Villin, an actin bundling protein found in the apical brush border of absorptive tissues, is one of the first structural genes to be transcriptionally activated in the embryonic intestinal endoderm. In the adult, villin is broadly expressed in every cell of the intestinal epithelium on both the vertical axis (crypt to villus tip) and the horizontal axis (duodenum through colon) of the intestine. Here, we document that a 12.4-kilobase region of the mouse villin gene drives high level expression of two different reporter genes (LacZ and Cre recombinase) within the entire intestinal epithelium of transgenic mice. Deletion of a portion of this transgene results in reduction of ␤-galactosidase activity in restricted domains of the small intestine (duodenum) and large intestine (cecum). In addition, expression is reduced in the crypt compartment throughout the intestine. Thus, the global expression pattern of villin in the intestine is apparently the consequence of an amalgam of distinct and individual domain-specific control processes. That is, expression of villin in the duodenum and cecum requires different regulatory sequences than the rest of the intestine, and the expression of villin in crypts is regulated by different circuitry than expression of villin on villus tips.

Fragile X syndrome is a leading heritable cause of mental retardation that results from the loss of FMR1 gene function. A Drosophila model for Fragile X syndrome, based on the loss of dfmr1 activity, exhibits phenotypes that bear similarity to Fragile X-related symptoms. Herein, we demonstrate that treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium can rescue courtship and mushroom body defects observed in these flies. Furthermore, we demonstrate that dfmr1 mutants display cognitive deficits in experience-dependent modification of courtship behavior, and treatment with mGluR antagonists or lithium restores these memory defects. These findings implicate enhanced mGluR signaling as the underlying cause of the cognitive, as well as some of the behavioral and neuronal, phenotypes observed in the Drosophila Fragile X model. They also raise the possibility that compounds having similar effects on metabotropic glutamate receptors may ameliorate cognitive and behavioral defects observed in Fragile X patients.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3 deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that SARS-CoV-2 spike protein (subunit 1 and 2), but not N protein, directly activates the alternative pathway of complement (APC). Complement dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert non-activator surfaces to activator surfaces by preventing the inactivation of the cell surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.

• Known pathogenic germ line variants in 12 genes can explain nearly 30% of families with inherited predisposition to MDS/AML. • Asymptomatic carriers of germ line RUNX1 mutations develop detectable clonal hematopoiesis with a cumulative risk of .80% by age 50 years.Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germ line GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were underrepresented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Lastly, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families. (Blood. 2015;126(22):2484-2490