G-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis.

Altered hepatic glucose fluxes are critical during the pathogenesis of type 2 diabetes. G protein-coupled receptors represent important regulators of hepatic glucose production. Recent studies have shown that hepatocytes express GPCRs that can couple to G, a subfamily of heterotrimeric G proteins that has attracted relatively little attention in the past.

Cryo-EM structure of the CBC-ALYREF complex.

In eukaryotes, RNAs transcribed by RNA Pol II are modified at the 5' end with a 7-methylguanosine (mG) cap, which is recognized by the nuclear cap binding complex (CBC). The CBC plays multiple important roles in mRNA metabolism, including transcription, splicing, polyadenylation, and export. It promotes mRNA export through direct interaction with a key mRNA export factor, ALYREF, which in turn links the TRanscription and EXport (TREX) complex to the 5' end of mRNA.

Optimizing NMR fragment-based drug screening for membrane protein targets.

NMR spectroscopy has played a pivotal role in fragment-based drug discovery by coupling detection of weak ligand-target binding with structural mapping of the binding site. Fragment-based screening by NMR has been successfully applied to many soluble protein targets, but only to a limited number of membrane proteins, despite the fact that many drug targets are membrane proteins. This is partly because of difficulties preparing membrane proteins for NMR-especially human membrane proteins-and because of the inherent complexity associated with solution NMR spectroscopy on membrane protein samples, which require the inclusion of membrane-mimetic agents such as micelles, nanodiscs, or bicelles.

Purinergic Ca signaling as a novel mechanism of drug tolerance in BRAF mutant melanoma.

Drug tolerance is a major cause of relapse after cancer treatment. In spite of intensive efforts, its molecular basis remains poorly understood, hampering actionable intervention. We report a previously unrecognized signaling mechanism supporting drug tolerance in BRAF-mutant melanoma treated with BRAF inhibitors that could be of general relevance to other cancers.

Independent regulation of Z-lines and M-lines during sarcomere assembly in cardiac myocytes revealed by the automatic image analysis software sarcApp.

Sarcomeres are the basic contractile units within cardiac myocytes, and the collective shortening of sarcomeres aligned along myofibrils generates the force driving the heartbeat. The alignment of the individual sarcomeres is important for proper force generation, and misaligned sarcomeres are associated with diseases, including cardiomyopathies and COVID-19. The actin bundling protein, α-actinin-2, localizes to the 'Z-Bodies" of sarcomere precursors and the 'Z-Lines' of sarcomeres, and has been used previously to assess sarcomere assembly and maintenance.

Clustering of Ca 1.3 L-type calcium channels by Shank3.

Clustering of L-type voltage-gated Ca channels (LTCCs) in the plasma membrane is increasingly implicated in creating highly localized Ca signaling nanodomains. For example, neuronal LTCC activation can increase phosphorylation of the nuclear CREB transcription factor by increasing Ca concentrations within a nanodomain close to the channel, without requiring bulk Ca increases in the cytosol or nucleus. However, the molecular basis for LTCC clustering is poorly understood.

Independent regulation of Z-lines and M-lines during sarcomere assembly in cardiac myocytes revealed by the automatic image analysis software sarcApp.

Sarcomeres are the basic contractile units within cardiac myocytes, and the collective shortening of sarcomeres aligned along myofibrils generates the force driving the heartbeat. The alignment of the individual sarcomeres is important for proper force generation, and misaligned sarcomeres are associated with diseases including cardiomyopathies and COVID-19. The actin bundling protein, α-actinin-2, localizes to the "Z-Bodies" of sarcomere precursors and the "Z-Lines" of sarcomeres, and has been used previously to assess sarcomere assembly and maintenance.

Efficacy and safety of Tregopil, a novel, ultra-rapid acting oral prandial insulin analog, as part of a basal-bolus regimen in type 2 diabetes: a randomized, active-controlled phase 2/3 study.

Background: Efficacy and safety of ultra-rapid acting oral prandial insulin Tregopil was compared with insulin aspart (IAsp) in patients with type 2 diabetes (T2D) on insulin glargine and metformin.

Research Design And Methods: In this open-label, active-controlled trial, patients with T2D, HbA ≥7%-≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized 1:1:1 to Tregopil (30 mg, = 30; 45 mg, = 31) and IAsp, = 30. Primary outcome was change from baseline (CFB) in HbA at week 24.

Cooperative RNA degradation stabilizes intermediate epithelial-mesenchymal states and supports a phenotypic continuum.

Multiple intermediate epithelial-mesenchymal transition (EMT) states reflecting hybrid epithelial and mesenchymal phenotypes were observed in physiological and pathological conditions. Previous theoretical models explaining multiple EMT states rely on regulatory loops involving transcriptional feedback, which produce three or four attractors. This is incompatible with the observed continuum-like EMT spectrum.

Compendium of proteins containing segments that exhibit zero-tolerance to amino acid variation in humans.

Genetic missense tolerance ratio (MTR) analysis systematically evaluates all possible segments in a given protein-encoding transcript found in the human population. This method scores each segment for the number of observed missense variants versus the number of silent mutations in that same segment. An MTR score of 0 indicates that no missense mutations are observed within a given segment.

Compendium of causative genes and their encoded proteins for common monogenic disorders.

A compendium is presented of inherited monogenic disorders that have a prevalence of >1:20,000 in the human population, along with their causative genes and encoded proteins. "Simple" monogenic diseases are those for which the clinical features are caused by mutations impacting a single gene, usually in a manner that alters the sequence of the encoded protein. Of course, for a given "monogenic disorder", there is sometimes more than one potential disease gene, mutations in any one of which is sufficient to cause phenotypes of that disorder.

Ion mobility-mass spectrometry reveals the role of peripheral myelin protein dimers in peripheral neuropathy.

Peripheral myelin protein (PMP22) is an integral membrane protein that traffics inefficiently even in wild-type (WT) form, with only 20% of the WT protein reaching its final plasma membrane destination in myelinating Schwann cells. Misfolding of PMP22 has been identified as a key factor in multiple peripheral neuropathies, including Charcot-Marie-Tooth disease and Dejerine-Sottas syndrome. While biophysical analyses of disease-associated PMP22 mutants show altered protein stabilities, leading to reduced surface trafficking and loss of PMP22 function, it remains unclear how destabilization of PMP22 mutations causes mistrafficking.

Bicelles Rich in both Sphingolipids and Cholesterol and Their Use in Studies of Membrane Proteins.

How the distinctive lipid composition of mammalian plasma membranes impacts membrane protein structure is largely unexplored, partly because of the dearth of isotropic model membrane systems that contain abundant sphingolipids and cholesterol. This gap is addressed by showing that phingomyelin and hlesterol-ich (SCOR) lipid mixtures with phosphatidylcholine can be cosolubilized by -dodecyl-β-melibioside to form bicelles. Small-angle X-ray and neutron scattering, as well as cryo-electron microscopy, demonstrate that these assemblies are stable over a wide range of conditions and exhibit the bilayered-disc morphology of ideal bicelles even at low lipid-to-detergent mole ratios.

Structures Illuminate Cardiac Ion Channel Functions in Health and in Long QT Syndrome.

The cardiac action potential is critical to the production of a synchronized heartbeat. This electrical impulse is governed by the intricate activity of cardiac ion channels, among them the cardiac voltage-gated potassium (K) channels KCNQ1 and hERG as well as the voltage-gated sodium (Na) channel encoded by . Each channel performs a highly distinct function, despite sharing a common topology and structural components.

Life During Wartime: A Personal Recollection of the Circa 1990 Prestegard Lab and Its Contributions to Membrane Biophysics.

A subjective account is presented of challenges and excitement of being a postdoctoral trainee in the lab of James H. Prestegard at Yale University in New Haven, Connecticut from 1989 to 1991. This includes accounts of the early development of bicelles and of oriented sample NMR results that contributed to our modern understanding of the properties of the water-lipid interface of disordered phase biological membranes.

NMR resonance assignments and secondary structure of a mutant form of the human KCNE1 channel accessory protein that exhibits KCNE3-like function.

KCNQ1 (Q1) is a voltage-gated potassium channel that is modulated by members of the KCNE family, the best-characterized being KCNE1 (E1) and KCNE3 (E3). The Q1/E1 complex generates a channel with delayed activation and increased conductance. This complex is expressed in cardiomyocytes where it provides the I current that is critical for the repolarization phase of the cardiac action potential.

De novo designed transmembrane peptides activating the α5β1 integrin.

Computationally designed transmembrane α-helical peptides (CHAMP) have been used to compete for helix-helix interactions within the membrane, enabling the ability to probe the activation of the integrins αIIbβ3 and αvβ3. Here, this method is extended towards the design of CHAMP peptides that inhibit the association of the α5β1 transmembrane (TM) domains, targeting the Ala-X3-Gly motif within α5. Our previous design algorithm was performed alongside a new workflow implemented within the widely used Rosetta molecular modeling suite.