Τρίτη 31 Μαρτίου 2020


An autoinhibitory intramolecular interaction proof-reads RNA recognition by the essential splicing factor U2AF2 [Biochemistry]
The recognition of cis-regulatory RNA motifs in human transcripts by RNA binding proteins (RBPs) is essential for gene regulation. The molecular features that determine RBP specificity are often poorly understood. Here, we combined NMR structural biology with high-throughput iCLIP approaches to identify a regulatory mechanism for U2AF2 RNA recognition. We...
Proceedings of the National Academy of Sciences current issue
12h
Specialized cytonemes induce self-organization of stem cells [Cell Biology]
Spatial cellular organization is fundamental for embryogenesis. Remarkably, coculturing embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) recapitulates this process, forming embryo-like structures. However, mechanisms driving ESC–TSC interaction remain elusive. We describe specialized ESC-generated cytonemes that react to TSC-secreted Wnts. Cytoneme formation and length are controlled by actin, intracellular...
Proceedings of the National Academy of Sciences current issue
12h
A key mammalian cholesterol synthesis enzyme, squalene monooxygenase, is allosterically stabilized by its substrate [Biochemistry]
Cholesterol biosynthesis is a high-cost process and, therefore, tightly regulated by both transcriptional and posttranslational negative feedback mechanisms in response to the level of cellular cholesterol. Squalene monooxygenase (SM, also known as squalene epoxidase or SQLE) is a rate-limiting enzyme in the cholesterol biosynthetic pathway and catalyzes epoxidation of squalene....
Proceedings of the National Academy of Sciences current issue
12h
Interleukin-2 druggability is modulated by global conformational transitions controlled by a helical capping switch [Biophysics and Computational Biology]
Interleukin-2 (IL-2) is a small α-helical cytokine that regulates immune cell homeostasis through its recruitment to a high-affinity heterotrimeric receptor complex (IL-2Rα/IL-2Rβ/γc). IL-2 has been shown to have therapeutic efficacy for immune diseases by preferentially expanding distinct T cell compartments, and several regulatory T cell (Treg)-biasing anti–IL-2 antibodies have been...
Proceedings of the National Academy of Sciences current issue
12h
Structural basis for DEAH-helicase activation by G-patch proteins [Biochemistry]
RNA helicases of the DEAH/RHA family are involved in many essential cellular processes, such as splicing or ribosome biogenesis, where they remodel large RNA–protein complexes to facilitate transitions to the next intermediate. DEAH helicases couple adenosine triphosphate (ATP) hydrolysis to conformational changes of their catalytic core. This movement results in...
Proceedings of the National Academy of Sciences current issue
12h
Influenza hemagglutinin drives viral entry via two sequential intramembrane mechanisms [Biophysics and Computational Biology]
Enveloped viruses enter cells via a process of membrane fusion between the viral envelope and a cellular membrane. For influenza virus, mutational data have shown that the membrane-inserted portions of the hemagglutinin protein play a critical role in achieving fusion. In contrast to the relatively well-understood ectodomain, a predictive mechanistic...
Proceedings of the National Academy of Sciences current issue
12h
Probing allosteric coupling in a constitutively open mutant of the ion channel KcsA using solid-state NMR [Biophysics and Computational Biology]
Transmembrane allosteric coupling is a feature of many critical biological signaling events. Here we test whether transmembrane allosteric coupling controls the potassium binding affinity of the prototypical potassium channel KcsA in the context of C-type inactivation. Activation of KcsA is initiated by proton binding to the pH gate upon an...
Proceedings of the National Academy of Sciences current issue
12h
ER membranes exhibit phase behavior at sites of organelle contact [Cell Biology]
The endoplasmic reticulum (ER) is the site of synthesis of secretory and membrane proteins and contacts every organelle of the cell, exchanging lipids and metabolites in a highly regulated manner. How the ER spatially segregates its numerous and diverse functions, including positioning nanoscopic contact sites with other organelles, is unclear....
Proceedings of the National Academy of Sciences current issue
12h
Decoding across sensory modalities reveals common supramodal signatures of conscious perception [Neuroscience]
An increasing number of studies highlight common brain regions and processes in mediating conscious sensory experience. While most studies have been performed in the visual modality, it is implicitly assumed that similar processes are involved in other sensory modalities. However, the existence of supramodal neural processes related to conscious perception...
Proceedings of the National Academy of Sciences current issue
12h
Rbm24 controls poly(A) tail length and translation efficiency of crystallin mRNAs in the lens via cytoplasmic polyadenylation [Developmental Biology]
Lens transparency is established by abundant accumulation of crystallin proteins and loss of organelles in the fiber cells. It requires an efficient translation of lens messenger RNAs (mRNAs) to overcome the progressively reduced transcriptional activity that results from denucleation. Inappropriate regulation of this process impairs lens differentiation and causes cataract...
Proceedings of the National Academy of Sciences current issue
12h
Synthesis of phosphoramidate-linked DNA by a modified DNA polymerase [Chemistry]
All known polymerases copy genetic material by catalyzing phosphodiester bond formation. This highly conserved activity proceeds by a common mechanism, such that incorporated nucleoside analogs terminate chain elongation if the resulting primer strand lacks a terminal hydroxyl group. Even conservatively substituted 3′-amino nucleotides generally act as chain terminators, and no...
Proceedings of the National Academy of Sciences current issue
12h
The intelligent knife (iKnife) and its intraoperative diagnostic advantage for the treatment of cervical disease [Chemistry]
Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue samples...
Proceedings of the National Academy of Sciences current issue
12h
Evolution of dispersal in a spatially heterogeneous population with finite patch sizes [Evolution]
Dispersal is one of the fundamental life-history strategies of organisms, so understanding the selective forces shaping the dispersal traits is important. In the Wright’s island model, dispersal evolves due to kin competition even when dispersal is costly, and it has traditionally been assumed that the living conditions are the same...
Proceedings of the National Academy of Sciences current issue
12h
Evidence for a pathogenic role of extrafollicular, IL-10-producing CCR6+B helper T cells in systemic lupus erythematosus [Immunology and Inflammation]
Interleukin 10 (IL-10) is an antiinflammatory cytokine, but also promotes B cell responses and plays a pathogenic role in systemic lupus erythematosus (SLE). CD4+CCR6+IL-7R+T cells from human tonsils produced IL-10 following stimulation by naïve B cells, which promoted B cell immunoglobulin G (IgG) production. These tonsillar CCR6+B helper T cells...
Proceedings of the National Academy of Sciences current issue
12h
Imaging local genetic influences on cortical folding [Neuroscience]
Recent progress in deciphering mechanisms of human brain cortical folding leave unexplained whether spatially patterned genetic influences contribute to this folding. High-resolution in vivo brain MRI can be used to estimate genetic correlations (covariability due to shared genetic factors) in interregional cortical thickness, and biomechanical studies predict an influence of...
Proceedings of the National Academy of Sciences current issue
12h
Hox genes maintain critical roles in the adult skeleton [Genetics]
Hox genes are indispensable for the proper patterning of the skeletal morphology of the axial and appendicular skeleton during embryonic development. Recently, it has been demonstrated that Hox expression continues from embryonic stages through postnatal and adult stages exclusively in a skeletal stem cell population. However, whether Hox genes continue...
Proceedings of the National Academy of Sciences current issue
12h
Parcellation of the striatal complex into dorsal and ventral districts [Neuroscience]
The striatal complex of basal ganglia comprises two functionally distinct districts. The dorsal district controls motor and cognitive functions. The ventral district regulates the limbic function of motivation, reward, and emotion. The dorsoventral parcellation of the striatum also is of clinical importance as differential striatal pathophysiologies occur in Huntington’s disease,...
Proceedings of the National Academy of Sciences current issue
12h
Iron sequestration by transferrin 1 mediates nutritional immunity in Drosophila melanogaster [Immunology and Inflammation]
Iron sequestration is a recognized innate immune mechanism against invading pathogens mediated by iron-binding proteins called transferrins. Despite many studies on antimicrobial activity of transferrins in vitro, their specific in vivo functions are poorly understood. Here we use Drosophila melanogaster as an in vivo model to investigate the role of...
Proceedings of the National Academy of Sciences current issue
12h
c-di-AMP hydrolysis by the phosphodiesterase AtaC promotes differentiation of multicellular bacteria [Microbiology]
Antibiotic-producing Streptomyces use the diadenylate cyclase DisA to synthesize the nucleotide second messenger c-di-AMP, but the mechanism for terminating c-di-AMP signaling and the proteins that bind the molecule to effect signal transduction are unknown. Here, we identify the AtaC protein as a c-di-AMP-specific phosphodiesterase that is also conserved in pathogens...
Proceedings of the National Academy of Sciences current issue
12h
A pheromone antagonist liberates female sea lamprey from a sensory trap to enable reliable communication [Evolution]
The evolution of male signals and female preferences remains a central question in the study of animal communication. The sensory trap model suggests males evolve signals that mimic cues used in nonsexual contexts and thus manipulate female behavior to generate mating opportunities. Much evidence supports the sensory trap model, but...
Proceedings of the National Academy of Sciences current issue
12h
Environmental reservoir dynamics predict global infection patterns and population impacts for the fungal disease white-nose syndrome [Environmental Sciences]
Disease outbreaks and pathogen introductions can have significant effects on host populations, and the ability of pathogens to persist in the environment can exacerbate disease impacts by fueling sustained transmission, seasonal epidemics, and repeated spillover events. While theory suggests that the presence of an environmental reservoir increases the risk of...
Proceedings of the National Academy of Sciences current issue
12h
Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread [Microbiology]
Nef is an accessory protein of primate lentiviruses that is essential for efficient replication and pathogenesis of HIV-1. A conserved feature of Nef proteins from different lentiviral lineages is the ability to modulate host protein trafficking and down-regulate a number of cell surface receptors to enhance replication and promote immune...
Proceedings of the National Academy of Sciences current issue
12h
Macroscopic information-based taste representations in insular cortex are shaped by stimulus concentration [Neuroscience]
Taste processing is an essential ability in all animals signaling potential harm or benefit of ingestive behavior. However, current evidence for cortical taste representations remains contradictory. To address this issue, high-resolution functional MRI (fMRI) and multivariate pattern analysis were used to characterize taste-related informational content in human insular cortex, which...
Proceedings of the National Academy of Sciences current issue
12h
Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease [Medical Sciences]
Weight loss by ketogenic diet (KD) has gained popularity in management of nonalcoholic fatty liver disease (NAFLD). KD rapidly reverses NAFLD and insulin resistance despite increasing circulating nonesterified fatty acids (NEFA), the main substrate for synthesis of intrahepatic triglycerides (IHTG). To explore the underlying mechanism, we quantified hepatic mitochondrial fluxes...
Proceedings of the National Academy of Sciences current issue
12h
PIMMS43 is required for malaria parasite immune evasion and sporogonic development in the mosquito vector [Microbiology]
After being ingested by a female Anopheles mosquito during a bloodmeal on an infected host, and before they can reach the mosquito salivary glands to be transmitted to a new host, Plasmodium parasites must establish an infection of the mosquito midgut in the form of oocysts. To achieve this, they...
Proceedings of the National Academy of Sciences current issue
12h
CCAP regulates feeding behavior via the NPF pathway in Drosophila adults [Neuroscience]
The intake of macronutrients is crucial for the fitness of any animal and is mainly regulated by peripheral signals to the brain. How the brain receives and translates these peripheral signals or how these interactions lead to changes in feeding behavior is not well-understood. We discovered that 2 crustacean cardioactive...
Proceedings of the National Academy of Sciences current issue
12h
Targeted inhibition of gut bacterial {beta}-glucuronidase activity enhances anticancer drug efficacy [Microbiology]
Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis...
Proceedings of the National Academy of Sciences current issue
12h
Honey bees harbor a diverse gut virome engaging in nested strain-level interactions with the microbiota [Microbiology]
The honey bee gut microbiota influences bee health and has become an important model to study the ecology and evolution of microbiota–host interactions. Yet, little is known about the phage community associated with the bee gut, despite its potential to modulate bacterial diversity or to govern important symbiotic functions. Here...
Proceedings of the National Academy of Sciences current issue
12h
Reply to Kloepfer and Gern: Independent studies suggest an arms race between influenza and rhinovirus: What next? [Biological Sciences]
It was very interesting to learn about Kloepfer et al.’s study investigating the link between asthma and influenza A H1N1 infection incidence and severity (1). Their finding that influenza A virus (IAV) infections reduced the subsequent risk of infection with human rhinoviruses (HRVs) was contrary to theories at the time...
Proceedings of the National Academy of Sciences current issue
12h
Vibrational exciton nanoimaging of phases and domains in porphyrin nanocrystals [Chemistry]
Much of the electronic transport, photophysical, or biological functions of molecular materials emerge from intermolecular interactions and associated nanoscale structure and morphology. However, competing phases, defects, and disorder give rise to confinement and many-body localization of the associated wavefunction, disturbing the performance of the material. Here, we employ vibrational excitons...
Proceedings of the National Academy of Sciences current issue
12h
Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells [Microbiology]
A novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused a large respiratory outbreak in Wuhan, China in December 2019, is currently spreading across many countries globally. Here, we show that a TMPRSS2-expressing VeroE6 cell line is highly susceptible to SARS-CoV-2 infection, making it useful for isolating and...
Proceedings of the National Academy of Sciences current issue
12h
A pair of esterases from a commensal gut bacterium remove acetylations from all positions on complex {beta}-mannans [Biochemistry]
β-mannans and xylans are important components of the plant cell wall and they are acetylated to be protected from degradation by glycoside hydrolases. β-mannans are widely present in human and animal diets as fiber from leguminous plants and as thickeners and stabilizers in processed foods. There are many fully characterized...
Proceedings of the National Academy of Sciences current issue
12h
A regional nuclear conflict would compromise global food security [Sustainability Science]
A limited nuclear war between India and Pakistan could ignite fires large enough to emit more than 5 Tg of soot into the stratosphere. Climate model simulations have shown severe resulting climate perturbations with declines in global mean temperature by 1.8 °C and precipitation by 8%, for at least 5...
Proceedings of the National Academy of Sciences current issue
12h
A little history goes a long way toward understanding why we study consciousness the way we do today [Neuroscience]
Consciousness is currently a thriving area of research in psychology and neuroscience. While this is often attributed to events that took place in the early 1990s, consciousness studies today are a continuation of research that started in the late 19th century and that continued throughout the 20th century. From the...
Proceedings of the National Academy of Sciences current issue
12h
Half-precessional cycle of thermocline temperature in the western equatorial Pacific and its bihemispheric dynamics [Earth, Atmospheric, and Planetary Sciences]
The El Niño−Southern Oscillation (ENSO), which is tightly coupled to the equatorial thermocline in the Pacific, is the dominant source of interannual climate variability, but its long-term evolution in response to climate change remains highly uncertain. This study uses Mg/Ca in planktonic foraminiferal shells to reconstruct sea surface and thermocline...
Proceedings of the National Academy of Sciences current issue
12h
Extreme weather events recorded by daily to hourly resolution biogeochemical proxies of marine giant clam shells [Earth, Atmospheric, and Planetary Sciences]
Paleoclimate research has built a framework for Earth’s climate changes over the past 65 million years or even longer. However, our knowledge of weather-timescale extreme events (WEEs, also named paleoweather), which usually occur over several days or hours, under different climate regimes is almost blank because current paleoclimatic records rarely...
Proceedings of the National Academy of Sciences current issue
12h
Estimating and leveraging protein diffusion on ion-exchange resin surfaces [Applied Physical Sciences]
Protein mobility at solid–liquid interfaces can affect the performance of applications such as bioseparations and biosensors by facilitating reorganization of adsorbed protein, accelerating molecular recognition, and informing the fundamentals of adsorption. In the case of ion-exchange chromatographic beads with small, tortuous pores, where the existence of surface diffusion is often...
Proceedings of the National Academy of Sciences current issue
12h
Sitting, squatting, and the evolutionary biology of human inactivity [Anthropology]
Recent work suggests human physiology is not well adapted to prolonged periods of inactivity, with time spent sitting increasing cardiovascular disease and mortality risk. Health risks from sitting are generally linked with reduced levels of muscle contractions in chair-sitting postures and associated reductions in muscle metabolism. These inactivity-associated health risks...
Proceedings of the National Academy of Sciences current issue
12h
Oxaliplatin Pt(IV) prodrugs conjugated to gadolinium-texaphyrin as potential antitumor agents [Pharmacology]
Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2) promoting enhanced cancer cell uptake, and 3) reactivating p53 in platinum-resistant models. Side by side comparative studies of these Pt(IV) conjugates to clinically approved platinum(II) agents and previously reported...
Proceedings of the National Academy of Sciences current issue
12h

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