Versatile Post-synthetic Modifications of Helical ß-Peptide Foldamers Derived from a Thioether-Containing Cyclic ß-Amino Acid.

We introduce a novel cyclic ß-amino acid, trans-(3S,4R)-4-aminotetrahydrothiophene-3-carboxylic acid (ATTC), as a versatile building block for designing peptide foldamers with controlled secondary structures. We synthesized and characterized a series of ß-peptide hexamers containing ATTC using various techniques, including X-ray crystallography, circular dichroism, and NMR spectroscopy. Our findings reveal that ATTC-containing foldamers can adopt 12-helical conformations similar to their isosteres and offer the possibility of fine-tuning their properties via post-synthetic modifications. In particular, chemoselective conjugation strategies demonstrate that ATTC provides unique post-synthetic modification opportunities, which expand their potential applications across diverse research areas. Collectively, our study highlights the versatility and utility of ATTC as an alternative to previously reported cyclic ß-amino acid building blocks in both structural and functional aspects, paving the way for future research in the realm of peptide foldamers and beyond.

Clinical features and oncological outcomes of primary female urethral cancer.

PURPOSE: Investigation of the clinical features and treatment outcomes of primary female urethral cancer (FUC) at a single institution. MATERIALS AND METHODS: We retrospectively reviewed 32 FUC patients during 1997-2017. We investigated preoperative risk factors predicting overall (overall survival [OS]) and recurrence-free survival (RFS) and reviewed clinical features, treatment modality, and oncologic outcomes according to pathology. The median follow-up duration and age was 56 months (range: 4-229) and 61 years (range: 15-82), respectively. RESULTS: The median OS and RFS were 70 and 16 months, respectively. A total of 19 (59.4%) patients received systemic chemotherapy, including 14 (43.8%) who received radiation therapy. Further, 22 patients (68.8%) underwent surgery. On univariate analysis, >T2, N+, and tumor size ≥3 cm were associated with poorer OS. There were 15 cases of distant metastasis and five local recurrences. Outcomes were poorest in adenocarcinoma (AC), moderate in clear cell carcinoma and transitional cell carcinoma, and best in squamous cell carcinoma (SCC). CONCLUSION: Female urethral lesions should be carefully examined to exclude FUC. Distal urethral SCC was responsive to surgical excision, but proximal urethral AC had poor oncological outcome even after extensive treatment. Due to the heterogeneity and poor prognosis of FUC, multimodal treatment is mandatory.

Comparative oncological outcomes after radical prostatectomy or external beam radiation therapy plus androgen deprivation therapy in men with clinical T3b prostate cancer.

OBJECTIVE: To compare oncological outcomes in men with clinical T3b prostate cancer who underwent radical prostatectomy or a combination of radiation therapy plus androgen deprivation therapy. METHODS: Men with clinical T3b prostate cancer who underwent radical prostatectomy or radiation therapy plus androgen deprivation therapy between 2007 and 2014 were evaluated. All patients were relatively healthy, with Eastern Cooperative Oncology Group performance status of 0 or 1 without nodal or distant metastasis. Cancer-specific survival was analyzed. Age, Charlson Comorbidity Index, biopsy Gleason score and pretreatment prostate-specific antigen were adjusted by propensity score matching. The Cox proportional hazards model was used to assess factors prognostic of cancer-specific survival. RESULTS: Of the 152 patients with clinical T3b prostate cancer, 45 underwent radical prostatectomy, and 107 underwent radiation therapy plus androgen deprivation therapy between 2007 and 2014. The mean cancer-specific survival was significantly longer in the radical prostatectomy than in the radiation therapy plus androgen deprivation therapy group (P = 0.029). Age, Charlson Comorbidity Index and pretreatment prostate-specific antigen were significantly higher in the radiation therapy plus androgen deprivation therapy group. In the propensity score matched population of 24 patients each, the median cancer-specific survival remained significantly longer in the radical prostatectomy than in the radiation therapy plus androgen deprivation therapy group (not reached vs 112.93 ± 11.94 months, P = 0.026). Multivariate analysis showed that undergoing radiation therapy plus androgen deprivation therapy was the only significant poor prognostic factor for cancer-specific survival (hazard ratio 6.694, 95% confidence interval 1.642-27.592, P = 0.008). CONCLUSION: Cancer-specific survival was significantly longer in men with clinical T3b prostate cancer who underwent radical prostatectomy than radiation therapy plus androgen deprivation therapy, suggesting that radical prostatectomy can be a better treatment option for the initial definitive treatment for these patients.

A cyclodextrin-decorated plasmonic gold nanosatellite substrate for selective detection of bipyridylium pesticides.

A cyclodextrin-decorated gold nanosatellite (AuNSL) substrate was developed as a surface-enhanced Raman scattering sensor for the selective sensing of bipyridylium pesticides such as paraquat (PQ), diquat (DQ), and difenzoquat (DIF). The AuNSL structure was fabricated via vacuum deposition of gold nanoparticles (AuNPs) on a gold nanopillar substrate, and a large density of hot-spots was formed for Raman signal enhancement. Thiolated ß-cyclodextrin (SH-CD) was surface-modified on the AuNSL as a chemical receptor. The detection limit of PQ, DQ, and DIF on the SH-CD-coated AuNSL (CD-AuNSL) was 0.05 ppm for each, and showed linear correlation in a concentration range of 10 ppm-0.05 ppm. Then, selective bipyridylium pesticide detection was performed by comparing the Raman intensity of each pesticide with and without the washing step. After the washing step, 90% of the PQ, DQ, and DIF Raman signals were maintained on the CD-AuNSL substrate with a uniform selectivity in a mapping area of 200 µm × 200 µm. Furthermore, selective pesticide detection was performed using a ground-apple solution without pretreatment. Raman signals were clearly observed after the washing step and they showed a limit of detection down to a concentration of 0.05 ppm for each pesticide. Principal component analysis (PCA) of the binary and ternary mixtures of PQ, DQ, and DIF showed that each component could be easily identified via the typical Raman fingerprint analysis. The developed CD-AuNSL is expected to be applied for various chemical sensors, especially for pyridine-containing toxic substances in the environment and metabolite biomarkers in biofluids.

Hybrid ileal pouch with concomitant anti-refluxing and refluxing ureteroileal anastomosis.

PURPOSE: We report our preliminary experience of using a hybrid ileal pouch, assessing oncologic outcomes, complications, voiding, and renal function. METHODS: The study included 25 patients with bladder cancer treated with radical cystectomy with a hybrid ileal pouch with concomitant anti-refluxing and refluxing anastomosis, performed by a single surgeon. The patients were divided into two groups (first and last cases) according to the surgery date. Postoperative complications, separate renal function by renal scan, voiding function by uroflowmetry with residual urine, and oncologic outcomes were assessed. RESULTS: The surgery duration was shorter in the last cases than the first cases. The voiding volume increased with time. There were 23 cases of grade 3 complication in 12 patients and one case of grade 4 complication (sepsis). In the first cases, ureterovesical stenosis occurred in five cases, whereas in the last cases, there were no cases of stenosis. In separate renal function, there was no difference between the left and right side or between the first and last cases. CONCLUSIONS: The hybrid ileal pouch showed acceptable oncologic and functional outcomes and complications; therefore, it can be used according to the appropriate surgical situation with a relatively short bowel segment during neobladder construction.

Multiregion gene expression profiling reveals heterogeneity in molecular subtypes and immunotherapy response signatures in lung cancer.

Intra-tumor heterogeneity may be present at all molecular levels. Genomic intra-tumor heterogeneity at the exome level has been reported in many cancer types, but comprehensive gene expression intra-tumor heterogeneity has not been well studied. Here, we delineated the gene expression intra-tumor heterogeneity by exploring gene expression profiles of 35 tumor regions from 10 non-small cell lung cancer tumors (three or four regions/tumor), including adenocarcinoma, squamous cell carcinoma, large-cell carcinoma, and pleomorphic carcinoma of the lung. Using Affymetrix Gene 1.0 ST arrays, we generated the gene expression data for every sample. Inter-tumor heterogeneity was generally higher than intra-tumor heterogeneity, but some tumors showed a substantial level of intra-tumor heterogeneity. The analysis of various clinically relevant gene expression signatures including molecular subtype, epithelial-to-mesenchymal transition, and anti-PD-1 resistance signatures also revealed heterogeneity between different regions of the same tumor. The gene expression intra-tumor heterogeneity we observed was associated with heterogeneous tumor microenvironments represented by stromal and immune cells infiltrated. Our data suggest that RNA-based prognostic or predictive molecular tests should be carefully conducted in consideration of the gene expression intra-tumor heterogeneity.

Enantioselective Synthesis of Oxetanes Bearing All-Carbon Quaternary Stereocenters via Iridium-Catalyzed C-C Bond-Forming Transfer Hydrogenation.

Oxetanes bearing all-carbon quaternary stereocenters are readily prepared through the iridium-catalyzed anti-diastereo- and enantioselective C-C coupling of primary alcohols and isoprene oxide. Based on this methodology, an oxetane containing analogue of haloperidol was prepared. A related azetidine formation is also described.

Gender- and age-group-specific associations between physical performance and bone mineral density, falls, and osteoporotic fractures in Koreans: the Chungju Metabolic Disease Cohort study.

Several factors increase the risk of fragility fracture, including low bone mineral density, falls, and poor physical performance. The associations among these factors have been investigated; however, most of the subjects of previous studies were either elderly men or elderly women, and the associations were controversial. The aim of this study was to evaluate the associations between physical performance and bone mineral density, and the history of falls and fractures, stratified by gender and age group. We analyzed 5368 subjects who were aged 50 years or older, including 1288 younger men (younger than 70 years), 1615 younger women (younger than 70 years), 1087 older men (70 years or older), and 1378 older women (70 years or older). We used the one-leg standing time (OLST) for assessing static balance and the timed up-and-go test (TUGT) for assessing dynamic balance. The subjects in the worst performance quartile for the OLST were more likely to have osteoporosis than those in the best performance quartile. Additionally, women who had experienced a fracture during the past 2 years were 1.68 times more likely to be in the worst performance quartile for the OLST than women without a previous fracture. Although the TUGT time was not associated with either the incidence of osteoporosis or the fracture history, the odds ratios for falling were 1.51 and 1.28 as the TUGT time increased by one standard deviation in younger men and younger women, respectively. The findings of the present study show that the OLST was associated with the incidence of osteoporosis and previous fracture and that the TUGT time was associated with the incidence of falling.

Utility of near-infrared light devices for pediatric peripheral intravenous cannulation: a systematic review and meta-analysis.

We investigated the utility of near-infrared (NIR) light devices for peripheral intravenous cannulation (PIVC) in pediatric patients. We searched three databases, MEDLINE, EMBASE, and the Cochrane CENTRAL. Randomized controlled trials that compared PIVC using NIR light devices and the "traditional" method (with no assistive device) were included. The primary outcome was a failure rate at the first attempt, and the effect size was measured by the risk ratio for failure. Subgroup analysis was performed according to control group risk for failure at first attempt as an indicator of difficult procedure (low vs. high). Eleven studies were included in the meta-analysis. There was no significant difference in the primary outcome between the two methods (risk ratio 1.03, confidence interval 0.89-1.20, I 2 = 48 %). In a subgroup analysis, the subgroup difference between subsets of low and high control group risk was significant (I 2 = 83 %). In the subset of the high control group risk, using NIR light devices showed a lower risk for failure than the traditional method (risk ratio 0.81, confidence interval 0.64-1.01, I 2 = 0 %). CONCLUSION: Using NIR light devices did not have an impact on overall failure rate at the first attempt at PIVC in pediatric patients. What is Known: • Near-infrared light devices have been used to help vascular access especially for the pediatric patients. But, their utilities reported in previous studies were conflicting. What is New: • From this study, we could not find out overall benefit of using near-infrared light devices for pediatric peripheral intravenous cannulation. But, this device might be useful for the patients in a difficult condition of successful cannulation.

A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing.

The identification of the molecular events that drive cancer transformation is essential to the development of targeted agents that improve the clinical outcome of lung cancer. Many studies have reported genomic driver mutations in non-small-cell lung cancers (NSCLCs) over the past decade; however, the molecular pathogenesis of >40% of NSCLCs is still unknown. To identify new molecular targets in NSCLCs, we performed the combined analysis of massively parallel whole-genome and transcriptome sequencing for cancer and paired normal tissue of a 33-yr-old lung adenocarcinoma patient, who is a never-smoker and has no familial cancer history. The cancer showed no known driver mutation in EGFR or KRAS and no EML4-ALK fusion. Here we report a novel fusion gene between KIF5B and the RET proto-oncogene caused by a pericentric inversion of 10p11.22-q11.21. This fusion gene overexpresses chimeric RET receptor tyrosine kinase, which could spontaneously induce cellular transformation. We identified the KIF5B-RET fusion in two more cases out of 20 primary lung adenocarcinomas in the replication study. Our data demonstrate that a subset of NSCLCs could be caused by a fusion of KIF5B and RET, and suggest the chimeric oncogene as a promising molecular target for the personalized diagnosis and treatment of lung cancer.

The transcriptional landscape and mutational profile of lung adenocarcinoma.

All cancers harbor molecular alterations in their genomes. The transcriptional consequences of these somatic mutations have not yet been comprehensively explored in lung cancer. Here we present the first large scale RNA sequencing study of lung adenocarcinoma, demonstrating its power to identify somatic point mutations as well as transcriptional variants such as gene fusions, alternative splicing events, and expression outliers. Our results reveal the genetic basis of 200 lung adenocarcinomas in Koreans including deep characterization of 87 surgical specimens by transcriptome sequencing. We identified driver somatic mutations in cancer genes including EGFR, KRAS, NRAS, BRAF, PIK3CA, MET, and CTNNB1. Candidates for novel driver mutations were also identified in genes newly implicated in lung adenocarcinoma such as LMTK2, ARID1A, NOTCH2, and SMARCA4. We found 45 fusion genes, eight of which were chimeric tyrosine kinases involving ALK, RET, ROS1, FGFR2, AXL, and PDGFRA. Among 17 recurrent alternative splicing events, we identified exon 14 skipping in the proto-oncogene MET as highly likely to be a cancer driver. The number of somatic mutations and expression outliers varied markedly between individual cancers and was strongly correlated with smoking history of patients. We identified genomic blocks within which gene expression levels were consistently increased or decreased that could be explained by copy number alterations in samples. We also found an association between lymph node metastasis and somatic mutations in TP53. These findings broaden our understanding of lung adenocarcinoma and may also lead to new diagnostic and therapeutic approaches.

Exosomal proteins in the aqueous humor as novel biomarkers in patients with neovascular age-related macular degeneration.

Age-related macular degeneration (AMD) describes the progressive degeneration of the retinal pigment epithelium (RPE), retina, and choriocapillaris and is the leading cause of blindness in people over 50. The molecular mechanisms underlying this multifactorial disease remain largely unknown. To uncover novel secretory biomarkers related to the pathogenesis of AMD, we adopted an integrated approach to compare the proteins identified in the conditioned medium (CM) of cultured RPE cells and the exosomes derived from CM and from the aqueous humor (AH) of AMD patients by LC-ESI-MS/MS. Finally, LC-MRM was performed on the AH from patients and controls, which revealed that cathepsin D, cytokeratin 8, and four other proteins increased in the AH of AMD patients. The present study has identified potential biomarkers and therapeutic targets for AMD treatment, such as proteins related to the autophagy-lysosomal pathway and epithelial-mesenchymal transition, and demonstrated a novel and effective approach to identifying AMD-associated proteins that might be secreted by RPE in vivo in the form of exosomes. The proteomics-based characterization of this multifactorial disease could help to match a particular marker to particular target-based therapy in AMD patients with various phenotypes.

Normal weight obesity in Korean adults.

BACKGROUND: A better way to define obesity is in terms of the percentage of body fat (BF). Subjects with normal weight, but excess BF are vulnerable to cardiovascular diseases. OBJECTIVE: To evaluate the prevalence and characteristics of subjects having normal weight obesity (NWO) using optimal cut-offs of the BF percentage reflecting risk factors for cardiovascular disease (CVD) in Korean adults. DESIGN AND SETTING: The Korea National Health and Nutrition Examination Survey in the Korean population conducted in 2009-2010. PARTICIPANTS: We surveyed 5313 men and 6904 women aged 20 years or older. MEASUREMENTS: We investigated the relations between the BF percentage (measured by dual-energy X-ray absorptiometry) and obesity-related risk factors for CVD (diabetes mellitus, hypertension and dyslipidaemia) in Korean adults. NWO was defined as the combination of a normal body mass index (BMI; 18·5-22·9 kg/m(2) in Asian subjects) and BF percentages above the determined cut-off values. RESULTS: There were strong and graded associations of increasing BF percentages with the prevalence of CVD risk factors. The first cut-off values (defined as being overweight) in men and women were 20·6% and 33·4% BF, respectively, and the second cut-off values (defined as obesity) were 25·7% and 36·0% BF. Thirty-two per cent of normal weight adults had BF percentages greater than or equal to the overweight or obesity cut-offs (NWO). Subjects with NWO had a lower appendicular skeletal muscle mass, a more atherogenic lipid profile and greater insulin resistance. CONCLUSIONS: Obesity can be defined as 26% BF or greater in Korean men and 36% BF or greater in Korean women. There was a high prevalence of clustering of cardiometabolic abnormalities among subjects with NWO.

Prevalence of systemic lupus erythematosus in South Korea: an administrative database study.

BACKGROUND: Systemic lupus erythematosus (SLE) is a rare autoimmune disease for which a population-based survey on the prevalence of the disease in South Korea has not yet been conducted. Our goal was to estimate the nationwide prevalence of SLE. METHODS: The International Classification of Diseases, Tenth Revision (ICD-10) code for SLE diagnosis-M32-was tentatively given when patients were suspected to have SLE before 2009. As such, the positive predictive value (PPV) of the M32 code shown in medical bills reflecting true SLE was uncertain. We attempted to estimate the prevalence of SLE in South Korea using national administrative database data from 2004-2006. We approximated the actual number of SLE patients by analyzing a list of SLE-coded patients provided by the National Health Insurance (NHI) and Health Insurance Review and Assessment Service. Prevalence was estimated by multiplying the PPV of the M32 diagnostic code by the number of patients receiving the code. The PPV was determined by three methods: direct investigation of the medical records of patients randomly selected from the SLE-coded patients list; assessment of all SLE patients treated at 56 selected hospitals in South Korea; and extrapolation from sub-groups at a single institute to the sub-groups of the national NHI data. RESULTS: The estimated number of national SLE cases was between 9000 and 11,000, depending on the method of ascertainment, corresponding to a prevalence of 18.8-21.7 per 100,000 people. CONCLUSIONS: This is the first report of a nationwide prevalence survey of SLE in South Korea. National databases may serve as a resource for epidemiologic studies of rare autoimmune diseases like SLE.

Association between insulin resistance and periodontitis in Korean adults.

OBJECTIVE: Recent studies have proposed an association between periodontitis and metabolic abnormalities. We investigated the association between insulin resistance and periodontitis among Korean adults. METHODS: A cross-sectional analysis was conducted using the Korea National Health and Nutrition Examination Survey 2008-2010. A total of 16,720 non-diabetic subjects over 18 years old were evaluated (7060 men and 9660 women). Periodontal status was assessed by the Community Periodontal Index. Insulin resistance was measured using the homeostasis model assessment of insulin resistance (HOMA-IR). Participants in the highest and lowest quartile of HOMA-IR were defined as insulin-resistant and insulin-sensitive respectively. RESULTS: The prevalence of periodontitis increased significantly with higher HOMA-IR quartiles in post-menopausal women (p for linear association = 0.019). Among post-menopausal women, participants in the highest quartile of HOMA-IR were significantly more likely to have periodontitis compared to those in the lowest quartile [adjusted odds ratio (OR), 1.47; 95% confidence interval (CI), 1.07-2.01]. Moreover, obese post-menopausal women showed an increased association between insulin resistance and periodontitis (adjusted OR, 1.92; 95% CI,1.29-2.87). However, this association was not found in men or pre-menopausal women. CONCLUSIONS: Our results suggest that insulin resistance may be associated with periodontitis, especially when combined with obesity, among post-menopausal women in Korea.

Clinical Utility of Whole-Genome Analysis as One-for-All Test for Breast Cancer: A Case Series.

Introduction: Breast cancer exhibits vast genomic diversity, leading to varied clinical manifestations. Integrating molecular subtyping with in-depth genomic profiling is pivotal for informed treatment choices and prognostic insights. Whole-genome clinical analysis provides a holistic view of genome-wide variations, capturing structural changes and affirming tumor suppressor gene loss of heterozygosity. Case Presentation: Here we detail four unique breast cancer cases from Seoul St. Mary's Hospital, highlighting the actionable benefits and clinical value of whole-genome sequencing (WGS). As an all-in-one test, WGS demonstrates significant clinical utility in these cases, including: (1) detecting homologous recombination deficiency with underlying somatic causal variants (case 1), (2) distinguishing double primary cancer from metastasis (case 2), (3) uncovering microsatellite instability (case 3), and (4) identifying rare germline pathogenic variants in TP53 gene (case 4). Our observations underscore the enhanced clinical relevance of WGS-based testing beyond pinpointing a few driver mutations in conventional targeted panel sequencing platforms. Conclusion: With genomic advancements and decreasing sequencing costs, WGS stands out as a transformative tool in oncology, paving the way for personalized treatment plans rooted in individual genetic blueprints.

Strategies to Improve Smoking Cessation for Participants in Lung Cancer Screening Program: Analysis of Factors Associated with Smoking Cessation in Korean Lung Cancer Screening Project (K-LUCAS).

PURPOSE: Smoking cessation intervention is one of the key components of successful lung cancer screening program. We investigated the effectiveness and related factors of smoking cessation services provided to the participants in a population-based lung cancer screening trial. MATERIALS AND METHODS: The Korean Lung Cancer Screening Project (K-LUCAS) is a nationwide, multi-center lung cancer screening trial that evaluates the feasibility of implementing population-based lung cancer screening. All 5,144 current smokers who participated in the K-LUCAS received a mandatory smoking cessation counseling. Changes in smoking status were followed up using a telephone survey in 6 months after lung cancer screening participation. The lung cancer screening's impact on smoking cessation is analyzed by variations in the smoking cessation interventions provided in screening units. RESULTS: Among 4,136 survey responders, participant's motivation to quit smoking increased by 9.4% on average after lung cancer screening. After 6 months from the initial screening, 24.3% of participants stopped smoking, and 10.6% of participants had not smoked continuously for at least 6 months after screening. Over 80% of quitters stated that participation in lung cancer screening motivated them to quit smoking. Low-cost public smoking cessation program combined with lung cancer screening increased the abstinence rates. The smokers were three times more likely to quit smoking when the smoking cessation counseling was provided simultaneously with low-dose computed tomography screening results than when provided separately. CONCLUSION: A mandatory smoking cessation intervention integrated with screening result counselling by a physician after participation in lung cancer screening could be effective for increasing smoking cessation attempts.

Quantitative and qualitative mutational impact of ionizing radiation on normal cells.

The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites), and complex genomic rearrangements (CGRs), including chromoplexy, chromothripsis, and SV by breakage-fusion-bridge cycles. Our findings suggest that 1 Gy IR exposure causes an average of 2.33 mutational events per Gb genome, comprising 2.15 indels, 0.17 SVs, and 0.01 CGRs, despite a high level of inter-cellular stochasticity. The mutational burden was dependent on total irradiation dose, regardless of dose rate or cell type. The findings were further validated in IR-induced secondary cancers and single cells without clonalization. Overall, our study highlights a comprehensive and clear picture of IR effects on normal mammalian genomes.

Epigenetic regulation of cholinergic receptor M1 (CHRM1) by histone H3K9me3 impairs Ca(2+) signaling in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded trinucleotide CAG repeat in the gene coding for huntingtin. Deregulation of chromatin remodeling is linked to the pathogenesis of HD but the mechanism remains elusive. To identify what genes are deregulated by trimethylated histone H3K9 (H3K9me3)-dependent heterochromatin, we performed H3K9me3-ChIP genome-wide sequencing combined with RNA sequencing followed by platform integration analysis in stable striatal HD cell lines (STHdhQ7/7 and STHdhQ111/111) cells. We found that genes involving neuronal synaptic transmission including cholinergic receptor M1 (CHRM1), cell motility, and neuronal differentiation pathways are downregulated while their promoter regions are highly occupied with H3K9me3 in HD. Moreover, we found that repression of CHRM1 gene expression by H3K9me3 impairs Ca(2+)-dependent neuronal signal transduction in stable cell lines expressing mutant HD protein. Thus, our data indicate that the epigenetic modifications, such as aberrant H3K9me3-dependent heterochromatin plasticity, directly contribute to the pathogenesis of HD.

TIARA: a database for accurate analysis of multiple personal genomes based on cross-technology.

High-throughput genomic technologies have been used to explore personal human genomes for the past few years. Although the integration of technologies is important for high-accuracy detection of personal genomic variations, no databases have been prepared to systematically archive genomes and to facilitate the comparison of personal genomic data sets prepared using a variety of experimental platforms. We describe here the Total Integrated Archive of Short-Read and Array (TIARA; http://tiara.gmi.ac.kr) database, which contains personal genomic information obtained from next generation sequencing (NGS) techniques and ultra-high-resolution comparative genomic hybridization (CGH) arrays. This database improves the accuracy of detecting personal genomic variations, such as SNPs, short indels and structural variants (SVs). At present, 36 individual genomes have been archived and may be displayed in the database. TIARA supports a user-friendly genome browser, which retrieves read-depths (RDs) and log2 ratios from NGS and CGH arrays, respectively. In addition, this database provides information on all genomic variants and the raw data, including short reads and feature-level CGH data, through anonymous file transfer protocol. More personal genomes will be archived as more individuals are analyzed by NGS or CGH array. TIARA provides a new approach to the accurate interpretation of personal genomes for genome research.