ASTE Simultaneous HCN(4-3) and HCO+(4-3) Observations of the Two Luminous Infrared Galaxies NGC 4418 and Arp 220

We report the results of HCN(J=4-3) and HCO+(J=4-3) observations of two luminous infrared galaxies (LIRGs), NGC 4418 and Arp 220, made using the Atacama Submillimeter Telescope Experiment (ASTE). The ASTE wide-band correlator provided simultaneous observations of HCN(4-3) and HCO+(4-3) lines, and a precise determination of their flux ratios. Both galaxies showed high HCN(4-3) to HCO+(4-3) flux ratios of >2, possibly due to AGN-related phenomena. The J = 4-3 to J = 1-0 transition flux ratios for HCN (HCO+) are similar to those expected for fully thermalized (sub-thermally excited) gas in both sources, in spite of HCN's higher critical density. If we assume collisional excitation and neglect an infrared radiative pumping process, our non-LTE analysis suggests that HCN traces gas with significantly higher density than HCO+. In Arp 220, we separated the double-peaked HCN(4-3) emission into the eastern and western nuclei, based on velocity information. We confirmed that the eastern nucleus showed a higher HCN(4-3) to HCN(1-0) flux ratio, and thus contained a larger amount of highly excited molecular gas than the western nucleus.Comment: 21 pages, 4 figures, accepted for publication in PASJ (Vol.62, No.1, 2010 Feb 25 issue

HCN to HCO^+ Millimeter Line Diagnostics of AGN Molecular Torus I : Radiative Transfer Modeling

We explore millimeter line diagnostics of an obscuring molecular torus modeled by a hydrodynamic simulation with three-dimensional nonLTE radiative transfer calculations. Based on the results of high-resolution hydrodynamic simulation of the molecular torus around an AGN, we calculate intensities of HCN and HCO^{+} rotational lines as two representative high density tracers. The three-dimensional radiative transfer calculations shed light on a complicated excitation state in the inhomogeneous torus, even though a spatially uniform chemical structure is assumed. Our results suggest that HCN must be much more abundant than HCO^{+} in order to obtain a high ratio ($R_{HCN/HCO+}\sim 2$) observed in some of the nearby galaxies. There is a remarkable dispersion in the relation between integrated intensity and column density, indicative of possible shortcomings of HCN(1-0) and HCO^{+}(1-0) lines as high density tracers. The internal structures of the inhomogeneous molecular torus down to subparsec scale in external galaxies will be revealed by the forthcoming Atacama Large Millimeter/submillimeter Array (ALMA). The three-dimensional radiative transfer calculations of molecular lines with high-resolution hydrodynamic simulation prove to be a powerful tool to provide a physical basis for molecular line diagnostics of the central regions of external galaxies.Comment: 29 pages, 13 figures, Accepted for publication in ApJ, For high resolution figures see http://alma.mtk.nao.ac.jp/~masako/MS72533v2.pd

V3 Tip-Dependent Species Specificity of HIV-1 Env

Molecular interactions of the variable envelope gp120 subunit of HIV-1 with two cellular receptors are the first step of viral infection, thereby playing pivotal roles in determining viral infectivity and cell tropism. However, the underlying regulatory mechanisms for interactions under gp120 spontaneous variations largely remain unknown. Here, we show an allosteric mechanism in which a single gp120 mutation remotely controls the ternary interactions between gp120 and its receptors for the switch of viral cell tropism. Virological analyses showed that a G310R substitution at the tip of the gp120 V3 loop selectively abolished the viral replication ability in human cells, despite evoking enhancement of viral replication in macaque cells. Molecular dynamics (MD) simulations predicted that the G310R substitution at a site away from the CD4 interaction site selectively impeded the binding ability of gp120 to human CD4. Consistently, virions with the G310R substitution exhibited a reduced binding ability to human lymphocyte cells. Furthermore, the G310R substitution influenced the gp120-CCR5 interaction in a CCR5-type dependent manner as assessed by MD simulations and an infectivity assay using exogenously expressed CCR5s. Interestingly, an I198M mutation in human CCR5 restored the infectivity of the G310R virus in human cells. Finally, MD simulation predicted amino acid interplays that physically connect the V3 loop and gp120 elements for the CD4 and CCR5 interactions. Collectively, these results suggest that the V3 loop tip is a cis-allosteric regulator that remotely controls intra- and intermolecular interactions of HIV-1 gp120 for balancing ternary interactions with CD4 and CCR5

Virological characterization of HIV-1 CA-NTD mutants constructed in a virus-lineage reflected manner

Capsid (CA) protein is a major virion-constituent of all retroviruses including human immunodeficiency virus type 1 (HIV-1), and is essential for early and late phases in viral replication cycle through interaction with numerous cellular factors. In particular, N-terminal domain (NTD) of HIV-1 CA has been frequently and well reported to bind to various host cell proteins that considerably affect viral replication potential. In this study, in order to better define biological bases of the CA-NTD for HIV-1 replication, we performed an extensive mutational analysis in an unprecedented manner. By aligning CA-NTD sequences derived from representative infectious molecular clones of HIV-1, HIV-2, and simian immunodeficiency virus isolated from the rhesus macaque (SIVmac), a number of amino acids specific to HIV-1 were selected, and were replaced with those from SIVmac at the corresponding sites. Mutant viruses thus generated were then examined for multi-cycle infectivity, single-cycle infectivity, and ability to produce progeny virions. While some CA-NTD mutations affected viral replication ability to varying degrees, those in helix 7 abolished viral growth potential without exception. These results highlight functional importance of non-conserved amino acids in helix 7, and give new insights into functionality of HIV-1 CA-NTD

Virological characterization of HIV-1 CA-NTD mutants constructed in a virus-lineage reflected manner

Capsid (CA) protein is a major virion-constituent of all retroviruses including human immunodeficiency virus type 1 (HIV-1), and is essential for early and late phases in viral replication cycle through interaction with numerous cellular factors. In particular, N-terminal domain (NTD) of HIV-1 CA has been frequently and well reported to bind to various host cell proteins that considerably affect viral replication potential. In this study, in order to better define biological bases of the CA-NTD for HIV-1 replication, we performed an extensive mutational analysis in an unprecedented manner. By aligning CA-NTD sequences derived from representative infectious molecular clones of HIV-1, HIV-2, and simian immunodeficiency virus isolated from the rhesus macaque (SIVmac), a number of amino acids specific to HIV-1 were selected, and were replaced with those from SIVmac at the corresponding sites. Mutant viruses thus generated were then examined for multi-cycle infectivity, single-cycle infectivity, and ability to produce progeny virions. While some CA-NTD mutations affected viral replication ability to varying degrees, those in helix 7 abolished viral growth potential without exception. These results highlight functional importance of non-conserved amino acids in helix 7, and give new insights into functionality of HIV-1 CA-NTD

Solvable Optimal Velocity Models and Asymptotic Trajectory

In the Optimal Velocity Model proposed as a new version of Car Following Model, it has been found that a congested flow is generated spontaneously from a homogeneous flow for a certain range of the traffic density. A well-established congested flow obtained in a numerical simulation shows a remarkable repetitive property such that the velocity of a vehicle evolves exactly in the same way as that of its preceding one except a time delay $T$. This leads to a global pattern formation in time development of vehicles' motion, and gives rise to a closed trajectory on $\Delta x$-$v$ (headway-velocity) plane connecting congested and free flow points. To obtain the closed trajectory analytically, we propose a new approach to the pattern formation, which makes it possible to reduce the coupled car following equations to a single difference-differential equation (Rondo equation). To demonstrate our approach, we employ a class of linear models which are exactly solvable. We also introduce the concept of ``asymptotic trajectory'' to determine $T$ and $v_B$ (the backward velocity of the pattern), the global parameters associated with vehicles' collective motion in a congested flow, in terms of parameters such as the sensitivity $a$, which appeared in the original coupled equations.Comment: 25 pages, 15 eps figures, LaTe

治験の品質向上を目的としたチェックリストの作成

治験は医薬品の開発において必須であり，その過程では逸脱を防ぎ，データの質を確保することが必要である．CRC（clinical research coordinator）の立場から，治験依頼者と医療機関の意思疎通のためのミーティングをより効率的に活用し，治験の品質の向上を行うためのチェックリストを作成した． T大学病院臨床試験管理センターのCRCがこれまでのミーティングにおいて経験した問題点を抽出し，それらを統合してミーティングチェックリストの原案を作成した．原案を平成１６年５月～６月に治験が開始された６件において主担当CRCが使用し，必要時には修正，補充を行い，それらを追記内容として直接チェックリストに記載した．治験開始後にこれらのチェックリストを回収し，追記内容等について検討した． 詳細な追記は，除外基準や費用の負担（特定療養費の期間に関する規定，入院時の取り扱いなど）などの項目で見られた．画像の取り扱い，同種同効薬と併用禁止薬，条件付き可能薬の一般名表記等においても指摘があった．追加項目として受託事例数が，修正項目として表記方法やレイアウトについての意見があった．これらを総合的に評価し，またあまりに詳細なリストは実用的ではないという意見なども取り入れ，除外基準は疾患名を列記しチェックする形に，また検査，投薬に関しては詳しい内容とするなどの変更を加え，最終的なチェックリストとした． 治験における逸脱の原因として，治験依頼者，治験責任医師の間での記載内容の解釈の微妙な不一致の関与の可能性が指摘されている．その克服にはCRCが中心となった品質保証のシステム化が必要であり，今回作成したチェックリストの活用などが有用と考えられる．今後は逸脱防止を目的とし，チェックリストの改良や活用法の検討を重ね対応するとともに，チェックリスト使用の有用性に関する評価を行う予定である．In clinical trials, the emphasis is on following the study protocol and maintaining subject numbers. Numerous conditions are described in the protocol for each clinical study, and misunderstandings sometimes occur between the sponsor and investigators. At times, these differing interpretations of the protocol can result in study violations. The clinical research coordinator （CRC） plays a crucial role in the efficient progress of clinical trials by arranging close communication between the sponsor, participants, and investigators. In order to minimize misconceptions in study protocols, the CRC can be recruited to optimize communication between the sponsor and investigators. We have developed a checklist to ensure the clarification of protocol details before the beginning of clinical trials. The CRC used and modified the checklist during the mandatory introductory meetings for six trials that began in May and June of ２００４. Various points, such as concomitant medications, expense issues, and eligibility and exclusion criteria, were pointed out in the modification process. Further study is warranted to evaluate the benefit of the modified meeting checklist to minimize protocol violations in clinical trials

CRC業務における看護師の専門性の意義に関する検討

治験の質の向上に治験コーディネーター（CRC）業務の充実は不可欠である．今回，CRC業務における看護師としての専門性を解析し，さらに専門性をどのようにCRC 業務の質向上に結びつけるかに関して検討した． 進行期肺癌に対する抗癌剤の治験（２００２．２～２００３．５）を対象に，実際にCRCが行った支援業務の中で，看護師としての専門性が有意義であった項目を解析した． CRC業務を被支援者別に分類すると，被験者２０，医師２２，他部署１９項目となった．うち５項目（インフォムドコンセント同席／説明補助，診察時同席／介助，観察／計測，情報提供，スケジュール管理）が２被支援者にまたがる支援内容であり，いずれも被験者に接する場での業務であった．個々の項目についてCRCの意義を検討すると，この治験は末期癌の患者を対象としていたため，疾患が憎悪するのではないかという不安の中で，同意取得時と４週毎の効果判定時の心理的サポートが，治験の遂行におけるCRCの大きな役割であった．このような治験対象患者への心理的サポートは看護師だからこそできる業務であり，そこにCRC活動における看護師の専門性の意義が認められた． 以上より，被験者に接する場での治験支援活動は，特に看護師の専門性を活かし，治験の質を向上させうるCRC業務であると考えられた．The clinical research coordinator (CRC) coordinates close communication among participants, sponsor and investigators, and plays a crucial role in the efficient progress of clinical trials. In Japan, various occupations, such as nurses, pharmacists, are involved in CRC works in each institution. Besides the common works as CRC, it could be a beneficial strategy to respect speciality of each occupations for promotion of quality of clinical trials. We analyzed nurse specialty in CRC works in a clinical trial for approval of a drug for lung cancer at Tokushima University Hospital. In 28 patients who gave informed consent for the clinical trial, 5 patients did not fulfill the criteria, and 21 patients were withdrawn from the study, because of adverse events or disease progression during the trial. We retrospectively analyzed and classified functions of CRC into three categories, support for patients, support for investigators and support for others, and found 20 roles, 22 roles and 19 roles in each category, respectively. Five roles, assistance in informed consent, assistance in physical examinations, measurement of various markers, disclosure of information and schedule management, were commonly included in support for patients and in support for investigators. Among various roles classified into three categories, the five roles commonly observed in two categories seems to be important. Since care for the participants is essential in these roles, promotion of quality in these roles in clinical trials though the nurse speciality can be considered as a suitable strategy for the better implementation of clinical trials