African genetic diversity and adaptation inform a precision medicine agenda.

The deep evolutionary history of African populations, since the emergence of modern humans more than 300,000 years ago, has resulted in high genetic diversity and considerable population structure. Selected genetic variants have increased in frequency due to environmental adaptation, but recent exposures to novel pathogens and changes in lifestyle render some of them with properties leading to present health liabilities. The unique discoverability potential from African genomic studies promises invaluable contributions to understanding the genomic and molecular basis of health and disease. Globally, African populations are understudied, and precision medicine approaches are largely based on data from European and Asian-ancestry populations, which limits the transferability of findings to the continent of Africa. Africa needs innovative precision medicine solutions based on African data that use knowledge and implementation strategies aligned to its climatic, cultural, economic and genomic diversity.

Transcriptomic remodeling of gastric cells by Helicobacter pylori outer membrane vesicles.

BACKGROUND: Outer membrane vesicles (OMVs) are spontaneously released by Gram-negative bacteria and influence bacteria-host interactions by acting as a delivery system for bacterial components and by interacting directly with host cells. Helicobacter pylori, a pathogenic bacterium that chronically colonizes the human stomach, also sheds OMVs, and their impact on bacterial-mediated diseases is still being elucidated. MATERIALS AND METHODS: Transcriptomic profiling of the human gastric cell line MKN74 upon challenge with H. pylori OMVs compared to control and infected cells was performed using the Ion AmpliSeq™ Transcriptome Human Gene Expression Panel to understand the gene expression changes that human gastric epithelial cells might undergo when exposed to H. pylori OMVs. RESULTS: H. pylori OMVs per se modify the gene expression profile of gastric epithelial cells, adding another layer of (gene) regulation to the already complex host-bacteria interaction. The most enriched pathways include those related to amino acid metabolism, mitogen-activated protein kinase signaling, autophagy, and ferroptosis, whereas the cell cycle, DNA replication, and DNA repair were the most downregulated. The transcriptomic changes induced by OMVs were mostly similar to those induced by the parental bacteria, likely amplifying the effects of the bacterium itself. CONCLUSIONS: Our data provide a valuable portrayal of the transcriptomic remodeling of gastric cells induced by H. pylori OMVs. It demonstrates the breadth of cellular pathways and genes affected by OMVs, most previously unreported, which can be further dissected for the underlying molecular mediators and explored to understand the pathobiology of the full spectrum of H. pylori-mediated diseases.

Sub-Saharan African information potential to unveil adaptations to infectious disease.

Sub-Saharan Africa is the most promising region of the world to conduct high-throughput studies to unveil adaptations to infectious diseases due to several reasons, namely, the longest evolving time-depth in the Homo sapiens phylogenetic tree (at least two-third older than any other worldwide region); the continuous burden of infectious diseases (still number one in health/life threat); and the coexistence of populations practising diverse subsistence modes (nomadic or seminomadic hunter-gatherers and agropastoralists, and sedentary agriculturalists, small urban and megacity groups). In this review, we will present the most up-to-date results that shed light on three main hypotheses related with this adaptation. One is the hypothesis of coevolution between host and pathogen, given enough time for the establishment of this highly dynamic relationship. The second hypothesis enunciates that the agricultural transition was responsible for the increase of the infectious disease burden, due to the huge expansion of the sedentary human population and the cohabitation with domesticates as main reservoirs of pathogens. The third hypothesis states that the boosting of our immune system against pathogens by past selection may have resulted in maladaptation of the developed hygienic societies, leading to an increase of allergic, inflammatory and autoimmune disorders. Further work will enlighten the biological mechanisms behind these main adaptations, which can be insightful for translation into diagnosis, prognosis and treatment interventions.

First insight into oral microbiome diversity in Papua New Guineans reveals a specific regional signature.

The oral microbiota is a highly complex and diversified part of the human microbiome. Being located at the interface between the human body and the exterior environment, this microbiota can deepen our understanding of the environmental impacts on the global status of human health. This research topic has been well addressed in Westernized populations, but these populations only represent a fraction of human diversity. Papua New Guinea hosts very diverse environments and one of the most unique human biological diversities worldwide. In this study we performed the first known characterization of the oral microbiome in 85 Papua New Guinean individuals living in different environments, using a qualitative and quantitative approach. We found a significant geographical structure of the Papua New Guineans oral microbiome, especially in the groups most isolated from urban spaces. In comparison to other global populations, two bacterial genera related to iron absorption were significantly more abundant in Papua New Guineans and Aboriginal Australians, which suggests a shared oral microbiome signature. Further studies will be needed to confirm and explore this possible regional-specific oral microbiome profile.

Therapeutic Potential of Resveratrol for Glioma: A Systematic Review and Meta-Analysis of Animal Model Studies.

Gliomas are aggressive malignant brain tumors, with poor prognosis despite available therapies, raising the necessity for finding new compounds with therapeutic action. Numerous preclinical investigations evaluating resveratrol's anti-tumor impact in animal models of glioma have been reported; however, the variety of experimental circumstances and results have prevented conclusive findings about resveratrol's effectiveness. Several databases were searched during May 2023, ten publications were identified, satisfying the inclusion criteria, that assess the effects of resveratrol in murine glioma-bearing xenografts. To determine the efficacy of resveratrol, tumor volume and animal counts were retrieved, and the data were then subjected to a random effects meta-analysis. The influence of different experimental conditions and publication bias on resveratrol efficacy were evaluated. Comparing treated to untreated groups, resveratrol administration decreased the tumor volume. Overall, the effect's weighted standardized difference in means was -2.046 (95%CI: -3.156 to -0.936; p-value < 0.001). The efficacy of the treatment was observed for animals inoculated with both human glioblastoma or rat glioma cells and for different modes of resveratrol administration. The combined administration of resveratrol and temozolomide was more effective than temozolomide alone. Reducing publication bias did not change the effectiveness of resveratrol treatment. The findings suggest that resveratrol slows the development of tumors in animal glioma models.

Evaluation of the Cytotoxic and Antiviral Effects of Small Molecules Selected by In Silico Studies as Inhibitors of SARS-CoV-2 Cell Entry.

The spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) relies on host cell surface glycans to facilitate interaction with the angiotensin-converting enzyme 2 (ACE-2) receptor. This interaction between ACE2 and the spike protein is a gateway for the virus to enter host cells and may be targeted by antiviral drugs to inhibit viral infection. Therefore, targeting the interaction between these two proteins is an interesting strategy to prevent SARS-CoV-2 infection. A library of glycan mimetics and derivatives was selected for a virtual screening performed against both ACE2 and spike proteins. Subsequently, in vitro assays were performed on eleven of the most promising in silico compounds to evaluate: (i) their efficacy in inhibiting cell infection by SARS-CoV-2 (using the Vero CCL-81 cell line as a model), (ii) their impact on ACE2 expression (in the Vero CCL-81 and MDA-MB-231 cell lines), and (iii) their cytotoxicity in a human lung cell line (A549). We identified five synthetic compounds with the potential to block SARS-CoV-2 infection, three of them without relevant toxicity in human lung cells. Xanthene 1 stood out as the most promising anti-SARS-CoV-2 agent, inhibiting viral infection and viral replication in Vero CCL-81 cells, without causing cytotoxicity to human lung cells.

How empathy, perceived parental care, and overprotection indexes are affected by participants' sex: investigating cultural differences.

Culture seems to affect how empathy's development is influenced by parental behaviors. Considering that empathy is a social ability whose development is affected by many environmental and biological factors, differences can be expected in the way fathers and mothers care for and protect their sons and daughters, as social roles are influenced by culture. The objective of this research was to assess to what extent empathy, perceived parental care, and overprotection are affected by the offspring's sex. 477 adults participated in the study and three instruments were used: the Brazilian versions of the Parental Bonding Instrument, the Interpersonal Reactivity Index, and the Empathy Quotient. Pearson correlation, multiple linear regression, and moderation analyses were conducted. Maternal and paternal care were related to empathy variables for women in the Brazilian context, whereas the perceived parenting behaviors of care and overprotection did not show significant associations with empathy for male participants. Preliminary analysis also suggests that the offspring's sex influences paternal care expressed through variables such as perspective taking and combined cognitive empathy. This study's outcomes suggest that the way Brazilian parents behave is dependent on their offspring's sex. The main results were discussed in comparison to literature that used distinct cultural samples, especially to the outcomes found in British reports, to identify Brazilian parents' behaviors specificities and their association with the autonomous-relational parenting orientation.

Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression.

OBJECTIVE: Intratumor heterogeneity drives cancer progression and therapy resistance. However, it has yet to be determined whether and how subpopulations of cancer cells interact and how this interaction affects the tumour. DESIGN: We have studied the spontaneous flow of extracellular vesicles (EVs) between subpopulations of cancer cells: cancer stem cells (CSC) and non-stem cancer cells (NSCC). To determine the biological significance of the most frequent communication route, we used pancreatic ductal adenocarcinoma (PDAC) orthotopic models, patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs). RESULTS: We demonstrate that PDAC tumours establish an organised communication network between subpopulations of cancer cells using EVs called the EVNet). The EVNet is plastic and reshapes in response to its environment. Communication within the EVNet occurs preferentially from CSC to NSCC. Inhibition of this communication route by impairing Rab27a function in orthotopic xenographs, GEMMs and PDXs is sufficient to hamper tumour growth and phenocopies the inhibition of communication in the whole tumour. Mechanistically, we provide evidence that CSC EVs use agrin protein to promote Yes1 associated transcriptional regulator (YAP) activation via LDL receptor related protein 4 (LRP-4). Ex vivo treatment of PDXs with antiagrin significantly impairs proliferation and decreases the levels of activated YAP.Patients with high levels of agrin and low inactive YAP show worse disease-free survival. In addition, patients with a higher number of circulating agrin+ EVs show a significant increased risk of disease progression. CONCLUSION: PDAC tumours establish a cooperation network mediated by EVs that is led by CSC and agrin, which allows tumours to adapt and thrive. Targeting agrin could make targeted therapy possible for patients with PDAC and has a significant impact on CSC that feeds the tumour and is at the centre of therapy resistance.

Human Genomic Diversity Where the Mediterranean Joins the Atlantic.

Throughout the past few years, a lively debate emerged about the timing and magnitude of the human migrations between the Iberian Peninsula and the Maghreb. Several pieces of evidence, including archaeological, anthropological, historical, and genetic data, have pointed to a complex and intermingled evolutionary history in the western Mediterranean area. To study to what extent connections across the Strait of Gibraltar and surrounding areas have shaped the present-day genomic diversity of its populations, we have performed a screening of 2.5 million single-nucleotide polymorphisms in 142 samples from southern Spain, southern Portugal, and Morocco. We built comprehensive data sets of the studied area and we implemented multistep bioinformatic approaches to assess population structure, demographic histories, and admixture dynamics. Both local and global ancestry inference showed an internal substructure in the Iberian Peninsula, mainly linked to a differential African ancestry. Western Iberia, from southern Portugal to Galicia, constituted an independent cluster within Iberia characterized by an enriched African genomic input. Migration time modeling showed recent historic dates for the admixture events occurring both in Iberia and in the North of Africa. However, an integrative vision of both paleogenomic and modern DNA data allowed us to detect chronological transitions and population turnovers that could be the result of transcontinental migrations dating back from Neolithic times. The present contribution aimed to fill the gaps in the modern human genomic record of a key geographic area, where the Mediterranean and the Atlantic come together.

The Comoros Show the Earliest Austronesian Gene Flow into the Swahili Corridor.

At the dawn of the second millennium, the expansion of the Indian Ocean trading network aligned with the emergence of an outward-oriented community along the East African coast to create a cosmopolitan cultural and trading zone known as the Swahili Corridor. On the basis of analyses of new genome-wide genotyping data and uniparental data in 276 individuals from coastal Kenya and the Comoros islands, along with large-scale genetic datasets from the Indian Ocean rim, we reconstruct historical population dynamics to show that the Swahili Corridor is largely an eastern Bantu genetic continuum. Limited gene flows from the Middle East can be seen in Swahili and Comorian populations at dates corresponding to historically documented contacts. However, the main admixture event in southern insular populations, particularly Comorian and Malagasy groups, occurred with individuals from Island Southeast Asia as early as the 8th century, reflecting an earlier dispersal from this region. Remarkably, our results support recent archaeological and linguistic evidence-based suggestions that the Comoros archipelago was the earliest location of contact between Austronesian and African populations in the Swahili Corridor.

Effects of the endocrine disruptor vinclozolin in male reproduction: a systematic review and meta-analysis†.

Endocrine-disrupting chemicals have become an issue of scientific and public discussion. Vinclozolin (VNZ) is a fungicide that competitively antagonizes the binding of natural androgens to their receptor, disturbing the function of tissues that are sensitive to these hormones, as is the case of the male reproductive organs. A systematic review with meta-analyses of rodent studies was conducted to answer the following question: Does exposure to VNZ affect sperm parameters and testicular/epididymal weight? The methodology was prespecified according to the Cochrane Handbook for Systematic Reviews and PRISMA recommendations. Sixteen articles met the inclusion criteria, comprising a total of 1189 animals. The risk of publication bias was assessed using the Trim and Fill adjustment, funnel plot, and Egger regression test. Heterogeneity and inconsistency across the findings were tested using the Q-statistic and I2 of Higgins, respectively. Sensitivity was also analyzed. Statistical analysis was performed on Comprehensive Meta-Analysis software (Version 2.0), using random models and weighted mean differences along with a 95% confidence interval. Sperm motility, counts, daily sperm production (evidence of publication bias), and epididymis weight were decreased in VNZ-treated animals. Exposure length and dose, as well as the time point of exposure, influenced the obtained results. Despite the moderate/high heterogeneity observed, the sensitivity analysis overall demonstrated the robustness of the findings. The quality scores of the included studies were superior to 4 in a total of 9, then classified as good. The obtained data corroborate the capability of VNZ exposure to disrupt spermatogenic output and compromise male fertility.

Comparative analysis of glucose and carcinoembryonic antigen in the diagnosis of pancreatic mucinous cysts: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Pancreatic cystic fluid (PCF) analysis is useful to distinguish between different cyst types and to guide management. The aim of our study was to compare the diagnostic accuracy of glucose level with carcinoembryonic antigen (CEA) in PCF for mucinous cyst diagnosis. METHODS: We identified studies with PCF obtained by EUS before surgery, with cysts classified as mucinous and nonmucinous according to surgical specimens. A random-effects model was used for quantitative meta-analysis. Pooled sensitivities, specificities, and summary receiver operating characteristic (ROC) curve analysis were conducted. RESULTS: For CEA, we included 31 studies with 5268 patients, of which 2083 were referred for surgery. For glucose, we included 4 studies with 345 patients, of which 275 were referred for surgery. Glucose performed better than CEA for mucinous cysts diagnosis (premalignant and malignant) with sensitivities of .90 (95% confidence interval [CI], .85-.94) and .67 (95% CI, .65-.70), specificities of .82 (95% CI, .72-.89) and .80 (95% CI, 0.76-0.83), and areas under the ROC curve of .96 and .79, respectively. Glucose had a higher sensitivity (90%), with uncommon false-negative results, making it an excellent biomarker to exclude a mucinous cyst. Sensitivity analysis demonstrated that the findings of the current meta-analysis are robust. CONCLUSION: Glucose level in PCF is more accurate than CEA for preoperative diagnosis of mucinous cysts. It may become a useful first-line test, particularly in small cysts with a limited volume of PCF. Larger studies are awaited to confirm glucose as the single test for mucinous cyst diagnosis.

A comparative analysis of glucose and carcinoembryonic antigen in diagnosis of pancreatic mucinous cysts: a systematic review and meta-analysis.

BACKGROUND/AIMS: Pancreatic cystic fluid (PCF) analysis is useful to distinguish between different cyst types and guide management. The aim of our study was to compare the diagnostic accuracy of glucose level with carcinoembryonic antigen (CEA) in PCF for mucinous cyst diagnosis. METHODS: We identified studies with PCF obtained by EUS before surgery, with cysts classified as mucinous and nonmucinous according to surgical specimens. A random effects model was used for quantitative meta-analysis. Pooled sensitivities, specificities, and summary receiver operating characteristic (SROC) curve analysis were conducted. RESULTS: For CEA, we included 31 studies with 5268 patients, of which 2083 were referred for surgery and for glucose we included 5 studies with 460 patients, of which 275 were referred for surgery. Glucose performed better than CEA for mucinous cysts diagnosis (premalignant and malignant) with sensitivities of 0.91 (95% CI, 0.86-0.94) and 0.67 (95% CI, 0.65-0.70), specificities of 0.75 (95% CI, 0.68-0.82) and 0.80 (95% CI, 0.76-0.83), and areas under the ROC curve (AUC) of 0.95 and 0.79, respectively. Glucose had a higher sensitivity (91%), with uncommon false negative results, making it an excellent biomarker to exclude a mucinous cyst. Sensitivity analysis demonstrated that the findings of the current meta-analysis are robust. CONCLUSION: Glucose level in PCF is more accurate than CEA for preoperative diagnosis of mucinous cysts. It may become a useful first line test, particularly in small cysts with limited volume of PCF. Larger studies are awaited to confirm glucose as the single test for mucinous cyst diagnosis.

The Upper Digestive Tract Microbiome and Oesophageal Squamous Cell Carcinoma: Epidemiology, Pathogenesis, and Clinical Implications in Africa.

The study of the microbiome has significantly contributed to our understanding of complex diseases including cancer, with a profound influence of the microbiota on clinical prognosis and the efficacy of cancer treatments. Oesophageal cancer is positioned amongst the most aggressive malignant diseases, resulting from a complex interaction between anthropometric, genetic, immune response, and environmental factors. Oesophageal squamous cell carcinoma (OSCC) is the most common type of oesophageal cancer and is a serious burden in Eastern Africa, in the area known as the African oesophageal cancer corridor (AOCC). OSCC is often diagnosed at a late stage, with patients already suffering from severe malnutrition and dehydration due to swallowing difficulties, leading to high mortality rates. So far, aetiological factors have been individually analysed with an inappropriate contextualisation. The upper digestive tract microbiome has been proposed to contribute to the onset and progression of OSCC but with limited understanding of the mechanisms behind this interaction. Data on African populations are limited, and the aetiology of AOCC is still poorly understood. This review discusses the current knowledge of the aetiology of OSCC in Africa, with special focus on the probable influence of the upper digestive tract microbiota.

Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort.

BACKGROUND: Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests. METHODS: The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries. RESULTS: Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results. CONCLUSIONS: This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening.

Genetic variation patterns of ß-thalassemia in Western Andalusia (Spain) reveal a structure of specific mutations within the Iberian Peninsula.

BACKGROUND: Analyses of the genomic variation in the western Mediterranean population are being used to reveal its evolutionary history and to understand the molecular basis of particular diseases. AIM: To observe the ß-thalassemia mutational spectrum in western Andalusia, Spain, in the context of the Mediterranean. In addition, associations between disease and neutral gene variants within the ß-globin gene (HBB) were also evaluated. SUBJECTS AND METHODS: This study included 63 unrelated individuals diagnosed with ß-thalassemia. In addition, 97 unrelated, healthy subjects of the same territory were also analysed as proxies of the normal genetic background. Allele associations and population genetic structure analyses were performed using different methodologies. RESULTS: Data have revealed a rather restricted spectrum of ß-thalassemia mutations in the analysed sample. Although the detected variants fit well with the Mediterranean pattern, certain singularities support a structure of some specific ß-thalassemia alleles. The IVSI-1 (G > A) shows a strong regionalisation. The spatial correlogram revealed a typically narrow wave structure, presumably linked to genetic isolation and genetic drift. CONCLUSIONS: The long history of endemic malaria in the study territory, the rather high consanguinity rates among its autochthonous population, and other demographic features have been used here to understand the western Andalusian ß-thalassemia molecular portrait.

Genome-Wide Characterization of Arabian Peninsula Populations: Shedding Light on the History of a Fundamental Bridge between Continents.

The Arabian Peninsula (AP) was an important crossroad between Africa, Asia, and Europe, being the cradle of the structure defining these main human population groups, and a continuing path for their admixture. The screening of 741,000 variants in 420 Arabians and 80 Iranians allowed us to quantify the dominant sub-Saharan African admixture in the west of the peninsula, whereas South Asian and Levantine/European influence was stronger in the east, leading to a rift between western and eastern sides of the Peninsula. Dating of the admixture events indicated that Indian Ocean slave trade and Islamization periods were important moments in the genetic makeup of the region. The western-eastern axis was also observable in terms of positive selection of diversity conferring lactose tolerance, with the West AP developing local adaptation and the East AP acquiring the derived allele selected in European populations and existing in South Asia. African selected malaria resistance through the DARC gene was enriched in all Arabian genomes, especially in the western part. Clear European influences associated with skin and eye color were equally frequent across the Peninsula.

A different view on fine-scale population structure in Western African populations.

Due to its long genetic evolutionary history, Africans exhibit more genetic variation than any other population in the world. Their genetic diversity further lends itself to subdivisions of Africans into groups of individuals with a genetic similarity of varying degrees of granularity. It remains challenging to detect fine-scale structure in a computationally efficient and meaningful way. In this paper, we present a proof-of-concept of a novel fine-scale population structure detection tool with Western African samples. These samples consist of 1396 individuals from 25 ethnic groups (two groups are African American descendants). The strategy is based on a recently developed tool called IPCAPS. IPCAPS, or Iterative Pruning to CApture Population Structure, is a genetic divisive clustering strategy that enhances iterative pruning PCA, is robust to outliers and does not require a priori computation of haplotypes. Our strategy identified in total 12 groups and 6 groups were revealed as fine-scale structure detected in the samples from Cameroon, Gambia, Mali, Southwest USA, and Barbados. Our finding helped to explain evolutionary processes in the analyzed West African samples and raise awareness for fine-scale structure resolution when conducting genome-wide association and interaction studies.

The prognostic value of NRF2 in breast cancer patients: a systematic review with meta-analysis.

PURPOSE: Nuclear factor E2-related factor 2 (NRF2) is a transcription factor that plays a major role in the regulation of intracellular antioxidant response. The effect of NRF2 overexpression in many malignancies is still unclear and recent meta-analysis correlated NRF2 overexpression with poor prognosis in a variety of human cancers. However, the effect of NRF2 overexpression in breast cancer is still unclear. Thus, the main goal of this work was to clarify the role of NRF2 expression in survival and relapse of breast cancer patients by performing a systematic review according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement, followed by a meta-analysis. METHODS: The electronic search was conducted in PubMed, Scopus, SciELO, Web of Science and Embase between November of 2017 and September of 2018. To be included, studies should evaluate NRF2 expression in breast cancer tissue, through immunohistochemistry and/or mRNA and had to report one or more of the following outcomes: overall survival (OS), disease-free survival (DFS), mean survival and median survival. RESULTS: For the meta-analysis, seven studies were included and NRF2 expression was correlated with OS and DFS. It was observed that compared to patients with low NRF2 expression, patients with NRF2 overexpression had poorer OS with a hazard ratio of 1.82 (95% CI 1.32-2.50; p value < 0.0001), and poorer DFS, with a hazard ratio of 1.79 (95% CI 1.07-3.01; p value = 0.03). CONCLUSIONS: These results suggest that tumours that overexpress NRF2 have a worse clinical outcome. Thus, NRF2 expression could be a marker for the prognostic of breast cancer patients and, in the future, it would be pertinent to focus on improving treatment efficacy for patients with NRF2 overexpression.

Papuan mitochondrial genomes and the settlement of Sahul.

New Guineans represent one of the oldest locally continuous populations outside Africa, harboring among the greatest linguistic and genetic diversity on the planet. Archeological and genetic evidence suggest that their ancestors reached Sahul (present day New Guinea and Australia) by at least 55,000 years ago (kya). However, little is known about this early settlement phase or subsequent dispersal and population structuring over the subsequent period of time. Here we report 379 complete Papuan mitochondrial genomes from across Papua New Guinea, which allow us to reconstruct the phylogenetic and phylogeographic history of northern Sahul. Our results support the arrival of two groups of settlers in Sahul within the same broad time window (50-65 kya), each carrying a different set of maternal lineages and settling Northern and Southern Sahul separately. Strong geographic structure in northern Sahul remains visible today, indicating limited dispersal over time despite major climatic, cultural, and historical changes. However, following a period of isolation lasting nearly 20 ky after initial settlement, environmental changes postdating the Last Glacial Maximum stimulated diversification of mtDNA lineages and greater interactions within and beyond Northern Sahul, to Southern Sahul, Wallacea and beyond. Later, in the Holocene, populations from New Guinea, in contrast to those of Australia, participated in early interactions with incoming Asian populations from Island Southeast Asia and continuing into Oceania.