A Conserved Arginine-Rich Motif within the Hypervariable N-Domain of Drosophila Centromeric Histone H3 (CenH3CID) Mediates BubR1 Recruitment

Centromere identity is determined epigenetically by deposition of CenH3, a centromere-specific histone H3 variant that dictates kinetochore assembly. The molecular basis of the contribution of CenH3 to centromere/kinetochore functions is, however, incompletely understood, as its interactions with the rest of centromere/kinetochore components remain largely uncharacterised at the molecular/structural level.Here, we report on the contribution of Drosophila CenH3(CID) to recruitment of BubR1, a conserved kinetochore protein that is a core component of the spindle attachment checkpoint (SAC). This interaction is mediated by the N-terminal domain of CenH3(CID) (NCenH3(CID)), as tethering NCenH3(CID) to an ectopic reporter construct results in BubR1 recruitment and BubR1-dependent silencing of the reporter gene. Here, we also show that this interaction depends on a short arginine (R)-rich motif and that, most remarkably, it appears to be evolutionarily conserved, as tethering constructs carrying the highly divergent NCenH3 of budding yeast and human also induce silencing of the reporter. Interestingly, though NCenH3 shows an exceedingly low degree of conservation, the presence of R-rich motives is a common feature of NCenH3 from distant species. Finally, our results also indicate that two other conserved sequence motives within NCenH3(CID) might also be involved in interactions with kinetochore components.These results unveil an unexpected contribution of the hypervariable N-domain of CenH3 to recruitment of kinetochore components, identifying simple R-rich motives within it as evolutionary conserved structural determinants involved in BubR1 recruitment

Female Sexual Polymorphism and Fecundity Consequences of Male Mating Harassment in the Wild

Genetic and phenotypic variation in female response towards male mating attempts has been found in several laboratory studies, demonstrating sexually antagonistic co-evolution driven by mating costs on female fitness. Theoretical models suggest that the type and degree of genetic variation in female resistance could affect the evolutionary outcome of sexually antagonistic mating interactions, resulting in either rapid development of reproductive isolation and speciation or genetic clustering and female sexual polymorphisms. However, evidence for genetic variation of this kind in natural populations of non-model organisms is very limited. Likewise, we lack knowledge on female fecundity-consequences of matings and the degree of male mating harassment in natural settings. Here we present such data from natural populations of a colour polymorphic damselfly. Using a novel experimental technique of colour dusting males in the field, we show that heritable female colour morphs differ in their propensity to accept male mating attempts. These morphs also differ in their degree of resistance towards male mating attempts, the number of realized matings and in their fecundity-tolerance to matings and mating attempts. These results show that there may be genetic variation in both resistance and tolerance to male mating attempts (fitness consequences of matings) in natural populations, similar to the situation in plant-pathogen resistance systems. Male mating harassment could promote the maintenance of a sexual mating polymorphism in females, one of few empirical examples of sympatric genetic clusters maintained by sexual conflict

Characteristics and Treatment Outcomes of Patients with MDR and XDR Tuberculosis in a TB Referral Hospital in Beijing: A 13-Year Experience

Background: Information on treatment outcomes among hospitalized patients with multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are scarce in China. Methodology/Principal Findings: We conducted this retrospective study to analyze the characteristics and treatment outcomes in MDR- and XDR-TB patients in the 309 Hospital in Beijing, China during 1996-2009. Socio-demographic and clinical data were retrieved from medical records and analyzed. Logistic regression analysis was performed to identify risk factors associated with poor treatment outcomes and Cox proportional hazards regression model was further used to determine risk factors associated with death in TB patients. Among the 3,551 non-repetitive hospitalized TB patients who had drug susceptibility testing (DST) results, 716 (20.2%) had MDR-TB and 51 (1.4%) had XDR-TB. A total of 3,270 patients who had medical records available were used for further analyses. Treatment success rates (cured and treatment completed) were 90.9%, 53.4% and 29.2% for patients with non-MDR-TB, patients with MDR-TB excluding XDR-TB and patients with XDR-TB, respectively. Independent risk factors associated with poor treatment outcomes in MDR-TB patients included being a migrant (adjusted OR = 1.77), smear-positivity at treatment onset (adjusted OR = 1.94) and not receiving 3 or more potentially effective drugs (adjusted OR = 3.87). Independent risk factors associated with poor treatment outcomes in XDR-TB patients were smear-positivity at treatment onset (adjusted OR = 10.42) and not receiving 3 or more potentially effective drugs (adjusted OR = 14.90). The independent risk factors associated with death in TB patients were having chronic obstructive pulmonary disease (adjusted HR = 5.25) and having hypertension (adjusted HR = 4.31). Conclusions/Significance: While overall satisfactory treatment success for non-MDR-TB patients was achieved, more intensive efforts should be made to better manage MDR- and XDR-TB cases in order to improve their treatment outcomes and to minimize further emergence of so-called totally drug-resistant TB cases. © 2011 Liu et al.published_or_final_versio

Differential responses of osteoblasts and macrophages upon Staphylococcus aureus infection

Background Staphylococcus aureus (S. aureus) is one of the primary causes of bone infections which are often chronic and difficult to eradicate. Bacteria like S. aureus may survive upon internalization in cells and may be responsible for chronic and recurrent infections. In this study, we compared the responses of a phagocytic cell (i.e. macrophage) to a non-phagocytic cell (i.e. osteoblast) upon S. aureus internalization. Results We found that upon internalization, S. aureus could survive for up to 5 and 7 days within macrophages and osteoblasts, respectively. Significantly more S. aureus was internalized in macrophages compared to osteoblasts and a significantly higher (100 fold) level of live intracellular S. aureus was detected in macrophages compared to osteoblasts. However, the percentage of S. aureus survival after infection was significantly lower in macrophages compared to osteoblasts at post-infection days 1–6. Interestingly, macrophages had relatively lower viability in shorter infection time periods (i.e. 0.5-4 h; significant at 2 h) but higher viability in longer infection time periods (i.e. 6–8 h; significant at 8 h) compared to osteoblasts. In addition, S. aureusinfection led to significant changes in reactive oxygen species production in both macrophages and osteoblasts. Moreover, infected osteoblasts had significantly lower alkaline phosphatase activity at post-infection day 7 and infected macrophages had higher phagocytosis activity compared to non-infected cells. Conclusions S. aureus was found to internalize and survive within osteoblasts and macrophages and led to differential responses between osteoblasts and macrophages. These findings may assist in evaluation of the pathogenesis of chronic and recurrent infections which may be related to the intracellular persistence of bacteria within host cells

Molecular evolution of cyclin proteins in animals and fungi

<p>Abstract</p> <p>Background</p> <p>The passage through the cell cycle is controlled by complexes of cyclins, the regulatory units, with cyclin-dependent kinases, the catalytic units. It is also known that cyclins form several families, which differ considerably in primary structure from one eukaryotic organism to another. Despite these lines of evidence, the relationship between the evolution of cyclins and their function is an open issue. Here we present the results of our study on the molecular evolution of A-, B-, D-, E-type cyclin proteins in animals and fungi.</p> <p>Results</p> <p>We constructed phylogenetic trees for these proteins, their ancestral sequences and analyzed patterns of amino acid replacements. The analysis of infrequently fixed atypical amino acid replacements in cyclins evidenced that accelerated evolution proceeded predominantly during paralog duplication or after it in animals and fungi and that it was related to aromorphic changes in animals. It was shown also that evolutionary flexibility of cyclin function may be provided by consequential reorganization of regions on protein surface remote from CDK binding sites in animal and fungal cyclins and by functional differentiation of paralogous cyclins formed in animal evolution.</p> <p>Conclusions</p> <p>The results suggested that changes in the number and/or nature of cyclin-binding proteins may underlie the evolutionary role of the alterations in the molecular structure of cyclins and their involvement in diverse molecular-genetic events.</p

Women's subsistence strategies predict fertility across cultures, but context matters

Data, Materials, and Software Availability. Anonymized CSV file data have been deposited in OSF (https://osf.io/8d9n2/?view_only=9e07c25 e06414f7a8d041e80e8539e5c) (49).Supporting Information is available online at: https://www.pnas.org/doi/suppl/10.1073/pnas.2318181121/suppl_file/pnas.2318181121.sapp.pdf .While it is commonly assumed that farmers have higher, and foragers lower, fertility compared to populations practicing other forms of subsistence, robust supportive evidence is lacking. We tested whether subsistence activities—incorporating market integration—are associated with fertility in 10,250 women from 27 small-scale societies and found considerable variation in fertility. This variation did not align with group-level subsistence typologies. Societies labeled as “farmers” did not have higher fertility than others, while “foragers” did not have lower fertility. However, at the individual level, we found strong evidence that fertility was positively associated with farming and moderate evidence of a negative relationship between foraging and fertility. Markers of market integration were strongly negatively correlated with fertility. Despite strong cross-cultural evidence, these relationships were not consistent in all populations, highlighting the importance of the socioecological context, which likely influences the diverse mechanisms driving the relationship between fertility and subsistence.A.E.P. received funding from the Medical Research Council MRC (grant no. MR/P014216/1). J.S. acknowledges Institute for Advanced Study in Toulouse funding from the French National Research Agency (ANR) under the Investments for the Future (Investissements d’Avenir) program, grant ANR-17-EURE-0010. This material is based upon work supported while S.M. served at the National Science Foundation (NSF)

ICAR: endoscopic skull‐base surgery

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