Marisa Oliveira

The Image of the Barbarian in Early India

The concept of the barbarian in early India arises out of the curious situation of the arrival of Indo-Aryan-speaking nomadic pastoralists in northern India who came into contact with the indigenous population (possibly the remnants of the urban civilization of the Indus) and regarded them as barbarians. The earliest distinction made by the Aryan speakers was a linguistic distinction and, to a smaller extent, a physical distinction. The Indo-Aryan speakers spoke Sanskrit whereas the indigenous peoples probably spoke Dravidian and Munda. However the distinction was not one of binary opposition—in fact it admitted to many nuances and degrees of variation, hence the complication of trying to trace the history of the concept. The distinction was rarely clearly manifest and based either on language, ethnic origins or culture. Political status, ritual status and economic power, all tended to blur the contours of the distinction. Added to this has been the confusion introduced by those who tend to identify language with race and who thereby see all speakers of Sanskrit as members of that nineteenth-century myth, the Aryan race.

OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans

Ethnic groups can display differential genetic susceptibility to infectious diseases. The arthropod-born viral dengue disease is one such disease, with empirical and limited genetic evidence showing that African ancestry may be protective against the haemorrhagic phenotype. Global ancestry analysis based on high-throughput genotyping in admixed populations can be used to test this hypothesis, while admixture mapping can map candidate protective genes. A Cuban dengue fever cohort was genotyped using a 2.5 million SNP chip. Global ancestry was ascertained through ADMIXTURE and used in a fine-matched corrected association study, while local ancestry was inferred by the RFMix algorithm. The expression of candidate genes was evaluated by RT-PCR in a Cuban dengue patient cohort and gene set enrichment analysis was performed in a Thai dengue transcriptome. OSBPL10 and RXRA candidate genes were identified, with most significant SNPs placed in inferred weak enhancers, promoters and lncRNAs. OSBPL10 had significantly lower expression in Africans than Europeans, while for RXRA several SNPs may differentially regulate its transcription between Africans and Europeans. Their expression was confirmed to change through dengue disease progression in Cuban patients and to vary with disease severity in a Thai transcriptome dataset. These genes interact in the LXR/RXR activation pathway that integrates lipid metabolism and immune functions, being a key player in dengue virus entrance into cells, its replication therein and in cytokine production. Knockdown of OSBPL10 expression in THP-1 cells by two shRNAs followed by DENV2 infection tests led to a significant reduction in DENV replication, being a direct functional proof that the lower OSBPL10 expression profile in Africans protects this ancestry against dengue disease.

Early Holocenic and Historic mtDNA African Signatures in the Iberian Peninsula: The Andalusian Region as a Paradigm

Determining the timing, identity and direction of migrations in the Mediterranean Basin, the role of “migratory routes” in and among regions of Africa, Europe and Asia, and the effects of sex-specific behaviors of population movements have important implications for our understanding of the present human genetic diversity. A crucial component of the Mediterranean world is its westernmost region. Clear features of transcontinental ancient contacts between North African and Iberian populations surrounding the maritime region of Gibraltar Strait have been identified from archeological data. The attempt to discern origin and dates of migration between close geographically related regions has been a challenge in the field of uniparental-based population genetics. Mitochondrial DNA (mtDNA) studies have been focused on surveying the H1, H3 and V lineages when trying to ascertain north-south migrations, and U6 and L in the opposite direction, assuming that those lineages are good proxies for the ancestry of each side of the Mediterranean. To this end, in the present work we have screened entire mtDNA sequences belonging to U6, M1 and L haplogroups in Andalusians—from Huelva and Granada provinces—and Moroccan Berbers. We present here pioneer data and interpretations on the role of NW Africa and the Iberian Peninsula regarding the time of origin, number of founders and expansion directions of these specific markers. The estimated entrance of the North African U6 lineages into Iberia at 10 ky correlates well with other L African clades, indicating that U6 and some L lineages moved together from Africa to Iberia in the Early Holocene. Still, founder analysis highlights that the high sharing of lineages between North Africa and Iberia results from a complex process continued through time, impairing simplistic interpretations. In particular, our work supports the existence of an ancient, frequently denied, bridge connecting the Maghreb and Andalusia.

Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome

Ethnic diversity has been long considered as one of the factors explaining why the severe forms of dengue are more prevalent in Southeast Asia than anywhere else. Here we take advantage of the admixed profile of Southeast Asians to perform coupled association-admixture analyses in Thai cohorts. For dengue shock syndrome (DSS), the significant haplotypes are located in genes coding for phospholipase C members (PLCB4 added to previously reported PLCE1), related to inflammation of blood vessels. For dengue fever (DF), we found evidence of significant association with CHST10, AHRR, PPP2R5E and GRIP1 genes, which participate in the xenobiotic metabolism signaling pathway. We conducted functional analyses for PPP2R5E, revealing by immunofluorescence imaging that the coded protein co-localizes with both DENV1 and DENV2 NS5 proteins. Interestingly, only DENV2-NS5 migrated to the nucleus, and a deletion of the predicted top-linking motif in NS5 abolished the nuclear transfer. These observations support the existence of differences between serotypes in their cellular dynamics, which may contribute to differential infection outcome risk. The contribution of the identified genes to the genetic risk render Southeast and Northeast Asian populations more susceptible to both phenotypes, while African populations are best protected against DSS and intermediately protected against DF, and Europeans the best protected against DF but the most susceptible against DSS.

Population genetics-informed meta-analysis in seven genes associated with risk to dengue fever disease

Population genetics theory predicted that rare frequent markers would be the main contributors for heritability of complex diseases, but meta-analyses of genome-wide association studies are revealing otherwise common markers, present in all population groups, as the identified candidate genes. In this work, we applied a population-genetics informed meta-analysis to 10 markers located in seven genes said to be associated with dengue fever disease. Seven markers (in PLCE1, CD32, CD209, OAS1 and OAS3 genes) have high-frequency and the other three (in MICB and TNFA genes) have intermediate frequency. Most of these markers have high discriminatory power between population groups, but their frequencies follow the rules of genetic drift, and seem to have not been under strong selective pressure. There was a good agreement in directional consistency across trans-ethnic association signals, in East Asian and Latin American cohorts, with heterogeneity generated by randomness between studies and especially by low sample sizes. This led to confirm the following significant associations: with DF, odds ratio of 0.67 for TNFA-rs1800629-A; with DHF, 0.82 for CD32-rs1801274-G; with DSS, 0.55 for OAS3-rs2285933-G, 0.80 for PLCE1-rs2274223-G and 1.32 for MICB-rs3132468-C. The overall genetic risks confirmed sub-Saharan African populations and descendants as the best protected against the severer forms of the disease, while Southeast and Northeast Asians are the least protected ones. European and close neighbours are the best protected against dengue fever, while, again, Southeast and Northeast Asians are the least protected ones. These risk scores provide important predictive information for the largely naïve European and North American regions, as well as for Africa where misdiagnosis with other hemorrhagic diseases is of concern.

Outcomes from a cohort of patients with acute kidney injury subjected to continuous venovenous hemodiafiltration: The role of negative fluid balance

Background Several factors influence the outcomes in acute kidney injury (AKI), especially in intensive care unit (ICU) patients. In this scenario, continuous renal replacement therapies (CRRT) are used to control metabolic derangements and blood volume. Knowing this fact, it may be possible to change the course of the disease and decrease the high mortality rate observed. Thus, we aimed to evaluate the main risk factors for death in AKI patients needing CRRT. Results This was a prospective, observational cohort study of ICU patients (N = 183) with AKI who underwent continuous venovenous hemodiafiltration (CVVHDF) as their initial dialysis modality choice. The patients were predominantly male (62.8%) and their median age was 65 (55–76) years. The most frequent comorbidities were cardiovascular disease (39.3%), hypertension (32.8%), diabetes (24%), and cirrhosis (20.7%). The main cause of AKI was sepsis (52.5%). At beginning of CVVHDF, 152 patients (83%) were using vasopressors. The median SAPS 3 and SOFA score at ICU admission was 61 (50–74) and 10 (7–12), respectively. The dialysis dose delivered was 33.2 (28.9–38.7) ml/kg/h. The median time between ICU admission and CVVHDF initiation was 2 (1–4) days. The median cumulative fluid balance during the CVVHDF period was -1838 (-5735 +2993) ml. The mortality rate up to90 days was 58%. The independent mortality risk factors in propensity score model were: chronic obstructive pulmonary disease (OR = 3.44[1.14–10.4; p = 0.028]), hematologic malignancy (OR = 5.14[1.66–15.95; p = 0.005]), oliguria (OR = 2.36[1.15–4.9; p = 0.02]), positive daily fluid balance during CVVHDF (OR = 4.55[2.75–13.1; p<0.001]), and total SOFA score on first dialysis day (OR = 1.27[1.12–1.45; p<0.001]). Conclusions Dialysis-related factors may influence the outcomes. In our cohort, positive daily fluid balance during CRRT was associated with lower survival. Multicenter, randomized studies are needed to assess fluid balance as a primary outcome to define the best strategy in this patient population.