Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

What Causes Bank Failure and 2008 Financial Crisis?

[[abstract]]For the single year of 2009, the number of insolvent banks reached 631, which was more than any year of previous crisis since Great Depression of 1930s for the US. Although risk taking of banks, especially in real estate loans, is gauged to be the cause for the 2008 financial crises in the US, it has not been empirically tested. Therefore, the purpose of this paper is to investigate whether the risk taking, especially in real estate loans, is the underlying reason for the bank failure and 2008 financial crisis. The traditional risk taking process is complicated by the implementation of loan securitization. If the securitization process is complete and immediate, bank risk should be reduced and cannot be easily observed even when banks have high risk-taking operation. Risk can be observed only when the process of securitization is incomplete. A comprehensive risk taking indicators, including ten loan ratios and thirty-eight indicators for asset quality which never used before, are created to represent the risk-taking behavior of commercial banks. The empirical results of this paper show that both asset quality indicators and loan ratio indicators of total loans generate significant impacts on the probability of bank failure. The results further show risk taking in real estate loans, not in other types of loans, is significant for the likelihood of bank failure. So the results in this paper do disclose that risk taking, especially in real estate loans, is the cause of bank failure and 2008 banking crisis. 2009 年美國銀行倒閉及發生問題的數目高達631 家是自1930 年代經濟大 蕭條以來最多的一年，雖然輿論皆認為商業銀行的高風險營運策略（尤其在不動 產放款）是銀行倒閉及金融風暴的起因，然而實證研究卻相當稀少。因此本文擬 針對銀行高風險營運策略（尤其在不動產放款）是否為銀行倒閉及金融風暴的起 因來進行實證探討。 實證的困難在於資產證券化會降低賬面上的風險水準，尤其是當證券化過程 快速且完整時，即使銀行實際進行高風險承作，其風險承作水準仍無可觀察，唯 有證券化過程遲緩且不完整，銀行採取冒險策略時其風險水準才無法透過證券化 完全消除，也才可觀察驗證。 本文有別於其他文獻，不僅使用總放款的攸關風險承作指標，而且還使用各 種放款完整且詳盡的風險承作指標，共包括三十八個資產品質指標及十個放款比 率指標來偵測真正導致銀行倒閉的關鍵性原因。實證結果發現銀行總放款之資產 品質及放款比率指標的確會對銀行倒閉機率有顯著影響。此外，本文還進一步發 現銀行在不動產放款的冒險策略的確是導致銀行倒閉的關鍵性原因，在其它放款 類別則未具有顯著證據。因此，本文證實出銀行在放款的冒險策略，尤其是在不 動產放款的高風險承作的確為銀行倒閉及金融危機發生的主因之一

Novel histone deacetylase inhibitor AR-42 exhibits antitumor activity in pancreatic cancer cells by affecting multiple biochemical pathways

<div><p>Objective</p><p>Pancreatic cancer is one of the most lethal types of cancer with a 5-year survival rate of ~5%. Histone deacetylases (HDACs) participate in many cellular processes, including carcinogenesis, and pharmacological inhibition of HDACs has emerged as a potential therapeutic strategy. In this study, we explored antitumor activity of the novel HDAC inhibitor AR-42 in pancreatic cancer.</p><p>Methods</p><p>Human pancreatic cancer cell lines BxPC-3 and PANC-1 were used in this study. Real-time PCR, RT-PCR, and western blotting were employed to investigate expression of specific genes and proteins, respectively. Translocation of apoptosis-inducing factor was investigated by immunofluorescence and subcellular fractionation. The number of apoptotic cells, cell cycle stages, and reactive oxygen species (ROS) generation levels were determined by flow cytometry. Cell invasiveness was examined by the Matrigel invasion assay. Efficacy of AR-42 <i>in vivo</i> was evaluated by utilizing BxPC-3 xenograft mouse model.</p><p>Results</p><p>AR-42 inhibited pancreatic cancer cell proliferation by causing G2/M cell cycle arrest via regulating expression levels of genes and proteins involved in cell cycle. AR-42 also induced ROS generation and DNA damage, triggering apoptosis of pancreatic cancer cells via both caspase-3-dependent and caspase-3-independent pathways. In addition, AR-42 increased expression levels of negative regulators of p53 (miR-125b, miR-30d, and miR33), which could contribute to lower expression level of mutant p53 in pancreatic cancer cells. Cell invasion assay showed that AR-42 reduced cancer cell aggressiveness and significantly diminished BxPC-3 xenograft tumor growth <i>in vivo</i>.</p><p>Conclusion</p><p>AR-42, a novel HDAC inhibitor, inhibited pancreatic cancer cells by regulating p53 expression, inducing cell cycle arrest, particularly at the G2/M stage, and activating multiple apoptosis pathways. Additionally, AR-42 inhibited cell invasiveness and potently suppressed pancreatic cancer tumors <i>in vivo</i>. We conclude that by virtue of its multiple mechanisms of action, AR-42 possesses a considerable potential as an antitumor agent in pancreatic cancer.</p></div

<i>In vivo</i> efficacy of AR-42 in BxPC-3 xenografted mice.

<p><b>(A)</b> BxPC-3 xenograft tumor volumes in mice treated via oral gavage with either vehicle or AR-42 (25, 50 mg/kg) every other day for 29 days. <b>(B)</b> Representative tumors from animals treated with vehicle or AR-42 (25, 50 mg/kg) <b>(C)</b> Body weight of xenografted mice in vehicle- and AR-42-treated groups. Data are presented as the mean ± standard deviation of measurements in 6 mice per group. Statistical significance of differences from the values in control group is indicated as follows: <i>*P <0</i>.<i>05</i>, <i>**P <0</i>.<i>01</i>, <i>***P <0</i>.<i>001</i>. (D) Western blot showing the expression of p53, survivin and cleaved caspase-3 proteins as analyzed from tumor protein extracts in each treatment group.</p

Schematic representation of multiple mechanisms affected by AR-42 during inhibition of pancreatic cancer cell growth.

<p>Schematic representation of multiple mechanisms affected by AR-42 during inhibition of pancreatic cancer cell growth.</p

AR-42 induced ROS production and caused DNA damage in pancreatic cancer cells.

<p><b>(A</b>) BxPC-3 cells were treated by 1 μM AR-42 for 24 h. Concentrations of H₂O₂ and NAC comprised 1.467 mM and 25 mM, respectively. ROS generation was analyzed by flow cytometry using 2,7-dichlorodihydrofluorescein diacetate. All data are representative of three independent experiments with similar results. <b>(B)</b> Expression of γH₂AX was examined by western blot analysis.</p