Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of an Orphan Response Regulator Required for the Virulence of Francisella spp. and Transcription of Pathogenicity Island Genes

ABSTRACT Francisella tularensis is a category A agent of biowarfare/biodefense. Little is known about the regulation of virulence gene expression in Francisella spp. Comparatively few regulatory factors exist in Francisella, including those belonging to two-component systems (TCS). However, orphan members of typical TCS can be identified. To determine if orphan TCS members affect Francisella gene expression, a gene encoding a product with high similarity to the Salmonella PmrA response regulator (FTT1557c/FNU0663.2) was deleted in Francisella novicida (a model organism for F. tularensis). The F. novicida pmrA mutant was defective in survival/growth within human and murine macrophage cell lines and was 100% defective in virulence in mice at a dose of up to 108 CFU. In addition, the mutant strain demonstrated increased susceptibility to antimicrobial peptide killing, but no differences were observed between the lipid A of the mutant and the parental strain, as has been observed with pmrA mutants of other microbes. The F. novicida pmrA mutant was 100% protective as a single-dose vaccine when challenge was with 106 CFU of F. novicida but did not protect against type A Schu S4 wild-type challenge. DNA microarray analysis identified 65 genes regulated by PmrA. The majority of these genes were located in the region surrounding pmrA or within the Francisella pathogenicity island (FPI). These FPI genes are also regulated by MglA, but MglA does not regulate pmrA, nor does PmrA regulate MglA. Thus, the orphan response regulator PmrA is an important factor in controlling virulence in F. novicida, and a pmrA mutant strain is an effective vaccine against homologous challenge.
Caffeine-Withdrawal Headache. The Vågå Study of Headache Epidemiology

In connection with the Vågå study of headache epidemiology, a search was made for caffeine-withdrawal headache in 1741 parishioners. Female to male ratio 1.05; mean age 44.2 years (range 18-65 years). A face-to-face interview technique was used. The mean consumption of coffee was 4.7 cups a day. Males on an average consumed more coffee (5.1 ± 3.3 cups/day) than females (4.4 ± 3.1 cups/day). Neither in those with a high consumption of coffee: ≥10 cups a day (n = 134), nor in those with a considerable variation in consumption: ≥10 cups/day (n = 31) did there seem to be a definite increase in headache resembling caffeine-withdrawal headache, for instance during weekends. In seven parishioners, however, there did seem to be such a headache, and in two of them, the evidence was rather convincing. This headache generally seemed to be mild and global and occurred mainly in the morning hours on weekends. There was no nausea, no throbbing quality of the pain, and no reported use of analgesics. Coffee seemed to abate the headache. This frequency (0.4%) should, clearly, be regarded as a minimum figure. Caffeine-withdrawal headache at the grassroots level may be a rather rare, generally vague, symptom-poor headache.
Presynaptic cytomatrix protein Bassoon is localized at both excitatory and inhibitory synapses of rat brain

Bassoon is a 420‐kDa protein specifically localized at the active zone of presynaptic nerve terminals. It is thought to be involved in the structural organization of the neurotransmitter release site. We studied the distribution of Bassoon transcripts and protein in rat brain and assessed which types of presynaptic terminals contain the protein. As shown by in situ hybridization, Bassoon transcripts are widely distributed in the brain and occur primarily in excitatory neurons. In addition, examples of γ‐aminobutyric acid (GABA)‐ergic neurons expressing Bassoon are detected. At the light microscopic level, Bassoon immunoreactivity is found in synaptic neuropil regions throughout the brain, with the strongest expression in the hippocampus, the cerebellar cortex, and the olfactory bulb. Immunoelectron microscopy showed that Bassoon immunoreactivity is found in both asymmetric type 1 and symmetric type 2 synapses. Immunopositive asymmetric synapses include mossy fiber boutons and various spine and shaft synapses in the hippocampus and mossy fiber terminals and parallel fiber terminals in the cerebellum. Bassoon‐containing symmetric synapses are observed, e.g., between basket and granule cells in the hippocampus, between Golgi cells and granule cells, and between basket cells and Purkinje cells in the cerebellum. Within synaptic terminals, Bassoon appears highly concentrated at sites opposite to postsynaptic densities. In cultured hippocampal neurons, Bassoon was found to colocalize with GABAA and glutamate (GluR1) receptors. These data indicate that Bassoon is a component of the presynaptic apparatus of both excitatory glutamatergic and inhibitory GABAergic synapses. J. Comp. Neurol. 408:437–448, 1999. © 1999 Wiley‐Liss, Inc.
Dental erosive wear among Norwegian wine tasters

Abstract Objective. To assess the prevalence and severity of dental erosive wear among a group of professional wine tasters. Material and methods. Eighteen wine tasters currently employed at AS Vinmonopolet, Norway (3 women, 15 men; mean age 39 years) and 30 comparison participants (9 women, 21 men; mean age 39 years) were included in the study. The wine tasters were examined by four calibrated clinicians using the Visual Erosion Dental Examination system. Data concerning medical and dietary history, oral hygiene habits and occupational background were obtained from a self-completed questionnaire. Data were analyzed using Fisher's exact test, and examiner agreement was determined by means of linear-weighted kappa and the intra-class correlation coefficient. Results. Nine (50%) of the wine tasters and six (20%) of the comparison group showed clinical signs of dental erosion. Among the wine tasters, 39% had dentine involvement, compared to just 7% of the comparison group. The erosive lesions were mainly found on the occlusal surfaces of mandibular first molars in the wine tasters, whereas for the controls, the palatal surfaces of upper centrals were most often affected. Conclusions. There was a significant difference in the prevalence of dental erosive wear between the two groups, the wine tasters having a higher prevalence and more severely affected surfaces than the comparison group. Half of the wine tasters had no erosive wear and, for the other half, there was no relationship between the duration of their professional life and the extent of erosive wear.
Detection of minor populations of drug-resistant HIV-1 in acute seroconverters

Objective:The transmission of drug-resistant HIV-1 is a major health concern. To date, most clinical studies have relied on sequencing techniques for genotypic analyses which do not allow quantification of minority viral populations below 25%. As minor populations of drug-resistant HIV-1 could impact the efficiency of antiretroviral therapy, this study was performed to determine the prevalence of minor populations of drug-resistant HIV-1 in acute seroconverters. Design and methods:Forty-nine acute seroconverters from two clinical centers in Germany were included in the study. Individuals were identified between June 1999 and March 2003, and none had received antiretroviral therapy prior to sampling. Minor populations of drug-resistant variants were detected by quantitative real-time polymerase chain reaction using allele-discriminating oligonucleotides for three key resistance mutations: L90M (protease), K103N and M184V (reverse transcriptase). The approximate discriminative power was between 0.01 and 0.2%. Results:Drug-resistant variants were detected in 10 of 49 patients (20.4%). The L90M mutation was found in one of 49 (2%), the K103N mutation in five of 49 (10.2%) and the M184V mutation in six of 49 (12.2%) patients, respectively. In five of the 10 individuals with detectable drug-resistant virus (50%), the detected population represented a minor viral quasi-species (< 25% of viruses) and was not detected by direct sequencing. Conclusions:The prevalence of minor populations of drug-resistant HIV-1 in acute seroconverters can be frequently detected and may impact the success of antiretroviral therapy.
Phylogenetic and case-control study on hepatitis E virus infection in Germany.

BACKGROUND Hepatitis E is a classic water-borne disease in developing countries. In Germany, hepatitis E virus (HEV) infections are notifiable. The number of non-travel-associated infections has increased in recent years, but the route of transmission in most is unknown. Our objective was to determine risk factors for autochthonous HEV infections in Germany. METHODS Cases of HEV met clinical definitions and were confirmed by laboratory analysis (defined as detection of HEV by polymerase chain reaction [PCR] or immunoglobulin M by serologic testing). PCR products from blood or stool samples were genotyped for phylogenetic analysis. A case-control study included case subjects with autochthonous HEV infection and matched control subjects who were randomly recruited from a population-based telephone list. RESULTS From May 2006 through August 2007, 76 of 96 persons for whom HEV infection had been reported to the routine surveillance system were interviewed. Sixty-six persons had disease that fulfilled the inclusion criteria: 45 (68%) had autochthonous infection, and 21 (32%) had travel-associated disease. Genotypes 3 or 4 were present in 15 of 15 persons with autochthonous infection, and genotype 1 was present in 8 of 9 persons with travel-associated infection. In conditional logistic regression involving 45 case subjects and 135 control subjects, consumption of offal (41% vs. 19%; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.2-6.2) and wild-boar meat (20% vs. 7%; OR, 4.3; 95% CI, 1.2-15.9) were independently associated with autochthonous HEV infection. CONCLUSION Hepatitis E is endemic in Germany and likely exists as a food-borne zoonosis. Implicated meat products should be investigated to provide recommendations for preventive measures.
Tumor acidosis enhances cytotoxic effects and autophagy inhibition by salinomycin on cancer cell lines and cancer stem cells

Sustained autophagy contributes to the metabolic adaptation of cancer cells to hypoxic and acidic microenvironments. Since cells in such environments are resistant to conventional cytotoxic drugs, inhibition of autophagy represents a promising therapeutic strategy in clinical oncology. We previously reported that the efficacy of hydroxychloroquine (HCQ), an autophagy inhibitor under clinical investigation is strongly impaired in acidic tumor environments, due to poor uptake of the drug, a phenomenon widely associated with drug resistance towards many weak bases. In this study we identified salinomycin (SAL) as a potent inhibitor of autophagy and cytotoxic agent effective on several cancer cell lines under conditions of transient and chronic acidosis. Since SAL has been reported to specifically target cancer-stem cells (CSC), we used an established model of breast CSC and CSC derived from breast cancer patients to examine whether this specificity may be associated with autophagy inhibition. We indeed found that CSC-like cells are more sensitive to autophagy inhibition compared to cells not expressing CSC markers. We also report that the ability of SAL to inhibit mammosphere formation from CSC-like cells was dramatically enhanced in acidic conditions. We propose that the development and use of clinically suitable SAL derivatives may result in improved autophagy inhibition in cancer cells and CSC in the acidic tumor microenvironment and lead to clinical benefits.
Power electronics for renewable sea wave energy

This paper has an objective to combine and disseminate information on sea wave energy converters. The potential of sea wave energy is very high and over one thousands patents exists, however, only selected projects supported by EC are presented. At the beginning a basic terms and methods of sea wave energy capture are discussed. Further several most important sea wave energy conversion prototypes are shown. The generators and power electronics solutions for Power Take Off system are presented on the example of Wave Dragon MW sea wave energy converter. The Wave Dragon MW captures power from the sea waves by means of low-head turbines and converts it into rotating mechanical power. Problems which can appear in mechanical power to electrical power conversion in Wave Dragon MW can be expected to be similar as in wind turbine. However, subject of the mechanical energy conversion from sea waves to electrical energy is not well identified and further research should be curried out. Additionally, specific problems of grid connected AC-DC-AC converters under grid voltage distortions (harmonics and voltage dips) are discussed. Some simulated and experimental oscillograms that illustrate properties of the presented systems are shown.
Protective effects of ellagic acid and other plant phenols on benzo[a]pyrene-induced neoplasia in mice.

The inhibitory effects of three phenolic compounds (ferulic, chlorogenic and ellagic acids) on benzo[a]pyrene- and 7,12-dimethylbenz[a]anthracene-induced neoplasia have been investigated in mice. Ellagic acid was the most potent antagonist of tumorigenesis since this compound is active, by i.p. administration or added in the diet, on benzo[a]pyrene-induced pulmonary adenoma formation in A/J mice and, after topical application, on 7,12-dimethylbenz[a]anthracene-induced skin tumorigenesis in NMRI Swiss mice. If ellagic acid has little or no effect on the number of tumor bearing animals, the incidence of pulmonary tumors per animal is decreased by greater than 50%. Ferulic acid and chlorogenic acid (5 X 100 mg/kg, by i.p. route) were also active, but less than ellagic acid, against the lung carcinogenesis by benzo[a]-pyrene (100 mg/kg, i.p.) but were totally ineffective against the formation of skin tumors by 7,12-dimethylbenz[a]anthracene. These results remarkably paralleled the in vitro antimutagenic effects of these compounds shown by Wood et al. on benzo[a]pyrene. It must be noted that ellagic acid only exerted, by i.p. route, a severe toxicity after four injections of 100 mg/kg, in oil suspension, whereas the oral administration in the diet (a daily dose of 100 mg/kg during 15 days) did not cause any toxicity.
Employee Turnover and Organizational Performance: Testing a Hypothesis from Classical Public Administration

Empirical studies of public employee turnover, particularly using turnover as an independent variable, are rare; and most of the literature assumes turnover to have a negative impact on organizations. This study examines a provocative but little supported hypothesis that has recently emerged in the private sector literature-that turnover may provide positive benefits to the organization, at least up to a point. Using data from several hundred public organizations over a nine-year period, we test the proposition that moderate levels of turnover may positively affect organizational performance. We find that while turnover is indeed negatively related to performance for the organization's primary goal, it does have the hypothesized nonlinear relationship for a secondary output that is characterized by greater task difficulty.
Comparison of molecular changes in lung cancers in HIV-positive and HIV-indeterminate subjects.

CONTEXT Human immunodeficiency virus (HIV) infection has been associated with an increasing incidence of malignancy, and HIV-infected persons have an increased incidence of primary lung carcinoma compared with the general population. OBJECTIVE To investigate the molecular changes present in HIV-associated lung tumors and compare them with those present in lung carcinomas arising in HIV-indeterminate subjects ("sporadic tumors"). DESIGN Convenience sample. SUBJECTS Archival tissues from 11 HIV-positive persons and from 35 persons of indeterminate HIV status. SETTING University-based medical centers and affiliated hospitals. MAIN OUTCOME MEASURES Analysis of frequency of loss of heterozygosity (LOH) and microsatellite alteration (MA) using polymerase chain reaction and 16 polymorphic microsatellite markers at 8 chromosomal regions frequently deleted in lung cancer. Presence of HIV and human papillomavirus (HPV) sequences. RESULTS The overall frequency of LOH at all chromosomal regions tested and the frequencies at most of the individual regions were similar in the 2 groups. Frequency of MA present in the HIV-associated tumors (0.18) was 6-fold higher than in sporadic tumors (0.03) (P<.001). At least 1 MA was present in 10 (91%) of 11 HIV-associated tumors vs 17 (48%) of 35 sporadic tumors (P=.02). Molecular changes were independent of tumor stage and gender. HIV and HPV sequences were not detected in the HIV-associated lung carcinomas. CONCLUSIONS Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated lung carcinomas. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated tumors.
PZT material properties at UHF and microwave frequencies derived from FBAR measurements

Lead zirconate titanate (PZT) is a high dielectric constant, /spl epsiv//sub r//sup S/, high coupling, k/sub t//sup 2/, piezoelectric material with possible application to film bulk acoustic resonators (FBAR) at low microwave frequencies. PZT is a widely used material at audio and low MHz range frequencies, but the high acoustic attenuation of PZT tends to preclude its use above UHF. Likewise, the bulk dielectric/piezoelectric/elastic (DPE) properties are well known at low frequencies, but the thin film properties have not been as well measured into the microwave range. To obtain better data, the material properties of thin film PZT deposited by several methods were measured at GHz frequencies from air- or silicon-backed FBARs fabricated on silicon wafers. PZT thin films, deposited by metal-organic chemical vapor deposition (MOCVD), sol-gel deposition, RF sputtering, or jet vapor deposition, were obtained from various sources. The films examined ranged from 0.4 to 2 /spl mu/m in thickness, and were deposited on thin (/spl sim/0.1 /spl mu/m) Pt or Ir bottom electrodes. The samples had compositions within the tetragonal phase (Zr/Ti = 30/70, 40/60) or near the morphotropic phase boundary (Zr/Ti = 50/50). Scattering parameter, S/sub 11/, vs frequency measurements were made. Using the Mason equivalent circuit model, the DPE coefficients were extracted by varying parameters in the Mason model until the predicted S/sub 11/ vs frequency fitted the measured data. The devices exhibited /spl epsiv//sub r//sup S/ in the range of 300 to 500, k/sub t//sup 2/ between 5% and 35%, and acoustic attenuation from 400 to 2100 dB/cm at 1 GHz.
Comprehensive genetic analysis of seven large families with mismatch repair proficient colorectal cancer

Approximately 40% of colorectal cancer (CRC) families with a diagnosis of hereditary nonpolyposis CRC on the basis of clinical criteria are not a consequence of mismatch repair (MMR) deficiency. Such families provide supporting evidence for the existence of a hitherto unidentified highly penetrant gene mutation. To gain further understanding of MMR‐competent familial colorectal cancer (FCC), we studied seven large families with an unexplained predisposition for CRC to identify genetic regions that could harbor CRC risk factors. First, we conducted a genome‐wide linkage scan using 10K single‐nucleotide polymorphism (SNP) arrays to search for disease loci. Second, we studied the genomic profiles of the tumors of affected family members to identify commonly altered genomic regions likely to harbor tumor suppressor genes. Finally, we studied the possible role of recently identified low‐risk variants in the familial aggregation of CRC in these families. Linkage analysis did not reveal clear regions of linkage to CRC. However, our results provide support linkage to 3q, a region that has previously been linked to CRC susceptibility. Tumor profiling did not reveal any genomic regions commonly targeted in the tumors studied here. Overall, the genomic profiles of the tumors show some resemblance to sporadic CRC, but additional aberrations were also present. Furthermore, the FCC families did not appear to have an enrichment of low‐risk CRC susceptibility loci. These data suggest that factors other than a highly penetrant risk factor, such as low or moderate‐penetrance risk factors, may explain the increased cancer risk in a subset of familial CRCs. © 2010 Wiley‐Liss, Inc.
A new high-speed low-voltage charge pump for PLL applications

The various nonideal phenomena in the charge pump circuits are discussed in this paper. The relevant effects and solutions are also presented. Based on the above analysis, we propose a new simple charge pump circuit, which is suitable for high speed PLL circuits and can work at a low supply. The charge pump is designed in a standard CMOS 0.18 mum technology. The SPECTRE simulation results show the capability of high-frequency operation (1GHz) with very low-power consumption (28muW) at the 1V power supply. Moreover, the output waveform does not exhibit spurious jumps
Action Potentials: To the Nucleus and Beyond

The neuronal nucleus is now widely accepted as playing a vital role in maintaining long-term changes in synaptic effectiveness. To act, however, the nucleus must be appropriately relayed with information regarding the latest round of synaptic plasticity. Several constraints of doing so in a neuron pertain to the often significant spatial distance of synapses from the nucleus and the number of synapses required for such a signal to reach functional levels in the nucleus. Largely based on the sensitivity of transcriptional responses to NMDA receptor antagonists, it has been postulated that the signals are physically relayed by biochemical messengers from the synapse to the nucleus. Alternatively, a second, less often considered but equally viable method of signal transduction may be initiated by action potentials generated proximal to the nucleus, wherefrom the signal can be relayed directly by calcium or indirectly by biochemical second messengers. We consider action potential-dependent signaling to the nucleus to have its own computational advantages over the synapse-to-nucleus signal for some functions. This minireview summarizes the logic and experimental support for these two modes of signaling and attempts to validate the action potential model as playing an important role in transcriptional regulation relating specifically to long-term synaptic plasticity.
Class-AB output stage design for high-speed three-stage op-amps

A new design approach for three-stage operational amplifiers (op-amps) is proposed. It allows to actually implement a symmetrical push-pull class-AB amplifier output stage for well-established three-stage amplifiers using a feedforward transconductance stage. Compared with the conventional design practice, the proposed approach leads to a significant improvement of the symmetry between the positive and the negative op-amp step response, resulting in similar values of the positive/negative settling time. The new approach proves to be very useful in order to fully exploit the potentiality allowed by the op-amp in terms of speed performances. Design examples in a commercial 0.35-µm CMOS prove the effectiveness of the proposed strategy.