Concise Synthesis of Naphthalene-Based 14-Aza-12-Oxasteroids.

A concise, transition metal-free four-step synthetic pathway has been developed for the synthesis of tetracyclic heterosteroidal compounds, 14-aza-12-oxasteroids, starting from readily available 2-naphthol analogues. After conversion of 2-naphthols to 2-naphthylamines by the Bucherer reaction, subsequent selective C-acetylation was achieved via the Sugasawa reaction and reduction of the acetyl group using borohydride, which resulted into the corresponding amino-alcohols. The naphthalene-based amino-alcohols underwent double dehydrations and double intramolecular cyclization with oxo-acids leading to one-pot formation of a C-N bond, a C-O bond and an amide bond in tandem, to generate two additional rings completing the steroidal framework.

Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.

The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target.

Impacts of chloride-form anion exchange seawater regeneration performance.

Seawater was investigated as an alternative regenerant source to conventional salt-imported brine solutions in an anion exchange process treating surficial Florida coastal groundwater for the removal of sulfate and organics. Bench-scale column testing revealed that filtered Sarasota Bay seawater efficiently regenerated the anion resin media; however, sulfate exchange capacity decreased by 8.42% compared with conventional 10% salt regeneration methods.

Physician networks and potentially inappropriate opioid prescriptions.

Opioid overdose is a national health priority and curbing inappropriate prescribing is critical. In 2016, the Centers for Disease Control and Prevention (CDC) issued appropriate prescribing guidelines. Examine associations between care networks defined by shared patients and problematic opioid prescribing.

Kinase domain dimerization drives RIPK3-dependent necroptosis.

Necroptosis, an inflammatory form of cell death, is initiated by the activation of receptor-interacting protein kinase 3 (RIPK3), which depends on its interaction with RIPK1. Although catalytically inactive, the RIPK3 mutant D161N still stimulates RIPK1-dependent apoptosis and embryonic lethality in RIPK3 D161N homozygous mice. Whereas the absence of RIPK1 rescues RIPK3 D161N homozygous mice, we report that the absence of RIPK1 leads to embryonic lethality in RIPK3 D161N heterozygous mice.

Behavioral Health's Integration Within a Care Network and Health Care Utilization.

Objective: Examine how behavioral health (BH) integration affects health care costs, emergency department (ED) visits, and inpatient admissions.

Data Sources/study Setting: Truven Health MarketScan Research Databases.

Study Design: Social network analysis identified "care communities" (providers sharing a high number of patients) and measured BH integration in terms of how connected, or central, BH providers were to other providers in their community.

Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2.

Activating mutations in protein kinases drive many cancers. While how recurring point mutations affect kinase activity has been described, the effect of in-frame deletions is not well understood. We show that oncogenic deletions within the β3-αC loop of HER2 and BRAF are analogous to the recurrent EGFR exon 19 deletions.

Shining LIGHT on functional promiscuity in the TNF and TNFR superfamilies.

In this issue of Structure, Liu and colleagues report the structure of the TNF superfamily member LIGHT bound to decoy receptor 3 (DcR3). Both LIGHT and DcR3 interact with multiple binding partners. The authors identify a conserved interaction important for affinity as well as additional interactions that can be targeted to introduce selectivity.

Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling.

The Hedgehog (Hh) signal is transduced across the membrane by the heptahelical protein Smoothened (Smo), a developmental regulator, oncoprotein and drug target in oncology. We present the 2.3 Å crystal structure of the extracellular cysteine rich domain (CRD) of vertebrate Smo and show that it binds to oxysterols, endogenous lipids that activate Hh signaling.

Pseudomonas fluorescens orchestrates a fine metabolic-balancing act to counter aluminium toxicity.

Aluminium (Al), an environmental toxin, is known to disrupt cellular functions by perturbing iron (Fe) homeostasis. However, Fe is essential for such metabolic processes as the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, the two pivotal networks that mediate ATP production during aerobiosis. To counter the Fe conundrum induced by Al toxicity, Pseudomonas fluorescens utilizes isocitrate lyase and isocitrate dehydrogenase-NADP dependent to metabolize citrate when confronted with an ineffective aconitase provoked by Al stress.

Vaccinia virus proteins A52 and B14 Share a Bcl-2-like fold but have evolved to inhibit NF-kappaB rather than apoptosis.

Vaccinia virus (VACV), the prototype poxvirus, encodes numerous proteins that modulate the host response to infection. Two such proteins, B14 and A52, act inside infected cells to inhibit activation of NF-kappaB, thereby blocking the production of pro-inflammatory cytokines. We have solved the crystal structures of A52 and B14 at 1.