Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase.

p85/p110 phosphoinositide 3-kinase (PI3K) is a heterodimer composed of a p85-regulatory and a p110-catalytic subunit, which is involved in a variety of cellular responses including cytoskeletal organization, cell survival and proliferation. We describe here the cloning and characterization of p65-PI3K, a mutant of the regulatory subunit of PI3K, which includes the initial 571 residues of the wild type p85alpha-protein linked to a region conserved in the eph tyrosine kinase receptor family. We demonstrate that this mutation, obtained from a transformed cell, unlike previously engineered mutations of the regulatory subunit, induces the constitutive activation of PI3K and contributes to cellular transformation. This report links the PI3K enzyme to mammalian tumor development for the first time.     

Proteolytic refolding of the HIV-1 capsid protein amino-terminus facilitates viral core assembly.

After budding, the human immunodeficiency virus (HIV) must 'mature' into an infectious viral particle. Viral maturation requires proteolytic processing of the Gag polyprotein at the matrix-capsid junction, which liberates the capsid (CA) domain to condense from the spherical protein coat of the immature virus into the conical core of the mature virus. We propose that upon proteolysis, the amino-terminal end of the capsid refolds into a beta-hairpin/helix structure that is stabilized by formation of a salt bridge between the processed amino-terminus (Pro1) and a highly conserved aspartate residue (Asp51). The refolded amino-terminus then creates a new CA-CA interface that is essential for assembling the condensed conical core. Consistent with this model, we found that recombinant capsid proteins with as few as four matrix residues fused to their amino-termini formed spheres in vitro, but that removing these residues refolded the capsid amino-terminus and redirected protein assembly from spheres to cylinders. Moreover, point mutations throughout the putative CA-CA interface blocked capsid assembly in vitro, core assembly in vivo and viral infectivity. Disruption of the conserved amino-terminal capsid salt bridge also abolished the infectivity of Moloney murine leukemia viral particles, suggesting that lenti- and oncoviruses mature via analogous pathways.     

Pheromone-Dependent G1 Cell Cycle Arrest Requires Far1 Phosphorylation, but May Not Involve Inhibition of Cdc28-Cln2 Kinase, In Vivo

In yeast, the pheromone α-factor acts as an antiproliferative factor that induces G₁ arrest and cellular differentiation. Previous data have indicated that Far1, a factor dedicated to pheromone-induced cell cycle arrest, is under positive and negative posttranslational regulation. Phosphorylation by the pheromone-stimulated mitogen-activated protein (MAP) kinase Fus3 has been thought to enhance the binding of Far1 to G₁-specific cyclin-dependent kinase (Cdk) complexes, thereby inhibiting their catalytic activity. Cdk-dependent phosphorylation events were invoked to account for the high instability of Far1 outside early G₁ phase. To confirm any functional role of Far1 phosphorylation, we undertook a systematic mutational analysis of potential MAP kinase and Cdk recognition motifs. Two putative phosphorylation sites that strongly affect Far1 behavior were identified. A change of serine 87 to alanine prevents the cell cycle-dependent degradation of Far1, causing enhanced sensitivity to pheromone. In contrast, threonine 306 seems to be an important recipient of an activating modification, as substitutions at this position abolish the G₁ arrest function of Far1. Only the phosphorylated wild-type Far1 protein, not the T306-to-A substitution product, can be found in stable association with the Cdc28-Cln2 complex. Surprisingly, Far1-associated Cdc28-Cln2 complexes are at best moderately inhibited in immunoprecipitation kinase assays, suggesting unconventional inhibitory mechanisms of Far1.     

Spatio-temporal modelling of the first Chikungunya epidemic in an intra-urban setting: The role of socioeconomic status,environment and temperature

Three key elements are the drivers of Aedes-borne disease: mosquito infestation, virus circulating, and susceptible human population. However, information on these aspects is not easily available in low- and middle-income countries. We analysed data on factors that influence one or more of those elements to study the first chikungunya epidemic in Rio de Janeiro city in 2016. Using spatio-temporal models, under the Bayesian framework, we estimated the association of those factors with chikungunya reported cases by neighbourhood and week. To estimate the minimum temperature effect in a non-linear fashion, we used a transfer function considering an instantaneous effect and propagation of a proportion of such effect to future times. The sociodevelopment index and the proportion of green areas (areas with agriculture, swamps and shoals, tree and shrub cover, and woody-grass cover) were included in the model with time-varying coefficients, allowing us to explore how their associations with the number of cases change throughout the epidemic. There were 13627 chikungunya cases in the study period. The sociodevelopment index presented the strongest association, inversely related to the risk of cases. Such association was more pronounced in the first weeks, indicating that socioeconomically vulnerable neighbourhoods were affected first and hardest by the epidemic. The proportion of green areas effect was null for most weeks. The temperature was directly associated with the risk of chikungunya for most neighbourhoods, with different decaying patterns. The temperature effect persisted longer where the epidemic was concentrated. In such locations, interventions should be designed to be continuous and to work in the long term. We observed that the role of the covariates changes over time. Therefore, time-varying coefficients should be widely incorporated when modelling Aedes-borne diseases. Our model contributed to the understanding of the spatio-temporal dynamics of an urban Aedes-borne disease introduction in a tropical metropolitan city.     

Intergeneric hybridization between Psathyrostachys and Hordeum

A total of 38 intergeneric combinations with Hordeum and Psathyrostachys was attempted. Generally the seed set was high, and 23 new intergeneric hybrid combinations were synthesized by the aid of embryo culture technique. All combinations showed complete sterility. The meiotic pairing behaviour in 8 combinations is reported. On the basis of these data it is clear that the N genome in Psathyrostachys is distinct and shows no genomic relationship, neither with the "X" and I nor with the H genomes in Hordeum.     

Searching for the Oldest Baobab of Madagascar: Radiocarbon Investigation of Large Adansonia rubrostipa Trees

We extended our research on the architecture, growth and age of trees belonging to the genus Adansonia, by starting to investigate large individuals of the most widespread Malagasy species. Our research also intends to identify the oldest baobabs of Madagascar. Here we present results of the radiocarbon investigation of the two most representative Adansonia rubrostipa (fony baobab) specimens, which are located in south-western Madagascar, in the Tsimanampetsotse National Park. We found that the fony baobab called “Grandmother” consists of 3 perfectly fused stems of different ages. The radiocarbon date of the oldest sample was found to be 1136 ± 16 BP. We estimated that the oldest part of this tree, which is mainly hollow, has an age close to 1,600 yr. This value is comparable to the age of the oldest Adansonia digitata (African baobab) specimens. By its age, the Grandmother is a major candidate for the oldest baobab of Madagascar. The second investigated specimen, called the “polygamous baobab”, consists of 6 partially fused stems of different ages. According to dating results, this fony baobab is 1,000 yr old. This research is the first investigation of the structure and age of Malagasy baobabs.     

Dental Ontogeny in Pliocene and Early Pleistocene Hominins

Until recently, our understanding of the evolution of human growth and development derived from studies of fossil juveniles that employed extant populations for both age determination and comparison. This circular approach has led to considerable debate about the human-like and ape-like affinities of fossil hominins. Teeth are invaluable for understanding maturation as age at death can be directly assessed from dental microstructure, and dental development has been shown to correlate with life history across primates broadly. We employ non-destructive synchrotron imaging to characterize incremental development, molar emergence, and age at death in more than 20 Australopithecus anamensis, Australopithecus africanus, Paranthropus robustus and South African early Homo juveniles. Long-period line periodicities range from at least 6–12 days (possibly 5–13 days), and do not support the hypothesis that australopiths have lower mean values than extant or fossil Homo. Crown formation times of australopith and early Homo postcanine teeth fall below or at the low end of extant human values; Paranthropus robustus dentitions have the shortest formation times. Pliocene and early Pleistocene hominins show remarkable variation, and previous reports of age at death that employ a narrow range of estimated long-period line periodicities, cuspal enamel thicknesses, or initiation ages are likely to be in error. New chronological ages for SK 62 and StW 151 are several months younger than previous histological estimates, while Sts 24 is more than one year older. Extant human standards overestimate age at death in hominins predating Homo sapiens, and should not be applied to other fossil taxa. We urge caution when inferring life history as aspects of dental development in Pliocene and early Pleistocene fossils are distinct from modern humans and African apes, and recent work has challenged the predictive power of primate-wide associations between hominoid first molar emergence and certain life history variables.     

Genetic Population Structure Accounts for Contemporary Ecogeographic Patterns in Tropic and Subtropic-Dwelling Humans

Contemporary human populations conform to ecogeographic predictions that animals will become more compact in cooler climates and less compact in warmer ones. However, it remains unclear to what extent this pattern reflects plastic responses to current environments or genetic differences among populations. Analyzing anthropometric surveys of 232,684 children and adults from across 80 ethnolinguistic groups in sub-Saharan Africa, Asia and the Americas, we confirm that body surface-to-volume correlates with contemporary temperature at magnitudes found in more latitudinally diverse samples (Adj. R² = 0.14-0.28). However, far more variation in body surface-to-volume is attributable to genetic population structure (Adj. R² = 0.50-0.74). Moreover, genetic population structure accounts for nearly all of the observed relationship between contemporary temperature and body surface-to-volume among children and adults. Indeed, after controlling for population structure, contemporary temperature accounts for no more than 4% of the variance in body form in these groups. This effect of genetic affinity on body form is also independent of other ecological variables, such as dominant mode of subsistence and household wealth per capita. These findings suggest that the observed fit of human body surface-to-volume with current climate in this sample reflects relatively large effects of existing genetic population structure of contemporary humans compared to plastic response to current environments.     

Emotional Processing,Recognition, Empathy and Evoked Facial Expression in Eating Disorders: An Experimental Study to Map Deficits in Social Cognition

Background

Difficulties in social cognition have been identified in eating disorders (EDs), but the exact profile of these abnormalities is unclear. The aim of this study is to examine distinct processes of social-cognition in this patient group, including attentional processing and recognition, empathic reaction and evoked facial expression in response to discrete vignettes of others displaying positive (i.e. happiness) or negative (i.e. sadness and anger) emotions.

Method

One hundred and thirty-eight female participants were included in the study: 73 healthy controls (HCs) and 65 individuals with an ED (49 with Anorexia Nervosa and 16 with Bulimia Nervosa). Self-report and behavioural measures were used.

Results

Participants with EDs did not display specific abnormalities in emotional processing, recognition and empathic response to others’ basic discrete emotions. However, they had poorer facial expressivity and a tendency to turn away from emotional displays.

Conclusion

Treatments focusing on the development of non-verbal emotional communication skills might be of benefit for patients with EDs.