Pontocerebellar hypoplasia type 1b (PCH1b) is an autosomal recessive disorder that causes cerebellar hypoplasia and spinal motor neuron degeneration, leading to mortality in early childhood. PCH1b is caused by mutations in the RNA exosome subunit gene, EXOSC3. The RNA exosome is an evolutionarily conserved complex, consisting of nine different core subunits, and one or two 39-59 exoribonuclease subunits, that mediates several RNA degradation and processing steps. The goal of this study is to assess the functional consequences of the amino acid substitutions that have been identified in EXOSC3 in PCH1b patients. To analyze these EXOSC3 substitutions, we generated the corresponding amino acid substitutions in the Saccharomyces cerevisiae ortholog of EXOSC3, Rrp40. We find that the rrp40 variants corresponding to EXOSC3-G31A and -D132A do not affect yeast function when expressed as the sole copy of the essential Rrp40 protein. In contrast, the rrp40-W195R variant, corresponding to EXOSC3-W238R in PCH1b patients, impacts cell growth and RNA exosome function when expressed as the sole copy of Rrp40. The rrp40-W195R protein is unstable, and does not associate efficiently with the RNA exosome in cells that also express wild-type Rrp40. Consistent with these findings in yeast, the levels of mouse EXOSC3 variants are reduced compared to wild-type EXOSC3 in a neuronal cell line. These data suggest that cells possess a mechanism for optimal assembly of functional RNA exosome complex that can discriminate between wildtype and variant exosome subunits. Budding yeast can therefore serve as a useful tool to understand the molecular defects in the RNA exosome caused by PCH1b-associated amino acid substitutions in EXOSC3, and potentially extending to disease-associated substitutions in other exosome subunits.KEYWORDS pontocerebellar hypoplasia type 1b; RNA exosome; EXOSC3; Rrp40; EXOSC2; RNA processing/degradation T HE RNA exosome is an evolutionarily conserved ribonuclease complex that is responsible for several essential RNA processing and degradation steps (Mitchell et al. 1997;Allmang et al. 1999;Schneider and Tollervey 2013). Major exosome substrates include mRNA, rRNA, and small RNAs. In addition to degrading aberrant and unneeded transcripts, the RNA exosome also trims precursor RNAs, including 5.8S rRNA (Mitchell et al. 1996). The RNA exosome thus plays critical roles in both RNA degradation and maturation.The subunits of the RNA exosome complex are evolutionarily conserved and many were first identified in Saccharomyces cerevisiae in a screen for ribosomal RNA processing (rrp) mutants (Mitchell et al. 1996(Mitchell et al. , 1997Allmang et al. 1999). S. cerevisiae Rrp subunits correspond to human EXOSC subunits. The functions of the RNA exosome have been extensively characterized in budding yeast (Sloan et al. 2012), and many are conserved in humans (Schilders et al. 2005;Staals et al. 2010;Lubas et al. 2011Lubas et al. , 2015 the RNA exosome, six subunits comprise a core ring, and three putative RNA-binding sub...

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An overall, continuous downward trend in milk production and utilization can be observed in the U.S. during the last 30 years. The per capita dairy product consumption decreased by about 10% in every decade. Since dairy products supply an important portion of the nation's protein, and 75% of our calcium needs, it seems to be important to understand the causes of this decline. To overcome the decline, the rationale of a coordinated technological, nutritional, and marketing research approach is discussed in this paper. The future of the dairy problem is analyzed from three interrelated viewpoints: (a) product reserach to meet consumer needs, (b) nutrition research to promote consumer health, and (c) marketing research to explore consumer motivation.

Collapsing glomerulopathy is a variant of focal segmental glomerulosclerosis (FSGS) causing rapid renal failure. There has been an emergence of these cases among African American patients with COVID-19, especially those with the apolipoprotein L1 (APOL1) allele. We present a case of an African American patient with COVID-19 who tested positive for the APOL1 allele in the setting of acute renal deterioration. This provides a partial explanation for the increased burden of kidney failure in this population. As cases of COVID-19 persist, COVID-associated nephropathy (COVAN) should be suspected in patients with acute kidney injury and treatment tailored accordingly.

Hashimoto's encephalopathy (HE), also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a rare autoimmune disease that remains poorly understood. Here, we report a patient who experienced numerous comatose relapses early in the disease course. Despite prolonged corticotherapy, cognitive deficits have persisted through the two-year post-diagnosis follow-up. This case highlights the protracted nature of HE.