Cyst expansion in polycystic kidney disease (PKD) involves progressive fluid accumulation, which is believed to require chloride transport by the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Herein is reported that small-molecule CFTR inhibitors of the thiazolidinone and glycine hydrazide classes slow cyst expansion in in vitro and in vivo models of PKD. More than 30 CFTR inhibitor analogs were screened in an MDCK cell model, and near-complete suppression of cyst growth was found by tetrazolo-CFTR inh -172, a tetrazolo-derived thiazolidinone, and Ph-GlyH-101, a phenyl-derived glycine hydrazide, without an effect on cell proliferation. These compounds also inhibited cyst number and growth by Ͼ80% in an embryonic kidney cyst model involving 4-d organ culture of embryonic day 13.5 mouse kidneys in 8-Br-cAMP-containing medium. Subcutaneous delivery of tetrazolo-CFTR inh -172 and Ph-GlyH-101 to neonatal, kidney-specific PKD1 knockout mice produced stable, therapeutic inhibitor concentrations of Ͼ3 M in urine and kidney tissue. Treatment of mice for up to 7 d remarkably slowed kidney enlargement and cyst expansion and preserved renal function. These results implicate CFTR in renal cyst growth and suggest that CFTR inhibitors may hold therapeutic potential to reduce cyst growth in PKD.

Species assemble into communities through ecological and evolutionary processes. Phylogenetic niche conservatism—the tendency of species to retain ancestral ecological distributions—is thought to influence which species from a regional species pool can persist in a particular environment. We analyzed data for seed plants in China to test hypotheses about the distribution of species within regional floras. Of 16 environmental variables, actual evapotranspiration, minimum temperature of the coldest month, and annual precipitation most strongly influenced regional species richness, phylogenetic dispersion, and phylogenetic diversity for both gymnosperms (cone-bearing plants) and angiosperms (flowering plants). For most evolutionary clades at, and above, the family level, the relationships between metrics of phylogenetic dispersion (i.e., average phylogenetic distance among species), or phylogenetic diversity, and the 3 environmental variables were consistent with the tropical niche conservatism hypothesis, which predicts closer phylogenetic relatedness and reduced phylogenetic diversity with increasing environmental stress. The slopes of the relationships between phylogenetic relatedness and the 3 environmental drivers identified in this analysis were steeper for primarily tropical clades, implying greater niche conservatism, than for primarily temperate clades. These observations suggest that the distributions of seed plants across large-scale environmental gradients in China are constrained by conserved adaptations to the physical environment, i.e., phylogenetic niche conservatism.

Nanotechnology plays a significant role in drug development. As carriers, polymeric nanoparticles can deliver vaccine antigens, proteins, and drugs to the desired site of action. Polymeric nanoparticles with lower cytotoxicity can protect the delivered antigens or drugs from degradation under unfavorable conditions via a mucosal administration route; further, the uptake of nanoparticles by antigen-presenting cells can increase and induce potent immune responses. Additionally, nanomaterials are widely used in vaccine delivery systems because nanomaterials can make the vaccine antigen long-acting. This review focuses on some biodegradable polymer materials such as natural polymeric nanomaterials, chemically synthesized polymer materials, and biosynthesized polymeric materials, and points out the advantages and the direction of research on degradable polymeric materials. The application and future perspectives of polymeric materials as delivery carriers and vaccine adjuvants in the field of drugs and vaccines are presented. With the increase of knowledge and fundamental understandings of polymer-based nanomaterials, means of integrating some other attractive properties, such as slow release, target delivery, and alternative administration methods and delivery pathways are feasible. Polymer-based nanomaterials have great potential for the development of novel vaccines and drug systems for certain needs, including single-dose and needle-free deliveries of vaccine antigens and drugs in the future.

(AQP8) is a watertransporting protein expressed in organs of the mammalian gastrointestinal tract (salivary gland, liver, pancreas, small intestine, and colon) and in the testes, heart, kidney, and airways. We studied the phenotype of AQP8-null mice, and mice lacking AQP8, together with AQP1 or AQP5. AQP8-knockout mice lacked detectable AQP8 transcript and protein, and had reduced water permeability in plasma membranes from testes. Breeding of AQP8 heterozygous mice yielded AQP8-null mice, whose number, survival, and growth were not different from those of wild-type mice. Organ weight and serum/urine chemistries were similar in wild-type and AQP8-null mice, except for increased testicular weight in the null mice (4.8 Ϯ 0.7 vs. 7.3 Ϯ 0.3 mg/g body wt). Urinary concentrating ability in AQP8-null mice was unimpaired as assessed by urine osmolality (3,590 Ϯ 360 mosmol/ kgH2O) and weight loss (22 Ϯ 2%) after 36-h water deprivation; urinary concentrating ability was similarly impaired in AQP1-null mice vs. AQP8/AQP1 double-knockout mice. Agonist-driven fluid secretion in salivary gland was not different in AQP8 vs. wild-type mice (ϳ1 l ⅐ min Ϫ1 ⅐ g body wt Ϫ1 ) or in AQP5-null mice vs. AQP8/ AQP5 double-knockout mice. Closed intestinal loop measurements in vivo indicated unimpaired osmotically driven water transport, active fluid absorption, and cholera toxin-driven fluid secretion in AQP8-null mice. After 21 days on a 50% fat diet, wild-type and AQP8-null mice had similar weight gain (ϳ15 g), with no evidence of steatorrhea or abnormalities in blood chemistries, except for mild hypertriglyceridemia in the null mice. The mild phenotype of AQP8-null mice was surprising in view of the multiple phenotype abnormalities found in mouse models of AQP1-5 deficiency. water channel; transgenic mice; testes; kidney; gastrointestinal tract AQUAPORINS (AQP) are a family of water-transporting proteins expressed in cell membranes in many animal and plant species and in lower organisms. At least 10 homologous aquaporins are expressed in various organs in mammals, where they facilitate osmotically driven passage of water across cell membranes or epithelial layers. A phenotype analysis of mice lacking aquaporins individually or in combination has been informative in defining their role in osmotically driven water transport and active fluid absorption/secretion in many tissues, such as AQP1-4 in the urinary concentrating mechanism (24 -26, 53), AQP1 in aqueous fluid (56) and cerebrospinal fluid (36) secretion, and AQP5 in gland secretion (23,43). Also, several unanticipated phenotypes were found, such as altered brain swelling and neural signal transduction in AQP4 deficiency (3, 28, 37) and dry skin with reduced glycerol content in AQP3 deficiency (12). Phenotype studies have also revealed the tissue-specific expression of aquaporins without demonstrable physiological import. For example, in the lung, despite substantial reduction of transalveolar osmotic water permeability, AQP1 and AQP5 knockout mice had unimpaired lung function, alv...

The vegetative insecticidal proteins (Vip), secreted by many Bacillus thuringiensis strains during their vegetative growth stage, are genetically distinct from known insecticidal crystal proteins (ICPs) and represent the second-generation insecticidal toxins. Compared with ICPs, the insecticidal mechanisms of Vip toxins are poorly understood. In particular, there has been no report of a definite receptor of Vip toxins to date. In the present study, we identified the scavenger receptor class C like protein (Sf-SR-C) from the Spodoptera frugiperda (Sf9) cells membrane proteins that bind to the biotin labeled Vip3Aa, via the affinity magnetic bead method coupled with HPLC-MS/MS. We then certified Vip3Aa protoxin could interact with Sf-SR-C in vitro and ex vivo. In addition, downregulation of SR-C expression in Sf9 cells and Spodoptera exigua larvae midgut reduced the toxicity of Vip3Aa to them. Coincidently, heterologous expression of Sf-SR-C in transgenic Drosophila midgut significantly enhanced the virulence of Vip3Aa to the Drosophila larvae. Moreover, the complement control protein domain and MAM domain of Sf-SR-C are involved in the interaction with Vip3Aa protoxin. Furthermore, endocytosis of Vip3Aa mediated by Sf-SR-C correlates with its insecticidal activity. Our results confirmed for the first time that Sf-SR-C acts as a receptor for Vip3Aa protoxin and provides an insight into the mode of action of Vip3Aa that will significantly facilitate the study of its insecticidal mechanism and application.