Finding good drug leads de novo from large chemical libraries, real or virtual, is not an easy task. High-throughput screening is often plagued by low hit rates and many leads that are toxic or exhibit poor bioavailability. Exploiting the secondary activity of marketed drugs, on the other hand, may help in generating drug leads that can be optimized for the observed side-effect target, while maintaining acceptable bioavailability and toxicity profiles. Here, we describe an efficient computational methodology to discover leads to a protein target from safe marketed drugs. We applied an in silico ''drug repurposing'' procedure for identification of nonsteroidal antagonists against the human androgen receptor (AR), using multiple predicted models of an antagonist-bound receptor. The library of marketed oral drugs was then docked into the best-performing models, and the 11 selected compounds with the highest docking score were tested in vitro for AR binding and antagonism of dihydrotestosterone-induced AR transactivation. The phenothiazine derivatives acetophenazine, fluphenazine, and periciazine, used clinically as antipsychotic drugs, were identified as weak AR antagonists. This in vitro biological activity correlated well with endocrine side effects observed in individuals taking these medications. Further computational optimization of phenothiazines, combined with in vitro screening, led to the identification of a nonsteroidal antiandrogen with improved AR antagonism and marked reduction in affinity for dopaminergic and serotonergic receptors that are the primary target of phenothiazine antipsychotics.androgen receptor ͉ drug design ͉ prostate cancer C urrent approaches for discovery of novel chemical leads against a molecular target rely heavily on high-throughput screening (HTS) and to a lesser extent on virtual ligand screening (VLS) techniques. HTS has provided rapid lead identification for numerous drug targets (1-8); however, HTS also has major drawbacks, including a significant level of false positives and false negatives and low hit rates for many targets (9). Successful leads from HTS can also suffer from poor bioavailability and unwanted toxicity profiles of compounds. These problems result partially from the nature of the chemical libraries used for HTS. Furthermore, because the pharmacological properties of most compound libraries are largely unknown, there is an additional high risk that optimization of hits identified with HTS will not be sufficient for their evolution into real drugs.In contrast, retrospective analysis of marketed drugs reveals that their physicochemical and structural properties are clustered around preferred values and scaffolds (10). In addition, some chemical motifs are associated with high biological activity and often confer activity against more than one target/receptor (11-16). These motifs have been referred to as ''privileged structures'' (11). These observations lead to an assumption that the chemical space of potential drugs is limited. Consequently, currently marketed...
Minimizing the adverse consequences of sea-level change presents a key societal challenge. New modelling is necessary to examine the implications of global policy decisions that determine future greenhouse gas emissions and local policies around coastal risk that influence where and how we live.
The objective of this study was to systematically assess the bifidogenic effect of three commonly used prebiotic products using in vitro cultures of infant fecal samples. Fresh stool samples collected from six term infants, each exclusively fed human milk (n ؍ 3) or infant formula (n ؍ 3), at 28 days of age were used as inocula. The following prebiotic products were added at concentrations applicable to infant formula: Vivinal IN). The growth of total bacteria, Bifidobacterium, Bacteroides, Bifidobacterium longum, and Escherichia coli was quantified using specific quantitative PCR (qPCR). Bifidobacterium was also enumerated on selective Beerens agar plates, with representative colonies identified by sequencing of their 16S rRNA genes. Volatile fatty acids (VFA) and pH in the cultures were also determined. Irrespective of the feeding methods, the GOS product, either alone or in combination with Beneo HP, resulted in substantially higher growth of total bifidobacteria, and much of this growth was attributed to growth of B. longum. Beneo Synergy 1 also increased the abundance of total bifidobacteria and B. longum. Corresponding to the increases in these two bacterial groups, acetic acid concentrations were higher, while there was a trend of lower E. coli levels and pH. The lower pH and higher acetic acid concentration might be directly responsible for the lower E. coli population. At the concentrations studied, the GOS product was more bifidogenic and potent in inhibiting E. coli than the other products tested. These results suggest that supplementation of infant formula with GOS may increase intestinal bifidobacteria and benefit infant health. It is generally accepted that human milk-fed infants and formulafed infants can have different gut microbiomes. The demonstrated differences in the gut microbiomes include a greater abundance of Bifidobacterium and a lower abundance of clostridia and enteric bacteria in human milk-fed infants than in formula-fed infants (1, 2). Such differences in gut microbiomes are believed to contribute to the benefits associated with human milk feeding, such as protection against infection and allergy (3-5), as well as long-term health and neurodevelopment (5-7). Human milk contains high levels of more than 200 structures of nondigestible oligosaccharides (8, 9), whereas cow milk contains virtually no oligosaccharides (10). Therefore, without supplementation, oligosaccharides are nearly absent in cow milk-based infant formulas. The difference in nondigestible oligosaccharides between human milk and infant formula is believed to be a main reason for the observed differences in intestinal microbiomes between infants receiving these two types of feeding (9, 11).Nondigestible oligosaccharides can be added to infant formula as prebiotics to increase its oligosaccharide content (12). However, the prebiotics commercially available for inclusion in infant formula are limited in variety, and the nondigestible oligosaccharides contained in most prebiotic products are much simpler in structu...
Visual attention plays an essential role in selecting task-relevant and ignoring task-irrelevant information, for both object features and their locations. In the real world, multiple objects with multiple features are often simultaneously present in a scene. When spatial attention selects an object, how are the task-relevant and task-irrelevant features represented in the brain? Previous literature has shown conflicting results on whether and how irrelevant features are represented in visual cortex. In an fMRI task, we used a modified inverted encoding model (IEM, e.g., Sprague & Serences, 2015) to test whether we can reconstruct the task-relevant and task-irrelevant features of spatially attended objects in a multi- feature (color + orientation), multi-item display. Subjects were briefly shown an array of three colored, oriented gratings. Subjects were instructed as to which feature (color or orientation) was relevant before each block, and on each trial were asked to report the task-relevant feature of the object that appeared at a spatially pre-cued location, using a continuous color or orientation wheel. By applying the IEM, we achieved reliable feature reconstructions for the task-relevant features of the attended object from visual ROIs (V1 and V4v) and Intraparietal sulcus. Preliminary searchlight analyses showed that task-irrelevant features of attended objects could be reconstructed from activity in some intraparietal areas, but the reconstructions were much weaker and less reliable compared with task-relevant features. These results suggest that both relevant and irrelevant features may be represented in visual and parietal cortex but in different forms. Our method provides potential tools to noninvasively measure unattended feature representations and probe the extent to which spatial attention acts as a "glue" to bind task-relevant and task-irrelevant features.
The common human epilepsies are associated with distinct patterns of reduced cortical thickness, detectable on neuroimaging, with important clinical consequences. To explore underlying mechanisms, we layered MRI-based cortical structural maps from a large-scale epilepsy neuroimaging study onto highly spatially-resolved human brain gene expression data, identifying >2,500 genes overexpressed in regions of reduced cortical thickness, compared to relatively-protected regions. The resulting set of differentially-expressed genes shows enrichment for microglial markers, and in particular, activated microglial states.Parallel analyses of cell-specific eQTLs show enrichment in human genetic signatures of epilepsy severity, but not epilepsy causation. Post mortem brain tissue from humans with epilepsy shows excess activated microglia. In an experimental model, depletion of activated microglia prevents cortical thinning, but not the development of chronic seizures. These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.
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