APOBECs orchestrate genomic and epigenomic editing across health and disease.

APOBEC proteins can deaminate cytosine residues in DNA and RNA. This can lead to somatic mutations, DNA breaks, RNA modifications, or DNA demethylation in a selective manner. APOBECs function in various cellular compartments and recognize different nucleic acid motifs and structures. They orchestrate a wide array of genomic and epigenomic modifications, thereby affecting various cellular functions positively or negatively, including immune editing, viral and retroelement restriction, DNA damage responses, DNA demethylation, gene expression, and tissue homeostasis. Furthermore, the cumulative increase in genomic and epigenomic editing with aging could also, at least in part, be attributed to APOBEC function. We synthesize our cumulative understanding of APOBEC activity in a unifying overview and discuss their genomic and epigenomic impact in physiological, pathological, and technological contexts.

The effects of reducing chronic inflammation in overweight women on serum hepcidin and iron absorption with and without supplemental ascorbic acid.

Although hepcidin synthesis is stimulated by inflammation and inhibited by Fe deficiency, the strength of their opposing effects on serum hepcidin (SHep) in humans remains unclear. It was recently shown that an inflammatory stimulus in anaemic women did not increase SHep or decrease Fe absorption. The enhancing effect of ascorbic acid on Fe absorption may not be effective during inflammation because of increased SHep. Our study aim was to test whether reducing inflammation in Fe-depleted overweight (OW) women with low-grade inflammation would lower SHep and improve Fe absorption with and without ascorbic acid, compared with normal-weight (NW) women without inflammation. Before and after 14 d of anti-inflammatory treatment (3 × 600 mg ibuprofen daily) in OW and NW women (n 36; 19-46 years of age), we measured SHep and fractional Fe absorption (FIA) (erythrocyte Fe incorporation) from 57Fe- and 58Fe-labelled test meals with and without ascorbic acid. There were significant group effects on IL-6, C-reactive protein, serum ferritin and SHep (for all, P < 0·05). There was a significant treatment effect on SHep (P < 0·05): in OW women, treatment decreased IL-6 by approximately 30 % and SHep by approximately 45 %. However, there were no significant treatment or group effects on FIA. Body Fe stores (BIS) were a significant positive predictor of SHep before and after treatment (P < 0·001), but IL-6 was not. Reducing chronic inflammation in OW women halved SHep but did not affect Fe absorption with or without ascorbic acid, and the main predictor of Fe absorption was BIS.

Multiple sclerosis in Central America and Caribbean countries: frequency and clinical characterization of an emergent disease.

Background: Multiple Sclerosis (MS) is a common neurological disease among white populations of European origin. Frequencies among Latin Americans continue to be studied, however, epidemiologic, and clinical characterization studies lack from Central American and Caribbean countries. Ethnicity in these countries is uniformly similar with a prevalent Mestizo population. Methods and results: Data from January 2014 to December 2019 from Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, Panama, Dominican Republic, and Aruba on demographic, clinical, MRI and phenotypic traits were determined in coordinated studies: ENHANCE, a population-based, retrospective, observational study on incidence and clinical characteristics, and from the subgroup with MS national registries (Aruba, Dominican Republic, Honduras, and Panama), data on prevalence, phenotypes and demographics. Expanded Disability Status Scale (EDSS), and therapeutic schemes were included. ENHANCE data from 758 patients disclosed 79.8% of Mestizo ethnicity; 72.4% female; median age at onset 31.0 years and 33.2 at diagnosis. The highest incidence rate was from Aruba, 2.3-3.5 × 100,000 inhabitants, and the lowest, 0.07-0.15 × 100,000, from Honduras. Crude prevalence rates per 100,000 inhabitants fluctuated from 27.3 (Aruba) to 1.0 (Honduras). Relapsing MS accounted for 87.4% of cases; EDSS <3.0 determined in 66.6% (mean disease duration: 9.1 years, SD ± 5.0); CSF oligoclonal bands 85.7%, and 87% of subjects hydroxyvitamin D deficient. Common initial therapies were interferon and fingolimod. Switching from interferon to fingolimod was the most common escalation step. The COVID-19 pandemic affected follow-up aspects of these studies. Conclusion: This is the first study providing data on frequencies and clinical characteristics from 8 countries from the Central American and Caribbean region, addressing MS as an emergent epidemiologic disorder. More studies from these areas are encouraged.

Integrative OMICS Data-Driven Procedure Using a Derivatized Meta-Analysis Approach.

The wealth of high-throughput data has opened up new opportunities to analyze and describe biological processes at higher resolution, ultimately leading to a significant acceleration of scientific output using high-throughput data from the different omics layers and the generation of databases to store and report raw datasets. The great variability among the techniques and the heterogeneous methodologies used to produce this data have placed meta-analysis methods as one of the approaches of choice to correlate the resultant large-scale datasets from different research groups. Through multi-study meta-analyses, it is possible to generate results with greater statistical power compared to individual analyses. Gene signatures, biomarkers and pathways that provide new insights of a phenotype of interest have been identified by the analysis of large-scale datasets in several fields of science. However, despite all the efforts, a standardized regulation to report large-scale data and to identify the molecular targets and signaling networks is still lacking. Integrative analyses have also been introduced as complementation and augmentation for meta-analysis methodologies to generate novel hypotheses. Currently, there is no universal method established and the different methods available follow different purposes. Herein we describe a new unifying, scalable and straightforward methodology to meta-analyze different omics outputs, but also to integrate the significant outcomes into novel pathways describing biological processes of interest. The significance of using proper molecular identifiers is highlighted as well as the potential to further correlate molecules from different regulatory levels. To show the methodology's potential, a set of transcriptomic datasets are meta-analyzed as an example.

Modelling liver cancer microenvironment using a novel 3D culture system.

The tumor microenvironment and its contribution to tumorigenesis has been a focal highlight in recent years. A two-way communication between the tumor and the surrounding microenvironment sustains and contributes to the growth and metastasis of tumors. Progression and metastasis of hepatocellular carcinoma (HCC) have been reported to be exceedingly influenced by diverse microenvironmental cues. In this study, we present a 3D-culture model of liver cancer to better mimic in vivo tumor settings. By creating novel 3D co-culture model that combines free-floating and scaffold-based 3D-culture techniques of liver cancer cells and fibroblasts, we aimed to establish a simple albeit reproducible ex vivo cancer microenvironment model that captures tumor-stroma interactions. The model presented herein exhibited unique gene expression and protein expression profiles when compared to 2D and 3D mono-cultures of liver cancer cells. Our results showed that in vivo like conditions cannot be mimicked by simply growing cancer cells as spheroids, but by co-culturing them with 3D fibroblast with which they were able to crosstalk. This was evident by the upregulation of several pathways involved in HCC, and the increase in secreted factors by co-cultured cancer cells, many of which are also involved in tumor-stroma interactions. Compared to the conventional 2D culture, the proposed model exhibits an increase in the expression of genes associated with development, progression, and poor prognosis of HCC. Our results correlated with an aggressive outcome that better mirrors in vivo HCC, and therefore, a more reliable platform for molecular understanding of HCC.

Maternal iron kinetics and maternal-fetal iron transfer in normal-weight and overweight pregnancy.

BACKGROUND: Inflammation during pregnancy may aggravate iron deficiency (ID) by increasing serum hepcidin and reducing iron absorption. This could restrict iron transfer to the fetus, increasing risk of infant ID and its adverse effects. OBJECTIVES: We aimed to assess whether iron bioavailability and/or iron transfer to the fetus is impaired in overweight/obese (OW) pregnant women with adiposity-related inflammation, compared with normal-weight (NW) pregnant women. METHODS: In this prospective study, we followed NW (n = 43) and OW (n = 40) pregnant women who were receiving iron supplements from the 14th week of gestation to term and followed their infants to age 6 mo. We administered 57Fe and 58Fe in test meals mid-second and mid-third trimester, and measured tracer kinetics throughout pregnancy and infancy. RESULTS: In total, 38 NW and 36 OW women completed the study to pregnancy week 36, whereas 30 NW and 27 OW mother-infant pairs completed the study to 6 mo postpartum. Both groups had comparable iron status, hemoglobin, and serum hepcidin throughout pregnancy. Compared with the NW, the OW pregnant women had 1) 43% lower fractional iron absorption (FIA) in the third trimester (P = 0.033) with median [IQR] FIA of 23.9% [11.4%-35.7%] and 13.5% [10.8%-19.5%], respectively; and 2) 17% lower maternal-fetal iron transfer from the first tracer (P = 0.051) with median [IQR] maternal-fetal iron transfer of 4.8% [4.2%-5.4%] and 4.0% [3.6%-4.6%], respectively. Compared with the infants born to NW women, infants born to OW women had lower body iron stores (BIS) with median [IQR] 7.7 [6.3-8.8] and 6.6 [4.6-9.2] mg/kg body weight at age 6 mo, respectively (P = 0.024). Prepregnancy BMI was a negative predictor of maternal-fetal iron transfer (ß = -0.339, SE = 0.144, P = 0.025) and infant BIS (ß = -0.237, SE = 0.026, P = 0.001). CONCLUSIONS: Compared with NW, OW pregnant women failed to upregulate iron absorption in late pregnancy, transferred less iron to their fetus, and their infants had lower BIS. These impairments were associated with inflammation independently of serum hepcidin.This trial was registered at clinicaltrials.gov as NCT02747316.

Neuromyelitis Optica Spectrum Disorder in Central America and the Caribbean: A Multinational Clinical Characterization Study.

Here, a study of NMOSD in Central America and the Caribbean with a multinational collaborative, multicentric and descriptive approach involving 25 institutions from 9 countries is presented. Demographics, clinical manifestations, expanded disability scale status (EDSS), brain and spinal cord MRI, serological anti-AQP4-IgG and anti-MOG-IgG antibodies, and cerebrospinal fluid (CSF) oligoclonal bands were included. A central serological repository utilized the cell-based assay. The specimens outside of this network employed diverse methodologies. Data were collected at the Gorgas Commemorative Institute of Health Studies (ICGES), Panama, and included 186 subjects, of which 84% were females (sex ratio of 5.6:1). Mestizos constituted 72% of the study group. The median age was 42.5 years (IQR: 32.0-52.0). Associated autoimmune diseases (8.1%) were myasthenia gravis, Sjögren's syndrome and systemic lupus erythematosus. The most common manifestation was optic neuritis-transverse myelitis (42.5%). A relapsing course was described in 72.3% of cases. EDSS scores of 0-3.5 were reported in 57.2% of cases and higher than 7.0 in 14.5%. Positive anti-AQP4-IgG antibody occurred in 59.8% and anti-MOG-IgG antibody in 11.5% of individuals. Antibody testing was lacking for 13.4% of patients. The estimated crude prevalence of NMOSD from Panama and the Dominican Republic was 1.62/100,000 (incidence of 0.08-0.41) and 0.73/100,000 (incidence 0.02-0.14), respectively. This multinational study contributes additional insights and data on the understanding of NMOSD in this Latin American region.

Acute Transverse Myelitis (ATM):Clinical Review of 43 Patients With COVID-19-Associated ATM and 3 Post-Vaccination ATM Serious Adverse Events With the ChAdOx1 nCoV-19 Vaccine (AZD1222).

Introduction: Although acute transverse myelitis (ATM) is a rare neurological condition (1.34-4.6 cases per million/year) COVID-19-associated ATM cases have occurred during the pandemic. Case-finding methods: We report a patient from Panama with SARS-CoV-2 infection complicated by ATM and present a comprehensive clinical review of 43 patients with COVID-19-associated ATM from 21 countries published from March 2020 to January 2021. In addition, 3 cases of ATM were reported as serious adverse events during the clinical trials of the COVID-19 vaccine ChAdOx1 nCoV-19 (AZD1222). Results: All patients had typical features of ATM with acute onset of paralysis, sensory level and sphincter deficits due to spinal cord lesions demonstrated by imaging. There were 23 males (53%) and 20 females (47%) ranging from ages 21- to 73- years-old (mean age, 49 years), with two peaks at 29 and 58 years, excluding 3 pediatric cases. The main clinical manifestations were quadriplegia (58%) and paraplegia (42%). MRI reports were available in 40 patients; localized ATM lesions affected ≤3 cord segments (12 cases, 30%) at cervical (5 cases) and thoracic cord levels (7 cases); 28 cases (70%) had longitudinally-extensive ATM (LEATM) involving ≥4 spinal cord segments (cervicothoracic in 18 cases and thoracolumbar-sacral in 10 patients). Acute disseminated encephalomyelitis (ADEM) occurred in 8 patients, mainly women (67%) ranging from 27- to 64-years-old. Three ATM patients also had blindness from myeloneuritis optica (MNO) and two more also had acute motor axonal neuropathy (AMAN). Conclusions: We found ATM to be an unexpectedly frequent neurological complication of COVID-19. Most cases (68%) had a latency of 10 days to 6 weeks that may indicate post-infectious neurological complications mediated by the host's response to the virus. In 32% a brief latency (15 hours to 5 days) suggested a direct neurotropic effect of SARS-CoV-2. The occurrence of 3 reported ATM adverse effects among 11,636 participants in the AZD1222 vaccine trials is extremely high considering a worldwide incidence of 0.5/million COVID-19-associated ATM cases found in this report. The pathogenesis of ATM remains unknown, but it is conceivable that SARS-CoV-2 antigens -perhaps also present in the AZD1222 COVID-19 vaccine or its chimpanzee adenovirus adjuvant- may induce immune mechanisms leading to the myelitis.

Integrative Analysis of Incongruous Cancer Genomics and Proteomics Datasets.

Cancer is a complex disease characterized by molecular heterogeneity and the involvement of several cellular mechanisms throughout its evolution and pathogenesis. Despite the great efforts made to untangle these mechanisms, cancer pathophysiology remains far from clear. So far, panels of biomarkers have been reported from high-throughput data generated through different platforms. These biomarkers are primarily focused on one type of coding molecules such as transcripts or proteins, mainly due to the apparent heterogeneity of output data resulting from the use of various techniques specific to the molecular type. Hence, there is a major need to understand how these molecules interact and complement each other to be able to explain the deregulated processes involved. The breadth of large-scale data availability as well as the lack of in-depth analysis of publicly available data has raised concerns and enabled opportunities for new strategies to analyze "Big data" more comprehensively. Here, a new protocol to perform integrative analysis based on a systems biology approach is described. The foundation of the approach relies on groups of datasets from published studies compared within the original described groups and organized in a designated format to allow the integration and cross-comparison among different studies and different platforms. This approach follows an unbiased hypothesis-free methodology that will facilitate the identification of commonalities among different data-set sources, and ultimately map and characterize specific molecular pathways using significantly deregulated molecules. This in turn will generate novel insights about the mechanisms deregulated in complex diseases such as cancer.

Integrative analysis of Multiple Sclerosis using a systems biology approach.

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammatory-demyelinating events in the central nervous system. Despite more than 40 years of MS research its aetiology remains unknown. This study aims to identify the most frequently reported and consistently regulated molecules in MS in order to generate molecular interaction networks and thereby leading to the identification of deregulated processes and pathways which could give an insight of the underlying molecular mechanisms of MS. Driven by an integrative systems biology approach, gene-expression profiling datasets were combined and stratified into "Non-treated" and "Treated" groups and additionally compared to other disease patterns. Molecular identifiers from dataset comparisons were matched to our Multiple Sclerosis database (MuScle; www.padb.org/muscle ). From 5079 statistically significant molecules, correlation analysis within groups identified a panel of 16 high-confidence genes unique to the naïve MS phenotype, whereas the "Treated" group reflected a common pattern associated with autoimmune disease. Pathway and gene-ontology clustering identified the Interferon gamma signalling pathway as the most relevant amongst all significant molecules, and viral infections as the most likely cause of all down-stream events observed. This hypothesis-free approach revealed the most significant molecular events amongst different MS phenotypes which can be used for further detailed studies.

CVD and Oxidative Stress.

Nowadays, it is known that oxidative stress plays at least two roles within the cell, the generation of cellular damage and the involvement in several signaling pathways in its balanced normal state. So far, a substantial amount of time and effort has been expended in the search for a clear link between cardiovascular disease (CVD) and the effects of oxidative stress. Here, we present an overview of the different sources and types of reactive oxygen species in CVD, highlight the relationship between CVD and oxidative stress and discuss the most prominent molecules that play an important role in CVD pathophysiology. Details are given regarding common pharmacological treatments used for cardiovascular distress and how some of them are acting upon ROS-related pathways and molecules. Novel therapies, recently proposed ROS biomarkers, as well as future challenges in the field are addressed. It is apparent that the search for a better understanding of how ROS are contributing to the pathophysiology of CVD is far from over, and new approaches and more suitable biomarkers are needed for the latter to be accomplished.