Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Exploring mood disorders and treatment options using human stem cells.

Despite their global prevalence, the mechanisms for mood disorders like bipolar disorder and major depressive disorder remain largely misunderstood. Mood stabilizers and antidepressants, although useful and effective for some, do not have a high responsiveness rate across those with these conditions. One reason for low responsiveness to these drugs is patient heterogeneity, meaning there is diversity in patient characteristics relating to genetics, etiology, and environment affecting treatment. In the past two decades, novel induced pluripotent stem cell (iPSC) research and technology have enabled the use of human-derived brain cells as a new model to study human disease that can help account for patient variance. Human iPSC technology is an emerging tool to better understand the molecular mechanisms of these disorders as well as a platform to test novel treatments and existing pharmaceuticals. This literature review describes the use of iPSC technology to model bipolar and major depressive disorder, common medications used to treat these disorders, and novel patient-derived alternative treatment methods for non-responders stemming from past publications, as well as presenting new data derived from these models.

Serum soluble mediators as prognostic biomarkers for morbidity, disease outcome, and late-relapsing hepatitis in yellow fever patients.

This study described a soluble mediator storm in acute Yellow Fever/YF infection along the kinetics timeline towards convalescent disease. The analyses of the YF Viral RNAnemia, chemokines, cytokines, and growth factors were performed in YF patients at acute/(D1-15) and convalescent/(D16-315) phases. Patients with acute YF infection displayed a trimodal viremia profile spreading along D3, D6, and D8-14. A massive storm of mediators was observed in acute YF. Higher levels of mediators were observed in YF with higher morbidity scores, patients under intensive care, and those progressing to death than in YF patients who progress to late-relapsing hepatitis/L-Hep. A unimodal peak of biomarkers around D4-6 with a progressive decrease towards D181-315 was observed in non-L-Hep patients, while a bimodal pattern with a second peak around D61-90 was associated with L-Hep. This study provided a comprehensive landscape of evidence that distinct immune responses drive pathogenesis, disease progression, and L-Hep in YF patients.

Adapting lean management to prevent healthcare-associated infections: a low-cost strategy involving Kamishibai cards to sustain bundles' compliance.

Lean healthcare visual management has been successfully integrated into infection control programs, leading to lower healthcare-associated infection (HAI) rates and greater provider compliance with evidence-based prevention practices; however, its implementation during quality improvement (QI) initiatives in limited-resource settings has not yet been well exploited. We aimed to describe a low-cost strategy involving Kamishibai cards to sustain bundles' adherence to prevent HAIs in a middle-income country. This descriptive case study evaluated the implementation of a lean healthcare visual management tool-Kamishibai board (K-board)-during a nationwide QI collaborative preventing three critical HAIs in 189 adult and pediatric/neonatal intensive care units (ICUs) from September 2021 to January 2023. Considering a limited-resource setting, our team adapted a K-board using simple, cheap, and easy-to-handle materials for routine monitoring of QI procedures, including safety bundles' compliance. After test prototypes, the final K-board version was implemented. The chart materials and assembly cost BRL 80.00 (USD 15.48). Before launching, expert working group meetings were held to shape the contents, refine technical issues, and prepare the ICU teams for implementation. After starting, plan-do-study-act cycles were conducted according to the Breakthrough Series model. Participating ICU teams, including leaders and front-line health workers, performed bedside audits following a weekly chronogram. Two indicators were calculated: the percentage of ICUs in which K-boards were being implemented and whether bundles' compliance was addressed in the K-board. Audit data were recorded in 'SimpleQI'. After 17 months of this initiative, 177 (93.7%) participating ICUs had included this visual management tool in their daily care routines. When more than 94 (>50%) ICUs posted K-board data, the mean compliance for the bundles for each HAI was sustained above 85%. A lean healthcare visual management tool can be adapted to local settings, including healthcare facilities with limited resources. K-board seems to be a feasible method for auditing evidence-based practices in medical care, including safety bundles to simultaneously prevent three types of HAIs.

Proteomics profile of mesenchymal stromal cells and extracellular vesicles in normoxic and hypoxic conditions.

BACKGROUND AIMS: Although bone marrow-derived mesenchymal stromal cells (MSCs) have demonstrated success in pre-clinical studies, they have shown only mild therapeutic effects in clinical trials. Hypoxia pre-conditioning may optimize the performance of bone marrow-derived MSCs because it better reflects the physiological conditions of their origin. It is not known whether changes in the protein profile caused by hypoxia in MSCs can be extended to the extracellular vesicles (EVs) released from them. The aim of this study was to evaluate the proteomics profile of MSCs and their EVs under normoxic and hypoxic conditions. METHODS: Bone marrow-derived MSCs were isolated from six healthy male Wistar rats. After achieving 80% confluence, MSCs were subjected to normoxia (MSC-Norm) (21% oxygen, 5% carbon dioxide, 74% nitrogen) or hypoxia (MSC-Hyp) (1% oxygen, 5% carbon dioxide, 94% nitrogen) for 48 h. Cell viability and oxygen consumption rate were assessed. EVs were extracted from MSCs for each condition (EV-Norm and EV-Hyp) by ultracentrifugation. Total proteins were isolated from MSCs and EVs and prepared for mass spectrometry. EVs were characterized by nanoparticle tracking analysis. Proteomics data were analyzed by PatternLab 4.0, Search Tool for the Retrieval of Interacting Genes/Proteins, Gene Ontology, MetaboAnalyst and Reactome software. RESULTS: Cell viability was higher in MSC-Hyp than MSC-Norm (P = 0.007). Basal respiration (P = 0.001), proton leak (P = 0.004) and maximal respiration (P = 0.014) were lower in MSC-Hyp than MSC-Norm, and no changes in adenosine triphosphate-linked and residual respiration were observed. The authors detected 2177 proteins in MSC-Hyp and MSC-Norm, of which 147 were identified in only MSC-Hyp and 512 were identified in only MSC-Norm. Furthermore, 718 proteins were identified in EV-Hyp and EV-Norm, of which 293 were detected in only EV-Hyp and 30 were detected in only EV-Norm. Both MSC-Hyp and EV-Hyp showed enrichment of pathways and biological processes related to glycolysis, the immune system and extracellular matrix organization. CONCLUSIONS: MSCs subjected to hypoxia showed changes in their survival and metabolic activity. In addition, MSCs under hypoxia released more EVs, and their content was related to expression of regulatory proteins of the immune system and extracellular matrix organization. Because of the upregulation of proteins involved in glycolysis, gluconeogenesis and glucose uptake during hypoxia, production of reactive oxygen species and expression of immunosuppressive properties may be affected.

Inositol monophosphatase 1 (IMPA1) mutation in intellectual disability patients impairs neurogenesis but not gliogenesis.

A homozygous mutation in the inositol monophosphatase 1 (IMPA1) gene was recently identified in nine individuals with severe intellectual disability (ID) and disruptive behavior. These individuals belong to the same family from Northeastern Brazil, which has 28 consanguineous marriages and 59 genotyped family members. IMPA1 is responsible for the generation of free inositol from de novo biosynthesis and recycling from inositol polyphosphates and participates in the phosphatidylinositol signaling pathway. To understand the role of IMPA1 deficiency in ID, we generated induced pluripotent stem cells (iPSCs) from patients and neurotypical controls and differentiated these into hippocampal dentate gyrus-like neurons and astrocytes. IMPA1-deficient neuronal progenitor cells (NPCs) revealed substantial deficits in proliferation and neurogenic potential. At low passage NPCs (P1 to P3), we observed cell cycle arrest, apoptosis, progressive change to a glial morphology and reduction in neuronal differentiation. These observations were validated by rescuing the phenotype with myo-inositol supplemented media during differentiation of patient-derived iPSCs into neurons and by the reduction of neurogenic potential in control NPCs-expressing shIMPA1. Transcriptome analysis showed that NPCs and neurons derived from ID patients have extensive deregulation of gene expression affecting pathways necessary for neurogenesis and upregulation of gliogenic genes. IMPA1 deficiency did not affect cell cycle progression or survival in iPSCs and glial progenitor cells or astrocyte differentiation. Therefore, this study shows that the IMPA1 mutation specifically affects NPC survival and neuronal differentiation.

Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients.

Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li-responsive (LR) and Li-non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on the LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/ß-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/ß-catenin signaling pathway by inhibiting GSK-3ß and releasing ß-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/ß-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3ß, upregulated LEF1 and Wnt/ß-catenin gene targets, increased transcriptional activity of complex ß-catenin/TCF/LEF1, and reduced excitability in NR neurons. In addition, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/ß-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.

Forecasting the seasonal dynamics of Trichoplusia ni (Lep.: Noctuidae) on three Brassica crops through neural networks.

The cabbage looper, Trichoplusia ni Hübner (Lep.: Noctuidae), is a destructive pest of Brassica crops. Their larvae defoliate plants, leading to reduced crop yield. Understanding and modeling pest seasonal dynamics is central to management programs because it allows one to set up sampling and control efforts. This study aimed to train, with field-collected data, artificial neural networks (ANN) for T. ni forecasting on Brassica crops. ANNs were used due to their suitability to fit complex models with multiple predictors. Three weather variables (air temperature, rainfall, and relative humidity lagged at different intervals from the day of pest assessment) and three host plants (broccoli, cabbage, and cauliflower) along with another plant-related variable (days after transplanting) were used as input variables to build ANNs with different topologies. Two outputs (T. ni eggs or larvae) were tested to verify which one would yield more precise models. ANNs forecasting T. ni eggs performed better, based on Pearson's correlation (rv) of observed with fitted values. The winning ANN (rv = 0.706) had weather data lagged by 15 days, 2 neurons in the hidden layer, hyperbolic tangent as the activation function, and resilient propagation as the learning algorithm. Broccoli and cauliflower were the hosts with major contributions for T. ni occurrence. Rainfall was the primary environmental predictor and affected T. ni negatively. Therefore, the winning ANN may be used to forecast T. ni egg densities 15 days in advance, allowing for timely management of this pest.

Schools reopening and the COVID-19 pandemic: a case study from Macaé, Rio de Janeiro, Brazil.

Since the first reported case of COVID-19 in Brazil, the public and private educational system started to close. Up to November 2020, scientific discussions about the return of schooling activities have been rarely performed by the national scientific community and police-makers. The great delay of school returning in Brazil contrasts with successful international strategies of school reopening worldwide and seems counterintuitive with the reopening of non-essential activities. Here, important issues to be considered before and during school reopening are reviewed and discussed. COVID-19 testing is essential to avoid disease spreading, but high cost of individual RT-qPCRs impairs an extensive testing strategy for school returning. To reduce costs and increase the speed of diagnosis, we tested the efficiency of a pooled-sample PCR strategy in a cohort of the educational staff in the city of Macaé/RJ, finding five asymptomatic individuals (0,66%) among the 754 people tested. Thus, a polled-sample PCR testing strategy of the educational staff might prevent infection spreading in schools at a reasonable cost. We discuss how our test strategy could be coupled with internationally recognized safety rules to allow for a safe school return and how countries from different world regions are dealing with educational activities during COVID-19 pandemic.

Dentists' awareness and knowledge of evidence- based dentistry principles, methods and practices: a systematic review.

Introduction As an attempt to provide supporting evidence for the formulation of future educational strategies on knowledge translation, this systematic review assessed and synthesised the available evidence related to the dentists' awareness, perceived and actual knowledge of evidence-based dentistry (EBD) principles, methods and practices.Methods Primary studies that considered dentists' reports collected from interviews, questionnaires, or conversation sessions were selected. Studies enrolling students, dental hygienists, or other health professionals were not included. Reviews, editorials, letters, study protocols, articles presenting knowledge translation strategies and initiatives, examples of EBD approaches to specific clinical questions, and guidelines focused on EBD implementation were also excluded. Cochrane, Embase, PubMed, Scopus and Web of Science databases were searched. Grey literature was partially covered by the Google Scholar search and the reference lists of the pre-selected studies. The study search was concluded in February 2021. Descriptive data of the selected studies were synthesised, and the risk of bias was assessed according to the National Institutes of Health Quality Assessment Tool for observational cohort and cross-sectional studies.Results Twenty-one articles were included. High percentages of dentists were aware of EBD. Variable proportions of professionals declared to have some understanding of EBD, although few presented actual knowledge of principles, methods and practices.Discussion Methodologically, most studies presented limitations regarding sample representativity, participation rates, detailing of the outcome measures, and validation of the assessment tools. Additionally, extensive overall ranges of responses were often observed across the studies, possibly as a result of heterogeneity across samples and assessment tools. The authors thus suggest developing valid questionnaires including all dimensions (awareness, perceived knowledge and actual knowledge) within an assessment tool. This would contribute to establishing knowledge translation strategies to overcome specific gaps in EBD knowledge.

Mitochondria-Rich Fraction Isolated From Mesenchymal Stromal Cells Reduces Lung and Distal Organ Injury in Experimental Sepsis.

OBJECTIVES: To ascertain whether systemic administration of mitochondria-rich fraction isolated from mesenchymal stromal cells would reduce lung, kidney, and liver injury in experimental sepsis. DESIGN: Animal study. SETTING: Laboratory investigation. SUBJECTS: Sixty C57BL/6 male mice. INTERVENTIONS: Sepsis was induced by cecal ligation and puncture; sham-operated animals were used as control. At 24 hours after surgery, cecal ligation and puncture and Sham animals were further randomized to receive saline or mitochondria-rich fraction isolated from mesenchymal stromal cells (3 × 106) IV. At 48 hours, survival, peritoneal bacterial load, lung, kidney, and liver injury were analyzed. Furthermore, the effects of mitochondria on oxygen consumption rate and reactive oxygen species production of lung epithelial and endothelial cells were evaluated in vitro. MEASUREMENTS AND MAIN RESULTS: In vitro exposure of lung epithelial and endothelial cells from cecal ligation and puncture animals to mitochondria-rich fraction isolated from mesenchymal stromal cells restored oxygen consumption rate and reduced total reactive oxygen species production. Infusion of exogenous mitochondria-rich fraction from mesenchymal stromal cells (mitotherapy) reduced peritoneal bacterial load, improved lung mechanics and histology, and decreased the expression of interleukin-1ß, keratinocyte chemoattractant, indoleamine 2,3-dioxygenase-2, and programmed cell death protein 1 in lung tissue, while increasing keratinocyte growth factor expression and survival rate in cecal ligation and puncture-induced sepsis. Mitotherapy also reduced kidney and liver injury, plasma creatinine levels, and messenger RNA expressions of interleukin-18 in kidney, interleukin-6, indoleamine 2,3-dioxygenase-2, and programmed cell death protein 1 in liver, while increasing nuclear factor erythroid 2-related factor-2 and superoxide dismutase-2 in kidney and interleukin-10 in liver. CONCLUSIONS: Mitotherapy decreased lung, liver, and kidney injury and increased survival rate in cecal ligation and puncture-induced sepsis.

Enhanced production of prodigiosin by Serratia marcescens UCP 1549 using agrosubstrates in solid-state fermentation.

This work aimed to investigate the production of prodigiosin by S. marcescens UCP 1549 in solid-state fermentation (SSF), as a sustainable alternative for reducing the production costs and environmental impact. Thus, different agro-industrial substrates were used in the formulation of the prodigiosin production medium, obtaining the maximum yield of pigment (119.8 g/kg dry substrate) in medium consisting of 5 g wheat bran, 5% waste soybean oil and saline solution. The pigment was confirmed as prodigiosin by the maximum absorbance peak at 535 nm, Rf 0.9 in TLC, and the functional groups by infrared spectrum (FTIR). Prodigiosin demonstrated stability at different values of temperature, pH and NaCl concentrations and antimicrobial properties, as well as not show any toxicity. These results confirm the applicability of SSF as a sustainable and promising technology and wheat bran as potential agrosubstrate to produce prodigiosin, making the bioprocess economic and competitive for industrial purposes.

Safety and immunogenicity of 17DD attenuated yellow fever vaccine in howler monkeys (Alouatta spp.).

BACKGROUND: Alouatta spp. are highly susceptible to yellow fever (YF) infection and develop an often fatal disease. The threat posed by an outbreak started in 2016 leads us to investigate vaccination as a potential tool in preventing YF in non-human primates (NHP). METHODS: Susceptible howler monkeys were immunized with three different concentrations of the human Brazilian commercial YF17DD vaccine. Post-vaccination viremia/RNAemia, immunogenicity, and safety were characterized. RESULTS: The vaccine did not produce YF clinical manifestations in any of the NHPs. After immunization, all animals seroconverted demonstrating the ability of the YF vaccine to induce humoral response in Alouatta species. CONCLUSIONS: The present work has demonstrated the safe and immunogenic profile of the existing YF 17DD vaccine in howler monkeys. This knowledge may support further studies with other susceptible monkey species and provide a possible solution for controlling epizootics and preventing the devastation of endangered species.

Treatment with the essential amino acid L-tryptophan reduces masticatory impairments in experimental cerebral palsy.

Purpose Children with cerebral palsy (CP) often exhibit difficulties in feeding resulting from deficits in chewing. This study investigates the therapeutic potential of L-tryptophan (TRI) to reduce deficits in chewing in rats subjected to an experimental model of CP.Methods A total of 80 Wistar albino rats were used. Pups were randomly assigned to 4 experimental groups: Control Saline, Control TRI, CP Saline, and CP TRI groups. The experimental model of CP was based on the combination of perinatal anoxia associated with postnatal sensorimotor restriction of the hind limbs. TRI was administered subcutaneously during the lactation period. Anatomical and behavioral parameters were evaluated during maturation, including body weight gain, food intake, chewing movements, relative weight and the distribution of the types of masseter muscle fibers.Results The induction of CP limited body weight gain, decreased food intake and led to impairment in the morphological and functional parameters of chewing. Moreover, for a comparable amount of food ingested, CP TRI animals grew the most. In addition, supplementation with TRI improved the number of chewing movements, and increased the weight and proportion of type IIB fibers of the masseter in rats subjected to CP.Conclusion These results demonstrate that experimental CP impaired the development of mastication and that TRI supplementation increased masticatory maturation in animals subjected to CP.

Effect of subdoses of sugarcane ripeners on lettuce physiology in a drift scenario.

In order to understand the physiological effects of ripeners in sensitive crops, the objective of this work was to evaluate the effect of subdoses of the ripeners glyphosate, trinexapac-ethyl and sulfometuron methyl commonly used in sugarcane, in the growth of lettuce cultivar 'Lucy Brown' and 'Vanda'. To address the effects of the products in the lettuce physiology, analyses of fresh weight, dry weight, number of leaves, chlorophyll content, quantum efficiency of photosystem II, lipid peroxidation (MDA), hydrogen peroxide (H2O2), glutathione reductase (GR), guaiacol peroxidase (GPOX) were performed. We observed that among the products tested, glyphosate had minor impact on plant growth, compared to trinexapac-ethyl and sulfometuron methyl. All products induced a decrease in chlorophyll content for both cultivars. Chlorophyll A fluorescence suffered a major reduction with trinexapac-ethyl and sulfometuron methyl in 'Vanda' and no differences were observed for 'Lucy Brown'. MDA content and enzyme quantification varied by cultivar and the sugarcane ripener tested. By disturbing chlorophyll content and quantum efficiency of photosystem II, through these sugarcane ripeners did not have direct mode of action affecting photosystem II, they can cause some level of damage and activate different mechanisms and at different times, in response to stress. In this sense, it is possible to observe that reduced doses of glyphosate, trinexapac ethyl, and sulfometuron methyl affect the development of lettuce at different levels and trigger an oxidative response that was cultivar dependent.

Wet and warm conditions contribute to the occurrence of the neotropical butterfly Ascia monuste orseis Godart (Lepidoptera: Pieridae) on Brassica crops.

Ascia monuste orseis Godart (Lepidoptera: Pieridae) is a neotropical butterfly distributed in South America. During the larval stage, this insect causes economic losses on Brassica crops. Wet and warm conditions are known to increase subspecies occurrence, but it remains unclear why these conditions are more suitable. In this study, we have shown that both conditions are highly favourable for A. monuste orseis. We determined the thermal requirements for immature development and then created models for A. monuste orseis occurrence using Climex algorithm. Two models were built: one for the year-round presence and other for seasonal suitability. We validated the models using subspecies occurrence records and monitoring in two Brazilian regions (Northeast and Southeast). The minimum, optimum and maximum temperature for immature development were estimated at 16.37, 29.16 and 34.95 °C, respectively. The model for year-round presence indicated tropical areas as highly suitable for A. monuste orseis occurrence (with 88% of accuracy) and the seasonal models showed unsuitable areas in some parts of South America during cold and dry periods. Such predictions were observed in the monitored areas where A. monuste orseis was not found. These results can be associated with the mortality caused by low temperature to immature stages and drought conditions that may induce adult migration to moist habitats. Thus, we suggest that A. monuste orseis occurs mainly during wet and warm seasons on Brassica crops due to deleterious effects caused by cold and dry conditions. This information can be used to improve A. monuste orseis management in Brassica crops.

Onset and duration of symptoms of loss of smell/taste in patients with COVID-19: A systematic review.

OBJECTIVE: The aim of the study was to conduct a systematic review of the literature to investigate the time of onset and duration of symptoms of loss of smell and taste in patients diagnosed with COVID-19. METHODS: Two independent authors performed a systematic review of the Medline/PubMed, SCOPUS, COCHRANE, Lilacs and Web of Science electronic databases. The time of onset and duration of symptoms were considered primary outcomes. The sex and age of individuals, the geographical location of the study, the prevalence of symptoms, other associated symptoms, associated comorbidities, and the impact on quality of life and eating habits were considered secondary outcomes. RESULTS: Our search generated 17 articles. Many of the studies reported that the onset of anosmia and ageusia occurred 4 to 5 days after the manifestation of other symptoms of the infection and that these symptoms started to disappear after one week, with more significant improvements in the first two weeks. CONCLUSION: The present study concludes that the onset of symptoms of loss of smell and taste, associated with COVID-19, occurs 4 to 5 days after other symptoms, and that these symptoms last from 7 to 14 days. Findings, however, varied and there is therefore a need for further studies to clarify the occurrence of these symptoms. This would help to provide early diagnosis and reduce contagion by the virus.

The ribosome assembly factor Nop53 controls association of the RNA exosome with pre-60S particles in yeast.

Eukaryotic ribosomal biogenesis is a high-energy-demanding and complex process that requires hundreds of trans-acting factors to dynamically build the highly-organized 40S and 60S subunits. Each ribonucleoprotein complex comprises specific rRNAs and ribosomal proteins that are organized into functional domains. The RNA exosome complex plays a crucial role as one of the pre-60S-processing factors, because it is the RNase responsible for processing the 7S pre-rRNA to the mature 5.8S rRNA. The yeast pre-60S assembly factor Nop53 has previously been shown to associate with the nucleoplasmic pre-60S in a region containing the "foot" structure assembled around the 3' end of the 7S pre-rRNA. Nop53 interacts with 25S rRNA and with several 60S assembly factors, including the RNA exosome, specifically, with its catalytic subunit Rrp6 and with the exosome-associated RNA helicase Mtr4. Nop53 is therefore considered the adaptor responsible for recruiting the exosome complex for 7S processing. Here, using proteomics-based approaches in budding yeast to analyze the effects of Nop53 on the exosome interactome, we found that the exosome binds pre-ribosomal complexes early during the ribosome maturation pathway. We also identified interactions through which Nop53 modulates exosome activity in the context of 60S maturation and provide evidence that in addition to recruiting the exosome, Nop53 may also be important for positioning the exosome during 7S processing. On the basis of these findings, we propose that the exosome is recruited much earlier during ribosome assembly than previously thought, suggesting the existence of additional interactions that remain to be described.

Collagen I and collagen III polymorphisms in women with pelvic organ prolapse.

AIMS: Verify the presence of the single nucleotide polymorphisms rs1800012 of the collagen I (COL1A1) and rs1800255 of the collagen III (COL3A1) genes and their association with pelvic organ prolapse (POP) in Brazilian women and to determine risk factors for POP. METHODS: We assessed 826 postmenopausal women divided into POP (stages III and IV) and control groups (stages 0 and I) by examination and peripheral blood sample collection. DNA sequences of interest were analyzed by real-time reverse-transcriptase polymerase chain reaction. We used logistic regression analyses, recessive and codominance models of inheritance, and P < .05 for significance. RESULTS: Six-hundred and thirty-four postmenopausal women were included: 348 (54.8%) POP cases and 286 (45.1%) controls. The frequencies of GG, GA, and AA genotypes for COL1A1 were 69.12%, 20.24%, and 10.59% in POP group and 71.79%, 20%, and 8.21% in controls; GG, GT, and TT for COL3A1 were 37.54%, 59.53%, and 2.93% in POP group and 36.24%, 60.14%, and 3.62% in controls. There were no genotypic or allelic association with POP phenotype that link both SNPs rs1800012 and rs1800255 to increased risk of POP. Vaginal delivery (odds ratio [OR] = 13; 95% confidence interval [CI] [4.00-47.08]), POP family history (OR = 3.1; 95% CI [1.49-6.50]), diabetes mellitus (OR = 2.3; 95% CI [1.08-5.21]), number of pregnancies (OR = 1.2; 95% CI [1.05-1.36]), and age (OR = 1.1; 95% CI [1.09-1.19]), were variables of increased risk for POP (P < .05 for all). CONCLUSION: Our study suggests lack of association between DNA polymorphisms rs1800012 of COL1A1 and rs1800255 of COL3A1 with advanced POP. Vaginal delivery, POP family history, diabetes mellitus, number of pregnancies, and age are risk factors for POP.

Hypervolemic hyponatremia and transplant-free survival in children with cirrhosis due to biliary atresia.

BACKGROUND: Biliary atresia is the number one cause of cirrhosis and liver transplantation in children. Hyponatremia is the most important electrolytic disturbance observed in decompensated cirrhosis. Studies of hyponatremia in cirrhotic children are scarce and those that exist have defined hyponatremia as serum sodium < 130 mEq/L lasting for at least 7 days. METHODS: We evaluated transplant-free survival (Kaplan-Meier) of children with cirrhosis due to biliary atresia and serum sodium < 130 mEq/L persisting for 1, 2-6, and ≥7 days. This was a single-center, historical cohort that included all patients aged ≤ 18 years on a liver transplantation waiting list. RESULTS: We studied 128 patients. The overall frequency of hyponatremia was 30.5% (39/128). Thirteen patients (10.2%) had hyponatremia when put on the list, and 20.3% developed it during follow-up. The Kaplan-Meier overall transplant-free survival rate was 83.3%. Patients with persistent hyponatremia for at least two days had the lowest transplant-free survival. Glomerular filtration rate (P = .00, RR = 0.96, IC 95% = 0.94-0.99), BMI/age Z-score (P = .02, RR = 0.59, IC 95% = 0.39-0.91), INR (P = .00, RR = 1.43, IC 95% = 1.17-1.74), and serum sodium (P = .04, RR = 0.91, IC 95% = 0.84-0.99) were independently associated with transplant-free survival. We did not observe any difference in mortality prediction after adding sodium to the original PELD score. CONCLUSIONS: We conclude that persistent hyponatremia lasting at least two days may herald poor prognosis for children with cirrhosis due to biliary atresia.