Non-cytotoxic 1,2,3-triazole tethered fused heterocyclic ring derivatives display Tax protein inhibition and impair HTLV-1 infected cells

Human T cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that infects approximately 10–20 million people worldwide and causes an aggressive neoplasia (adult T-cell leukemia/lymphoma - ATL). Therapeutic approaches for the treatment of ATL have variable effectiveness and poor prognosis, thus requiring strategies to identify novel compounds with activity on infected cells. In this sense, we initially screened a small series of 25 1,2,3-triazole derivatives to discover cell proliferation inhibitors and apoptosis inducers in HTLV-1-infected T-cell line (MT-2) for further assessment of their effect on viral tax activity through inducible-tax reporter cell line (Jurkat LTR-GFP). Eight promising compounds (02, 05, 06, 13, 15, 21, 22 and 25) with activity ≥70% were initially selected, based on a suitable cell-based assay using resazurin reduction method, and evaluated towards cell cycle, apoptosis and Tax/GFP expression analyses through flow cytometry. Compound 02 induced S phase cell cycle arrest and compounds 05, 06, 22 and 25 promoted apoptosis. Remarkably, compounds 22 and 25 also reduced GFP expression in an inducible-tax reporter cell, which suggests an effect on Tax viral protein. More importantly, compounds 02, 22 and 25 were not cytotoxic in human hepatoma cell line (Huh-7). Therefore, the discovery of 3 active and non-cytotoxic compounds against HTLV-1-infected cells can potentially contribute, as an initial promising strategy, to the development process of new drugs against ATL

Correlation between endometrial dating of luteal phase days 6 and 10 of the same menstrual cycle

CONTEXT: Endometrial maturation, important in the diagnosis of infertile couples, has been evaluated since 1950 using the Noyes criteria. Nevertheless, there is no consensus regarding the most suitable period of the luteal phase for performing the biopsy. OBJETIVE: This study evaluated the correlation between the histological dating of two endometrial biopsies performed in the same menstrual cycle, on luteal phase days six and ten.DESIGN: Prospective study. SETTING: Human Reproduction Division of the Federal University of São Paulo, referral center. PATIENTS:Twenty-five women complaining of infertility had their menstrual cycles monitored by ultrasound and LH plasma levels, to obtain evidence of ovulation. PROCEDURES: Endometrial biopsies were performed on luteal phase days LH+6 and LH+10 (luteal phase day 1 = LH+1 = the day that follows LH peak). Dating was done according to morphometric criteria, in which an endometrium sample is considered out of phase if the minimum maturation delay is one day. On day LH+6, blood was drawn for plasma progesterone level determination. RESULTS: All patients had an ovulatory cycle (mean LH peak: 47.4 U/L; mean follicular diameter on LH peak day: 18.9 mm; mean endometrial thickness on LH peak day: 10.3 mm; mean plasma progesterone level on day LH+6: 14.4 ng/ml). 14 patients had both biopsies in phase; 5 patients had out of phase biopsies only on day LH+6; 3 had out of phase biopsies only on day LH+10 and 3 patients had out of phase biopsies on both days. McNemar's test showed no statistical difference between these data (p>33.36%). CONCLUSIONS: The correlation found between the endometrial datings suggests that biopsies performed on either of these two days are suitable for evaluation of endometrial maturation.CONTEXTO: A verificação da maturidade endometrial, elemento diagnóstico necessário na avaliação do casal com queixa de infertilidade, vem sendo feita desde 1950 através do critério de datação histológica de Noyes. No entanto, não existe um consenso em relação ao período da fase lútea mais adequado para a colheita. OBJETIVO: Avaliar a correlação entre as datações histológicas de duas amostras de endométrio colhidas nos dias 6 e 10 da fase lútea de um mesmo ciclo menstrual. LOCAL: Setor de Reprodução Humana da Universidade Federal de São Paulo (UNIFESP). TIPO DE ESTUDO: Estudo prospectivo. Constou da comparação entre duas datações de endométrio num mesmo ciclo menstrual. PARTICIPANTES: 25 pacientes com queixa de infertilidade tiveram um ciclo menstrual monitorizado por ultra-sonografia e medida plasmática de LH, para demonstração de ovulação. PROCEDIMENTO: Biópsias de endométrio foram feitas nos dias LH+6 e LH+10 da fase lútea, considerando-se o dia seguinte ao do pico de LH como LH+1. A datação foi feita de acordo com critério morfométrico, considerando-se o endométrio como fora de fase, se o atraso de maturação mínimo fosse de um dia. No dia LH+6 foi feita dosagem de progesterona plasmática. RESULTADOS: Todas as pacientes apresentaram ciclos ovulatórios (média dos valores de pico de LH: 47,3 U/L; média dos diâmetros foliculares no dia do pico de LH: 18,9 mm; média das espessuras do endométrio no dia do pico de LH: 10,3 mm; média das concentrações de progesterona plasmática no dia LH+6: 14,4 ng/ml.). Em 14 pacientes, as duas biópsias estavam em fase. Houve atraso de maturação apenas no dia LH+6 em cinco pacientes; apenas no dia LH+10 em três pacientes e, nos dois dias, em três pacientes. Não houve diferença estatística entre esses valores (teste de McNemar, p=33,36%). CONCLUSÕES: Os resultados sugerem que a colheita do endométrio em qualquer dos dias (sexto ou décimo) da fase lútea fornece resultados semelhantes em relação à maturidade endometrial.Universidade Federal de São Paulo (UNIFESP)UNIFESPSciEL

Demonstration of the event identification capabilities of the NEXT-White detector

In experiments searching for neutrinoless double-beta decay, the possibility of identifying the two emitted electrons is a powerful tool in rejecting background events and therefore improving the overall sensitivity of the experiment. In this paper we present the first measurement of the efficiency of a cut based on the different event signatures of double and single electron tracks, using the data of the NEXT-White detector, the first detector of the NEXT experiment operating underground. Using a 228Th calibration source to produce signal-like and background-like events with energies near 1.6 MeV, a signal efficiency of 71.6 ± 1.5 stat± 0.3 sys% for a background acceptance of 20.6 ± 0.4 stat± 0.3 sys% is found, in good agreement with Monte Carlo simulations. An extrapolation to the energy region of the neutrinoless double beta decay by means of Monte Carlo simulations is also carried out, and the results obtained show an improvement in background rejection over those obtained at lower energies. [Figure not available: see fulltext.

Radiogenic backgrounds in the NEXT double beta decay experiment

Natural radioactivity represents one of the main backgrounds in the search for neutrinoless double beta decay. Within the NEXT physics program, the radioactivity- induced backgrounds are measured with the NEXT-White detector. Data from 37.9 days of low-background operations at the Laboratorio Subterráneo de Canfranc with xenon depleted in 136Xe are analyzed to derive a total background rate of (0.84±0.02) mHz above 1000 keV. The comparison of data samples with and without the use of the radon abatement system demonstrates that the contribution of airborne-Rn is negligible. A radiogenic background model is built upon the extensive radiopurity screening campaign conducted by the NEXT collaboration. A spectral fit to this model yields the specific contributions of 60Co, 40K, 214Bi and 208Tl to the total background rate, as well as their location in the detector volumes. The results are used to evaluate the impact of the radiogenic backgrounds in the double beta decay analyses, after the application of topological cuts that reduce the total rate to (0.25±0.01) mHz. Based on the best-fit background model, the NEXT-White median sensitivity to the two-neutrino double beta decay is found to be 3.5σ after 1 year of data taking. The background measurement in a Qββ±100 keV energy window validates the best-fit background model also for the neutrinoless double beta decay search with NEXT-100. Only one event is found, while the model expectation is (0.75±0.12) events. [Figure not available: see fulltext.]

Astrobiological Complexity with Probabilistic Cellular Automata

Search for extraterrestrial life and intelligence constitutes one of the major endeavors in science, but has yet been quantitatively modeled only rarely and in a cursory and superficial fashion. We argue that probabilistic cellular automata (PCA) represent the best quantitative framework for modeling astrobiological history of the Milky Way and its Galactic Habitable Zone. The relevant astrobiological parameters are to be modeled as the elements of the input probability matrix for the PCA kernel. With the underlying simplicity of the cellular automata constructs, this approach enables a quick analysis of large and ambiguous input parameters' space. We perform a simple clustering analysis of typical astrobiological histories and discuss the relevant boundary conditions of practical importance for planning and guiding actual empirical astrobiological and SETI projects. In addition to showing how the present framework is adaptable to more complex situations and updated observational databases from current and near-future space missions, we demonstrate how numerical results could offer a cautious rationale for continuation of practical SETI searches.Comment: 37 pages, 11 figures, 2 tables; added journal reference belo