Decompressive craniectomy inside malignant middle cerebral artery infarct The institutional expertise

The fortuitously discovered antiaging membrane protein αKlotho (Klotho) is highly expressed in the kidney, and deletion of the Klotho gene in mice causes a phenotype strikingly similar to that of chronic kidney disease (CKD). Klotho functions as a co-receptor for fibroblast growth factor 23 (FGF23) signaling, whereas its shed extracellular domain, soluble Klotho (sKlotho), carrying glycosidase activity, is a humoral factor that regulates renal health. Low sKlotho in CKD is associated with disease progression, and sKlotho supplementation has emerged as a potential therapeutic strategy for managing CKD. Here, we explored the structure-function relationship and post-translational modifications of sKlotho variants to guide the future design of sKlotho-based therapeutics. Chinese hamster ovary (CHO)- and human embryonic kidney (HEK)-derived WT sKlotho proteins had varied activities in FGF23 co-receptor and β-glucuronidase assays in vitro and distinct properties in vivo Sialidase treatment of heavily sialylated CHO-sKlotho increased its co-receptor activity 3-fold, yet it remained less active than hyposialylated HEK-sKlotho. MS and glycopeptide-mapping analyses revealed that HEK-sKlotho is uniquely modified with an unusual N-glycan structure consisting of N,N'-di-N-acetyllactose diamine at multiple N-linked sites, one of which at Asn-126 was adjacent to a putative GalNAc transfer motif. Site-directed mutagenesis and structural modeling analyses directly implicated N-glycans in Klotho's protein folding and function. Moreover, the introduction of two catalytic glutamate residues conserved across glycosidases into sKlotho enhanced its glucuronidase activity but decreased its FGF23 co-receptor activity, suggesting that these two functions might be structurally divergent. These findings open up opportunities for rational engineering of pharmacologically enhanced sKlotho therapeutics for managing kidney disease. © 2020 Zhong et al.Gout is a common arthritis caused by monosodium urate crystals. The heritability of serum urate levels is estimated to be 30‒70%; however, common genetic variants account for only 7.9% of the variance in serum urate levels. This discrepancy is an example of "missing heritability." The "missing heritability" suggests that variants associated with uric acid levels are yet to be found. By using genomic sequences of the ToMMo cohort, we identified rare variants of the SLC22A12 gene that affect the urate transport activity of URAT1. URAT1 is a transporter protein encoded by the SLC22A12 gene. We grouped the participants with variants affecting urate uptake by URAT1 and analyzed the variance of serum urate levels. The results showed that the heritability explained by the SLC22A12 variants of men and women exceeds 10%, suggesting that rare variants underlie a substantial portion of the "missing heritability" of serum urate levels. Copyright © 2020, Genetics.Epithelial cells form intercellular junctions to strengthen cell-cell adhesion and limit diffusion, allowing epithelia to function as dynamic tissues and barriers separating internal and external environments. Junctions form as epithelial cells differentiate; clusters of junction proteins first concentrate apically, then mature into continuous junctional belts that encircle and connect each cell. In mammals and Drosophila, atypical protein kinase C (aPKC) is required for junction maturation, although how it contributes to this process is poorly understood. A role for the Caenorhabditis elegans aPKC homologue PKC-3 in junction formation has not been described previously. Here, we show that PKC-3 is essential for junction maturation as epithelia first differentiate. Using a temperature-sensitive allele of pkc-3 that causes junction breaks in the spermatheca and leads to sterility, we identify intragenic and extragenic suppressors that render pkc-3 mutants fertile. Intragenic suppressors include an unanticipated stop-to-stop mutation in the pkc-3 gene, providing evidence for the importance of stop codon identity in gene activity. One extragenic pkc-3 suppressor is a loss-of-function allele of the lethal(2) giant larvae homologue lgl-1, which antagonizes aPKC within epithelia of Drosophila and mammals but was not known previously to function in C. elegans epithelia. Finally, two extragenic suppressors are loss-of-function alleles of sups-1, a previously uncharacterized gene. We show that SUPS-1 is an apical extracellular matrix protein expressed in epidermal cells, suggesting that it non-autonomously regulates junction formation in the spermatheca. These findings establish a foundation for dissecting the role of PKC-3 and interacting genes in epithelial junction maturation. Copyright © 2020, Genetics.OBJECTIVES Efforts to study potential overuse of NICU admissions and hospital variation in practice are often hindered by a lack of an appropriate data source. We examined the concordance of hospital-level NICU admission rates between birth certificate data and California Children's Services (CCS) data to inform the utility of birth certificate data in studying hospital variation in NICU admissions. METHODS We analyzed birth certificate data from California in 2012 and hospital-specific summary data from CCS regarding NICU admissions. NICU admission rates were calculated for both data sets while using CCS data as the gold standard. The difference between birth certificate-based and CCS-based NICU admission rates was assessed by using the Wilcoxon signed rank test, and concordance between the 2 rates was evaluated by using Lin's concordance correlation coefficient and Kendall's W concordance coefficient. RESULTS Among a total of 103 hospitals that were linked between the 2 data sets, birth certificate data generally underreported NICU admission rates compared with CCS data (median = 7.72% vs 11.51%; P less then .001). However, in a subset of 35 hospitals where the difference in NICU admission rates between the 2 data sets was small, the birth certificate-based NICU admission rate showed good concordance with the rate from CCS data (Lin's concordance correlation coefficient = 0.91; 95% confidence interval 0.84-0.95; Kendall's W concordance coefficient = 0.99; P less then .001). Selleck β-Nicotinamide Hospitals with good-concordance data did not differ from other hospitals in the institutional characteristics assessed. CONCLUSIONS For a selected subset of hospitals, birth certificate data may offer a reasonable means to investigate hospital variation in NICU admissions. Copyright © 2020 by the American Academy of Pediatrics.