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See detailBistability in oxidative stress response determines the migration behavior of phytoplankton in turbulence
Carrara, Francesco; Sengupta, Anupam UL; Behrendt, Lars et al

in Proceedings of the National Academy of Sciences of the United States of America (2021), 118(5), 2005944118

Turbulence is an important determinant of phytoplankton physiology, often leading to cell stress and damage. Turbulence affects phytoplankton migration both by transporting cells and by triggering ... [more ▼]

Turbulence is an important determinant of phytoplankton physiology, often leading to cell stress and damage. Turbulence affects phytoplankton migration both by transporting cells and by triggering switches in migratory behavior, whereby vertically migrating cells can actively invert their direction of migration upon exposure to turbulent cues. However, a mechanistic link between single-cell physiology and vertical migration of phytoplankton in turbulence is currently missing. Here, by combining physiological and behavioral experiments with a mathematical model of stress accumulation and dissipation, we show that the mechanism responsible for the switch in the direction of migration in the marine raphidophyte Heterosigma akashiwo is the integration of reactive oxygen species (ROS) signaling generated by turbulent cues. Within timescales as short as tens of seconds, the emergent downward-migrating subpopulation exhibited a twofold increase in ROS, an indicator of stress, 15% lower photosynthetic efficiency, and 35% lower growth rate over multiple generations compared to the upward-migrating subpopulation. The origin of the behavioral split as a result of a bistable oxidative stress response is corroborated by the observation that exposure of cells to exogenous stressors (H2O2, UV-A radiation, or high irradiance), in lieu of turbulence, caused comparable ROS accumulation and an equivalent split into the two subpopulations. By providing a mechanistic link between the single-cell mechanics of swimming and physiology on the one side and the emergent population-scale migratory response and impact on fitness on the other, the ROS-mediated early warning response we discovered contributes to our understanding of phytoplankton community composition in future ocean conditions. [less ▲]

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See detailComprehensive characterization of amino acidpositions in protein structures reveals moleculareffect of missense variants
iqbal, Sumaiya; Perez-Palma, Eduardo; Jespersen, Jakob B. et al

in Proceedings of the National Academy of Sciences of the United States of America (2020)

Interpretation of the colossal number of genetic variants identified from sequencing applications is one of the major bottlenecks in clinical genetics, with the inference of the effect of amino acid ... [more ▼]

Interpretation of the colossal number of genetic variants identified from sequencing applications is one of the major bottlenecks in clinical genetics, with the inference of the effect of amino acid-substituting missense variations on protein structure and function being especially challenging. Here we characterize the three-dimensional (3D) amino acid positions affected in pathogenic and population variants from 1,330 disease-associated genes using over 14,000 experimentally solved human protein structures. By measuring the statistical burden of variations (i.e., point mutations) from all genes on 40 3D protein features, accounting for the structural, chemical, and functional context of the variations’ positions, we identify features that are generally associated with pathogenic and population missense variants. We then perform the same amino acid-level analysis individually for 24 protein functional classes, which reveals unique characteristics of the positions of the altered amino acids: We observe up to 46% divergence of the class-specific features from the general characteristics obtained by the analysis on all genes, which is consistent with the structural diversity of essential regions across different protein classes. We demonstrate that the function-specific 3D features of the variants match the readouts of mutagenesis experiments for BRCA1 and PTEN, and positively correlate with an independent set of clinically interpreted pathogenic and benign missense variants. Finally, we make our results available through a web server to foster accessibility and downstream research. Our findings represent a crucial step toward translational genetics, from highlighting the impact of mutations on protein structure to rationalizing the variants’ pathogenicity in terms of the perturbed molecular mechanisms. [less ▲]

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See detailThe neural signature of numerosity by separating numerical and continuous magnitude extraction in visual cortex with frequency-tagged EEG.
Van Rinsveld, Amandine; Guillaume, Mathieu; Kohler, Peter J. et al

in Proceedings of the National Academy of Sciences of the United States of America (2020), 117(11), 5726-5732

The ability to handle approximate quantities, or number sense, has been recurrently linked to mathematical skills, although the nature of the mechanism allowing to extract numerical information (i.e ... [more ▼]

The ability to handle approximate quantities, or number sense, has been recurrently linked to mathematical skills, although the nature of the mechanism allowing to extract numerical information (i.e., numerosity) from environmental stimuli is still debated. A set of objects is indeed not only characterized by its numerosity but also by other features, such as the summed area occupied by the elements, which often covary with numerosity. These intrinsic relations between numerosity and nonnumerical magnitudes led some authors to argue that numerosity is not independently processed but extracted through a weighting of continuous magnitudes. This view cannot be properly tested through classic behavioral and neuroimaging approaches due to these intrinsic correlations. The current study used a frequency-tagging EEG approach to separately measure responses to numerosity as well as to continuous magnitudes. We recorded occipital responses to numerosity, total area, and convex hull changes but not to density and dot size. We additionally applied a model predicting primary visual cortex responses to the set of stimuli. The model output was closely aligned with our electrophysiological data, since it predicted discrimination only for numerosity, total area, and convex hull. Our findings thus demonstrate that numerosity can be independently processed at an early stage in the visual cortex, even when completely isolated from other magnitude changes. The similar implicit discrimination for numerosity as for some continuous magnitudes, which correspond to basic visual percepts, shows that both can be extracted independently, hence substantiating the nature of numerosity as a primary feature of the visual scene. [less ▲]

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See detailNeuroticism may not reflect emotional variability
Kalokerinos, Elise K.; Murphy, Sean C.; Koval, Peter et al

in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2020), 117(17), 9270--9276

Neuroticism is one of the major traits describing human personality, and a predictor of mental and physical disorders with profound public health significance. Individual differences in emotional ... [more ▼]

Neuroticism is one of the major traits describing human personality, and a predictor of mental and physical disorders with profound public health significance. Individual differences in emotional variability are thought to reflect the core of neuroticism. However, the empirical relation between emotional variability and neuroticism may be partially the result of a measurement artifact reflecting neuroticism’s relation with higher mean levels—rather than greater variability—of negative emotion. When emotional intensity is measured using bounded scales, there is a dependency between variability and mean levels: at low (or high) intensity, it is impossible to demonstrate high variability. As neuroticism is positively associated with mean levels of negative emotion, this may account for the relation between neuroticism and emotional variability. In a metaanalysis of 11 studies (<jats:italic>N</jats:italic> = 1,205 participants; 83,411 observations), we tested whether the association between neuroticism and negative emotional variability was clouded by a dependency between variability and the mean. We found a medium-sized positive association between neuroticism and negative emotional variability, but, when using a relative variability index to correct for mean negative emotion, this association disappeared. This indicated that neuroticism was associated with experiencing more intense, but not more variable, negative emotions. Our findings call into question theory, measurement scales, and data suggesting that emotional variability is central to neuroticism. In doing so, they provide a revisionary perspective for understanding how this individual difference may predispose to mental and physical disorders. [less ▲]

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See detailFailure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency
Veiga-da-Cunha, Maria; Chevalier, Nathalie; Stephenne, Xavier et al

in Proceedings of the National Academy of Sciences of the United States of America (2019), 116(4), 1241-1250

Neutropenia presents an important clinical problem in patients with G6PC3 or G6PT deficiency, yet why neutropenia occurs is unclear. We discovered that G6PC3 and G6PT collaborate to dephosphorylate a ... [more ▼]

Neutropenia presents an important clinical problem in patients with G6PC3 or G6PT deficiency, yet why neutropenia occurs is unclear. We discovered that G6PC3 and G6PT collaborate to dephosphorylate a noncanonical metabolite (1,5anhydroglucitol-6-phosphate; 1,5AG6P) which is produced when glucose-phosphorylating enzymes erroneously act on 1,5-anhydroglucitol, a food-derived polyol present in blood. In patients or mice with G6PC3 or G6PT deficiency, 1,5AG6P accumulates and inhibits the first step of glycolysis. This is particularly detrimental in neutrophils, since their energy metabolism depends almost entirely on glycolysis. Consistent with our findings, we observed that treatment with a 1,5anhydroglucitol-lowering drug treats neutropenia in G6PC3deficient mice. Our findings highlight that the elimination of noncanonical side products by metabolite-repair enzymes makes an important contribution to mammalian physiology. [less ▲]

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See detailFast and accurate quantum Monte Carlo for molecular crystals
Zen, Andrea; Brandenburg, Jan Gerit; Klimes, Jiri et al

in Proceedings of the National Academy of Sciences of the United States of America (2018), 115

Computer simulation plays a central role in modern-day materials science. The utility of a given computational approach depends largely on the balance it provides between accuracy and computational cost ... [more ▼]

Computer simulation plays a central role in modern-day materials science. The utility of a given computational approach depends largely on the balance it provides between accuracy and computational cost. Molecular crystals are a class of materials of great technological importance which are challenging for even the most sophisticated ab initio electronic structure theories to accurately describe. This is partly because they are held together by a balance of weak intermolecular forces but also because the primitive cells of molecular crystals are often substantially larger than those of atomic solids. Here, we demonstrate that diffusion quantum Monte Carlo (DMC) delivers subchemical accuracy for a diverse set of molecular crystals at a surprisingly moderate computational cost. As such, we anticipate that DMC can play an important role in understanding and predicting the properties of a large number of molecular crystals, including those built from relatively large molecules which are far beyond reach of other high-accuracy methods. [less ▲]

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See detailSelective visual representation of letters and words in the left ventral occipito-temporal cortex with intracerebral recordings.
Lochy, Aliette UL; Jacques, Corentin; Maillard, Louis et al

in Proceedings of the National Academy of Sciences of the United States of America (2018), 115(32), 7595-7604

We report a comprehensive cartography of selective responses to visual letters and words in the human ventral occipito-temporal cortex (VOTC) with direct neural recordings, clarifying key aspects of the ... [more ▼]

We report a comprehensive cartography of selective responses to visual letters and words in the human ventral occipito-temporal cortex (VOTC) with direct neural recordings, clarifying key aspects of the neural basis of reading. Intracerebral recordings were performed in a large group of patients (n = 37) presented with visual words inserted periodically in rapid sequences of pseudofonts, nonwords, or pseudowords, enabling classification of responses at three levels of word processing: letter, prelexical, and lexical. While letter-selective responses are found in much of the VOTC, with a higher proportion in left posterior regions, prelexical/lexical responses are confined to the middle and anterior sections of the left fusiform gyrus. This region overlaps with and extends more anteriorly than the visual word form area typically identified with functional magnetic resonance imaging. In this region, prelexical responses provide evidence for populations of neurons sensitive to the statistical regularity of letter combinations independently of lexical responses to familiar words. Despite extensive sampling in anterior ventral temporal regions, there is no hierarchical organization between prelexical and lexical responses in the left fusiform gyrus. Overall, distinct word processing levels depend on neural populations that are spatially intermingled rather than organized according to a strict postero-anterior hierarchy in the left VOTC. [less ▲]

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See detailTargeting autophagy inhibits growth by enhancing NK cells infiltration in a CCL5-dependent manner
Mgrditchian, T; Arakelian, T; Paggetti, J et al

in Proceedings of the National Academy of Sciences of the United States of America (2017), 114((44)), 9271-9279

While blocking tumor growth by targeting autophagy is well established, its role on the infiltration of natural killer (NK) cells into tumors remains unknown. Here, we investigate the impact of targeting ... [more ▼]

While blocking tumor growth by targeting autophagy is well established, its role on the infiltration of natural killer (NK) cells into tumors remains unknown. Here, we investigate the impact of targeting autophagy gene Beclin1 (BECN1) on the infiltration of NK cells into melanomas. We show that, in addition to inhibiting tumor growth, targeting BECN1 increased the infiltration of functional NK cells into melanoma tumors. We provide evidence that driving NK cells to the tumor bed relied on the ability of autophagy-defective tumors to transcriptionally overexpress the chemokine gene CCL5 Such infiltration and tumor regression were abrogated by silencing CCL5 in BECN1-defective tumors. Mechanistically, we show that the up-regulated expression of CCL5 occurred through the activation of its transcription factor c-Jun by a mechanism involving the impairment of phosphatase PP2A catalytic activity and the subsequent activation of JNK. Similar to BECN1, targeting other autophagy genes, such as ATG5, p62/SQSTM1, or inhibiting autophagy pharmacologically by chloroquine, also induced the expression of CCL5 in melanoma cells. Clinically, a positive correlation between CCL5 and NK cell marker NKp46 expression was found in melanoma patients, and a high expression level of CCL5 was correlated with a significant improvement of melanoma patients' survival. We believe that this study highlights the impact of targeting autophagy on the tumor infiltration by NK cells and its benefit as a novel therapeutic approach to improve NK-based immunotherapy. [less ▲]

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See detailHDAC1 links early life stress to schizophrenia-like phenotypes.
Bahari-Javan, Sanaz; Varbanov, Hristo; Halder, Rashi UL et al

in Proceedings of the National Academy of Sciences of the United States of America (2017)

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See detailErythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults
Hootman, Katie C.; Trezzi, Jean-Pierre UL; Kraemer, Lisa UL et al

in Proceedings of the National Academy of Sciences of the United States of America (2017)

Metabolomic markers associated with incident central adiposity gain were investigated in young adults. In a 9-mo prospective study of university freshmen (n = 264). Blood samples and anthropometry ... [more ▼]

Metabolomic markers associated with incident central adiposity gain were investigated in young adults. In a 9-mo prospective study of university freshmen (n = 264). Blood samples and anthropometry measurements were collected in the first 3 d on campus and at the end of the year. Plasma from individuals was pooled by phenotype [incident central adiposity, stable adiposity, baseline hemoglobin A1c (HbA1c) > 5.05%, HbA1c < 4.92%] and assayed using GC-MS, chromatograms were analyzed using MetaboliteDetector software, and normalized metabolite levels were compared using Welch’s t test. Assays were repeated using freshly prepared pools, and statistically significant metabolites were quantified in a targeted GC-MS approach. Isotope tracer studies were performed to determine if the potential marker was an endogenous human metabolite in men and in whole blood. Participants with incident central adiposity gain had statistically significantly higher blood erythritol [P < 0.001, false discovery rate (FDR) = 0.0435], and the targeted assay revealed 15-fold [95% confidence interval (CI): 13.27, 16.25] higher blood erythritol compared with participants with stable adiposity. Participants with baseline HbA1c > 5.05% had 21-fold (95% CI: 19.84, 21.41) higher blood erythritol compared with participants with lower HbA1c (P < 0.001, FDR = 0.00016). Erythritol was shown to be synthesized endogenously from glucose via the pentose-phosphate pathway (PPP) in stable isotope-assisted ex vivo blood incubation experiments and through in vivo conversion of erythritol to erythronate in stable isotope-assisted dried blood spot experiments. Therefore, endogenous production of erythritol from glucose may contribute to the association between erythritol and obesity observed in young adults. [less ▲]

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See detailNit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione
Peracchi, Alessio; Veiga-da-Cunha, Maria; Kuhara, Tomiko et al

in Proceedings of the National Academy of Sciences of the United States of America (2017), 1613736114

The mammalian gene Nit1 (nitrilase-like protein 1) encodes a protein that is highly conserved in eukaryotes and is thought to act as a tumor suppressor. Despite being ∼35% sequence identical to ω-amidase ... [more ▼]

The mammalian gene Nit1 (nitrilase-like protein 1) encodes a protein that is highly conserved in eukaryotes and is thought to act as a tumor suppressor. Despite being ∼35% sequence identical to ω-amidase (Nit2), the Nit1 protein does not hydrolyze efficiently α-ketoglutaramate (a known physiological substrate of Nit2), and its actual enzymatic function has so far remained a puzzle. In the present study, we demonstrate that both the mammalian Nit1 and its yeast ortholog are amidases highly active toward deaminated glutathione (dGSH; i.e., a form of glutathione in which the free amino group has been replaced by a carbonyl group). We further show that Nit1-KO mutants of both human and yeast cells accumulate dGSH and the same compound is excreted in large amounts in the urine of Nit1-KO mice. Finally, we show that several mammalian aminotransferases (transaminases), both cytosolic and mitochondrial, can form dGSH via a common (if slow) side-reaction and provide indirect evidence that transaminases are mainly responsible for dGSH formation in cultured mammalian cells. Altogether, these findings delineate a typical instance of metabolite repair, whereby the promiscuous activity of some abundant enzymes of primary metabolism leads to the formation of a useless and potentially harmful compound, which needs a suitable “repair enzyme” to be destroyed or reconverted into a useful metabolite. The need for a dGSH repair reaction does not appear to be limited to eukaryotes: We demonstrate that Nit1 homologs acting as excellent dGSH amidases also occur in Escherichia coli and other glutathione-producing bacteria. [less ▲]

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See detailNurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease
Spathis, Athanasios; Asvos, Xenophon; Ziavra, Despina et al

in Proceedings of the National Academy of Sciences of the United States of America (2017)

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See detail70S-scanning initiation is a novel and frequent initiation mode of ribosomal translation in bacteria.
Yamamoto, Hiroshi; Wittek, Daniela; Gupta, Romi et al

in Proceedings of the National Academy of Sciences of the United States of America (2016), 113(9), 1180-9

According to the standard model of bacterial translation initiation, the small ribosomal 30S subunit binds to the initiation site of an mRNA with the help of three initiation factors (IF1-IF3). Here, we ... [more ▼]

According to the standard model of bacterial translation initiation, the small ribosomal 30S subunit binds to the initiation site of an mRNA with the help of three initiation factors (IF1-IF3). Here, we describe a novel type of initiation termed "70S-scanning initiation," where the 70S ribosome does not necessarily dissociate after translation of a cistron, but rather scans to the initiation site of the downstream cistron. We detailed the mechanism of 70S-scanning initiation by designing unique monocistronic and polycistronic mRNAs harboring translation reporters, and by reconstituting systems to characterize each distinct mode of initiation. Results show that 70S scanning is triggered by fMet-tRNA and does not require energy; the Shine-Dalgarno sequence is an essential recognition element of the initiation site. IF1 and IF3 requirements for the various initiation modes were assessed by the formation of productive initiation complexes leading to synthesis of active proteins. IF3 is essential and IF1 is highly stimulating for the 70S-scanning mode. The task of IF1 appears to be the prevention of untimely interference by ternary aminoacyl (aa)-tRNA*elongation factor thermo unstable (EF-Tu)*GTP complexes. Evidence indicates that at least 50% of bacterial initiation events use the 70S-scanning mode, underscoring the relative importance of this translation initiation mechanism. [less ▲]

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See detailLeft cortical specialization for visual letter strings predicts rudimentary knowledge of letter-sound association in preschoolers.
Lochy, Aliette UL; Van Reybroeck, Marie; Rossion, Bruno

in Proceedings of the National Academy of Sciences of the United States of America (2016), 113(30), 8544-9

Reading, one of the most important cultural inventions of human society, critically depends on posterior brain areas of the left hemisphere in proficient adult readers. In children, this left hemispheric ... [more ▼]

Reading, one of the most important cultural inventions of human society, critically depends on posterior brain areas of the left hemisphere in proficient adult readers. In children, this left hemispheric cortical specialization for letter strings is typically detected only after approximately 1 y of formal schooling and reading acquisition. Here, we recorded scalp electrophysiological (EEG) brain responses in 5-y-old (n = 40) prereaders presented with letter strings appearing every five items in rapid streams of pseudofonts (6 items per second). Within 2 min of recording only, letter strings evoked a robust specific response over the left occipito-temporal cortex at the predefined frequency of 1.2 Hz (i.e., 6 Hz/5). Interindividual differences in the amplitude of this electrophysiological response are significantly related to letter knowledge, a preschool predictor of later reading ability. These results point to the high potential of this rapidly collected behavior-free measure to assess reading ability in developmental populations. These findings were replicated in a second experiment (n = 26 preschool children), where familiar symbols and line drawings of objects evoked right-lateralized and bilaterally specific responses, respectively, showing the specificity of the early left hemispheric dominance for letter strings. Collectively, these findings indicate that limited knowledge of print in young children, before formal education, is sufficient to develop specialized left lateralized neuronal circuits, thereby pointing to an early onset and rapid impact of left hemispheric reentrant sound mapping on posterior cortical development. [less ▲]

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See detailPrehistoric genomes reveal the genetic foundation and cost of horse domestication.
Schubert, Mikkel; Jonsson, Hakon; Chang, Dan et al

in Proceedings of the National Academy of Sciences of the United States of America (2014), 111(52), 5661-9

The domestication of the horse approximately 5.5 kya and the emergence of mounted riding, chariotry, and cavalry dramatically transformed human civilization. However, the genetics underlying horse ... [more ▼]

The domestication of the horse approximately 5.5 kya and the emergence of mounted riding, chariotry, and cavalry dramatically transformed human civilization. However, the genetics underlying horse domestication are difficult to reconstruct, given the near extinction of wild horses. We therefore sequenced two ancient horse genomes from Taymyr, Russia (at 7.4- and 24.3-fold coverage), both predating the earliest archeological evidence of domestication. We compared these genomes with genomes of domesticated horses and the wild Przewalski's horse and found genetic structure within Eurasia in the Late Pleistocene, with the ancient population contributing significantly to the genetic variation of domesticated breeds. We furthermore identified a conservative set of 125 potential domestication targets using four complementary scans for genes that have undergone positive selection. One group of genes is involved in muscular and limb development, articular junctions, and the cardiac system, and may represent physiological adaptations to human utilization. A second group consists of genes with cognitive functions, including social behavior, learning capabilities, fear response, and agreeableness, which may have been key for taming horses. We also found that domestication is associated with inbreeding and an excess of deleterious mutations. This genetic load is in line with the "cost of domestication" hypothesis also reported for rice, tomatoes, and dogs, and it is generally attributed to the relaxation of purifying selection resulting from the strong demographic bottlenecks accompanying domestication. Our work demonstrates the power of ancient genomes to reconstruct the complex genetic changes that transformed wild animals into their domesticated forms, and the population context in which this process took place. [less ▲]

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See detailSpeciation with gene flow in equids despite extensive chromosomal plasticity.
Jonsson, Hakon; Schubert, Mikkel; Seguin-Orlando, Andaine et al

in Proceedings of the National Academy of Sciences of the United States of America (2014), 111(52), 18655-60

Horses, asses, and zebras belong to a single genus, Equus, which emerged 4.0-4.5 Mya. Although the equine fossil record represents a textbook example of evolution, the succession of events that gave rise ... [more ▼]

Horses, asses, and zebras belong to a single genus, Equus, which emerged 4.0-4.5 Mya. Although the equine fossil record represents a textbook example of evolution, the succession of events that gave rise to the diversity of species existing today remains unclear. Here we present six genomes from each living species of asses and zebras. This completes the set of genomes available for all extant species in the genus, which was hitherto represented only by the horse and the domestic donkey. In addition, we used a museum specimen to characterize the genome of the quagga zebra, which was driven to extinction in the early 1900s. We scan the genomes for lineage-specific adaptations and identify 48 genes that have evolved under positive selection and are involved in olfaction, immune response, development, locomotion, and behavior. Our extensive genome dataset reveals a highly dynamic demographic history with synchronous expansions and collapses on different continents during the last 400 ky after major climatic events. We show that the earliest speciation occurred with gene flow in Northern America, and that the ancestor of present-day asses and zebras dispersed into the Old World 2.1-3.4 Mya. Strikingly, we also find evidence for gene flow involving three contemporary equine species despite chromosomal numbers varying from 16 pairs to 31 pairs. These findings challenge the claim that the accumulation of chromosomal rearrangements drive complete reproductive isolation, and promote equids as a fundamental model for understanding the interplay between chromosomal structure, gene flow, and, ultimately, speciation. [less ▲]

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See detailDistinct antimicrobial peptide expression determines host species-specific bacterial associations
Franzenburg, Sören; Walter, Jonas UL; Künzel, Sven et al

in Proceedings of the National Academy of Sciences of the United States of America (2013), 110(39), 37303738

Animals are colonized by coevolved bacterial communities, which contribute to the host’s health. This commensal microbiota is often highly specific to its host-species, inferring strong selective ... [more ▼]

Animals are colonized by coevolved bacterial communities, which contribute to the host’s health. This commensal microbiota is often highly specific to its host-species, inferring strong selective pressures on the associated microbes. Several factors, including diet, mucus composition, and the immune system have been proposed as putative determinants of host-associated bacterial communities. Here we report that species-specific antimicrobial peptides account for different bacterial communities associated with closely related species of the cnidarian Hydra. Gene family extensions for potent antimicrobial peptides, the arminins, were detected in four Hydra species, with each species possessing a unique composition and expression profile of arminins. For functional analysis, we inoculated arminin-deficient and control polyps with bacterial consortia characteristic for different Hydra species and compared their selective preferences by 454 pyrosequencing of the bacterial microbiota. In contrast to control polyps, arminin-deficient polyps displayed decreased potential to select for bacterial communities resembling their native microbiota. This finding indicates that species-specific antimicrobial peptides shape species-specific bacterial associations. [less ▲]

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See detailImmune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production
Michelucci, Alessandro UL; Cordes, Thekla UL; Ghelfi, Jenny UL et al

in Proceedings of the National Academy of Sciences of the United States of America (2013)

Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an ... [more ▼]

Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an enzyme producing itaconic acid (also known as methylenesuccinic acid) through the decarboxylation of cis-aconitate, a tricarboxylic acid cycle intermediate. Using a gain-and-loss-of-function approach in both mouse and human immune cells, we found Irg1 expression levels correlating with the amounts of itaconic acid, a metabolite previously proposed to have an antimicrobial effect. We purified IRG1 protein and identified its cis-aconitate decarboxylating activity in an enzymatic assay. Itaconic acid is an organic compound that inhibits isocitrate lyase, the key enzyme of the glyoxylate shunt, a pathway essential for bacterial growth under specific conditions. Here we show that itaconic acid inhibits the growth of bacteria expressing isocitrate lyase, such as Salmonella enterica and Mycobacterium tuberculosis. Furthermore, Irg1 gene silencing in macrophages resulted in significantly decreased intracellular itaconic acid levels as well as significantly reduced antimicrobial activity during bacterial infections. Taken together, our results demonstrate that IRG1 links cellular metabolism with immune defense by catalyzing itaconic acid production. [less ▲]

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See detailAneuploidy underlies a multicellular phenotypic switch.
Tan, Zhihao; Hays, Michelle; Cromie, Gareth A. et al

in Proceedings of the National Academy of Sciences of the United States of America (2013), 110(30), 12367-72

Although microorganisms are traditionally used to investigate unicellular processes, the yeast Saccharomyces cerevisiae has the ability to form colonies with highly complex, multicellular structures ... [more ▼]

Although microorganisms are traditionally used to investigate unicellular processes, the yeast Saccharomyces cerevisiae has the ability to form colonies with highly complex, multicellular structures. Colonies with the "fluffy" morphology have properties reminiscent of bacterial biofilms and are easily distinguished from the "smooth" colonies typically formed by laboratory strains. We have identified strains that are able to reversibly toggle between the fluffy and smooth colony-forming states. Using a combination of flow cytometry and high-throughput restriction-site associated DNA tag sequencing, we show that this switch is correlated with a change in chromosomal copy number. Furthermore, the gain of a single chromosome is sufficient to switch a strain from the fluffy to the smooth state, and its subsequent loss to revert the strain back to the fluffy state. Because copy number imbalance of six of the 16 S. cerevisiae chromosomes and even a single gene can modulate the switch, our results support the hypothesis that the state switch is produced by dosage-sensitive genes, rather than a general response to altered DNA content. These findings add a complex, multicellular phenotype to the list of molecular and cellular traits known to be altered by aneuploidy and suggest that chromosome missegregation can provide a quick, heritable, and reversible mechanism by which organisms can toggle between phenotypes. [less ▲]

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See detailRole of methyl-induced polarization in ion binding
Rossi, Mariana; Tkatchenko, Alexandre UL; Rempe, Susan B. et al

in Proceedings of the National Academy of Sciences of the United States of America (2013), 110(32), 12978-12983

The chemical property of methyl groups that renders them indispensable to biomolecules is their hydrophobicity. Quantum mechanical studies undertaken here to understand the effect of point substitutions ... [more ▼]

The chemical property of methyl groups that renders them indispensable to biomolecules is their hydrophobicity. Quantum mechanical studies undertaken here to understand the effect of point substitutions on potassium (K-) channels illustrate quantitatively how methyl-induced polarization also contributes to biomolecular function. K- channels regulate transmembrane salt concentration gradients by transporting K+ ions selectively. One of the K+ binding sites in the channel's selectivity filter, the S4 site, also binds Ba2+ ions, which blocks K+ transport. This inhibitory property of Ba2+ ions has been vital in understanding K-channel mechanism. In most K-channels, the S4 site is composed of four threonine amino acids. The K channels that carry serine instead of threonine are significantly less susceptible to Ba2+ block and have reduced stabilities. We find that these differences can be explained by the lower polarizability of serine compared with threonine because serine carries one less branched methyl group than threonine. A T -> S substitution in the S4 site reduces its polarizability, which, in turn, reduces ion binding by several kilocalories per mole. Although the loss in binding affinity is high for Ba2+, the loss in K+ binding affinity is also significant thermodynamically, which reduces channel stability. These results highlight, in general, how biomolecular function can rely on the polarization induced by methyl groups especially those that are proximal to charged moieties, including ions titratable amino acids, sulfates, phosphates, and nucleotides. [less ▲]

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