Axonal Fiber Terminations Concentrate on Gyri

Convoluted cortical folding and neuronal wiring are 2 prominent attributes of the mammalian brain. However, the macroscale intrinsic relationship between these 2 general cross-species attributes, as well as the underlying principles that sculpt the architecture of the cerebral cortex, remains unclear. Here, we show that the axonal fibers connected to gyri are significantly denser than those connected to sulci. In human, chimpanzee, and macaque brains, a dominant fraction of axonal fibers were found to be connected to the gyri. This finding has been replicated in a range of mammalian brains via diffusion tensor imaging and high–angular resolution diffusion imaging. These results may have shed some lights on fundamental mechanisms for development and organization of the cerebral cortex, suggesting that axonal pushing is a mechanism of cortical folding

Genetic mapping and evolutionary analysis of human-expanded cognitive networks

Cognitive brain networks such as the default-mode network (DMN), frontoparietal network, and salience network, are key functional networks of the human brain. Here we show that the rapid evolutionary cortical expansion of cognitive networks in the human brain, and most pronounced the DMN, runs parallel with high expression of human-accelerated genes (HAR genes). Using comparative transcriptomics analysis, we present that HAR genes are differentially more expressed in higher-order cognitive networks in humans compared to chimpanzees and macaques and that genes with high expression in the DMN are involved in synapse and dendrite formation. Moreover, HAR and DMN genes show significant associations with individual variations in DMN functional activity, intelligence, sociability, and mental conditions such as schizophrenia and autism. Our results suggest that the expansion of higher-order functional networks subserving increasing cognitive properties has been an important locus of genetic changes in recent human brain evolution

Chimpanzee (Pan troglodytes) Precentral Corticospinal System Asymmetry and Handedness: A Diffusion Magnetic Resonance Imaging Study

Most humans are right handed, and most humans exhibit left-right asymmetries of the precentral corticospinal system. Recent studies indicate that chimpanzees also show a population-level right-handed bias, although it is less strong than in humans.We used in vivo diffusion-weighted and T1-weighted magnetic resonance imaging (MRI) to study the relationship between the corticospinal tract (CST) and handedness in 36 adult female chimpanzees. Chimpanzees exhibited a hemispheric bias in fractional anisotropy (FA, left>right) and mean diffusivity (MD, right>left) of the CST, and the left CST was centered more posteriorly than the right. Handedness correlated with central sulcus depth, but not with FA or MD.These anatomical results are qualitatively similar to those reported in humans, despite the differences in handedness. The existence of a left>right FA, right>left MD bias in the corticospinal tract that does not correlate with handedness, a result also reported in some human studies, suggests that at least some of the structural asymmetries of the corticospinal system are not exclusively related to laterality of hand preference

Cross-species cortical alignment identifies different types of anatomical reorganization in the primate temporal lobe

Evolutionary adaptations of temporo-parietal cortex are considered to be a critical specialization of the human brain. Cortical adaptations, however, can affect different aspects of brain architecture, including local expansion of the cortical sheet or changes in connectivity between cortical areas. We distinguish different types of changes in brain architecture using a computational neuroanatomy approach. We investigate the extent to which between-species alignment, based on cortical myelin, can predict changes in connectivity patterns across macaque, chimpanzee, and human. We show that expansion and relocation of brain areas can predict terminations of several white matter tracts in temporo-parietal cortex, including the middle and superior longitudinal fasciculus, but not the arcuate fasciculus. This demonstrates that the arcuate fasciculus underwent additional evolutionary modifications affecting the temporal lobe connectivity pattern. This approach can flexibly be extended to include other features of cortical organization and other species, allowing direct tests of comparative hypotheses of brain organization

Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity.

Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with ERD-3111 being the most promising compound. ERD-3111 exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability in mice, rats, and dogs. Oral administration of ERD-3111 effectively reduces the levels of wild-type and mutated ERα proteins in tumor tissues. ERD-3111 achieves tumor regression or complete tumor growth inhibition in the parental MCF-7 xenograft model with wild-type ER and two clinically relevant ESR1 mutated models in mice. ERD-3111 is a promising ERα degrader for further extensive evaluations for the treatment of ER+ breast cancer.http://deepblue.lib.umich.edu/bitstream/2027.42/177662/2/Discovery of ERD-3111.pdfPublished onlin

Structure-Based Discovery of 4‑(6-Methoxy-2-methyl-4-(quinolin-4-yl)‑9<i>H</i>‑pyrimido[4,5‑<i>b</i>]­indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor

We have designed and synthesized 9<i>H</i>-pyrimido­[4,5-<i>b</i>]­indole-containing compounds to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9<i>H</i>-pyrimido­[4,5-<i>b</i>]­indole core, we identified a series of small molecules showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9<i>H</i>-pyrimido­[4,5-<i>b</i>]­indol-7-yl)-3,5-dimethyl­isoxazole (<b>31</b>) has excellent microsomal stability and good oral pharmacokinetics in rats and mice. Orally administered, <b>31</b> achieves significant antitumor activity in the MV4;11 leukemia and MDA-MB-231 triple-negative breast cancer xenograft models in mice. Determination of the cocrystal structure of <b>31</b> with BRD4 BD2 provides a structural basis for its high binding affinity to BET proteins. Testing its binding affinities against other bromodomain-containing proteins shows that <b>31</b> is a highly selective inhibitor of BET proteins. Our data show that <b>31</b> is a potent, selective, and orally active BET inhibitor

Structure-Based Discovery of 4‑(6-Methoxy-2-methyl-4-(quinolin-4-yl)‑9<i>H</i>‑pyrimido[4,5‑<i>b</i>]­indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor

We have designed and synthesized 9<i>H</i>-pyrimido­[4,5-<i>b</i>]­indole-containing compounds to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9<i>H</i>-pyrimido­[4,5-<i>b</i>]­indole core, we identified a series of small molecules showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9<i>H</i>-pyrimido­[4,5-<i>b</i>]­indol-7-yl)-3,5-dimethyl­isoxazole (<b>31</b>) has excellent microsomal stability and good oral pharmacokinetics in rats and mice. Orally administered, <b>31</b> achieves significant antitumor activity in the MV4;11 leukemia and MDA-MB-231 triple-negative breast cancer xenograft models in mice. Determination of the cocrystal structure of <b>31</b> with BRD4 BD2 provides a structural basis for its high binding affinity to BET proteins. Testing its binding affinities against other bromodomain-containing proteins shows that <b>31</b> is a highly selective inhibitor of BET proteins. Our data show that <b>31</b> is a potent, selective, and orally active BET inhibitor

Axonal Fiber Terminations Concentrate on Gyri

Convoluted cortical folding and neuronal wiring are 2 prominent attributes of the mammalian brain. However, the macroscale intrinsic relationship between these 2 general cross-species attributes, as well as the underlying principles that sculpt the architecture of the cerebral cortex, remains unclear. Here, we show that the axonal fibers connected to gyri are significantly denser than those connected to sulci. In human, chimpanzee, and macaque brains, a dominant fraction of axonal fibers were found to be connected to the gyri. This finding has been replicated in a range of mammalian brains via diffusion tensor imaging and high–angular resolution diffusion imaging. These results may have shed some lights on fundamental mechanisms for development and organization of the cerebral cortex, suggesting that axonal pushing is a mechanism of cortical folding

Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor

We report the structure-based discovery of CF53 (<b>28</b>) as a highly potent and orally active inhibitor of bromodomain and extra-terminal (BET) proteins. By the incorporation of a NH-pyrazole group into the 9H-pyrimido­[4,5-<i>b</i>]­indole core, we identified a series of compounds that bind to BRD4 BD1 protein with <i>K</i>_i values of <1 nM and achieve low nanomolar potencies in the cell growth inhibition of leukemia and breast cancer cells. The most-promising compound, CF53, possesses excellent oral pharmacokinetic properties and achieves significant antitumor activity in both triple-negative breast cancer and acute leukemia xenograft models in mice. Determination of the co-crystal structure of CF53 with the BRD4 BD1 protein provides a structural basis for its high binding affinity to BET proteins. CF53 is very selective over non-BET bromodomain-containing proteins. These data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclinical development