A Novel TGFβ Receptor Inhibitor, IPW-5371, Prevents Diet-induced Hepatic Steatosis and Insulin Resistance in Irradiated Mice.

As the number of cancer survivors increases and the risk of accidental radiation exposure rises, there is a pressing need to characterize the delayed effects of radiation exposure and develop medical countermeasures. Radiation has been shown to damage adipose progenitor cells and increase liver fibrosis, such that it predisposes patients to developing metabolic-associated fatty liver disease (MAFLD) and insulin resistance. The risk of developing these conditions is compounded by the global rise of diets rich in carbohydrates and fats.

Effects of Simulated 5-Ion Galactic Cosmic Radiation on Function and Structure of the Mouse Heart.

Missions into deep space will expose astronauts to the harsh space environment, and the degenerative tissue effects of space radiation are largely unknown. To assess the risks, in this study, male BALB/c mice were exposed to 500 mGy 5-ion simulated GCR (GCRsim) at the NASA Space Radiation Laboratory. In addition, male and female CD1 mice were exposed to GCRsim and administered a diet containing Transforming Growth Factor-beta (TGF-β)RI kinase (ALK5) inhibitor IPW-5371 as a potential countermeasure.

IPW-5371 mitigates the delayed effects of acute radiation exposure in WAG/RijCmcr rats when started 15 days after PBI with bone marrow sparing.

Purpose: To test IPW-5371 for the mitigation of the delayed effects of acute radiation exposure (DEARE). Survivors of acute radiation exposure are at risk for developing delayed multi-organ toxicities; however, there are no FDA-approved medical countermeasures (MCM) to mitigate DEARE.

Methods: WAG/RijCmcr female rat model of partial-body irradiation (PBI), by shielding part of one hind leg, was used to test IPW-5371 (7 and 20 mg kgd) for mitigation of lung and kidney DEARE when started 15 d after PBI.

Rat Models of Partial-body Irradiation with Bone Marrow-sparing (Leg-out PBI) Designed for FDA Approval of Countermeasures for Mitigation of Acute and Delayed Injuries by Radiation.

The goal of this study was to develop rat models of partial body irradiation with bone-marrow sparing (leg-out PBI) to test medical countermeasures (MCM) of both acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE) under the FDA animal rule. The leg-out PBI models were developed in female and male WAG/RijCmcr rats at doses of 12.5-14.

Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction.

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the life span.

Macrocyclic MEK1/2 inhibitor with efficacy in a mouse model of cardiomyopathy caused by lamin A/C gene mutation.

Signaling mediated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) is involved in numerous cellular processes. Mitogen-activated protein kinase kinases (MEK1/2) catalyze the phosphorylation of ERK1/2, converting it into an active kinase that regulates the expression of numerous genes and cellular processes. Inhibitors of MEK1/2 have demonstrated preclinical and clinical efficacy in certain cancers and types of cardiomyopathy.

IPW-5371 Proves Effective as a Radiation Countermeasure by Mitigating Radiation-Induced Late Effects.

There is an ongoing and significant need for radiation countermeasures to reduce morbidities and mortalities associated with exposure of the heart and lungs from a radiological or nuclear incidents. Radiation-induced late effects occur months to years after exposure, stemming from significant tissue damage and remodeling, resulting in fibrosis and loss of function. TGF-β is reported to play a role in both pulmonary and cardiac fibrosis.

3-heterocyclyl quinolone inhibitors of the HCV NS5B polymerase.

The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system.

Diamino-1,2,4-triazole derivatives are selective inhibitors of TYK2 and JAK1 over JAK2 and JAK3.

Tyrosine kinase 2 (TYK2) is required for signaling of interleukin-23 (IL-23), which plays a key role in rheumatoid arthritis. Presented is the design and synthesis of 1,2,4-triazoles, and the evaluation of their inhibitory activity against the Janus associated kinases TYK2 and JAKs 1-3.

Assessment of the water quality and ecosystem health of the Great Barrier Reef (Australia): conceptual models.

Run-off containing increased concentrations of sediment, nutrients, and pesticides from land-based anthropogenic activities is a significant influence on water quality and the ecologic conditions of nearshore areas of the Great Barrier Reef World Heritage Area, Australia. The potential and actual impacts of increased pollutant concentrations range from bioaccumulation of contaminants and decreased photosynthetic capacity to major shifts in community structure and health of mangrove, coral reef, and seagrass ecosystems. A detailed conceptual model underpins and illustrates the links between the main anthropogenic pressures or threats (dry-land cattle grazing and intensive sugar cane cropping) and the production of key contaminants or stressors of Great Barrier Reef water quality.

Inhibiting TGF-beta signaling restores immune surveillance in the SMA-560 glioma model.

Transforming growth factor-beta (TGF-beta) is a proinvasive and immunosuppressive cytokine that plays a major role in the malignant phenotype of gliomas. One novel strategy of disabling TGF-beta activity in gliomas is to disrupt the signaling cascade at the level of the TGF-beta receptor I (TGF-betaRI) kinase, thus abrogating TGF-beta-mediated invasiveness and immune suppression. SX-007, an orally active, small-molecule TGF-betaRI kinase inhibitor, was evaluated for its therapeutic potential in cell culture and in an in vivo glioma model.

Small-scale temporal variation and the effect of urbanisation on extracellular enzyme activity in streams.

The activity of six extracellular enzymes involved in the degradation of dissolved organic carbon compounds was measured in two highly urbanised and two minimally impacted streams east of Melbourne, Australia, using 4-methylumbelliferyl-substrates. Small-scale temporal variation in enzyme activity was determined by repeatedly sampling the same point in the water column, while the effect of flow was determined by sampling in regions of higher and lower flow in both stream types. Replicate samples showed that enzyme activity was not significantly different over small (minutes) time scales.

Assessing long-term pH change in an Australian river catchment using monitoring and palaeolimnological data.

Reviews of stream monitoring data suggest that there has been significant acidification (>1.0 pH unit at some sites) of Victorian streamwaters over the past 3 decades. To assess whether these declines are within the range of natural variability, we developed a diatom model for inferring past pH and applied it to a ca.

Asymmetric synthesis of the carbapenam core from serine.

The stereospecific synthesis of the functionalized carbapenam core 16 from the serine-derived trisubstituted pyrrolidine 9 is reported. The synthetic strategy relies on synthesizing an appropriately functionalized pyrrolidine, followed by an intramolecular azetidone formation utilizing a modified Mukiyama reagent. The efficient one-pot conversion of the benzenesulfonamide-protected pyrrolidine 9 to the Cbz-protected pyrrolidine 10 is also reported.

Nutrient budget for Saguling Reservoir, West Java, Indonesia.

A preliminary nutrient budget for Saguling Reservoir is reported as a first attempt to quantify the behaviour of nutrients entering this reservoir. This work is part of a larger Indonesia-Australia collaborative research and training project, involving Padjadjaran University and Monash University, established to study nutrient dynamics in Saguling Reservoir. Saguling Reservoir, the first of a chain of three large reservoirs (Saguling, Cirata and Jatilahur), built on the Citarum River in central Java, was completed in 1985.

Luxury uptake of phosphorus by sediment bacteria.

This note reports the results of experiments aimed at confirming the luxury uptake of phosphorus (P) by sediment bacteria as polyphosphate (Poly-P). Aerobic suspensions of sediments from two different sites were spiked with 1 mg P/L as orthophosphate and augmented with acetate (a fermentation product) or glucose. The orthophosphate was rapidly taken up over a period of a few hours.

Conformationally Constrained 7-Azabicyclo[2.2.1]heptane Amino Acids. Synthesis of a Glutamic Acid Analogue.

We report the synthesis of 2-substituted 7-azabicyclo[2.2.1]heptane glutamic acid analogue 27 from L-serine.