These data indicate that the coding region of OAT1 has low genetic and functional diversity and suggest that coding region variants of OAT1 may not contribute substantially to interindividual differences in renal elimination of xenobiotics.

Cell-to-cell variability plays a critical role in cellular responses and decision-making in a population, and transcriptional bursting has been broadly studied by experimental and theoretical approaches as the potential source of cell-to-cell variability. Although molecular mechanisms of transcriptional bursting have been proposed, there is little consensus. An unsolved key question is whether transcriptional bursting is intertwined with many transcriptional regulatory factors or is an intrinsic characteristic of RNA polymerase on DNA. Here we design an in vitro single-molecule measurement system to analyse the kinetics of transcriptional bursting. The results indicate that transcriptional bursting is caused by interplay between RNA polymerases on DNA. The kinetics of in vitro transcriptional bursting is quantitatively consistent with the gene-nonspecific kinetics previously observed in noisy gene expression in vivo. Our kinetic analysis based on a cellular automaton model confirms that arrest and rescue by trailing RNA polymerase intrinsically causes transcriptional bursting.

Abstract-Tumor-necrosis factor-␣ (TNF-␣) is a proinflammatory cytokine with a wide variety of biological effects. The most important source of this cytokine is monocytes/macrophages. It is a potent agonist in the activation of endothelial cells; however, the precise role of endothelial cells as a source of TNF-␣ is not known. In the present study, we addressed the possibility that TNF-␣ is produced by cultured human umbilical vein endothelial cells (

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The sarcomere, the minimal mechanical unit of muscle, is composed of myosins, which self-assemble into thick filaments that interact with actin-based thin filaments in a highly-structured lattice. This complex imposes a geometric restriction on myosin in force generation. However, how single myosins generate force within the restriction remains elusive and conventional synthetic filaments do not recapitulate the symmetric bipolar filaments in sarcomeres. Here we engineered thick filaments using DNA origami that incorporate human muscle myosin to directly visualize the motion of the heads during force generation in a restricted space. We found that when the head diffuses, it weakly interacts with actin filaments and then strongly binds preferentially to the forward region as a Brownian ratchet. Upon strong binding, the two-step lever-arm swing dominantly halts at the first step and occasionally reverses direction. Our results illustrate the usefulness of our DNA origami-based assay system to dissect the mechanistic details of motor proteins.

During the Sakai outbreak of Escherichia coli O157:H7 infection, which was linked to contaminated cafeteria school lunches, there were several treatment modalities with regard to antimicrobial drugs. Patient outcomes among three hospitals with different modalities were compared retrospectively. Hemolytic uremic syndrome did not develop in any of the 15 patients treated with oral fluoroquinolone therapy; however, HUS did develop in three of 15 patients treated with intravenous (i.v.) fosfomycin and in two of 12 patients treated with i.v. cefotaxime and oral fosfomycin. The results indicate that oral fluoroquinolone therapy administered within 3 days of illness is effective in preventing the development of HUS; however, prospective randomized double-blind studies on early antimicrobial therapy of O157 hemorrhagic colitis are necessary. Several antibiotics, including fluoroquinolones, were reported to induce the production or release of Shiga-like toxins (STX) from E. coli O157:H7 in vitro. Although patients were examined for fecal STX, no STX were detected in the stools of patients treated with oral fluoroquinolones. In fact, treatment with fluoroquinolones for 5 days eradicated E. coli O157 in all patients.

motor proteins are force-generating nanomachines that are highly adaptable to their everchanging biological environments and have a high energy conversion efficiency. Here we constructed an imaging system that uses optical tweezers and a DnA handle to visualize elementary mechanical processes of a nanomachine under load. We apply our system to myosin-V, a well-known motor protein that takes 72 nm 'hand-over-hand' steps composed of a 'lever-arm swing' and a 'Brownian search-and-catch'. We find that the lever-arm swing generates a large proportion of the force at low load ( < 0.5 pn), resulting in 3 k B T of work. At high load (1.9 pn), however, the contribution of the Brownian search-and-catch increases to dominate, reaching 13 k B T of work. We believe the ability to switch between these two forcegeneration modes facilitates myosin-V function at high efficiency while operating in a dynamic intracellular environment.1 Soft Biosystem Group, Laboratories for Nanobiology, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan. 2 Graduate School of Medicine, Osaka University, 1-3 Yamadaoka, Suita, 565-0871, Japan. switching of myosin-V motion between the lever-arm swing and Brownian search-and-catch

Abstract.The Growject® database on human GH treatment in Turner syndrome was analyzed in the Turner Syndrome Research Collaboration, and the relationships of the frequencies of spontaneous breast development and spontaneous menarche with karyotype and GH treatment were investigated. One hundred and three cases started GH treatment with 0.5 IU/kg/ week (0.5 IU group), and their dose was increased to 0.35 mg/kg/wk midway through the treatment course. Another 109 cases started GH at a dose of 0.35 mg/kg/wk (0.35 mg group). Spontaneous breast development was observed in 77 (36.3%) of the 212 patients, and spontaneous menarche occurred in 31 patients (14.6%). The frequency of spontaneous breast development was significantly lower in patients with the 45,X karyotype and significantly higher in patients with a structural abnormality of the second X chromosome. The frequency of spontaneous menarche was significantly higher in patients with mosaicism characterized by X monosomy and a cellular line with no structural abnormality of the X chromosome. No significant differences in frequencies of spontaneous breast development and spontaneous menarche were observed between the two dose groups, indicating that GH treatment does not increase the frequency of spontaneous puberty.