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Changing dynamics of the drug overdose epidemic in the United States from 1979 through 2016

Hace 11 horas 2 mins

Better understanding of the dynamics of the current U.S. overdose epidemic may aid in the development of more effective prevention and control strategies. We analyzed records of 599,255 deaths from 1979 through 2016 from the National Vital Statistics System in which accidental drug poisoning was identified as the main cause of death. By examining all available data on accidental poisoning deaths back to 1979 and showing that the overall 38-year curve is exponential, we provide evidence that the current wave of opioid overdose deaths (due to prescription opioids, heroin, and fentanyl) may just be the latest manifestation of a more fundamental longer-term process. The 38+ year smooth exponential curve of total U.S. annual accidental drug poisoning deaths is a composite of multiple distinctive subepidemics of different drugs (primarily prescription opioids, heroin, methadone, synthetic opioids, cocaine, and methamphetamine), each with its own specific demographic and geographic characteristics.

Asteroseismic detection of latitudinal differential rotation in 13 Sun-like stars

Hace 11 horas 2 mins

The differentially rotating outer layers of stars are thought to play a role in driving their magnetic activity, but the underlying mechanisms that generate and sustain differential rotation are poorly understood. We report the measurement using asteroseismology of latitudinal differential rotation in the convection zones of 40 Sun-like stars. For the most significant detections, the stars’ equators rotate approximately twice as fast as their midlatitudes. The latitudinal shear inferred from asteroseismology is much larger than predictions from numerical simulations.

Unlocking P(V): Reagents for chiral phosphorothioate synthesis

Hace 11 horas 2 mins

Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation of this chiral motif has long been hampered by the systemic use of phosphorus(III) [P(III)]–based reagent systems as the sole practical means of oligonucleotide assembly. A fundamentally different approach is described herein: the invention of a P(V)-based reagent platform for programmable, traceless, diastereoselective phosphorus-sulfur incorporation. The power of this reagent system is demonstrated through the robust and stereocontrolled synthesis of various nucleotidic architectures, including ASOs and CDNs, via an efficient, inexpensive, and operationally simple protocol.

Measurement of a superconducting qubit with a microwave photon counter

Hace 11 horas 2 mins

Fast, high-fidelity measurement is a key ingredient for quantum error correction. Conventional approaches to the measurement of superconducting qubits, involving linear amplification of a microwave probe tone followed by heterodyne detection at room temperature, do not scale well to large system sizes. We introduce an approach to measurement based on a microwave photon counter demonstrating raw single-shot measurement fidelity of 92%. Moreover, the intrinsic damping of the photon counter is used to extract the energy released by the measurement process, allowing repeated high-fidelity quantum nondemolition measurements. Our scheme provides access to the classical outcome of projective quantum measurement at the millikelvin stage and could form the basis for a scalable quantum-to-classical interface.

Self-assembly of lattices with high structural complexity from a geometrically simple molecule

Hace 11 horas 2 mins

Here we report an anomalous porous molecular crystal built of C–H···N-bonded double-layered roof-floor components and wall components of a segregatively interdigitated architecture. This complicated porous structure consists of only one type of fully aromatic multijoint molecule carrying three identical dipyridylphenyl wedges. Despite its high symmetry, this molecule accomplishes difficult tasks by using two of its three wedges for roof-floor formation and using its other wedge for wall formation. Although a C–H···N bond is extremely labile, the porous crystal maintains its porosity until thermal breakdown of the C–H···N bonds at 202°C occurs, affording a nonporous polymorph. Though this nonporous crystal survives even at 325°C, it can retrieve the parent porosity under acetonitrile vapor. These findings show how one can translate simplicity into ultrahigh complexity.

Ancient steroids establish the Ediacaran fossil Dickinsonia as one of the earliest animals

Hace 11 horas 2 mins

The enigmatic Ediacara biota (571 million to 541 million years ago) represents the first macroscopic complex organisms in the geological record and may hold the key to our understanding of the origin of animals. Ediacaran macrofossils are as "strange as life on another planet" and have evaded taxonomic classification, with interpretations ranging from marine animals or giant single-celled protists to terrestrial lichens. Here, we show that lipid biomarkers extracted from organically preserved Ediacaran macrofossils unambiguously clarify their phylogeny. Dickinsonia and its relatives solely produced cholesteroids, a hallmark of animals. Our results make these iconic members of the Ediacara biota the oldest confirmed macroscopic animals in the rock record, indicating that the appearance of the Ediacara biota was indeed a prelude to the Cambrian explosion of animal life.

Fossils reveal the complex evolutionary history of the mammalian regionalized spine

Hace 11 horas 2 mins

A unique characteristic of mammals is a vertebral column with anatomically distinct regions, but when and how this trait evolved remains unknown. We reconstructed vertebral regions and their morphological disparity in the extinct forerunners of mammals, the nonmammalian synapsids, to elucidate the evolution of mammalian axial differentiation. Mapping patterns of regionalization and disparity (heterogeneity) across amniotes reveals that both traits increased during synapsid evolution. However, the onset of regionalization predates increased heterogeneity. On the basis of inferred homology patterns, we propose a "pectoral-first" hypothesis for region acquisition, whereby evolutionary shifts in forelimb function in nonmammalian therapsids drove increasing vertebral modularity prior to differentiation of the vertebral column for specialized functions in mammals.

Programmable protein circuits in living cells

Hace 11 horas 2 mins

Synthetic protein-level circuits could enable engineering of powerful new cellular behaviors. Rational protein circuit design would be facilitated by a composable protein-protein regulation system in which individual protein components can regulate one another to create a variety of different circuit architectures. In this study, we show that engineered viral proteases can function as composable protein components, which can together implement a broad variety of circuit-level functions in mammalian cells. In this system, termed CHOMP (circuits of hacked orthogonal modular proteases), input proteases dock with and cleave target proteases to inhibit their function. These components can be connected to generate regulatory cascades, binary logic gates, and dynamic analog signal-processing functions. To demonstrate the utility of this system, we rationally designed a circuit that induces cell death in response to upstream activators of the Ras oncogene. Because CHOMP circuits can perform complex functions yet be encoded as single transcripts and delivered without genomic integration, they offer a scalable platform to facilitate protein circuit engineering for biotechnological applications.

Engineered CRISPR-Cas9 nuclease with expanded targeting space

Hace 11 horas 2 mins

The RNA-guided endonuclease Cas9 cleaves its target DNA and is a powerful genome-editing tool. However, the widely used Streptococcus pyogenes Cas9 enzyme (SpCas9) requires an NGG protospacer adjacent motif (PAM) for target recognition, thereby restricting the targetable genomic loci. Here, we report a rationally engineered SpCas9 variant (SpCas9-NG) that can recognize relaxed NG PAMs. The crystal structure revealed that the loss of the base-specific interaction with the third nucleobase is compensated by newly introduced non–base-specific interactions, thereby enabling the NG PAM recognition. We showed that SpCas9-NG induces indels at endogenous target sites bearing NG PAMs in human cells. Furthermore, we found that the fusion of SpCas9-NG and the activation-induced cytidine deaminase (AID) mediates the C-to-T conversion at target sites with NG PAMs in human cells.

Gordon Research Conferences

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New Products

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Afraid to fail? Reach out

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Comment on "U-Th dating of carbonate crusts reveals Neandertal origin of Iberian cave art"

Hace 11 horas 2 mins

Hoffmann et al. (Reports, 23 February 2018, p. 912) report the discovery of parietal art older than 64,800 years and attributed to Neanderthals, at least 25 millennia before the oldest parietal art ever found. Instead, critical evaluation of their geochronological data seems to provide stronger support for an age of 47,000 years, which is much more consistent with the archaeological background in hand.

Bacterial antagonism in host-associated microbial communities

Hace 11 horas 2 mins

Antagonistic interactions are abundant in microbial communities and contribute not only to the composition and relative proportions of their members but also to the longer-term stability of a community. This Review will largely focus on bacterial antagonism mediated by ribosomally synthesized peptides and proteins produced by members of host-associated microbial communities. We discuss recent findings on their diversity, functions, and ecological impacts. These systems play key roles in ecosystem defense, pathogen invasion, spatial segregation, and diversity but also confer indirect gains to the aggressor from products released by killed cells. Investigations into antagonistic bacterial interactions are important for our understanding of how the microbiota establish within hosts, influence health and disease, and offer insights into potential translational applications.

The periodic coloration in birds forms through a prepattern of somite origin

Hace 11 horas 2 mins

The periodic stripes and spots that often adorn animals’ coats have been largely viewed as self-organizing patterns, forming through dynamics such as Turing’s reaction-diffusion within the developing skin. Whether preexisting positional information also contributes to the periodicity and orientation of these patterns has, however, remained unclear. We used natural variation in colored stripes of juvenile galliform birds to show that stripes form in a two-step process. Autonomous signaling from the somite sets stripe position by forming a composite prepattern marked by the expression profile of agouti. Subsequently, agouti regulates stripe width through dose-dependent control of local pigment production. These results reveal that early developmental landmarks can shape periodic patterns upstream of late local dynamics, and thus constrain their evolution.

A gut-brain neural circuit for nutrient sensory transduction

Hace 11 horas 2 mins

The brain is thought to sense gut stimuli only via the passive release of hormones. This is because no connection has been described between the vagus and the putative gut epithelial sensor cell—the enteroendocrine cell. However, these electrically excitable cells contain several features of epithelial transducers. Using a mouse model, we found that enteroendocrine cells synapse with vagal neurons to transduce gut luminal signals in milliseconds by using glutamate as a neurotransmitter. These synaptically connected enteroendocrine cells are referred to henceforth as neuropod cells. The neuroepithelial circuit they form connects the intestinal lumen to the brainstem in one synapse, opening a physical conduit for the brain to sense gut stimuli with the temporal precision and topographical resolution of a synapse.

Challenges for commercializing perovskite solar cells

Hace 11 horas 2 mins

Perovskite solar cells (PSCs) have witnessed rapidly rising power conversion efficiencies, together with advances in stability and upscaling. Despite these advances, their limited stability and need to prove upscaling remain crucial hurdles on the path to commercialization. We summarize recent advances toward commercially viable PSCs and discuss challenges that remain. We expound the development of standardized protocols to distinguish intrinsic and extrinsic degradation factors in perovskites. We review accelerated aging tests in both cells and modules and discuss the prediction of lifetimes on the basis of degradation kinetics. Mature photovoltaic solutions, which have demonstrated excellent long-term stability in field applications, offer the perovskite community valuable insights into clearing the hurdles to commercialization.

Cellular checkpoint control using programmable sequential logic

Hace 11 horas 2 mins

Biological processes that require orderly progression, such as growth and differentiation, proceed via regulatory checkpoints where the cell waits for signals before continuing to the next state. Implementing such control would allow genetic engineers to divide complex tasks into stages. We present genetic circuits that encode sequential logic to instruct Escherichia coli to proceed through a linear or cyclical sequence of states. These are built with 11 set-reset latches, designed with repressor-based NOR gates, which can connect to each other and sensors. The performance of circuits with up to three latches and four sensors, including a gated D latch, closely match predictions made by using nonlinear dynamics. Checkpoint control is demonstrated by switching cells between multiple circuit states in response to external signals over days.

Address harassment now

Hace 11 horas 2 mins

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