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1.  Understanding the Cu-Zn brass alloys using a short-range-order cluster model: significance of specific compositions of industrial alloys 
Scientific Reports  2014;4:7065.
Metallic alloys show complex chemistries that are not yet understood so far. It has been widely accepted that behind the composition selection lies a short-range-order mechanism for solid solutions. The present paper addresses this fundamental question by examining the face-centered-cubic Cu-Zn α-brasses. A new structural approach, the cluster-plus-glue-atom model, is introduced, which suits specifically for the description of short-range-order structures in disordered systems. Two types of formulas are pointed out, [Zn-Cu12]Zn1~6 and [Zn-Cu12](Zn,Cu)6, which explain the α-brasses listed in the American Society for Testing and Materials (ASTM) specifications. In these formulas, the bracketed parts represent the 1st-neighbor cluster, and each cluster is matched with one to six 2nd-neighbor Zn atoms or with six mixed (Zn,Cu) atoms. Such a cluster-based formulism describes the 1st- and 2nd-neighbor local atomic units where the solute and solvent interactions are ideally satisfied. The Cu-Ni industrial alloys are also explained, thus proving the universality of the cluster-formula approach in understanding the alloy selections. The revelation of the composition formulas for the Cu-(Zn,Ni) industrial alloys points to the common existence of simple composition rules behind seemingly complex chemistries of industrial alloys, thus offering a fundamental and practical method towards composition interpretations of all kinds of alloys.
doi:10.1038/srep07065
PMCID: PMC4233332  PMID: 25399835
2.  Photo-induced processes in collagen-hypericin system revealed by fluorescence spectroscopy and multiphoton microscopy 
Biomedical Optics Express  2014;5(5):1355-1362.
Collagen is the main structural protein and the key determinant of mechanical and functional properties of tissues and organs. Proper balance between synthesis and degradation of collagen molecules is critical for maintaining normal physiological functions. In addition, collagen influences tumor development and drug delivery, which makes it a potential cancer therapy target. Using second harmonic generation, two-photon excited fluorescence microscopy, and spectrofluorimetry, we show that the natural pigment hypericin induces photosensitized destruction of collagen-based tissues. We demonstrate that hypericin–mediated processes in collagen fibers are irreversible and may be used for the treatment of cancer and collagen-related disorders.
doi:10.1364/BOE.5.001355
PMCID: PMC4026910  PMID: 24877000
(190.1900) Diagnostic applications of nonlinear optics; (170.3880) Medical and biological imaging; (180.4315) Nonlinear microscopy
3.  A stress-induced cellular aging model with postnatal neural stem cells 
Cell Death & Disease  2014;5(3):e1116-.
Aging refers to the physical and functional decline of the tissues over time that often leads to age-related degenerative diseases. Accumulating evidence implicates that the senescence of neural stem cells (NSCs) is of paramount importance to the aging of central neural system (CNS). However, exploration of the underlying molecular mechanisms has been hindered by the lack of proper aging models to allow the mechanistic examination within a reasonable time window. In the present study, we have utilized a hydroxyurea (HU) treatment protocol and effectively induced postnatal subventricle NSCs to undergo cellular senescence as determined by augmented senescence-associated-β-galactosidase (SA-β-gal) staining, decreased proliferation and differentiation capacity, increased G0/G1 cell cycle arrest, elevated reactive oxygen species (ROS) level and diminished apoptosis. These phenotypic changes were accompanied by a significant increase in p16, p21 and p53 expression, as well as a decreased expression of key proteins in various DNA repair pathways such as xrcc2, xrcc3 and ku70. Further proteomic analysis suggests that multiple pathways are involved in the HU-induced NSC senescence, including genes related to DNA damage and repair, mitochondrial dysfunction and the increase of ROS level. Intriguingly, compensatory mechanisms may have also been initiated to interfere with apoptotic signaling pathways and to minimize the cell death by downregulating Bcl2-associated X protein (BAX) expression. Taken together, we have successfully established a cellular model that will be of broad utilities to the molecular exploration of NSC senescence and aging.
doi:10.1038/cddis.2014.82
PMCID: PMC3973228  PMID: 24625975
aging; neural stem cells; cellular senescence model; stress; DNA damage
4.  Traditional Cardiovascular Risk Factors Explain the Minority of the Variability in Carotid Plaque 
Background
Subclinical atherosclerotic plaque is an important marker of increased vascular risk. Identifying factors underlying the variability in burden of atherosclerotic carotid plaque unexplained by traditional vascular risk factors may help target novel preventive strategies.
Methods
As a part of the carotid substudy of the Northern Manhattan Study (NOMAS), 1,790 stroke-free individuals (mean age 69±9; 60% women; 61% Hispanic, 19% black, 18% white) were assessed for total plaque area (TPA) burden using 2D carotid ultrasound imaging. Multiple linear regression models were constructed. Model 1 used pre-specified traditional risk factors: age, sex, LDL-cholesterol, diabetes mellitus, pack-years of smoking, blood pressure (BP), and treatment for BP; and Model 2, an addition of socioeconomic and less traditional risk factors. The contributions of the components of the Framingham heart risk score (FRS) and the NOMAS global vascular risk score (GVRS) to the TPA were explored.
Results
Prevalence of carotid plaque was 58%. Mean TPA was 13±19mm2. Model 1 explained 19.5% of the variance in TPA burden (R2=0.195). Model 2 explained 21.9% of TPA burden. Similarly, FRS explained 18.8% and NOMAS GVRS 21.5% of the TPA variance.
Conclusions
The variation in preclinical carotid plaque burden is largely unexplained by traditional and less traditional vascular risk factors, suggesting that other unaccounted environmental and genetic factors play an important role in the determination of atherosclerotic plaque. Identification of these factors may lead to new approaches to prevent stroke and cardiovascular disease.
doi:10.1161/STROKEAHA.112.651059
PMCID: PMC3383876  PMID: 22550054
preclinical atherosclerosis; carotid plaque; plaque area; carotid ultrasound; epidemiology; risk factors
5.  Cytochrome-c mediated a bystander response dependent on inducible nitric oxide synthase in irradiated hepatoma cells 
He, M | Ye, S | Ren, R | Dong, C | Xie, Y | Yuan, D | Shao, C
British Journal of Cancer  2012;106(5):889-895.
Background:
Radiation-induced bystander effect (RIBE) has important implication in tumour radiotherapy, but the bystander signals are still not well known.
Methods:
The role of cytochrome-c (cyt-c) and free radicals in RIBE on human hepatoma cells HepG2 was investigated by detecting the formation of bystander micronuclei (MN) and the generation of endogenous cyt-c, inducible nitric oxide (NO) synthase (iNOS), NO, and reactive oxygen species (ROS) molecules.
Results:
When HepG2 cells were cocultured with an equal number of irradiated HepG2 cells, the yield of MN in the nonirradiated bystander cells was increased in a manner depended on radiation dose and cell coculture time, but it was diminished when the cells were treated with cyclosporin A (CsA), an inhibitor of cyt-c release. Meanwhile the CsA treatment inhibited radiation-induced NO but not ROS. Both of the depressed bystander effect and NO generation in the CsA-treated cells were reversed when 5 μ cyt-c was added in the cell coculture medium. But these exogenous cyt-c-mediated overproductions of NO and bystander MN were abolished when the cells were pretreated with s-methylisothiourea sulphate, an iNOS inhibitor.
Conclusion:
Radiation-induced cyt-c has a profound role in regulating bystander response through an iNOS-triggered NO signal but not ROS in HepG2 cells.
doi:10.1038/bjc.2012.9
PMCID: PMC3305951  PMID: 22274409
ionising radiation; bystander effect; cytochrome-c; iNOS; ROS
6.  Apical membrane rupture and backward bile flooding in acetaminophen-induced hepatocyte necrosis 
Cell Death & Disease  2011;2(7):e183-.
Morphological changes of hepatocyte death have so far only been described on cells in culture or in tissue sections. Using a high-resolution and high-magnification multiphoton microscopic system, we recorded in living mice serial changes of acetaminophen (APAP)-induced hepatocyte necrosis in relevance to metabolism of a fluorogenic bile solute. Initial changes of hepatocyte injury included basal membrane disruption and loss of mitochondrial membrane potential. An overwhelming event of rupture at adjacent apical membrane resulting in flooding of bile into these hepatocytes might ensue. Belbs formed on basal membrane and then dislodged into the sinusoid circulation. Transmission electron microscopy disclosed a necrotic hepatocyte depicting well the changes after apical membrane rupture and bile flooding. Administration of the antidote N-acetylcysteine dramatically reduced the occurrence of apical membrane rupture. The present results demonstrated a hidden but critical step of apical membrane rupture leading to irreversible APAP-induced hepatocyte injury.
doi:10.1038/cddis.2011.68
PMCID: PMC3199717  PMID: 21776021
acetaminophen; hepatocyte necrosis; multiphoton microscopy; intravital imaging
7.  PROTEIN KINASE Cα MEDIATES A NOVEL FORM OF PLASTICITY IN THE ACCESSORY OLFACTORY BULB 
Neuroscience  2009;163(3):811-824.
Modification of synapses in the accessory olfactory bulb (AOB) is believed to underlie pheromonal memory that enables mate recognition in mice. The memory, which is acquired with single-trial learning forms only with coincident noradrenergic and glutamatergic inputs to the AOB. The mechanisms by which glutamate and norepinephrine (NE) alter the AOB synapses are not well understood. Here we present results that not only reconcile the earlier, seemingly contradictory, observations on the role of glutamate and NE in changing the AOB synapses, but also reveal novel mechanisms of plasticity. Our studies suggest that initially, glutamate acting at Group II metabotropic receptors and NE acting at α2-adrenergic receptors inhibit N-type and R-type Ca2+ channels in mitral cells via a G-Protein. The N-type and R-type Ca2+ channel inhibition is reversed by activation of α1-adrenergic receptors and protein kinase Cα (PKCα). Based on these results, we propose a hypothetical model for a new kind of synaptic plasticity in the AOB that accounts for the previous behavioral data on pheromonal memory. According to this model, initial inhibition of the Ca2+ channels suppresses the GABAergic inhibitory feedback to mitral cells, causing disinhibition and Ca2+ influx. NE also activates phospholipase C (PLC) through α1-adrenergic receptors generating inositol 1,4,5-trisphosphate and diacylglycerol (DAG). Calcium and DAG together activate protein kinase Cα (PKCα) which switches the disinhibition to increased inhibition of mitral cells. Thus, PKCα is likely to be a coincidence detector integrating glutamate and NE input in the AOB and bridging the short-term signaling to long-term structural changes resulting in enhanced inhibition of mitral cells that is thought to underlie memory formation.
doi:10.1016/j.neuroscience.2009.06.069
PMCID: PMC2748972  PMID: 19580852
8.  Coupled Flow-Structure-Biochemistry Simulations of Dynamic Systems of Blood Cells Using an Adaptive Surface Tracking Method 
Journal of fluids and structures  2009;25(5):936-953.
A method for the computation of low Reynolds number dynamic blood cell systems is presented. The specific system of interest here is interaction between cancer cells and white blood cells in an experimental flow system. Fluid dynamics, structural mechanics, six-degree-of freedom motion control and surface biochemistry analysis components are coupled in the context of adaptive octree-based grid generation. Analytical and numerical verification of the quasi-steady assumption for the fluid mechanics is presented. The capabilities of the technique are demonstrated by presenting several three-dimensional cell system simulations, including the collision/interaction between a cancer cell and an endothelium adherent polymorphonuclear leukocyte (PMN) cell in a shear flow.
doi:10.1016/j.jfluidstructs.2009.02.002
PMCID: PMC2765665  PMID: 20160939
Computational Fluid Dynamics (CFD); Computational Structural Mechanics (CSM); Octree grid generation; Blood cells; Adaptive grid generation
9.  Lhermitte's Sign Developing after IMRT for Head and Neck Cancer 
Background. Lhermitte's sign (LS) is a benign form of myelopathy with neck flexion producing an unpleasant electric-shock sensation radiating down the extremities. Although rare, it can occur after head and neck radiotherapy. Results. We report a case of Lhermitte's developing after curative intensity-modulated radiotherapy (IMRT) for a patient with locoregionally advanced oropharyngeal cancer. IMRT delivers a conformal dose of radiation in head and neck cancer resulting in a gradient of radiation dose throughout the spinal cord. Using IMRT, more dose is delivered to the anterior spinal cord than the posterior cord. Conclusions. Lhermitte's sign can develop after IMRT for head and neck cancer. We propose an anterior spinal cord structure, the spinothalamic tract to be the target of IMRT-caused LS.
doi:10.1155/2010/907960
PMCID: PMC2902147  PMID: 20628529
10.  Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans 
Molecular Psychiatry  2009;14(12):1105-1118.
We studied seven genes that reflect events relevant to antidepressant action at four sequential levels: (1) entry into the brain, (2) binding to monoaminergic transporters, and (3) distal effects at the transcription level, resulting in (4) changes in neurotrophin and neuropeptide receptors. Those genes are ATP-binding cassette subfamily B member 1 (ABCB1), the noradrenaline, dopamine, and serotonin transporters (SLC6A2, SLC6A3 and SLC6A4), cyclic AMP-responsive element binding protein 1 (CREB1), corticotropin-releasing hormone receptor 1 (CRHR1) and neurotrophic tyrosine kinase type 2 receptor (NTRK2). Sequence variability for those genes was obtained in exonic and flanking regions. A total of 56 280 000 bp across were sequenced in 536 unrelated Mexican Americans from Los Angeles (264 controls and 272 major depressive disorder (MDD)). We detected in those individuals 419 single nucleotide polymorphisms (SNPs); the nucleotide diversity was 0.00054±0.0001. Of those, a total of 204 novel SNPs were identified, corresponding to 49% of all previously reported SNPs in those genes: 72 were in untranslated regions, 19 were in coding sequences of which 7 were non-synonymous, 86 were intronic and 27 were in upstream/downstream regions. Several SNPs or haplotypes in ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1 and NTRK2 were associated with MDD, and in ABCB1, SLC6A2 and NTRK2 with antidepressant response. After controlling for age, gender and baseline 21-item Hamilton Depression Rating Scale (HAM-D21) score, as well as correcting for multiple testing, the relative reduction of HAM-D21 score remained significantly associated with two NTRK2-coding SNPs (rs2289657 and rs56142442) and the haplotype CAG at rs2289658 (splice site), rs2289657 and rs2289656. Further studies in larger independent samples will be needed to confirm these associations. Our data indicate that extensive assessment of sequence variability may contribute to increase understanding of disease susceptibility and drug response. Moreover, these results highlight the importance of direct re-sequencing of key candidate genes in ethnic minority groups in order to discover novel genetic variants that cannot be simply inferred from existing databases.
doi:10.1038/mp.2009.92
PMCID: PMC2834349  PMID: 19844206
nucleotide polymorphism; antidepressant response; desipramine; fluoxetine; major depression
11.  Immunoediting of leukocyte functions within the tumor microenvironment promotes cancer metastasis development* 
Biorheology  2009;46(4):265-279.
Attachment of tumor cells to the endothelium (EC) under flow conditions is critical for migration of tumor cells out of the vascular system to establish metastases. We found that neutrophils (PMN) increased melanoma cell extravasation. Endogenous IL-8 liberated from melanoma cells or from PMN induced by melanoma cells contributed to PMN-facilitated melanoma cell arrest on the EC in the microcirculation. Functional blocking of IL-8 receptors on PMN or neutralizing soluble IL-8 in the tumor circulation decreased the level of CD11b/CD18 up-regulation on PMN and subsequently reduced melanoma cell extravasation. We also found that targeting mutant V600EB-Raf interrupted melanoma cell extravasation in vitro and subsequent lung metastasis development in vivo. B-Raf encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. Results showed that inhibition of V600EB-Raf reduced IL-8 secretion from melanoma cells and reduced the capacity of IL-8 production from the tumor microenvironment involving PMN. Furthermore, reduction in inter-cellular adhesion molecule-1 (ICAM-1) expression on melanoma cells was found after V600EB-Raf knockdown. These results provide new evidence for the complex role of secreted chemokine and PMN-melanoma adhesion in the recruitment of metastatic cancer cells to the EC, which are significant in fostering new approaches to cancer treatment through anti-inflammatory therapeutics.
doi:10.3233/BIR-2009-0545
PMCID: PMC2777629  PMID: 19721189
PMN; melanoma; endothelium; shear flow; cytokine signaling; extravasation
12.  Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response 
Molecular psychiatry  2008;13(8):800-812.
There are clinical parallels between the nature and course of depressive symptoms in major depressive disorder (MDD) and those of inflammatory disorders. However, the characterization of a possible immune system dysregulation in MDD has been challenging. Emerging data support the role of T-cell dysfunction. Here we report the association of MDD and antidepressant response to genes important in the modulation of the hypothalamic-pituitary-adrenal axis and immune functions in Mexican Americans with major depression. Specifically, single nucleotide polymorphisms (SNPs) in two genes critical for T-cell function are associated with susceptibility to MDD: PSMB4 (proteasome β4 subunit), important for antigen processing, and TBX21 (T bet), critical for differentiation. Our analyses revealed a significant combined allele dose-effect: individuals who had one, two and three risk alleles were 2.3, 3.2 and 9.8 times more likely to have the diagnosis of MDD, respectively. We found associations of several SNPs and antidepressant response; those genes support the role of T cell (CD3E, PRKCH, PSMD9 and STAT3) and hypothalamic-pituitary-adrenal axis (UCN3) functions in treatment response. We also describe in MDD increased levels of CXCL10/IP-10, which decreased in response to antidepressants. This further suggests predominance of type 1 T-cell activity in MDD. T-cell function variations that we describe here may account for 47.8% of the attributable risk in Mexican Americans with moderate MDD. Immune function genes are highly variable; therefore, different genes might be implicated in distinct population groups.
doi:10.1038/mp.2008.59
PMCID: PMC2650233  PMID: 18504423
TBX21; PSMB4; major depression; genetic; SNP; cytokine
14.  Second primary neoplasms among 53 159 haematolymphoproliferative malignancy patients in Sweden, 1958–1996: a search for common mechanisms 
British Journal of Cancer  2001;85(7):997-1005.
The Swedish Family-Cancer Database was used to analyse site-specific risk of second primary malignancies following 53 159 haematolymphoproliferative disorders (HLPD) diagnosed between 1958 and 1996. Standardized incidence ratio (SIR) of a second malignancy was calculated as the ratio of observed to expected numbers of second malignancies by applying site-, sex-, age-, period-, residence- and occupation-specific rates in the corresponding population in the Database to the appropriate person-years at risk. Among 18 960 patients with non-Hodgkin's lymphoma (NHL), there was over a 3-fold significant increase in cancer of the tongue, small intestine, nose, kidney and nervous system, squamous cell carcinoma (SCC) of the skin, NHL, Hodgkin's disease (HD) and lymphoid and myeloid leukaemia. Among 5353 patients with HD, there was over a 4-fold significant increase in cancer of the salivary glands, nasopharynx and thyroid, NHL and myeloid leukaemia, and over a 1.6-fold increase in cancer of the stomach, colon, lung, breast, skin (melanoma and SCC), nervous system and soft tissues and lymphoid leukaemia. Among 28 846 patients with myeloma and leukaemia, there was a significant increase in cancer of the skin, nervous system and non-thyroid endocrine glands and all HLPD except for myeloma. Our findings showed some clustering between first and second primaries among Epstein–Barr virus-, ultraviolet radiation- and immunosuppression-related cancers. © 2001 Cancer Research Campaignhttp://www.bjcancer.com
doi:10.1054/bjoc.2001.1998
PMCID: PMC2375099  PMID: 11592772
second malignancies; haematolymphoproliferative disorders; Epstein–Barr virus; immunosuppression; follow-up study
15.  Sibling risks in cancer: clues to recessive or X-linked genes? 
British Journal of Cancer  2001;84(3):388-391.
A systematic analysis of cancer risks to offspring and to siblings of cancer cases was carried out based on the nation-wide Swedish Family-Cancer Database. For all 13 cancer sites examined, risks to both offspring and siblings of cases of cancer at the same site were significantly elevated. The relative risk to siblings was approximately 2 fold more than the offspring risk for cancers of the prostate, testis, kidney and bladder, suggesting that recessive or X-linked susceptibility genes may be important for these cancers. Risks to siblings of cases where a parent was also affected were increased >20 fold over population rates for colorectal, ovarian, prostate and renal cancer, and for leukaemia, consistent with the effects of rare high-risk susceptibility alleles. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2000.1585
PMCID: PMC2363751  PMID: 11161404
familial cancer; liability; heredity; cancer modelling; genetic epidemiology
16.  Cancers in the first-degree relatives of children with brain tumours 
British Journal of Cancer  2000;83(3):407-411.
We used the nationwide Swedish Family-Cancer Database with 2060 childhood brain tumours diagnosed in the period 1958–1996 to analyse the risk of this tumour by parental cancers and in siblings of childhood brain tumour probands. Groups of patients were compared by calculating standardized incidence ratios (SIRs) for brain tumours in offspring. 1.3% of brain tumour patients had a parent with nervous system cancer; SIRs were 2.4 and 1.88 for diagnostic ages < 5 and < 15 years, respectively. The data showed distinct patterns of familial risks for childhood brain tumours, the SIR was 10.26 for brain astrocytoma given a parent with meningioma. Parental colon cancer was associated with offspring ependymoma (SIR 3.70), and parental salivary gland cancers with offspring medulloblastoma (SIR 13.33, but two cases only). SIR for sibling nervous system cancer from childhood brain tumour probands was 3.55 up to age 61. © 2000 Cancer Research Campaign
doi:10.1054/bjoc.2000.1252
PMCID: PMC2374571  PMID: 10917560
astrocytoma; medulloblastoma; ependymoma; meningioma; second cancer
17.  Inner but Not Outer Membrane Leaflets Control the Transition from Glycosylphosphatidylinositol-anchored Influenza Hemagglutinin-induced Hemifusion to Full Fusion 
The Journal of Cell Biology  1997;136(5):995-1005.
Cells that express wild-type influenza hemagglutinin (HA) fully fuse to RBCs, while cells that express the HA-ectodomain anchored to membranes by glycosylphosphatidylinositol, rather than by a transmembrane domain, only hemifuse to RBCs. Amphipaths were inserted into inner and outer membrane leaflets to determine the contribution of each leaflet in the transition from hemifusion to fusion. When inserted into outer leaflets, amphipaths did not promote the transition, independent of whether the agent induces monolayers to bend outward (conferring positive spontaneous monolayer curvature) or inward (negative curvature). In contrast, when incorporated into inner leaflets, positive curvature agents led to full fusion. This suggests that fusion is completed when a lipidic fusion pore with net positive curvature is formed by the inner leaflets that compose a hemifusion diaphragm. Suboptimal fusion conditions were established for RBCs bound to cells expressing wild-type HA so that lipid but not aqueous dye spread was observed. While this is the same pattern of dye spread as in stable hemifusion, for this “stunted” fusion, lower concentrations of amphipaths in inner leaflets were required to promote transfer of aqueous dyes. Also, these amphipaths induced larger pores for stunted fusion than they generated within a stable hemifusion diaphragm. Therefore, spontaneous curvature of inner leaflets can affect formation and enlargement of fusion pores induced by HA. We propose that after the HA-ectodomain induces hemifusion, the transmembrane domain causes pore formation by conferring positive spontaneous curvature to leaflets of the hemifusion diaphragm.
PMCID: PMC2132481  PMID: 9060465
18.  Prediction of susceptibility to major depression by a model of interactions of multiple functional genetic variants and environmental factors 
Molecular Psychiatry  2012;17(6):624-633.
Major depressive disorder (MDD) is the most common psychiatric disorder and the second overall cause of disability. Even though a significant amount of the variance in the MDD phenotype is explained by inheritance, specific genetic variants conferring susceptibility to MDD explain only a minimal proportion of MDD causality. Moreover, genome-wide association studies have only identified two small-sized effect loci that reach genome-wide significance. In this study, a group of Mexican-American patients with MDD and controls recruited for a pharmacogenetic study were genotyped for nonsynonymous single-nucleotide polymorphisms (nsSNPs) and used to explore the interactions of multiple functional genetic variants with risk-classification tree analysis. The risk-classification tree analysis model and linkage disequilibrium blocks were used to replicate exploratory findings in the database of genotypes and phenotypes (dbGaP) for major depression, and pathway analysis was performed to explore potential biological mechanisms using the branching events. In exploratory analyses, we found that risk-classification tree analysis, using 15 nsSNPs that had a nominal association with MDD diagnosis, identified multiple increased-MDD genotype clusters and significant additive interactions in combinations of genotype variants that were significantly associated with MDD. The results in the dbGaP for major depression disclosed a multidimensional dependent phenotype constituted of MDD plus significant modifiers (smoking, marriage status, age, alcohol abuse/dependence and gender), which then was used for the association tree analysis. The reconstructed tree analysis for the dbGaP data showed robust reliability and replicated most of the genes involved in the branching process found in our exploratory analyses. Pathway analysis using all six major events of branching (PSMD9, HSD3B1, BDNF, GHRHR, PDE6C and PDLIM5) was significant for positive regulation of cellular and biological processes that are relevant to growth and organ development. Our findings not only provide important insights into the biological pathways underlying innate susceptibility to MDD but also offer a predictive framework based on interactions of multiple functional genetic variants and environmental factors. These findings identify novel targets for therapeutics and for translation into preventive, clinical and personalized health care.
doi:10.1038/mp.2012.13
PMCID: PMC3359641  PMID: 22449891
BDNF; depression; gene–environment interactions; genetics; GHRHR; risk tree classification analysis

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