Tamoxifen, the gold standard drug for endocrine therapy for breast cancer, modulates the phosphorylation status of the TAU protein in Alzheimer’s disease by inhibiting CDK5 kinase activity. Its binding to p25 prevents CDK5/p25 complexation and hence a decrease of CDK5 activity. In breast tumors, this complex is involved in the proliferation and survival of cancer cells, as well as in the disease’s prognosis. Still, the molecular stability of the CDK5/p25 complex following tamoxifen exposure in this cancer type has not yet been clearly deciphered. Here, we report the functional characterization of CDK5 and its p25 regulatory subunit in the absence and presence of tamoxifen. In addition, two novel inhibitors of the kinase activity of the CDK5/p25 complex are identified, both of which would reduce the risk of recurrence of estrogen receptor-positive (ER+) breast cancers and prevent drawbacks induced by tamoxifen exposure. Accordingly, 6His-CDK5 and 6His-p25 have been expressed and purified. Fluorescence anisotropy measurements have been used to assess that the two proteins do form an active complex, and thermodynamic parameters of their interaction were measured. It was also confirmed that tamoxifen directly binds to p25 and inhibits CDK5 kinase activity. Similar observations were obtained using 4-hydroxytamoxifen, an active metabolized form of tamoxifen. Two novel compounds have been identified here that harbor a benzofuran moiety and were shown to target directly p25, and their bindings resulted in decreased CDK5 kinase activity. This encouraging alternative opens the way to the ensuing chemical optimization of this scaffold. It also promises a more specific therapeutic approach that may both tackle the pathological signaling in breast cancer and provide a potential new drug for Alzheimer’s disease.

Maternal mortality is a major global health challenge. Although progress has been made globally in reducing maternal deaths, measurement remains challenging given the many causes and frequent underreporting of maternal deaths. We developed the Global Maternal Health microsimulation model for women in 200 countries and territories, accounting for individual fertility preferences and clinical histories. Demographic, epidemiologic, clinical and health system data were synthesized from multiple sources, including the medical literature, Civil Registration Vital Statistics systems and Demographic and Health Survey data. We calibrated the model to empirical data from 1990 to 2015 and assessed the predictive accuracy of our model using indicators from 2016 to 2020. We projected maternal health indicators from 1990 to 2050 for each country and estimate that between 1990 and 2020 annual global maternal deaths declined by over 40% from 587,500 (95% uncertainty intervals (UI) 520,600-714,000) to 337,600 (95% UI 307,900-364,100), and are projected to decrease to 327,400 (95% UI 287,800-360,700) in 2030 and 320,200 (95% UI 267,100-374,600) in 2050. The global maternal mortality ratio is projected to decline to 167 (95% UI 142-188) in 2030, with 58 countries above 140, suggesting that on current trends, maternal mortality Sustainable Development Goal targets are unlikely to be met. Building on the development of our structural model, future research can identify context-specific policy interventions that could allow countries to accelerate reductions in maternal deaths.

Climate change is considered the greatest threat to global health. Greenhouse gases as well as global surface temperatures have increased causing more frequent and intense heat and cold waves, wildfires, floods, drought, altered rainfall patterns, hurricanes, thunderstorms, air pollution, and windstorms. These extreme weather events have direct and indirect effects on the immune system, leading to allergic disease due to exposure to pollen, molds, and other environmental pollutants. In this review, we will focus on immune mechanisms associated with allergy and asthma-related health risks induced by climate change events. We will review current understanding of the molecular and cellular mechanisms by which the changing environment mediates these effects.

The Sustainable Development Goals include a target to reduce the global maternal mortality ratio (MMR) to less than 70 maternal deaths per 100,000 live births by 2030, with no individual country exceeding 140. However, on current trends the goals are unlikely to be met. We used the empirically calibrated Global Maternal Health microsimulation model, which simulates individual women in 200 countries and territories to evaluate the impact of different interventions and strategies from 2022 to 2030. Although individual interventions yielded fairly small reductions in maternal mortality, integrated strategies were more effective. A strategy to simultaneously increase facility births, improve the availability of clinical services and quality of care at facilities, and improve linkages to care would yield a projected global MMR of 72 (95% uncertainty interval (UI) = 58-87) in 2030. A comprehensive strategy adding family planning and community-based interventions would have an even larger impact, with a projected MMR of 58 (95% UI = 46-70). Although integrated strategies consisting of multiple interventions will probably be needed to achieve substantial reductions in maternal mortality, the relative priority of different interventions varies by setting. Our regional and country-level estimates can help guide priority setting in specific contexts to accelerate improvements in maternal health.

The American Heart Association and American Stroke Association (AHA/ASA) endorsed 15 process measures for acute ischemic stroke (AIS) to improve the quality of care. Identifying the highest-value measures could reduce the administrative burden of quality measure adoption while retaining much of the value of quality improvement.

Given the increasing prevalence of wildfires worldwide, understanding the effects of wildfire air pollutants on human health-particularly in specific immunologic pathways-is crucial. Exposure to air pollutants is associated with cardiorespiratory disease; however, immune and epithelial barrier alterations require further investigation.