[1] Two large-scale cross-hole pumping tests were conducted at depths of 191-226 m and 662-706 m in deep boreholes at the Mizunami Underground Research Laboratory (MIU) construction site in central Japan. During these two tests, induced groundwater responses were monitored at many observation intervals at various depths in different boreholes at the site. We analyze the two cross-hole pumping tests using transient hydraulic tomography (THT) based on an efficient sequential successive linear estimator to compute the hydraulic conductivity (K) and specific storage (S s ) tomograms, as well as their uncertainties in three dimensions. The equivalent K and S s estimates obtained using asymptotic analysis treating the medium to be homogeneous served as the mean parameter estimates for the 3-D stochastic inverse modeling effort. Results show several, distinct, high K and low S s zones that are continuous over hundreds of meters, which appear to delineate fault zones and their connectivity. The THT analysis of the tests also identified a low K zone which corresponds with a known fault zone trending NNW and has been found to compartmentalize groundwater flow at the site. These results corroborate well with observed water level records, available fault information, and coseismic groundwater level responses during several large earthquakes. The successful application of THT to cross-hole pumping tests conducted in fractured granite at this site suggests that THT is a promising approach to delineate large-scale K and S s heterogeneities, fracture connectivity, and to quantify uncertainty of the estimated fields.

Metabolic reprogramming has been widely recognized as a hallmark of malignancy. The uptake and metabolism of amino acids are aberrantly upregulated in many cancers that display addiction to particular amino acids. Amino acids facilitate the survival and proliferation of cancer cells under genotoxic, oxidative, and nutritional stress. Thus, targeting amino acid metabolism is becoming a potential therapeutic strategy for cancer patients. In this review, we will systematically summarize the recent progress of amino acid metabolism in malignancy and discuss their interconnection with mammalian target of rapamycin complex 1 (mTORC1) signaling, epigenetic modification, tumor growth and immunity, and ferroptosis. Finally, we will highlight the potential therapeutic applications.

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Hearing loss is the most common sensory disorder. While gene therapy has emerged as a promising treatment of inherited diseases like hearing loss, it is dependent on the identification of gene delivery vectors. Adeno-associated virus (AAV) vector-mediated gene therapy has been approved in the US for treating a rare inherited eye disease but no safe and efficient vectors have been identified that can target the diverse types of inner ear cells. Here, we identify an AAV variant, AAV-inner ear (AAV-ie), for gene delivery in mouse inner ear. Our results show that AAV-ie transduces the cochlear supporting cells (SCs) with high efficiency, representing a vast improvement over conventional AAV serotypes. Furthermore, after AAV-ie-mediated transfer of the Atoh1 gene, we find that many SCs trans-differentiated into new HCs. Our results suggest that AAV-ie is a useful tool for the cochlear gene therapy and for investigating the mechanism of HC regeneration.