A Hybrid Multimodal Emotion Recognition Framework for UX Evaluation Using Generalized Mixture Functions.

Multimodal emotion recognition has gained much traction in the field of affective computing, human-computer interaction (HCI), artificial intelligence (AI), and user experience (UX). There is growing demand to automate analysis of user emotion towards HCI, AI, and UX evaluation applications for providing affective services. Emotions are increasingly being used, obtained through the videos, audio, text or physiological signals. This has led to process emotions from multiple modalities, usually combined through ensemble-based systems with static weights. Due to numerous limitations like missing modality data, inter-class variations, and intra-class similarities, an effective weighting scheme is thus required to improve the aforementioned discrimination between modalities. This article takes into account the importance of difference between multiple modalities and assigns dynamic weights to them by adapting a more efficient combination process with the application of generalized mixture (GM) functions. Therefore, we present a hybrid multimodal emotion recognition (H-MMER) framework using multi-view learning approach for unimodal emotion recognition and introducing multimodal feature fusion level, and decision level fusion using GM functions. In an experimental study, we evaluated the ability of our proposed framework to model a set of four different emotional states (Happiness, Neutral, Sadness, and Anger) and found that most of them can be modeled well with significantly high accuracy using GM functions. The experiment shows that the proposed framework can model emotional states with an average accuracy of 98.19% and indicates significant gain in terms of performance in contrast to traditional approaches. The overall evaluation results indicate that we can identify emotional states with high accuracy and increase the robustness of an emotion classification system required for UX measurement.

Analysis of phototoxin taste closely correlates nucleophilicity to type 1 phototoxicity.

Pigments often inflict tissue-damaging and proaging toxicity on light illumination by generating free radicals and reactive oxygen species (ROS). However, the molecular mechanism by which organisms sense phototoxic pigments is unknown. Here, we discover that Transient Receptor Potential Ankyrin 1-A isoform [TRPA1(A)], previously shown to serve as a receptor for free radicals and ROS induced by photochemical reactions, enables Drosophila melanogaster to aphotically sense phototoxic pigments for feeding deterrence. Thus, TRPA1(A) detects both cause (phototoxins) and effect (free radicals and ROS) of photochemical reactions. A group of pigment molecules not only activates TRPA1(A) in darkness but also generates free radicals on light illumination. Such aphotic detection of phototoxins harboring the type 1 (radical-generating) photochemical potential requires the nucleophile-sensing ability of TRPA1. In addition, agTRPA1(A) from malaria-transmitting mosquitoes Anopheles gambiae heterologously produces larger current responses to phototoxins than Drosophila TRPA1(A), similar to their disparate nucleophile responsiveness. Along with TRPA1(A)-stimulating capabilities, type 1 phototoxins exhibit relatively strong photo-absorbance and low energy gaps between the highest occupied molecular orbital and the lowest unoccupied molecular orbital. However, TRPA1(A) activation is more highly concordant to type 1 phototoxicity than are those photochemical parameters. Collectively, nucleophile sensitivity of TRPA1(A) allows flies to taste potential phototoxins for feeding deterrence, preventing postingestive photo-injury. Conversely, pigments need to bear high nucleophilicity (electron-donating propensity) to act as type 1 phototoxins, which is consistent with the fact that transferring photoexcited electrons from phototoxins to other molecules causes free radicals. Thus, identification of a sensory mechanism in Drosophila reveals a property fundamental to type 1 phototoxins.

WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation.

WIP1 (wild-type p53-induced phosphatase 1) functions as a homeostatic regulator of the ataxia telangiectasia mutated (ATM)-mediated signaling pathway in response to ionizing radiation (IR). Here we identify homeodomain-interacting protein kinase 2 (HIPK2) as a protein kinase that targets WIP1 for phosphorylation and proteasomal degradation. In unstressed cells, WIP1 is constitutively phosphorylated by HIPK2 and maintained at a low level by proteasomal degradation. In response to IR, ATM-dependent AMPKα2-mediated HIPK2 phosphorylation promotes inhibition of WIP1 phosphorylation through dissociation of WIP1 from HIPK2, followed by stabilization of WIP1 for termination of the ATM-mediated double-strand break (DSB) signaling cascade. Notably, HIPK2 depletion impairs IR-induced γ-H2AX foci formation, cell-cycle checkpoint activation, and DNA repair signaling, and the survival rate of hipk2+/- mice upon γ-irradiation is markedly reduced compared to wild-type mice. Taken together, HIPK2 plays a critical role in the initiation of DSB repair signaling by controlling WIP1 levels in response to IR.

Abundance of C-terminal binding protein isoform is a prerequisite for exit from pluripotency in mouse embryonic stem cells.

Unlike lower organisms, mammals have 2 C-terminal binding protein (Ctbp) isoforms, Ctbp1 and Ctbp2. Ctbp2 is revealed as a key factor involved in determining cell fate decisions by regulating the epigenetic state in active embryonic stem cell (ESC) genes. However, the molecular mechanism underlying how Ctbp1 and Ctbp2 have different roles remains elusive. Here we demonstrate that Ctbp isoform abundance is important for mouse embryonic ESCs (mESCs) to exit from pluripotency. Temporal expression patterns of Ctbp isoforms were quite different; Ctbp2 is more highly expressed in mESCs and decreases during differentiation, while Ctbp1 is constantly expressed at a lower level. Ctbp2 knockdown, but not Ctbp1 knockdown, in mESCs resulted in impaired exit from pluripotency. Interestingly, Ctbp1 and Ctbp2 overexpression in Ctbp2-knockdown mESCs leads to exiting from pluripotency in a manner similar to that of wild-type mESCs. Quantification of Ctbp1 and Ctbp2 revealed that differentiation ability correlates with abundance of Ctbp isoform in undifferentiated mESCs, suggesting that a sufficient amount of Ctbp isoform is a prerequisite for exiting from pluripotency. The results support the contention that 2 redundant Ctbp isoforms regulate elaborate differentiation via temporally distinctive regulatory patterns in mESCs.-Suh, M. Y., Kim, T. W., Lee, H.-T., Shin, J., Kim, J.-H., Jang, H., Kim, H. J., Kim, S.-T., Cho, E.-J., Youn, H.-D. Abundance of C-terminal binding protein isoform is a prerequisite for exit from pluripotency in mouse embryonic stem cells.

OCT4 directly regulates stemness and extracellular matrix-related genes in human germ cell tumours.

Germ cell tumours (GCTs) are one of the most threatening malignancies in young men and women. Although several reports have suggested the importance of OCT4 in human GCTs, its role has not been clearly investigated on a molecular level. In this study, we revealed GCT-specific direct transcriptional target genes of OCT4. Conditional knockdown of OCT4 in GCT cell lines reduced cell proliferation by affecting both cell cycle and death. Knockdown of OCT4 also reduced stemness of GCTs, as assessed by the expression of other stemness factors, alkaline phosphatase staining, and tumour sphere formation ability. Analysis of whole mRNA expression patterns among GCT cells harbouring endogenous, depleted, and rescued OCT4 revealed 1133 OCT4 target genes in GCT. Combined analysis of both the chromatin binding signature of OCT4 and the genes whose expression levels were changed by OCT4 revealed 258 direct target genes of OCT4 in GCTs. In a similar way, 594 direct target genes in normal embryonic stem cells (ESCs) were identified. Among these two sets of OCT4 direct target genes, 38 genes were common between GCTs and ESCs, most of which were related to regulation of pluripotency, and 220 genes were specific to GCTs, most of which were related to focal adhesion and extracellular matrix organisation. These results provide a molecular basis for how OCT4 regulates GCT stemness and will aid our understanding of the role of OCT4 in other cancers.

Acetylation of Smc3 by Eco1 is required for S phase sister chromatid cohesion in both human and yeast.

Sister chromatid cohesion is normally established in S phase in a process that depends on the cohesion establishment factor Eco1, a conserved acetyltransferase. However, due to the lack of known in vivo substrates, how Eco1 regulates cohesion is not understood. Here we report that yeast Eco1 and its human ortholog, ESCO1, both acetylate Smc3, a component of the cohesin complex that physically holds the sister chromatid together, at two conserved lysine residues. Mutating these lysine residues to a nonacetylatable form leads to increased loss of sister chromatid cohesion and genome instability in both yeast and human. In addition, we clarified that the acetyltransferase activity of Eco1 is essential for its function. Our study thus identified a molecular target for the acetyltransferase Eco1 and revealed that Smc3 acetylation is a conserved mechanism in regulating sister chromatid cohesion.

Modulation of lysine methylation in myocyte enhancer factor 2 during skeletal muscle cell differentiation.

Myocyte enhancer factor 2 (MEF2) is a family of transcription factors that regulates many processes, including muscle differentiation. Due to its many target genes, MEF2D requires tight regulation of transcription activity over time and by location. Epigenetic modifiers have been suggested to regulate MEF2-dependent transcription via modifications to histones and MEF2. However, the modulation of MEF2 activity by lysine methylation, an important posttranslational modification that alters the activities of transcription factors, has not been studied. We report the reversible lysine methylation of MEF2D by G9a and LSD1 as a regulatory mechanism of MEF2D activity and skeletal muscle differentiation. G9a methylates lysine-267 of MEF2D and represses its transcriptional activity, but LSD1 counteracts it. This residue is highly conserved between MEF2 members in mammals. During myogenic differentiation of C2C12 mouse skeletal muscle cells, the methylation of MEF2D by G9a decreased, on which MEF2D-dependent myogenic genes were upregulated. We have also identified lysine-267 as a methylation/demethylation site and demonstrate that the lysine methylation state of MEF2D regulates its transcriptional activity and skeletal muscle cell differentiation.

TAK1-ECSIT-TRAF6 complex plays a key role in the TLR4 signal to activate NF-κB.

ECSIT (evolutionarily conserved signaling intermediate in Toll pathways) is known as a multifunctional regulator in different signals, including Toll-like receptors (TLRs), TGF-ß, and BMP. Here, we report a new regulatory role of ECSIT in TLR4-mediated signal. By LPS stimulation, ECSIT formed a high molecular endogenous complex including TAK1 and TRAF6, in which ECSIT interacted with each protein and regulated TAK1 activity, leading to the activation of NF-κB. ECSIT-knockdown THP-1 (ECSIT(KD) THP-1) cells exhibited severe impairments in NF-κB activity, cytokine production, and NF-κB-dependent gene expression, whereas those were dramatically restored by reintroduction of wild type (WT) ECSIT gene. Interestingly, ECSIT mutants, which lack a specific interacting domain for either TAK1 or TRAF6, could not restore these activities. Moreover, no significant changes in both NF-κB activity and cytokine production induced by TLR4 could be seen in TAK1(KD) or TRAF6(KD) THP-1 cells transduced by WT ECSIT, strongly suggesting the essential requirement of TAK1-ECSIT-TRAF6 complex in TLR4 signaling. Taken together, our data demonstrate that the ECSIT complex, including TAK1 and TRAF6, plays a pivotal role in TLR4-mediated signals to activate NF-κB.

Phosphorylation and ubiquitination-dependent degradation of CABIN1 releases p53 for transactivation upon genotoxic stress.

CABIN1 acts as a negative regulator of p53 by keeping p53 in an inactive state on chromatin. Genotoxic stress causes rapid dissociation of CABIN1 and activation of p53. However, its molecular mechanism is still unknown. Here, we reveal the phosphorylation- and ubiquitination-dependent degradation of CABIN1 upon DNA damage, releasing p53 for transcriptional activation. The DNA-damage-signaling kinases, ATM and CHK2, phosphorylate CABIN1 and increase the degradation of CABIN1 protein. Knockdown or overexpression of these kinases influences the stability of CABIN1 protein showing that their activity is critical for degradation of CABIN1. Additionally, CABIN1 was found to undergo ubiquitin-dependent proteasomal degradation mediated by the CRL4DDB2 ubiquitin ligase complex. Both phosphorylation and ubiquitination of CABIN1 appear to be relevant for controlling the level of CABIN1 protein upon genotoxic stress.

Genome-wide association study for serum complement C3 and C4 levels in healthy Chinese subjects.

Complement C3 and C4 play key roles in the main physiological activities of complement system, and their deficiencies or over-expression are associated with many clinical infectious or immunity diseases. A two-stage genome-wide association study (GWAS) was performed for serum levels of C3 and C4. The first stage was conducted in 1,999 healthy Chinese men, and the second stage was performed in an additional 1,496 subjects. We identified two SNPs, rs3753394 in CFH gene and rs3745567 in C3 gene, that are significantly associated with serum C3 levels at a genome-wide significance level (P = 7.33 × 10(-11) and P = 1.83 × 10(-9), respectively). For C4, one large genomic region on chromosome 6p21.3 is significantly associated with serum C4 levels. Two SNPs (rs1052693 and rs11575839) were located in the MHC class I area that include HLA-A, HLA-C, and HLA-B genes. Two SNPs (rs2075799 and rs2857009) were located 5' and 3' of C4 gene. The other four SNPs, rs2071278, rs3763317, rs9276606, and rs241428, were located in the MHC class II region that includes HLA-DRA, HLA-DRB, and HLA-DQB genes. The combined P-values for those eight SNPs ranged from 3.19 × 10(-22) to 5.62 × 10(-97). HBsAg-positive subjects have significantly lower C3 and C4 protein concentrations compared with HBsAg-negative subjects (P<0.05). Our study is the first GWAS report which shows genetic components influence the levels of complement C3 and C4. Our significant findings provide novel insights of their related autoimmune, infectious diseases, and molecular mechanisms.

A genome wide association study of genetic loci that influence tumour biomarkers cancer antigen 19-9, carcinoembryonic antigen and α fetoprotein and their associations with cancer risk.

OBJECTIVE: Tumour biomarkers are used as indicators for cancer screening and as predictors for therapeutic responses and prognoses in cancer patients. We aimed to identify genetic loci that influence concentrations of cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) and α fetoprotein (AFP), and investigated the associations between the significant single nucleotide polymorphisms (SNPs) with risks of oesophageal squamous cell (OSCC), pancreatic and hepatocellular cancers. DESIGN: We carried out a genome wide association study on plasma CA19-9, CEA and AFP concentrations in 3451 healthy Han Chinese and validated the results in 10 326 individuals. Significant SNPs were further investigated in three case control studies (2031 OSCC cases and 2044 controls; 981 pancreatic cancer cases and 1991 controls; and 348 hepatocellular cancer cases and 359 controls). RESULTS: The analyses showed association peaks on three genetic loci for CA19-9 (FUT6-FUT3 at 19p13.3, FUT2-CA11 at 19q13.3 and B3GNT3 at 19p13.1; p=1.16×10(-13)-3.30×10(-290)); four for CEA (ABO at 9q34.2, FUT6 at 19p13.3, FUT2 at 19q13.3 and FAM3B at 21q22.3; p=3.33×10(-22)-5.81×10(-209)); and two for AFP (AFP at 4q11-q13 and HISPPD2A at 15q15.3; p=3.27×10(-18) and 1.28×10(-14)). These explained 17.14% of the variations in CA19-9, 8.95% in CEA and 0.57% in AFP concentrations. Significant ABO variants were also associated with risk of OSCC and pancreatic cancers, and AFP variants with risk of hepatocellular cancer (p<0.05). CONCLUSIONS: This study identified several loci associated with CA19-9, CEA and AFP concentrations. The ABO variants were associated with risk of OSCC and pancreatic cancers and AFP variants with risk of hepatocellular cancer.

Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men.

Circulating androgen levels are often used as indicators of physiological or pathological conditions. More than half of the variance for circulating androgen levels is thought to be genetically influenced. A genome-wide association study (GWAS) has identified two loci, SHBG at 17p13 and FAM9B at Xp22, for serum testosterone (T) levels; however, these explain only a small fraction of inter-individual variability. To identify additional genetic determinants of androgen levels, a GWAS of baseline serum T and dihydrotestosterone (DHT) levels was conducted in 3225 men of European ancestry from the REduction by DUtasteride of Prostate Cancer Events (REDUCE) study. Cross-validation was used to confirm the observed associations between the drug (n = 1581) and placebo (n = 1644) groups of REDUCE. In addition to confirming the associations of two known loci with serum T levels (rs727428 in SHBG: P = 1.26 × 10(-12); rs5934505 in FAM9B: P = 1.61 × 10(-8)), we identified a new locus, JMJD1C at 10q21 that was associated with serum T levels at a genome-wide significance level (rs10822184: P = 1.12 × 10(-8)). We also observed that the SHBG locus was associated with serum DHT levels (rs727428: P = 1.47 × 10(-11)). Moreover, two additional variants in SHBG [rs72829446, in strong linkage equilibrium with the missense variant D356N (rs6259), and rs1799941] were also independently associated with circulating androgen levels in a statistical scale. These three loci (JMJD1C, SHBG and FAM9B) were estimated to account for ~5.3 and 4.1% of the variance of serum T and DHT levels. Our findings may provide new insights into the regulation of circulating androgens and potential targets for androgen-based therapy.

Genome-wide association study identifies novel loci associated with serum level of vitamin B12 in Chinese men.

Vitamin B12 (VitB12 or cobalamin) is an essential cofactor in several metabolic pathways. Clinically, VitB12 deficiency is associated with pernicious anemia, neurodegenerative disorder, cardiovascular disease and gastrointestinal disease. Although previous genome-wide association studies (GWAS) identified several genes, including FUT2, CUBN, TCN1 and MUT, that may influence VitB12 levels in European populations, common genetic determinants of VitB12 remain largely unknown, especially in Asian populations. Here we performed a GWAS in 1999 healthy Chinese men and replicated the top findings in an independent Chinese sample with 1496 subjects. We identified four novel genomic loci that were significantly associated with serum level of VitB12 at a genome-wide significance level of 5.00 × 10(-8). These four loci were MS4A3 (11q12.1; rs2298585; P= 2.64 × 10(-15)), CLYBL (13q32; rs41281112; P= 9.23 × 10(-10)), FUT6 (19p13.3; rs3760776; P= 3.68 × 10(-13)) and 5q32 region (rs10515552; P= 3.94 × 10(-8)). In addition, we also confirmed the association with the serum level of VitB12 for the previously reported FUT2 gene and identified one novel non-synonymous single-nucleotide polymorphism in FUT2 gene in this Chinese population (19q13.33; rs1047781; P= 3.62 × 10(-36)). The new loci identified offer new insights into the biochemical pathways involved in determining the serum level of VitB12 and provide opportunities to better delineate the role of VitB12 in health and disease.

A genome-wide association and gene-environment interaction study for serum triglycerides levels in a healthy Chinese male population.

Triglyceride (TG) is a complex phenotype influenced by both genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified genes or loci affecting lipid levels; however, such studies in Chinese populations are limited. A two-stage GWAS were conducted to identify genetic variants that were associated with TG in a Chinese population of 3495 men. Gene-environment interactions on serum TG levels were further investigated for the seven single nucleotide polymorphisms (SNPs) that were studied in both stages. Two previously reported SNPs (rs651821 in APOA5, rs328 in LPL) were replicated in the second stage, and the combined P-values were 9.19 × 10(-26) and 1.41 × 10(-9) for rs651821 and rs328, respectively. More importantly, a significant interaction between aldehyde dehydrogenase 2 (ALDH2) rs671 and alcohol consumption on serum TG levels were observed (P = 3.34 × 10(-5)). Rs671 was significantly associated with serum TG levels in drinkers (P = 1.90 × 10(-10)), while no association was observed in non-drinkers (P > 0.05). For drinkers, men carrying the AA/AG genotype have significantly lower serum TG levels, compared with men carrying the GG genotype. For men with the GG genotype, the serum TG levels increased with the quantity of alcohol intake (P = 1.28 × 10(-8) for trend test). We identified a novel, significant interaction effect between alcohol consumption and the ALDH2 rs671 polymorphism on TG levels, which suggests that the effect of alcohol intake on TG occurs in a two-faceted manner. Just one drink can increase TG level in susceptible individuals who carry the GG genotype, while individuals carrying AA/AG genotypes may actually benefit from moderate drinking.

Genome-wide association study of sex hormones, gonadotropins and sex hormone-binding protein in Chinese men.

BACKGROUND: Sex hormones and gonadotropins exert a wide variety of effects in physiological and pathological processes. Accumulated evidence shows a strong heritable component of circulating concentrations of these hormones. Recently, several genome-wide association studies (GWASs) conducted in Caucasians have identified multiple loci that influence serum levels of sex hormones. However, the genetic determinants remain unknown in Chinese populations. In this study, we aimed to identify genetic variants associated with major sex hormones, gonadotropins, including testosterone, oestradiol, follicle-stimulating hormone (FSH), luteinising hormone (LH) and sex hormone binding globulin (SHBG) in a Chinese population. METHODS: A two-stage GWAS was conducted in a total of 3495 healthy Chinese men (1999 subjects in the GWAS discovery stage and 1496 in the confirmation stage). RESULTS: We identified a novel genetic region at 15q21.2 (rs2414095 in CYP19A1), which was significantly associated with oestradiol and FSH in the Chinese population at a genome-wide significant level (p=6.54×10(-31) and 1.59×10(-16), respectively). Another single nucleotide polymorphism in CYP19A1 gene was significantly associated with oestradiol level (rs2445762, p=7.75×10(-28)). In addition, we confirmed the previous GWAS-identified locus at 17p13.1 for testosterone (rs2075230, p=1.13×10(-8)) and SHBG level (rs2075230, p=4.75×10(-19)) in the Chinese population. CONCLUSIONS: This study is the first GWAS investigation of genetic determinants of FSH and LH. The identification of novel susceptibility loci may provide more biological implications for the synthesis and metabolism of these hormones. More importantly, the confirmation of the genetic loci for testosterone and SHBG suggests common genetic components shared among different ethnicities.

OnDev-LCT: On-Device Lightweight Convolutional Transformers towards federated learning.

Federated learning (FL) has emerged as a promising approach to collaboratively train machine learning models across multiple edge devices while preserving privacy. The success of FL hinges on the efficiency of participating models and their ability to handle the unique challenges of distributed learning. While several variants of Vision Transformer (ViT) have shown great potential as alternatives to modern convolutional neural networks (CNNs) for centralized training, the unprecedented size and higher computational demands hinder their deployment on resource-constrained edge devices, challenging their widespread application in FL. Since client devices in FL typically have limited computing resources and communication bandwidth, models intended for such devices must strike a balance between model size, computational efficiency, and the ability to adapt to the diverse and non-IID data distributions encountered in FL. To address these challenges, we propose OnDev-LCT: Lightweight Convolutional Transformers for On-Device vision tasks with limited training data and resources. Our models incorporate image-specific inductive biases through the LCT tokenizer by leveraging efficient depthwise separable convolutions in residual linear bottleneck blocks to extract local features, while the multi-head self-attention (MHSA) mechanism in the LCT encoder implicitly facilitates capturing global representations of images. Extensive experiments on benchmark image datasets indicate that our models outperform existing lightweight vision models while having fewer parameters and lower computational demands, making them suitable for FL scenarios with data heterogeneity and communication bottlenecks.

A comparison of Bayesian and frequentist approaches to incorporating external information for the prediction of prostate cancer risk.

We present the most comprehensive comparison to date of the predictive benefit of genetics in addition to currently used clinical variables, using genotype data for 33 single-nucleotide polymorphisms (SNPs) in 1,547 Caucasian men from the placebo arm of the REduction by DUtasteride of prostate Cancer Events (REDUCE®) trial. Moreover, we conducted a detailed comparison of three techniques for incorporating genetics into clinical risk prediction. The first method was a standard logistic regression model, which included separate terms for the clinical covariates and for each of the genetic markers. This approach ignores a substantial amount of external information concerning effect sizes for these Genome Wide Association Study (GWAS)-replicated SNPs. The second and third methods investigated two possible approaches to incorporating meta-analysed external SNP effect estimates - one via a weighted PCa 'risk' score based solely on the meta analysis estimates, and the other incorporating both the current and prior data via informative priors in a Bayesian logistic regression model. All methods demonstrated a slight improvement in predictive performance upon incorporation of genetics. The two methods that incorporated external information showed the greatest receiver-operating-characteristic AUCs increase from 0.61 to 0.64. The value of our methods comparison is likely to lie in observations of performance similarities, rather than difference, between three approaches of very different resource requirements. The two methods that included external information performed best, but only marginally despite substantial differences in complexity.

Ultrasound backscatter microscopy image-guided intraventricular gene delivery at murine embryonic age 9.5 and 10.5 produces distinct transgene expression patterns at the adult stage.

In utero injection of a retroviral vector into the embryonic telencephalon aided by ultrasound backscatter microscopy permits introduction of a gene of interest at an early stage of development. In this study, we compared the tissue distribution of gene expression in adult mice injected with retroviral vectors at different embryonic ages in utero. Following ultrasound image-guided gene delivery (UIGD) into the embryonic telencephalon, adult mice were subjected to whole-body luciferase imaging and immunohistochemical analysis at 6 weeks and 1 year postinjection. Luciferase activity was observed in a wide range of tissues in animals injected at embryonic age 9.5 (E9.5), whereas animals injected at E10.5 showed brain-localized reporter gene expression. These results suggest that mouse embryonic brain creates a closed and impermeable structure around E10. Therefore, by injecting a transgene before or after E10, transgene expression can be manipulated to be local or systemic. Our results also provide information that widens the applicability of UIGD beyond neuroscience studies.

Genetic markers associated with early cancer-specific mortality following prostatectomy.

BACKGROUND: This study sought to identify novel effectors and markers of localized but potentially life-threatening prostate cancer (PCa), by evaluating chromosomal copy number alterations (CNAs) in tumors from patients who underwent prostatectomy and correlating these with clinicopathologic features and outcome. METHODS: CNAs in tumor DNA samples from 125 patients in the discovery cohort who underwent prostatectomy were assayed with high-resolution Affymetrix 6.0 single-nucleotide polymorphism microarrays and then analyzed using the Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm. RESULTS: The assays revealed 20 significant regions of CNAs, 4 of them novel, and identified the target genes of 4 of the alterations. By univariate analysis, 7 CNAs were significantly associated with early PCa-specific mortality. These included gains of chromosomal regions that contain the genes MYC, ADAR, or TPD52 and losses of sequences that incorporate SERPINB5, USP10, PTEN, or TP53. On multivariate analysis, only the CNAs of PTEN (phosphatase and tensin homolog) and MYC (v-myc myelocytomatosis viral oncogene homolog) contributed additional prognostic information independent of that provided by pathologic stage, Gleason score, and initial prostate-specific antigen level. Patients whose tumors had alterations of both genes had a markedly elevated risk of PCa-specific mortality (odds ratio = 53; 95% CI = 6.92-405, P = 1 × 10(-4)). Analyses of 333 tumors from 3 additional distinct patient cohorts confirmed the relationship between CNAs of PTEN and MYC and lethal PCa. CONCLUSIONS: This study identified new CNAs and genes that likely contribute to the pathogenesis of localized PCa and suggests that patients whose tumors have acquired CNAs of PTEN, MYC, or both have an increased risk of early PCa-specific mortality.

Genome-wide association study identified novel genetic variant on SLC45A3 gene associated with serum levels prostate-specific antigen (PSA) in a Chinese population.

Prostate-specific antigen (PSA) is a commonly used cancer biomarker for prostate cancer, and is often included as part of routine physical examinations in China. Serum levels of PSA may be influenced by genetic factors as well as other factors. A genome-wide association study (GWAS) conducted in a European population successfully identified six genetic loci that were significantly associated with PSA level. In this study, we aimed to identify common genetic variants that are associated with serum level of PSA in a Chinese population. We also evaluated the effects of those variants by creating personalized PSA cutoff values. A two-stage GWAS of PSA level was performed among men age 20-69 years and self-reported cancer-free participants that underwent routine physical examinations at several hospitals in Guangxi Province, China. Single nucleotide polymorphisms (SNPs) significantly associated with PSA levels in the first stage of sample (N = 1,999) were confirmed in the second stage of sample (N = 1,496). Multivariate linear regression was used to assess the independent contribution of confirmed SNPs and known covariates, such as age, to the level of PSA. SNPs in three regions were significantly associated with levels of PSA in this two-stage GWAS, and had combined P values between 4.62 × 10(-17) and 6.45 × 10(-37). The three regions are located on 1q32.1 at SLC45A3, 10q11.23 at MSMB, and 19q13.33 at KLK3. The region 1q32.1 at SLC45A3 was identified as a novel locus. Genetic variants contributed significantly more to the variance of PSA level than known covariates such as age. Personalized cutoff values of serum PSA, calculated based on the inheritance of these associated SNPs, differ considerably among individuals. Identification of these genetic markers provides new insight into the molecular mechanisms of PSA. Taking individual variation into account, these genetic variants may improve the performance of PSA to predict prostate cancer.