A pan-influenza monoclonal antibody neutralizes H5 strains and prophylactically protects through intranasal administration.

Avian A(H5N1) influenza virus poses an elevated zoonotic threat to humans, and no pharmacological products are currently registered for fast-acting pre-exposure protection in case of spillover leading to a pandemic. Here, we show that an epitope on the stem domain of H5 hemagglutinin is highly conserved and that the human monoclonal antibody CR9114, targeting that epitope, potently neutralizes all pseudotyped H5 viruses tested, even in the rare case of substitutions in its epitope. Further, intranasal administration of CR9114 fully protects mice against A(H5N1) infection at low dosages, irrespective of pre-existing immunity conferred by the quadrivalent seasonal influenza vaccine. These data provide a proof-of-concept for broad, pre-exposure protection against a potential future pandemic using the intranasal administration route. Studies in humans should assess if autonomous administration of a broadly-neutralizing monoclonal antibody is safe and effective and can thus contribute to pandemic preparedness.

Concurrent X chromosome inactivation and upregulation during non-human primate preimplantation development revealed by single-cell RNA-sequencing.

In mammals, dosage compensation of X-linked gene expression between males and females is achieved by inactivation of a single X chromosome in females, while upregulation of the single active X in males and females leads to X:autosome dosage balance. Studies in human embryos revealed that random X chromosome inactivation starts at the preimplantation stage and is not complete by day 12 of development. Alternatively, others proposed that dosage compensation in human preimplantation embryos is achieved by dampening expression from the two X chromosomes in females. Here, we characterize X-linked dosage compensation in another primate, the marmoset (Callithrix jacchus). Analyzing scRNA-seq data from preimplantation embryos, we detected upregulation of XIST at the morula stage, where female embryos presented a significantly higher expression of XIST than males. Moreover, we show an increase of X-linked monoallelically expressed genes in female embryos between the morula and late blastocyst stages, indicative of XCI. Nevertheless, dosage compensation was not achieved by the late blastocyst stage. Finally, we show that X:autosome dosage compensation is achieved at the 8-cell stage, and demonstrate that X chromosome dampening in females does not take place in the marmoset. Our work contributes to the elucidation of primate X-linked dosage compensation.

Relative to what? Dynamic updating of fluency standards and between-participants illusions of truth.

Previous research has shown that fluency effects are driven by discrepancies between current and baseline fluency. Thus, illusions of truth associated with repetition (which increases statement fluency and its perceived truth-value relative to new statements) are less likely to occur when participants judge pure lists of either all-repeated or all-new statements and comparisons are between-participants, than when participants judge mixed lists and comparisons are within-participants. Still, there are demonstrations of between-participants illusions of truth in the literature. In this manuscript, we explain the emergence of between-participants truth effects in terms of hypothetical dynamic updating of fluency standards. The findings of two experiments provide evidence for this hypothesis by showing that between-participants truth effects occur most strongly for the first elements of the statement list but are reduced over time. The findings suggest that the dynamics of fluency experiences contribute to the truth effect and should be taken into account when investigating illusions of truth.

The attractiveness-positivity link: Let's contextualize it.

The statement "what is beautiful is good" reflects a persuasive heuristic that may be supported either by a general association of attractiveness with positivity or by a specific association with the perceived credibility of an attractive source. In one study (N = 58), we approach this question using an explicit and an implicit measure (Stroop Task) to assess whether attractiveness is more likely associated with valenced words when these are related (vs. unrelated) to credibility. Results show that this effect occurs but only for the implicit measure. When the word-face associations were made at an explicit level, we found a general association between positivity and attractiveness, unrestricted to the dimension of credibility. We discuss how these results inform about attractiveness as a shortcut to judgments of validity.

Early X chromosome inactivation during human preimplantation development revealed by single-cell RNA-sequencing.

In female mammals, one X chromosome is transcriptionally inactivated (XCI), leading to dosage compensation between sexes, fundamental for embryo viability. A previous study using single-cell RNA-sequencing (scRNA-seq) data proposed that female human preimplantation embryos achieve dosage compensation by downregulating both Xs, a phenomenon named dampening of X expression. Using a novel pipeline on those data, we identified a decrease in the proportion of biallelically expressed X-linked genes during development, consistent with XCI. Moreover, we show that while the expression sum of biallelically expressed X-linked genes decreases with embryonic development, their median expression remains constant, rejecting the hypothesis of X dampening. In addition, analyses of a different dataset of scRNA-seq suggest the appearance of X-linked monoallelic expression by the late blastocyst stage in females, another hallmark of initiation of XCI. Finally, we addressed the issue of dosage compensation between the single active X and autosomes in males and females for the first time during human preimplantation development, showing emergence of X to autosome dosage compensation by the upregulation of the active X chromosome in both male and female embryonic stem cells. Our results show compelling evidence of an early process of X chromosome inactivation during human preimplantation development.

At Term, XmO and XpO Mouse Placentas Show Differences in Glucose Metabolism in the Trophectoderm-Derived Outer Zone.

Genetic mouse model (39,XO) for human Turner Syndrome (45,XO) harboring either a single maternally inherited (Xm) or paternally inherited (Xp) chromosome show a pronounced difference in survival rate at term. However, a detailed comparison of XmO and XpO placentas to explain this difference is lacking. We aimed to investigate the morphological and molecular differences between XmO and XpO term mouse placentas. We observed that XpO placentas at term contained a significantly larger area of glycogen cells (GCs) in their outer zone, compared to XmO, XX, and XY placentas. In addition, the outer zone of XpO placentas showed higher expression levels of lactate dehydrogenase (Ldha) than XmO, XX, and XY placentas, suggestive of increased anaerobic glycolysis. In the labyrinth, we detected significantly lower expression level of trophectoderm (TE)-marker keratin 19 (Krt19) in XpO placentas than in XX placentas. The expression of other TE-markers was comparable as well as the area of TE-derived cells between XO and wild-type labyrinths. XpO placentas exhibited specific defects in the amount of GCs and glucose metabolism in the outer zone, suggestive of increased anaerobic glycolysis, as a consequence of having inherited a single Xp chromosome. In conclusion, the XpO genotype results in a more severe placental phenotype at term, with distinct abnormalities regarding glucose metabolism in the outer zone.

The differential effects of fluency due to repetition and fluency due to color contrast on judgments of truth.

Two experiments contrast the effects of fluency due to repetition and fluency due to color contrast on judgments of truth, after participants learn to associate high levels of fluency with falseness (i.e., a reversal of the fluency-truth link). Experiment 1 shows that the interpretation of fluency as a sign of truth is harder to reverse when learning is promoted with repetition rather than with perceptual fluency. Experiment 2 shows that when color contrast and repetition are manipulated orthogonally, the reversal of the truth effect learned with color contrast does not generalize to repetition. These results suggest specificities in the processing experiences generated by different sources of fluency, and that their influences can be separated in contexts that allow the contrast of their distinctive features. We interpret and discuss these results in light of the research addressing the convergence vs. dissociation of the effects elicited by different fluency sources.

A relação da agressividade e do crime nas constituições subjetiva e social / The relationship between aggression and crime in subjective and social constitutions / La relación de agresión y el crimen en las constituciones subjetiva y social

Aborda-se a relação entre crime, sociedade e sujeito, tendo como referência as articulações freudianas. Objetiva-se demonstrar como a noção psicanalítica de estruturação da Civilização, através do Mito do Parricídio e, analogamente, a constituição subjetiva, por intermédio do Complexo de Édipo, revelam o crime como um desejo sumariamente humano e constitutivo. Investiga-se de que forma tais constituições se apresentam na teoria freudiana, esclarecendo os enlaces do sujeito com a sociedade, que geram um Mal-Estar, localizado como uma exigência de ordem pulsional. Conclui-se o manuscrito com a ponderação de que, embora o ato violento desfaça o arranjo social existente, a fundação da cultura exige a identificação e o reconhecimento entre os irmãos como possibilidade de estabelecimento de um laço social fundador da cultura.

This paper approaches the relation between crime, society and the subject, taking Freudians theoretical articulations as reference. The aim is to show how the psychoanalytical notion of Civilization's structure, through the Parricide's Myth and, analogously, the subjective constitution, through Oedipus Complex, reveal the crime as a briefly human and constitutive desire. It investigates how such constitutions are introduced in Freudian Theory, enlightening the bond between subject and society, which generates a discomfort as a requirement of the order of drives and instincts. With due consideration, the research concludes that although the violent act undo the existing social arrangement, the culture foundation requires the identification and recognition among brothers as possibility of establishing a social bond founder of culture.

Se abordo la relación entre el crimen, la sociedad y el sujeto, con referencia a las articulaciones teóricas freudianas. Se objetiva demuestrar cómo la noción psicoanalítica de la estructuración de la civilización, y análogamente, la constitución subjetiva por intermedio del complejo de Edipo, revelan el tema del crimen como un deseo humano y sumariamente constitutivo. Se investiga cómo las constituciones se presentan en la teoría freudiana, aclarando los enlaces del sujeto con la sociedad en medio de los deseos y prohibiciones, que genera un Malestar situado como una exigencia de orden pulsional. Se concluye el manuscrito con la ponderación que, aunque el acto violento deshace el contrato social existente, la fundación de la cultura requiere la identificación y el reconocimiento entre los hermanos como posibilidad de establecimiento de un lazo social fundador de la cultura.

Aberrant patterns of X chromosome inactivation in a new line of human embryonic stem cells established in physiological oxygen concentrations.

One of the differences between murine and human embryonic stem cells (ESCs) is the epigenetic state of the X chromosomes in female lines. Murine ESCs (mESCs) present two transcriptionally active Xs that will undergo the dosage compensation process of XCI upon differentiation, whereas most human ESCs (hESCs) spontaneously inactivate one X while keeping their pluripotency. Whether this reflects differences in embryonic development of mice and humans, or distinct culture requirements for the two kinds of pluripotent cells is not known. Recently it has been shown that hESCs established in physiological oxygen levels are in a stable pre-XCI state equivalent to that of mESCs, suggesting that culture in low oxygen concentration is enough to preserve that epigenetic state of the X chromosomes. Here we describe the establishment of two new lines of hESCs under physiological oxygen level and the characterization of the XCI state in the 46,XX line BR-5. We show that a fraction of undifferentiated cells present XIST RNA accumulation and single H3K27me foci, characteristic of the inactive X. Moreover, analysis of allele specific gene expression suggests that pluripotent BR-5 cells present completely skewed XCI. Our data indicate that physiological levels of oxygen are not sufficient for the stabilization of the pre-XCI state in hESCs.

A comparative transcriptome analysis reveals expression profiles conserved across three Eimeria spp. of domestic fowl and associated with multiple developmental stages.

Coccidiosis of the domestic fowl is a worldwide disease caused by seven species of protozoan parasites of the genus Eimeria. The genome of the model species, Eimeria tenella, presents a complexity of 55-60MB distributed in 14 chromosomes. Relatively few studies have been undertaken to unravel the complexity of the transcriptome of Eimeria parasites. We report here the generation of more than 45,000 open reading frame expressed sequence tag (ORESTES) cDNA reads of E. tenella, Eimeria maxima and Eimeria acervulina, covering several developmental stages: unsporulated oocysts, sporoblastic oocysts, sporulated oocysts, sporozoites and second generation merozoites. All reads were assembled to constitute gene indices and submitted to a comprehensive functional annotation pipeline. In the case of E. tenella, we also incorporated publicly available ESTs to generate an integrated body of information. Orthology analyses have identified genes conserved across different apicomplexan parasites, as well as genes restricted to the genus Eimeria. Digital expression profiles obtained from ORESTES/EST countings, submitted to clustering analyses, revealed a high conservation pattern across the three Eimeria spp. Distance trees showed that unsporulated and sporoblastic oocysts constitute a distinct clade in all species, with sporulated oocysts forming a more external branch. This latter stage also shows a close relationship with sporozoites, whereas first and second generation merozoites are more closely related to each other than to sporozoites. The profiles were unambiguously associated with the distinct developmental stages and strongly correlated with the order of the stages in the parasite life cycle. Finally, we present The Eimeria Transcript Database (http://www.coccidia.icb.usp.br/eimeriatdb), a website that provides open access to all sequencing data, annotation and comparative analysis. We expect this repository to represent a useful resource to the Eimeria scientific community, helping to define potential candidates for the development of new strategies to control coccidiosis of the domestic fowl.

Random X inactivation and extensive mosaicism in human placenta revealed by analysis of allele-specific gene expression along the X chromosome.

Imprinted inactivation of the paternal X chromosome in marsupials is the primordial mechanism of dosage compensation for X-linked genes between females and males in Therians. In Eutherian mammals, X chromosome inactivation (XCI) evolved into a random process in cells from the embryo proper, where either the maternal or paternal X can be inactivated. However, species like mouse and bovine maintained imprinted XCI exclusively in extraembryonic tissues. The existence of imprinted XCI in humans remains controversial, with studies based on the analyses of only one or two X-linked genes in different extraembryonic tissues. Here we readdress this issue in human term placenta by performing a robust analysis of allele-specific expression of 22 X-linked genes, including XIST, using 27 SNPs in transcribed regions. We show that XCI is random in human placenta, and that this organ is arranged in relatively large patches of cells with either maternal or paternal inactive X. In addition, this analysis indicated heterogeneous maintenance of gene silencing along the inactive X, which combined with the extensive mosaicism found in placenta, can explain the lack of agreement among previous studies. Our results illustrate the differences of XCI mechanism between humans and mice, and highlight the importance of addressing the issue of imprinted XCI in other species in order to understand the evolution of dosage compensation in placental mammals.

Syphilis at the crossroad of phylogenetics and paleopathology.

The origin of syphilis is still controversial. Different research avenues explore its fascinating history. Here we employed a new integrative approach, where paleopathology and molecular analyses are combined. As an exercise to test the validity of this approach we examined different hypotheses on the origin of syphilis and other human diseases caused by treponemes (treponematoses). Initially, we constructed a worldwide map containing all accessible reports on palaeopathological evidences of treponematoses before Columbus's return to Europe. Then, we selected the oldest ones to calibrate the time of the most recent common ancestor of Treponema pallidum subsp. pallidum, T. pallidum subsp. endemicum and T. pallidum subsp. pertenue in phylogenetic analyses with 21 genetic regions of different T. pallidum strains previously reported. Finally, we estimated the treponemes' evolutionary rate to test three scenarios: A) if treponematoses accompanied human evolution since Homo erectus; B) if venereal syphilis arose very recently from less virulent strains caught in the New World about 500 years ago, and C) if it emerged in the Americas between 16,500 and 5,000 years ago. Two of the resulting evolutionary rates were unlikely and do not explain the existent osseous evidence. Thus, treponematoses, as we know them today, did not emerge with H. erectus, nor did venereal syphilis appear only five centuries ago. However, considering 16,500 years before present (yBP) as the time of the first colonization of the Americas, and approximately 5,000 yBP as the oldest probable evidence of venereal syphilis in the world, we could not entirely reject hypothesis C. We confirm that syphilis seems to have emerged in this time span, since the resulting evolutionary rate is compatible with those observed in other bacteria. In contrast, if the claims of precolumbian venereal syphilis outside the Americas are taken into account, the place of origin remains unsolved. Finally, the endeavor of joining paleopathology and phylogenetics proved to be a fruitful and promising approach for the study of infectious diseases.

MAOA and GYG2 are submitted to X chromosome inactivation in human fibroblasts.

X chromosome inactivation (XCI) is a comprehensively studied phenomenon that helped to highlight the heritable nature of epigenetic modifications. Although it consists of the transcriptional inactivation of a whole X chromosome in females, some genes escape this process and present bi-allelic expression. Using human fibroblasts with skewed inactivation, we determined allele-specific expression of two X-linked genes previously described to escape XCI in rodent/human somatic cell hybrids, MAOA and GYG2, and the pattern of DNA methylation of their 5' end. Results from these complementary methodologies let us to conclude that both genes are subjected to X inactivation in normal human fibroblasts, indicating that hybrid cells are not an adequate system for studying epigenotypes. We emphasize the need of an analysis of XCI in normal human cell lines, helping us to determine more precisely which X-linked genes contribute to differences among genders and to the phenotypes associated with sex chromosomes aneuploidies.