Cyclic and Acyclic Defensins Inhibit Human Immunodeficiency Virus Type-1 Replication by Different Mechanisms

Defensins are antimicrobial peptides expressed by plants and animals. In mammals there are three subfamilies of defensins, distinguished by structural features: α, β and θ. Alpha and β-defensins are linear peptides with broad anti-microbial activity that are expressed by many mammals including humans. In contrast, θ-defensins are cyclic anti-microbial peptides made by several non-human primates but not humans. All three defensin types have anti-HIV-1 activity, but their mechanisms of action differ. We studied the anti-HIV-1 activity of one defensin from each group, HNP-1 (α), HBD-2 (β) and RTD-1 (θ). We examined how each defensin affected HIV-1 infection and demonstrated that the cyclic defensin RTD-1 inhibited HIV-1 entry, while acyclic HNP-1 and HBD-2 inhibited HIV-1 replication even when added 12 hours post-infection and blocked viral replication after HIV-1 cDNA formation. We further found that all three defensins downmodulated CXCR4. Moreover, RTD-1 inactivated X4 HIV-1, while HNP-1 and HBD-2 inactivated both X4 and R5 HIV-1. The data presented here show that acyclic and cyclic defensins block HIV-1 replication by shared and diverse mechanisms. Moreover, we found that HNP-1 and RTD-1 directly inhibited firefly luciferase enzymatic activity, which may affect the interpretation of previously published data

Retour d’expérience sur les apports du géographe dans l’observation des effets du changement climatique

L’adaptation au changement climatique constitue un défi sociétal dont le géographe doit s’emparer. Sa capacité d’appréhender le territoire et ses acteurs, ainsi que sa vision holistique, en font un interlocuteur privilégié des politiques publiques d’aménagement. A partir d’un retour d’expérience concernant la métropole lyonnaise, cette publication démontre le rôle joué par le géographe dans la structuration et l’innovation, selon une démarche intégrée et au sein d’une structure plurielle d’observation scientifique.Adaptation to climate change can be currently considered as a societal challenge that geographers must tackle. Their capacity to understand the territory and its actors, and their holistic vision, make them privileged partners of the public urban planners. This paper, concerning an ongoing project about the Greater Lyon, highlights the role of geographers in the structuration and innovation, according to an integrated process and within a plural scientific observation structure

Propriedades psicométricas e invariância de medida de uma escala de autoeficácia acadêmica em estudantes universitários de cinco países da América Latina

Our objective was to analyze the measurement invariance of the Academic Situations Specific Perceived Self-Efficacy Scale (ASSPSES) among Peruvian, Mexican, Colombian, Argentinean, and Brazilian college students, and its relationship with academic emotional exhaustion (AEE). In addition to the ASSPSES, the Emotional Exhaustion Scale (EES) was used. Two thousand one hundred forty-two college students (70.26% women) between the ages of 16 and 35 (M = 21.79 years) participated. The one-dimensional structure of ASSPSES was corroborated in each sample with a confirmatory factor analysis and the measurement invariance analysis was carried out with a multi-group factor analysis (MGFA) and with the differential item functioning. The relationship with the AEE was tested with the Pearson correlation coefficient. Regard the results, in all of the samples, the one-dimensional model presented adequate psychometric indicators with respect to both dimensionality and reliability. Similarly, regarding the analysis of measurement invariance, a strong variance was attained, and DIF is weak, which together with the MGFA results provides favorable evidence of measurement invariance. We conclude that ASSPSES is an invariant measure among the analyzed groups although replicating the study is necessary for the consolidation of the findings. These findings contribute to the understanding of the internal structure of the ASSPSES, something that had been awaiting evaluation, given how the scale is used in various contexts.El objetivo fue analizar la invarianza de medición de la Escala de Autoeficacia Percibida Específica para Situaciones Académicas (EAPESA) entre estudiantes universitarios peruanos, mexicanos, colombianos, argentinos y brasileños, y su relación con el agotamiento emocional académico (AEA). Además de la EAPESA, se usó la Escala de Cansancio Emocional (ECE). Participaron 2142 estudiantes universitarios (70.26 % mujeres) entre los 16 y 35 años (M = 21.79). La estructura unidimensional de la EAPESA se corroboró en cada muestra con un análisis factorial confirmatorio, y la invarianza de medición se llevó a cabo con un análisis factorial de grupo múltiple (AFGM) y con el funcionamiento diferencial de los ítems (FDI). La relación con el AEA se evaluó con el coeficiente de correlación de Pearson. Respecto a los resultados, en todas las muestras el modelo unidimensional presentó adecuados indicadores psicométricos, tanto en lo que respecta a su dimensionalidad como en cuanto a su confiabilidad. Del mismo modo, en cuanto al análisis de invarianza de medición, se alcanza la invarianza fuerte, y el FDI es débil, lo que junto con el AFGM brinda evidencia favorable de invarianza de medición. Se concluye que la EAPESA es una medida invariante entre los grupos analizados, aunque es necesario replicar la investigación para consolidar los hallazgos. Estos resultados contribuyen a entender la estructura interna de la EAPESA, algo que estaba aguardando una valoración, ya que dicha escala es usada en varios contextos.El objetivo fue analizar la invarianza de medición de la Escala de Autoeficacia Percibida Específica para Situaciones Académicas (EAPESA) entre estudiantes universitarios peruanos, mexicanos, colombianos, argentinos y brasileños, y su relación con el agotamiento emocional académico (AEA). Además de la EAPESA, se usó la Escala de Cansancio Emocional (ECE). Participaron 2142 estudiantes universitarios (70.26% mujeres) entre los 16 y 35 años (M = 21.79). La estructura unidimensional de la EAPESA se corroboró en cada muestra con un análisis factorial confirmatorio, y la invarianza de medición se llevó a cabo con un análisis factorial de grupo múltiple (AFGM) y con el funcionamiento diferencial de los ítems (FDI). La relación con el AEA se evaluó con el coeficiente de correlación de Pearson. Respecto a los resultados, en todas las muestras el modelo unidimensional presentó adecuados indicadores psicométricos, tanto en lo que respecta a su dimensionalidad como en cuanto a su confiabilidad. Del mismo modo, en cuanto al análisis de invarianza de medición, se alcanza la invarianza fuerte, y el FDI es débil, lo que junto con el AFGM brinda evidencia favorable de invarianza de medición. Se concluye que la EAPESA es una medida invariante entre los grupos analizados, aunque es necesario replicar la investigación para consolidar los hallazgos. Estos resultados contribuyen a entender la estructura interna de la EAPESA, algo que estaba aguardando una valoración, ya que dicha escala es usada en varios contextos

ANTI-ESTROGEN CROSS RESISTANCE IN HUMAN BREAST CANCER

Abstract Introduction: Recently, the STAR study showed that raloxifene works at least as well as tamoxifen in preventing breast cancer. It is of interest to know whether raloxifene may be used in the treatment of breast cancer and whether it would be effective in those who have developed resistance to other anti-estrogens. Methods: Estrogen receptor positive (er+) and negative (er-) breast cancer cells were exposed to tamoxifen, raloxifene or faslodex for 48 hours and the efficacy and potency of these drugs determined. MCF-7 breast cancer sub-lines lines resistant to tamoxifen (TAMR), raloxifene (RALR) or faslodex (FASR) were developed and used to determine cross-resistance among anti-estrogens Results: The efficacy of tamoxifen, raloxifene, and faslodex in inhibiting the proliferation of MCF-7 estrogen receptor positive er+ breast cancer were equivalent though theirs potencies differed. However, anti-estrogens were unable to inhibit the growth of er-breast cancer cells. TAMR sub-lines were resistant to raloxifene and faslodex, while FASR sub-lines were resistant to tamoxifen and raloxifene. RALR sub-lines however, were sensitive to treatment with tamoxifen in vitro and in vivo. Conclusions: The anti-estrogens tamoxifen, raloxifene and faslodex are equally efficacious in inhibiting breast cancer growth in er+ tumors. RALR sub-lines are sensitive to tamoxifen treatment

Hispanic physicians' tobacco intervention practices: a cross-sectional survey study

BACKGROUND: U.S. Hispanic physicians constitute a considerable professional collective, and they may be most suited to attend to the health education needs of the growing U.S. Hispanic population. These educational needs include tobacco use prevention and smoking cessation. However, there is a lack of information on Hispanic physicians' tobacco intervention practices, their level of awareness and use of cessation protocols, and the type of programs that would best address their tobacco training needs. The purpose of this study was to assess the tobacco intervention practices and training needs of Hispanic physicians. METHODS: Data was collected through a validated survey instrument among a cross-sectional sample of self-reported Hispanic physicians. Data analyses included frequencies, descriptive statistics, and factorial analyses of variance. RESULTS: The response rate was 55.5%. The majority of respondents (73.3%) were middle-age males. Less than half of respondents routinely performed the most basic intervention: asking patients about smoking status (44.4%) and advising smoking patients to quit (42.2%). Twenty-five percent assisted smoking patients by talking to them about the health risks of smoking, providing education materials or referring them to cessation programs. Only 4.4% routinely arranged follow-up visits or phone calls for smoking patients. The majority of respondents (64.4%) indicated that they prescribe cessation treatments to less than 20% of smoking patients. A few (4.4%) routinely used behavioral change techniques or programs. A minority (15.6%) indicated that they routinely ask their patients about exposure to tobacco smoke, and 6.7% assisted patients exposed to secondhand smoke in understanding the health risks associated with environmental tobacco smoke (ETS). The most frequently encountered barriers preventing respondents from intervening with patients who smoke included: time, lack of training, lack of receptivity by patients, and lack of reimbursement by third party payers. There was no significant main effect of type of physician, nor was there an interaction effect (gender by type of physician), on tobacco-related practices. CONCLUSION: The results indicate that Hispanic physicians, similarly to U.S. physicians in general, do not meet the level of intervention recommended by health care agencies. The results presented will assist in the development of tobacco training initiatives for Hispanic physicians

Discovery of potent and selective inhibitors of the Escherichia coli M1-aminopeptidase via multicomponent solid-phase synthesis of tetrazole-peptidomimetics

The Escherichia coli neutral M1-aminopeptidase (ePepN) is a novel target identified for the development of antimicrobials. Here we describe a solid-phase multicomponent approach which enabled the discovery of potent ePepN inhibitors. The on-resin protocol, developed in the frame of the Distributed Drug Discovery (D3) program, comprises the implementation of parallel Ugi-azide four-component reactions with resin-bound amino acids, thus leading to the rapid preparation of a focused library of tetrazole-peptidomimetics (TPMs) suitable for biological screening. By dose-response studies, three compounds were identified as potent and selective ePepN inhibitors, as little inhibitory effect was exhibited for the porcine ortholog aminopeptidase. The study allowed for the identification of the key structural features required for a high ePepN inhibitory activity. The most potent and selective inhibitor (TPM 11) showed a non-competitive inhibition profile of ePepN. We predicted that both diastereomers of compound TPM 11 bind to a site distinct from that occupied by the substrate. Theoretical models suggested that TPM 11 has an alternative inhibition mechanism that doesn't involve Zn coordination. On the other hand, the activity landscape analysis provided a rationale for our findings. Of note, compound TMP 2 showed in vitro antibacterial activity against Escherichia coli. Furthermore, none of the three identified inhibitors is a potent haemolytic agent, and only two compounds showed moderate cytotoxic activity toward the murine myeloma P3X63Ag cells. These results point to promising compounds for the future development of rationally designed TPMs as antibacterial agents

Evidence for the accelerated expansion of the Universe from weak lensing tomography with COSMOS

We present a tomographic cosmological weak lensing analysis of the HST COSMOS Survey. Applying our lensing-optimized data reduction, principal component interpolation for the ACS PSF, and improved modelling of charge-transfer inefficiency, we measure a lensing signal which is consistent with pure gravitational modes and no significant shape systematics. We carefully estimate the statistical uncertainty from simulated COSMOS-like fields obtained from ray-tracing through the Millennium Simulation. We test our pipeline on simulated space-based data, recalibrate non-linear power spectrum corrections using the ray-tracing, employ photometric redshifts to reduce potential contamination by intrinsic galaxy alignments, and marginalize over systematic uncertainties. We find that the lensing signal scales with redshift as expected from General Relativity for a concordance LCDM cosmology, including the full cross-correlations between different redshift bins. For a flat LCDM cosmology, we measure sigma_8(Omega_m/0.3)^0.51=0.75+-0.08 from lensing, in perfect agreement with WMAP-5, yielding joint constraints Omega_m=0.266+0.025-0.023, sigma_8=0.802+0.028-0.029 (all 68% conf.). Dropping the assumption of flatness and using HST Key Project and BBN priors only, we find a negative deceleration parameter q_0 at 94.3% conf. from the tomographic lensing analysis, providing independent evidence for the accelerated expansion of the Universe. For a flat wCDM cosmology and prior w in [-2,0], we obtain w<-0.41 (90% conf.). Our dark energy constraints are still relatively weak solely due to the limited area of COSMOS. However, they provide an important demonstration for the usefulness of tomographic weak lensing measurements from space. (abridged)Comment: 26 pages, 25 figures, matches version accepted for publication by Astronomy and Astrophysic