Miracle-dz/UniFAR-FTUs huggingface dataset:
Telomerase as a target in diagnosis and treatment of cancer in postmenopausal women

Telomeres and telomerase are responsible for protection and maintenance of genomic stability of all eukaryotic cells. Several studies showed that one of the most distinguishing features of cancer cells is an increased expression and activity of telomerase, in contrast to somatic cells. This gives an opportunity for use of telomerase as a specific marker of cancer lesions or even as a molecular target. However, there are some questions concerning diagnostic specificity of this marker especially in the context of high proliferation potential of normal cells, such as the uterus and ovaries. The proliferation potential, however, decreases due to the menopause syndrome. Women’s age and hormonal changes influence the functioning of many tissues, including alterations in telomerase activity of endometrial and ovarian cancer cells. The different characteristics of telomerase activity and telomere length in cells of postmenopausal women give an opportunity to utilize the telomeres and telomerase for the development of new cancer diagnostic tests and therapeutic methods. This work is aimed to summarize the information about the significance of telomeres and telomerase in the diagnosis and treatment of cancer in postmenopausal women.
A New Type of Pyrrolidine Biosynthesis Is Involved in the Late Steps of Xenocoumacin Production in Xenorhabdus nematophila

Bacteria of the genus Xenorhabdus live in symbiosis with nematodes of the genus Steinernema, and both form an entomopathogenic complex that is used commercially to kill several different insect larvae. Briefly, the nematode carries the bacteria in the gut of its free-living state called infective juvenile (IJ). IJs actively search the soil for insect larvae. After an insect is identified, the nematode infects the insect and regurgitates the bacteria, which kill the insect within 24 h post-infection. The insect cadaver is then digested by the bacteria and the nematodes, and after several cycles of nematode development, new IJs are formed, which carry the bacteria in the gut and leave the now empty insect carcass to find new prey. As there have been hints in the literature that small molecules (e.g. , secondary metabolites) produced by the bacterium are either involved in the pathogenesis against the insect or the symbiosis towards the nematode, we have started to search for ACHTUNGTRENNUNGsecondary metabolites produced by different Xenorhabdus ACHTUNGTRENNUNGspecies. During this work, we could identify xenocoumacins (XCNs) I and II (1 and 2, respectively, in Scheme 1), which were isolated several years ago from different strains of Xenorhabdus nematophila. Although both compounds show antibiotic activity, 1 is much more active and additionally shows good activity against different fungi. Currently, both compounds are thought to be involved in killing bacteria living inside the insect gut, where these bacteria would compete with XenoACHTUNGTRENNUNGrhabdus for food in the dead insect. We could identify 1 and 2 in several Xenorhabdus strains by their characteristic fragmentation pattern in HRESI-MS (see below). Moreover, a detailed analysis of two different XCN producer strains, namely X. nematophila AN6/1 and X. kozodoii DSM 17907, under different cultivation conditions led to the identification of four new XCN derivatives named XCN III–VI (3–6). Whereas only traces of 3 and 4 are observed throughout the cultivation process in strain AN6/1, 5 and 6 start to accumulate in significant amounts after 1 and 2 have been formed (after 8 h); this indicates a structural relationship (Figure 1). Interestingly, only traces of 5 and 6 were observed in cultures grown with the adsorber resin Amberlite XAD-16, which seems to protect 1 and 2 from their transformation or degradation, as has also been observed for other secondary metabolites.
Immunogenicity of hepatitis A vaccination in decompensated cirrhotic patients

Hepatitis A virus (HAV) vaccination is recommended in chronic liver disease because of an increased morbidity and mortality associated with HAV superinfection. However, data regarding the efficacy of HAV vaccination in patients with advanced chronic liver disease is limited. We assessed the efficacy of a standard HAV vaccination schedule in decompensated chronic liver disease in comparison with compensated disease and defined clinical predictors associated with seroconversion. Eighty‐four anti‐HAV antibody–negative patients, 49 with compensated liver disease, and 35 with decompensated disease were enrolled. Seroconversion was measured by qualitative and quantitative anti‐HAV antibody measurements 1 month after each vaccine dose, and univariate/multivariate analysis was performed to define clinical predictors associated with seroconversion. One month after the primary dose, 71.4% of patients with compensated liver disease had detectable anti‐HAV antibody compared with 37.1% with decompensated liver disease (P < .05). One month after the booster dose, 98% of compensated patients seroconverted compared with 65.7% with decompensated disease (P < .05). The median serum antibody concentration in compensated liver disease was 76.4 mIU/mL at month 1 and 327.91 mIU/mL at month 7 compared with 20.0 mIU/mL and 102.57 mIU/mL, respectively, in decompensated disease. On multivariate analysis, Child‐Pugh class was the only factor predicting response to vaccination. Seroconversion after HAV vaccination was significantly less common in decompensated liver disease and the presence of advanced disease (Child‐Pugh class B/C) predicted a lower response rate. These findings indicate that the response to HAV vaccination in chronic liver disease is optimal when targeted to patients before the development of hepatic decompensation.
Assessment of Influenza Virus Hemagglutinin Stalk-Based Immunity in Ferrets

ABSTRACT Therapeutic monoclonal antibodies that target the conserved stalk domain of the influenza virus hemagglutinin and stalk-based universal influenza virus vaccine strategies are being developed as promising countermeasures for influenza virus infections. The pan-H1-reactive monoclonal antibody 6F12 has been extensively characterized and shows broad efficacy against divergent H1N1 strains in the mouse model. Here we demonstrate its efficacy against a pandemic H1N1 challenge virus in the ferret model of influenza disease. Furthermore, we recently developed a universal influenza virus vaccine strategy based on chimeric hemagglutinin constructs that focuses the immune response on the conserved stalk domain of the hemagglutinin. Here we set out to test this vaccination strategy in the ferret model. Both strategies, pretreatment of animals with a stalk-reactive monoclonal antibody and vaccination with chimeric hemagglutinin-based constructs, were able to significantly reduce viral titers in nasal turbinates, lungs, and olfactory bulbs. In addition, vaccinated animals also showed reduced nasal wash viral titers. In summary, both strategies showed efficacy in reducing viral loads after an influenza virus challenge in the ferret model. IMPORTANCE Influenza virus hemagglutinin stalk-reactive antibodies tend to be less potent yet are more broadly reactive and can neutralize seasonal and pandemic influenza virus strains. The ferret model was used to assess the potential of hemagglutinin stalk-based immunity to provide protection against influenza virus infection. The novelty and significance of the findings described in this report support the development of vaccines stimulating stalk-specific antibody responses.
Iontophoretic delivery of calcium for experimental hydrofluoric acid burns

ObjectiveTo examine the efficacy of iontophoretic delivery of calcium to experimental hydrofluoric acid burns. DesignProspective, controlled study. SettingInstitutional laboratory. SubjectsMale nude rats. InterventionsFor the in vitro experiment, a full-thickness skin from the back was set in a vertical flow-through diffusion cell. Calcium chloride was applied to the donor chamber, and transdermal transport of calcium was examined with or without a voltage gradient of 1.5 V. Either intact skin or skin whose stratum corneum was stripped with adhesive tapes was used. For the in vivo experiment, hydrofluoric acid burns were induced by dispensing 50% hydrofluoric acid (50 &mgr;L) on the backs of the nude rats, who were under pentobarbital anesthesia. Rats were divided into four groups (n = 5 for each group): control group (burned but not treated); topical group (treated with calcium gluconate jelly); infiltration group (intradermal and subcutaneous injection of calcium gluconate); and iontophoresis group (treated with iontophoresis of calcium chloride at 1.5 V). Burn areas were measured and pathologic findings were classified microscopically into five stages at 1 wk: stage 1, epidermal burn; stage 2, superficial dermal burn; stage 3, deep dermal burn; stage 4, full-thickness burn; and stage 5, burn affecting the skeletal muscle. Measurements and Main Results In the in vitro experiment, calcium concentrations increased significantly only in stripped skins with a 1.5-V gradient. In the in vitro experiment, burn areas were reduced significantly in the iontophoresis group compared with the other three groups. Pathologic findings were significantly improved in the iontophoresis group compared with the control group. This efficacy of iontophoresis was observed when it was initiated within 30 mins after hydrofluoric acid burn. ConclusionsThese results show that transdermal transport of calcium was enhanced in stripped skins by iontophoresis and that iontophoresis was more efficacious than topical or infiltration therapy for experimental hydrofluoric acid burns. Iontophoretic delivery of calcium seems to be easier than intra-arterial infusion and may be effective for the lesions where intra-arterial infusion is difficult.
The “Peeking” Effect in Supervised Feature Selection on Diffusion Tensor Imaging Data

We read with great interest the article by Haller et al[1][1] in the February 2013 issue of the American Journal of Neuroradiology . The authors used whole-brain diffusion tensor imaging–derived fractional anisotropy (FA) data, skeletonized through use of the standard tract-based spatial
The estimation of lactic acid using ceric sulphate.

Ashby, J. H. , Crook, E. M. & Datta, S. P. (1954a). Biochem. J. 56, 190. Ashby, J. H. , Crook, E. M. & Datta, S. P. (1954b). Biochem. J. 56, 198. Bates, R. C. & Acree, S. F. (1943). J. Re8. nat. Bur. Stand. 30, 129. Burton, K. & Krebs, H. A. (1953). Biochem. J. 54, 94. Cannan, R. K. & Kibrick, A. C. (1938). J. Amer. chem. Soc. 60, 2314. Evans, J. I. & Monk, C. B. (1952). Trane. Faraday Soc. 48, 934. Greenwald, I. , Redish, J. & Kibrick, A. C. (1940). J. biol. Chem. 185, 65. Guntelberg, E. (1926). Z. phy8. Chem. 123, 199. Harned, H. S. & Robinson, R. A. (1940). Tran8. Faraday Soc. 36, 973. Jones, H. W. & Monk, C. B. (1952). Tran8. Faraday Soc. 48, 929. Please, N. W. (1954). Biochem. J. 56, 196. Roche, J. (1950). In The Enzymes, 1 (1), 473. Ed. J. B. Sumner and K. Myrback. Academic Pres Inc. Stock, D. I. & Davies, C. W. (1948). Trans. Faraday Soc. 44, 856. Tabor, H. & Hastings, A. B. (1943). J. biol. Chem. 148, 627. Trevelyan, W. E. , Mann, P. F. E. & Harrison, J. S. (1952). Arch. Biochem. Biophy8. 39, 440.
IIIYeast sequencing report. Nucleotide sequence of D1OB, a Bam HI fragment on the small‐ring chromosome III of Saccharomyces cerevisiae

DlOB is a 5.3 kb BamHI fragment located between the H M L and HIS4 loci on the small-ring chromosome 111 of the yeast Saccharomyces cerevisiae, at about 15 kb from H M L and about 35 kb from HIS4 (Newlon et al., 1991). In this region of chromosome 111, few genes have been found and characterized so far (Mortimer et al., 1989). We have determined the complete sequence of 5337 base pairs of this fragment by a combination of chemical and enzymatical sequencing methods. The DlOB sequence was rather A+T rich with an overall G+C content of 33.5%, but several stretches of extremely high A+T content were found as well. Four open reading frames (ORFs) were detected, two of which were completely confined to the DlOBfragment. One of the latter appeared to be virtually unclonable in Escherichia coli when located on a smaller DNA fragment and is probably responsible for the growth-inhibiting effect of DlOB on E. coli. Comparison of the ORF regions with nucleic acid and protein databases did not reveal any significant homologies to catalogued sequences of any source. A large (2.5 kb) non-coding region was present in the central part of DlOB. Although DlOB subfragments displaying autonomous replicating sequence (ARS) activity were located here (ARS304; Newlon et al., 1991), no perfect match to the core ARS consensus was found and imperfect matches were scarce as well.
Pentobarbital Enhances γ-Aminobutyric Acid-Mediated Excitation Without Altering Synaptic Plasticity in Rat Hippocampus

BACKGROUND:Synaptic plasticity is thought to provide a molecular mechanism for learning and memory. N-methyl-d-aspartate receptor-mediated plasticity requires that N-methyl-d-aspartate receptor activation coincides with postsynaptic depolarizing potentials (DPSPA's). Pentobarbital, in high concentrations, enhances DPSPA's, but high concentrations suppress synaptic plasticity, probably by impairing glutamatergic transmission. Here we tested the hypothesis that low concentrations of pentobarbital can enhance DPSPA's and modify the induction of synaptic plasticity. METHODS:Studies were performed in vitro on rat hippocampal slices. With glutamate transmission blocked, intracellular recording from CA1 neurons was used to investigate the influence of 5 μM pentobarbital on DPSPA's and neuron excitability evoked by high frequency (100 Hz) stimulation. With glutamate transmission intact, extracellular recording was used to examine the effect of 5 μM pentobarbital on the induction of long-term depression and long-term potentiation of synaptic transmission by conditioning stimuli applied to the Schaffer collateral pathway. RESULTS:High frequency stimulation generated typical DPSPA's that were mediated by γ-aminobutyric acidA receptors and dependent upon HCO3−. Pentobarbital (5 μM) increased the amplitude, but not the width, at half-maximal amplitude of DPSPA's (P < 0.01). Pentobarbital increased the probability of action potential generation during the DPSPA's. Pentobarbital did not alter the induction of long-term depression or long-term potentiation. CONCLUSIONS:Despite increasing the amplitude of DPSPA's, 5 μM pentobarbital did not alter the induction of synaptic plasticity by a range of conventional conditioning stimuli. These results do not support the hypothesis that excitatory effects of pentobarbital may alter synaptic plasticity.
Vesicle-to-cytosol transport of disulfide-linked cargo mediated by an amphipathic cell-penetrating peptide

The effect of linker stability on the intracellular localization and apoptotic activity of cytochrome c (Cyt c) conjugated to an amphipathic cell-penetrating peptide (CPP), model amphipathic peptide (MAP), was tested in HeLa cells. While conjugates linked with a stable thioether cross-linkage were only found in the vesicular compartment, a portion of the conjugate linked with a reducible disulfide bond was also detected in the cytosol. The apoptotic function of the reducible and non-reducible Cyt c-MAP conjugates was also evaluated quantitatively using the caspase 3 and annexin V/propidium iodide detection assays in the presence of a proteasome inhibitor used to inhibit cytosolic Cyt c degradation. Analysis for early phase apoptosis revealed that linker stability was important for biological activity. Only the reducible disulfide-linked Cyt c-MAP conjugate, and not free Cyt c or thioether-linked Cyt c-MAP, initiated apoptosis in proteasome-inhibited cells which correlated with the cytosolic localization profiles of the proteins. The co-treatment of disulfide-linked Cyt c-MAP with a disulfide reduction inhibitor decreased the amount of Cyt c delivered to the cytosol, which correlated with a lack of apoptotic activity. These findings indicated the presence of a vesicle-to-cytosolic delivery process for disulfide-linked MAP conjugates, which can be used to improve CPP-based drug delivery systems transporting cargo to cytosolic sites.
Explaining Cross-Cohort Differences in Life Cycle Earnings

College-educated workers entering the labor market in 1940 experienced a 4-fold increase in their labor earnings between the ages of 25 and 55; in contrast, the increase was 2.6-fold for those entering the market in 1980. For workers without a college education these figures are 3.6-fold and 1.5-fold, respectively. Why are earnings profiles flatter for recent cohorts? We build a parsimonious model of schooling and human capital accumulation on the job and calibrate it to earnings statistics of workers from the 1940 cohort. The model accounts for 99 percent of the flattening of earnings profiles for workers with a college education between the 1940 and the 1980 cohorts (52 percent for workers without a college education). The flattening in our model results from a single exogenous factor: the increasing price of skills. The higher skill price induces (i) higher college enrollment for recent cohorts and thus a change in the educational composition of workers and (ii) higher human capital at the start of work life for college-educated workers in the recent cohorts, which implies lower earnings growth over the life cycle.
UNCERTAINTY ANALYSIS OF THE ESTIMATED INGESTION RATES USED TO DERIVE THE METHYLMERCURY REFERENCE DOSE

The U.S. EPA's Reference Dose (RfD) for methylmercury (MeHg) uses a simple one-compartment toxicokinetic model to estimate ingestion doses in mg/kg-day from measured concentrations of mercury in hair. The model includes a number of input variables for which point estimates are made. Uncertainty in the inputs is addressed by the use of a 3-fold uncertainty factor. There are, however, published ranges for each variable which are used to develop distributions for each of the inputs. Monte Carlo output of the model is generated. The 90% confidence interval spans a 3-fold to 5-fold range of ingestion doses for any given concentration of mercury in hair. The hair:blood mercury concentration ratio contributes most to the variance of the output. The results indicate that the uncertainty factor of three is appropriate.
CD4+ T-Cell Reconstitution Reduces Cytomegalovirus in the Immunocompromised Brain

ABSTRACT Cytomegalovirus (CMV) infection is the most common opportunistic infection of the central nervous system in patients with human immunodeficiency virus or AIDS or on immunosuppressive drug therapy. Despite medical management, infection may be refractory to treatment and continues to cause significant morbidity and mortality. We investigated adoptive transfer as an approach to treat and prevent neurotropic CMV infection in an adult immunodeficient mouse model. SCID mice were challenged with intracranial murine CMV (MCMV) and reconstituted with MCMV- or vesicular stomatitis virus (VSV)-sensitized splenocytes, T cells, or T-cell subsets. T cells labeled with vital dye or that constitutively generated green fluorescent protein (GFP) were identified in the brain as early as 3 days following peripheral transfer. Regardless of specificity, activated T cells localized to regions of the brain containing CMV, however, only those specific for CMV were effective at clearing virus. Reconstitution with unsorted MCMV-immune splenocytes, enriched T-cell fractions, or CD4+ cells significantly reduced virus levels in the brain within 7 days and also prevented clinical disease, in significant contrast with mice given VSV-immune unsorted splenocytes, MCMV-immune CD8+ T cells, and SCID control mice. Results suggest CMV-immune T cells (particularly CD4+) rapidly cross the blood-brain barrier, congregate at sites of specific CMV infection, and functionally eliminate acute CMV within the brain. In addition, when CMV-immune splenocytes were administered prior to a peripheral CMV challenge, CMV entry into the immunocompromised brain was prevented. Systemic adoptive transfer may be a rapid and effective approach to preventing CMV entrance into the brain and for reducing neurotropic infection.
Evidence of an abnormal intramuscular component of fatigue in multiple sclerosis

The goals of this study were to investigate muscle fatigue in patients with multiple sclerosis (MS), and to determine the relationships between muscle fatigue, clinical status, and perceived fatigue. The fatigability of the anterior tibial muscle was quantitated in patients and controls during 9 min of intermittent stimulation (used to eliminate central sources of muscle fatigue). During exercise, the decline in tetanic force, phosphocreatine, and intracellular pH was greater in patients than in controls. The compound muscle action potential amplitude did not decrease during exercise, indicating that there was no failure of neuromuscular transmission during fatigue. Thus, the excessive fatigue in MS developed from sources beyond the muscle membrane. Following exercise, the recovery of tetanic force was delayed in patients (a pattern that suggests abnormal excitation–contraction coupling), whereas the recovery of metabolites was complete in both groups. Muscular fatigue was correlated with clinical disability but not with perceived fatigue. These results suggests that fatigue in MS has both central (perception, upper motor neuron dysfunction) and peripheral (impaired metabolism and excitation–contraction coupling) components. © 1995 John Wiley &Sons, Inc.
Financial Contracting with an Informed Investor ∗

We provide a simple model with a privately informed principal who provides nancing to a project in which an agent exerts e ort that a ects the probability of success. When restricting the space of contracts to debt contracts, we show that the equilibrium that gives the highest pro t to the principal is a pooling equilibrium in which the allocation of cashow rights and the e ort of the entrepreneur are independent of the principal's private information. We then analyze whether the principal, given her informational advantage will have a tendency to be too aggressive or too conservative in her nancing policy. In this respect we show that in the best equilibrium the set of types for which there is abusive lending is non-empty if and only if there is over-lending. We then extend the analysis to an unrestricted set of contracts and show that, under some mild conditions, the results above are robust. JEL Codes: D82, G24, G32.
Impact sourcing ventures and local communities: a frame alignment perspective

Using qualitative methods, this paper explores how impact sourcing (ImS) ventures frame their activities to marginalized communities. In doing so, the paper attempts to unearth the social–psychological processes undergirding ImS strategies. The findings highlight the difficulties faced by ImS ventures in operationalizing their strategic intent. More specifically, the paper provides insights into how different and diverse framings are used by ImS ventures to influence the local community. From a strategic perspective, the paper suggests that framings related to progress, family, material benefit and egalitarianism can help overcome the inevitable tensions and misunderstandings with the community. Drawing on the findings, we develop a process model that describes how competing framings of an ImS venture and the community could eventually align. Theoretically, the paper illuminates the day to day micro‐processes of reality negotiation between socially driven information technology – business process outsourcing businesses and the local communities they seek to impact.