Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis

Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochondrial-dependent cell death. This study investigated the therapeutic potential of a selective cyclophilin inhibitor (GS-642362), which does not block calcineurin function, in mouse models of tubular cell necrosis and renal fibrosis. Mice underwent bilateral renal ischemia/reperfusion injury (IRI) and were killed 24 h later: treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. In the second model, mice underwent unilateral ureteric obstruction (UUO) surgery and were killed 7 days later; treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. GS-642362 treatment gave a profound and dose-dependent protection from acute renal failure in the IRI model. This protection was associated with reduced tubular cell death, including a dramatic reduction in neutrophil infiltration. In the UUO model, GS-642362 treatment significantly reduced tubular cell death, macrophage infiltration, and renal fibrosis. This protective effect was independent of the upregulation of IL-2 and activation of the stress-activated protein kinases (p38 and JNK). In conclusion, GS-642362 was effective in suppressing both acute kidney injury and renal fibrosis. These findings support further investigation of cyclophilin blockade in other types of acute and chronic kidney disease.     

Environmental factors controlling phytoplankton dynamics in a large floodplain river with emphasis on cyanobacteria

Harmful algal blooms are occurring in large river ecosystems and at the mouth of large rivers with increasing frequency. In lentic systems, the chemical and physical conditions that promote harmful algal blooms are somewhat predictable but tracking prevalence and conditions that promote harmful algal blooms in lotic systems is much more difficult. We captured two of the most extreme discharge years within the last 20 years occurring in the Upper Mississippi River, allowing a natural experiment that evaluated how major shifts in discharge drive environmental variation and associated shifts in phytoplankton. Statistical models describing significant environmental covariates for phytoplankton assemblages and specific taxa were developed and used to identify management‐relevant numeric breakpoints at which environmental variables may promote the growth of specific phytoplankton and/or cyanobacteria. Our analyses supported that potentially toxin‐producing cyanobacteria dominate under high phosphorus concentration, low nitrogen concentration, low nitrogen‐to‐phosphorus ratio, low turbulence, low flushing, adequate light and warm temperatures. Cyanobacteria dominated in 2009 when low discharge and low flushing likely led to optimal growth environments for Dolichospermum, Aphanizomenon and Microcystis. Rarely will a single factor lead to the dominance, but multiple positive factors working in concert can lead to cyanobacteria proliferation in large rivers. Certain isolated backwaters with high phosphorus, low nitrogen, warm water temperatures and low potential for flushing could benefit from increased connection to channel inputs to reduce cyanobacterial dominance. Numerous examples of this type of habitat currently exist in the Upper Mississippi River and could benefit from reconnection to channel habitats.     

Hepatic patatin-like phospholipase domain-containing protein 3 sequence,single nucleotide polymorphism presence,protein confirmation,and responsiveness to energy balance in dairy cows

Patatin-like phospholipase domain-containing protein 3 (PNPLA3), commonly known as adiponutrin, is part of a novel subfamily of triglyceride lipase enzymes with potential effects on triglyceride metabolism in adipose and hepatic tissues. The predicted bovine PNPLA3 sequence has been identified, but expression of the gene had not been examined. The objectives of this study were to confirm the predicted bovine PNPLA3 gene sequence, determine expression of the bovine PNPLA3 gene in response to whole-animal energy balance, identify single nucleotide polymorphisms present in dairy cows, and verify the presence of the protein in the liver. Using liver biopsy samples collected from cows at +28 d relative to calving (DRTC), RNA was isolated and used to generate a cDNA template for amplification of the entire predicted coding sequence of PNPLA3 via PCR. To determine if energy balance alters the expression of PNPLA3, RNA was isolated and mRNA expression quantified in liver samples from mid-lactation cows after a 5-d ad libitum period (n = 5) and after a subsequent 5-d 50% feed restriction period (n = 5), and in samples collected from cows at −14, +1, +14, and +28 DRTC (n = 16). The presence of PNPLA3 protein was detected by Western blot in liver protein samples collected at +28 DRTC. Expression of hepatic PNPLA3 was decreased after a period of feed restriction (8.14 vs. 1.08 ± 2.17 arbitrary units, ad libitum vs. fasted). Expression of PNPLA3 mRNA was decreased at +1 and +14 DRTC compared with −14 DRTC (23.35, 7.28, 10.17, and 14.5 ± 4.9 arbitrary units, −14, +1, +14, and +28 DRTC, respectively). The presence of PNPLA3 protein was detected as a 55-kDa band in hepatic protein isolations from liver tissue collected at +28 DRTC. These data confirm the presence and sequence of the bovine hepatic PNPLA3 gene and single nucleotide polymorphisms. Furthermore, these data indicate responsiveness of bovine hepatic PNPLA3 to energy balance.     

Anisotropic loss of toughness with physical aging of work toughened polycarbonate

We have studied the response of mechanically toughened and physically aged polycarbonate primarily using Charpy impact and ultrasonic wave speed measurements. The toughening was conducted through plastic compression on as‐received PC. The Charpy impact tests showed anisotropic toughening, both in the absorbed energy and in the mode of fracture. The amount of toughening with plastic compression, even though anisotropic, is centered around the response of annealed and quenched samples, which represent the response of an unaged PC. There was an anisotropic drop in the toughness of some samples with aging. The time of this drop was uncorrelated in the different directions and disappeared for the highly toughened samples. This transition was bimodal and statistically distributed between either a fully ductile or a fully brittle failure. As the samples were prepared in a manner to remove induced residual stresses, this drop in toughening may be associated with an intrinsic anisotropic thermal aging of the deformed material. POLYM. ENG. SCI., 54:794–804, 2014. © 2013 Society of Plastics Engineers     

Polymers used to influence cell fate in 3D geometry: New trends

The extracellular matrix (ECM) is a hydrogel-like structure comprised of several different biopolymers, encompassing a wide range of biological, chemical, and mechanical properties. The composition, organization, and assembly of the ECM play a critical role in cell function. Cellular behavior is guided by interactions that occur between cells and their local microenvironment, and this interrelationship plays a significant role in determining physiological functions. Bioengineering approaches have been developed to mimic native tissue microenvironments by fabricating novel bioactive hydrogel scaffolds. This review explores material designs and fabrication approaches that are guiding the design of hydrogels as tissue engineered scaffolds. As the fundamental biology of the cellular microenvironment is often the inspiration for material design, the review focuses on modifications to control bioactive cues such as adhesion molecules and growth factors, and summarizes the current applications of biomimetic scaffolds that have been used in vitro as well as in vivo.