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Hypoxic-ischemic injury has been linked with increased risk for developing Alzheimer’s disease (AD). The underlying mechanism of this association is poorly understood. Here, we report distinct roles for hypoxia-inducible factor-1α (Hif-1α) in the regulation of BACE1 and γ-secretase activity, two proteases involved in the production of amyloid-beta (Aβ). We have demonstrated that Hif-1α upregulates both BACE1 and γ-secretase activity for Aβ production in brain hypoxia-induced either by cerebral hypoperfusion or breathing 10% O(2). Hif-1α binds to γ-secretase, which elevates the amount of active γ-secretase complex without affecting the level of individual subunits in hypoxic-ischemic mouse brains. Additionally, the expression of full length Hif-1α increases BACE1 and γ-secretase activity in primary neuronal culture, whereas a transcriptionally incompetent Hif-1α variant only activates γ-secretase. These findings indicate that Hif-1α transcriptionally upregulates BACE1 and nontranscriptionally activates γ-secretase for Aβ production in hypoxic-ischemic conditions. Consequently, Hif-1α-mediated Aβ production may be an adaptive response to hypoxic-ischemic injury, subsequently leading to increased risk for AD. Preventing the interaction of Hif-1α with γ-secretase may therefore be a promising therapeutic strategy for AD treatment.

Marine sponges are abundant filter-feeders in benthic ecosystems and many host copious microorganisms. Sponges and their symbionts have emerged as major players within marine biogeochemical cycles, facilitating uptake and release of carbon, nitrogen, and sulfur. Sponge holobionts' role in transforming dissolved carbon and nitrogen is well established; however, the same depth of understanding has not yet been extended to phosphorus. In this aquaria-based study

Acute limb ischemia of the upper extremity is less frequently encountered than in the lower extremity. The etiology is typically cardioembolic. Axillary-femoral stump syndrome is a rare complication associated with an occluded axillary-femoral bypass graft. We present the case of recurrent acute limb ischemia of the upper extremity whose embolic source was a retained cuff of a previously explanted axillary-profunda bypass graft. The patient failed anticoagulation after an initial embolectomy and after a recurrent embolism from the retained cuff, ultimately required cuff exclusion with a covered stent.

Impairments in the vesicular packaging of dopamine result in an accumulation of dopamine in the cytosol. Cytosolic dopamine is vulnerable to two metabolic processes - enzymatic catabolism and enzymatic- or auto-oxidation - that form toxic metabolites and generate reactive oxygen species. Alterations in the expression or activity of the vesicular monoamine transporter 2 (VMAT2), which transports monoamines such as dopamine from the cytosol into the synaptic vesicle, result in dysregulated dopamine packaging. Here, we developed a series of assays using the fluorescent false neurotransmitter 206 (FFN206) to visualize VMAT2-mediated vesicular packaging at baseline and following pharmacological and toxicological manipulations. As proof of principle, we observed a significant reduction in vesicular FFN206 packaging after treatment with the VMAT2 inhibitors reserpine (IC(50): 73.09 nM), tetrabenazine (IC(50): 30.41 nM), methamphetamine (IC(50): 2.399 μM), and methylphenidate (IC(50): 94.33 μM). We then applied the assay to investigate the consequences on vesicular packaging by environmental toxicants including the pesticides paraquat, rotenone, and chlorpyrifos, as well as the halogenated compounds unichlor, perfluorooctanesulfonic acid, Paroil, Aroclor 1260, and hexabromocyclododecane. Several of the environmental toxicants showed minor impairment of vesicular FFN206 loading, suggesting that the toxicants are weak VMAT2 inhibitors at the concentrations tested. The assay presented here can be applied to investigate the effect of additional pharmacological compounds and environmental toxicants on vesicular function, which will provide insight into how exposures to such factors are involved in the pathogenesis of monoaminergic diseases such as Parkinson’s disease, and the assay can be used to identify pharmacological agents that influence VMAT2 activity.

Efficient nutrient cycles mediated by symbiotic microorganisms with their hosts are vital to support the high productivity of coral reef ecosystems. In these ecosystems, marine sponges are important habitat-forming organisms in the benthic community and harbor abundant microbial symbionts. However, few studies have reviewed the critical microbially mediated nutrient cycling processes in marine sponges. To bridge this gap, in this review article, we summarize existing knowledge and recent advances in understanding microbially mediated carbon (C), nitrogen (N), phosphorus (P) and sulfur (S) cycles in sponges, propose a conceptual model that describes potential interactions and constraints in the major nutrient cycles, and suggest that shifting redox state induced by animal behavior like sponge pumping can exert great influence on the activities of symbiotic microbial communities. Constraints include the lack of knowledge on spatial and temporal variations and host behavior; more studies are needed in these areas. Sponge microbiomes may have a significant impact on the nutrient cycles in the world’s coral reef ecosystems.