The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.

Management, nutrition, production, and genetics are the main reasons for the decline in fertility in the modern dairy cow. Selection for the single trait of milk production with little consideration for traits associated with reproduction in the modern dairy cow has produced an antagonistic relationship between milk yield and reproductive performance. The outcome is a multi-factorial syndrome of subfertility during lactation; thus, to achieve a better understanding and derive a solution, it is necessary to integrate a range of disciplines, including genetics, nutrition, immunology, molecular biology, endocrinology, metabolic and reproductive physiology, and animal welfare. The common theme underlying the process is a link between nutritional and metabolic inputs that support complex interactions between the gonadotropic and somatotropic axes. Multiple hormonal and metabolic signals from the liver, pancreas, muscle, and adipose tissues act on brain centers regulating feed intake, energy balance, and metabolism. Among these signals, glucose, fatty acids, insulin-like growth factor-I, insulin, growth hormone, ghrelin, leptin, and perhaps myostatin appear to play key roles. Many of these factors are affected by changes in the somatotropic axis that are a consequence of, or are needed to support, high milk production. Ovarian tissues also respond directly to metabolic inputs, with consequences for folliculogenesis, steroidogenesis, and the development of the oocyte and embryo. Little doubt exists that appropriate nutritional management before and after calving is essential for successful reproduction. Changes in body composition are related to the processes that lead to ovulation, estrus, and conception. However, better indicators of body composition and measures of critical metabolites are required to form precise nutritional management guidelines to optimize reproductive outcomes. The eventual solution to the reduction in fertility will be a new strategic direction for genetic selection that includes fertility-related traits. However, this will take time to be effective, so, in the short term, we need to gain a greater understanding of the interactions between nutrition and fertility to better manage the issue. A greater understanding of the phenomenon will also provide markers for more targeted genetic selection. This review highlights many fruitful directions for research, aimed at the development of strategies for nutritional management of reproduction in the high-producing subfertile dairy cow.

Multiple sclerosis (MS) is a chronic demyelinating disease in which it has only recently been suggested that damage to neuronal structures plays a key role. Here, we uncovered a link between the release of lipid breakdown products, found in the brain and cerebrospinal fluid (CSF) of MS patients as well as in experimental autoimmune encephalomyelitis, and neuronal damage mediated by microglial activation. The concentrations of the breakdown product 7-ketocholesterol detected in the CSF of MS patients were capable of inducing neuronal damage via the activation and migration of microglial cells in living brain tissue. 7-ketocholesterol rapidly entered the nucleus and activated poly(ADP-ribose)-polymerase (PARP)-1, followed by the expression of migration-regulating integrins CD11a and intercellular adhesion molecule 1. These findings reveal a novel mechanism linking demyelination and progressive neuronal damage, which might represent an underlying insidious process driving disease beyond a primary white matter phenomenon and rendering the microglial PARP-1 a possible antiinflammatory therapeutic target.