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Yi Zhao - Top 30 Publications

Varied pathological and therapeutic response effects associated with CHCHD2 mutant and risk variants.

Mutations and polymorphic risk variant of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) have been associated with late-onset Parkinson disease. In vivo pathological evidence of CHCHD2 mutations is currently lacking. Utilizing transgenic Drosophila model, we examined the relative pathophysiologic effect of the pathogenic (c.182C>T, p.Thr61Ile and c.434G>A, p.Arg145Gln) and the risk (c.5C>T, p.Pro2Leu) CHCHD2 variants. All the transgenic models exhibited locomotor dysfunction which could be exacerbated by rotenone exposure, dopaminergic neuron degeneration, reduction in lifespan, mitochondrial dysfunction, oxidative stress and impairment in synaptic transmission. However, both mutants showed more severe early motor dysfunction, dopaminergic neuronal loss and higher hydrogen peroxide production compared to risk variant. p.Thr61Ile (co-segregated in three independent PD families) displayed the most severe phenotype followed by p.Arg145Gln (present only in index patient). We treated the transgenic flies with Ebselen, a mitochondrial hydrogen peroxide scavenger compound and Ebselen appears to be more effective in ameliorating motor function in the mutant than the risk variant models. We provide the first in vivo evidence of the pathological effects associated with CHCHD2 mutations. There was a difference in the pathological and drug response effects between the pathogenic and the risk variants. Ebselen may be a useful neuroprotective drug for carriers of CHCHD2 mutations. This article is protected by copyright. All rights reserved.

A genome-wide association study identifies six novel risk loci for primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.

The long non-coding RNA NONHSAG026900 predicts prognosis as a favorable biomarker in patients with diffuse large B-cell lymphoma.

Long non-coding RNAs are known to be involved in cancer progression, but their biological functions and prognostic values are still largely unexplored in diffuse large B-cell lymphoma. In this study, long non-coding RNAs expression was characterized in 1,403 samples including normal and diffuse large B-cell lymphoma by repurposing 7 microarray datasets. Compared with any stage of normal B cells, NONHSAG026900 expression was significantly decreased in tumor samples. And in germinal center B-cell subtype, the significantly higher expression of NONHSAG026900 indicated it was a favorable prognosis biomarker. Then the prognostic power of NONHSAG026900 was validated with another independent dataset and NONHSAG026900 improved the predictive power of International Prognostic Index as an independent factor. Moreover, functional prediction and validation demonstrated that NONHSAG026900 could inhibit cell cycle activity to restrain tumor proliferation. These findings identified NONHSAG026900 as a novel prognostic biomarker and offered a new therapeutic target for diffuse large B-cell lymphoma patients.

Elevated levels of TL1A are associated with disease activity in patients with systemic sclerosis.

TL1A is a member of the TNF superfamily. It performs significantly in the pathogenesis of rheumatic and autoimmune diseases partly through regulating the Th17 pathway. The clinical implication of circulating TL1A in patients with systemic sclerosis (SSc) remains unclear, and correlation between TL1A and Th17-related cytokines in the pathogenesis of SSc needs to be discussed. We measured serum levels of TL1A and Th17-related cytokines by ELISA in 47 patients with SSc, 56 patients with SLE, and 53 healthy subjects, and investigated association of these cytokines with clinical manifestations and laboratory variables. TL1A in relation to Th17-related cytokines were examined. In addition, the transcript level of TL1A in peripheral blood mononuclear cells (PBMCs) was determined by real-time reverse transcription polymerase chain reaction (real-time PCR). Serum TL1A levels were higher in patients with SSc than in healthy controls (P = 0.001), but were lower compared with SLE patients (P = 0.004). Diffuse cutaneous SSc or limited cutaneous SSc patients reported elevated expression of TL1A than those in healthy controls (P = 0.002, P = 0.007). Patients with active disease showed significantly higher expression of TL1A when compared with less active disease (P = 0.014). SSc patients with arthritis, elevated IgG titer, ESR >30 mm/h, and CRP >5 mg/l displayed elevated expression of TL1A, respectively. Serum levels of IL-17 and IL-21 were increased in SSc patients compared with healthy controls and positively related to TL1A levels (r s = 0.373, P = 0.010; r s = 0.370, P = 0.011, respectively). Moreover, TL1A mRNA expression in PBMCs was significantly higher in patients with SSc compared with healthy controls (P < 0.001). TL1A may play a role in the development of SSc.

AZD0530 sensitizes drug-resistant ALK-positive lung cancer cells by inhibiting SRC signaling.

Most tumors develop resistance to targeted cancer drugs, even though these drugs have produced substantial clinical responses. Here we established anaplastic lymphoma kinase (ALK)-positive drug-resistant lung cancer cell lines, which are resistant to ceritinib (LDK378). We found that ceritinib treatment resulted in robust upregulation of SRC activity, as measured by the phosphorylation of the SRC substrate paxillin. Knockdown of SRC alone with siRNA effectively sensitized ceritinib resistance in ALK-positive cells. Furthermore, SRC inhibition by AZD0530 was effective in ALK-resistant cancer cells. Thus, ALK inhibition by ceritinib may lead to upregulation of SRC signaling, and AZD0530 could serve as a potential drug in the clinic to treat ALK-resistant lung cancer patients.

Generation of a human induced pluripotent stem cell (iPSC) line carrying the Parkinson's disease linked LRRK2 variant S1647T.

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 64-year old male Parkinson's disease (PD) patient with S1647T variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model will be useful for further function studies and therapeutic screening.

Development of a human induced pluripotent stem cell (iPSC) line from a Parkinson's disease patient carrying the N551K variant in LRRK2 gene.

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 64-year old male Parkinson's disease (PD) patient with N551K variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model can complement in vivo PD models for pathophysiological studies and drug screening.

Derivation of human induced pluripotent stem cell (iPSC) line with LRRK2 gene R1398H variant in Parkinson's disease.

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 72-year old female Parkinson's disease (PD) patient with R1398H variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model provides a good platform for studying the mechanism of PD, and also for drug testing and gene therapy studies.

Reprogramming of a human induced pluripotent stem cell (iPSC) line from a Parkinson's disease patient with a R1628P variant in the LRRK2 gene.

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 59-year old male Parkinson's disease (PD) patient with R1628P variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model will provide a good resource for further pathophysiological studies of PD.

Astragaloside IV inhibits PMA-induced EPCR shedding through MAPKs and PKC pathway.

Astragaloside IV (AS-IV), a main active substance isolated from Astragalus membranaceus Bunge, has been shown to have multiple pharmacological effects. Endothelial cell protein C receptor (EPCR) is a marker of inflammation, and is also a major member of protein C (PC) anti-coagulation system. EPCR can be cut off from the cell surface by tumor necrosis factor-α converting enzyme (TACE), which is controlled through mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) pathways. To develop novel therapeutic drug for EPCR shedding, the effect of AS-IV was studied in phorbol-12-myristate 13-acetate (PMA)-induced human umbilical vein endothelial cells (HUVECs) and the potential molecular mechanism of AS-IV action was investigated. The results showed that AS-IV could significantly inhibit PMA-induced EPCR shedding. In further study, AS-IV suppressed the expression and activity of TACE. In addition, AS-IV could decrease the phosphorylation of MAPK such as janus kinase (JNK) and p38, and inhibit activation of PKC through the prevention of non-phosphorylation and phosphorylation of specific PKC isoforms in PMA-stimulated HUVECs. These findings indicate that AS-IV may be used as a natural medicine to treat EPCR-related systemic inflammation and cardiovascular diseases by targeting MAPK and PKC pathway.

Mechanism of immune evasion in breast cancer.

Breast cancer (BC) is the most common malignant tumor among women, with high morbidity and mortality. Its onset, development, metastasis, and prognosis vary among individuals due to the interactions between tumors and host immunity. Many diverse mechanisms have been associated with BC, with immune evasion being the most widely studied to date. Tumor cells can escape from the body's immune response, which targets abnormal components and foreign bodies, using different approaches including modification of surface antigens and modulation of the surrounding environment. In this review, we summarize the mechanisms and factors that impact the immunoediting process and analyze their functions in detail.

Bilirubin augments Ca(2+) load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels.

Neonatal brain is particularly vulnerable to pathological levels of bilirubin which elevates and overloads intracellular Ca(2+), leading to neurotoxicity. However, how voltage-gated calcium channels (VGCCs) are functionally involved in excess calcium influx remains unknown. By performing voltage-clamp recordings from bushy cells in the ventral cochlear nucleus (VCN) in postnatal rat pups (P4-17), we found the total calcium current density was more than doubled over P4-17, but the relative weight of VGCC subtypes changed dramatically, being relatively equal among T, L, N, P/Q and R-type at P4-6 to predominantly L, N, R over T and P/Q at P15-17. Surprisingly, acute administration of bilirubin augmented the VGCC currents specifically mediated by high voltage-activated (HVA) P/Q-type calcium currents. This augment was attenuated by intracellular loading of Ca(2+) buffer EGTA or calmodulin inhibitory peptide. Our findings indicate that acute exposure to bilirubin increases VGCC currents, primarily by targeting P/Q-type calcium channels via Ca(2+) and calmodulin dependent mechanisms to overwhelm neurons with excessive Ca(2+). Since P/Q-subtype calcium channels are more prominent in neonatal neurons (e.g. P4-6) than later stages, we suggest this subtype-specific enhancement of P/Q-type Ca(2+) currents likely contributes to the early neuronal vulnerability to hyperbilirubinemia in auditory and other brain regions.

Characterization of the B Cell Receptor Repertoire in the Intestinal Mucosa and of Tumor-Infiltrating Lymphocytes in Colorectal Adenoma and Carcinoma.

The B cells inhabited in mucosa play a vital role in mediating homeostasis with autoantigens and external Ags. Tumor-infiltrating lymphocytes are potential prognostic markers and therapeutic agents for cancer. However, the spatial heterogeneity of the B cell repertoire in intestinal mucosa and the tumor-infiltrating lymphocytes in colorectal cancer (CRC) remain poorly understood. In this study, we developed an unbiased method to amplify the IgH repertoire, as well as a bioinformatic pipeline to process these high-throughput sequencing data. With biopsies from seven intestinal mucosal segments, we uncovered their strong spatial homogeneity among the large intestine, where the clone overlap rate was up to 62.21%. The heterogeneity between terminal ileum and large intestine was also observed, including discrepant isotype distribution and low clone overlap rate. With tumor and adjacent normal mucosal tissues from CRC and colorectal advanced adenoma (AD) patients, we observed a similar IgH profile between tumor and adjacent normal mucosal tissues in AD, as well as a slight difference in CRC. Interestingly, we found distinct repertoire properties in the CRC tumor from AD and normal mucosa. Finally, we identified 1445 public clones for the normal mucosa, and 22 public clones for the CRC tumor with characteristic features. These data may be of potential use in clinical prognosis, diagnosis, and treatment of CRC.

XBP1-LOX Axis is critical in ER stress-induced growth of lung adenocarcinoma in 3D culture.

Rapid growth of tumor cells needs to consume large amounts of oxygen and glucose, due to lack of blood supply within the tumor, cells live in an environment that lack of oxygen and nutrients. This environment results in endoplasmic reticulum (ER) stress and activates the UPR (unfolded protein response). More and more evidence suggests UPR provides a growth signal pathway required for tumor growth. In the present study, we investigated the relationship between XBP1, one transcription factor in UPR, and the expression of LOX. We found that ER stress induces high expression of XBP1, one transcription factor in UPR, in both 2D culture and 3D culture; but only promotes growth of lung adenocarcinoma cells in in vitro 3D culture other than 2D culture. In 3D culture, we further showed that knockdown XBP1 expression can block Tm/Tg-induced cell growth. LOX genes may be key downstream effector of XBP1. Knockdown LOX expression can partially block XBP1-induced cell growth. Then we showed XBP1 suppressed by RNA interference (RNAi) can reduce the expression of LOX. For the first time, it is being shown that XBP1 can regulate the expression of LOX to promote cell growth.

GWAS-linked PPARGC1A variant in Asian patients with essential tremor.

Several microRNAs could predict survival in patients with hepatitis B-related liver cancer.

MicroRNAs as biomarkers play an important role in the tumorigenesis process, including hepatocellular carcinomas (HCCs). In this paper, we used The Cancer Genome Atlas (TCGA) database to mine hepatitis B-related liver cancer microRNAs that could predict survival in patients with hepatitis B-related liver cancer. There were 93 cases of HBV-HCC and 49 cases of adjacent normal controls included in the study. Kaplan-Meier survival analysis of a liver cancer group versus a normal control group of differentially expressed genes identified eight genes with statistical significance. Compared with the normal liver cell line, hepatocellular carcinoma cell lines had high expression of 8 microRNAs, albeit at different levels. A Cox proportional hazards regression model for multivariate analysis showed that four genes had a significant difference. We established classification models to distinguish short survival time and long survival time of liver cancers. Eight genes (mir9-3, mir10b, mir31, mir519c, mir522, mir3660, mir4784, and mir6883) were identified could predict survival in patients with HBV-HCC. There was a significant correlation between mir10b and mir31 and clinical stages (p < 0.05). A random forests model effectively estimated patient survival times.

Effective method of measuring the radioactivity of  131I-capsule prior to radioiodine therapy with significant reduction of the radiation exposure to the medical staff.

Radiation Protection in Radiology, Nuclear Medicine and Radio Oncology is of the utmost importance. Radioiodine therapy is a frequently used and effective method for the treatment of thyroid disease. Prior to each therapy the radioactivity of the [ 131I]-capsule must be determined to prevent misadministration. This leads to a significant radiation exposure to the staff. We describe an alternative method, allowing a considerable reduction of the radiation exposure. Two [ 131I]-capsules (A01=2818.5; A02=73.55.0 MBq) were measured multiple times in their own delivery lead containers - that is to say, [ 131I]-capsules remain inside the containers during the measurements (shielded measurement) using a dose calibrator and a well-type and a thyroid uptake probe. The results of the shielded measurements were correlated linearly with the [ 131I]-capsules radioactivity to create calibration curves for the used devices. Additional radioactivity measurements of 50 [ 131I]-capsules of different radioactivities were done to validate the shielded measuring method. The personal skin dose rate (HP(0.07)) was determined using calibrated thermo luminescent dosimeters. The determination coefficients for the calibration curves were R2>0.9980 for all devices. The relative uncertainty of the shielded measurement was <6.8%. At a distance of 10 cm from the unshielded capsule the HP(0.07) was 46.18 μSv/(GBq⋅s), and on the surface of the lead container containing the [ 131I]-capsule the HP(0.07) was 2.99 and 0.27 μSv/(GBq⋅s) for the two used container sizes. The calculated reduction of the effective dose by using the shielded measuring method was, depending on the used container size, 74.0% and 97.4%, compared to the measurement of the unshielded [ 131I]-capsule using a dose calibrator. The measured reduction of the effective radiation dose in the practice was 56.6% and 94.9 for size I and size II containers. The shielded [ 131I]-capsule measurement reduces the radiation exposure to the staff significantly and offers the same accuracy of the unshielded measurement in the same amount of time. In order to maintain the consistency of the measuring method, monthly tests have to be done by measuring a [ 131I]-capsule with known radioactivity. PACS number(s): 93.85.Np, 92.20.Td, 87.50.yk, 87.53.Bn.

Dual Functional LipoMET Mediates Envelope-type Nanoparticles to Combinational Oncogene Silencing and Tumor Growth Inhibition.

The success of small interfering RNA (siRNA)-mediated gene silencing for cancer therapy is still limited because of its instability and poor intracellular internalization. Traditional cationic carriers cannot adequately meet the need for clinical application of siRNA. We herein report a dual-functional liposome containing a cholesterol derivative of metformin, i.e., LipoMET, which takes advantage of the fusogenic activity as well as intrinsic tumor apoptosis inducing ability of biguanide moiety to achieve a combinational anti-oncogenic effect. In this study, the vascular endothelial growth factor (VEGF)-specific siRNAs were first electrostatically condensed into a ternary nanocomplex composed of polycation and hyaluronate, which was subsequently enveloped by LipoMET through membrane fusion. In comparison with common cationic control group, the resulting envelope-type nanoparticles ([email protected] nanoparticles [NPs]) showed the ability of rapid cellular internalization and effective endosomal escape of siRNA during intracellular trafficking studies. Systemic administration of the targeted LipoMETs was capable of inducing apoptosis and tumor growth inhibition in the NCI-H460 xenograft model. When carrying VEGF-specific siRNAs, [email protected] NPs remarkably downregulated the expression of VEGF and led to even more tumor suppression in vivo. Thus, LipoMET originated envelope-type nanoparticles may serve as a potential dual-functional siRNA delivery system to improve therapeutic effect of oncogene silencing.

Potential Value of miR-221/222 as Diagnostic, Prognostic, and Therapeutic Biomarkers for Diseases.

microRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by base pairing with their target messenger RNAs. Dysregulation of miRNAs is involved in the pathological initiation and progression of many human diseases. miR-221 and miR-222 (miR-221/222) are two highly homologous miRNAs, and they are significantly overexpressed in several types of human diseases. Silencing miR-221/222 could represent a promising approach for therapeutic studies. In the present review, we will describe the potential value of miR-221/222 as diagnostic, prognostic, and therapeutic biomarkers in various diseases including cancer and inflammatory diseases.

Intrapartum intervention rates and perinatal outcomes following induction of labour compared to expectant management at term from an Australian perinatal centre.

Induction of labor (IOL) is a common obstetric intervention, yet its impact on intervention rates and perinatal outcomes is conflicting.

Collective effect of personal behavior induced preventive measures and differential rate of transmission on spread of epidemics.

In the present work, the effect of personal behavior induced preventive measures is studied on the spread of epidemics over scale free networks that are characterized by the differential rate of disease transmission. The role of personal behavior induced preventive measures is parameterized in terms of variable λ, which modulates the number of concurrent contacts a node makes with the fraction of its neighboring nodes. The dynamics of the disease is described by a non-linear Susceptible Infected Susceptible model based upon the discrete time Markov Chain method. The network mean field approach is generalized to account for the effect of non-linear coupling between the aforementioned factors on the collective dynamics of nodes. The upper bound estimates of the disease outbreak threshold obtained from the mean field theory are found to be in good agreement with the corresponding non-linear stochastic model. From the results of parametric study, it is shown that the epidemic size has inverse dependence on the preventive measures (λ). It has also been shown that the increase in the average degree of the nodes lowers the time of spread and enhances the size of epidemics.

Enzyme-Initiated Free-Radical Polymerization of Molecularly Imprinted Polymer Nanogels on a Solid Phase with an Immobilized Radical Source.

An enzyme-mediated synthetic approach is described for the preparation of molecularly imprinted polymer nanoparticles (MIP-NPs) in aqueous media. Horseradish peroxidase (HRP) was used to initiate the polymerization of methacrylate or vinyl monomers and cross-linkers by catalyzing the generation of free radicals. To prevent entrapment of the enzyme in the cross-linked polymer, and to enable it to be reused, HRP was immobilized on a solid support. MIPs based on 4-vinylpyridine and 1,4-bis(acryloyl)piperazine for the recognition of 2,4-dichlorophenoxyacetic acid (2,4-D) and salicylic acid were synthesized in an aqueous medium. MIPs for the protein trypsin were also synthesized. MIP nanoparticles with sizes between 50 and 300 nm were obtained with good binding properties, a good imprinting effect, and high selectivity for the target molecule. The reusability of immobilized HRP for MIP synthesis was shown for several batches.

Corrigendum: Exon-intron circular RNAs regulate transcription in the nucleus.

Comparative primate obstetrics: Observations of 15 diurnal births in wild gelada monkeys (Theropithecus gelada) and their implications for understanding human and nonhuman primate birth evolution.

The birth process has been studied extensively in many human societies, yet little is known about this essential life history event in other primates. Here, we provide the most detailed account of behaviors surrounding birth for any wild nonhuman primate to date.

Continental-scale pollution of estuaries with antibiotic resistance genes.

Antibiotic resistance genes (ARGs) have moved from the environmental resistome into human commensals and pathogens, driven by human selection with antimicrobial agents. These genes have increased in abundance in humans and domestic animals, to become common components of waste streams. Estuarine habitats lie between terrestrial/freshwater and marine ecosystems, acting as natural filtering points for pollutants. Here, we have profiled ARGs in sediments from 18 estuaries over 4,000 km of coastal China using high-throughput quantitative polymerase chain reaction, and investigated their relationship with bacterial communities, antibiotic residues and socio-economic factors. ARGs in estuarine sediments were diverse and abundant, with over 200 different resistance genes being detected, 18 of which were found in all 90 sediment samples. The strong correlations of identified resistance genes with known mobile elements, network analyses and partial redundancy analysis all led to the conclusion that human activity is responsible for the abundance and dissemination of these ARGs. Such widespread pollution with xenogenetic elements has environmental, agricultural and medical consequences.

Annular Plaques With Skin Atrophy in a Young Patient.

Effect of Dendrobium officinale Extraction on Gastric Carcinogenesis in Rats.

Dendrobium officinale (Tie Pi Shi Hu in Chinese) has been widely used to treat different diseases in China. Anticancer effect is one of the important effects of Dendrobium officinale. However, the molecular mechanism of its anticancer effect remains unclear. In the present study, gastric carcinogenesis in rats was used to evaluate the effect of Dendrobium officinale on cancer, and its pharmacological mechanism was explored. Dendrobium officinale extracts (4.8 and 2.4 g/kg) were orally administered to the rats of the gastric carcinogenesis model. Compared with the cancer model group, the high dose of Dendrobium officinale extracts significantly inhibited the rate of carcinogenesis. Further analysis revealed that Dendrobium officinale extracts could regulate the DNA damage, oxidative stress, and cytokines related with carcinogenesis and induce cell apoptosis in order to prevent gastric cancer.

Akt3 is a privileged first responder in isozyme-specific electrophile response.

Isozyme-specific post-translational regulation fine tunes signaling events. However, redundancy in sequence or activity renders links between isozyme-specific modifications and downstream functions uncertain. Methods to study this phenomenon are underdeveloped. Here we use a redox-targeting screen to reveal that Akt3 is a first-responding isozyme sensing native electrophilic lipids. Electrophile modification of Akt3 modulated downstream pathway responses in cells and Danio rerio (zebrafish) and markedly differed from Akt2-specific oxidative regulation. Digest MS sequencing identified Akt3 C119 as the privileged cysteine that senses 4-hydroxynonenal. A C119S Akt3 mutant was hypomorphic for all downstream phenotypes shown by wild-type Akt3. This study documents isozyme-specific and chemical redox signal-personalized physiological responses.

Screening and analysis of breast cancer genes regulated by the human mammary microenvironment in a humanized mouse model.

Tumor microenvironments play critical regulatory roles in tumor growth. Although mouse cancer models have contributed to the understanding of human tumor biology, the effectiveness of mouse cancer models is limited by the inability of the models to accurately present humanized tumor microenvironments. Previously, a humanized breast cancer model in severe combined immunodeficiency mice was established, in which human breast cancer tissue was implanted subcutaneously, followed by injection of human breast cancer cells. It was demonstrated that breast cancer cells showed improved growth in the human mammary microenvironment compared with a conventional subcutaneous mouse model. In the present study, the novel mouse model and microarray technology was used to analyze changes in the expression of genes in breast cancer cells that are regulated by the human mammary microenvironment. Humanized breast and conventional subcutaneous mouse models were established, and orthotopic tumor cells were obtained from orthotopic tumor masses by primary culture. An expression microarray using Illumina HumanHT-12 v4 Expression BeadChip and database analyses were performed to investigate changes in gene expression between tumors from each microenvironment. A total of 94 genes were differentially expressed between the primary cells cultured from the humanized and conventional mouse models. Significant upregulation of genes that promote cell proliferation and metastasis or inhibit apoptosis, such as SH3-domain binding protein 5 (BTK-associated), sodium/chloride cotransporter 3 and periostin, osteoblast specific factor, and genes that promote angiogenesis, such as KIAA1618, was also noted. Other genes that restrain cell proliferation and accelerate cell apoptosis, including tripartite motif containing TRIM36 and NES1, were downregulated. The present results revealed differences in various aspects of tumor growth and metabolism between the two model groups and indicated the functional changes specific to the human mammary microenvironment.

Intersystem Crossing Rates of Isolated Fullerenes: Theoretical Calculations.

Although the triplet states of fullerenes have prosperous applications, it remains unclear how the structural parameters of singlet and triplet states control the intersystem crossing (ISC) rates. Here, electronic structure calculations (reorganization energy, driving force, and spin-orbit coupling) and a rate theory (Marcus formula) are employed to quantitatively predict the ISC rates of isolated fullerenes Cn (n = 60-110). The results demonstrate that the driving force is not the only factor to predict the ISC rates. For instance, although C80, C82, and C110 have the favorable driving force, the ISC rates are close to zero because of small spin obit couplings, whereas small ISC rates of C96 and C100 result from quite small reorganization energies. Meanwhile, in addition to well-known C60 and C70, C92 possesses good ISC property with obviously large ISC rate. C92 also has a higher triplet-state energy than singlet-state oxygen energy; it may thus have a good photoactive property.