Advances in AIDS Chemotherapy: The Asymmetric Synthesis of CRIXIVAN®

The discovery and development of an efficient, practical asymmetric synthesis of the HIV Protease inhibitor CRIXIVAN® is described. Particular emphasis is placed on the selective installation of each of the five stereogenic centers as well as design strategies associated with the preparation of a complex pharmaceutical agent needed in multiton quantities

Tropospheric Ozone Assessment Report: assessment of global-scale model performance for global and regional ozone distributions, variability, and trends

The goal of the Tropospheric Ozone Assessment Report (TOAR) is to provide the research community with an up-to-date scientific assessment of tropospheric ozone, from the surface to the tropopause. While a suite of observations provides significant information on the spatial and temporal distribution of tropospheric ozone, observational gaps make it necessary to use global atmospheric chemistry models to synthesize our understanding of the processes and variables that control tropospheric ozone abundance and its variability. Models facilitate the interpretation of the observations and allow us to make projections of future tropospheric ozone and trace gas distributions for different anthropogenic or natural perturbations. This paper assesses the skill of current-generation global atmospheric chemistry models in simulating the observed present-day tropospheric ozone distribution, variability, and trends. Drawing upon the results of recent international multi-model intercomparisons and using a range of model evaluation techniques, we demonstrate that global chemistry models are broadly skillful in capturing the spatio-temporal variations of tropospheric ozone over the seasonal cycle, for extreme pollution episodes, and changes over interannual to decadal periods. However, models are consistently biased high in the northern hemisphere and biased low in the southern hemisphere, throughout the depth of the troposphere, and are unable to replicate particular metrics that define the longer term trends in tropospheric ozone as derived from some background sites. When the models compare unfavorably against observations, we discuss the potential causes of model biases and propose directions for future developments, including improved evaluations that may be able to better diagnose the root cause of the model-observation disparity. Overall, model results should be approached critically, including determining whether the model performance is acceptable for the problem being addressed, whether biases can be tolerated or corrected, whether the model is appropriately constituted, and whether there is a way to satisfactorily quantify the uncertainty

Medial collateral ligament injuries of the knee: current treatment concepts

The medial collateral ligament is one of the most commonly injured ligaments of the knee. Most injuries result from a valgus force on the knee. The increased participation in football, ice hockey, and skiing has all contributed to the increased frequency of MCL injuries. Prophylactic knee bracing in contact sports may prevent injury; however, performance may suffer. The majority of patients who sustain an MCL injury will achieve their pre-injury activity level with non-operative treatment alone; however, those with combined ligamentous injuries may require acute operative care. Accurate characterization of each aspect of the injury will help to determine the optimum treatment plan

Corporate Social Responsibility/Sustainability Reporting Among the Fortune Global 250: Greenwashing or Green Supply Chain?

The sustainability reporting efforts of MNCs who are members of the Fortune Global 250 (FG250) was investigated. The focus was on sustainability reporting by MNCs of supply chain impacts. The reporting of FG250 MNCs was examined to determine if greenwashing was occurring or whether MNCs had committed to operating a green supply chain. A mixed methodology was used consisting of quantitative analysis of twenty-five MNC CSR/sustainability reports which were randomly selected from the FG250 listing. Qualitative analysis using content analysis was also conducted on the reports. Both methodologies concentrated on the sustainability reporting of the selected MNCs in regard to their supply chain. Findings were mixed as there were great variations among the MNCs in their level of sustainability reporting about their supply chains. Some MNCs did not report on the activities of their supply chain at all (20%), the majority of the MNCs reported on their supply chain impacts at the value and goal level (48%), while the rest reported at the management approach level (32%). A majority of the sampled MNCs could be accused of greenwashing due to the lack of detailed quantitative information provided by the MNCs on the environmental impacts of their supply chai

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe