Coevolution of language and tools in the human brain: An ALE meta-analysis of neural activation during syntactic processing and tool use.

Language and complex tool use are often cited as behaviors unique to humans and may be evolutionarily linked owing to the underlying cognitive processes they have in common. We executed a quantitative activation likelihood estimation (ALE) meta-analysis (GingerALE 2.3) on published, whole-brain neuroimaging studies to identify areas associated with syntactic processing and/or tool use in humans. Significant clusters related to syntactic processing were identified in areas known to be related to language production and comprehension, including bilateral Broca's area in the inferior frontal gyrus. Tool use activation clusters were all in the left hemisphere and included the primary motor cortex and premotor cortex, in addition to other areas involved with sensorimotor transformation. Activation shared by syntactic processing and tool use was only significant at one cluster, located in the pars opercularis of the left inferior frontal gyrus. This minimal overlap between syntactic processing and tool use activation from our meta-analysis of neuroimaging studies indicates that there is not a widespread common neural network between the two. Broca's area may serve as an important hub that was initially recruited in early human evolution in the context of simple tool use, but was eventually co-opted for linguistic purposes, including the sequential and hierarchical ordering processes that characterize syntax. In the future, meta-analyses of additional components of language may allow for a more comprehensive examination of the functional networks that underlie the coevolution of human language and complex tool use.

Thymosin ß4 and the anti-fibrotic switch

Wound healing involves a rapid response to the injury by circulating cells, followed by inflammation with an influx of inflammatory cells that release various factors. Soon after, cellular proliferation begins to replace the damaged cells and extracellular matrix, and then tissue remodeling restores normal tissue function. Various factors can lead to pathological wound healing when excessive and irreversible connective tissue/extracellular matrix deposition occurs, resulting in fibrosis. The process is initiated when immune cells, such as macrophages, release soluble factors that stimulate fibroblasts. TGFß is the most well-characterized macrophage derived pro-fibrotic mediator. Other soluble mediators of fibrosis include connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), and interleukin 10 (IL-10). Thymosin ß4 (Tß4) has shown therapeutic benefit in preventing fibrosis/scarring in various animal models of fibrosis/scarring. The mechanism of action of Tß4 appears related, in part, to a reduction in the inflammatory response, including a reduction in macrophage infiltration, decreased levels of TGFß and IL-10, and reduced CTGF activation, resulting in both prevention of fibroblast conversion to myofibroblasts and production of normally aligned collagen fibers. The amino N-terminal end of Tß4, SDKP (serine-aspartate-lysine-proline), appears to contain the majority of anti-fibrotic activity and has shown excellent efficacy in many animal models of fibrosis, including liver, lung, heart, and kidney fibrosis. Ac-SDKP not only prevents fibrosis but can reverse fibrosis. Unanswered questions and future directions will be presented with regard to therapeutic uses alone and in combination with already approved drugs for fibrosis.

The novel estrogen receptor modulator STX attenuates Amyloid-ß neurotoxicity in the 5XFAD mouse model of Alzheimer's disease.

Based on previous evidence that the non-steroidal estrogen receptor modulator STX mitigates the effects of neurotoxic Amyloid-ß (Aß) in vitro, we have evaluated its neuroprotective benefits in a mouse model of Alzheimer's disease. Cohorts of 5XFAD mice, which begin to accumulate cerebral Aß at two months of age, were treated with orally-administered STX starting at 6 months of age for two months. After behavioral testing to evaluate cognitive function, biochemical and immunohistochemical assays were used to analyze key markers of mitochondrial function and synaptic integrity. Oral STX treatment attenuated Aß-associated mitochondrial toxicity and synaptic toxicity in the brain, as previously documented in cultured neurons. STX also moderately improved spatial memory in 5XFAD mice. In addition, STX reduced markers for reactive astrocytosis and microgliosis surrounding amyloid plaques, and also unexpectedly reduced overall levels of cerebral Aß in the brain. The neuroprotective effects of STX were more robust in females than in males. These results suggest that STX may have therapeutic potential in Alzheimer's Disease.