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Structure of the phosphoinositide 3-kinase (PI3K) p110{gamma}-p101 complex reveals molecular mechanism of GPCR activation

The class IB phosphoinositide 3-kinase (PI3K), PI3K, is a master regulator of immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3K function is the association of the p110 catalytic subunit to either a p101 or p84 regulatory subunit, which mediates activation by G protein–coupled receptors. Here,...

Sustained oxygenation accelerates diabetic wound healing by promoting epithelialization and angiogenesis and decreasing inflammation

Nonhealing diabetic wounds are common complications for diabetic patients. Because chronic hypoxia prominently delays wound healing, sustained oxygenation to alleviate hypoxia is hypothesized to promote diabetic wound healing. However, sustained oxygenation cannot be achieved by current clinical approaches, including hyperbaric oxygen therapy. Here,...

Histone citrullination by PADI4 is required for HIF-dependent transcriptional responses to hypoxia and tumor vascularization

Hypoxia-inducible factors (HIFs) activate transcription of target genes by recruiting coactivators and chromatin-modifying enzymes. Peptidylarginine deiminase 4 (PADI4) catalyzes the deimination of histone arginine residues to citrulline. Here, we demonstrate that PADI4 expression is induced by hypoxia in a HIF-dependent manner in breast cancer and...

Synthesis of medicinally relevant oxalylamines via copper/Lewis acid synergistic catalysis

Allylamines have long been recognized as valuable synthons because of their excellent reactivity in organic synthesis. Here, an efficient amination reaction of allenyl ethers via copper/Lewis acid synergistic catalysis has been established, providing straightforward access to diverse functionalized Z-oxalylamines and E-halogenated oxalylamines in good...

Environmental vulnerability of the global ocean epipelagic plankton community interactome

Marine plankton form complex communities of interacting organisms at the base of the food web, which sustain oceanic biogeochemical cycles and help regulate climate. Although global surveys are starting to reveal ecological drivers underlying planktonic community structure and predicted climate change responses, it is unclear how community-scale species...

Myths and facts about getting an academic faculty position in neuroscience

We at the National Institute of Neurological Disorders and Stroke routinely receive questions and statements from trainees and faculty that suggest widespread beliefs about the necessity of a National Institutes of Health K99/R00 award, other prior funding, and/or specific types of publications for obtaining one’s first tenure-track position in neuroscience....

High-purity production and precise editing of DNA base editing ribonucleoproteins

Ribonucleoprotein (RNP) complex–mediated base editing is expected to be greatly beneficial because of its reduced off-target effects compared to plasmid- or viral vector–mediated gene editing, especially in therapeutic applications. However, production of recombinant cytosine base editors (CBEs) or adenine base editors (ABEs) with ample yield and high...

Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage

Double-strand breaks (DSBs) are harmful lesions and a major cause of genome instability. Studies have suggested a link between the nuclear envelope and the DNA damage response. Here, we show that lamin B1, a major component of the nuclear envelope, interacts directly with 53BP1 protein, which plays a pivotal role in the DSB repair. This interaction...

No ordinary proteins: Adsorption and molecular orientation of monoclonal antibodies

The interaction of monoclonal antibodies (mAbs) with air/water interfaces plays a crucial role in their overall stability in solution. We aim to understand this behavior using pendant bubble measurements to track the dynamic tension reduction and x-ray reflectivity to obtain the electron density profiles (EDPs) at the surface. Native immunoglobulin...

Basal nucleation and the prevalence of ascending swarms in Long Valley caldera

Earthquake swarms are ubiquitous in volcanic systems, being manifestations of underlying nontectonic processes such as magma intrusions or volatile fluid transport. The Long Valley caldera, California, is one such setting where episodic earthquake swarms and persistent uplift suggest the presence of active magmatism. We quantify the long-term spatial...

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