The recruitment and activation of phosphatidylinositol 4-phosphate 5-kinases α critically regulate CD28-dependent signaling responses

CD28 costimulatory receptor is a crucial determinant of the outcome of T lymphocyte activation. The engagement of CD28 by its natural ligands, B7.1/CD80 or B7.2/CD86, expressed on the surface of professional APC, lowers T cell receptor (TCR) activation threshold, thus leading to the enhancement of early signalling events necessary for efficient cytokine production, cell cycle progression, survival and regulation of T cells effector responses. CD28 is also able to act as a unique signalling receptor and to deliver TCR-independent autonomous signals, which account for its critical role in the regulation of pro-inflammatory cytokine/chemokine production and T cell survival. Most of the CD28-dependent signalling functions are initiated by the recruitment and activation of class IA phosphatidylinositol 3-kinase (PI3K), The intracytoplasmic domain of CD28 contains a N-terminal YMNM motif that following phosphorylation binds the p85 subunit of phosphatidylinositol 3-kinase (PI3K). Once activated, PI3K catalyzes the conversion of phosphatidylinositol 4,5-biphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3) and generates the docking sites for key signalling proteins. PIP2 plays a critical role in the regulation of both cytoskeleton dynamics and second messenger generation. Indeed, PIP2 is the common source for two major distinct signalling cascades involving PI3K and PLCγ1 that often colocalize in the same signalling complexes competing for the common pool of substrate. Consequently, PIP2 levels decrease following receptor activation, thus suggesting that stimulation of PIP2 synthesis may be an essential regulatory step to sustain the activation of both PI3K and PLCγ1 following CD28 engagement. The main biosynthetic pathway of PIP2 involves phosphorylation of phosphatidylinositol 4-monophosphate (PI4P) at the D5 position of the inositol ring by PIP5K. Three PIP5K isoforms (α, β and γ) have been identified. Several data obtained in different cell systems evidenced differential subcellular localizations of each isoform. PIP5Kα, for instance, is localized at the plasma membrane, where it guarantees the local availability of PIP2. Here we show that CD28 stimulation by both B7.1/CD80 or agonistic Abs induces the recruitment and activation of PIP5Kα in human primary CD4+ T lymphocytes. This event leads to the neo-synthesis of PIP2 that is consumed by CD28-activated PI3K. By either small interference RNA (siRNA)-driven cell silencing or overexpressing a kinase dead mutant, we evidenced that PIP5Kα activation is required for both CD28 autonomous signals regulating IL-8 gene expression as well as for CD28/TCR-induced Ca2+ mobilization, NF-AT nuclear translocation and IL-2 gene transcription. Our findings identify PIP5Kα as a critical mediator of CD28-dependent responses

Intersegmental Coordination in the Kinematics of Prehension Movements of Macaques

The most popular model to explain how prehensile movements are organized assumes that they comprise two "components", the reaching component encoding information regarding the object's spatial location and the grasping component encoding information on the object's intrinsic properties such as size and shape. Comparative kinematic studies on grasping behavior in the humans and in macaques have been carried out to investigate the similarities and differences existing across the two species. Although these studies seem to favor the hypothesis that macaques and humans share a number of kinematic features it remains unclear how the reaching and grasping components are coordinated during prehension movements in free-ranging macaque monkeys. Twelve hours of video footage was filmed of the monkeys as they snatched food items from one another (i.e., snatching) or collect them in the absence of competitors (i.e., unconstrained). The video samples were analyzed frame-by-frame using digitization techniques developed to perform two-dimensional post-hoc kinematic analyses of the two types of actions. The results indicate that only for the snatching condition when the reaching variability increased there was an increase in the amplitude of maximum grip aperture. Besides, the start of a break-point along the deceleration phase of the velocity profile correlated with the time at which maximum grip aperture occurred. These findings suggest that macaques can spatially and temporally couple the reaching and the grasping components when there is pressure to act quickly. They offer a substantial contribution to the debate about the nature of how prehensile actions are programmed

Supervivencia de una pequeña población trasladada de Procolobus kirkii en la isla de Pemba

A survey to evaluate the distribution of Procolobus kirkii on Pemba island (Tanzania) was conducted, 20 years after they had been translocated from Zanzibar in the Ngezi forest park. A team of both expert and trained observers, guided by the authors, censused 68.3 linear km of forest, corresponding to an estimated area of 3.5 km2 (63.6%) of the protected Ngezi forested area of 5.5 km2. Nineteen groups of Cercopithecus aethiops were observed, with a total of 166 animals and an estimated density of 47.43 individuals per km2, and only one troop of Procolobus kirkii. Supplemented by interviewing the local people we obtained an estimate of 15–30 P. kirkii, including a small troop outside the protected area. This small population survived but did not increase, possibly due to adverse relations with humans.Se realizó un estudio para evaluar la distribución de Procolobus kirkii en la isla de Pemba (Tanzania), veinte años después de que fuera trasladada desde Zanzíbar al Parque Ngezi. Un equipo de observadores expertos y entrenados, guiados por los autores, efectuó un censo a lo largo de 68,3 km lineales de bosque, correspondiente a un área estimada de 3,5 km2 (63,6%) del área protegida del bosque de Ngezi de 5,5 km2. Se observaron 19 grupos de Cercopithecus aethiops, con un total de 166 animales y una densidad estimada de 47,43 individuos/km2, y sólo un grupo de Procolobus kirkii. Complementando los datos con entrevistas a la población local se obtuvo una estimación de 15–30 ejemplares de P. kirkii, incluyendo un pequeño grupo localizado fuera del área protegida. Este pequeño grupo sobrevivía pero no se incrementaba en número, posiblemente debido a las relaciones adversas con los humanos

China\u27s Unbalanced Development, And What We Can Learn From It

This paper argues that China’s development is unbalanced, and to see the unbalance we must divide the concept of development into different categories representing its different aspects, such as economic, urban, social, and sustainable. By looking at the different characteristics of development through time, it is possible to see where the unbalance lies. Furthermore, we learn that by categorizing the nature of development, we can gain a more comprehensive insight into the development of individual countries. In conclusion, this paper proposes the creation of a possible Development Index, as it can provide greater understanding of each country’s development

CD28 between tolerance and autoimmunity: The side effects of animal models [version 1; referees: 2 approved]

Regulation of immune responses is critical for ensuring pathogen clearance and for preventing reaction against self-antigens. Failure or breakdown of immunological tolerance results in autoimmunity. CD28 is an important co-stimulatory receptor expressed on T cells that, upon specific ligand binding, delivers signals essential for full T-cell activation and for the development and homeostasis of suppressive regulatory T cells. Many in vivo mouse models have been used for understanding the role of CD28 in the maintenance of immune homeostasis, thus leading to the development of CD28 signaling modulators that have been approved for the treatment of some autoimmune diseases. Despite all of this progress, a deeper understanding of the differences between the mouse and human receptor is required to allow a safe translation of pre-clinical studies in efficient therapies. In this review, we discuss the role of CD28 in tolerance and autoimmunity and the clinical efficacy of drugs that block or enhance CD28 signaling, by highlighting the success and failure of pre-clinical studies, when translated to humans

Human Homosexuality: A Paradigmatic Arena for Sexually Antagonistic Selection?

Sexual conflict likely plays a crucial role in the origin and maintenance of homosexuality in our species. Although environmental factors are known to affect human homosexual (HS) preference, sibling concordances and population patterns related to HS indicate that genetic components are also influencing this trait in humans. We argue that multilocus, partially X-linked genetic factors undergoing sexually antagonistic selection that promote maternal female fecundity at the cost of occasional male offspring homosexuality are the best candidates capable of explaining the frequency, familial clustering, and pedigree asymmetries observed in HS male proband families. This establishes male HS as a paradigmatic example of sexual conflict in human biology. HS in females, on the other hand, is currently a more elusive phenomenon from both the empirical and theoretical standpoints because of its fluidity and marked environmental influence. Genetic and epigenetic mechanisms, the latter involving sexually antagonistic components, have been hypothesized for the propagation and maintenance of female HS in the population. However, further data are needed to truly clarify the evolutionary dynamics of this trait

Attitudes towards urban howler monkeys (Alouatta caraya) in Paraguay

Acknowledgements A special thanks goes to all the staff, interns and volunteers of Para La Tierra (particularly Karina Atkinson, Joseph Sarvary and Paul Smith), who provided advice about this research. Marco Alesci would like to communicate his appreciation also to Paulo Fernando for his Spanish translation of the semi-structured interviews. Thank you to Fran O’Leary for making the map of the study site. Thank you to Michelle VanCompernolle and Susan Smith for comments on earlier drafts of the manuscripts. Rebecca L. Smith is grateful to the PRONII program of Conacyt. Fundación Para La Tierra is grateful to the estate of Don Julio Contreras for their endless support of PLT’s activities. All authors are grateful to two anonymous reviewers and to Júlio César Bicca-Marques for their insightful and helpful comments that greatly improved the manuscript. Finally, we express our immense gratitude to the Pilar community for their incredible hospitality and friendliness that made this research possible.Peer reviewedPublisher PD

Profiling acquired pedophilic behavior: Retrospective analysis of 66 Italian forensic cases of pedophilia

Neurological disorders can be mis-diagnosed as psychiatric ones. This might happen to pedophilia emerging as a symptom of brain insult (i.e. acquired pedophilic behavior). This paper aims to delineate a behavioral profile that might help to identify defendants whose pedophilic behavior is likely to be the consequence of a neurological disorder. Through a systematic review of the literature, seventeen clinical and behavioral variables of the modus operandi and victimology that can distinguish between acquired and developmental pedophilic behavior have been collected. Seven of these were found to be consistent behavioral indicators (i.e. red flags) for acquired pedophilia. Cluster hierarchical analysis on the seventeen variables collected through the systematic review of the literature on cases of acquired pedophilic behavior was applied to a new dataset including 66 Italian closed cases of pedophilia. Stepwise regression and correlation analyses were carried out to further examine the differences between the clusters identified in the cluster analysis. Results revealed that the new sample was partitioned into two clusters. Individuals with ascertained acquired pedophilia were grouped together. The clusters widely differed for the prevalence of red flags (mean number of red flags in each cluster: 2.14 ± 0.79 vs 4.96 ± 0.93, p < 0.001), while no between cluster difference emerged for the other clinical and behavioral variables. Regression analysis provided a robust model that included the three most significant red flags that explain over 64.5% of the variance (absence of masking, spontaneous confession and offenders older age). An organic origin of pedophilic behavior should be suspected if red flags are present in a defendant charged with pedophilia. In those cases, an in depth trans-disciplinary neuroscientific investigation is advocated. The behavioral profile identified might help to provide a proper assessment of defendants