Bacterial production of the tunicate-derived antitumor cyclic depsipeptide didemnin B.

Natural products obtained from marine invertebrates such as sponges and tunicates are attractive sources of drugs. However, a critical obstacle in the development of these compounds is the problem of supply. In most cases, neither chemical synthesis nor mariculture of invertebrates is economically feasible.

HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells.

The availability of pluripotent stem cells offers the possibility of using such cells to model hepatic disease and development. With this in mind, we previously established a protocol that facilitates the differentiation of both human embryonic stem cells and induced pluripotent stem cells into cells that share many characteristics with hepatocytes. The use of highly defined culture conditions and the avoidance of feeder cells or embryoid bodies allowed synchronous and reproducible differentiation to occur.

Toward a new approach for determination of solute's charge distribution to analyze interatomic electrostatic interactions in quantum mechanical/molecular mechanical simulations.

We present an alternative approach to determine "density-dependent property"-derived charges for molecules in the condensed phase. In the case of a solution, it is essential to take into consideration the electron polarization of molecules in the active site of this system. The solute and solvent molecules in this site have to be described by a quantum mechanical technique and the others are allowed to be treated by a molecular mechanical method (QM/MM scheme).

Gait balance disorder by thalamic infarction with the disorder of interstitial nucleus of cajal.

The interstitial nucleus of Cajal (INC) is thought to play an important role in torsional/vertical eye position and head posture, and disorders of the INC induce abnormal ocular movements and head tilt. Our patients with ocular tilt reactions simultaneously also had disturbances in ambulatory balance, yet no reports address the loss of balance control induced by disorders of the INC. We examined the ambulatory disturbances induced by INC lesion.

Regulatory mechanism for the stimulatory action of genistein on glucose uptake in vitro and in vivo.

Genistein, an isoflavone, is known to possess diverse biological functions such as antioxidative and anti-inflammatory actions. It also acts like estrogen and inhibits several tyrosine kinases. Genistein was reported to suppress insulin-mediated glucose uptake in adipocytes.

Design, Synthesis, and Antitumor Activity of 4-Halocolchicines and Their Pro-drugs Activated by Cathepsin B.

Novel colchicine derivatives possessing various substituents at the C4 position were prepared. Among them, 4-halo derivatives 3-6 were found to exhibit higher activity against cancer cell lines (A549, HT29, HCT116) as well as on mice transplanted with the HCT116 human colorectal carcinoma cell line than colchicine (1). Further, utilizing the 4-substituted colchicines, we prepared pro-drugs having a dipeptide side chain and demonstrated that these pro-drugs were activated by cathepsin B, an enzyme overexpressed in tumor cells, and exhibited selective toxicity to the tumor cells.

Differential response related to genotoxicity in multiple organs of cirrhotic rats.

Purpose: The aim of this study was to use the single cell gel (comet) assay to investigate whether blood, liver, heart, kidney, and brain are particularly sensitive organs for DNA damage in cirrhotic rats to predict genetic instability induced by cirrhosis.

Methods: A total of 16 male Wistar rats (negative control, n = 8; experimental, n = 8) were submitted to bile duct ligation during 28 days.

Results: Cirrhosis was able to induce genetic damage in liver and brain cells, as depicted by the mean tail moment.

RBP-J promotes the maturation of neuronal progenitors.

During brain development, neurons and glias are generated from neural stem cells and more limited intermediate neural progenitors (INPs). Numerous studies have revealed the mechanisms of development of neural stem cells. However, the signaling pathways that govern the development of INPs are largely unknown.

Anthropogenic Pu distribution in Tropical East Pacific.

The geographical distribution of the anthropogenic radionuclides (238)Pu and (239+240)Pu in the Tropical East Pacific in 2003 was studied from the viewpoint of material migration. We measured the contents of Pu isotopes in seawater and in sediment from the sea bottom. The distributions of Pu isotopes, together with those of coexisting nitrate and phosphate species and dissolved oxygen, are discussed in relation to the potential temperature and potential density (sigma-θ).

An autopsied case of V180I Creutzfeldt-Jakob disease presenting with panencephalopathic-type pathology and a characteristic prion protein type.

A 73-year-old Japanese woman showed slowly progressive aphasia, apraxia and dementia. She had no family history of prion disease or dementia. One year later she showed parkinsonism and corticobasal degeneration was initially suspected.

Effect of sevelamer and calcium-based phosphate binders on coronary artery calcification and accumulation of circulating advanced glycation end products in hemodialysis patients.

Background: Some trials have indicated that coronary artery calcification progresses more slowly in sevelamer-treated dialysis patients than in those using calcium-based binders. Effects of phosphate binders on circulating advanced glycation end products (AGEs) are unknown.

Study Design: Randomized trial with parallel-group design.

Impact of chronic kidney disease on clinical and angiographic results following implantation of sirolimus-eluting coronary stents.

Although sirolimus-eluting stent (SES) is effective to reduce restenosis, the effect of SES for patients with chronic kidney disease (CKD) has been ambiguous. SES were exclusively implanted into 304 lesions in 195 patients. Forty-seven percent of the patients had diabetes.

The effect of recombinant E-cadherin substratum on the differentiation of endoderm-derived hepatocyte-like cells from embryonic stem cells.

Generation of specific lineages of cells from embryonic stem (ES) cells is pre-requisite to use these cells in pre-clinical applications. Here, we developed a recombinant E-cadherin substratum for generation of hepatic progenitor populations at single cell level. This artificial acellular feeder layer supports the stepwise differentiation of ES cells to cells with characteristics of definitive endoderm, hepatic progenitor cells, and finally cells with phenotypic and functional characteristics of hepatocytes.

Ab initio electron correlated studies on the intracluster reaction of NO+ (H2O)(n) → H3O+ (H2O)(n-2) (HONO) (n = 4 and 5).

Hydrated nitrosonium ion clusters NO(+)(H(2)O)(n) (n = 4 and 5) were investigated by using MP2/aug-cc-pVTZ level of theory to clarify isomeric reaction pathways for formation of HONO and fully hydrated hydride ions. We found some new isomers and transition state structures in each hydration number, whose lowest activation energies of the intracluster reactions were found to be 4.1 and 3.

Transcriptional control of hepatocyte differentiation.

The liver is the largest glandular organ in the body and plays a central role in controlling metabolism. During hepatogenesis, complex developmental processes must generate an array of cell types that are spatially arranged to generate a hepatic architecture that is essential to support liver function. The processes that control the ultimate formation of the liver are diverse and complex and in many cases poorly defined.

[A new anti-mycobacterial agent, rifabutin].

This is a review of non-clinical and clinical study results of rifabutin (Mycobutin, RBT) which was approved as a new anti-mycobacterial agent 38 years after rifampicin (RFP) was approved in Japan. The anti-bacterial actions of RBT were similar to those of RFP, but its potency was stronger (4 to 32 times in MIC90). RBT showed excellent penetration in cells (9 times in neutrophil, 15 times in monocyte, against plasma concentration) and in tissues (5 to 10 times in pulmonary tissue).

Unveiling thermal transitions of polymers in subnanometre pores.

The thermal transitions of confined polymers are important for the application of polymers in molecular scale devices and advanced nanotechnology. However, thermal transitions of ultrathin polymer assemblies confined in subnanometre spaces are poorly understood. In this study, we show that incorporation of polyethylene glycol (PEG) into nanochannels of porous coordination polymers (PCPs) enabled observation of thermal transitions of the chain assemblies by differential scanning calorimetry.

A minimal implementation of the AMBER-GAUSSIAN interface for ab initio QM/MM-MD simulation.

For applying to a number of theoretical methodologies based on an ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics method connecting AMBER9 with GAUSSIAN03, we have developed an AMBER-GAUSSIAN interface (AG-IF), which can be one of the simplest architectures. In the AG-IF, only a few subroutines addition is necessary to retrieve the QM/MM energy and forces, obtained by GAUSSIAN, for solving a set of Newtonian equations of motion in AMBER. It is, therefore, easy to be modified for individual applications since AG-IF utilizes most of those functions originally equipped not only in AMBER but also in GAUSSIAN.

Influence of hydrostatic pressure on dynamics and spatial distribution of protein partial molar volume: time-resolved surficial Kirkwood-Buff approach.

The influence of hydrostatic pressure on the partial molar volume (PMV) of the protein apomyoglobin (AMb) was investigated by all-atom molecular dynamics (MD) simulations. Using the time-resolved Kirkwood-Buff (KB) approach, the dynamic behavior of the PMV was identified. The simulated time average value of the PMV and its reduction by 3000 bar pressurization correlated with experimental data.

Structural dynamics of clamshell rotation during the incipient relaxation process of photodissociated carbonmonoxy myoglobin: statistical analysis by the perturbation ensemble method.

The structural dynamics of the clamshell rotation of photodissociated carbonmonoxy myoglobin, which is expected to be important for hemoglobin allostery, is investigated by the perturbation ensemble method. In this method, many pairs of perturbed and unperturbed molecular dynamics trajectories are ensemble-averaged to cancel out thermal noises and to detect subtle changes. The number of MD trajectory pairs, in this work 2000 pairs, should be determined to obtain physical properties of interest with statistically meaningful precisions.

An optimum strategy for solution chemistry using semiempirical molecular orbital method. II. Primary importance of reproducing electrostatic interaction in the QM/MM framework.

For the purpose of executing direct dynamic and statistical calculation of chemical reactions in solution, we proposed an optimum strategy using semiempirical molecular orbital (MO) method with neglect of diatomic differential overlap (NDDO) approximation with specific solution reaction parameters (SSRPs), that is, the NDDO-SSRP method. It has been further extended to develop the NDDO-MAIS-SSRP method, which is the NDDO-SSRP method reinforced with the method adopted for intermolecular studies (MAIS), to correct the description of the intermolecular core-core repulsion interaction energy. In this strategy, the empirical parameters of the semiempirical MO method are optimized individually for a target chemically reacting molecular system by reference to the ab initio MO calculation data for a lot of instantaneous geometries on the potential energy surface near the reaction path.

Sofalcone, a gastric mucosa protective agent, increases vascular endothelial growth factor via the Nrf2-heme-oxygenase-1 dependent pathway in gastric epithelial cells.

Sofalcone, 2'-carboxymethoxy-4,4-bis(3-methyl-2-butenyloxy)chalcone, is an anti-ulcer agent that is classified as a gastric mucosa protective agent. Recent studies indicate heat shock proteins such as HSP32, also known as heme-oxygenase-1(HO-1), play important roles in protecting gastrointestinal tissues from several stresses. We have previously reported that sofalcone increases the expression of HO-1 in adipocytes and pre-adipocytes, although the effect of sofalcone on HO-1 induction in gastrointestinal tissues is not clear.

[Depression screening test for patients with metastatic gastric and colorectal cancer].

The prevalence of depression has been reported to be higher in cancer patients, especially those of advanced stage, compared to normal controls. However, depression is often under-recognized in clinical oncology settings. And this psychological problem is not routinely assessed even in patients with inoperable metastatic cancer who often have psychological disorders.

4- and 6-(p-Sulphamoylphenyl)androstenediones: Studies of aromatase inhibitor-based oestrone sulphatase inhibition.

4-(p-Sulphamoylphenyl)androstenedione (3) and 6alpha-p-sulphamoylphenyl analogues 12-14 were synthesised and tested as aromatase inhibitors as well as oestrone sulphatase inhibitors in human placental microsomes. All of the p-sulphamoylphenyl compounds synthesised were powerful inhibitors of aromatase with apparent K(i) values ranging between 30 and 97nM. In addition, the aromatase inhibitory activities of 6alpha-p-hydroxyphenyl compounds 9-11, which may be produced from their respective sulphamoylphenyl compounds by action of oestrone sulphatase, were also high in a range of 23 and 75nM of the K(i) values.

Intravascular ultrasound criteria for determination of optimal longitudinal positioning of sirolimus-eluting stents.

Background: Several studies have indicated that the clinical outcomes of sirolimus-eluting stents (SES) are significantly associated with longitudinal positioning of the stent relative to the underlying plaque distribution.

Methods And Results: Optimal SES landing was determined using unique stepwise intravascular ultrasound (IVUS) criteria, mainly targeting the sites with plaque burden <50% (plaque area/external elastic membrane area x100). To verify the criteria, (1) achievability and (2) actual impact on clinical and angiographic outcomes were assessed.