Catálogo de publicaciones - revistas

<jats:p>Excipients, considered “inactive ingredients,” are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant <jats:italic>K</jats:italic><jats:sub>d</jats:sub> values of 320 and 210 nM, respectively. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets.</jats:p>

<jats:p>Alloys that have high strengths at high temperatures are crucial for a variety of important industries including aerospace. Alloys with ordered superlattice structures are attractive for this purpose but generally suffer from poor ductility and rapid grain coarsening. We discovered that nanoscale disordered interfaces can effectively overcome these problems. Interfacial disordering is driven by multielement cosegregation that creates a distinctive nanolayer between adjacent micrometer-scale superlattice grains. This nanolayer acts as a sustainable ductilizing source, which prevents brittle intergranular fractures by enhancing dislocation mobilities. Our superlattice materials have ultrahigh strengths of 1.6 gigapascals with tensile ductilities of 25% at ambient temperature. Simultaneously, we achieved negligible grain coarsening with exceptional softening resistance at elevated temperatures. Designing similar nanolayers may open a pathway for further optimization of alloy properties.</jats:p>

<jats:p>A defining step in the biogenesis of a membrane protein is the insertion of its hydrophobic transmembrane helices into the lipid bilayer. The nine-subunit endoplasmic reticulum (ER) membrane protein complex (EMC) is a conserved co- and posttranslational insertase at the ER. We determined the structure of the human EMC in a lipid nanodisc to an overall resolution of 3.4 angstroms by cryo–electron microscopy, permitting building of a nearly complete atomic model. We used structure-guided mutagenesis to demonstrate that substrate insertion requires a methionine-rich cytosolic loop and occurs via an enclosed hydrophilic vestibule within the membrane formed by the subunits EMC3 and EMC6. We propose that the EMC uses local membrane thinning and a positively charged patch to decrease the energetic barrier for insertion into the bilayer.</jats:p>

<jats:p>The electromagnetic near field enables subwavelength applications such as near-field microscopy and nanoparticle manipulation. Present methods to structure the near field rely on optical antenna theory, involving nanostructures that locally convert propagating waves into confined near-field patterns. We developed a theory of remote rather than local near-field shaping, based on cascaded mode conversion and interference of counterpropagating guided waves with different propagation constants. We demonstrate how to structure at will the longitudinal and transverse variation of the near field, allowing for distributions beyond the conventional monotonic decay of the evanescent field. We provide an experimental realization that confirms our theory. Our method applies to fields with arbitrary polarization states and mode profiles, providing a path toward three-dimensional control of the near field.</jats:p>

<jats:p>The rational design of enzymes is an important goal for both fundamental and practical reasons. Here, we describe a process to learn the constraints for specifying proteins purely from evolutionary sequence data, design and build libraries of synthetic genes, and test them for activity in vivo using a quantitative complementation assay. For chorismate mutase, a key enzyme in the biosynthesis of aromatic amino acids, we demonstrate the design of natural-like catalytic function with substantial sequence diversity. Further optimization focuses the generative model toward function in a specific genomic context. The data show that sequence-based statistical models suffice to specify proteins and provide access to an enormous space of functional sequences. This result provides a foundation for a general process for evolution-based design of artificial proteins.</jats:p>

<jats:p>Lightweight, ultrathin, and flexible electromagnetic interference (EMI) shielding materials are needed to protect electronic circuits and portable telecommunication devices and to eliminate cross-talk between devices and device components. Here, we show that a two-dimensional (2D) transition metal carbonitride, Ti<jats:sub>3</jats:sub>CNT<jats:italic><jats:sub>x</jats:sub></jats:italic> MXene, with a moderate electrical conductivity, provides a higher shielding effectiveness compared with more conductive Ti<jats:sub>3</jats:sub>C<jats:sub>2</jats:sub>T<jats:italic><jats:sub>x</jats:sub></jats:italic> or metal foils of the same thickness. This exceptional shielding performance of Ti<jats:sub>3</jats:sub>CNT<jats:italic><jats:sub>x</jats:sub></jats:italic> was achieved by thermal annealing and is attributed to an anomalously high absorption of electromagnetic waves in its layered, metamaterial-like structure. These results provide guidance for designing advanced EMI shielding materials but also highlight the need for exploring fundamental mechanisms behind interaction of electromagnetic waves with 2D materials.</jats:p>

<jats:p>The guanosine triphosphatase (GTPase) Rab32 coordinates a cell-intrinsic host defense mechanism that restricts the replication of intravacuolar pathogens such as <jats:italic>Salmonella</jats:italic>. Here, we show that this mechanism requires aconitate decarboxylase 1 (IRG1), which synthesizes itaconate, a metabolite with antimicrobial activity. We find that Rab32 interacts with IRG1 on <jats:italic>Salmonella</jats:italic> infection and facilitates the delivery of itaconate to the <jats:italic>Salmonella</jats:italic>-containing vacuole. Mice defective in IRG1 rescued the virulence defect of a <jats:italic>S. enterica</jats:italic> serovar Typhimurium mutant specifically defective in its ability to counter the Rab32 defense mechanism. These studies provide a link between a metabolite produced in the mitochondria after stimulation of innate immune receptors and a cell-autonomous defense mechanism that restricts the replication of an intracellular bacterial pathogen.</jats:p>

<jats:p>The Caribbean was one of the last regions of the Americas to be settled by humans, but where they came from and how and when they reached the islands remain unclear. We generated genome-wide data for 93 ancient Caribbean islanders dating between 3200 and 400 calibrated years before the present and found evidence of at least three separate dispersals into the region, including two early dispersals into the Western Caribbean, one of which seems connected to radiation events in North America. This was followed by a later expansion from South America. We also detected genetic differences between the early settlers and the newcomers from South America, with almost no evidence of admixture. Our results add to our understanding of the initial peopling of the Caribbean and the movements of Archaic Age peoples in the Americas.</jats:p>