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Poor visuospatial skills can disrupt activities of daily living. The cerebellum has been implicated in visuospatial processing, and patients with cerebellar injury often exhibit poor visuospatial skills, as measured by impaired memory for the figure within the Rey-Osterrieth complex figure task (ROCF). Visuospatial skills are an inherent aspect of the ROCF; however, figure organization (i.e., the order in which the figure is reconstructed by the participant) can influence recall ability. The objective of this study was to examine and compare visuospatial and organization skills in people with cerebellar ataxia. We administered the ROCF to patients diagnosed with cerebellar ataxia and healthy controls. The cerebellar ataxia group included patients that carried a diagnosis of spinocerebellar ataxia (any subtype), autosomal dominant cerebellar ataxia, or cerebellar ataxia with unknown etiology. Primary outcome measures were organization and recall performance on the ROCF, with supplemental information derived from cognitive tests of visuospatial perception, working memory, processing speed, and motor function. Cerebellar ataxia patients revealed impaired figure organization relative to that of controls. Figure copy was impaired in the patients, but their subsequent recall performance was normal, suggesting compensation from initial organization and copying strategies. In controls, figure organization predicted recall performance, but this relationship was not observed in the patients. Instead, processing speed predicted patients' recall accuracy. Supplemental tasks indicated that visual perception was intact in the cerebellar ataxia group and that performance deficits were more closely tied to organization strategies than with visuospatial skills. [ABSTRACT FROM AUTHOR]

Hepatoblastoma (HB) is the most common pediatric liver cancer. Although long-term survival of HB is generally favorable, it depends on clinical stage, tumor histology, and a variety of biochemical and molecular features. HB appears almost exclusively before the age of 3 years, is represented by seven histological subtypes, and is usually associated with highly heterogeneous somatic mutations in the catenin β1 (CTNNB1) gene, which encodes β-catenin, a Wnt ligand–responsive transcriptional co-factor. Numerous recurring β-catenin mutations, not previously documented in HB, have also been identified in various other pediatric and adult cancer types. Little is known about the underlying factors that determine the above HB features and behaviors or whether non-HB–associated β-catenin mutations are tumorigenic when expressed in hepatocytes. Here, we investigated the oncogenic properties of 14 different HB– and non-HB–associated β-catenin mutants encoded by Sleeping Beauty vectors following their delivery into the mouse liver by hydrodynamic tail-vein injection. We show that all β-catenin mutations, as well as WT β-catenin, are tumorigenic when co-expressed with a mutant form of yes-associated protein (YAP). However, tumor growth rates, histologies, nuclear-to-cytoplasmic partitioning, and metabolic and transcriptional landscapes were strongly influenced by the identities of the β-catenin mutations. These findings provide a context for understanding at the molecular level the notable biological diversity of HB. [ABSTRACT FROM AUTHOR]

Eukaryotic cell metabolism consists of processes that generate available energy, such as glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (Oxphos), and those that consume it, including macromolecular synthesis, the maintenance of ionic gradients, and cellular detoxification. By converting pyruvate to acetyl-CoA (AcCoA), the pyruvate dehydrogenase (PDH) complex (PDC) links glycolysis and the TCA cycle. Surprisingly, disrupting the connection between glycolysis and the TCA cycle by inactivation of PDC has only minor effects on cell replication. However, the molecular basis for this metabolic re-equilibration is unclear. We report here that CRISPR/Cas9-generated PDH-knockout (PDH-KO) rat fibroblasts reprogrammed their metabolism and their response to short-term c-Myc (Myc) oncoprotein overexpression. PDH-KO cells replicated normally but produced surprisingly little lactate. They also exhibited higher rates of glycolysis and Oxphos. In addition, PDH-KO cells showed altered cytoplasmic and mitochondrial pH, redox states, and mitochondrial membrane potential (ΔΨM). Conditionally activated Myc expression affected some of these parameters in a PDH-dependent manner. PDH-KO cells had increased oxygen consumption rates in response to glutamate, but not to malate, and were depleted in all TCA cycle substrates between α-ketoglutarate and malate despite high rates of glutaminolysis, as determined by flux studies with isotopically labeled glutamine. Malate and pyruvate were diverted to produce aspartate, thereby potentially explaining the failure to accumulate lactate. Weconclude thatPDH-KO cells maintain proliferative capacity by utilizing glutamine to supply high rates of AcCoA-independent flux through the bottom portion of the TCA cycle while accumulating pyruvate and aspartate that rescue their redox defects. [ABSTRACT FROM AUTHOR]