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Calcium signals drive an endless array of cellular responses including secretion, contraction, transcription, cell division, and growth. The ubiquitously expressed Orai family of plasma membrane (PM) ion channels mediate Ca2+ entry signals triggered by the Ca2+ sensor Stromal Interaction Molecule (STIM) proteins of the endoplasmic reticulum (ER). The 2 proteins interact within curiously obscure ER-PM junctions, driving an allosteric gating mechanism for the Orai channel. Although key to Ca2+ signal generation, molecular understanding of this activation process remain obscure. Crystallographic structural analyses reveal much about the exquisite hexameric core structure of Orai channels. But how STIM proteins bind to the channel periphery and remotely control opening of the central pore, has eluded such analysis. Recent studies apply both crystallography and single-particle cryogenic electron microscopy (cryo-EM) analyses to probe the structure of Orai mutants that mimic activation by STIM. The results provide new understanding on the open state of the channel and how STIM proteins may exert remote allosteric control of channel gating.

Although the consequences of teen births for both mothers and children have been studied for decades, few studies have taken a broader look at the potential payoffs—and drawbacks—of being born to older mothers. A broader examination is important given the growing gap in maternal ages at birth for children born to mothers with low and high socioeconomic status. Drawing data from the Children of the NLSY79, our examination of this topic distinguishes between the value for children of being born to a mother who delayed her first birth and the value of the additional years between her first birth and the birth of the child whose achievements and behaviors at ages 10-13 are under study. We find that each year the mother delays a first birth is associated with a 0.02 to 0.04 standard deviation increase in school achievement and a similar-sized reduction in behavior problems. Coefficients are generally as large for additional years between the first and given birth. Results are fairly robust to the inclusion of cousin and sibling fixed effects, which attempt to address some omitted variable concerns. Our mediational analyses show that the primary pathway by which delaying first births benefits children is by enabling mothers to complete more years of schooling.

In many excitable cells, KATP channels respond to intracellular adenosine nucleotides: ATP inhibits while ADP activates. We present two structures of the human pancreatic KATP channel, containing the ABC transporter SUR1 and the inward-rectifier K+ channel Kir6.2, in the presence of Mg2+ and nucleotides. These structures, referred to as quatrefoil and propeller forms, were determined by single-particle cryo-EM at 3.9 Å and 5.6 Å, respectively. In both forms, ATP occupies the inhibitory site in Kir6.2. The nucleotide-binding domains of SUR1 are dimerized with Mg2+-ATP in the degenerate site and Mg2+-ADP in the consensus site. A lasso extension forms an interface between SUR1 and Kir6.2 adjacent to the ATP site in the propeller form and is disrupted in the quatrefoil form. These structures support the role of SUR1 as an ADP sensor and highlight the lasso extension as a key regulatory element in ADP’s ability to override ATP inhibition. A hormone called insulin finely controls the amount of sugar in the blood. When the blood sugar content is high, a group of cells in the pancreas release insulin; when it is low, they stop. In these cells, the level of sugar in the blood modifies the ratio of two molecules: ATP, the body’s energy currency, and ADP, a molecule closely related to ATP. Changes in the ATP/ADP ratio are therefore a proxy of the variations in blood sugar levels. In these pancreatic cells, a membrane protein called ATP sensitive potassium channel, KATP channel for short, acts as a switch that turns on and off the production of insulin. ATP and ADP control that switch, with the two molecules having opposite effects on the channel – ATP deactivates it, ADP activates it. The changes in ATP/ADP ratio – and by extension in blood sugar levels – are therefore coupled with the release of insulin. However, how KATP channels sense the changes in the ATP/ADP ratio in these cells is still unclear. In particular, ATP levels are usually high and constant: ATP is then continuously deactivating the channels, and it is unclear how ADP ever activates them. Here, Lee et al. use a microscopy technique that can image biological molecules at the atomic scale to look at the structure of human pancreatic KATP channels. The 3D reconstruction maps show that KATP channels have binding sites for ATP but also one for ADP. This ADP site acts as a sensor that can detect even small changes in ADP levels in the cell. The maps also reveal a dynamic lasso-like structure connecting the ATP and ADP binding areas. This domain may play a vital role in allowing ADP to override ATP’s control of the channel. The presence of the ADP sensor and the lasso structure could explain how KATP channels monitor changes in the ATP/ADP ratio and can therefore control the release of insulin based on blood sugar levels. Defects in the KATP channels of the pancreas are present in genetic diseases where infants produce too much or too little insulin. Understanding the structure of these channels and how they work may help scientists to design new drugs to treat these conditions.

ObjectiveDNA-based testing of pancreatic cyst fluid (PCF) is a useful adjunct to the evaluation of pancreatic cysts (PCs). Mutations in KRAS/GNAS are highly specific for intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), while TP53/PIK3CA/PTEN alterations are associated with advanced neoplasia. A prospective study was performed to evaluate preoperative PCF DNA testing.DesignOver 43-months, 626 PCF specimens from 595 patients were obtained by endoscopic ultrasound (EUS)-fine needle aspiration and assessed by targeted next-generation sequencing (NGS). Molecular results were correlated with EUS findings, ancillary studies and follow-up. A separate cohort of 159 PCF specimens was also evaluated for KRAS/GNAS mutations by Sanger sequencing.Results KRAS/GNAS mutations were identified in 308 (49%) PCs, while alterations in TP53/PIK3CA/PTEN were present in 35 (6%) cases. Based on 102 (17%) patients with surgical follow-up, KRAS/GNAS mutations were detected in 56 (100%) IPMNs and 3 (30%) MCNs, and associated with 89% sensitivity and 100% specificity for a mucinous PC. In comparison, KRAS/GNAS mutations by Sanger sequencing had a 65% sensitivity and 100% specificity. By NGS, the combination of KRAS/GNAS mutations and alterations in TP53/PIK3CA/PTEN had an 89% sensitivity and 100% specificity for advanced neoplasia. Ductal dilatation, a mural nodule and malignant cytopathology had lower sensitivities (42%, 32% and 32%, respectively) and specificities (74%, 94% and 98%, respectively).ConclusionsIn contrast to Sanger sequencing, preoperative NGS of PCF for KRAS/GNAS mutations is highly sensitive for IPMNs and specific for mucinous PCs. In addition, the combination of TP53/PIK3CA/PTEN alterations is a useful preoperative marker for advanced neoplasia.

The development of hybrid quantum systems is central to the advancement of emerging quantum technologies, including quantum information science and quantum-assisted sensing. The recent demonstration of high-quality single-crystal diamond resonators has led to significant interest in a hybrid system consisting of nitrogen–vacancy centre spins that interact with the resonant phonon modes of a macroscopic mechanical resonator through crystal strain. However, the nitrogen–vacancy spin–strain interaction has not been well characterized. Here, we demonstrate dynamic, strain-mediated coupling of the mechanical motion of a diamond cantilever to the spin of an embedded nitrogen–vacancy centre. Via quantum control of the spin, we quantitatively characterize the axial and transverse strain sensitivities of the nitrogen–vacancy ground-state spin. The nitrogen–vacancy centre is an atomic scale sensor and we demonstrate spin-based strain imaging with a strain sensitivity of 3 × 10 −6 strain Hz −1/2 . Finally, we show how this spin-resonator system could enable coherent spin–phonon interactions in the quantum regime. Hybrid systems composed of defect centres in diamond and mechanical resonators are promising for studies in quantum information science and optomechanics. Here, the authors show direct coupling of the spin of a nitrogen–vacancy centre to a diamond cantilever through lattice strain.

Key Points Histone acetyltransferase (HAT) enzymes are a diverse group of proteins that are evolutionarily conserved from yeast to humans. Although originally identified as enzymes that acetylate histones, a growing number of non-histone substrates have been identified for HATs, which implies a more general role in regulating the function of an ever-growing number of proteins. Based on structural evidence, HAT enzymes can accommodate a number of substrates; therefore, the functions of these enzymes are much more varied than simply modifying histones post-translationally. Although the HAT enzyme is the catalytic subunit that is required for activity, it is the context in which these enzymes exist that provides the enzyme with specificity. Most HAT enzymes exist in multiprotein complexes, and it is these proteins that allow the enzymes to carry out specific functions in the cell. Many HAT-associated proteins contain domains, which can recognize and bind modified protein residues. This includes bromo-, chromo- and PHD (plant homeodomain) domains, which are able to bind modified histones. HAT enzymes carry out several functions in the cell, ranging from repairing regions of DNA damage to maintaining overall genomic integrity. Future work needs to focus on understanding developmental and tissue-specific HAT complexes while continuing to explore the mechanisms by which an organism maintains the balance of acetylation. Histone acetyltransferases (HATs) are highly diverse multiprotein complexes that carry out diverse functions, ranging from repairing regions of DNA damage to maintaining overall genomic integrity. HATs are regulated by associated factors and by the dynamic interplay with existing histone modifications. Over the past 10 years, the study of histone acetyltransferases (HATs) has advanced significantly, and a number of HATs have been isolated from various organisms. It emerged that HATs are highly diverse and generally contain multiple subunits. The functions of the catalytic subunit depend largely on the context of the other subunits in the complex. We are just beginning to understand the specialized roles of HAT complexes in chromosome decondensation, DNA-damage repair and the modification of non-histone substrates, as well as their role in the broader epigenetic landscape, including the role of protein domains within HAT complexes and the dynamic interplay between HAT complexes and existing histone modifications.

Effects associated with early child care and out-of-school time (OST) during middle childhood were examined in a large sample of U.S. adolescents (N = 958). Both higher quality early child care AND more epochs of organized activities (afterschool programs and extracurricular activities) during middle childhood were linked to higher academic achievement at age 15. Differential associations were found in the behavioral domain. Higher quality early child care was associated with fewer externalizing problems, whereas more hours of early child care was linked to greater impulsivity. More epochs of organized activities was associated with greater social confidence. Relations between early child care and adolescent outcomes were not mediated or moderated by OST arrangements in middle childhood, consistent with independent, additive relations of these nonfamilial settings.

In this randomized study of patients with upper gastrointestinal bleeding, infusion of omeprazole, as compared with placebo, before endoscopy reduced the incidence of endoscopic treatment (19.1% vs. 28.4%, P=0.007) and, among patients with peptic ulcers, resulted in fewer actively bleeding ulcers and more ulcers with clean bases. These findings suggest that infused omeprazole is beneficial for patients with upper gastrointestinal bleeding who are awaiting endoscopy. In patients with upper gastrointestinal bleeding, infusion of omeprazole before endoscopy reduced the incidence of endoscopic treatment (19.1% vs. 28.4%) and, among patients with peptic ulcers, resulted in fewer actively bleeding ulcers and more ulcers with clean bases. In patients with bleeding peptic ulcers, we previously showed that infusion of a high-dose proton-pump inhibitor after hemostasis had been achieved during endoscopy reduced recurrent bleeding and improved clinical outcomes. 1 The adjuvant use of high-dose proton-pump inhibitors in endoscopic therapy has also been endorsed in two consensus statements 2 , 3 and confirmed in two meta-analyses. 4 , 5 Clot formation over arteries is pH dependent; a gastric pH above 6 is thought to be critical for platelet aggregation. 6 When given intravenously and at a high dose, proton-pump inhibitors can be used to maintain a neutral gastric pH. 7 In clinical practice, treatment with proton-pump . . .