Understanding asymmetric switching times in accumulation mode organic electrochemical transistors.

Understanding the factors underpinning device switching times is crucial for the implementation of organic electrochemical transistors in neuromorphic computing, bioelectronics and real-time sensing applications. Existing models of device operation cannot explain the experimental observations that turn-off times are generally much faster than turn-on times in accumulation mode organic electrochemical transistors. Here, using operando optical microscopy, we image the local doping level of the transistor channel and show that turn-on occurs in two stages-propagation of a doping front, followed by uniform doping-while turn-off occurs in one stage. We attribute the faster turn-off to a combination of engineering as well as physical and chemical factors including channel geometry, differences in doping and dedoping kinetics and the phenomena of carrier-density-dependent mobility. We show that ion transport limits the operation speed in our devices. Our study provides insights into the kinetics of organic electrochemical transistors and guidelines for engineering faster organic electrochemical transistors.

Chain Length Dependence of Electron Transport in an n-Type Conjugated Polymer with a Rigid-Rod Chain Topology.

Most currently known n-type conjugated polymers have a semiflexible chain topology, and their charge carrier mobilities are known to peak at modest chain lengths of below 40-60 repeat units. Herein, we show that the field-effect electron mobility of a model n-type conjugated polymer that has a rigid-rod chain topology grows continuously without saturation, even at a chain length exceeding 250 repeat units. We found the mechanism underlying the novel chain length-dependent electron transport to originate from the reduced structural disorder and energetic disorder with the increasing degree of polymerization inherent to the rigid-rod chain topology. Furthermore, we demonstrate a unique chain length-dependent decay of threshold voltage, which is rationalized by decreased trap densities and trap depths with respect to the degree of polymerization. Our findings provide new insights into the role of polymer chain topology in electron transport and demonstrate the promise of rigid-rod chain architectures for the design of future high-mobility conjugated polymers.

Hydration of a Side-Chain-Free n-Type Semiconducting Ladder Polymer Driven by Electrochemical Doping.

We study the organic electrochemical transistor (OECT) performance of the ladder polymer poly(benzimidazobenzophenanthroline) (BBL) in an attempt to better understand how an apparently hydrophobic side-chain-free polymer is able to operate as an OECT with favorable redox kinetics in an aqueous environment. We examine two BBLs of different molecular masses from different sources. Regardless of molecular mass, both BBLs show significant film swelling during the initial reduction step. By combining electrochemical quartz crystal microbalance gravimetry, in-operando atomic force microscopy, and both ex-situ and in-operando grazing incidence wide-angle X-ray scattering (GIWAXS), we provide a detailed structural picture of the electrochemical charge injection process in BBL in the absence of any hydrophilic side-chains. Compared with ex-situ measurements, in-operando GIWAXS shows both more swelling upon electrochemical doping than has previously been recognized and less contraction upon dedoping. The data show that BBL films undergo an irreversible hydration driven by the initial electrochemical doping cycle with significant water retention and lamellar expansion that persists across subsequent oxidation/reduction cycles. This swelling creates a hydrophilic environment that facilitates the subsequent fast hydrated ion transport in the absence of the hydrophilic side-chains used in many other polymer systems. Due to its rigid ladder backbone and absence of hydrophilic side-chains, the primary BBL water uptake does not significantly degrade the crystalline order, and the original dehydrated, unswelled state can be recovered after drying. The combination of doping induced hydrophilicity and robust crystalline order leads to efficient ionic transport and good stability.

Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma.

Tumor-associated B7-H1 molecules inhibit antitumor immunity in some malignancies. We found that B7-H1 expression on patient myeloma cells and human myeloma cell lines (HMCLs) was upregulated by cultivating the cells with autologous stromal cells and the human stromal cell line HS-5. Among major cytokines produced by HS-5 cells, interleukin (IL)-6-induced B7-H1 expression on HMCLs. Moreover, HS-5 cell-mediated B7-H1 expression was downregulated by inhibiting IL-6. B7-H1(+) HMCLs were more proliferative and less susceptible to antimyeloma chemotherapy compared with B7-H1(-) HMCLs. Moreover, the former cells showed higher levels of Bcl-2 and FasL expression than the latter. Finally, B7-H1 molecules on HMCLs induced T-cell apoptosis and anergy of tumor-specific T cells. Consistent with these in vitro observations, patients whose myeloma cells expressed high levels of B7-H1 had higher myeloma cell percentages in the bone marrow (BM) and higher serum lactate dehydrogenase levels compared with other myeloma patients. In addition, B7-H1 expression levels were often upregulated after myeloma patients relapsed or became refractory to therapy. Our data indicate that the BM microenvironment upregulates B7-H1 expression on myeloma cells, which links to the two biological actions of inducing T-cell downregulation and enhancing aggressive myeloma-cell characteristics. Modulating the B7-H1 pathway may be worthwhile in myeloma.

Effects of cyclosporin A on cell fusion in a monkey kidney cell line persistently infected with measles virus.

The authors studied the effects of immunosuppressive peptide cyclosporin A (CsA) on cell fusion efficiency in cells persistently infected with measles virus (448-PI-Vero cells). Treatment of 448-PI-Vero cells with 5 microM CsA enhanced the infusion. In addition, the expression of measles virus antigen on cell surface was increased by treatment with CsA. The addition of phenothiazine, an anti-calmodulin drug, enhanced the fusion of 448-PI-Vero cells in the presence of CsA, although treatment with phenothiazine alone did not affect polykaryocyte formation. The enhancement of fusion efficiency in 448-PI-Vero cells by CsA was suppressed by oligopeptide Z-D-Phe-Phe-Gly, a synthetic oligopeptide that inhibits fusion induced by measles virus. Since the cell content of major virus-specific polypeptides, such as hemagglutinin, nucleoprotein or matrix protein is the same as in untreated controls, this fusion enhancement may be related to transport and accumulation of measles virus glycoproteins.

In-vivo delivery of therapeutic proteins by genetically-modified cells: comparison of organoids and human serum albumin alginate-coated beads.

We have designed a self-assembling multimeric soluble CD4 molecule by inserting the C-terminal fragment of the alpha chain of human C4-binding protein (C4bp alpha) at the C-terminal end of human soluble CD4 genes. This CD4-C4bp alpha fusion protein (sMulti-CD4) and two other reference molecules, a fusion protein of human serum albumin (HSA) and the first two domains of CD4 (HSA-CD4) and monomeric soluble CD4 (sMono-CD4), were delivered in vivo by genetically modified 293 cells. These cells were implanted in mice as organoids and also encapsulated in HSA alginate-coated beads. sMulti-CD4 showed an apparent molecular weight of about 300-350 kDa, in accordance with a possible heptamer formula. sMulti-CD4 produced either in cell culture or in vivo in mice appeared to be a better invitro inhibitor of HIV infection than sMono-CD4. Plasma levels of sMulti-CD4, HSA-CD4, and sMono-CD4 reached approximately 2,300, 2,700, and 170 ng/mL, respectively, 13 weeks after in-vivo organoid implantation, which had formed tumours at that time. This suggests that the plasma half-life of sMulti-CD4 is much longer than that of sMono-CD4. The 293 xenogeneic cells encapsulated in HSA alginate-coated beads remained alive and kept secreting sMono-CD4 or HSA-CD4 continuously at significant levels for 18 weeks in nude mice, without tumour formation. When implanted in immunocompetent Balb/c mice, they were rejected two to three weeks after implantation. In contrast, encapsulated BL4 hybridoma cells remained alive and kept secreting BL4 anti-CD4 mAb for at least four weeks in Balb/c mice. These results suggest the clinical potential of the C4bp-multimerizing system, which could improve both the biological activity and the poor in-vivo pharmacokinetic performance of a monomeric functional protein like soluble CD4. These data also show that a systemic delivery of therapeutic proteins, including immunoglobulins, can be obtained by the in-vivo implantation of engineered allogeneic cells encapsulated in HSA alginate-coated beads.

Identification of two initiator elements in the bidirectional promoter of the human dihydrofolate reductase and mismatch repair protein 1 genes.

The human dihydrofolate reductase (DHFR) gene and mismatch repair protein 1 (MRP1) genes are organized in a head-to-head configuration separated by an 90 base pair sequence. We have previously shown that as small as a 114 bp promoter sequences is sufficient for accurate and efficient initiation of divergent transcription. In this study, the mechanism of accurate transcription initiation in vivo from this short bidirectional promoter was analyzed by a newly developed highly sensitive primer extension assay. The GC boxes in the middle of this sequence were essential for bidirectional promoter activity, but not sufficient for accurate initiation. The sequences overlapping the transcription initiation sites of the DHFR and MRP1 genes were shown to function as the initiator, which directs transcription from an internal site. These initiators were strictly position dependent and were active only when located from 40 to 50 base pairs downstream from the GC box. Although there is no apparent sequence homology between two initiators, a common nuclear factor bound to these elements. Existence of two initiators located on both sides of the middle GC box seems to be the molecular basis of bidirectional activity of this short DNA sequence.

[Extravascular lung water in patients after cardiac surgery].

Extravascular lung water (EVLW) measured by a double indicator dilution method using thermal-dye indicator was evaluated in 204 patients after cardiac surgery during last 7 years. The measurement of EVLW was done at 2, 4, 8, 24 and 48 hours after extracorporeal circulation (ECC), EVLW showed no significant change except transient decrease at 4 hours after ECC, average of that was 7.62 +/- 3.58 ml/kg, EVLW of group I (MVR) and group III (AVR + MVR) were significantly higher than those of group II (AVR), group IV (noncyanotic congenital heart disease) and group V (A-C bypass). EVLW of 7 patients with postoperative pulmonary edema was 14.47 +/- 4.44 ml/kg, and that was significantly higher than those of others (7.54 +/- 3.06 ml/kg). EVLW of the patients using bubble oxygenator (8.60 +/- 3.90 ml/kg) was significantly higher than those of membrane oxygenator (7.15 +/- 3.40 ml/kg). Postoperative EVLW correlated with mean pulmonary artery pressure (mPAP), mean left atrial pressure (LAP) and microvascular hydrostatic pressure (PMV), and showed inverse correlation with cardiac index (CI). But there was no correlation of EVLW with duration of ECC. In the preoperative parameter, EVLW correlated with age, mPAP, mean pulmonary wedge pressure (mPAWP), PMV, serum BUN and serum creatinine, and showed inverse correlation with CI, %VC, FEV%, PSP test and creatinine clearance. We concluded that the patients with mitral valve disease who have high mPAP and LAP, respiratory and renal dysfunction and old aged preoperatively showed upward trend of EVLW. In perioperative management, care must be taken in such patients and membrane oxygenator was thought useful for prevention of pulmonary edema.(ABSTRACT TRUNCATED AT 250 WORDS)

A GC box in the bidirectional promoter is essential for expression of the human dihydrofolate reductase and mismatch repair protein 1 genes.

The human dihydrofolate reductase and mismatch repair protein 1 genes are organized in a head-to-head configuration separated by an 88 base-pair segment and directed by a bidirectional promoter. In vivo transient assays of the site directed mutant promoters using firefly luciferase as a reporter showed that an AT-rich sequence, ACAAATA, in the GC-rich promoter sequence is not required for transcription. However, two out of four GC boxes were shown to function as bidirectional positive regulatory elements. Among them, a GC box at the midpoint of the region between the two initiation sites is essential for supporting minimal bidirectional activity.

[A study on surgical cases of pulmonary aneurysm].

We performed 830 cases of open heart surgery in the past 12 years and two of those cases were complicated by pulmonary aneurysm. The first case was a 21-year-old female with annuloaortic ectasia and treated by partial resection and plication of the pulmonary aneurysm associating of partial resection and plication of the pulmonary aneurysm associating of Bentall's procedure. Pathological examination revealed the findings of Aortitis syndrome, i.e., inflammatory granuloma with round cells infiltration and fragmentation of elastic fibers in the medial as well as adventitial layers. The second case, a reoperation case, was a 44-year-old female with valvular disease, MSR, TSR, Pr and treated by partial resection of the pulmonary aneurysm associating with MVR, TVR, and PA valve plasty. Pathological examination revealed hyalin and necrobiotic degeneration of the media. Both cases involved had pulmonary hypertension suggesting a role for pulmonary hypertension along with organic changes of the vessel in the pathogenesis of the aneurysm.