Conductivity Contrast and Tunneling Charge Transport in the Vortexlike Ferroelectric Domain Patterns of Multiferroic Hexagonal YMnO_{3}.

We deduce the intrinsic conductivity properties of the ferroelectric domain walls around the topologically protected domain vortex cores in multiferroic YMnO_{3}. This is achieved by performing a careful equivalent-circuit analysis of dielectric spectra measured in single-crystalline samples with different vortex densities. The conductivity contrast between the bulk domains and the less conducting domain boundaries is revealed to reach up to a factor of 500 at room temperature, depending on the sample preparation. Tunneling of localized defect charge carriers is the dominant charge-transport process in the domain walls that are depleted of mobile charge carriers. This work demonstrates that, via equivalent-circuit analysis, dielectric spectroscopy can provide valuable information on the intrinsic charge-transport properties of ferroelectric domain walls, which is of high relevance for the design of new domain-wall-based microelectronic devices.

Polar Dynamics at the Jahn-Teller Transition in Ferroelectric GaV4S8.

We present a dielectric spectroscopy study of the polar dynamics linked to the orbitally driven ferroelectric transition in the Skyrmion host GaV(4)S(8). By combining THz and MHz-GHz spectroscopy techniques, we succeed in detecting the relaxational dynamics arising from coupled orbital and polar fluctuations in this material and trace its temperature dependence in the paraelectric as well as in the ferroelectric phase. The relaxation time significantly increases when approaching the critical temperature from both sides of the transition. It is natural to assume that these polar fluctuations map the orbital dynamics at the Jahn-Teller transition. Because of the first-order character of the orbital-ordering transition, the relaxation time shows an enormous jump of about 5 orders of magnitude at the polar and structural phase transition.

Bicyclic nucleoside synthesis: a photochemical approach.

The synthesis of a series of bicyclic nucleosides using photolytic ring-expansion of cyclobutanones is reported. The cyclobutanone precursors were prepared by [2+2] cycloaddition of a series of cyclic alkenes with chlorinated ketenes, derived from dichloro- and trichloroacetyl chloride. The synthesis of the nucleosides was achieved through photolysis of cyclobutanone precursors with 6-chloropurine by UV irradiation. The generality of this method was investigated and the absolute stereochemistry was assigned by NMR spectroscopy. The photoproducts demonstrated a marked preference for the 2'-exo conformation.

Effect of ACE and AT-2 inhibitors on mortality and progression to microalbuminuria in a nested case-control study of diabetic nephropathy in diabetes mellitus type 2: results from the GENDIAN study.

INTRODUCTION: There is an established role of clinical risk factors such as arterial hypertension and smoking in causing cardiovascular morbidity and diabetic nephropathy (DNP). Genetic factors increase the risk for DNP. To examine the genetic risk, we initiated a case-control study with predefined follow-up examinations. We describe the study design and baseline characteristics under special consideration of comedication, and give preliminary results of the 4-year follow-up. METHODS: We enrolled all 477 patients with DNP receiving maintenance hemodialysis in 30 centers in Southern Germany between August 1999 and January 2000. As controls, we enrolled all 482 diabetes mellitus type 2 patients without urinary microalbuminuria in two examinations on consecutive days and without other signs of renal disease in a large diabetes clinic from September 2000 to September 2001. Follow-up examinations are performed 4 and 6 years after inclusion by questionnaire and telephone interview to determine mortality and new morbidity. Controls progressing to novel DNP at follow-up, as defined by semiquantitative dipstick urinary albumin/creatinine ratio > 30 mg/g, are defined as cases in the study's nested case control component. RESULTS: At study inclusion in cases and controls, respectively, mean age was 67.3 +/- 8.2 and 58.1 +/- 11.2 years and duration of diabetes mellitus was 15.6 +/- 9.6 (at dialysis initiation) and 11.0 +/- 8.6 years. 328 controls (of which 25 had died and 14 did not perform urinalysis) were subjected to follow-up at 4 years, at a mean of 3.5 +/- 0.8 years after inclusion. 51.2% (n = 148) of living controls remained normalbuminuric, 33.9% (n = 98) had microor macroalbuminuria, and in 14.9% (n = 43) the dipstick test was inconclusive. There was no significant difference in progression to micro- or macroalbuminuria between controls treated with ACE or AT-2 inhibitors at baseline or not. Renal function as estimated by the abbreviated MDRD formula declined from 86.8 +/- 21.0 to 82.5 +/- 22.3 ml/min/1.73 m2 (p < 0.001). The decline was significant in patients on ACE or AT-2 inhibitors at baseline and not in patients without such medication at baseline. DISCUSSION: GENDIAN is a large case-control study designed to evaluate clinical and genetic determinants of DNP and other complications of long-standing diabetes mellitus type 2. We observed an association of ACE or AT-2 inhibitor therapy with cardiovascular comorbidity and a significant decline in renal function after a 4-year follow-up.

Induction and modulation of anchorage-independent growth by platelet-derived growth factor, fibroblast growth factor, and transforming growth factor-beta.

Transforming growth factors (TGFs) reversibly induce the anchorage-independent growth of nontransformed cells. TGF activity is often monitored by the growth of normal rat kidney (NRK) fibroblasts in soft agar, and it is known that more than one growth factor is involved in the regulation of their soft agar growth. To more clearly define the growth factors responsible for the soft agar growth of NRK cells, the effects of four growth factors were examined: platelet-derived growth factor (PDGF); TGF-beta; epidermal growth factor (EGF); and fibroblast growth factor (FGF). This study determined that PDGF induces the soft agar growth of NRK cells, in both plasma-supplemented medium and serum-free medium supplemented with FGF, and neither TGF-beta nor an EGF-related growth factor is required for this effect. It was also determined that FGF, which alone does not induce the soft agar growth of these cells, potentiates the responses of NRK cells to various combinations of PDGF, TGF-beta, and EGF. Interestingly, the effect of TGF-beta was found to depend on the growth factor composition of the medium. In the absence of EGF, TGF-beta partially inhibits the soft agar growth response of NRK cells to PDGF, whereas, in the presence of EGF, TGF-beta increases their response to PDGF. These findings indicate that at least four unrelated growth factors regulate the anchorage-independent growth of NRK cells. These findings have important implications for the use of NRK cells to assay TGFs.

Isolation and characterization of A-431 cells that retain high epidermal growth factor binding capacity and respond to epidermal growth factor by growth stimulation.

A-431 cells, which exhibit large numbers of epidermal growth factor (EGF) receptors and respond to EGF by growth inhibition, are widely used to study EGF receptors and the effects of EGF. In this report, we describe the isolation and characterization of variant A-431 cells that respond to EGF by growth stimulation. One variant, which is referred to as A-431R-1, has been characterized in detail. EGF stimulates both monolayer and soft agar growth of A-431R-1 cells cultured in serum-free medium. In contrast to the original A-431 cells, growth of A-431R-1 cells is not inhibited by EGF, even at high concentrations. Scatchard analysis of EGF binding to A-431R-1 cells and A-431 cells indicates that both cell populations exhibit approximately 1.8 x 10(6) EGF receptors per cell. Thus, unlike other variants of A-431 cells that are not inhibited by EGF, A-431R-1 cells exhibit as many EGF receptors as the parental A-431 cells. It was also determined that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate reduces EGF binding to the high affinity receptors of A-431R-1 cells; whereas, transforming growth factor type beta did not significantly affect EGF binding. Our results suggest that A-431R-1 cells should be useful for studying the biochemical effects of EGF and for examining why some cells are inhibited by EGF, whereas others are stimulated by EGF.

Regulatory effects of cell density on the binding of transforming growth factor beta, epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor.

The work described in this paper demonstrates that the cellular binding of transforming growth factor beta, epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor is reduced as cell density is increased. The reduction in transforming growth factor beta binding was observed in five different cell lines. Examination of several of the cell lines, under conditions where transforming growth factor beta binding is reduced, revealed that epidermal growth factor binding, platelet-derived growth factor binding, and fibroblast growth factor binding are also reduced. In the case of NRK-49F cells, the reduction in transforming growth factor beta binding results from a decrease in the number of high-affinity receptors and not from a change in receptor affinity. Similarly, it was determined that the reduction in epidermal growth factor binding is due to a selective reduction in the high-affinity receptors for epidermal growth factor. Overall, the data suggest that the effect of cell density on growth factor binding, which we refer to as density-induced down regulation of growth factor receptors, differs both from down regulation induced by a specific growth factor and from receptor transmodulation.

Magnetoelectric effects in the skyrmion host material Cu2OSeO3.

Insulating helimagnetic Cu2OSeO3 shows sizeable magnetoelectric effects in its skyrmion phase. Using magnetization measurements, magneto-current analysis and dielectric spectroscopy, we provide a thorough investigation of magnetoelectric coupling, polarization and dielectric constants of the ordered magnetic and polar phases of single-crystalline Cu2OSeO3 in external magnetic fields up to 150 mT and at temperatures below 60 K. From these measurements we construct a detailed phase diagram. Especially, the skyrmion phase and the metamagnetic transition of helical to conical spin order are characterized in detail. Finally we address the question if there is any signature of polar order that can be switched by an external electric field, which would imply multiferroic behaviour of Cu2OSeO3.

Synthesis and HIV inhibition activity of 2',3'-dideoxy-3'-C-hydroxymethyl nucleosides.

A series if 2',3'-dideoxy-3'-C-hydroxymethyl purine nucleosides were prepared based on the photochemical ring expansion of a chiral cyclobutanone precursor, (2S)-trans-2,3-bis[(benzoyloxy)methyl]cyclobutanone, in the presence of a 6-substituted purine. Both alpha- and beta-anomers are produced in this transformation. Deprotection was effected by reaction of the photoadducts with saturated methanolic ammonia. Nine purine nucleosides were tested for their inhibitory effect of HIV IIIB virus on H9 cells. The 6-hexyloxy and adenine derivatives 4e,c, respectively, appeared to be most effective at inhibiting viral reproduction with 4c comparable in activity to ddI and AZT.

The elimination profiles of oxaprozin in equine urine and serum after a 4.8-g dose.

A method for the extraction of oxaprozin from equine urine and serum and its quantitation by high-performance liquid chromatography-ultraviolet detection is presented. Confirmation of oxaprozin in postadministration extracts was accomplished by gas chromatographic- mass spectrometric analysis of methylated extracts or liquid chromatography with tandem mass spectrometry daughter ion mass spectra of underivatized extracts. Daypro, a formulation of oxaprozin, was administered orally at a dose of 4.8 g to four standardbred mares. Urine and serum samples were collected to 120 h postadministration. Base hydrolysis of equine urine before extraction resulted in an increase in the amount of oxaprozin measured, an indication of conjugation by ester formation. The urinary elimination profiles of each horse were significantly different from each other with more than one peak in oxaprozin concentration before the 29-31-h collection time. After this collection time, the differences between the oxaprozin urinary concentrations of each horse follow each other more closely. The peak average urinary concentrations of oxaprozin were 25.1 and 17.0 microg/mL at collection times of 8-10 and 18-22 h, respectively. The latest detection of oxaprozin in urine was at the last collection time of 119-121 h postadministration at a concentration close to the detection limit of approximately 0.1 microg/mL. The serum elimination profiles do not vary between horses as much as the urinary elimination profiles. The peak average serum concentration was 49.0 microg/mL at a collection time of 6 h postadministration. The latest detection was at the last collection time of 120 h. Oxaprozin is metabolized in the horse by hydroxylation. Two major urinary metabolites were isolated and identified as hydroxylated oxaprozin. The two urinary metabolites were isolated from equine postadministration urine and analyzed by mass spectrometry and proton nuclear magnetic resonance spectroscopy, which showed that the hydroxylation had occurred at the para positions of the two aromatic rings.

Neisseria gonorrhoeae in asymptomatic prepubertal household contacts of children with gonococcal infection.

This report describes the occurrence of gonococcal infection among prepubertal household contacts of children younger than 12 years of age. The records of 14 index cases (12 females and 2 males) reported during the period January 1979 and June 1983 were reviewed. Among 31 asymptomatic contacts of 10 index cases, nine (29%) had positive cultures (5 females and 4 males). Three were siblings of the index cases, and six were other children in the index households. The predominant site of positive cultures was the throat (7/9). This high recovery rate of gonococci among young asymptomatic household contacts makes clear the need for aggressive surveillance of prepubertal household contacts of children with gonococcal infection, and the importance of culturing all three sites, e.g., vagina/urethra, rectum, and throat.

Photochemical synthesis of novel dideoxynucleosides.

A series of 2',3'-dideoxynucleosides based on the apiose family was prepared from photochemical ring-expansion of a common cyclobutanone precursor. The starting ketone, (+/-) 3-[2'-(benzoyloxy)ethyl]-2,2-dimethylcyclobutanone (12) was prepared from commercially available (+/-)alpha-pinene. Since the optically pure antipodes of alpha-pinene are also commercially available, these nucleosides can be prepared optically pure using the identical procedure.

Fibroblast growth factor induces the soft agar growth of two non-transformed cell lines.

Recent studies have determined that fibroblast growth factor (FGF) potentiates the soft agar growth responses of NRK-49F cells to several combinations of transforming growth factors (TGFs). In the current study, two other non-transformed cell lines, NR-6 and AKR-2B, which do not spontaneously form colonies in soft agar, were examined for their soft agar growth responses to FGF. Both the acidic form and basic form of FGF were found to induce the soft agar growth of these cells. In the case of NR-6 cells, the effects of TGF-beta were also examined. TFG-beta potentiated the soft agar growth response of NR-6 cells to FGF, but on its own did not induce soft agar growth. Attempts to identify other factors capable of modulating the response of these cells to FGF, led to the finding that both 12-O-tetra-decanoylphorbol-13-acetate and retinoic acid suppress FGF-induced soft agar growth of NR-6 cells and AKR-2B cells. The finding that FGF induces the soft agar growth of both non-transformed cell lines, together with the findings of others that both forms of FGF are angiogenic, lends further support to the suggestion that FGF plays a significant role in the in vivo growth of some, and possibly many, tumors.

Preparation and binding of radioactively labeled porcine transforming growth factor type beta.

This report describes the labeling of porcine transforming growth factor type beta (TGF-beta) with 125-iodine. Its binding to NRK cells and three other cell lines has been examined. The data indicate that NRK cells exhibit approximately 10,000 receptors for porcine TGF-beta per cell, with an apparent dissociation constant of 45 pM. The binding of porcine 125I-TGF-beta can be blocked by porcine, murine and human TGF-beta but not by several well characterized growth factors. In all respects examined, the binding observed with porcine 125I-TGF-beta appears to be the same as that observed with human TGF-beta. The findings reported here argue that porcine 125I-TGF-beta can be used to quantitate TGF-beta receptors on a wide range of mammalian cells.

Comparative analysis of conjugative plasmids mediating gentamicin resistance in Staphylococcus aureus.

Five gentamicin-resistant clinical isolates of Staphylococcus aureus were found to contain self-transmissible plasmids of 32 to 37 megadaltons in size. Restriction endonuclease digests of the plasmids were markedly similar to those of reference plasmids of unrelated geographical origin, thus suggesting the significant contribution of common conjugal plasmids to the emergence of gentamicin resistance in S. aureus populations.

Production and utilization of growth factors related to fibroblast growth factor by embryonal carcinoma cells and their differentiated cells.

Previous studies have established that embryonal carcinoma (EC) cells produce several different growth factors, but express few, if any, receptors for epidermal growth factor, platelet-derived growth factor, or transforming growth factor type-beta. In this study, the production and utilization of fibroblast growth factor (FGF) by EC cells and their differentiated cells were investigated. We have determined that EC cells produce a heat-labile, heparin-binding factor that competes with FGF for binding to membrane receptors and appears to be immunologically related to FGF. The same or a similar factor is produced by three different EC cell lines, including a multipotent human EC cell line. However, production of this factor is apparently reduced when each EC cell line differentiates. Unlike the parental EC cells, the differentiated cells respond to FGF by growth stimulation and the growth responses to FGF correlate with increased binding of FGF. Although the binding data indicate that both the EC cells and their differentiated cells exhibit high affinity receptors for FGF, the differentiated cells express these receptors at levels approximately 10-fold higher. These findings suggest that the FGF-related growth factor could influence the growth of EC cells or their differentiated cells.

Isolation and preliminary characterization of a plasmid mutant derepressed for conjugal transfer in Staphylococcus aureus.

The plasmid pCRG1600 is a 52.9-kb self-transmissible plasmid coding for resistance to aminoglycoside and beta-lactam antibiotics in Staphylococcus aureus. When transferred by transduction, plasmid deletion mutants affecting one or more antibiotic-resistance genes were readily obtained. Of these, one derivative (pCRG1690) was found to exhibit a conjugal transfer frequency ca. 100-fold higher than that of the wild-type plasmid. A preliminary physical-genetic map of pCRG1600 located tra in a 14.6-kb region within the 16.9-kb XbaI-A fragment. An 8.5-kb deletion to the left of tra in pCRG1690 was specifically associated with the increased conjugal transferability of the plasmid. Thus, pCRG1690 appears similar to plasmids derepressed for conjugal transfer (drd) in gram-negative bacterial species.

Structures of poly(dA-dT, ip5dU) containing various small amounts of the antiherpetic 5-isopropyl-2'-deoxyuridine.

Three different concentrations of the antiherpetic agent 5-isopropyl-2'-deoxyuridine (ip5dU) were introduced into the synthetic DNA poly(dA-dT) to analyze resulting copolymers by electron microscopy, UV absorption and CD spectroscopy. The poly(dA-dT, ip5dU) containing 1.3 and 4.3% ip5dU did not much differ from the parent poly(dA-dT) but poly (dA-dT, ip5dU) with 7.1% ip5dU behaved in an unusual way. Results are explained by the notion that if bulky isopropyls occur sufficiently close to each other then stable hairpins protruding from the double helix are formed, presumably to accommodate the ip5dU-s into the loops.

Three small nucleolar RNAs of unique nucleotide sequences.

Three small RNA species were detected in human cells, and their cDNAs were synthesized and cloned. These RNAs are nucleolar, are 207, 154, and 135 nucleotides long, and are named E1, E2, and E3, respectively, and their unique nucleotide sequences suggest that they may belong to an additional family of small nucleolar RNAs. The 5' ends of these three RNAs do not appear to have a trimethylguanosine cap or another type of cap. Apparent homologs of these three RNAs were detected in mouse, rabbit, and frog cells, suggesting their universal importance. They are housekeeping RNA species, since they are present in all rabbit tissues analyzed.

Genes for E1, E2, and E3 small nucleolar RNAs.

We have found earlier three small nucleolar RNA (snoRNA) species, named E1, E2, and E3, that have unique nucleotide sequences and may participate in ribosome formation. The present report shows that there is a monophosphate at the 5' end of each of these three snoRNAs, suggesting that their 5' termini are formed by RNA processing. E1, E2, and E3 human genomic sequences were isolated. Apparently, the E2 and E3 loci are genes for the main E2 and E3 RNA species, based on their full homology, while the E1 locus is a gene for an E1 RNA sequence variant in HeLa cells. These loci do not have any of the intragenic or flanking sequences known to be functional in other genes. The E1 gene is located within the first intron of the gene for RCC1, a protein that regulates onset of mitosis. There is substantial sequence homology between the human E3 gene and flanking regions, and intron 8 and neighboring exons of the gene for mouse translation initiation factor 4AII. Injection of the human E1, E2, and E3 genes into Xenopus oocytes generated sequence-specific transcripts of the approximate sizes of the respective snoRNAs. We discuss why the available results are compatible with specific transcription and processing occurring in frog oocytes.