SASSCAL WeatherNet: present state, challenges, and achievements of the regional climatic observation network and database

Automatic weather stations (AWSs) serve a number of goals in the SASSCAL context and beyond. A suffi cient cover and density in geographical space is needed to record spatial climatic variability and to feed climate models and forecast services. In addition, research projects using an ecosystem approach require robust information on local weather. In response to these goals and under consideration of the low density of climate stations in the SASSCAL region (Angola, Botswana, Namibia, South Africa, and Zambia), the establishment of a network of weather stations was initiated in 2009?2010. Th e SASSCAL network, meanwhile, includes 154 AWSs and has achieved a reputation for providing unprecedented progress in terms of coverage and access to climatic data for the SASSCAL region. Th is paper presents the most important strategic and technical steps, from setting up the station network for data transmission and data quality controls to the Internet publication of the SASSCAL WeatherNet climatic data. As estações meteorológicas automáticas (AWSs) servem uma série de fi ns no contexto do SASSCAL e mais além. São necessárias uma cobertura e densidade sufi cientes no espaço geográfi co para registar a variabilidade espacial climática e alimentar os modelos climáticos e serviços de previsão. Além disso, projectos de investigação que usam uma abordagem ecossistémica requerem informação robusta sobre as condições meteorológicas locais. Em resposta a estes objectivos, e considerando a baixa densidade de estações climáticas na região do SASSCAL (Angola, Botswana, Namíbia, África do Sul e Zâmbia), foi iniciado o estabelecimento de uma rede de estações meteorológicas em 2009-2010. Entretanto, a rede do SASSCAL inclui 154 AWSs e alcançou uma reputação de proporcionar progresso sem precedentes em termos de cobertura e acesso a dados climáticos para a região do SASSCAL. Este artigo apresenta as etapas estratégicas e técnicas mais importantes, desde a criação da rede de estações para a transmissão e controlo da qualidade dos dados até à publicação online dos dados climáticos da SASSCAL WeatherNet

Discovery of Clinical Candidate 1‑{[(2<i>S</i>,3<i>S</i>,4<i>S</i>)‑3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin‑1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design

Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound <b>40</b>). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration

A highly virulent variant of HIV-1 circulating in the Netherlands

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV-CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences-is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence