Dosage Compensation of Trisomy 21 and Its Implications for Hematopoietic Pathogenesis in Down Syndrome

Down Syndrome (DS), the most common aneuploidy seen in live-borns, is caused by trisomy for chromosome 21. DS imposes high risks for multiple health issues involving various systems of the body. The genetic complexity of trisomy 21 and natural variation between all individuals has impeded understanding of the specific cell pathologies and pathways involved. In addition, chromosomal disorders have been considered outside the hopeful progress in gene therapies for single-gene disorders. Here we test the feasibility of correcting imbalanced expression of genes across an extra chromosome by expression of a single gene, XIST, the key player in X chromosome inactivation. We targeted a large XIST transgene into one chromosome 21 in DS iPS cells, and demonstrated XIST RNA spreads and induces heterochromatin and gene silencing across that autosome in cis. By making XIST inducible, this allows direct comparison of effects of trisomy 21 expression on cell function and phenotypes. Importantly, XIST-induction during in vitro hematopoiesis normalized excess production of differentiated blood cell types (megakaryocytes and erythrocytes), known to confer high risk for myeloproliferative disorder and leukemia. In contrast, trisomy silencing enhances production of iPS and neural stem cells, consistent with DS clinical features. Further analysis revealed that trisomy 21 initially impacts the endothelial hematopoietic transition (EHT) to generate excess CD43+ progenitors, and also increases their colony forming potential. Furthermore, results provide evidence for a key role for enhanced IGF signaling, involving over-expression of non-chromosome 21 genes controlled by trisomy 21. Finally, experiments to examine trisomy effects on angiogenesis showed no effect on production of endothelial cells, but it remains unclear whether trisomic cells may differ in ability to form vessels. Collectively, this thesis demonstrates proof-of-principle for XIST-mediated “trisomy silencing”. Phenotypic improvement of hematopoietic and neural stem cells demonstrates the value for research into DS pathogenesis, but also provides a foundation of potential for future development of “chromosome therapy” for DS patients

Learning Deep Latent Spaces for Multi-Label Classification

Multi-label classification is a practical yet challenging task in machine learning related fields, since it requires the prediction of more than one label category for each input instance. We propose a novel deep neural networks (DNN) based model, Canonical Correlated AutoEncoder (C2AE), for solving this task. Aiming at better relating feature and label domain data for improved classification, we uniquely perform joint feature and label embedding by deriving a deep latent space, followed by the introduction of label-correlation sensitive loss function for recovering the predicted label outputs. Our C2AE is achieved by integrating the DNN architectures of canonical correlation analysis and autoencoder, which allows end-to-end learning and prediction with the ability to exploit label dependency. Moreover, our C2AE can be easily extended to address the learning problem with missing labels. Our experiments on multiple datasets with different scales confirm the effectiveness and robustness of our proposed method, which is shown to perform favorably against state-of-the-art methods for multi-label classification.Comment: published in AAAI-201

Spermatic Cord Metastasis of Primary Hepatocellular Carcinoma Presenting as an Inguinal Mass: A Case Report

Most spermatic cord masses are benign, and malignant spermatic cord tumors are uncommon. Spermatic cord metastases originating from hepatocellular carcinoma (HCC) have not been previously reported in the English language literature as determined by a PubMed search. We report a male patient who presented with a painful palpable mass in the right inguinal area. The patient was diagnosed with HCC in 2004 and undertook a nonsurgical approach to control the cancer. A radical orchiectomy was performed, and the pathological report showed metastatic HCC in the spermatic cord. The patient received palliative radiation therapy because of a positive surgical margin. No recurrence was noted after 6 months of followup

Designing primers and evaluation of the efficiency of propidium monoazide – Quantitative polymerase chain reaction for counting the viable cells of Lactobacillus gasseri and Lactobacillus salivarius

AbstractThe purpose of this study is to evaluate the efficiency of using propidium monoazide (PMA) real-time quantitative polymerase chain reaction (qPCR) to count the viable cells of Lactobacillus gasseri and Lactobacillus salivarius in probiotic products. Based on the internal transcription spacer and 23S rRNA genes, two primer sets specific for these two Lactobacillus species were designed. For a probiotic product, the total deMan Rogosa Sharpe plate count was 8.65±0.69 log CFU/g, while for qPCR, the cell counts of L. gasseri and L. salivarius were 8.39±0.14 log CFU/g and 8.57±0.24 log CFU/g, respectively. Under the same conditions, for its heat-killed product, qPCR counts for L. gasseri and L. salivarius were 6.70±0.16 log cells/g and 7.67±0.20 log cells/g, while PMA-qPCR counts were 5.33±0.18 log cells/g and 5.05±0.23 log cells/g, respectively. For cell dilutions with a viable cell count of 8.5 log CFU/mL for L. gasseri and L. salivarius, after heat killing, the PMA-qPCR count for both Lactobacillus species was near 5.5 log cells/mL. When the PMA-qPCR counts of these cell dilutions were compared before and after heat killing, although some DNA might be lost during the heat killing, significant qPCR signals from dead cells, i.e., about 4–5 log cells/mL, could not be reduced by PMA treatment. Increasing PMA concentrations from 100 μM to 200 μM or light exposure time from 5 minutes to 15 minutes had no or, if any, only minor effect on the reduction of qPCR signals from their dead cells. Thus, to differentiate viable lactic acid bacterial cells from dead cells using the PMA-qPCR method, the efficiency of PMA to reduce the qPCR signals from dead cells should be notable

Using the Norm Activation Model to Predict the Pro-Environmental Behaviors of Public Servants at the Central and Local Governments in Taiwan

An understanding of the environmental value-action gap between public servants at the central and local governments is essential for the effective implementation of environmental policies, which is limited in the extant literature. This study has adopted the norm activation model to explore the pro-environmental behaviors of public servants at the central and local governments in Taiwan. A total of 7567 valid questionnaires were collected, and significant differences were evident between public servants at the central (n = 3400) and local (n = 4167) governments in personal norms, awareness of consequences, ascription of responsibility, and pro-environmental behaviors. Findings revealed that personal norms were the key factors predicting pro-environmental behaviors of public servants at both the central and local governments. Results also indicated that the awareness of consequences by public servants at the central government had a direct effect on their pro-environmental behaviors, which in turn had a significant effect on their ascription of responsibility. In contrast, awareness of consequences by public servants at the local government had no significant direct effect on their pro-environmental behaviors and had only a weak positive effect on their ascription of responsibility

VoiceBank-2023: A Multi-Speaker Mandarin Speech Corpus for Constructing Personalized TTS Systems for the Speech Impaired

Services of personalized TTS systems for the Mandarin-speaking speech impaired are rarely mentioned. Taiwan started the VoiceBanking project in 2020, aiming to build a complete set of services to deliver personalized Mandarin TTS systems to amyotrophic lateral sclerosis patients. This paper reports the corpus design, corpus recording, data purging and correction for the corpus, and evaluations of the developed personalized TTS systems, for the VoiceBanking project. The developed corpus is named after the VoiceBank-2023 speech corpus because of its release year. The corpus contains 29.78 hours of utterances with prompts of short paragraphs and common phrases spoken by 111 native Mandarin speakers. The corpus is labeled with information about gender, degree of speech impairment, types of users, transcription, SNRs, and speaking rates. The VoiceBank-2023 is available by request for non-commercial use and welcomes all parties to join the VoiceBanking project to improve the services for the speech impaired.Comment: submitted to 26th International Conference of the ORIENTAL-COCOSD

Effect of Surface Geology on Ground Motions: The Case of Station TAP056 - Chutzuhu Site

In the Tatun mountain area of northern Taiwan are two strong motion stations approximately 2.5 km apart, TAP056 and TAP066 of the TSMIP network. The accelerometer at station TAP056 is often triggered by earthquakes, but that at TAP066 station is not. Comparisons of vertical and horizontal peak ground accelerations reveal PGA in the vertical, east-west, and north-south components at TAP056 station to be 3.89, 7.57, and 5.45 times those at station TAP066, respectively. The PGA ratio does not seem to be related to earthquake source or path. Fourier spectra of earthquake records at station TAP056 always have approximately the same dominant frequency; however, those at station TAP066 are different due to different sources and paths of different events. This shows that spectra at TAP056 station are mainly controlled by local site effects. The spectral ratios of TAP056/TAP066 show the S-wave is amplified at around 8 ~ 10 Hz. The horizontal/vertical spectral ratios of station TAP056 also show a dominant frequency at about 6 and 8 ~ 10 Hz. After dense microtremor surveying and the addition of one accelerometer just 20 meters away from the original observation station, we can confirm that the top soft soil layer upon which the observation station is constructed generates the local site response at station TAP056

Paternal Tobacco Smoke Correlated to Offspring Asthma and Prenatal Epigenetic Programming

Rationale: Little is known about effects of paternal tobacco smoke (PTS) on the offspring’s asthma and its prenatal epigenetic programming.Objective: To investigate whether PTS exposure was associated with the offspring’s asthma and correlated to epigenetic CG methylation of potential tobacco-related immune genes: LMO2, GSTM1 or/and IL-10 genes.Measurements and Main Results: In a birth cohort of 1,629 newborns, we measured exposure rates of PTS (23%) and maternal tobacco smoke (MTS, 0.2%), cord blood DNA methylation, infant respiratory tract infection, childhood DNA methylation, and childhood allergic diseases. Infants with prenatal PTS exposure had a significantly higher risk of asthma by the age of 6 than those without (p = 0.026). The PTS exposure doses at 0, <20, and ≧20 cigarettes per day were significantly associated with the trend of childhood asthma and the increase of LMO2-E148 (p = 0.006), and IL10_P325 (p = 0.008) CG methylation. The combination of higher CG methylation levels of LMO2_E148, IL10_P325, and GSTM1_P266 corresponded to the highest risk of asthma by 43.48%, compared to other combinations (16.67–23.08%) in the 3-way multi-factor dimensionality reduction (MDR) analysis. The LMO2_P794 and GSTM1_P266 CG methylation levels at age 0 were significantly correlated to those at age of 6.Conclusions: Prenatal PTS exposure increases CG methylation contents of immune genes, such as LMO2 and IL-10, which significantly retained from newborn stage to 6 years of age and correlated to development of childhood asthma. Modulation of the LMO2 and IL-10 CG methylation and/or their gene expression may provide a regimen for early prevention of PTS-associated childhood asthma.Descriptor number: 1.10 Asthma Mediators.Scientific Knowledge on the Subject: It has been better known that maternal tobacco smoke (MTS) has an impact on the offspring’s asthma via epigenetic modification. Little is known about effects of paternal tobacco smoke (PTS) on the offspring’s asthma and its prenatal epigenetic programming.What This Study Adds to the Field: Prenatal tobacco smoke (PTS) can program epigenetic modifications in certain genes, such as LMO2 and IL-10, and that these modifications are correlated to childhood asthma development. The higher the PTS exposure dose the higher the CG methylation levels are found. The combination of higher CG methylation levels of LMO2_E148, IL10_P325 and GSTM1_P266 corresponded to the highest risk of asthma. Measuring the DNA methylation levels of certain genes might help to predict high-risk populations for childhood asthma and provide a potential target to prevent the development of childhood asthma