Summary The synthesis of selenoproteins requires the translational recoding of the UGA stop codon as selenocysteine. During selenium deficiency, there is a hierarchy of selenoprotein expression, with certain selenoproteins synthesized at the expense of others. The mechanism by which the limiting selenocysteine incorporation machinery is preferentially utilized to maintain the expression of essential selenoproteins has not been elucidated. Here, we demonstrate that eukaryotic initiation factor 4a3 (eIF4a3) is involved in the translational control of a subset of selenoproteins. The interaction of eIF4a3 with the selenoprotein mRNA prevents the binding of SECIS binding Protein 2, which is required for selenocysteine insertion, thereby inhibiting the synthesis of the selenoprotein. Furthermore, the expression of eIF4a3 is regulated in response to selenium. Based on knockdown and overexpression studies, eIF4a3 is necessary and sufficient to mediate selective translational repression in cells. Our results support a model in which eIF4a3 links selenium status with differential selenoprotein expression.

Abstract. Outbreaks of arthropod-borne viral infections occur periodically across Kenya. However, limited surveillance takes place during interepidemic periods. Using serum samples obtained from asymptomatic persons across Kenya in 2000-2004, we assessed (by indirect immunofluorescent assay) prevalence of IgG against yellow fever virus (YFV), West Nile virus (WNV), tick-borne encephalitis virus (TBEV), dengue virus serotypes 1-4 (DENV1-4), and chikungunya virus (CHIKV). Older persons on the Indian Ocean coast were more likely to be seropositive than children inland: YFV = 42% versus 6%, WNV = 29% versus 6%, TBEV = 16% versus 6%, DENV-1 = 63% versus 9%, DENV-2 = 67% versus 7%, DENV-3 = 55% versus 6%, DENV-4 = 44% versus 8%, and CHIKV = 37% versus 20%. Among inland samples, children in lowlands were more likely to be seropositive for CHIKV (42% versus 0%) than children in highlands. In Kenya, transmission of arboviral infection continues between known epidemics and remains common across the country.

No abstract

Centrosomes are major microtubule-organizing centers of animal cells that consist of two centrioles. In mitotic cells, centrosomes are duplicated to serve as the poles of the mitotic spindle, while in quiescent cells, centrosomes move to the apical membrane where the oldest centriole is transformed into a basal body to assemble a primary cilium. We recently showed that mitochondrial outer membrane porin VDAC3 localizes to centrosomes where it negatively regulates ciliogenesis. We show here that the other two family members, VDAC1 and VDAC2, best known for their function in mitochondrial bioenergetics, are also found at centrosomes. Like VDAC3, centrosomal VDAC1 is predominantly localized to the mother centriole, while VDAC2 localizes to centriolar satellites in a microtubule-dependent manner. Down-regulation of VDAC1 leads to inappropriate ciliogenesis, while its overexpression suppresses cilia formation, suggesting that VDAC1 and VDAC3 both negatively regulate ciliogenesis. However, this negative effect on ciliogenesis is not shared by VDAC2, which instead appears to promote maturation of primary cilia. Moreover, because overexpression of VDAC3 cannot compensate for depletion of VDAC1, our data suggest that while the entire VDAC family localizes to centrosomes, they have non-redundant functions in cilogenesis.

OPOs reported a high volume of HIV+ referrals annually, of which a subset will be medically eligible for donation. Particularly in areas of high HIV prevalence, OPOs require ongoing support to implement the HOPE Act.

No abstract

Summary Activation of NOTCH signaling in human hematopoietic stem/progenitor cells (HSPCs) by treatment with an engineered Delta-like ligand (DELTA1 ext-IgG [DXI]) has enabled ex vivo expansion of short-term HSPCs, but the effect on long-term repopulating hematopoietic stem cells (LTR-HSCs) remains uncertain. Here, we demonstrate that ex vivo culture of human adult HSPCs with DXI under low oxygen tension limits ER stress in LTR-HSCs and lineage-committed progenitors compared with normoxic cultures. A distinct HSC gene signature was upregulated in cells cultured with DXI in hypoxia and, after 21 days of culture, the frequency of LTR-HSCs increased 4.9-fold relative to uncultured cells and 4.2-fold compared with the normoxia + DXI group. NOTCH and hypoxia pathways intersected to maintain undifferentiated phenotypes in cultured HSPCs. Our work underscores the importance of mitigating ER stress perturbations to preserve functional LTR-HSCs in extended cultures and offers a clinically feasible platform for the expansion of human HSPCs.

With new practice guidelines, it is important to understand how liver transplant (LT) centers have incorporated direct-acting antivirals (DAAs) into the management of hepatitis C virus-infected (HCV+) candidates and recipients. To explore how DAAs have affected LT centers’ willingness to treat HCV+ candidates and recipients and to use HCV+ donors, we surveyed high volume US LT centers (11/2014–12/2015) regarding practices for HCV+ candidates, recipients, and donors, before vs. after DAAs. We used the Scientific Registry of Transplant Recipients to compare centers’ number of LTs, HCV+ recipients, and HCV+ donors in the years before (1/1/2012–12/31/2013) and after (1/1/2016–12/31/2017) survey administration. Of 80 centers contacted, 57 (71%) responded, representing 69% of the total volume of LTs in 2013. After DAAs, most centers increased treating candidates with low (≤15) model for end-stage liver disease (MELD) (85.2%), intermediate/high (>15) MELD (92.6%), and hepatocellular carcinoma (79.6%). There was consensus to treat low MELD candidates (90.7% “most of the time/always”), but less certainty for intermediate/high MELD candidates (27.8% “sometimes”). Universal post-LT HCV treatment increased (7.4% vs. 57.4%). After DAAs, 42.6% were more willing to use HCV+ donors for HCV+ candidates, and 38.9% were willing to consider using HCV+ donors for HCV- candidates. Overall, with DAAs, centers were more willing to treat HCV+ candidates and recipients and to use HCV+ donors; recent recommendations may help to guide treatment decisions for intermediate/high MELD candidates.