Retrotransposon-Encoded Reverse Transcriptase in the Genesis, Progression and Cellular Plasticity of Human Cancer

LINE-1 (Long Interspersed Nuclear Elements) and HERVs (Human Endogenous Retroviruses) are two families of autonomously replicating retrotransposons that together account for about 28% of the human genome. Genes harbored within LINE-1 and HERV retrotransposons, particularly those encoding the reverse transcriptase (RT) enzyme, are generally expressed at low levels in differentiated cells, but their expression is upregulated in transformed cells and embryonic tissues. Here we discuss a recently discovered RT-dependent mechanism that operates in tumorigenesis and reversibly modulates phenotypic and functional variations associated with tumor progression. Downregulation of active LINE-1 elements drastically reduces the tumorigenic potential of cancer cells, paralleled by reduced proliferation and increased differentiation. Pharmacological RT inhibitors (e.g., nevirapine and efavirenz) exert similar effects on tumorigenic cell lines, both in culture and in animal models. The HERV-K family play a distinct complementary role in stress-dependent transition of melanoma cells from an adherent, non-aggressive, to a non-adherent, highly malignant, growth phenotype. In synthesis, the retrotransposon-encoded RT is increasingly emerging as a key regulator of tumor progression and a promising target in a novel anti-cancer therapy

Magnetic Reversal Time in Open Long Range Systems

Topological phase space disconnection has been recently found to be a general phenomenon in isolated anisotropic spin systems. It sets a general framework to understand the emergence of ferromagnetism in finite magnetic systems starting from microscopic models without phenomenological on-site barriers. Here we study its relevance for finite systems with long range interacting potential in contact with a thermal bath. We show that, even in this case, the induced magnetic reversal time is exponentially large in the number of spins, thus determining {\it stable} (to any experimental observation time) ferromagnetic behavior. Moreover, the explicit temperature dependence of the magnetic reversal time obtained from the microcanonical results, is found to be in good agreement with numerical simulations. Also, a simple and suggestive expression, indicating the Topological Energy Threshold at which the disconnection occurs, as a real energy barrier for many body systems, is obtained analytically for low temperature

Microthyriaceae sp., an endophytic fungus

In screening for natural products with antiparasitic activity, an endophytic fungus, strain F2611, isolated from above-ground tissue of the tropical grass Paspalum conjugatum (Poaceae) in Panama, was chosen for bioactive principle elucidation. Cultivation on malt extract agar (MEA) followed by bioassayguided chromatographic fractionation of the extract led to the isolation of the new polyketide integrasone B (1) and two known mycotoxins, sterigmatocystin (2) and secosterigmatocystin (3). Sterigmatocystin (2) was found to be the main antiparasitic compound in the fermentation extract of this fungus, possessing potent and selective antiparasitic activity against Trypanosoma cruzi, the cause of Chagas disease, with an IC50 value of 0 13 lmol l 1. Compounds 2 and 3 showed high cytotoxicity against Vero cells (IC50 of 0 06 and 0 97 lmol l 1, respectively). The new natural product integrasone B (1), which was co-purified from the active fractions, constitutes the second report of a natural product possessing an epoxyquinone with a lactone ring and exhibited no significant biological activity. Strain F2611 represents a previously undescribed taxon within the Microthyriaceae (Dothideomycetes, AscomycotaIn screening for natural products with antiparasitic activity, an endophytic fungus, strain F2611, isolated from above-ground tissue of the tropical grass Paspalum conjugatum (Poaceae) in Panama, was chosen for bioactive principle elucidation. Cultivation on malt extract agar (MEA) followed by bioassayguided chromatographic fractionation of the extract led to the isolation of the new polyketide integrasone B (1) and two known mycotoxins, sterigmatocystin (2) and secosterigmatocystin (3). Sterigmatocystin (2) was found to be the main antiparasitic compound in the fermentation extract of this fungus, possessing potent and selective antiparasitic activity against Trypanosoma cruzi, the cause of Chagas disease, with an IC50 value of 0 13 lmol l 1. Compounds 2 and 3 showed high cytotoxicity against Vero cells (IC50 of 0 06 and 0 97 lmol l 1, respectively). The new natural product integrasone B (1), which was co-purified from the active fractions, constitutes the second report of a natural product possessing an epoxyquinone with a lactone ring and exhibited no significant biological activity. Strain F2611 represents a previously undescribed taxon within the Microthyriaceae (Dothideomycetes, AscomycotaLaboratory of Tropical Bioorganic Chemistry, Faculty of Natural Exact Sciences and Technology, University of Panama, Panama City, Republic of Panama Smithsonian Tropical Research Institute, Balboa, Panama City, Republic of Panama Centro de Biodiversidade, Gen omica Integrativa e Funcional (BioFIG), Universidade de Lisboa, Faculdade de Ci^encias, Edif ıcio ICAT/TecLabs, Campus da FCUL, Campo Grande, Lisboa, Portugal Institute for Advanced Scientific Investigation and High Technology Services, National Secretariat of Science, Technology, and Innovation, City of Knowledge, Panama City, Republic of Panama School of Plant Sciences, The University of Arizona, Tucson, AZ, USA Department of Biology, University of Utah, Salt Lake City, UT, USA Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, US

Comparison of the in vitro invasive capabilities of Plasmodium falciparum schizonts isolated by Percoll gradient or using magnetic based separation

<p>Abstract</p> <p>Background</p> <p>Percoll gradient centrifugation is often used for synchronization, enrichment, or isolation of a particular stage of <it>Plasmodium falciparum</it>. However, Percoll, a hyperosmotic agent, may have harmful effects on the parasites. Magnetic bead column (MBC) separation has been used as an alternative. This is a report of a head-to-head comparison of the <it>in vitro </it>invasive capabilities of parasites isolated by either of the two methods.</p> <p>Methods</p> <p>The <it>P. falciparum </it>laboratory strain isolate 7G8 was grown <it>in vitro </it>using standard procedures and synchronized using 5% sorbitol. On separate days when the schizont parasitaemia was >1%, the culture was split and half was processed by Percoll gradient centrifugation and the other half by magnetic bead column separation. Both processed parasites were placed back in culture and allowed to invade new uninfected erythrocytes.</p> <p>Results</p> <p>In 10 paired assays, the mean efficiency of invasion of 7G8 parasites treated by Percoll gradient centrifugation was 35.8% that of those treated by magnetic bead column separation (95% CI, p = 0.00067) A paired <it>t </it>test with two tails was used for these comparisons.</p> <p>Conclusions</p> <p>In this comparison, magnetic bead column separation of 7G8 schizonts resulted in higher viability and efficiency of invasion than utilizing Percoll gradient centrifugation.</p

Marine cyanobacteria-derived serotonin receptor 2C active fraction induces psychoactive behavioral effects in mice

Context—Marine cyanobacteria offer a robust resource for natural products drug discovery due to the secondary metabolites they produce. Objective—To identify novel cyanobacterial compounds that exhibit CNS psychoactive effects. Materials and methods—Cyanobacteria were collected from Las Perlas Archipelago, Panama and subjected to dichloromethane/methanol extraction and fractionation by column chromatography before being screened for affinity against a panel of CNS targets. A 50:50 ethyl acetate:methanol fraction of one cyanobacterial extract (2064H) was subjected to HPLC and the major peak was isolated (2064H3). At a dose of 20 μg per animal, 2064H and 2064H3 were tested in mice using behavioral assays that included the forced swim, open field, and formalin tests.Context—Marine cyanobacteria offer a robust resource for natural products drug discovery due to the secondary metabolites they produce. Objective—To identify novel cyanobacterial compounds that exhibit CNS psychoactive effects. Materials and methods—Cyanobacteria were collected from Las Perlas Archipelago, Panama and subjected to dichloromethane/methanol extraction and fractionation by column chromatography before being screened for affinity against a panel of CNS targets. A 50:50 ethyl acetate:methanol fraction of one cyanobacterial extract (2064H) was subjected to HPLC and the major peak was isolated (2064H3). At a dose of 20 μg per animal, 2064H and 2064H3 were tested in mice using behavioral assays that included the forced swim, open field, and formalin tests

N-terminal probrain natriuretic peptide is a stronger predictor of cardiovascular mortality than C-reactive protein and albumin excretion rate in elderly patients with type 2 diabetes: the Casale Monferrato population-based study.

OBJECTIVE: To study whether N-terminal probrain natriuretic peptide (NT-proBNP) is a short-term independent predictor of both all-cause and cardiovascular (CV) mortality in type 2 diabetic patients and to establish whether albuminuria and C-reactive protein (CRP) affect this relationship. RESEARCH DESIGN AND METHODS: The prospective study included 1,825 type 2 diabetic patients from the population-based cohort of the Casale Monferrato study. CV risk factors, preexisting CVD, and NT-proBNP levels were evaluated at baseline. All-cause and CV mortality were assessed 5.5 years after baseline examination. Multivariate Cox proportional hazards modeling was used to estimate mortality hazard ratios (HRs). RESULTS: During the follow-up period, 390 people died (175 for CVD) out of 9,101 person-years of observations. A significantly increased mortality risk by quartiles of NT-proBNP was observed (test for trend, P < 0.001). NT-proBN P values >91 pg/mL conferred HRs of 2.05 (95% CI 1.47–2.86) for all-cause and 4.47 (2.38–8.39) for CV mortality, independently of CV risk factors, including CRP and albumin excretion rate (AER). The association was also significant for modest rises in NT-proBNP levels and in patients without microalbuminuria and CVD at baseline (upper quartiles HRs 3.82 [95% CI 1.24–13.75]) and 3.14 [1.00–9.94]). Albuminuria and NT-proBNP had an additive effect on mortality, though the association was stronger for NT-proBNP. CONCLUSIONS: NT-proBNP is a strong independent predictor of short-term CV mortality risk in elderly people with type 2 diabetes, including those without preexisting CVD. This association is evident even in people with slightly increased values, is not modified by CRP, and is additive to that provided by AER

Rest-Frame R-band Lightcurve of a z~1.3 Supernova Obtained with Keck Laser Adaptive Optics

We present Keck diffraction limited H-band photometry of a z~1.3 Type Ia supernova (SN) candidate, first identified in a Hubble Space Telescope (HST) search for SNe in massive high redshift galaxy clusters. The adaptive optics (AO) data were obtained with the Laser Guide Star facility during four observing runs from September to November 2005. In the analysis of data from the observing run nearest to maximum SN brightness, the SN was found to have a magnitude H=23.9 +/- 0.14 (Vega). We present the H-band (approximately rest-frame R) light curve and provide a detailed analysis of the AO photometric uncertainties. By constraining the aperture correction with a nearby (4" separation) star we achieve 0.14 magnitude photometric precision, despite the spatially varying AO PSF.Comment: 11 pages, 8 figures, Accepted for Publication in AJ Updated the citations, fixed typo

Dermoscopy and reflectance confocal microscopy of solitary flat pink lesions: A new combined score to diagnose amelanotic melanoma

BackgroundDifferential diagnosis of amelanotic/hypomelanotic melanoma among solitary flat pink lesions is challenging, due to limited clinical and dermoscopic clues. Dermoscopy and reflectance confocal microscopy assessments improve diagnostic accuracy, but their combined capacity among solitary flat pink lesions is yet to be defined.ObjectivesTo determine (i) whether diagnostic accuracy is improved with combined dermoscopy and reflectance confocal microscopy, (ii) a model to estimate probability of flat amelanotic/hypomelanotic melanoma among solitary flat pink lesions.MethodsA retrospective single-centre study of solitary flat pink lesions, excised for suspected malignancy between 2011 and 2022 was performed. Images were independently evaluated by two dermatologists, blinded to histopathological diagnosis. Diagnostic performance was evaluated on the receiver operating characteristic curve and the area under the curve. Predictive features were identified by univariate and multivariate logistic regression analyses. A final predictive nomogram of independent risk factors was calculated by backward likelihood ratio. Hypothesis being tested was formulated before data collection.ResultsA total of 184 patients (87 females, 47.3%) were included; mean age was 57.6 years (19-95). Combined dermoscopy and reflectance confocal microscopy was more sensitive (83%, CI 69.2-92.4 and 91.5%, CI 79.6-97.6) than dermoscopy alone (76.6%, CI 62.0-87.7 and 85.1%, CI 71.7-93.8). Predictive features defined the new model, including linear irregular vessels (4.26-folds, CI 1.5-12.1), peripheral pigment network (6.07-folds, CI 1.83-20.15), remnants of pigmentation (4.3-folds, CI 1.27-14.55) at dermoscopy and atypical honeycomb (9.98-folds, CI 1.91-51.96), disarranged epidermal pattern (15.22-folds, CI 2.18-106.23), dendritic pagetoid cells in the epidermis (3.77-folds, CI 1.25-11.26), hypopigmented pagetoid cells (27.05-folds, CI 1.57-465.5), and dense and sparse nests (3.68-folds, CI 1.24-10.96) in reflectance confocal microscopy. Diagnostic accuracy of the model was high (AUC 0.91).ConclusionsAdjunctive reflectance confocal microscopy increases diagnostic sensitivity of flat amelanotic/hypomelanotic melanoma differential diagnosis. The proposed model requires validation