochondrial cytochrome c oxidase 1 gene mutations, suggesting that MT-CO1 gene mutation may be causal in POI.

Background: Infantile spasms (IS) is a specific type of epileptic encephalopathy associated with severe developmental disabilities. Genetic factors are strongly implicated in IS, however, the exact genetic defects remain unknown in the majority of cases. Rare mutations in a single gene or in copy number variants (CNVs) have been implicated in IS of children in Western countries. The objective of this study was to dissect the role of copy number variations in Chinese children with infantile spasms., Methods: We used the Agilent Human Genome CGH microarray 180 K for genome-wide detection of CNVs. Real-time qPCR was used to validate the CNVs. We performed genomic and medical annotations for individual CNVs to determine the pathogenicity of CNVs related to IS., Results: We report herein the first genome-wide CNV analysis in children with IS, detecting a total of 14 CNVs in a cohort of 47 Chinese children with IS. Four CNVs (4/47 = 8.5%) (1q21.1 gain; 1q44, 2q31.1, and 17p13 loss) are considered to be pathogenic. The CNV loss at 17p13.3 contains PAFAH1B1 (LIS1), a causative gene for lissencephaly. Although the CNVs at 1q21.1, 1q44, and 2q23.1 have been previously implicated in a wide spectrum of clinical features including autism spectrum disorders (ASD) and generalized seizure, our study is the first report identifying them in individuals with a primary diagnosis of IS. The CNV loss in the 1q44 region contains HNRNPU, a strong candidate gene recently suggested in IS by the whole exome sequencing of children with IS. The CNV loss at 2q23.1 includes MBD5, a methyl-DNA binding protein that is a causative gene of ASD and a candidate gene for epileptic encephalopathy. We also report a distinct clinical presentation of IS, microcephaly, intellectual disability, and absent hallux in a case with the 2q23.1 deletion., Conclusion: Our findings strongly support the role of CNVs in infantile spasms and expand the clinical spectrum associate with 2q23.1 deletion. In particular, our study implicates the HNRNPU and MBD5 genes in Chinese children with IS. Our study also supports that the molecular mechanisms of infantile spasms appear conserved among different ethnic backgrounds.

Paraquat (PQ) is a common herbicide and PQ poisoning is a major medical problem in Asia. However, few studies have focused on the acute neurotoxic changes caused by PQ. Here we report the acute neurotoxicological findings of rats treated with lethal dose of PQ. In substantia nigra (SN) and striatum we found obvious microglia (labeled by Iba-1) activation within one week. In SN and hippocampus, we detected increased oxidative stress in the neurons based on NeuN/8-OHdG immunofluorescence double labeling and laser cofocal microscopy. Moreover, we provided ultrastructural evidences of astrocyte edema and neurons apoptosis in rat brain by electron microscopy. Further studies will be needed with non-lethal dose of PQ to confirm these results and demonstrate the direct CNS toxicity of PQ., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Paraquat (PQ) is an organic heterocyclic herbicide that is widely used throughout the world. Epidemiological and neuropathological studies have shown that chronic exposure to PQ increases the risk of Parkinson's disease. Patients with acute PQ poisoning show damage to the lungs, liver, and kidneys, and some also show symptoms of central nervous system (CNS) toxicity. However, few studies have focused on the acute neurotoxic changes caused by PQ. Dynamic pathological changes in the human brain cannot be explored in animal models. Thus, to elucidate the impact of acute PQ poisoning on the CNS, neuroimaging studies of poisoned victims, and especially survivors, should be performed. This study reports the first application of magnetic resonance imaging (MRI) techniques on patients with acute PQ poisoning, including survivors. We found significant abnormal signals in the brains of two patients during the acute post-poisoning phase. Using susceptibility weighted imaging (SWI), we documented changes in the corrected phase values for the extrapyramidal ganglia of survivors, and these values correlate with excessive iron deposition. Our diffusion tensor imaging (DTI) results were suggestive of microstructural changes in the extrapyramidal ganglia and hippocampus after PQ poisoning. These neuroimaging results provide an indirect demonstration that acute PQ neurotoxicity exerts a sustained effect during the acute and recovery stages of poisoning., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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It is particularly meaningful to investigate natural selection in African Americans (AfA) due to the high mortality their African ancestry has experienced in history. In this study, we examined 491,526 autosomal single nucleotide polymorphisms (SNPs) genotyped in 5210 individuals and conducted a genome-wide search for selection signals in 1890 AfA. Several genomic regions showing an excess of African or European ancestry, which were considered the footprints of selection since population admixture, were detected based on a commonly used approach. However, we also developed a new strategy to detect natural selection both pre- and post-admixture by reconstructing an ancestral African population (AAF) from inferred African components of ancestry in AfA and comparing it with indigenous African populations (IAF). Interestingly, many selection-candidate genes identified by the new approach were associated with AfA-specific high-risk diseases such as prostate cancer and hypertension, suggesting an important role these disease-related genes might have played in adapting to a new environment. CD36 and HBB, whose mutations confer a degree of protection against malaria, were also located in the highly differentiated regions between AAF and IAF. Further analysis showed that the frequencies of alleles protecting against malaria in AAF were lower than those in IAF, which is consistent with the relaxed selection pressure of malaria in the New World. There is no overlap between the top candidate genes detected by the two approaches, indicating the different environmental pressures AfA experienced pre- and post-population admixture. We suggest that the new approach is reasonably powerful and can also be applied to other admixed populations such as Latinos and Uyghurs.

Genetic studies of Tibetans, an ethnic group with a long-lasting presence on the Tibetan Plateau which is known as the highest plateau in the world, may offer a unique opportunity to understand the biological adaptations of human beings to high-altitude environments. We conducted a genome-wide study of 1,000,000 genetic variants in 46 Tibetans (TBN) and 92 Han Chinese (HAN) for identifying the signals of high-altitude adaptations (HAAs) in Tibetan genomes. We discovered the most differentiated variants between TBN and HAN at chromosome 1q42.2 and 2p21. EGLN1 (or HIFPH2, MIM 606425) and EPAS1 (or HIF2A, MIM 603349), both related to hypoxia-inducible factor, were found most differentiated in the two regions, respectively. Strong positive correlations were also observed between the frequency of TBN-dominant haplotypes in the two gene regions and altitude in East Asian populations. Linkage disequilibrium and further haplotype network analyses of world-wide populations suggested the antiquity of the TBN-dominant haplotypes and long-term persistence of the natural selection. Finally, a "dominant haplotype carrier" hypothesis could describe the role of the two genes in HAA. All of our population genomic and statistical analyses indicate that EPAS1 and EGLN1 are most likely responsible for HAA of Tibetans. Interestingly, one each but not both of the two genes were also identified by three recent studies. We reanalyzed the available data and found the escaped top signal (EPAS1) could be recaptured with data quality control and our approaches. Based on this experience, we call for more attention to be paid to controlling data quality and batch effects introduced in public data integration. Our results also suggest limitations of extended haplotype homozygosity-based method due to its compromised power in case the natural selection initiated long time ago and particularly in genomic regions with recombination hotspots.

It has been shown that the human genome contains extensive copy number variations (CNVs). Investigating the medical and evolutionary impacts of CNVs requires the knowledge of locations, sizes and frequency distribution of them within and between populations. However, CNV study of Chinese minorities, which harbor the majority of genetic diversity of Chinese populations, has been underrepresented considering the same efforts in other populations. Here we constructed, to our knowledge, a first CNV map in seven Chinese populations representing the major linguistic groups in China with 1,440 CNV regions identified using Affymetrix SNP 6.0 Array. Considerable differences in distributions of CNV regions between populations and substantial population structures were observed. We showed that ∼35% of CNV regions identified in minority ethnic groups are not shared by Han Chinese population, indicating that the contribution of the minorities to genetic architecture of Chinese population could not be ignored. We further identified highly differentiated CNV regions between populations. For example, a common deletion in Dong and Zhuang (44.4% and 50%), which overlaps two keratin-associated protein genes contributing to the structure of hair fibers, was not observed in Han Chinese. Interestingly, the most differentiated CNV deletion between HapMap CEU and YRI containing CCL3L1 gene reported in previous studies was also the highest differentiated regions between Tibetan and other populations. Besides, by jointly analyzing CNVs and SNPs, we found a CNV region containing gene CTDSPL were in almost perfect linkage disequilibrium between flanking SNPs in Tibetan while not in other populations except HapMap CHD. Furthermore, we found the SNP taggability of CNVs in Chinese populations was much lower than that in European populations. Our results suggest the necessity of a full characterization of CNVs in Chinese populations, and the CNV map we constructed serves as a useful resource in further evolutionary and medical studies.

To date, most genome-wide association studies (GWAS) and studies of fine-scale population structure have been conducted primarily on Europeans. Han Chinese, the largest ethnic group in the world, composing 20% of the entire global human population, is largely underrepresented in such studies. A well-recognized challenge is the fact that population structure can cause spurious associations in GWAS. In this study, we examined population substructures in a diverse set of over 1700 Han Chinese samples collected from 26 regions across China, each genotyped at approximately 160K single-nucleotide polymorphisms (SNPs). Our results showed that the Han Chinese population is intricately substructured, with the main observed clusters corresponding roughly to northern Han, central Han, and southern Han. However, simulated case-control studies showed that genetic differentiation among these clusters, although very small (F(ST) = 0.0002 approximately 0.0009), is sufficient to lead to an inflated rate of false-positive results even when the sample size is moderate. The top two SNPs with the greatest frequency differences between the northern Han and southern Han clusters (F(ST) > 0.06) were found in the FADS2 gene, which associates with the fatty acid composition in phospholipids, and in the HLA complex P5 gene (HCP5), which associates with HIV infection, psoriasis, and psoriatic arthritis. Ingenuity Pathway Analysis (IPA) showed that most differentiated genes among clusters are involved in cardiac arteriopathy (p < 10(-101)). These signals indicating significant differences among Han Chinese subpopulations should be carefully explained in case they are also detected in association studies, especially when sample sources are diverse.

Background: The molecular etiology of hearing impairment in Chinese has not been thoroughly investigated. Study of GJB2 gene revealed that 30.4% of the patients with hearing loss in Inner Mongolia carried GJB2 mutations. The SLC26A4 gene mutations and relevant phenotype are analyzed in this study., Methods: One hundred and thirty-five deaf patients were included. The coding exons of SLC26A4 gene were sequence analyzed in 111 patients, not including 22 patients carrying bi-allelic GJB2 mutations or one patient carrying a known GJB2 dominant mutation as well as one patient with mtDNA 1555A>G mutation. All patients with SLC26A4 mutations or variants were subjected to high resolution temporal bone CT scan and those with confirmed enlarged vestibular aqueduct and/or other inner ear malformation were then given further ultrasound scan of thyroid and thyroid hormone assays., Results: Twenty-six patients (19.26%, 26/135) were found carrying SLC26A4 mutation. Among them, 17 patients with bi-allelic SLC26A4 mutations were all confirmed to have EVA or other inner ear malformation by CT scan. Nine patients were heterozygous for one SLC26A4 mutation, including 3 confirmed to be EVA or EVA and Mondini dysplasia by CT scan. The most common mutation, IVS7-2A>G, accounted for 58.14% (25/43) of all SLC26A4 mutant alleles. The shape and function of thyroid were confirmed to be normal by thyroid ultrasound scan and thyroid hormone assays in 19 of the 20 patients with EVA or other inner ear malformation except one who had cystoid change in the right side of thyroid. No Pendred syndrome was diagnosed., Conclusion: In Inner Mongolia, China, mutations in SLC26A4 gene account for about 12.6% (17/135) of the patients with hearing loss. Together with GJB2 (23/135), SLC26A4 are the two most commonly mutated genes causing deafness in this region. Pendred syndrome is not detected in this deaf population. We established a new strategy that detects SLC26A4 mutations prior to the temporal bone CT scan to find EVA and inner ear malformation patients. This model has a unique advantage in epidemiologic study of large deaf population.

Objective: To investigate the contribution of GJB6 gene (encoding connexin 30) mutation in Chinese population with sporadic non-syndromic hearing impairment., Method: Three hundred and seventy-two nonsyndromic hearing impairment patients and 182 normal controls were first tested for GJB6 del(GJB6 > D13S1830) using specific PCR primers. Then PCR was performed with a pair of primer flanking the whole coding sequence of GJB6 gene. Sequencing of GJB6 whole coding sequence PCR products was subsequently applied in all subjects with hearing loss and normal controls., Result: None of the patients and normal controls carried GJB6 del (GJB6 > D13S1830). Two single base pair changes were detected , one in the patient group and the other in the control group. The mutation found in the patient group was not detected in the control subjects., Conclusion: Mutation of GJB6 gene is not frequent in Chinese non-syndromic hearing-loss population. Screening for GJB6 gene can be ranked as unconventional deaf gene test in China temporarily.

Objective: To analyze clinical manifestation of patients from two families with dilated vestibular aqueduct syndrome (DVAS). Their genotypic patterns were discriminated with the genetic testing methods for PDS gene., Method: The twin sisters from pedigree and the brother and sister from pedigree 2 all suffered from sensorineural hearing loss. All patients from these two families were confirmed to have enlarged vestibular aqueduct by temporal bone CT scan. Exon 7+8 and their flanking area sequences were analyzed by direct sequencing. All other exons and their flanking sequences were screened by DHPLC. The amplicons of exons which showed abnormal DHPLC wave pattern were further sequenced., Result: The parents of two families are non-consanguineous, hearing normal couples with no other family members with hearing loss. Both families have two offspring with DVAS. The clinical features of all patients were progressive hearing loss, good communication ability but with thickness pronunciation. Both twin sisters from pedigree are homozygous for the splice site mutation (IVS 7-2 A-G) affecting the 3 splice site consensus sequence of intron 7. The brother and sister of pedigree 2 are compound heterozygotes for 1199 ins T mutation and a missense mutation (1229 C-T)., Conclusion: Familial DVLS is typical hereditary disease. The patients with DVLS have similar clinical manifestation and the same genotypic changes in PDS.