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Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia.

Introduction Natural orifice translumenal endoscopic surgery (NOTES) is a rapidly evolving field that provides endoscopic access to the peritoneum via a natural orifice. One important requirement of this technique is the need to minimize the risk of clinically significant peritoneal contamination. We report the bacterial load and contamination of the peritoneal cavity in ten patients who underwent diagnostic transgastric endoscopic peritoneoscopy. Methods Patients participating in this trial were scheduled to undergo diagnostic laparoscopy for evaluation of presumed pancreatic cancer. Findings at diagnostic laparoscopy were compared with those of diagnostic transgastric endoscopic peritoneoscopy, using an orally placed gastroscope, blinding the endoscopist to the laparoscopic findings. We performed no gastric decontamination. Diagnostic findings, operative times, and clinical course were recorded. Gastroscope and peritoneal fluid aspirates were obtained prior to and after the gastrotomy. Each sample was sent for bacterial colony counts, culture, and identification of species. Results Ten patients, with an average age of 63.7 years, have completed the protocol. All patients underwent diagnostic laparoscopy followed by successful transgastric access and diagnostic peritoneoscopy. The average time for laparoscopy was 7.2 min, compared with 18 min for transgastric instrumentation. Bacterial sampling was obtained in all ten patients. The average number of colony-forming units (CFU) in the gastroscope aspirate was 132.1 CFU/ml, peritoneal aspirates prior to creation of a gastrotomy showed 160.4 CFU/ml, and peritoneal sampling after gastrotomy had an average of 642.1 CFU/ml. There was no contamination of the peritoneal cavity with species isolated from the gastroscope aspirate. No infectious complications or leaks were noted at 30-day follow-up. Conclusions There was no clinically significant contamination of the peritoneal cavity from the gastroscope after transgastric endoscopic instrumentation in humans. Transgastric instrumentation does contaminate the abdominal cavity but, the pathogens do not mount a clinically significant response in terms of either the species or the bacterial load.

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax , and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi . We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria. The lipid kinase phosphatidylinositol-4-OH kinase (PI(4)K) is identified as a target of the imidazopyrazines, a new antimalarial compound class that can inhibit several Plasmodium species at each stage of the parasite life cycle; the imidazopyrazines exert their inhibitory action by interacting with the ATP-binding pocket of PI(4)K. A multifunction target for antimalarials To eliminate malaria completely it is necessary to cure an individual of all stages in the malaria parasite's life cycle including the symptomatic blood-stage infection and the preceding liver-stage infection (to prevent relapse) and also to block transmission to mosquitoes. Here Elizabeth Winzeler and colleagues identify phosphatidylinositol-4-OH kinase (PI(4)K) as a potential drug target that is essential to fatty acid metabolism in all stages of the Plasmodium parasite. The authors show that a family of compounds with an imidazopyrazine core, distinct from known antimalarials, inhibits PI(4)K and also inhibits the development of multiple Plasmodium species at each stage of the life cycle. Their analyses reveal that the imidazopyrazines interact with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4 phosphate and interfering with cell division.

Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of > 4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.

Precise measurement of the cosmic microwave background (CMB) radiation holds the key to a surprising quantity of knowledge about cosmology and the early universe. Measurement of the power spectrum of the CMB yields information about inflation and gravitational waves in the early universe, the mass of the neutrino, and the number of effective neutrino species. As CMB photons pass through our universe, the interaction they have with its contents yield even more information. Scattering of the CMB photons off of the electrons in galaxy clusters can be used to extract the movement of those galaxy clusters, and gravitational lensing of the CMB photons tells the story of the evolution of massive structures in our universe. Extracting this information requires an extreme level of precision and care in the detection of these photons. This dissertation covers a number of subjects related to measuring CMB photons with telescopes in Chile. I first discuss the superconducting transition edge sensors used on some of these telescopes, and the testing and characterization of these sensors for the Simons Observatory. It is necessary to multiplex the detector signals to reduce thermal load on the cryostat cold stages, so I then discuss testing and characterization strategies for superconducting multiplexers. This begins with characterization of the time domain multiplexing chips used on Advanced ACTPol, and leads into characterization of microwave multiplexing chips like those that will be used in the Simons Observatory. Next, I present methods for designing and optimizing wide area CMB survey strategies from Chile, including the strategies that are used in Advanced ACTPol and the strategies that will be used in the Simons Observatory. I then describe recent results from the Atacama Cosmology Telescope that this work has contributed to. I conclude by summarizing the improvements we will see in measurements of the CMB from new observatories in the coming years.

Abstract Dysfunctional liver regeneration following surgical resection remains a major cause of postoperative mortality and has no therapeutic options. Without targeted therapies, the current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration represents an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration with an emphasis on diseased models, which represent a significant portion of patients who require surgical resection and are often not studied. Utilizing a clinically approved small molecule inhibitor as a parent compound, standard medicinal chemistry approaches were utilized to generate a small molecule inhibitor targeting serine/threonine kinase 4/3 (MST1/2) with reduced off-target effects. This compound, mCLC846, was then applied to preclinical models of murine partial hepatectomy, which included models of diet-induced metabolic dysfunction-associated steatohepatitis (MASH). mCLC846 demonstrated on target inhibition of MST1/2 and reduced epidermal growth factor receptor inhibition. The inhibitory effects resulted in restored pancreatic beta-cell function and survival under diabetogenic conditions. Liver-specific cell-line exposure resulted in Yes-associated protein activation. Oral delivery of mCLC846 perioperatively resulted in accelerated murine liver regeneration and improved survival in diet-induced MASH models. Bulk transcriptional analysis of regenerating liver remnants suggested that mCLC846 enhanced the normal regenerative pathways and induced them following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided a survival benefit in models of diet-induced MASH.

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here, we identify a lipid kinase, phosphatidylinositol 4-kinase (PI4K), as the target of imidazopyrazines, a novel antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens, P. falciparum and P. vivax, and inhibit liver stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI4K, altering the intracellular distribution of phosphatidylinositol 4-phosphate. Collectively, our data define PI4K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of SREBP1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here, we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in liver that lead to hypertriglyceridemia.

A long lasting challenge in polymer science is to design polymers that combine desired mechanical properties such as tensile strength, fracture toughness, and elasticity into one structure. A novel biomimetic modular polymer design is reported here to address this challenge. Following the molecular mechanism used in nature, modular polymers containing multiple loops were constructed by using precise and strong hydrogen bonding units. Single-molecule force-extension experiments revealed the sequential unfolding of loops as a chain is stretched. The excellent correlation between the single-molecule and the bulk properties successfully demonstrates our biomimetic concept of using modular domain structure to achieve advanced polymer properties.