Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases.

Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased Vmax with unchanged Km), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes.

New tyrannosaur from the mid-Cretaceous of Uzbekistan clarifies evolution of giant body sizes and advanced senses in tyrant dinosaurs.

Tyrannosaurids--the familiar group of carnivorous dinosaurs including Tyrannosaurus and Albertosaurus--were the apex predators in continental ecosystems in Asia and North America during the latest Cretaceous (ca. 80-66 million years ago). Their colossal sizes and keen senses are considered key to their evolutionary and ecological success, but little is known about how these features developed as tyrannosaurids evolved from smaller basal tyrannosauroids that first appeared in the fossil record in the Middle Jurassic (ca. 170 million years ago). This is largely because of a frustrating 20+ million-year gap in the mid-Cretaceous fossil record, when tyrannosauroids transitioned from small-bodied hunters to gigantic apex predators but from which no diagnostic specimens are known. We describe the first distinct tyrannosauroid species from this gap, based on a highly derived braincase and a variety of other skeletal elements from the Turonian (ca. 90-92 million years ago) of Uzbekistan. This taxon is phylogenetically intermediate between the oldest basal tyrannosauroids and the latest Cretaceous forms. It had yet to develop the giant size and extensive cranial pneumaticity of T. rex and kin but does possess the highly derived brain and inner ear characteristic of the latest Cretaceous species. Tyrannosauroids apparently developed huge size rapidly during the latest Cretaceous, and their success in the top predator role may have been enabled by their brain and keen senses that first evolved at smaller body size.

Peripherally inserted central catheter placement in a multidisciplinary intensive care unit: A preliminary study demonstrating safety and procedural time in critically ill subjects.

OBJECTIVE: Peripherally inserted central catheters are a popular means of obtaining central venous access in critically ill patients. However, there is limited data regarding the rapidity of the peripherally inserted central catheter procedure in the presence of acute illness or obesity, both of which may impede central venous catheter placement. We aimed to determine the feasibility, safety, and duration of peripherally inserted central catheter placement in critically ill patients, including obese patients and patients in shock. METHODS: This retrospective cohort study was performed using data on 55 peripherally inserted central catheters placed in a 30-bed multidisciplinary intensive care unit in Mayo Clinic Hospital, Phoenix, Arizona. Information on the time required to complete each step of the peripherally inserted central catheter procedure, associated complications, and patient characteristics was obtained from a prospectively assembled internal quality assurance database created through random convenience sampling. RESULTS: The Median Procedure Time, beginning with the first needle puncture and ending when the procedure is complete, was 14 (interquartile range: 9-20) min. Neither critical illness nor obesity resulted in a statistically significant increase in the time required to complete the peripherally inserted central catheter procedure. Three (5.5%) minor complications were observed. CONCLUSION: Critical illness and obesity do not delay the acquisition of vascular access when placing a peripherally inserted central catheter. Concerns of delayed vascular access in critically ill patients should not deter a physician from selecting a peripherally inserted central catheter to provide vascular access when it would otherwise be appropriate.

Neurosensory and Sinus Evolution as Tyrannosauroid Dinosaurs Developed Giant Size: Insight from the Endocranial Anatomy of Bistahieversor sealeyi.

Tyrannosaurus rex and other tyrannosaurid dinosaurs were apex predators during the latest Cretaceous, which combined giant size and advanced neurosensory systems. Computed tomography (CT) data have shown that tyrannosaurids had a trademark system of a large brain, large olfactory bulbs, elongate cochlear ducts, and expansive endocranial sinuses surrounding the brain and sense organs. Older, smaller tyrannosauroid relatives of tyrannosaurids developed some, but not all, of these features, raising the hypothesis that tyrannosaurid-style brains evolved before the enlarged tyrannosaurid-style sinuses, which might have developed only with large body size. This has been difficult to test, however, because little is known about the brains and sinuses of the first large-bodied tyrannosauroids, which evolved prior to Tyrannosauridae. We here present the first CT data for one of these species, Bistahieversor sealeyi from New Mexico. Bistahieversor had a nearly identical brain and sinus system as tyrannosaurids like Tyrannosaurus, including a large brain, large olfactory bulbs, reduced cerebral hemispheres, and optic lobes, a small tab-like flocculus, long and straight cochlear ducts, and voluminous sinuses that include a supraocciptal recess, subcondyar sinus, and an anterior tympanic recess that exits the braincase via a prootic fossa. When characters are plotted onto tyrannosauroid phylogeny, there is a two-stage sequence in which features of the tyrannosaurid-style brain evolved first (in smaller, nontyrannosaurid species like Timurlengia), followed by features of the tyrannosaurid-style sinuses (in the first large-bodied nontyrannosaurid tyrannosauroids like Bistahieversor). This suggests that the signature tyrannosaurid sinus system evolved in concert with large size, whereas the brain did not. Anat Rec, 303:1043-1059, 2020. © 2020 American Association for Anatomy.

The Braincase and Neurosensory Anatomy of an Early Jurassic Marine Crocodylomorph: Implications for Crocodylian Sinus Evolution and Sensory Transitions.

Modern crocodylians are a morphologically conservative group, but extinct relatives (crocodylomorphs) experimented with a wide range of diets, behaviors, and body sizes. Among the most unusual of these fossil groups is the thalattosuchians, an assemblage of marine-dwellers that transitioned from semiaquatic species (teleosaurids and kin) into purely open-ocean forms (metriorhynchids) during the Jurassic and Cretaceous Periods (ca 191-125 million years ago). Thalattosuchians can give insight into the origin of modern crocodylian morphologies and how anatomy and behavior change during a major evolutionary transition into a new habitat. Little is known, however, about their brains, sensory systems, cranial sinuses, and vasculature. We here describe the endocranial anatomy of a well-preserved specimen of the Jurassic semiaquatic teleosaurid Steneosaurus cf. gracilirostris using X-ray micro-CT. We find that this teleosaurid still had an ear well attuned to hear on land, but had developed large internal carotid and orbital arteries that likely supplied salt glands, previously thought to be present in only the fully pelagic metriorhynchids. There is no great gulf in endocranial anatomy between this teleosaurid and the metriorhynchids, and some of the features that later permitted metriorhynchids to invade the oceanic realm were apparently first developed in semiaquatic taxa. Compared to modern crocodylians, Steneosaurus cf. gracilirostris has a more limited set of pharyngotympanic sinuses, but it is unclear whether this relates to its aquatic habitat or represents the primitive condition of crocodylomorphs that was later elaborated. Anat Rec, 299:1511-1530, 2016. © 2016 Wiley Periodicals, Inc.