Genetic background modifies CNS‐mediated sensorimotor decline in the AD‐BXD mouse model of genetic diversity in Alzheimer's disease

Many patients with Alzheimer's dementia (AD) also exhibit noncognitive symptoms such as sensorimotor deficits, which can precede the hallmark cognitive deficits and significantly impact daily activities and an individual's ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and their relationship with cognitive decline remains poorly understood, due in part to a lack of translationally relevant animal models. To address this, we recently developed a novel model of genetic diversity in Alzheimer's disease, the AD‐BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD‐BXDs and the relationship to cognitive decline in these mice. We found that age‐ and AD‐related declines in coordination, balance and vestibular function vary significantly across the panel, indicating genetic background strongly influences the expressivity of the familial AD mutations used in the AD‐BXD panel and their impact on motor function. Although young males and females perform comparably regardless of genotype on narrow beam and inclined screen tasks, there were significant sex differences in aging‐ and AD‐related decline, with females exhibiting worse decline than males of the same age and transgene status. Finally, we found that AD motor decline is not correlated with cognitive decline, suggesting that sensorimotor deficits in AD may occur through distinct mechanisms. Overall, our results suggest that AD‐related sensorimotor decline is strongly dependent on background genetics and is independent of dementia and cognitive deficits, suggesting that effective therapeutics for the entire spectrum of AD symptoms will likely require interventions targeting each distinct domain involved in the disease.     

Human Intestinal Allografts Contain Functional Hematopoietic Stem and Progenitor Cells that Are Maintained by a Circulating Pool

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Pathway to domestic natural rubber production: a cradle-to-grave life cycle assessment of the first guayule automobile tire manufactured in the United States

The International Journal of Life Cycle Assessment - Guayule (Parthenium argentatum) is a perennial shrub that can be cultivated in the Southwestern US. It produces natural rubber that could be a...     

Unexpected equivalent potency of a constrained chromene enantiomeric pair rationalized by co-crystal structures in complex with estrogen receptor alpha

Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+?breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex with ERα revealed default (mimics the A-D rings of endogenous ligand estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for these enantiomers in the ERα degradation and MCF-7 anti-proliferation assays.     

Polymodal Nociception in Drosophila Requires Alternative Splicing of TrpA1

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