The protein composition of mitotic chromosomes determined using multiclassifier combinatorial proteomics.

Despite many decades of study, mitotic chromosome structure and composition remain poorly characterized. Here, we have integrated quantitative proteomics with bioinformatic analysis to generate a series of independent classifiers that describe the approximately 4,000 proteins identified in isolated mitotic chromosomes. Integrating these classifiers by machine learning uncovers functional relationships between protein complexes in the context of intact chromosomes and reveals which of the approximately 560 uncharacterized proteins identified here merits further study. Indeed, of 34 GFP-tagged predicted chromosomal proteins, 30 were chromosomal, including 13 with centromere-association. Of 16 GFP-tagged predicted nonchromosomal proteins, 14 were confirmed to be nonchromosomal. An unbiased analysis of the whole chromosome proteome from genetic knockouts of kinetochore protein Ska3/Rama1 revealed that the APC/C and RanBP2/RanGAP1 complexes depend on the Ska complex for stable association with chromosomes. Our integrated analysis predicts that up to 97 new centromere-associated proteins remain to be discovered in our data set.

Estimation and probabilistic projection of age- and sex-specific mortality rates across Brazilian municipalities between 2010 and 2030.

BACKGROUND: Mortality rate estimation in small areas can be difficult due the low number of events/exposure (i.e. stochastic error). If the death records are not completed, it adds a systematic uncertainty on the mortality estimates. Previous studies in Brazil have combined demographic and statistical methods to partially overcome these issues. We estimated age- and sex-specific mortality rates for all 5,565 Brazilian municipalities in 2010 and forecasted probabilistic mortality rates and life expectancy between 2010 and 2030. METHODS: We used a combination of the Tool for Projecting Age-Specific Rates Using Linear Splines (TOPALS), Bayesian Model, Spatial Smoothing Model and an ad-hoc procedure to estimate age- and sex-specific mortality rates for all Brazilian municipalities for 2010. Then we adapted the Lee-Carter model to forecast mortality rates by age and sex in all municipalities between 2010 and 2030. RESULTS: The adjusted sex- and age-specific mortality rates for all Brazilian municipalities in 2010 reveal a distinct regional pattern, showcasing a decrease in life expectancy in less socioeconomically developed municipalities when compared to estimates without adjustments. The forecasted mortality rates indicate varying regional improvements, leading to a convergence in life expectancy at birth among small areas in Brazil. Consequently, a reduction in the variability of age at death across Brazil's municipalities was observed, with a persistent sex differential. CONCLUSION: Mortality rates at a small-area level were successfully estimated and forecasted, with associated uncertainty estimates also generated for future life tables. Our approach could be applied across countries with data quality issues to improve public policy planning.

Cesarean sections and early-term births according to Robson classification: a population-based study with more than 17 million births in Brazil.

BACKGROUND: Cesarean section (CS) rates are increasing worldwide and are associated with negative maternal and child health outcomes when performed without medical indication. However, there is still limited knowledge about the association between high CS rates and early-term births. This study explored the association between CSs and early-term births according to the Robson classification. METHODS: A population-based, cross-sectional study was performed with routine registration data of live births in Brazil between 2012 and 2019. We used the Robson classification system to compare groups with expected high and low CS rates. We used propensity scores to compare CSs to vaginal deliveries (1:1) and estimated associations with early-term births using logistic regression. RESULTS: A total of 17,081,685 live births were included. Births via CS had higher odds of early-term birth (OR 1.32; 95% CI 1.32-1.32) compared to vaginal deliveries. Births by CS to women in Group 2 (OR 1.50; 95% CI 1.49-1.51) and 4 (OR 1.57; 95% CI 1.56-1.58) showed the highest odds of early-term birth, compared to vaginal deliveries. Increased odds of an early-term birth were also observed among births by CS to women in Group 3 (OR 1.30, 95% CI 1.29-1.31), compared to vaginal deliveries. In addition, live births by CS to women with a previous CS (Group 5 - OR 1.36, 95% CI 1.35-1.37), a single breech pregnancy (Group 6 - OR 1.16; 95% CI 1.11-1.21, and Group 7 - OR 1.19; 95% CI 1.16-1.23), and multiple pregnancies (Group 8 - OR 1.46; 95% CI 1.40-1.52) had high odds of an early-term birth, compared to live births by vaginal delivery. CONCLUSIONS: CSs were associated with increased odds of early-term births. The highest odds of early-term birth were observed among those births by CS in Robson Groups 2 and 4.

Relationship between the Bolsa Família national cash transfer programme and suicide incidence in Brazil: A quasi-experimental study.

BACKGROUND: Socioeconomic factors have been consistently associated with suicide, and economic recessions are linked to rising suicide rates. However, evidence on the impact of socioeconomic interventions to reduce suicide rates is limited. This study investigates the association of the world's largest conditional cash transfer programme with suicide rates in a cohort of half of the Brazilian population. METHODS AND FINDINGS: We used data from the 100 Million Brazilian Cohort, covering a 12-year period (2004 to 2015). It comprises socioeconomic and demographic information on 114,008,317 individuals, linked to the "Bolsa Família" programme (BFP) payroll database, and nationwide death registration data. BFP was implemented by the Brazilian government in 2004. We estimated the association of BFP using inverse probability of treatment weighting, estimating the weights for BFP beneficiaries (weight = 1) and nonbeneficiaries by the inverse probability of receiving treatment (weight = E(ps)/(1-E(ps))). We used an average treatment effect on the treated (ATT) estimator and fitted Poisson models to estimate the incidence rate ratios (IRRs) for suicide associated with BFP experience. At the cohort baseline, BFP beneficiaries were younger (median age 27.4 versus 35.4), had higher unemployment rates (56% versus 32%), a lower level of education, resided in rural areas, and experienced worse household conditions. There were 36,742 suicide cases among the 76,532,158 individuals aged 10 years, or older, followed for 489,500,000 person-years at risk. Suicide rates among beneficiaries and nonbeneficiaries were 5.4 (95% CI = 5.32, 5.47, p < 0.001) and 10.7 (95% CI = 10.51, 10.87, p < 0.001) per 100,000 individuals, respectively. BFP beneficiaries had a lower suicide rate than nonbeneficiaries (IRR = 0.44, 95% CI = 0.42, 0.45, p < 0.001). This association was stronger among women (IRR = 0.36, 95% CI = 0.33, 0.38, p < 0.001), and individuals aged between 25 and 59 (IRR = 0.41, 95% CI = 0.40, 0.43, p < 0.001). Study limitations include a lack of control for previous mental disorders and access to means of suicide, and the possible under-registration of suicide cases due to stigma. CONCLUSIONS: We observed that BFP was associated with lower suicide rates, with similar results in all sensitivity analyses. These findings should help to inform policymakers and health authorities to better design suicide prevention strategies. Targeting social determinants using cash transfer programmes could be important in limiting suicide, which is predicted to rise with the economic recession, consequent to the Coronavirus Disease 2019 (COVID-19) pandemic.

Differences in risk factors for incident and recurrent preterm birth: a population-based linkage of 3.5 million births from the CIDACS birth cohort.

BACKGROUND: Preterm birth (PTB) is a syndrome resulting from a complex list of underlying causes and factors, and whether these risk factors differ in the context of prior PTB history is less understood. The aim of this study was to explore whether PTB risk factors in a second pregnancy were different in women with versus without previous PTB. METHODS: We conducted a population-based cohort study using data from the birth cohort of the Center for Data and Knowledge Integration for Health (CIDACS) for the period 2001 to 2015. We used longitudinal transition models with multivariate logistic regression to investigate whether risk factors varied between incident and recurrent PTB. RESULTS: A total of 3,528,050 live births from 1,764,025 multiparous women were analyzed. We identified different risk factors (Pdifference <0.05) between incident and recurrent PTB. The following were associated with an increased chance for PTB incidence, but not recurrent: household overcrowding (OR 1.09), maternal race/ethnicity [(Black/mixed-OR 1.04) and (indigenous-OR 1.34)], young maternal age (14 to 19 years-OR 1.16), and cesarean delivery (OR 1.09). The following were associated with both incident and recurrent PTB, respectively: single marital status (OR 0.85 vs 0.90), reduced number of prenatal visits [(no visit-OR 2.56 vs OR 2.16) and (1 to 3 visits-OR 2.44 vs OR 2.24)], short interbirth interval [(12 to 23 months-OR 1.04 vs OR 1.22) and (<12 months, OR 1.89, 95 vs OR 2.58)], and advanced maternal age (35-49 years-OR 1.42 vs OR 1.45). For most risk factors, the point estimates were higher for incident PTB than recurrent PTB. CONCLUSIONS: The risk factors for PTB in the second pregnancy differed according to women's first pregnancy PTB status. The findings give the basis for the development of specific prevention strategies for PTB in a subsequent pregnancy.

CoronaVac vaccine is effective in preventing symptomatic and severe COVID-19 in pregnant women in Brazil: a test-negative case-control study.

BACKGROUND: More doses of CoronaVac have been administered worldwide than any other COVID-19 vaccine. However, the effectiveness of COVID-19 inactivated vaccines in pregnant women is still unknown. We estimated the vaccine effectiveness (VE) of CoronaVac against symptomatic and severe COVID-19 in pregnant women in Brazil. METHODS: We conducted a test-negative design study in all pregnant women aged 18-49 years with COVID-19-related symptoms in Brazil from March 15, 2021, to October 03, 2021, linking records of negative and positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) tests to national vaccination records. We also linked records of test-positive cases with notifications of severe, hospitalised or fatal COVID-19. Using logistic regression, we estimated the adjusted odds ratio and VE against symptomatic COVID-19 and against severe COVID-19 by comparing vaccine status in test-negative subjects to test-positive symptomatic cases and severe cases. RESULTS: Of the 19,838 tested pregnant women, 7424 (37.4%) tested positive for COVID-19 and 588 (7.9%) had severe disease. Only 83% of pregnant women who received the first dose of CoronaVac completed the vaccination scheme. A single dose of the CoronaVac vaccine was not effective at preventing symptomatic COVID-19. The effectiveness of two doses of CoronaVac was 41% (95% CI 27.1-52.2) against symptomatic COVID-19 and 85% (95% CI 59.5-94.8) against severe COVID-19. CONCLUSIONS: A complete regimen of CoronaVac in pregnant women was effective in preventing symptomatic COVID-19 and highly effective against severe illness in a setting that combined high disease burden and marked COVID-19-related maternal deaths.

Barrier proteins and eosinophilic esophagitis in children: the role of E-cadherin and filaggrin.

This study aimed to assess the protein expression of E-cadherin and filaggrin (FLG) in the oesophagus of paediatric and adolescent patients diagnosed with eosinophilic esophagitis (EoE). It is a cross-sectional study conducted with 24 patients with EoE and 17 control patients, from June 2015 to June 2018. The histological analyses were performed by a trained pathologist. The protein expression of E-cadherin and FLG in oesophageal biopsy fragments was determined using an immunohistochemical technique. The epidemiological data were retrieved from medical records. There were no statistical differences in age and sex between case-patients and control patients. Food allergy was significantly higher in patients with EoE, as was the number of eosinophils present in the oesophageal biopsy materials. The immunohistochemical studies did not indicate FLG expression in any patient from the two groups. E-cadherin showed significantly reduced expression in patients with EoE. We concluded that FLG did not seem to play an important role in the mucosal alteration in EoE and that E-cadherin under expression could be a promising marker of epithelial damage in these patients.

Associations between cesarean delivery and child mortality: A national record linkage longitudinal study of 17.8 million births in Brazil.

BACKGROUND: There is an increasing use of cesarean delivery (CD) based on preference rather than on medical indication. However, the extent to which nonmedically indicated CD benefits or harms child survival remains unclear. Our hypothesis was that in groups with a low indication for CD, this procedure would be associated with higher child mortality and in groups with a clear medical indication CD would be associated with improved child survival chances. METHODS AND FINDINGS: We conducted a population-based cohort study in Brazil by linking routine data on live births between January 1, 2012 and December 31, 2018 and assessing mortality up to 5 years of age. Women with a live birth who contributed records during this period were classified into one of 10 Robson groups based on their pregnancy and delivery characteristics. We used propensity scores to match CD with vaginal deliveries (1:1) and prelabor CD with unscheduled CD (1:1) and estimated associations with child mortality using Cox regressions. A total of 17,838,115 live births were analyzed. After propensity score matching (PSM), we found that live births to women in groups with low expected frequencies of CD (Robson groups 1 to 4) had a higher death rate up to age 5 years if they were born via CD compared with vaginal deliveries (HR = 1.25, 95% CI: 1.22 to 1.28; p < 0.001). The relative rate was greatest in the neonatal period (HR = 1.39, 95% CI: 1.34 to 1.45; p < 0.001). There was no difference in mortality rate when comparing offspring born by a prelabor CD to those born by unscheduled CD. For the live births to women with a CD in a prior pregnancy (Robson group 5), the relative rates for child mortality were similar for those born by CD compared with vaginal deliveries (HR = 1.05, 95% CI: 1.00 to 1.10; p = 0.024). In contrast, for live births to women in groups with high expected rates of CD (Robson groups 6 to 10), the child mortality rate was lower for CD than for vaginal deliveries (HR = 0.90, 95% CI: 0.89 to 0.91; p < 0.001), particularly in the neonatal period (HR = 0.84, 95% CI: 0.83 to 0.85; p < 0.001). Our results should be interpreted with caution in clinical practice, since relevant clinical data on CD indication were not available. CONCLUSIONS: In this study, we observed that in Robson groups with low expected frequencies of CD, this procedure was associated with a 25% increase in child mortality. However, in groups with high expected frequencies of CD, the findings suggest that clinically indicated CD is associated with a reduction in child mortality.

Long-term impact of a conditional cash transfer programme on maternal mortality: a nationwide analysis of Brazilian longitudinal data.

BACKGROUND: Reducing poverty and improving access to health care are two of the most effective actions to decrease maternal mortality, and conditional cash transfer (CCT) programmes act on both. The aim of this study was to evaluate the effects of one of the world's largest CCT (the Brazilian Bolsa Familia Programme (BFP)) on maternal mortality during a period of 11 years. METHODS: The study had an ecological longitudinal design and used all 2548 Brazilian municipalities with vital statistics of adequate quality during 2004-2014. BFP municipal coverage was classified into four levels, from low to consolidated, and its duration effects were measured using the average municipal coverage of previous years. We used negative binomial multivariable regression models with fixed-effects specifications, adjusted for all relevant demographic, socioeconomic, and healthcare variables. RESULTS: BFP was significantly associated with reductions of maternal mortality proportionally to its levels of coverage and years of implementation, with a rate ratio (RR) reaching 0.88 (95%CI 0.81-0.95), 0.84 (0.75-0.96) and 0.83 (0.71-0.99) for intermediate, high and consolidated BFP coverage over the previous 11 years. The BFP duration effect was stronger among young mothers (RR 0.77; 95%CI 0.67-0.96). BFP was also associated with reductions in the proportion of pregnant women with no prenatal visits (RR 0.73; 95%CI 0.69-0.77), reductions in hospital case-fatality rate for delivery (RR 0.78; 95%CI 0.66-0.94) and increases in the proportion of deliveries in hospital (RR 1.05; 95%CI 1.04-1.07). CONCLUSION: Our findings show that a consolidated and durable CCT coverage could decrease maternal mortality, and these long-term effects are stronger among poor mothers exposed to CCT during their childhood and adolescence, suggesting a CCT inter-generational effect. Sustained CCT coverage could reduce health inequalities and contribute to the achievement of the Sustainable Development Goal 3.1, and should be preserved during the current global economic crisis due to the COVID-19 pandemic.

Rrp5 binding at multiple sites coordinates pre-rRNA processing and assembly.

In vivo UV crosslinking identified numerous preribosomal RNA (pre-rRNA) binding sites for the large, highly conserved ribosome synthesis factor Rrp5. Intramolecular complementation has shown that the C-terminal domain (CTD) of Rrp5 is required for pre-rRNA cleavage at sites A0-A2 on the pathway of 18S rRNA synthesis, whereas the N-terminal domain (NTD) is required for A3 cleavage on the pathway of 5.8S/25S rRNA synthesis. The CTD was crosslinked to sequences flanking A2 and to the snoRNAs U3, U14, snR30, and snR10, which are required for cleavage at A0-A2. The NTD was crosslinked to sequences flanking A3 and to the RNA component of ribonuclease MRP, which cleaves site A3. Rrp5 could also be directly crosslinked to several large structural proteins and nucleoside triphosphatases. A key role in coordinating preribosomal assembly and processing was confirmed by chromatin spreads. Following depletion of Rrp5, cotranscriptional cleavage was lost and preribosome compaction greatly reduced.

Shifts towards overweight and double burden of malnutrition among socio-economically vulnerable children: a longitudinal ecological analysis of Brazilian municipalities.

OBJECTIVE: To investigate the shifts and factors associated with different scenarios resulting from the prevalence of child stunting and overweight in Brazilian municipalities. DESIGN: This is an ecological study using municipality-level panel data of stunting and overweight prevalence and socio-economic characteristics from 2008 to 2014. The municipalities were classified according to the WHO-UNICEF prevalence thresholds for stunting and overweight and were categorised into four nutritional scenarios: no burden (prevalence of stunting < 20 % and overweight < 10 %), stunting burden (prevalence of stunting ≥ 20 % and overweight < 10 %), overweight burden (prevalence of stunting < 20 % and overweight ≥ 10 %) and double burden (prevalence of stunting ≥ 20 % and overweight ≥ 10 %). SETTING: Totally, 4443 Brazilian municipalities. PARTICIPANTS: Aggregated data of children under 5 years old enrolled in the Brazil's conditional cash transfer programme (Bolsa Família). RESULTS: A mean reduction from 14·2 % to 12·7 % in the prevalence of stunting and an increase from 17·2 % to 18·4 % in the prevalence of overweight were observed. The predominant scenarios were overweight burden and double burden. The odds of both scenarios increased with higher gross domestic product (GDP) per capita and decreased with higher unemployment rates. Stunting and double burden decreased with higher expected years of schooling, and stunting burden increased with household crowding. CONCLUSION: Our findings indicate an advanced nutrition transition stage in Brazil, associated mainly with municipal GDP per capita growth, which has contributed to increasing the burden of overweight alone or coexisting with stunting (double burden) among children in the most socio-economically vulnerable strata of the population.

Tissue-specific control of brain-enriched miR-7 biogenesis.

MicroRNA (miRNA) biogenesis is a highly regulated process in eukaryotic cells. Several mature miRNAs exhibit a tissue-specific pattern of expression without an apparent tissue-specific pattern for their corresponding primary transcripts. This discrepancy is suggestive of post-transcriptional regulation of miRNA abundance. Here, we demonstrate that the brain-enriched expression of miR-7, which is processed from the ubiquitous hnRNP K pre-mRNA transcript, is achieved by inhibition of its biogenesis in nonbrain cells in both human and mouse systems. Using stable isotope labeling by amino acids in cell culture (SILAC) mass spectrometry combined with RNase-assisted RNA pull-down, we identified Musashi homolog 2 (MSI2) and Hu antigen R (HuR) proteins as inhibitors of miR-7 processing in nonneural cells. This is achieved through HuR-mediated binding of MSI2 to the conserved terminal loop of pri-miR-7. Footprinting and electrophoretic gel mobility shift analysis (EMSA) provide further evidence for a direct interaction between pri-miR-7-1 and the HuR/MSI2 complex, resulting in stabilization of the pri-miR-7-1 structure. We also confirmed the physiological relevance of this inhibitory mechanism in a neuronal differentiation system using human SH-SY5Y cells. Finally, we show elevated levels of miR-7 in selected tissues from MSI2 knockout (KO) mice without apparent changes in the abundance of the pri-miR-7 transcript. Altogether, our data provide the first insight into the regulation of brain-enriched miRNA processing by defined tissue-specific factors.

Effect of the Brazilian cash transfer programme on suicide rates: a longitudinal analysis of the Brazilian municipalities.

PURPOSE: There is a growing awareness of the economic and contextual factors that may play a role in the aetiology of suicide. The Programa Bolsa Família (PBF) the Brazilian conditional cash transfer programme, established in 2004, aims to attenuate the effects of poverty of Brazilians. Our study aims to evaluate the effect of Bolsa Família Programme (BFP) coverage on suicide rates in Brazilian municipalities. METHODS: We conducted an ecological study using 2004-2012 panel data for 5507 Brazilian municipalities. We calculated age-standardized suicide rates for each municipality and year. BFP coverage was categorized according to three levels (< 30%, ≥ 30% and < 70% and ≥ 70%) and duration (coverage ≤ 70% for all years, ≥ 70% for 1 year, ≥ 70% for 2 years, ≥ 70% for 3 or more years). We used negative binomial regression models with fixed effects, adjusting for socio-economic, demographic and social welfare co-variables. RESULTS: An increase in BFP coverage was associated with a reduction in suicide rates. The strongest effect was observed when in addition to greater municipal coverage (RR 0.942, 95% CI 0.936-0.947), the duration of the high coverage was maintained for 3 years or more (RR 0.952 95% CI 0.950-0.954). CONCLUSIONS: The results provide evidence that the conditional cash transfer programme may reduce suicide in Brazilian municipalities, mitigating the effect of poverty on suicide incidence.

Resistance of the wild tomato Solanum habrochaites to Phytophthora infestans is governed by a major gene and polygenes.

This work aimed to study the inheritance of resistance to Phytophthora infestans in tomato plants, using the maximum likelihood estimation function. The susceptible cultivar Santa Clara (Solanum lycopersicum) was used as the female genitor and the P. infestans resistant S. habrochaites f. glabratum accession (BGH 6902) as the male genitor. F1 plants from the crossing were self-pollinated to produce F2 progenies, and also backcrossed with PR and PS to produce BC1:R and BC1:S generations, respectively. The tomato plants were inoculated 50 days after transplanting. Disease severity was evaluated via a diagrammatic scale. Comparison of the genetic models created using the maximum likelihood function revealed that the inheritance of resistance to P. infestans in S. habrochaites is conferred by a major gene with additive and dominance effects, polygenes with additive effects, plus the environmental effect. Vertical resistance can be explored using genes with major effects. Programs of recurrent and maker-assisted selection are considered efficient strategies with which to select genotypes that hold P. infestans resistance conferred by polygenes.

Mechanism for Aar2p function as a U5 snRNP assembly factor.

Little is known about how particle-specific proteins are assembled on spliceosomal small nuclear ribonucleoproteins (snRNPs). Brr2p is a U5 snRNP-specific RNA helicase required for spliceosome catalytic activation and disassembly. In yeast, the Aar2 protein is part of a cytoplasmic precursor U5 snRNP that lacks Brr2p and is replaced by Brr2p in the nucleus. Here we show that Aar2p and Brr2p bind to different domains in the C-terminal region of Prp8p; Aar2p interacts with the RNaseH domain, whereas Brr2p interacts with the Jab1/MPN domain. These domains are connected by a long, flexible linker, but the Aar2p-RNaseH complex sequesters the Jab1/MPN domain, thereby preventing binding by Brr2p. Aar2p is phosphorylated in vivo, and a phospho-mimetic S253E mutation in Aar2p leads to disruption of the Aar2p-Prp8p complex in favor of the Brr2p-Prp8p complex. We propose a model in which Aar2p acts as a phosphorylation-controlled U5 snRNP assembly factor that regulates the incorporation of the particle-specific Brr2p. The purpose of this regulation may be to safeguard against nonspecific RNA binding to Prp8p and/or premature activation of Brr2p activity.

Proteomics Analysis with a Nano Random Forest Approach Reveals Novel Functional Interactions Regulated by SMC Complexes on Mitotic Chromosomes.

Packaging of DNA into condensed chromosomes during mitosis is essential for the faithful segregation of the genome into daughter nuclei. Although the structure and composition of mitotic chromosomes have been studied for over 30 years, these aspects are yet to be fully elucidated. Here, we used stable isotope labeling with amino acids in cell culture to compare the proteomes of mitotic chromosomes isolated from cell lines harboring conditional knockouts of members of the condensin (SMC2, CAP-H, CAP-D3), cohesin (Scc1/Rad21), and SMC5/6 (SMC5) complexes. Our analysis revealed that these complexes associate with chromosomes independently of each other, with the SMC5/6 complex showing no significant dependence on any other chromosomal proteins during mitosis. To identify subtle relationships between chromosomal proteins, we employed a nano Random Forest (nanoRF) approach to detect protein complexes and the relationships between them. Our nanoRF results suggested that as few as 113 of 5058 detected chromosomal proteins are functionally linked to chromosome structure and segregation. Furthermore, nanoRF data revealed 23 proteins that were not previously suspected to have functional interactions with complexes playing important roles in mitosis. Subsequent small-interfering-RNA-based validation and localization tracking by green fluorescent protein-tagging highlighted novel candidates that might play significant roles in mitotic progression.

Kicking against the PRCs - A Domesticated Transposase Antagonises Silencing Mediated by Polycomb Group Proteins and Is an Accessory Component of Polycomb Repressive Complex 2.

The Polycomb group (PcG) and trithorax group (trxG) genes play crucial roles in development by regulating expression of homeotic and other genes controlling cell fate. Both groups catalyse modifications of chromatin, particularly histone methylation, leading to epigenetic changes that affect gene activity. The trxG antagonizes the function of PcG genes by activating PcG target genes, and consequently trxG mutants suppress PcG mutant phenotypes. We previously identified the ANTAGONIST OF LIKE HETEROCHROMATIN PROTEIN1 (ALP1) gene as a genetic suppressor of mutants in the Arabidopsis PcG gene LIKE HETEROCHROMATIN PROTEIN1 (LHP1). Here, we show that ALP1 interacts genetically with several other PcG and trxG components and that it antagonizes PcG silencing. Transcriptional profiling reveals that when PcG activity is compromised numerous target genes are hyper-activated in seedlings and that in most cases this requires ALP1. Furthermore, when PcG activity is present ALP1 is needed for full activation of several floral homeotic genes that are repressed by the PcG. Strikingly, ALP1 does not encode a known chromatin protein but rather a protein related to PIF/Harbinger class transposases. Phylogenetic analysis indicates that ALP1 is broadly conserved in land plants and likely lost transposase activity and acquired a novel function during angiosperm evolution. Consistent with this, immunoprecipitation and mass spectrometry (IP-MS) show that ALP1 associates, in vivo, with core components of POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), a widely conserved PcG protein complex which functions as a H3K27me3 histone methyltransferase. Furthermore, in reciprocal pulldowns using the histone methyltransferase CURLY LEAF (CLF), we identify not only ALP1 and the core PRC2 components but also plant-specific accessory components including EMBRYONIC FLOWER 1 (EMF1), a transcriptional repressor previously associated with PRC1-like complexes. Taken together our data suggest that ALP1 inhibits PcG silencing by blocking the interaction of the core PRC2 with accessory components that promote its HMTase activity or its role in inhibiting transcription. ALP1 is the first example of a domesticated transposase acquiring a novel function as a PcG component. The antagonistic interaction of a modified transposase with the PcG machinery is novel and may have arisen as a means for the cognate transposon to evade host surveillance or for the host to exploit features of the transposition machinery beneficial for epigenetic regulation of gene activity.

Impact of the New Mental Health Services on Rates of Suicide and Hospitalisations by Attempted Suicide, Psychiatric Problems, and Alcohol Problems in Brazil.

A sizeable proportion of all suicides have mental health issues in the background. The association between access to mental health care in the community and decreased suicide rates is inconsistent in the literature. Brazil undertook a major psychiatric reform strengthening psychiatric community-based care. To evaluate the impact of the new Brazilian community mental health care units (CAPS-Psychosocial-Community-Centres) on municipal rates of suicide, and hospitalisations by attempted suicide, psychiatric and alcohol problems. We performed robust multivariable negative binomial regression models with fixed effect for panel data from all 5507 Brazilian municipalities. Suicide and hospitalization rates were calculated by sex and standardised by age for each municipality and year from 2008 to 2012. The main variable of interest was municipal CAPS coverage. CAPS municipal coverage was associated with lower suicide rates but this was not statistically significant (RR: 0.981; 95% CI 0.952-1.011). However, increased CAPS coverage was associated with lower hospitalizations for attempted suicide (RR: 0.887; 95% CI 0.841-0.935), psychiatric (RR: 0.841; 95% CI 0.821-0.862), and alcohol problems (RR: 0.882; 95% CI 0.860-0.904). Our results suggest that access to community mental health services seems to reduce hospitalisations due to attempted suicide, psychiatric and alcohol problems but not suicidal rates. Therefore, increased investments in community mental health services in low-middle-income countries might decrease costs associated with potentially avoidable hospitalizations.

Developing new platform chemicals: what is required for a new bio-based molecule to become a platform chemical in the bioeconomy?

This paper proposes a framework with six dimensions that can be useful for evaluating the potential and the current stage of a bio-based platform chemical. The framework considers the technological and strategic challenges to be fulfilled by a company that intends to lead a platform based on a bio-based chemical. A platform chemical should be an intermediate molecule, with a structure able to generate a number of derivatives, that is produced at a competitive cost, capable of allowing exploitation of the scale and scope economies, and inserted within a complete innovation ecosystem that is able to create value with governance mechanisms that are capable of allowing coordination of the innovation process and facilitation of the value capture by the focal company leading the platform, in our case the producer of the platform molecule. Based on these six dimensions, three potential platform chemicals - succinic acid, butanol and farnesene - are compared and discussed. It is possible to identify important differences concerning the technological dimensions and the strategic dimensions as well. Two of the molecules - farnesene and succinic acid - adhere to most of the conditions required to structure a platform chemical. However, the innovation ecosystem is not complete and the governance mechanisms are still under development, so it is not clear if they will be capable of allowing a favorable position for value capture by the platform leader. Butanol structuring for a platform does not seem promising. The potential of the molecule is apparently not high and the strategic initiatives are in general not focused on innovation ecosystem structuring.

Patterns of Care and Outcome of Elderly Women Diagnosed With Cervical Cancer in the Developing World.

Scarce data exist about the impact of age in cervical cancer (CC) patients in the developing world. The objective of the current study was to examine the patterns of care and outcome of elderly patients treated in a developing country. Medical records of patients treated from 2006-2009 at the Brazilian National Cancer Institute were reviewed. Patients were divided between women 70 years or older and women younger than 70 years. The χ tests were used and odds ratios were calculated. Survival was examined using the Kaplan-Meier method. Single and multivariate Cox proportional hazards modeling were used. A total of 1482 patients were analyzed: 1339 patients younger than 70 years and 143 patients 70 years or older. A marked difference in treatment was noted, even after stratifying by disease stage. Only 21% of the older patients underwent surgical treatment compared with 27.6% of the younger. After adjusting for confounding variables, the hazard ratio for death from CC in the elderly was 1.05 (95% confidence interval, 0.81-1.36; P = 0.11). These results corroborate previous data from developed countries: elderly patients have more advanced disease at diagnosis, and age is an important factor in the allocation of treatment for patients with CC. Worse outcome seemed to be mainly the result of more advanced stage and treatment allocation rather than age itself.