Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compounds which have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacological and toxicological outcomes. Therefore, it is widely recognized that metabolism studies of a new chemical entity need to be addressed early in the drug discovery process. This paper describes an overview of the metabolism of currently available anti-HIV drugs.Da identificação do HIV como o agente causador da AIDS, ao desenvolvimento de fármacos antirretrovirais eficazes, os avanços científicos na pesquisa sobre o HIV nos últimos vinte e seis anos foram marcantes. Atualmente, existem vinte e cinco fármacos anti-HIV formalmente aprovados pelo FDA para utilização clínica no tratamento da AIDS. Estes compostos são divididos em seis classes: inibidores nucleosídeos de transcriptase reversa (INTR), inibidores nucleotídeos de transcriptase reversa (INtTR), inibidores não-nucleosídeos de transcriptase reversa (INNTR), inibidores de protease (IP), inibidores da entrada celular ou inibidores de fusão (IF), inibidores de co-receptores (ICR) e inibidores de integrase (INI). O metabolismo consiste em um dos maiores determinantes do perfil farmacocinético de um fármaco. A formação de metabólitos ativos ou tóxicos terá impacto nas respostas farmacológicas ou toxicológicas do fármaco. Portanto, é amplamente reconhecido que estudos do metabolismo de uma nova entidade química devem ser realizados durante as fases iniciais do processo de desenvolvimento de fármacos. Este artigo descreve uma abordagem do metabolismo dos fármacos anti-HIV atualmente disponíveis na terapêutica

Bleaching studies on Al-hole ([AlO₄/h]⁰) electron spin resonance (ESR) signal in sedimentary quartz

Electron spin resonance (ESR) dating of sediments using quartz is most commonly used for older sediments (>100 ka), since large residuals render the ESR signal unsuitable for dating young sediments. The multiple-centre approach (utilising both Ti and [AlO4/h]0 signals) is usually used to test the resetting of the signals used for ESR dating. Here we work towards a better understanding of, and correction for, the residual signal in ESR samples of sedimentary quartz. We undertook multiple-centre ESR measurements using quartz [AlO4/h]0 and Ti signals on young aeolian samples of different grain sizes which have been independently dated using optically stimulated luminescence (OSL). Our results demonstrate that [AlO4/h]0 signal yields residuals indicating equivalent doses of about 500 Gy, substantially older than expected for the known OSL equivalent doses in the range of 8–37 Gy. The decay of [AlO4/h]0 signal as function of bleaching time can be represented by an exponential function. We investigate the dependence of the residual magnitude of the ESR signal as a function of the previous given dose and observe an exponential increase in the residual signal with dose. Such observations are consistent with the results of luminescence process modelling conducted for a model comprising two luminescence centres and several traps, one of which is a so-called deep disconnected trap that cannot be emptied during optical stimulation. We propose that bleaching occurs through an electron-hole recombination process with electrons released from optically sensitive traps. In addition to our new insights into the bleaching mechanisms of the [AlO4/h]0 ESR signal, we discuss the implications for the procedures used for performing residual dose corrections in ESR dating. We recommend that modern analogues be used in addition to laboratory-bleached samples when performing residual dose corrections

Core-shell processing of natural pigment: Upper Palaeolithic red ochre from Lovas, Hungary

Ochre is the common archaeological term for prehistoric pigments. It is applied to a range of uses, from ritual burials to cave art to medications. While a substantial number of Palaeolithic paint mining pits have been identified across Europe, the link between ochre use and provenance, and their antiquity, has never yet been identified. Here we characterise the mineralogical signature of core-shell processed ochre from the Palaeolithic paint mining pits near Lovas in Hungary, using a novel integration of petrographic and mineralogical techniques. We present the first evidence for core-shell processed, natural pigment that was prepared by prehistoric people from hematitic red ochre. This involved combining the darker red outer shell with the less intensely coloured core to efficiently produce an economical, yet still strongly coloured, paint. We demonstrate the antiquity of the site as having operated between 14-13 kcal BP, during the Epigravettian period. This is based on new radiocarbon dating of bone artefacts associated with the quarry site. The dating results indicate the site to be the oldest known evidence for core-shell pigment processing. We show that the ochre mined at Lovas was exported from the site based on its characteristic signature at other archaeological sites in the region. Our discovery not only provides a methodological framework for future characterisation of ochre pigments, but also provides the earliest known evidence for "value-adding" of products for trade. Copyright

Process analysis of 1MW MCFC plant

Molten carbonate fuel cells (MCFCs) have received a great deal of attention in recent years and are now at a pre-commercial stage. In this work, referring to the simulation experience of the Department of Environmental Engineering of the University of Genoa (DIAM), the process analysis of a reference 500kW MCFC plant will be presented. The new philosophy of distributed energy supply for the production and the distribution of electrical energy focuses its attention on plants with a power size in the range of 1\u201310MW. For this reason the simulation of a 1MW MCFC system will be considered, both on the basis of a 500kW plant scheme, and taking into account some modifications for improving its performance, and the results of the simulation will be discussed

Climate variability over the last 35,000 years recorded in marine and terrestrial archives in the Australian region: an OZ-INTIMATE compilation

The Australian region spans some 60° of latitude and 50° of longitude and displays considerable regional climate variability both today and during the Late Quaternary. A synthesis of marine and terrestrial climate records, combining findings from the Southern Ocean, temperate, tropical and arid zones, identifies a complex response of climate proxies to a background of changing boundary conditions over the last 35,000 years. Climate drivers include the seasonal timing of insolation, greenhouse gas content of the atmosphere, sea level rise and ocean and atmospheric circulation changes. Our compilation finds few climatic events that could be used to construct a climate event stratigraphy for the entire region, limiting the usefulness of this approach. Instead we have taken a spatial approach, looking to discern the patterns of change across the continent. The data identify the clearest and most synchronous climatic response at the time of the Last Glacial Maximum (LGM) (21 ± 3 ka), with unambiguous cooling recorded in the ocean, and evidence of glaciation in the highlands of tropical New Guinea, southeast Australia and Tasmania. Many terrestrial records suggest drier conditions, but with the timing of inferred snowmelt, and changes to the rainfall/runoff relationships, driving higher river discharge at the LGM. In contrast, the deglaciation is a time of considerable south-east to north-west variation across the region. Warming was underway in all regions by 17 ka. Post-glacial sea level rise and its associated regional impacts have played an important role in determining the magnitude and timing of climate response in the north-west of the continent in contrast to the southern latitudes. No evidence for cooling during the Younger Dryas chronozone is evident in the region, but the Antarctic cold reversal clearly occurs south of Australia. The Holocene period is a time of considerable climate variability associated with an intense monsoon in the tropics early in the Holocene, giving way to a weakened monsoon and an increasingly El Niño-dominated ENSO to the present. The influence of ENSO is evident throughout the southeast of Australia, but not the southwest. This climate history provides a template from which to assess the regionality of climate events across Australia and make comparisons beyond our region.Jessica M. Reeves, Timothy T. Barrows, Timothy J .Cohen, Anthony S. Kiem, Helen C.Bostock, Kathryn E. Fitzsimmons ... et al. (OZ-INTIMATE Members

Is there gender bias when creative directors judge advertising? Name cue effect in ad evaluation

A lack of women in creative departments has been documented in previous research. These departments are seen as a male fraternity subculture in advertising agencies, where women experience many difficulties in their career progress. One of these drawbacks is gender bias in the selection of ideas' process. Male creative directors are believed to promote ideas created by men within a homosocial environment. This female perception, that emerged from previous qualitative research, is studied experimentally for the first time. Almost 90 advertising creative directors and higher level positions, assessed ads created by students in an advertising university course. In the current study we explore the effects of ad gender authorship. Results revealed an absence of gender bias based on ad name cues, neither the gender of the ad creators nor the creatives affected the evaluations. The findings are discussed and future research is proposed

Meeting Paris agreement objectives will temper seabird winter distribution shifts in the North Atlantic Ocean

International audienceWe explored the implications of reaching the Paris Agreement Objective of limiting global warming to <2°C for the future winter distribution of the North Atlantic sea-bird community. We predicted and quantified current and future winter habitats of five North Atlantic Ocean seabird species (Alle alle, Fratercula arctica, Uria aalge, Uria lomvia and Rissa tridactyla) using tracking data for ~1500 individuals through resource selection functions based on mechanistic modeling of seabird energy requirements, and a dynamic bioclimate envelope model of seabird prey. Future winter distributions were predicted to shift with climate change, especially when global warming exceed 2°C under a “no mitigation” scenario, modifying seabird wintering hotspots in the North Atlantic Ocean. Our findings suggest that meeting Paris agreement objectives will limit changes in seabird selected habitat location and size in the North Atlantic Ocean during the 21st century. We thereby provide key information for the design of adaptive marine-protected areas in a changing ocea

Meeting Paris agreement objectives will temper seabird winter distribution shifts in the North Atlantic Ocean

International audienceWe explored the implications of reaching the Paris Agreement Objective of limiting global warming to <2°C for the future winter distribution of the North Atlantic sea-bird community. We predicted and quantified current and future winter habitats of five North Atlantic Ocean seabird species (Alle alle, Fratercula arctica, Uria aalge, Uria lomvia and Rissa tridactyla) using tracking data for ~1500 individuals through resource selection functions based on mechanistic modeling of seabird energy requirements, and a dynamic bioclimate envelope model of seabird prey. Future winter distributions were predicted to shift with climate change, especially when global warming exceed 2°C under a “no mitigation” scenario, modifying seabird wintering hotspots in the North Atlantic Ocean. Our findings suggest that meeting Paris agreement objectives will limit changes in seabird selected habitat location and size in the North Atlantic Ocean during the 21st century. We thereby provide key information for the design of adaptive marine-protected areas in a changing ocea

Climate variability over the last 35,000 years recorded in marine and terrestrial archives in the Australian region: An OZ-INTIMATE compilation

The Australian region spans some 60° of latitude and 50° of longitude and displays considerable regional climate variability both today and during the Late Quaternary. A synthesis of marine and terrestrial climate records, combining findings from the Southern Ocean, temperate, tropical and arid zones, identifies a complex response of climate proxies to a background of changing boundary conditions over the last 35,000 years. Climate drivers include the seasonal timing of insolation, greenhouse gas content of the atmosphere, sea level rise and ocean and atmospheric circulation changes. Our compilation finds few climatic events that could be used to construct a climate event stratigraphy for the entire region, limiting the usefulness of this approach. Instead we have taken a spatial approach, looking to discern the patterns of change across the continent. The data identify the clearest and most synchronous climatic response at the time of the Last Glacial Maximum (LGM) (21 ± 3 ka), with unambiguous cooling recorded in the ocean, and evidence of glaciation in the highlands of tropical New Guinea, southeast Australia and Tasmania. Many terrestrial records suggest drier conditions, but with the timing of inferred snowmelt, and changes to the rainfall/runoff relationships, driving higher river discharge at the LGM. In contrast, the deglaciation is a time of considerable south-east to north-west variation across the region. Warming was underway in all regions by 17 ka. Post-glacial sea level rise and its associated regional impacts have played an important role in determining the magnitude and timing of climate response in the north-west of the continent in contrast to the southern latitudes. No evidence for cooling during the Younger Dryas chronozone is evident in the region, but the Antarctic cold reversal clearly occurs south of Australia. The Holocene period is a time of considerable climate variability associated with an intense monsoon in the tropics early in the Holocene, giving way to a weakened monsoon and an increasingly El Niño-dominated ENSO to the present. The influence of ENSO is evident throughout the southeast of Australia, but not the southwest. This climate history provides a template from which to assess the regionality of climate events across Australia and make comparisons beyond our region.14 page(s