NBR1-p62-Nrf2 mediates the anti-pulmonary fibrosis effects of protodioscin.

BACKGROUND: Idiopathic pulmonary fibrosis is a persistent disease of the lung interstitium for which there is no efficacious pharmacological therapy. Protodioscin, a steroidal saponin, possesses diverse pharmacological properties; however, its function in pulmonary fibrosis is yet to be established. Hence, in this investigation, it was attempted to figure out the anti-pulmonary fibrosis influences of protodioscin and its pharmacological properties related to oxidative stress. METHODS: A mouse lung fibrosis model was generated using tracheal injections of bleomycin, followed by intraperitoneal injection of different concentrations of protodioscin, and the levels of oxidative stress and fibrosis were detected in the lungs. Multiple fibroblasts were treated with TGF-ß to induce their transition to myofibroblasts. It was attempted to quantify myofibroblast markers' expression levels and reactive oxygen species levels as well as Nrf2 activation after co-incubation of TGF-ß with fibroblasts and different concentrations of protodioscin. The influence of protodioscin on the expression and phosphorylation of p62, which is associated with Nrf2 activation, were detected, and p62 related genes were predicted by STRING database. The effects of Nrf2 inhibitor or silencing of the Nrf2, p62 and NBR1 genes, respectively, on the activation of Nrf2 by protodioscin were examined. The associations between p62, NBR1, and Keap1 in the activation of Nrf2 by protodioscin was demonstrated using a co-IP assay. Nrf2 inhibitor were used when protodioscin was treated in mice with pulmonary fibrosis and lung tissue fibrosis and oxidative stress levels were detected. RESULTS: In vivo, protodioscin decreased the levels of fibrosis markers and oxidative stress markers and activated Nrf2 in mice with pulmonary fibrosis, and these effects were inhibited by Nrf2 inhibitor. In vitro, protodioscin decreased the levels of myofibroblast markers and oxidative stress markers during myofibroblast transition and promoted Nrf2 downstream gene expression, with reversal of these effects after Nrf2, p62 and NBR1 genes were silenced or Nrf2 inhibitors were used, respectively. Protodioscin promoted the binding of NBR1 to p62 and Keap1, thereby reducing Keap1-Nrf2 binding. CONCLUSION: The NBR1-p62-Nrf2 axis is targeted by protodioscin to reduce oxidative stress and inhibit pulmonary fibrosis.

Polygenic Risk Scores for Glaucoma Onset in the Ocular Hypertension Treatment Study.

Importance: Primary open-angle glaucoma (POAG) is a highly heritable disease, with 127 identified risk loci to date. Polygenic risk score (PRS) may provide a clinically useful measure of aggregate genetic burden and improve patient risk stratification. Objective: To assess whether a PRS improves prediction of POAG onset in patients with ocular hypertension. Design, Setting, and Participants: This was a post hoc analysis of the Ocular Hypertension Treatment Study. Data were collected from 22 US sites with a mean (SD) follow-up of 14.0 (6.9) years. A total of 1636 participants were followed up from February 1994 to December 2008; 1077 participants were enrolled in an ancillary genetics study, of which 1009 met criteria for this analysis. PRS was calculated using summary statistics from the largest cross-ancestry POAG meta-analysis, with weights trained using 8 813 496 variants from 449 186 cross-ancestry participants in the UK Biobank. Data were analyzed from July 2022 to December 2023. Exposures: From February 1994 to June 2002, participants were randomized to either topical intraocular pressure-lowering medication or close observation. After June 2002, both groups received medication. Main Outcomes and Measures: Outcome measures were hazard ratios for POAG onset. Concordance index and time-dependent areas under the receiver operating characteristic curve were used to compare the predictive performance of multivariable Cox proportional hazards models. Results: Of 1009 included participants, 562 (55.7%) were female, and the mean (SD) age was 55.9 (9.3) years. The mean (SD) PRS was significantly higher for 350 POAG converters (0.24 [0.95]) compared with 659 nonconverters (-0.12 [1.00]) (P < .001). POAG risk increased 1.36% (95% CI, 1.08-1.64) with each higher PRS decile, with conversion ranging from 9.52% (95% CI, 7.09-11.95) in the lowest PRS decile to 21.81% (95% CI, 19.37-24.25) in the highest decile. Comparison of low-risk and high-risk PRS tertiles showed a 2.0-fold increase in 20-year POAG risk for participants of European and African ancestries. In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year (95% CI, 0.01-1.03) decrease in age at diagnosis (P = .047). No significant linear association between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C index = 0.77) compared with the Ocular Hypertension Treatment Study baseline model (C index = 0.75) (P < .001). Each 1-SD higher PRS conferred a mean hazard ratio of 1.25 (95% CI, 1.13-1.44) for POAG onset. Conclusions and Relevance: Higher PRS was associated with increased risk for POAG in patients with ocular hypertension. The inclusion of a PRS improved the prediction of POAG onset. Trial Registration: ClinicalTrials.gov Identifier: NCT00000125.

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma.

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.

Reshaping the Substrate Binding Pocket of ß-Amino Acid Dehydrogenase for the Synthesis of Aromatic ß-Amino Acids.

By reshaping the substrate-binding pocket of ß-amino acid dehydrogenase (ß-AADH), some variants were obtained with up to 2560-fold enhanced activity toward the model substrates (S)-ß-homophenylalanine and (R)-ß-phenylalanine. A few aromatic ß-amino acids were prepared with >99% ee and high isolated yields via either kinetic resolution of racemates or reductive amination of the corresponding ß-keto acids. This work expands the catalytic capability of ß-AADHs and highlights their practical application in the synthesis of pharmaceutically relevant ß-amino acids.

Cyasterone ameliorates sepsis-related acute lung injury via AKT (Ser473)/GSK3ß (Ser9)/Nrf2 pathway.

BACKGROUND: Acute lung injury (ALI) is a severe disease that can lead to acute respiratory distress syndrome (ARDS), characterized by intractable hypoxemia, poor lung compliance, and respiratory failure, severely affecting patients' quality of life. The pathogenesis of ALI has not been fully elucidated yet, and sepsis is an important cause of ALI. Among the organ injuries caused by sepsis, the lungs are the earliest damaged ones. Radix cyathulae is reported to have analgesic, anti-inflammatory, and anti-aging effects. Cyasterone is extracted from Radix cyathulae. However, it is not known whether cyasterone has protective effects for ALI. This study aims to investigate the effect of cyasterone on sepsis-related ALI and its mechanism. METHODS: We used the cecal ligation peferation (CLP) method to establish a mouse sepsis model, and cyasterone was given intraperitoneally on days 1-3 to observe its preventive effect on sepsis-related acute lung injury. Primary murine peritoneal macrophages were used to investigate the molecular mechanism of cyasterone in vitro. RESULTS: Cyasterone pretreatment inhibits pro-inflammatory cytokine production, NLRP3 inflammasome activation, and oxidative stress in vivo and in vitro. In addition, cyasterone attenuates sepsis-induced ALI by activating nuclear factor erythroid2-related factor (Nrf2), which may be associated with AKT(Ser473)/GSK3ß(Ser9) pathway activation. CONCLUSIONS: Cyasterone defends against sepsis-induced ALI by inhibiting inflammatory responses and oxidative stress, which depends heavily on the upregulation of the Nrf2 pathway through phosphorylation of AKT(Ser473)/GSK3ß(Ser9). These results suggest cyasterone may be a valuable drug candidate for preventing sepsis-related ALI.

Asarinin attenuates bleomycin-induced pulmonary fibrosis by activating PPARγ.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that lacks effective treatment modalities. Once patients are diagnosed with IPF, their median survival is approximately 3-5 years. PPARγ is an important target for the prevention and treatment of pulmonary fibrosis. Asarinin is a lignan compound that can be extracted from food plant Asarum heterotropoides. In this study, we investigated the therapeutic effects of asarinin in a pulmonary fibrosis model constructed using bleomycin in mice and explored the underlying mechanisms. Intraperitoneal administration of asarinin to mice with pulmonary fibrosis showed that asarinin effectively attenuated pulmonary fibrosis, and this effect was significantly inhibited by the PPARγ inhibitor GW9662. Asarinin inhibited TGF-ß1-induced fibroblast-to-myofibroblast transition in vitro, while GW9662 and PPARγ gene silencing significantly inhibited this effect. In addition, asarinin inhibited not only the canonical Smad pathway of TGF-ß but also the non-canonical AKT and MAPK pathways by activating PPARγ. Our study demonstrates that asarinin can be used as a therapeutic agent for pulmonary fibrosis, and that PPARγ is its key target.

Deep Ocular Phenotyping Across Primary Open-Angle Glaucoma Genetic Burden.

Importance: Better understanding of primary open-angle glaucoma (POAG) genetics could enable timely screening and promote individualized disease risk prognostication. Objective: To evaluate phenotypic features across genetic burden for POAG. Design, Setting, and Participants: This was a cross-sectional, population-based study conducted from 2006 to 2010. Included participants were individuals from the UK Biobank aged 40 to 69 years. Individuals with non-POAG forms of glaucoma were excluded from the analysis. Data were statistically analyzed from October 2022 to January 2023. Main Outcomes and Measures: POAG prevalence based on structural coding, self-reports, and glaucoma-related traits. Results: Among 407 667 participants (mean [SD] age, 56.3 [8.1] years; 219 183 majority sex [53.8%]) were 14 171 POAG cases. Area under receiver operating characteristic curve for POAG detection was 0.748 in a model including polygenic risk score (PRS), age, sex, and ancestry. POAG prevalence in the highest decile of PRS was 7.4% (3005 of 40 644) vs 1.3% (544 of 40 795) in lowest decile (P < .001). A 1-SD increase in PRS was associated with 1.74 times higher odds of POAG (95% CI, 1.71-1.77), a 0.61-mm Hg increase in corneal-compensated intraocular pressure (IOP; 95% CI, 0.59-0.64), a -0.09-mm Hg decrease in corneal hysteresis (95% CI, -0.10 to -0.08), a 0.08-mm Hg increase in corneal resistance factor (95% CI, 0.06-0.09), and a -0.08-diopter decrease in spherical equivalent (95% CI, -0.11 to -0.07; P < .001 for all). A 1-SD increase in PRS was associated with a thinning of the macula-region retinal nerve fiber layer (mRNFL) of 0.14 µm and macular ganglion cell complex (GCC) of 0.26 µm (P < .001 for both). In the subset of individuals with fundus photographs, a 1-SD increase in PRS was associated with 1.42 times higher odds of suspicious optic disc features (95% CI, 1.19-1.69) and a 0.013 increase in cup-disc ratio (CDR; 95% CI, 0.012-0.014; P < .001 for both). A total of 22 of 5193 fundus photographs (0.4%) in decile 10 had disc hemorrhages, and 27 of 5257 (0.5%) had suspicious optic disc features compared with 9 of 5158 (0.2%) and 10 of 5219 (0.2%), respectively, in decile 1 (P < .001 for both). CDR in decile 10 was 0.46 compared with 0.41 in decile 1 (P < .001). Conclusion and Relevance: Results suggest that PRS identified a group of individuals at substantially higher risk for POAG. Higher genetic risk was associated with more advanced disease, namely higher CDR and corneal-compensated IOP, thinner mRNFL, and thinner GCC. Associations with POAG PRS and corneal hysteresis and greater prevalence of disc hemorrhages were identified. These results suggest that genetic risk is an increasingly important parameter for risk stratification to consider in clinical practice.

Polygenic Risk Score Improves Prediction of Primary Open Angle Glaucoma Onset in the Ocular Hypertension Treatment Study.

Objective or Purpose: Primary open-angle glaucoma (POAG) is a highly heritable disease with 127 identified risk loci. Polygenic risks score (PRS) offers a measure of aggregate genetic burden. In this study, we assess whether PRS improves risk stratification in patients with ocular hypertension. Design: A post-hoc analysis of the Ocular Hypertension Treatment Study (OHTS) data. Setting Participants and/or Controls: 1636 participants were followed from 1994 to 2020 across 22 sites. The PRS was computed for 1009 OHTS participants using summary statistics from largest cross-ancestry POAG metanalysis with weights trained using 8,813,496 variants from 488,395 participants in the UK Biobank. Methods Interventions or Testing: Survival regression analysis, with endpoint as development of POAG, predicted disease onset from PRS incorporating baseline covariates. Main Outcomes and Measures: Outcome measures were hazard ratios for POAG onset. Concordance index and time-dependent AUC were used to compare the predictive performance of multivariable Cox-Proportional Hazards models. Results: Mean PRS was significantly higher for POAG-converters (0.24 ± 0.95) than for non-converters (-0.12 ± 1.00) (p < 0.01). POAG risk increased 1.36% with each higher PRS decile, with conversion ranging from 9.5% in the lowest PRS decile to 21.8% in the highest decile. Comparison of low- and high-risk PRS tertiles showed a 1.8-fold increase in 20-year POAG risk for participants of European and African ancestries (p<0.01). In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year decrease in age at diagnosis, (p=0.05). No significant linear relationship between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C-index = 0.77) compared to OHTS baseline model (C-index=0.75) (p<0.01). One standard deviation higher PRS conferred a mean hazard ratio of 1.25 (CI=[1.13, 1.44]) for POAG onset. Conclusions: Higher PRS is associated with increased risk for, and earlier development of POAG in patients with ocular hypertension. Early treatment may mitigate the risk from high genetic burden, delaying clinically detectable disease by up to 5.2 years. The inclusion of a PRS improves the prediction of POAG onset.

Structure-based network analysis predicts mutations associated with inherited retinal disease.

With continued advances in gene sequencing technologies comes the need to develop better tools to understand which mutations cause disease. Here we validate structure-based network analysis (SBNA)1,2 in well-studied human proteins and report results of using SBNA to identify critical amino acids that may cause retinal disease if subject to missense mutation. We computed SBNA scores for genes with high-quality structural data, starting with validating the method using 4 well-studied human disease-associated proteins. We then analyzed 47 inherited retinal disease (IRD) genes. We compared SBNA scores to phenotype data from the ClinVar database and found a significant difference between benign and pathogenic mutations with respect to network score. Finally, we applied this approach to 65 patients at Massachusetts Eye and Ear (MEE) who were diagnosed with IRD but for whom no genetic cause was found. Multivariable logistic regression models built using SBNA scores for IRD-associated genes successfully predicted pathogenicity of novel mutations, allowing us to identify likely causative disease variants in 37 patients with IRD from our clinic. In conclusion, SBNA can be meaningfully applied to human proteins and may help predict mutations causative of IRD.

Abnormal neurite density and orientation dispersion in frontal lobe link to elevated hyperactive/impulsive behaviours in young adults with traumatic brain injury.

Traumatic brain injury is a major public health concern. A significant proportion of individuals experience post-traumatic brain injury behavioural impairments, especially in attention and inhibitory control domains. Traditional diffusion-weighted MRI techniques, such as diffusion tensor imaging, have provided tools to assess white matter structural disruptions reflecting the long-term brain tissue alterations associated with traumatic brain injury. The recently developed neurite orientation dispersion and density imaging is a more advanced diffusion MRI modality, which provides more refined characterization of brain tissue microstructures by assessing the neurite orientation dispersion and neurite density properties. In this study, neurite orientation dispersion and density imaging data from 44 young adults with chronic traumatic brain injury (who had no prior-injury diagnoses of any sub-presentation of attention deficits/hyperactivity disorder or experience of severe inattentive and/or hyperactive behaviours) and 45 group-matched normal controls were investigated, to assess the post-injury morphometrical and microstructural brain alterations and their relationships with the behavioural outcomes. Maps of fractional anisotropy, neurite orientation dispersion index and neurite density index were calculated. Vertex-wise and voxel-wise analyses were conducted for grey matter and white matter, respectively. Post hoc region-of-interest-based analyses were also performed. Compared to the controls, the group of traumatic brain injury showed significantly increased orientation dispersion index and significantly decreased neurite density index in various grey matter regions, as well as significantly decreased orientation dispersion index in several white matter regions. Brain-behavioural association analyses indicated that the reduced neurite density index of the left precentral gyrus and the reduced orientation dispersion index of the left superior longitudinal fasciculus were significantly associated with elevated hyperactive/impulsive symptoms in the patients with traumatic brain injury. These findings suggest that post-injury chronical neurite intracellular volume and angular distribution anomalies in the frontal lobe, practically the precentral area, can significantly contribute to the onset of hyperactive/impulsive behaviours in young adults with traumatic brain injury.

Mixed-Weight Neural Bagging for Detecting m6A Modifications in SARS-CoV-2 RNA Sequencing.

OBJECTIVE: The m6A modification is the most common ribonucleic acid (RNA) modification, playing a role in prompting the virus's gene mutation and protein structure changes in the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Nanopore single-molecule direct RNA sequencing (DRS) provides data support for RNA modification detection, which can preserve the potential m6A signature compared to second-generation sequencing. However, due to insufficient DRS data, there is a lack of methods to find m6A RNA modifications in DRS. Our purpose is to identify m6A modifications in DRS precisely. METHODS: We present a methodology for identifying m6A modifications that incorporated mapping and extracted features from DRS data. To detect m6A modifications, we introduce an ensemble method called mixed-weight neural bagging (MWNB), trained with 5-base RNA synthetic DRS containing modified and unmodified m6A. RESULTS: Our MWNB model achieved the highest classification accuracy of 97.85% and AUC of 0.9968. Additionally, we applied the MWNB model to the COVID-19 dataset; the experiment results reveal a strong association with biomedical experiments. CONCLUSION: Our strategy enables the prediction of m6A modifications using DRS data and completes the identification of m6A modifications on the SARS-CoV-2. SIGNIFICANCE: The Corona Virus Disease 2019 (COVID-19) outbreak has significantly influence, caused by the SARS-CoV-2. An RNA modification called m6A is connected with viral infections. The appearance of m6A modifications related to several essential proteins affects proteins' structure and function. Therefore, finding the location and number of m6A RNA modifications is crucial for subsequent analysis of the protein expression profile.

Topological Aberrance of Structural Brain Network Provides Quantitative Substrates of Post-Traumatic Brain Injury Attention Deficits in Children.

Background: Traumatic brain injury (TBI)-induced attention deficits are among the most common long-term cognitive consequences in children. Most of the existing studies attempting to understand the neuropathological underpinnings of cognitive and behavioral impairments in TBI have utilized heterogeneous samples and resulted in inconsistent findings. The current research proposed to investigate topological properties of the structural brain network in children with TBI and their relationship with post-TBI attention problems in a more homogeneous subgroup of children who had severe post-TBI attention deficits (TBI-A). Materials and Methods: A total of 31 children with TBI-A and 35 group-matched controls were involved in the study. Diffusion tensor imaging-based probabilistic tractography and graph theoretical techniques were used to construct the structural brain network in each subject. Network topological properties were calculated in both global level and regional (nodal) level. Between-group comparisons among the topological network measures and analyses for searching brain-behavioral were all corrected for multiple comparisons using Bonferroni method. Results: Compared with controls, the TBI-A group showed significantly higher nodal local efficiency and nodal clustering coefficient in left inferior frontal gyrus and right transverse temporal gyrus, whereas significantly lower nodal clustering coefficient in left supramarginal gyrus and lower nodal local efficiency in left parahippocampal gyrus. The temporal lobe topological alterations were significantly associated with the post-TBI inattentive and hyperactive symptoms in the TBI-A group. Conclusion: The results suggest that TBI-related structural re-modularity in the white matter subnetworks associated with temporal lobe may play a critical role in the onset of severe post-TBI attention deficits in children. These findings provide valuable input for understanding the neurobiological substrates of post-TBI attention deficits, and have the potential to serve as quantitatively measurable criteria guiding the development of more timely and tailored strategies for diagnoses and treatments to the affected individuals. Impact statement This study provides a new insight into the neurobiological substrates associated with post-traumatic brain injury attention deficits (TBI-A) in children, by evaluating topological alterations of the structural brain network. The results demonstrated that relative to group-matched controls, the children with TBI-A had significantly altered nodal local efficiency and nodal clustering coefficient in temporal lobe, which strongly linked to elevated inattentive and hyperactive symptoms in the TBI-A group. These findings suggested that white matter structural re-modularity in subnetworks associated with temporal lobe may serve as quantitatively measurable biomarkers for early prediction and diagnosis of post-TBI attention deficits in children.

Polyoxometalate-like sub-nanometer molybdenum(vi)-oxo clusters for sensitive, selective and stable H2O2 sensing.

Polyoxometalate-like molybdenum(vi)-oxo clusters ([Mo-oxo]n, n = 1-20) deposited on high surface-area carbon are developed as a biosensor for non-enzymatic electrochemical H2O2 detection. The sensor exhibits excellent electrocatalytic performance with a low detection limit, wide linear range, excellent sensitivity and stability. The composite can be stably deposited on screen-printed electrodes which combine microlitre analyses, long shelf-life and re-usability.

Multimodal neuroimaging-based prediction of adult outcomes in childhood-onset ADHD using ensemble learning techniques.

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and heterogeneous neurodevelopmental disorder, which is diagnosed using subjective symptom reports. Machine learning classifiers have been utilized to assist in the development of neuroimaging-based biomarkers for objective diagnosis of ADHD. However, existing basic model-based studies in ADHD report suboptimal classification performances and inconclusive results, mainly due to the limited flexibility for each type of basic classifier to appropriately handle multi-dimensional source features with varying properties. This study applied ensemble learning techniques (ELTs), a meta-algorithm that combine several basic machine learning models into one predictive model in order to decrease variance, bias, or improve predictions, in multimodal neuroimaging data collected from 72 young adults, including 36 probands (18 remitters and 18 persisters of childhood ADHD) and 36 group-matched controls. All currently available optimization strategies for ELTs (i.e., voting, bagging, boosting and stacking techniques) were tested in a pool of semifinal classification results generated by seven basic classifiers. The high-dimensional neuroimaging features for classification included regional cortical gray matter (GM) thickness and surface area, GM volume of subcortical structures, volume and fractional anisotropy of major white matter fiber tracts, pair-wise regional connectivity and global/nodal topological properties of the functional brain network for cue-evoked attention process. As a result, the bagging-based ELT with the base model of support vector machine achieved the best results, with significant improvement of the area under the receiver of operating characteristic curve (0.89 for ADHD vs. controls and 0.9 for ADHD persisters vs. remitters). Features of nodal efficiency in right inferior frontal gyrus, right middle frontal (MFG)-inferior parietal (IPL) functional connectivity, and right amygdala volume significantly contributed to accurate discrimination between ADHD probands and controls; higher nodal efficiency of right MFG greatly contributed to inattentive and hyperactive/impulsive symptom remission, while higher right MFG-IPL functional connectivity strongly linked to symptom persistence in adults with childhood ADHD. Considering their improved robustness than the commonly implemented basic classifiers, findings suggest that ELTs may have the potential to identify more reliable neurobiological markers for neurodevelopmental disorders.

Anatomical substrates of symptom remission and persistence in young adults with childhood attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder that emerges in childhood and persists into adulthood in a sizeable portion of afflicted individuals. The persistence of ADHD symptoms elevates the risk of adverse outcomes that result in substantial individual and societal burden. The objective of this study was to delineate neuroanatomical substrates associated with the diversity of adult outcomes of childhood ADHD, which may have considerable value for development of novel interventions that target mechanisms associated with recovery. Structural MRI and diffusion tensor imaging data from 32 young adults who were diagnosed with ADHD combined-type during childhood and 35 group-matched controls were analyzed. Adults with childhood ADHD were divided into 16 remitters and 16 persisters based on DSM-IV criteria. Compared to the controls, ADHD probands showed significantly reduced gray matter (GM) volume in right putamen and white matter (WM) volume in left parieto-insular fiber tracts. Within the ADHD probands, the remitters, as compared to persisters, showed significantly greater volume of right hippocampo-frontal and right parieto-insular WM fiber tracts, and those connecting caudate with the frontal, parietal, occipital, temporal, and insular cortices. Among ADHD probands, increased fractional anisotropy value of left caudate-parietal tract was significantly correlated with reduced hyperactive/impulsive symptoms. These findings suggest that optimal structural development in the WM tracts that connect caudate with cortical areas, especially in the caudate-parietal path, may play an important role in symptom remission in young adults with childhood ADHD.

Identification of Hepatocellular Carcinoma-Related Potential Genes and Pathways Through Bioinformatic-Based Analyses.

Background: Hepatocellular carcinoma (HCC) is one of the most prevalent tumors worldwide. However, the key roles of most molecules associated with tumor proliferation, invasion, and metastasis in HCC remain unclear. It is therefore important to explore potential mechanisms underlying tumorigenesis and to screen genes and pathways identified from such research for their role in pathogenesis. Materials and Methods: We selected microarray data GSE62043 consisting of paired tissue samples from 100 HCC patients, then these data were analyzed to identify differentially expressed genes (DEGs). Next, gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out to elucidate the biological processes, molecular function, cellular component (CC), and KEGG signaling pathways for the DEGs. We then constructed protein-protein interaction (PPI) networks, followed by a functional enrichment analysis, from which we obtained two significant gene modules. Finally, the gene expression data obtained from this test set were subjected to validation studies using an independent set of hepatocellular patient data archived in The Cancer Genome Atlas and Genotype-Tissue Expression (TCGA/GTEx) database. Results: A total of 425 DEGs were identified that met both of our criteria for significance: (1) a |log2-fold change (FC)| ≥ 1.2 and (2) an adjusted p value <0.01. From these data, two significant gene modules, containing 28 pathway-related hub genes, were identified. Conclusion: Through application of a test/validation algorithm using HCC datasets from two independent databases, we identified a number of genes that could serve as potential biomarkers for the molecular diagnosis and therapeutic intervention of HCC, including the known genes, IGF1, IGF2, NDC80, CDK1, CENPF, CDCA8, CCNB1, BIRC5, NCAPG, and CDCA5, and the novel genes, CENPU and SPC25, which are associated with cell cycle, mitotic cell cycle, and organelle organization.

A Review of Heterogeneity in Attention Deficit/Hyperactivity Disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects approximately 8%-12% of children worldwide. Throughout an individual's lifetime, ADHD can significantly increase risk for other psychiatric disorders, educational and occupational failure, accidents, criminality, social disability and addictions. No single risk factor is necessary or sufficient to cause ADHD. The multifactorial causation of ADHD is reflected in the heterogeneity of this disorder, as indicated by its diversity of psychiatric comorbidities, varied clinical profiles, patterns of neurocognitive impairment and developmental trajectories, and the wide range of structural and functional brain anomalies. Although evidence-based treatments can reduce ADHD symptoms in a substantial portion of affected individuals, there is yet no curative treatment for ADHD. A number of theoretical models of the emergence and developmental trajectories of ADHD have been proposed, aimed at providing systematic guides for clinical research and practice. We conducted a comprehensive review of the current status of research in understanding the heterogeneity of ADHD in terms of etiology, clinical profiles and trajectories, and neurobiological mechanisms. We suggest that further research focus on investigating the impact of the etiological risk factors and their interactions with developmental neural mechanisms and clinical profiles in ADHD. Such research would have heuristic value for identifying biologically homogeneous subgroups and could facilitate the development of novel and more tailored interventions that target underlying neural anomalies characteristic of more homogeneous subgroups.

The Impact of Callous-Unemotional Traits and Externalizing Tendencies on Neural Responsivity to Reward and Punishment in Healthy Adolescents.

Both externalizing behavior and callous-unemotional (CU) traits in youth are precursors to later criminal offending in adulthood. It is posited that disruptions in reward and punishment processes may engender problematic behavior, such that CU traits and externalizing behavior may be linked to a dominant reward response style (e.g., heightened responsivity to rewards) and deficient punishment-processing. However, prior research has generated mixed findings and work examining both the sole and joint contribution of CU traits and externalizing problems related to functional brain alterations is lacking. In this pilot functional magnetic resonance imaging study, we measured externalizing behavior and CU traits in a community sample of adolescents (n = 29) and examined their impacts on brain activity associated with anticipation and receipt of reward and punishment using the Modified Monetary Incentive Delay task. We found that CU traits were associated with greater activation of the ventral striatum (VST) during reward anticipation. However, this effect became non-significant after controlling for externalizing behavior, indicating substantial overlap between the CU and externalizing measures in explaining VST activation when anticipating reward. In addition, externalizing behavior (but not CU) was significantly negatively associated with amygdala activation during punishment receipt, even after controlling for CU traits. The present findings extend previous evidence of hyper-responsivity to reward and hypo-responsivity to punishment in relation to psychopathic traits and antisocial behavior to non-clinical, non-incarcerated youths.

Distinct topological properties of cue-evoked attention processing network in persisters and remitters of childhood ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing neurodevelopmental disorder that persists into adulthood in a sizeable portion of afflicted children. The persistence of ADHD elevates the risk for adverse outcomes that result in substantial individual and societal burden. The objective of this study is to assess neurobiological substrates associated with variability of clinical outcomes in childhood ADHD, which has considerable value for the development of novel interventions that target mechanisms associated with recovery. A total of 36 young adults who were diagnosed with ADHD combined-type during childhood and 33 group-matched controls were involved in the study. Adults with childhood ADHD were further divided into 17 persisters and 19 remitters based on DSM-5 criteria. Functional magnetic resonance imaging data during a cue-evoked attention task were collected from each subject. The cue-evoked attention processing network was constructed using graph theoretic techniques. Network properties, including global-, local-, and nodal-efficiency, and network hubs were computed. Group comparisons of the network properties were conducted. Significantly lower nodal efficiency in right inferior frontal gyrus and reduced left side frontal-parietal functional interactions were observed in both remitters and persisters relative to the controls. The ADHD persisters showed a unique pattern of significantly lower nodal efficiency in right middle frontal gyrus (MFG) and hyper-interactions between bilateral MFG. This study suggests that right MFG functional impairments may relate to inactive fronto-parietal functional interactions for sensory and cognitive information processing and symptom persistence in young adults with childhood ADHD.