Miracle-dz/UniFAR-FTUs huggingface dataset:
DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

DDS, 4,4′-diaminodiphenylsulfone, is the most common drug prescribed to treat Hansen disease patients. In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells. Because DDS treatment significantly enhances the antioxidant activity in humans, we examined its effect on lifespan extension. Here we show that DDS extends organismic lifespan using Caenorhabditis elegans as a model system. DDS treatment caused a delay in aging and decreased the levels of a mitochondrial complex. The oxygen consumption rate was also significantly lowered. Consistent with these data, paraquat treatment evoked less reactive oxygen species in DDS-treated worms, and these worms were less sensitive to paraquat. Interestingly enough, all of the molecular events caused by DDS treatment were consistently reproduced in mice treated with DDS for 3 mo and in the C2C12 muscle cell line. Structural prediction identified pyruvate kinase (PK) as a protein target of DDS. Indeed, DDS bound and inhibited PK in vitro and inhibited it in vivo, and a PK mutation conferred extended lifespan of C. elegans. Supplement of pyruvate to the media protected C2C12 cells from apoptosis caused by paraquat. Our findings establish the significance of DDS in lowering reactive oxygen species generation and extending the lifespan, which renders the rationale to examining the possible effect of DDS on human lifespan extension.
Kinetics of hepatitis B surface antigen–specific immune responses in acute and chronic hepatitis B or After HBs vaccination: Stimulation of the in vitro antibody response by interferon gamma

Because cellular and humoral immune responses against the hepatitis B virus (HBV) surface antigen (HBs) might be crucial to overcome HBV infection, HBs‐specific B‐ and T‐cell responses of HBV patients and HBs vaccine recipients were analyzed quantitatively and functionally. In patients with acute hepatitis B (AHB), transient high anti‐HBs–secreting B‐cell frequencies were observed early after clinical onset, whereas 1 patient who probably developed chronic infection and chronic HBV carriers had absent or weak B‐ and T‐cell responses. In HBs vaccine recipients, maximal HBs‐specific B‐ and T‐cell responses were detected after the first injection that decreased gradually before anti‐HBs antibodies appeared in serum. Years after vaccination, anti‐HBs–secreting B cells were enriched in the bone marrow. After in vitro stimulation with HBsAg, peripheral blood mononuclear cells (PBMC) of only 1 of 5 acute and 1 of 6 chronic HBV patients, but of all 6 vaccine recipients, secreted varying amounts of interferon gamma (IFN‐γ), but no interleukin‐4 (IL‐4) or IL‐5. Furthermore, the addition of IFN‐γ, but not of IL‐2, ‐4, ‐12, or IFN‐α, resulted in strong increases of anti‐HBs–secreting B cells in vaccine recipients and chronic carriers. In conclusion, circulating anti‐HBs–secreting B cells were significantly higher in early acute hepatitis B or early after HBs vaccination than in chronic hepatitis B and decreased in the follow‐up as a result of compartmentalization to lymphoid tissues. Release of IFN‐γ by antigen‐stimulated T cells might be critical for anti‐HBs formation.
Expression of the fat-1 gene diminishes prostate cancer growth in vivo through enhancing apoptosis and inhibiting GSK-3β phosphorylation

Epidemiologic studies inclusively indicate that “unhealthy” dietary fat intake is one of the potential risk factors for cancer. In dietary fat, there are two types of polyunsaturated fatty acids (PUFA), ω-3 (n-3) and ω-6 (n-6). Numerous studies support that the ratio of n-6/n-3 affects tumorigenesis. It was reported that adenoviral transfer of the fat-1 gene, which converts n-6 to n-3, into breast and lung cancer cells had an antitumor effect in vitro. However, the effects of the fat-1 gene expression on tumor growth in vivo have not been studied and the mechanisms remain unclear. Accordingly, prostate cancer DU145 and PC3 cells were transfected with either the fat-1 gene or a control vector. The cells that expressed the fat-1 gene had a lower n-6/n-3 PUFA ratio compared with the cells that expressed the control vector. The fat-1 gene expression significantly inhibited prostate cancer cell proliferation and invasion in vitro. The fat-1 and control vector-transfected prostate cancer cells were s.c. implanted into severe combined immunodeficient mice for 6 weeks. The fat-1 gene expression significantly diminished tumor growth in vivo, but the control vector had no effect. Finally, we evaluated signaling pathways that may be important for fat-1 gene function. Administration of n-3 PUFA induced caspase-3-mediated prostate cancer cell apoptosis in vitro. The fat-1 gene expression inhibited prostate cancer cell proliferation via reduction of GSK-3β phosphorylation and subsequent down-regulation of both β-catenin and cyclin D1. These results suggest that fat-1 gene transfer directly into tumor cells could be used as a novel therapeutic approach. [Mol Cancer Ther 2008;7(10):3203–11]
UNILATERAL SUPERIORLY-BASED NASOLABIAL ISLAND FLAP FOR THE RECONSTRUCTION OF THE PHILTRUM

We present a case of reconstruction of the philtrum with a unilateral superiorly-based nasolabial island flap following a secondary Millard's bilateral cheiloplasty in a 23-year-old man with cleft lip and palate. His philtrum consisted of a full-thickness skin graft transplanted at one of his previous operations.
A comparison of individual‐based genetic distance metrics for landscape genetics

A major aim of landscape genetics is to understand how landscapes resist gene flow and thereby influence population genetic structure. An empirical understanding of this process provides a wealth of information that can be used to guide conservation and management of species in fragmented landscapes and also to predict how landscape change may affect population viability. Statistical approaches to infer the true model among competing alternatives are based on the strength of the relationship between pairwise genetic distances and landscape distances among sampled individuals in a population. A variety of methods have been devised to quantify individual genetic distances, but no study has yet compared their relative performance when used for model selection in landscape genetics. In this study, we used population genetic simulations to assess the accuracy of 16 individual‐based genetic distance metrics under varying sample sizes and degree of population genetic structure. We found most metrics performed well when sample size and genetic structure was high. However, it was much more challenging to infer the true model when sample size and genetic structure was low. Under these conditions, we found genetic distance metrics based on principal components analysis were the most accurate (although several other metrics performed similarly), but only when they were derived from multiple principal components axes (the optimal number varied depending on the degree of population genetic structure). Our results provide guidance for which genetic distance metrics maximize model selection accuracy and thereby better inform conservation and management decisions based upon landscape genetic analysis.
Heme Oxygenase-mediated Resistance to Oxygen Toxicity in Hamster Fibroblasts*

The role of heme oxygenase (HO)-1 was evaluated in the oxygen-resistant hamster fibroblast cell line, O2R95, which moderately overexpress HO when compared with the parental cell line, HA-1. To suppress HO-1 expression, O2R95 were transfected with HO-1 antisense oligonucleotide or treated with tin-mesoporphyrin (SnMP). To increase HO-1 expression, cells were transfected with HO-1 cDNA in a pRC/cytomegalovirus (CMV) vector. All cells were challenged with a 48-h exposure to 95% O2 (hyperoxia). When HO activity was suppressed, O2R95 cells had significantly decreased cell viability, increased susceptibility to lipid peroxidation, and increased protein oxidation in hyperoxia. In contrast, further overexpression of HO-1 did not improve resistance to oxygen toxicity. Antisense-transfected cells and SnMP-treated cells with lowered HO activity showed increased levels of cellular heme compared with controls. In the HO-1 cDNA-transfected O2R95 cells, cellular heme was lowered compared with controls; however, cellular redox active iron levels were increased. We conclude that HO mediates cytoprotection to oxygen toxicity within a narrow range of expression. We speculate that this protective effect may be mediated in part through increased metabolism of the pro-oxidant heme but that higher levels of HO activity obviate protection by increased redox active iron release.
Fast Analysis of RCS Over a Frequency Band Using Pre-Corrected FFT/AIM and Asymptotic Waveform Evaluation Technique

The pre-corrected fast Fourier transform (PFFT)/adaptive integral method (AIM) is combined with the asymptotic waveform evaluation (AWE) technique to present fast RCS calculation for arbitrarily shaped three-dimensional PEC objects over a frequency band. The electric field integral equation (EFIE) is used to formulate the problem and the method of moments (MoM) is employed to solve the integral equation. By using the AWE method, the unknown equivalent current is expanded into a Taylor series around a frequency in the desired frequency band. Then, instead of solving the equivalent current at each frequency point, it is only necessary to solve for the coefficients of the Taylor series (called ldquomomentsrdquo) at each expansion point. Since the number of the expansion points is usually much smaller than that of the frequency points, the AWE can achieve fast frequency sweeping. To facilitate the analysis of large problems, in this paper, all the full matrices are stored in a sparse form and the PFFT/AIM method is employed to accelerate all the matrix-vector products on both sides of the matrix equation for the moments. Further, the incomplete LU preconditioner is used at each expansion point to improve the convergence behaviour of the matrix equation for the moments. The present method can deal with much larger problems than the conventional MoM-AWE method since the PFFT/AIM achieves considerable reduction in memory requirement and computation time. Numerical results will be presented to show the efficiency and capability of the method.
Candida albicans infection leads to barrier breakdown and a MAPK/NF‐κB mediated stress response in the intestinal epithelial cell line C2BBe1

Intestinal epithelial cells (IEC) form a tight barrier to the gut lumen. Paracellular permeability of the intestinal barrier is regulated by tight junction proteins and can be modulated by microorganisms and other stimuli. The polymorphic fungus Candida albicans, a frequent commensal of the human mucosa, has the capacity of traversing this barrier and establishing systemic disease within the host. Infection of polarized C2BBe1 IEC with wild‐type C. albicans led to a transient increase of transepithelial electric resistance (TEER) before subsequent barrier disruption, accompanied by a strong decline of junctional protein levels and substantial, but considerably delayed cytotoxicity. Time‐resolved microarray‐based transcriptome analysis of C. albicans challenged IEC revealed a prominent role of NF‐κB and MAPK signalling pathways in the response to infection. Hence, we inferred a gene regulatory network based on differentially expressed NF‐κB and MAPK pathway components and their predicted transcriptional targets. The network model predicted activation of GDF15 by NF‐κB was experimentally validated. Furthermore, inhibition of NF‐κB activation in C. albicans infected C2BBe1 cells led to enhanced cytotoxicity in the epithelial cells. Taken together our study identifies NF‐κB activation as an important protective signalling pathway in the response of epithelial cells to C. albicans.
Identification with monoclonal antibodies of hemolysin produced by clinical isolates of Escherichia coli

Murine monoclonal antibodies were generated against the 107,000-dalton hemolysin encoded by the hemolytic determinant from Escherichia coli LE 2001, and colony blotting was used to assay for production of the hemolysin by 35 hemolytic strains of E. coli and other hemolytic members of the family Enterobacteriaceae of clinical origin. All hemolytic E. coli strains gave positive reactions with two monoclonal antibodies. In contrast, none of the hemolytic, non-E. coli isolates yielded positive colony blots. In addition, Western blotting showed that the hemolysins produced by all clinical E. coli isolates had a similar molecular weight of about 107,000. Discrete antigenic variation may occur in the molecule, since a third monoclonal antibody did not react with the hemolysin from a number of wild-type E. coli strains. Western blot analysis was used to assess the presence of immunoglobulin G (IgG), IgA, and IgM antibodies to E. coli hemolysin in human sera. All 20 of the tested sera from healthy adults contained antibodies to the toxin, with various constellations among the antibody classes. In contrast, sera from five of eight infants aged 8 to 36 months contained no antihemolysin antibodies. We conclude that the 107,000-dalton hemolysin of E. coli is a widespread immunogen that is produced by most or all hemolytic E. coli strains in the human host.
Calcium-dependent Oligomerization of Synaptotagmins I and II

Synaptotagmins constitute a large family of membrane proteins characterized by their distinct distributions and different biochemical features. Genetic evidence suggests that members of this protein family are likely to function as calcium sensors in calcium-regulated events in neurons, although the precise molecular mechanism remains ill defined. Here we demonstrate that different synaptotagmin isoforms (Syt I, II, and IV) are present in the same synaptic vesicle population from rat brain cortex. In addition, Syt I and II co-localize on the same small synaptic vesicle (SSV), and they heterodimerize in the presence of calcium with a concentration dependence resembling that of the starting phase of SSV exocytosis (EC50 = 6 ± 4 μm). The association between Syt I and Syt II was demonstrated by immunoprecipitation of the native proteins and the recombinant cytoplasmic domains and by using fluorescence resonance energy transfer (FRET). Although a subpopulation of SSV containing Syt I and IV can be isolated, these two isoforms do not show a calcium-dependent interaction. These results suggest that the self-association of synaptotagmins with different calcium binding features may create a variety of calcium sensors characterized by distinct calcium sensitivities. This combinatorial hypothesis predicts that the probability of a single SSV exocytic event is determined, in addition to the gating properties of the presynaptic calcium channels, by the repertoire and relative abundance of distinct synaptotagmin isoforms present on the SSV surface.
Atypical primary sclerosing cholangitis cases associated with unusual pancreatitis.

BACKGROUND/AIMS We encountered one group of primary sclerosing cholangitis cases which met classic criteria, but demonstrated better clinical courses. METHODOLOGY We evaluated the clinical characteristics of several cases of primary sclerosing cholangitis, especially those associated with chronic pancreatitis. RESULTS Of a total of 25 cases, eight had a background of pancreatitis with unusual irregularly segmental or diffuse narrowing features on pancreatography. Abdominal ultrasonography and computed tomography also revealed segmental or diffuse enlargement of the pancreas. Pathological findings of surgical specimens in two cases pointed to lymphoplasmacytic sclerosing pancreatitis. The walls of the lower biliary ducts were also thickened with a similar appearance to the pancreatic ducts. In seven cases, cholangiography displayed stenosis of the lower part of the common bile duct and in one case, only the hepatic hilar region was affected. In this case both biliary and pancreatic lesions responded to steroid therapy simultaneously. One case developed hepatic hilar stenosis four months after a lesion in the lower part of the common bile duct had disappeared. The cases of primary sclerosing cholangitis with pancreatitis demonstrated better clinical courses than did typical cases of primary sclerosing cholangitis. Six cases were characterized by autoimmunological abnormalities. CONCLUSIONS We concluded that similar etiological agents might impact on both the pancreas and biliary tract, either simultaneously or in sequence. We propose new criteria for these atypical primary sclerosing cholangitis cases.
Enzyme‐linked immunosorbent assay of Escherichia coli O157:H7 in surface enhanced poly(methyl methacrylate) microchannels

A novel surface treatment method was developed to enhance polymer‐based microchannel enzyme‐linked immunosorbent assay (ELISA) for Escherichia coli O157:H7 detection. By applying an amine‐bearing polymer, poly(ethyleneimine) (PEI), onto poly(methyl methacrylate) (PMMA) surface at pH higher than 11, PEI molecules were covalently attached and their amine groups were introduced to PMMA surface. Zeta potential analysis and X‐ray photoelectron spectroscopy (XPS) demonstrated that the alkali condition is preferable for PEI attachment onto the PMMA surface. The amine groups on the PMMA surface were then functionalized with glutaraldehyde, whose aldehyde groups served as the active sites for binding the antibody by forming covalent bonds with the amine groups of the protein molecules. This surface modification greatly improved antibody binding efficiency and the microchannel ELISA for E. coli O157:H7 detection. Compared with untreated PMMA microchannels, ∼45 times higher signal and 3 times higher signal/noise ratio were achieved with the PEI surface treatment, which also shortened the time required for cells to bind to the microchannel surface to ∼2 min, much less than that usually required for the same ELISA carried out in 96‐well plates. The detection in the microchannel ELISA only required 5–8 cells per sample, which is also better than 15–30 cells required in multi‐well plates. With the high sensitivity, short assay time, and small reagent consumption, the microchannel ELISA can be economically used for fast detection of E. coli O157:H7. Biotechnol. Bioeng. 2007;98: 328–339. © 2007 Wiley Periodicals, Inc.
Development of Neurological Mouse Model for Toxoplasmosis Using Toxoplasma gondii Isolated from Chicken in Kenya

Animal models for the toxoplasmosis are scarce and have limitations. In this study, a neurological mouse model was developed in BALB/c mice infected intraperitoneally with 15 cysts of a Toxoplasma gondii isolate. The mice were monitored for 42 days and euthanized at different time points. Another group of mice were orally treated with dexamethasone (DXM: 2.66 mg/kg daily, 5.32 mg/kg daily) at 42 days after infection and monitored for a further 42 days. A mortality rate of 15% and 28.6% was observed in mice given 2.66 mg/kg/day and 5.32 mg/kg/day of DXM, respectively. The mean cyst numbers in the brain of DXM treated mice increased up to twofold compared with chronically infected untreated mice. Infections up to 42 days were associated with an increase in both IgM and IgG levels but following dexamethasone treatment, IgM levels declined but IgG levels continued on rising. The brain of toxoplasmosis infected mice showed mononuclear cellular infiltrations, neuronal necrosis, and cuffing. The severity of pathology was higher in mice treated with dexamethasone compared to the positive control groups. The findings of this study demonstrate that DXM-induced reactivation of chronic toxoplasmosis may be a useful development of laboratory animal model in outbred mice used for in vivo studies.
Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase II, randomized, placebo-controlled trial.

OBJECTIVE To assess the efficacy, safety, and biologic activity of atacicept in tumor necrosis factor antagonist-naive patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate. METHODS In this phase II study, patients with active RA (n = 311) were randomized 1:1:1:1 to receive placebo, atacicept 150 mg weekly with or without a 4-week loading period (twice-weekly dosing), or open-label adalimumab 40 mg every other week, for 25 weeks. The primary end point was 20% improvement in disease severity according to the American College of Rheumatology criteria, assessed using the C-reactive protein level (ACR20-CRP), at week 26. Secondary end points included additional assessments of efficacy, biologic activity, and safety. RESULTS The proportion of patients meeting the primary end point (ACR20-CRP response) did not differ significantly in the atacicept groups and the placebo group (46% in the placebo group, 45% in the atacicept loading group, and 58% in the atacicept nonloading group). In contrast, an ACR20-CRP response was observed in 71% of patients in the adalimumab group (P < 0.001 versus placebo). ACR50-CRP response rates were significantly higher in all active-treatment groups compared with placebo, but ACR70-CRP response rates were superior only in the adalimumab group. Atacicept treatment reduced the levels of serum IgG, IgA, and IgM rheumatoid factor and the levels of circulating mature B cells and plasma cells. The effects of treatment were similar with and without loading. Immunoglobulin levels returned toward baseline values during the treatment-free followup period (week 38). The most frequent adverse events associated with atacicept represented common illnesses. No serious infections occurred among patients treated with atacicept. CONCLUSION The primary end point (ACR20-CRP response) was not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action. Modest effects of atacicept were seen for some secondary efficacy end points. Treatment with atacicept raised no new safety concerns.
MurAA Is Required for Intrinsic Cephalosporin Resistance of Enterococcus faecalis

ABSTRACT Enterococcus faecalis is a low-GC Gram-positive bacterium that is intrinsically resistant to cephalosporins, antibiotics that target cell wall biosynthesis. To probe the mechanistic basis for intrinsic resistance, a library of transposon mutants was screened to identify E. faecalis strains that are highly susceptible to ceftriaxone, revealing a transposon mutant with a disruption in murAA. murAA is predicted to encode a UDP-N-acetylglucosamine 1-carboxyvinyl transferase that catalyzes the first committed step in peptidoglycan synthesis: phosphoenolpyruvate (PEP)-dependent conversion of UDP-N-acetylglucosamine to UDP-N-acetylglucosamine-enolpyruvate. In-frame deletion of murAA, but not its homolog in the E. faecalis genome (murAB), led to increased susceptibility of E. faecalis to cephalosporins. Furthermore, expression of murAA enhanced cephalosporin resistance in an E. faecalis mutant lacking IreK (formerly PrkC), a key kinase required for cephalosporin resistance. Further genetic analysis revealed that MurAA catalytic activity is necessary but not sufficient for this role. Collectively, our data indicate that MurAA and MurAB have distinct roles in E. faecalis physiology and suggest that MurAA possesses a unique property or activity that enables it to enhance intrinsic resistance of E. faecalis to cephalosporins.