Cytosolic phospholipase A 2α (cPLA 2α ) hydrolyzes arachidonic acid from cellular membrane phospholipids, thereby providing enzymatic substrates for the synthesis of eicosanoids, such as prostaglandins and leukotrienes. Considerable understanding of cPLA 2α function has been derived from investigations of the enzyme and from cPLA 2α -null mice, but knowledge of discrete roles for this enzyme in humans is limited. We investigated a patient hypothesized to have an inherited prostanoid biosynthesis deficiency due to his multiple, complicated small intestinal ulcers despite no use of cyclooxygenase inhibitors. Levels of thromboxane B 2 and 12-hydroxyeicosatetraenoic acid produced by platelets and leukotriene B 4 released from calcium ionophore-activated blood were markedly reduced, indicating defective enzymatic release of the arachidonic acid substrate for the corresponding cyclooxygenase and lipoxygenases. Platelet aggregation and degranulation induced by adenosine diphosphate or collagen were diminished but were normal in response to arachidonic acid. Two heterozygous single base pair mutations and a known SNP were found in the coding regions of the patient's cPLA 2α genes (p.[Ser111Pro]+[Arg485His; Lys651Arg]). The total PLA 2 activity in sonicated platelets was diminished, and the urinary metabolites of prostacyclin, prostaglandin E 2 , prostaglandin D 2 , and thromboxane A 2 were also reduced. These findings characterize what we believe is a novel inherited deficiency of cPLA 2 .

Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl À /H þ exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and-genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.

2006. Maximum body size among insular Komodo dragon populations covaries with large prey density. Á/ Oikos 112: 422 Á/429.This study documents variation in maximum body size of Komodo dragons (Varanus komodoensis ) among the four extant island populations in Komodo National Park and compares an indirect measure of deer density, the major prey item for large dragons, to differences in maximum body size among islands. The largest 15% of dragons from the large islands of Komodo and Rinca were significantly longer and heavier than the largest 15% of dragons on the small islands of Gili Motang and Nusa Kode. There was a 33% difference in snout vent length (SVL) between dragons found on Komodo and those found on Gili Motang, with mass varying by more than four-fold. Density of deer pellet groups between islands ranged from 5.869/0.75 groups per transect on Gili Motang to 20.739/1.02 groups per transect on Komodo Island. Maximal dragon SVL and mass was highly positively correlated with this index of deer density. Low prey density on the two small islands could constrain body size via energetic constraints. At present we can not deduce if insular body size variation has arisen through genotypic or phenotypic mechanisms.

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To establish a skeletal muscle profile for elite sprinters, we obtained muscle biopsy samples from the vastus lateralis, gastrocnemius and soleus of African cheetahs (Acinonyx jubatus). Muscle ultrastructure was characterized by the fiber type composition and mitochondrial volume density of each sample. Maximum enzyme activity, myoglobin content and mixed fiber metabolite content were used to assess the major biochemical pathways. The results demonstrate a preponderance of fast-twitch fibers in the locomotor muscles of cheetahs; 83% of the total number of fibers examined in the vastus lateralis and nearly 61% of the gastrocnemius were comprised of fast-twitch fibers. The total mitochondrial volume density of the limb muscles ranged from 2.0 to 3.9% for two wild cheetahs. Enzyme activities reflected the sprinting capability of the cheetah. Maximum activities for pyruvate kinase and lactate dehydrogenase in the vastus lateralis were 1519.00 +/- 203.60 and 1929.25 +/- 482.35 mumol min-1.g wet wt-1, respectively, and indicated a high capacity for glycolysis. This study demonstrates that the locomotor muscles of cheetahs are poised for anaerobically based exercise. Fiber type composition, mitochondrial content and glycolytic enzyme capacities in the locomotor muscles of these sprinting cats are at the extreme range of values for other sprinters bred or trained for this activity including greyhounds, thoroughbred horses and elite human athletes.