Genetic Stratigraphy of Key Demographic Events in Arabia

The issue of admixture in human populations is normally addressed by genome-wide (GW) studies, and several approaches have been developed to date admixture events [1,2,3,4,5]. Admixed populations bear chromosomes with segments of DNA from all contributing source groups, the size of which decreases over successive generations until recombination renders them undetectably short. Several algorithms attempt to date admixture events by inferring the size of the nuclear ancestry segments, and these can work well when dating recent episodes in human history, such as the sub-Saharan African input into the New World [6], but they fail to detect several known episodes that took place at earlier times, such as the African input into Iberia [1] and genetic exchanges across the Red Sea [7]. Simulations with the suite of methods available at the ADMIXTOOLS package indicated that these methods could detect admixture events as early as 500 generation ago, but real data did not allow the tracing of such old events [8]. A recent improved algorithm, called GLOBETROTTER, has been used to tackle the detection of the co-occurrence of several mixture events by decomposing each chromosome into a series of haplotypic chunks and then analysing each chunk independently [3], but the problem of detecting ancient events remains. Its application to the systematic screening of worldwide admixture events was able to reveal around 100 events, but all occurring over only the past 4,000 years [3

Field and Molecular Epidemiology: How Viral Sequencing Changed Transmission Inferences in the First Portuguese SARS-CoV-2 Infection Cluster

Field epidemiology and viral sequencing provide a comprehensive characterization of transmission chains and allow a better identification of superspreading events. However, very few examples have been presented to date during the COVID-19 pandemic. We studied the first COVID-19 cluster detected in Portugal (59 individuals involved amongst extended family and work environments), following the return of four related individuals from work trips to Italy. The first patient to introduce the virus would be misidentified following the traditional field inquiry alone, as shown by the viral sequencing in isolates from 23 individuals. The results also pointed out family, and not work environment, as the primary mode of transmission.This work was funded by Portuguese Foundation for Science and Technology (FCT; Research4COVID19 projects 198_596862267, 617_613735895, 186_596855206). FCT also financed the PhD grant to NP (SFRH/BD/136299/2018) and post-doc grant to VF (SFRH/BPD/114927/2016)

Afadin downregulation by helicobacter pylori Induces epithelial to mesenchymal transition in gastric cells

Afadin is a cytoplasmic protein of the adherens junctions, which regulates the formation and stabilization of both the adherens and the tight junctions. Aberrant expression of Afadin has been shown in cancer and its loss has been associated with epithelial-tomesenchymal transition (EMT). EMT is characterized by the change from an epithelial to a mesenchymal phenotype, with modifications on the expression of adhesion molecules and acquisition of a migratory and invasive cell behavior. While it is known that Helicobacter pylori disrupts the tight and the adherens junctions and induces EMT, the effect of the bacteria on Afadin is still unknown. The aim of this study was to disclose the effect of H. pylori on Afadin and its impact in the induction of an EMT phenotype in gastric cells. Using two different cell lines, we observed that H. pylori infection decreased Afadin protein levels, independently of CagA, T4SS, and VacA virulence factors. H. pylori infection of cell lines recapitulated several EMT features, displacing and downregulating multiple proteins from cell–cell junctions, and increasing the expression of ZEB1, Vimentin, Slug, N-cadherin, and Snail. Silencing of Afadin by RNAi promoted delocalization of junctional proteins from the cell–cell contacts, increased paracellular permeability, and decreased transepithelial electrical resistance, all compatible with impaired junctional integrity. Afadin silencing also led to increased expression of the EMT marker Snail, and to the formation of actin stress fibers, together with increased cell motility and invasion. Finally, and in line with our in vitro data, the gastric mucosa of individuals infected with H. pylori showed decrease/loss of Afadin membrane staining at cell–cell contacts significantly more frequently than uninfected individuals. In conclusion, Afadin is downregulated by H. pylori infection in vitro and in vivo, and its downregulation leads to the emergence of EMT and to the acquisition of an aggressive phenotype in gastric cells, which can contribute to gastric carcinogenesis.This article is a result of the project NORTE-01-0145-FEDER-000029, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). i3S was financed by ERDF funds through the COMPETE 2020 and Portugal 2020, and by Portuguese funds through FCT – Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação (POCI-01-0145-FEDER-007274). MM, JM, and ML have fellowships from FCT (SFRH/BD/95631/2013, SFRH/BD/116965/2016, and SFRH/BPD/110065/2015)

Projecting Ancient Ancestry in Modern-Day Arabians and Iranians: A Key Role of the Past Exposed Arabo-Persian Gulf on Human Migrations

The Arabian Peninsula is strategic for investigations centered on the early structuring of modern humans in the wake of the out-of-Africa migration. Despite its poor climatic conditions for the recovery of ancient human DNA evidence, the availability of both genomic data from neighboring ancient specimens and informative statistical tools allow modeling the ancestry of local modern populations. We applied this approach to a data set of 741,000 variants screened in 291 Arabians and 78 Iranians, and obtained insightful evidence. The west-east axis was a strong forcer of population structure in the Peninsula, and, more importantly, there were clear continuums throughout time linking western Arabia with the Levant, and eastern Arabia with Iran and the Caucasus. Eastern Arabians also displayed the highest levels of the basal Eurasian lineage of all tested modern-day populations, a signal that was maintained even after correcting for a possible bias due to a recent sub-Saharan African input in their genomes. Not surprisingly, eastern Arabians were also the ones with highest similarity with Iberomaurusians, who were, so far, the best proxy for the basal Eurasians amongst the known ancient specimens. The basal Eurasian lineage is the signature of ancient non-Africans who diverged from the common European-eastern Asian pool before 50,000 years ago, prior to the later interbred with Neanderthals. Our results appear to indicate that the exposed basin of the Arabo-Persian Gulf was the possible home of basal Eurasians, a scenario to be further investigated by searching ancient Arabian human specimens.This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through COMPETE 2020-Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia, Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Biomedical anthropological study in Arabian Peninsula based on high-throughput genomics” (POCI-01-0145-FEDER-016609), the Italian Ministry of Education, University and Research project Dipartimenti di Eccellenza Program (2018–2022)—Department of Biology and Biotechnology “L. Spallanzani,” University of Pavia (to A.T.). V.F. has a postdoc grant through FCT (SFRH/BPD/114927/2016). i3S is financed by FEDER-COMPETE 2020, Portugal 2020 and by Portuguese funds through FCT in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). Authors would like to thank Dr Francesco Bertolini for facilitating the research of A.R. in the last stage of the article preparation

Multi-tissue transcriptomic-informed in silico investigation of drugs for the treatment of dengue fever disease

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico–informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, “Adrenergic receptor antagonist”, “ATPase inhibitor”, “NF-kB pathway inhibitor” and “Serotonin receptor antagonist”, were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.Funding was provided by FEDER, Fundo Europeu de Desenvolvimento Regional funds, through the COMPETE 2020, Competitiveness and Internationalization Operational Programme (POCI), Portugal 2020, and by Portuguese funds through FCT/Ministério da Ciência, Tecnologia e Inovação, in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274)

Quantifying the legacy of the Chinese Neolithic on the maternal genetic heritage of Taiwan and Island Southeast Asia

There has been a long-standing debate concerning the extent to which the spread of Neolithic ceramics and Malay-Polynesian languages in Island Southeast Asia (ISEA) were coupled to an agriculturally driven demic dispersal out of Taiwan 4000 years ago (4 ka). We previously addressed this question using founder analysis of mitochondrial DNA (mtDNA) control-region sequences to identify major lineage clusters most likely to have dispersed from Taiwan into ISEA, proposing that the dispersal had a relatively minor impact on the extant genetic structure of ISEA, and that the role of agriculture in the expansion of the Austronesian languages was therefore likely to have been correspondingly minor. Here we test these conclusions by sequencing whole mtDNAs from across Taiwan and ISEA, using their higher chronological precision to resolve the overall proportion that participated in the “out-of-Taiwan” mid-Holocene dispersal as opposed to earlier, postglacial expansions in the Early Holocene. We show that, in total, about 20 % of mtDNA lineages in the modern ISEA pool result from the “out-of-Taiwan” dispersal, with most of the remainder signifying earlier processes, mainly due to sea-level rises after the Last Glacial Maximum. Notably, we show that every one of these founder clusters previously entered Taiwan from China, 6–7 ka, where rice-farming originated, and remained distinct from the indigenous Taiwanese population until after the subsequent dispersal into ISEA

Peripheral biomarkers to diagnose obstructive sleep apnea in adults: A systematic review and meta-analysis

Background: Obstructive Sleep Apnea (OSA) has been recognized as a major health concern worldwide, given its increasing prevalence, difficulties in diagnosis and treatment, and impact on health, economy, and society. Clinical guidelines highlight the need of biomarkers to guide OSA clinical decision-making, but so far, without success. In this systematic review and meta-analysis, registered on the International Prospective Register of Systematic Reviews database (ID CRD42020132556), we proposed to gather and further explore candidates identified in the literature as potential OSA biomarkers. Methods: Search strategies for eight different databases (PubMed/Medline, Cochrane Library, Biblioteca Virtual da Saúde, Web of Science, EMBASE, World Intellectual Property Organization database, and bioRxiV and medRxiV Preprint Servers) were developed. We identified studies exploring potential biomarkers of OSA, in peripheral samples of adults, with and without OSA, with no comorbidities defined in study inclusion criteria, published after the last systematic review and meta-analysis conducted on OSA biomarkers, until May 31st, 2020. Risk of bias was assessed through the 14-item Quality Assessment Tool for Diagnostic Accuracy Studies. Demographic, clinical, and candidate biomarkers' data were collected and analyzed via random effects meta-analyses. Findings: Among the 1512 unique studies screened, 120 met the inclusion criteria and 16 studies with low risk of bias were selected for meta-analyses. The selected 16 studies enrolled a total of 2156 participants, from which 1369 were diagnosed with OSA and 787 were disease-free controls. The assessed variables showed high heterogeneity. From the 38 biomarker candidates evaluated, only two were evaluated in more than one study. Most studies pinpointed candidates with more potential for OSA prognosis. ADAM29, FLRT2 and SLC18A3 mRNA levels in PBMCs, Endocan and YKL-40 levels in serum, and IL-6 and Vimentin levels in plasma revealed the most promising candidates for OSA diagnosis. Interpretation: Although the current systematic review and meta-analysis allowed us to identify candidates to further explore as potential biomarkers in future studies, it is evident that OSA biomarkers research is still at an early stage. Most findings derive from small-size single-center study cohorts and single-candidate studies. We point several gaps in current OSA biomarker research that may guide into new directions and approaches towards the identification of OSA biomarkers.info:eu-repo/semantics/publishedVersio

Shedding light on the african enigma: In vitro testing of homo sapiens-helicobacter pylori coevolution

The continuous characterization of genome-wide diversity in population and case- cohort samples, allied to the development of new algorithms, are shedding light on host ancestry impact and selection events on various infectious diseases. Especially interesting are the longstanding associations between humans and certain bacteria, such as the case of Helicobacter pylori, which could have been strong drivers of adaptation leading to coevolution. Some evidence on admixed gastric cancer cohorts have been suggested as supporting Homo-Helicobacter coevolution, but reliable experimental data that control both the bacterium and the host ancestries are lacking. Here, we conducted the first in vitro coinfection assays with dual humanand bacterium-matched and -mismatched ancestries, in African and European backgrounds, to evaluate the genome wide gene expression host response to H. pylori. Our results showed that: (1) the host response to H. pylori infection was greatly shaped by the human ancestry, with variability on innate immune system and metabolism; (2) African human ancestry showed signs of coevolution with H. pylori while European ancestry appeared to be maladapted; and (3) mismatched ancestry did not seem to be an important differentiator of gene expression at the initial stages of infection as assayed here.Funds were guaranteed by the project “Advancing cancer research: from basic knowledge to application”; NORTE-01-0145-FEDER-000029; Projetos Estruturados de I & D & I, funded by Norte 2020-Programa Operacional Regional do Norte. i3S is financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Competitiveness and Internationalization Operational Programme (POCI), Portugal 2020, and by Portuguese funds through FCT/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274)

Expression and clinical relevance of SOX9 in gastric cancer

Gastric cancer is one of the most frequent tumours and the third leading cause of cancer-related death worldwide. The investigation of new biomarkers that can predict patient outcome more accurately and allow better treatment and follow-up decisions is of crucial importance. SOX9 (sex-determining region Y (SRY)-box 9) is a regulator of cell fate decisions in embryogenesis and adulthood. Here, we sought to ascertain the relevance of SOX9 transcription factor as a prognostic marker in gastric cancer. SOX9 expression was analyzed by immunohistochemistry in 333 gastric adenocarcinoma cases, and its association with clinicopathological and follow-up data was evaluated. SOX9 nuclear expression was absent in 17% of gastric cancer cases and predicted worse disease-free survival (P = 0 03). SOX9 expression was associated with lower risk of relapse in Cox univariable analysis (HR = 0 58; 95% CI = 0 35-0.97; P = 0 04). The prognostic value of SOX9 was more pronounced in tumours with expansive growth (P = 0 01) or with venous invasion (P = 0 02). Two validation cohorts from the Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) confirmed that low SOX9 expression was significantly associated with poor patient outcome. In conclusion, we have identified SOX9 as a biomarker of disease relapse in gastric cancer patients. Further experiments are needed to elucidate its biological relevance at the cellular level.The authors wish to acknowledge the tumour and tissue bank at Hospital de São João for providing all the means to collect the human tissue samples included in this study. This work was supported by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). This work was also financed by the projects NORTE-01-0145-FEDER-000003 (DOCnet) and NORTE-07-0124-FEDER-000029 supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). BP and RB acknowledge FCT for financial support (grants SFRH/BPD/109794/2015 and SFRH/BPD/68276/2010, respectively)

Flow field of non-Newtonian fluids in impinging jets confined by slopping plane walls

An experimental investigation was carried out to characterize the flow field in a liquid impingingjet confined by slopping plane walls and emanating from a rectangular duct for various non-Newtonianfluids. These jets are frequently found in processes within the food and pharmaceutical industries, and theyare formed when a high velocity fluid impinges a solid surface leading to intense levels of heat and masstransfer. The experimental work is complemented by results from a numerical investigation for purelyviscous fluids. This work continues previous research, Cavadas et al (2006), on the same flow geometry forNewtonian fluids in laminar and turbulent flow regimes. Here detailed measurements of mean flow fieldswere carried out by laser-Doppler anemometry at inlet duct Reynolds numbers of Kozicki (1966) (Re*) of200 pertaining to the laminar flow regime. The two non-Newtonian fluids were aqueous solutions of xanthangum (XG) and polyacrylamide (PAA) at weight concentrations of 0.2% and 0.125%, respectively. ForNewtonian fluids, Cavadas et al (2006) found a characteristic three-dimensional helical flow inside therecirculation, starting at the symmetry plane and evolving towards the flat side walls. This helical floweliminates the separated flow region near the side walls and was also visualized in the non-Newtonian cases.Before reaching the flat side walls, the fluid in helical motion exits the recirculation and joins the main flowstream creating a near-wall jet which can be seen as velocity peaks near the walls in the spanwise profiles ofstreamwise velocity. The numerical simulations investigated the roles of shear-thinning and inertia on themain flow characteristics for purely viscous fluids at Reynolds numbers between 10 and 800. The length ofthe recirculation (XR) is constant in the central portion of the channel and decays to zero before reaching theflat side walls. At high Reynolds numbers a slight increase in XR at the edge of the core of the flow isapparent. As expected, inertia increases the length of the recirculation as for Newtonian fluids, but somewhatsurprisingly it also increases the three-dimensional nature of the flow by reducing the size of the central core.Shear-thinning enhances the role of inertia especially at high Reynolds numbers, whereas at low Reynoldsnumbers the behavior is quite similar for all fluids. All flow fields were found to be symmetric relative to x-zand x-y centre plane