Faculty Bibliography

The nucleus accumbens (NAc) is considered a hub of reward processing and a growing body of evidence has suggested its crucial role in the pathophysiology of major depressive disorder (MDD). However, inconsistent results have been reported by studies on reward network-focused resting-state functional MRI (rs-fMRI). In this study, we examined functional alterations of the NAc-based reward circuits in patients with MDD via meta- and mega-analysis. First, we performed a coordinated-based meta-analysis with a new SDM-PSI method for all up-to-date rs-fMRI studies that focused on the reward circuits of patients with MDD. Then, we tested the meta-analysis results in the REST-meta-MDD database which provided anonymous rs-fMRI data from 186 recurrent MDDs and 465 healthy controls. Decreased functional connectivity (FC) within the reward system in patients with recurrent MDD was the most robust finding in this study. We also found disrupted NAc FCs in the DMN in patients with recurrent MDD compared with healthy controls. Specifically, the combination of disrupted NAc FCs within the reward network could discriminate patients with recurrent MDD from healthy controls with an optimal accuracy of 74.7%. This study confirmed the critical role of decreased FC in the reward network in the neuropathology of MDD. Disrupted inter-network connectivity between the reward network and DMN may also have contributed to the neural mechanisms of MDD. These abnormalities have potential to serve as brain-based biomarkers for individual diagnosis to differentiate patients with recurrent MDD from healthy controls.

Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.

Aberrant topological organization of whole-brain networks has been inconsistently reported in studies of patients with major depressive disorder (MDD), reflecting limited sample sizes. To address this issue, we utilized a big data sample of MDD patients from the REST-meta-MDD Project, including 821 MDD patients and 765 normal controls (NCs) from 16 sites. Using the Dosenbach 160 node atlas, we examined whole-brain functional networks and extracted topological features (e.g., global and local efficiency, nodal efficiency, and degree) using graph theory-based methods. Linear mixed-effect models were used for group comparisons to control for site variability; robustness of results was confirmed (e.g., multiple topological parameters, different node definitions, and several head motion control strategies were applied). We found decreased global and local efficiency in patients with MDD compared to NCs. At the nodal level, patients with MDD were characterized by decreased nodal degrees in the somatomotor network (SMN), dorsal attention network (DAN) and visual network (VN) and decreased nodal efficiency in the default mode network (DMN), SMN, DAN, and VN. These topological differences were mostly driven by recurrent MDD patients, rather than first-episode drug naive (FEDN) patients with MDD. In this highly powered multisite study, we observed disrupted topological architecture of functional brain networks in MDD, suggesting both locally and globally decreased efficiency in brain networks.

OBJECTIVE:While gastrointestinal (GI) symptoms are very common in patients with major depressive disorder (MDD), few studies have investigated the neural basis behind these symptoms. In this study, we sought to elucidate the neural basis of GI symptoms in MDD patients by analyzing the changes in regional gray matter volume (GMV) and gray matter density (GMD) in brain structure. METHOD/METHODS:Subjects were recruited from 13 clinical centers and categorized into three groups, each of which is based on the presence or absence of GI symptoms: the GI symptoms group (MDD patients with at least one GI symptom), the non-GI symptoms group (MDD patients without any GI symptoms), and the healthy control group (HCs). Structural magnetic resonance images (MRI) were collected of 335 patients in the GI symptoms group, 149 patients in the non-GI symptoms group, and 446 patients in the healthy control group. The 17-item Hamilton Depression Rating Scale (HAMD-17) was administered to all patients. Correlation analysis and logistic regression analysis were used to determine if there was a correlation between the altered brain regions and the clinical symptoms. RESULTS:There were significantly higher HAMD-17 scores in the GI symptoms group than that of the non-GI symptoms group (P < 0.001). Both GMV and GMD were significant different among the three groups for the bilateral superior temporal gyrus, bilateral middle temporal gyrus, left lingual gyrus, bilateral caudate nucleus, right Fusiform gyrus and bilateral Thalamus (GRF correction, cluster-P < 0.01, voxel-P < 0.001). Compared to the HC group, the GI symptoms group demonstrated increased GMV and GMD in the bilateral superior temporal gyrus, and the non-GI symptoms group demonstrated an increased GMV and GMD in the right superior temporal gyrus, right fusiform gyrus and decreased GMV in the right Caudate nucleus (GRF correction, cluster-P < 0.01, voxel-P < 0.001). Compared to the non-GI symptoms group, the GI symptoms group demonstrated significantly increased GMV and GMD in the bilateral thalamus, as well as decreased GMV in the bilateral superior temporal gyrus and bilateral insula lobe (GRF correction, cluster-P < 0.01, voxel-P < 0.001). While these changed brain areas had significantly association with GI symptoms (P < 0.001), they were not correlated with depressive symptoms (P > 0.05). Risk factors for gastrointestinal symptoms in MDD patients (p < 0.05) included age, increased GMD in the right thalamus, and decreased GMV in the bilateral superior temporal gyrus and left Insula lobe. CONCLUSION/CONCLUSIONS:MDD patients with GI symptoms have more severe depressive symptoms. MDD patients with GI symptoms exhibited larger GMV and GMD in the bilateral thalamus, and smaller GMV in the bilateral superior temporal gyrus and bilateral insula lobe that were correlated with GI symptoms, and some of them and age may contribute to the presence of GI symptoms in MDD patients.

Cyclic nucleotide-gated (CNG) channels convert cyclic nucleotide (CN) binding and unbinding into electrical signals in sensory receptors and neurons. The molecular conformational changes underpinning ligand activation are largely undefined. We report both closed- and open-state atomic cryo-EM structures of a full-length Caenorhabditis elegans cyclic GMP-activated channel TAX-4, reconstituted in lipid nanodiscs. These structures, together with computational and functional analyses and a mutant channel structure, reveal a double-barrier hydrophobic gate formed by two S6 amino acids in the central cavity. cGMP binding produces global conformational changes that open the cavity gate located ~52 Å away but do not alter the structure of the selectivity filter-the commonly presumed activation gate. Our work provides mechanistic insights into the allosteric gating and regulation of CN-gated and nucleotide-modulated channels and CNG channel-related channelopathies.

Background: Breast cancer is one of the essential diseases that pose a severe threat to women's. RAS mutations and overexpression of the p21Ras protein is the leading causes of cancer development and progression, which has made the RAS gene and p21Ras as essential targets for therapy of RAS-driven cancers. Previously, we constructed KGHV300, which carries the anti-p21Ras single-chain variable fragment (scFv) and two tumor-specific promoters, the human telomerase reverse transcriptase (hTERT) and hypoxia response element (HRE) promoters, and it exhibited significant antitumor activity in several tumors including breast cancer. However, it has low targeting and toxic side effects on healthy tissues. It has been reported that cytokine-induced killer (CIK) cells can be used as a cell carrier to carry poxviruses, successfully evading the body's immune surveillance and passing the vascular endothelium and tumor tissue barriers. Thus, the use of CIK as a carrier for adenovirus maybe solve the shortcomings of the KGHV300.
Design(s): Firstly, to make the recombinant adenovirus infect CIK cells, we replaced the Fiber5 gene of skeleton virus plasmid pBHGE3 with Fiber35 gene of the plasmid pUC-F35 and formed a new skeleton virus plasmid pBHGE3-F35. Secondly, The plasmids pBHGE3-F35 and the shuttle virus plasmid pXC2p-scFv (Previously constructed) were co-transfected into HEK293 cells. The recombinant adenovirus was purified by Cesium chloride density gradient centrifugation and was called KGHV500. Thirdly, in vitro, the human breast cancer cell line MDA-MB-231 was employed to investigate the anti-tumor activity of KGHV500 using MTT, wound healing, and transwell invasion assays. Finally, in vivo, MDA-MB-231-transplanted tumors in nude mice were constructed and utilized to evaluate the treatment effect of the combination of CIK cells with KGHV500.
Result(s): KGHV500 was successfully constructed and purified. In vitro, KGHV500 could significantly inhibit proliferation, migration, and invasiveness and promote cell apoptosis in MDA-MB-231 cells. In vivo, CIK combined with KGHV500 not only enhanced the anti-tumor effect on MDA-MB-231 cell transplanted tumor but also reduced the toxic side effects of KGHV500 on various organs. (Figure presented)
Conclusion(s): CIK combined with KGHV500 could enhance the anti-breast cancer effect and safety, and it can be used as a strategy for the treatment of RAS-driven breast cancer in the future

Background: Glioma is the most prevalent type of brain tumors. The efficacy against high-grade gliomas still unsatisfied with currently available therapies. Ras gene, either mutations or overexpression caused by excessive upstream ligand/receptor activity could lead to tumorigenesis in multiple cancers including glioma. We hypothesize that targeting Ras is a reasonable and potential therapy for glioma treatment. Gene therapy delivered by adenovirus (Ads) is a promising trend in the treatment of glioma. The main issue of systemic delivery that clearance and decrease the level of circulating virus particles by neutralizing antibodies could be solved by cell-based drug carrier system. We previously constructed a broad-spectrum anti-p21Ras single-chain variable fragment antibody(scFv) and delivered by Ads KGHV500, where knob has modified to F35, CD46 as its receptor. In this study, we use cytokine-induced killer cells (CIKs) as a secondary carrier to delivery KGHV500 containing the anti-p21Ras scFv gene to investigate the anti-tumor effect of glioma cell line and its xenograft.
Design(s): Identifying Ras protein and CD46 expression in human glioma cell line U251 by immunohistochemistry (IHC). In vitro, the antitumor ability was determined by MTT assay, TUNEL assay, wound healing assay, transwell invasion assay. In vivo, nude-mice glioma tumor xenograft model was constructed, and CIKs was employed to deliver KGHV500 to mice by intravenous injection. The tumors growth volume were drawn, pathological changes and lesions were examined, the expression of p21Ras scFv and virus hexon were detected to evaluate targeting ability and safety.
Result(s): IHC showed the high expression of p21Ras in the cytoplasm and CD46 expression on the surface of U251 cells. In vitro, the KGHV500 treatment group demonstrated a higher inhibition efficiency on U251 cells migration, invasion, and proliferation, as well as higher apoptosis rate compared with control group. In vivo, tumor volume of the CIK+KGHV500 group was smallest among all groups. Compared with the KGHV500 group, tumor tissue expression of scFv and hexon was higher in CIK+KGHV500 group. The anti-p21Ras scFv was expressed only in the tumor and liver, spleen and kidney in the CIK+KGHV500 group, while those were detected in all tissues except brain in the KGHV500 group.
Conclusion(s): Our data suggest that KGHV500 and CIK cells as a co-vectors delivering anti-p21Ras scFv enhance the anti-tumor efficacy and safety, and possess a prospect for the treatment of Ras-related cancer

The trend of e-cigarette use among teens is ever increasing. Here we show the dysbiotic oral microbial ecology in e-cigarette users influencing the local host immune environment compared with non-smoker controls and cigarette smokers. Using 16S rRNA high-throughput sequencing, we evaluated 119 human participants, 40 in each of the three cohorts, and found significantly altered beta-diversity in e-cigarette users (p = 0.006) when compared with never smokers or tobacco cigarette smokers. The abundance of Porphyromonas and Veillonella (p = 0.008) was higher among vapers. Interleukin (IL)-6 and IL-1β were highly elevated in e-cigarette users when compared with non-users. Epithelial cell-exposed e-cigarette aerosols were more susceptible for infection. In vitro infection model of premalignant Leuk-1 and malignant cell lines exposed to e-cigarette aerosol and challenged by Porphyromonas gingivalis and Fusobacterium nucleatum resulted in elevated inflammatory response. Our findings for the first time demonstrate that e-cigarette users are more prone to infection.

BACKGROUND:Major depressive disorder (MDD) is known to be characterized by altered brain functional connectivity (FC) patterns. However, whether and how the features of dynamic FC would change in patients with MDD are unclear. In this study, we aimed to characterize dynamic FC in MDD using a large multi-site sample and a novel dynamic network-based approach. METHODS:Resting-state functional magnetic resonance imaging (fMRI) data were acquired from a total of 460 MDD patients and 473 healthy controls, as a part of the REST-meta-MDD consortium. Resting-state dynamic functional brain networks were constructed for each subject by a sliding-window approach. Multiple spatio-temporal features of dynamic brain networks, including temporal variability, temporal clustering and temporal efficiency, were then compared between patients and healthy subjects at both global and local levels. RESULTS:). Corresponding local changes in MDD were mainly found in the default-mode, sensorimotor and subcortical areas. Measures of temporal variability and characteristic temporal path length were significantly correlated with depression severity in patients (corrected p < 0.05). Moreover, the observed between-group differences were robustly present in both first-episode, drug-naïve (FEDN) and non-FEDN patients. CONCLUSIONS:Our findings suggest that excessive temporal variations of brain FC, reflecting abnormal communications between large-scale bran networks over time, may underlie the neuropathology of MDD.

Expression QTL (eQTL) detection has emerged as an important tool for unraveling the relationship between genetic risk factors and disease or clinical phenotypes. Most studies are predicated on the assumption that only a single causal variant explains the association signal in each interval. This greatly simplifies the statistical modeling, but is liable to biases in scenarios where multiple local causal-variants are responsible. Here, our primary goal was to address the prevalence of secondary cis-eQTL signals regulating peripheral blood gene expression locally, utilizing two large human cohort studies, each >2500 samples with accompanying whole genome genotypes. The CAGE (Consortium for the Architecture of Gene Expression) dataset is a compendium of Illumina microarray studies, and the Framingham Heart Study is a two-generation Affymetrix dataset. We also describe Bayesian colocalization analysis of the extent of sharing of cis-eQTL detected in both studies as well as with the BIOS RNAseq dataset. Stepwise conditional modeling demonstrates that multiple eQTL signals are present for ∼40% of over 3500 eGenes in both microarray datasets, and that the number of loci with additional signals reduces by approximately two-thirds with each conditioning step. Although <20% of the peak signals across platforms fine map to the same credible interval, the colocalization analysis finds that as many as 50-60% of the primary eQTL are actually shared. Subsequently, colocalization of eQTL signals with GWAS hits detected 1349 genes whose expression in peripheral blood is associated with 591 human phenotype traits or diseases, including enrichment for genes with regulatory functions. At least 10%, and possibly as many as 40%, of eQTL-trait colocalized signals are due to nonprimary cis-eQTL peaks, but just one-quarter of these colocalization signals replicated across the gene expression datasets. Our results are provided as a web-based resource for visualization of multi-site regulation of gene expression and its association with human complex traits and disease states.