Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models*

Although Tau accumulation is a feature of several neurodegenerative conditions, treatment options for these conditions are nonexistent. Targeting Tau kinases represents a potential therapeutic approach. Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC(50) values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay. Given the contribution of both CDK5/p25 and GSK3β to Tau phosphorylation, effective treatment of tauopathies may require dual kinase targeting

Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing

Abstract Recombinant adeno-associated viral (AAV) vectors are a promising gene delivery platform, but ongoing clinical trials continue to highlight a relatively narrow therapeutic window. Effective clinical translation is confounded, at least in part, by differences in AAV biology across animal species. Here, we tackle this challenge by sequentially evolving AAV capsid libraries in mice, pigs and macaques. We discover a highly potent, cross-species compatible variant (AAV.cc47) that shows improved attributes benchmarked against AAV serotype 9 as evidenced by robust reporter and therapeutic gene expression, Cre recombination and CRISPR genome editing in normal and diseased mouse models. Enhanced transduction efficiency of AAV.cc47 vectors is further corroborated in macaques and pigs, providing a strong rationale for potential clinical translation into human gene therapies. We envision that ccAAV vectors may not only improve predictive modeling in preclinical studies, but also clinical translatability by broadening the therapeutic window of AAV based gene therapies

Potential use of sugar cane bagasse ash as sand replacement for durable concrete

The increasing urban development, led by concrete, requires a higher availability of materials and energy, and it will be responsible for a high waste generation. To face the exploitation of natural resources, the use of fossil fuels and the reduction of waste disposal, new environmental-friendly strategies emerge accomplishing the circular economy principles. In this research, the use of poor reactive agro-industrial ashes as sand replacement in cement-based materials is investigated. Poor reactive sugar cane bagasse ashes (fly and bottom ash -SCB FA and SCB BA, respectively) from a power plant in Dominican Republic have been used in substitution rates of 10%, 20% and 30% of weight of sand. Physico-chemical characteristics of ashes are investigated and correlated to the performance of the bio-concretes. SCB FA showed being an enhancer of durability-related properties of the concrete even with high content of silica in form of quartz, due to the capability of modifying the microstructure of the concrete and an additional binding capacity of chlorides ions. Durability-related tests (open porosity test, electrical resistivity test, capillary absorption test and chloride migration test) have been conducted at 28, 60, 90 and 240days. Direct correlations exist when compared chloride migration resistance against porosity and electrical resistivity in concretes with SCB FA, not so for capillary absorption. This demonstrates the inadequacy of establishing conclusions about durability performance of bio-concretes based on durability tests when run independently. The use of agro-industrial ashes as substitutes of natural aggregates not only reduces the consumption of natural sand but can deliver bio-concretes with potential benefits in terms of compressive strength and durability

Candida auris : An emerging multidrug-resistant pathogen

Candida aurisis an emerging multidrug-resistant pathogen that can be difficult to identify using traditional biochemical methods. C. auris is capable of causing invasive fungal infections, particularly among hospitalized patients with significant medical comorbidities. Echinocandins are the empiric drugs of choice for C. auris, although not all isolates are susceptible and resistance may develop on therapy. Nosocomial C. auris outbreaks have been reported in a number of countries and aggressive infection control measures are paramount to stopping transmission