Lithium response in bipolar disorder: Epigenome-wide DNA methylation signatures and epigenetic aging.

Lithium (Li) is the first-line treatment for bipolar disorder (BD) even though only 30 % of BD patients are considered excellent responders. The mechanisms by which Li exerts its action are not clearly understood, but it has been suggested that specific epigenetic mechanisms, such as methylation processes, may play a role. In this regard, DNA methylation patterns can be used to estimate epigenetic age (EpiAge), which is accelerated in BD patients and reversed by Li treatment. Our first aim was to compare the DNA methylation profile in peripheral blood between BD patients categorized as excellent responders to Li (Ex-Rp) and non-responders (N-Rp). Secondly, EpiAge was estimated to detect differential age acceleration between the two groups. A total of 130 differentially methylated positions (DMPs) and 16 differentially methylated regions (DMRs) between Ex-Rp (n = 26) and N-Rp (n = 37) were identified (FDR adjusted p-value < 0.05). We found 122 genes mapping the DMPs and DMRs, nine of which (HOXB6, HOXB3, HOXB-AS3, TENM2, CACNA1B, ANK3, EEF2K, CYP1A1, and SORCS2) had previously been linked to Li response. We found genes related to the GSK3ß pathway to be highly represented. Using FUMA, we found enrichment in Gene Ontology Cell Component for the synapse. Gene network analysis highlighted functions related to the cell cycle, nervous system development and function, and gene expression. No significant differences in age acceleration were found between Ex-Rp and N-Rp for any of the epigenetic clocks analysed. Our findings indicate that a specific methylation pattern could determine the response to Li in BD patients. We also found that a significant portion of the differentially methylated genes are closely associated with the GSK3ß pathway, reinforcing the role of this system in Li response. Future longitudinal studies with larger samples will help to elucidate the epigenetic mechanisms underlying Li response.

A New Intervention for Implementation of Pharmacogenetics in Psychiatry: A Description of the PSY-PGx Clinical Study.

(1) Background Pharmacological treatment for psychiatric disorders has shown to only be effective in about one-third of patients, as it is associated with frequent treatment failure, often because of side effects, and a long process of trial-and-error pharmacotherapy until an effective and tolerable treatment is found. This notion emphasizes the urgency for a personalized medicine approach in psychiatry. (2) Methods This prospective patient- and rater-blinded, randomized, controlled study will investigate the effect of dose-adjustment of antidepressants escitalopram and sertraline or antipsychotics risperidone and aripiprazole according to the latest state-of-the-art international dosing recommendations for CYP2C19 and CYP2D6 metabolizer status in patients with mood, anxiety, and psychotic disorders. A total sample of N = 2500 will be recruited at nine sites in seven countries (expected drop-out rate of 30%). Patients will be randomized to a pharmacogenetic group or a dosing-as-usual group and treated over a 24-week period with four study visits. The primary outcome is personal recovery using the Recovery Assessment Scale as assessed by the patient (RAS-DS), with secondary outcomes including clinical effects (response or symptomatic remission), side effects, general well-being, digital phenotyping, and psychosocial functioning. (3) Conclusions This is, to our knowledge, the first international, multi-center, non-industry-sponsored randomized controlled trial (RCT) that may provide insights into the effectiveness and utility of implementing pharmacogenetic-guided treatment of psychiatric disorders, and as such, results will be incorporated in already available dosing guidelines.

Shotgun proteomics to characterize wastewater proteins.

Classically, the characterization of wastewater components has been restricted to the measurement of indirect parameters (chemical and biological oxygen demand, total nitrogen) and small molecules of interest in epidemiology or for environmental control. Despite the fact that metaproteomics has provided important knowledge about the microbial communities in these waters, practically nothing is known about other non-microbial proteins transported in the wastewater. The method described here has allowed us to perform a large-scale characterization of the wastewater proteome. Wastewater protein profiles have shown to be very different in different collection sites probably reflecting their human population and industrial activities. We believe that wastewater proteomics is opening the doors to the discovery of new environmental and health biomarkers and the development of new, more effective monitoring devices for issues like monitorization of population health, pest control, or control of industry discharges. The method developed is relatively simple and combines procedures for the separation of the soluble and particulate fractions of wastewater and their concentration, and conventional shotgun proteomics using high-resolution mass spectrometry for protein identification. •Unprecedented method for wastewater proteome characterization.•Proteins as new potential biomarkers for sewage chemical-information mining, wastewater epidemiology and environmental monitoring.•Wastewater protein profiles reflect human and industrial activities.

Sewage Protein Information Mining: Discovery of Large Biomolecules as Biomarkers of Population and Industrial Activities.

Wastewater-based epidemiology has been revealed as a powerful approach for surveying the health and lifestyle of a population. In this context, proteins have been proposed as potential biomarkers that complement the information provided by currently available methods. However, little is known about the range of molecular species and dynamics of proteins in wastewater and the information hidden in these protein profiles is still to be uncovered. In this study, we investigated the protein composition of wastewater from 10 municipalities in Catalonia with diverse populations and industrial activities at three different times of the year. The soluble fraction of this material was analyzed using liquid chromatography high-resolution tandem mass spectrometry using a shotgun proteomics approach. The complete proteomic profile, distribution among different organisms, and semiquantitative analysis of the main constituents are described. Excreta (urine and feces) from humans, and blood and other residues from livestock were identified as the two main protein sources. Our findings provide new insights into the characterization of wastewater proteomics that allow for the proposal of specific bioindicators for wastewater-based environmental monitoring. This includes human and animal population monitoring, most notably for rodent pest control (immunoglobulins (Igs) and amylases) and livestock processing industry monitoring (albumins).

Time-resolved transcriptomic profiling of the developing rabbit's lungs: impact of premature birth and implications for modelling bronchopulmonary dysplasia.

BACKGROUND: Premature birth, perinatal inflammation, and life-saving therapies such as postnatal oxygen and mechanical ventilation are strongly associated with the development of bronchopulmonary dysplasia (BPD); these risk factors, alone or combined, cause lung inflammation and alter programmed molecular patterns of normal lung development. The current knowledge on the molecular regulation of lung development mainly derives from mechanistic studies conducted in newborn rodents exposed to postnatal hyperoxia, which have been proven useful but have some limitations. METHODS: Here, we used the rabbit model of BPD as a cost-effective alternative model that mirrors human lung development and, in addition, enables investigating the impact of premature birth per se on the pathophysiology of BPD without further perinatal insults (e.g., hyperoxia, LPS-induced inflammation). First, we characterized the rabbit's normal lung development along the distinct stages (i.e., pseudoglandular, canalicular, saccular, and alveolar phases) using histological, transcriptomic and proteomic analyses. Then, the impact of premature birth was investigated, comparing the sequential transcriptomic profiles of preterm rabbits obtained at different time intervals during their first week of postnatal life with those from age-matched term pups. RESULTS: Histological findings showed stage-specific morphological features of the developing rabbit's lung and validated the selected time intervals for the transcriptomic profiling. Cell cycle and embryo development, oxidative phosphorylation, and WNT signaling, among others, showed high gene expression in the pseudoglandular phase. Autophagy, epithelial morphogenesis, response to transforming growth factor ß, angiogenesis, epithelium/endothelial cells development, and epithelium/endothelial cells migration pathways appeared upregulated from the 28th day of gestation (early saccular phase), which represents the starting point of the premature rabbit model. Premature birth caused a significant dysregulation of the inflammatory response. TNF-responsive, NF-κB regulated genes were significantly upregulated at premature delivery and triggered downstream inflammatory pathways such as leukocyte activation and cytokine signaling, which persisted upregulated during the first week of life. Preterm birth also dysregulated relevant pathways for normal lung development, such as blood vessel morphogenesis and epithelial-mesenchymal transition. CONCLUSION: These findings establish the 28-day gestation premature rabbit as a suitable model for mechanistic and pharmacological studies in the context of BPD.

Clinical characteristics of pediatric patients with acute respiratory distress syndrome due to COVID-19.

BACKGROUND: There are only a few reports of acute respiratory distress syndrome (ARDS) in patients with SARS-CoV-2 in pediatrics. This study aimed to describe the characteristics of critically ill pediatric patients with COVID-19, the frequency of ARDS, ventilatory mechanics and results of prone position. METHODS: We conducted a retrospective, observational study of patients admitted to the pediatric intensive care unit (PICU) between April 1 to September 30, 2020. RESULTS: Thirty-four patients were admitted to pediatric intensive care unit, 31.7% were SARS-CoV-2 positive. 13 presented ARDS, 11 required invasive mechanical ventilation, and seven were pronated as an oxygenation strategy. All patients classified as severe ARDS were pronated. Obesity was the most important comorbidity. The complications associated with ARDS were multisystemic inflammatory syndrome (8 vs. 4; p < 0.05) and acute kidney injury (8 vs. 3; p < 0.05). Procalcitonin was higher in patients with ARDS, as were the days of stay in PICU (p < 0.05). The success of the pronation maneuver was achieved 8 hours later , with the following results: arterial oxygen partial pressure to fractional inspired oxygen ratio 128 vs. 204, oxygenation index 8.9 vs. 5.9, static lung compliance 0.54 vs. 0.70 ml/cmH2O/kg, plateau pressure 24 vs. 19 cmH2O (p < 0.05). The use of narcotics was higher in the group with ARDS plus pronation 124 vs. 27 hours in the non-pronated (p < 0.01). Mortality associated with SARS-CoV-2 was 5.8%. CONCLUSIONS: ARDS was presented in 38.2% of the children admitted to PICU and was more frequent in obese patients. Pronation, performed in severe cases, improved oxygenation and lung mechanics indexes. No patient died of ARDS.

INTRODUCCIÓN: Existen pocos reportes de síndrome de dificultad respiratoria aguda (SDRA) con COVID-19 en pacientes pediátricos. El objetivo de este estudio fue describir las características de los pacientes pediátricos críticamente enfermos con COVID-19, la frecuencia del SDRA, la mecánica ventilatoria y los resultados de la posición prona. MÉTODOS: Se llevó a cabo un estudio retrospectivo y observacional de los pacientes ingresados del 1 de abril al 30 de septiembre de 2020. RESULTADOS: Ingresaron 34 pacientes a la unidad de terapia intensiva pediátrica (UTIP) con prueba positiva para SARS-CoV-2. De ellos, 13 presentaron SDRA, 11 requirieron ventilación mecánica invasiva y siete fueron pronados como estrategia de oxigenación. Todos los pacientes clasificados como SDRA graves fueron pronados. La obesidad fue la comorbilidad más importante. Las complicaciones asociadas con SDRA fueron el síndrome inflamatorio multisistémico (p < 0.05) y la lesión renal aguda (p < 0.05). La procalcitonina fue mayor en los pacientes con SDRA, al igual que los días de estancia en la UTIP (p < 0.05). El éxito de la maniobra de pronación se alcanzó 8 horas después.Los resultados observados fueron los siguientes relación presión arterial de oxígeno/fracción inspirada de oxígeno 128 vs. 204, índice de oxigenación 8.9 vs. 5.9, distensibilidad pulmonar estática 0.54 vs. 0.70 ml/cmH2O/kg, y presión meseta 24 vs. 19 cmH2O (p < 0.05). El uso de narcóticos fue mayor en el grupo de SDRA más pronación que en los no pronados (124 vs. 27 h; p < 0.01). La mortalidad asociada con SARS-CoV-2 fue del 5.8%. CONCLUSIONES: El SDRA se presentó en el 38.2% de los niños admitidos a UTIP, y con mayor frecuencia en los pacientes con obesidad. La maniobra de pronación aplicada en los casos severos, mejoró la oxigenación de la mécanica pulmonar. Ninguno de los pacientes falleció por SDRA.

Características clínicas de pacientes pediátricos con síndrome de dificultad respiratoria aguda asociado con COVID-19 / Clinical characteristics of pediatric patients with acute respiratory distress syndrome due to COVID-19

Resumen Introducción: Existen pocos reportes de síndrome de dificultad respiratoria aguda (SDRA) con COVID-19 en pacientes pediátricos. El objetivo de este estudio fue describir las características de los pacientes pediátricos críticamente enfermos con COVID-19, la frecuencia del SDRA, la mecánica ventilatoria y los resultados de la posición prona. Métodos: Se llevó a cabo un estudio retrospectivo y observacional de los pacientes ingresados del 1 de abril al 30 de septiembre de 2020. Resultados: Ingresaron 34 pacientes a la unidad de terapia intensiva pediátrica (UTIP) con prueba positiva para SARS-CoV-2. De ellos, 13 presentaron SDRA, 11 requirieron ventilación mecánica invasiva y siete fueron pronados como estrategia de oxigenación. Todos los pacientes clasificados como SDRA graves fueron pronados. La obesidad fue la comorbilidad más importante. Las complicaciones asociadas con SDRA fueron el síndrome inflamatorio multisistémico (p < 0.05) y la lesión renal aguda (p < 0.05). La procalcitonina fue mayor en los pacientes con SDRA, al igual que los días de estancia en la UTIP (p < 0.05). El éxito de la maniobra de pronación se alcanzó 8 horas después.Los resultados observados fueron los siguientes relación presión arterial de oxígeno/fracción inspirada de oxígeno 128 vs. 204, índice de oxigenación 8.9 vs. 5.9, distensibilidad pulmonar estática 0.54 vs. 0.70 ml/cmH2O/kg, y presión meseta 24 vs. 19 cmH2O (p < 0.05). El uso de narcóticos fue mayor en el grupo de SDRA más pronación que en los no pronados (124 vs. 27 h; p < 0.01). La mortalidad asociada con SARS-CoV-2 fue del 5.8%. Conclusiones: El SDRA se presentó en el 38.2% de los niños admitidos a UTIP, y con mayor frecuencia en los pacientes con obesidad. La maniobra de pronación aplicada en los casos severos, mejoró la oxigenación de la mécanica pulmonar. Ninguno de los pacientes falleció por SDRA.

Abstract Background: There are only a few reports of acute respiratory distress syndrome (ARDS) in patients with SARS-CoV-2 in pediatrics. This study aimed to describe the characteristics of critically ill pediatric patients with COVID-19, the frequency of ARDS, ventilatory mechanics and results of prone position. Methods: We conducted a retrospective, observational study of patients admitted to the pediatric intensive care unit (PICU) between April 1 to September 30, 2020. Results: Thirty-four patients were admitted to pediatric intensive care unit, 31.7% were SARS-CoV-2 positive. 13 presented ARDS, 11 required invasive mechanical ventilation, and seven were pronated as an oxygenation strategy. All patients classified as severe ARDS were pronated. Obesity was the most important comorbidity. The complications associated with ARDS were multisystemic inflammatory syndrome (8 vs. 4; p < 0.05) and acute kidney injury (8 vs. 3; p < 0.05). Procalcitonin was higher in patients with ARDS, as were the days of stay in PICU (p < 0.05). The success of the pronation maneuver was achieved 8 hours later , with the following results: arterial oxygen partial pressure to fractional inspired oxygen ratio 128 vs. 204, oxygenation index 8.9 vs. 5.9, static lung compliance 0.54 vs. 0.70 ml/cmH2O/kg, plateau pressure 24 vs. 19 cmH2O (p < 0.05). The use of narcotics was higher in the group with ARDS plus pronation 124 vs. 27 hours in the non-pronated (p < 0.01). Mortality associated with SARS-CoV-2 was 5.8%. Conclusions: ARDS was presented in 38.2% of the children admitted to PICU and was more frequent in obese patients. Pronation, performed in severe cases, improved oxygenation and lung mechanics indexes. No patient died of ARDS.

Biomarker candidates for progression and clinical management of COVID-19 associated pneumonia at time of admission.

COVID-19 pathophysiology is currently not fully understood, reliable prognostic factors remain elusive, and few specific therapeutic strategies have been proposed. In this scenario, availability of biomarkers is a priority. MS-based Proteomics techniques were used to profile the proteome of 81 plasma samples extracted in four consecutive days from 23 hospitalized COVID-19 associated pneumonia patients. Samples from 10 subjects that reached a critical condition during their hospital stay and 10 matched non-severe controls were drawn before the administration of any COVID-19 specific treatment and used to identify potential biomarkers of COVID-19 prognosis. Additionally, we compared the proteome of five patients before and after glucocorticoids and tocilizumab treatment, to assess the changes induced by the therapy on our selected candidates. Forty-two proteins were differentially expressed between patients' evolution groups at 10% FDR. Twelve proteins showed lower levels in critical patients (fold-changes 1.20-3.58), of which OAS3 and COG5 found their expression increased after COVID-19 specific therapy. Most of the 30 proteins over-expressed in critical patients (fold-changes 1.17-4.43) were linked to inflammation, coagulation, lipids metabolism, complement or immunoglobulins, and a third of them decreased their expression after treatment. We propose a set of candidate proteins for biomarkers of COVID-19 prognosis at the time of hospital admission. The study design employed is distinctive from previous works and aimed to optimize the chances of the candidates to be validated in confirmatory studies and, eventually, to play a useful role in the clinical practice.

Top-Down Proteomics Applied to Human Cerebrospinal Fluid.

Cerebrospinal fluid (CSF) is the fluid of choice to study pathologies and disorders of the central nervous system (CNS). Its composition, especially its proteins and peptides, holds the promise that it may reflect the pathological state of an individual. Traditionally, proteins and peptides in CSF have been analyzed using bottom-up proteomics technologies in the search of high proteome coverage. However, the limited protein sequence coverage of this technology means that information regarding post-translational modifications (PTMs) and alternative splice variants is lost. As an alternative technology, top-down proteomics offers low to medium proteome coverage, but high protein coverage enabling almost a full characterization of the proteins' primary structure. This allows us to precisely identify distinct molecular forms of proteins (proteoforms) as well as naturally occurring bioactive peptide fragments, which could be of critical biological relevance and would otherwise remain undetected with a classical proteomics approach.Here, we describe various strategies including sample preparation protocols, off-line intact protein prefractionation, and LC-MS/MS methods together with data analysis pipelines to analyze cerebrospinal fluid (CSF) by top-down proteomics. However, there is not a unique or standardized method and the selection of the top-down strategy will depend on the exact goal of the study. Here, we describe various top-down proteomics methods that enable rapid protein characterization and may be an excellent companion analytical workflow in the search for new protein biomarkers in neurodegenerative diseases.

Downregulated microRNAs in the colorectal cancer: diagnostic and therapeutic perspectives.

Colorectal cancer (CRC), the third most common cancer in the world, has no specific biomarkers that facilitate its diagnosis and subsequent treatment. The miRNAs, small single-stranded RNAs that repress the mRNA translation and trigger the mRNA degradation, show aberrant levels in the CRC, by which these molecules have been related with the initiation, progression, and drug-resistance of this cancer type. Numerous studies show the microRNAs influence the cellular mechanisms related to the cell cycle, differentiation, apoptosis, and migration of the cancer cells through the post-transcriptionally regulated gene expression. Specific patterns of the upregulated and down-regulated miRNA have been associated with the CRC diagnosis, prognosis, and therapeutic response. Concretely, the downregulated miRNAs represent attractive candidates, not only for the CRC diagnosis, but for the targeted therapies via the tumor-suppressing microRNA replacement. This review shows a general overview of the potential uses of the miRNAs in the CRC diagnosis, prognosis, and treatment with a special focus on the downregulated ones. [BMB Reports 2018; 51(11): 563-571].

Anti-fungal and anti-bacterial activities of ethanol extracts of selected traditional Chinese medicinal herbs.

OBJECTIVE: To evaluate in vitro antimicrobial activities of selected 58 ethno-medicinal plant extracts with a view to assess their therapeutic potential. METHODS: A total of 58 traditional Chinese medicinal plants were carefully selected based on the literature review and their traditional use. The antimicrobial activities of ethanol extracts of these medicinal plants were tested against fungi (Aspergillus fumigatus), yeast (Candida albicans), gram-negative (Acinetobacter baumannii and Pseudomonas aeruginosa) and gram-positive bacteria (Staphylococcus aureus). The activities were tested at three different concentrations of 1.00, 0.10 and 0.01 mg/mL. The data was analysed using Gene data Screener program. RESULTS: The measured antimicrobial activities indicated that out of the 58 plant extracts, 15 extracts showed anti-fungal activity and 23 extracts exhibited anti-bacterial activity. Eight plant extracts have exhibited both anti-bacterial and anti-fungal activities. For instance, Eucommia ulmoides, Polygonum cuspidatum, Poria cocos and Uncaria rhyncophylla showed activity against both bacterial and fungal strains, indicating their broad spectrum of activity. CONCLUSIONS: The results revealed that the ethanol extracts of 30 plants out of the selected 58 possess significant antimicrobial activities. It is interesting to note that the findings from the current study are consistent with the traditional use. A clear correlation has also been found between the antimicrobial activity and the flavonoid content of the plant extracts which is in agreement with the literature. Hence, the results presented here can be used to guide the selection of potential plant species for the isolation and structure elucidation of novel antimicrobial compounds in order to establish the structure-activity relationship. This in turn is expected to lead the way to the discovery of novel antimicrobial agents for therapeutic use.