To enter cells enveloped viruses use fusion-mediating glycoproteins to facilitate the merger of the viral and host cell membranes. These glycoproteins undergo large-scale irreversible refolding during membrane fusion. The paramyxovirus parainfluenza virus 5 (PIV5) mediates membrane merger through its fusion protein (F). The transmembrane (TM) domains of viral fusion proteins are typically required for fusion. The TM domain of F is particularly interesting in that it is potentially unusually long; multiple calculations suggest a TM helix length between 25 and 48 residues. Oxidative crosslinking of single cysteine substitutions indicates the F TM trimer forms a helical bundle within the membrane. To assess the functional role of the PIV5 F protein TM domain, alanine scanning mutagenesis was performed. Two residues located in the outer leaflet of the bilayer are critical for fusion. Multiple amino acid substitutions at these positions indicate the physical properties of the side chain play a critical role in supporting or blocking fusion. Analysis of intermediate steps in F protein refolding indicated that the mutants were not trapped at the open stalk intermediate or the prehairpin intermediate. Incorporation of a known F protein destabilizing mutation that causes a hyperfusogenic phenotype restored fusion activity to the mutants. Further, altering the curvature of the lipid bilayer by addition of oleic acid promoted fusion of the F protein mutants. In aggregate, these data indicate that the TM domain plays a functional role in fusion beyond merely anchoring the protein in the viral envelope and that it can affect the structures and steady-state concentrations of the various conformational intermediates en route to the final postfusion state. We suggest that the unusual length of this TM helix might allow it to serve as a template for formation of or specifically stabilize the lipid stalk intermediate in fusion.

In an article recently published in Pediatric Nephrology, Baddam and colleagues discuss the relatively underreported clinical problem of repeated episodes of acute kidney injury (AKI) in children with sickle cell disease (SCD). Their report is a cautionary note about the importance of repeated kidney injury on the background of underlying chronic kidney injury and its potential implications on long-term kidney outcome. In children and adults with SCD, this includes the effects of repeated vaso-occlusive crises and the management of these painful episodes with non-steroidal anti-inflammatory drugs. Here we review the scope of kidney involvement in SCD in children and discuss the potential short-and long-term consequences of AKI in children with SCD.

Dominant and recessive mutations in podocalyxin (PODXL) are associated with human kidney disease. Interestingly, some PODXL mutations manifest as anuria while others are associated with proteinuric kidney disease. PODXL heterozygosity is associated with adult-onset kidney disease and podocalyxin shedding into the urine is a common biomarker of a variety nephrotic syndromes. It is unknown, however, how various lesions in PODXL contribute to these disparate disease pathologies. Here we generated two mouse stains: one that deletes Podxl in developmentally mature podocytes (Podxl ∆pod) and a second that is heterozygous for podocalyxin in all tissues (Podxl +/−). We used histologic and ultrastructural analyses, as well as clinical chemistry assays to evaluate kidney development and function in these strains. In contrast to null knockout mice (Podxl −/−), which die shortly after birth from anuria and hypertension, Podxl ∆pod mice develop an acute congenital nephrotic syndrome characterized by focal segmental glomerulosclerosis (FSGS) and proteinuria. Podxl +/− mice, in contrast, have a normal lifespan, and fail to develop kidney disease under normal conditions. Intriguingly, although wild-type C57Bl/6 mice are resistant to puromycin aminonucleoside (PA)-induced nephrosis (PAN), Podxl +/− mice are highly sensitive and PA induces severe proteinuria and collapsing FSGS. In summary, we find that the developmental timepoint at which podocalyxin is ablated (immature vs. mature podocytes) has a profound effect on the urinary phenotype due to its critical roles in both the formation and the maintenance of podocyte ultrastructure. In addition, Podxl ∆pod and Podxl +/− mice offer powerful new mouse models to evaluate early biomarkers of proteinuric kidney disease and to test novel therapeutics.

The anatomical literature has indicated that the arterial supply to the thumb comes from the princeps pollicis artery. However, this simplified description does not often correlate with intraoperative findings. The purpose of this study was to investigate and clarify this important area of anatomy by dissection of fresh cadaver hands. 40 dissections were completed on 35 intravascularly injected and five non-injected hands. Five patterns were identified. The most common pattern showed both a superficial and deep vessel to the first web space in 54% of specimens. Dominant vessels included the superficial palmar branch of the radial artery in 8%, first palmar metacarpal artery in 18% and dorsal metacarpal artery in 8%. Only three specimens correlated with the textbook description. We conclude that the term "princeps pollicis" is actually a misnomer.