The effect of metabolism-related lifestyle and clinical risk factors on digestive system cancers in East Asian populations: a two-sample Mendelian randomization analysis.

Metabolic factors play a critical role in the development of digestive system cancers (DSCs), and East Asia has the highest incidence of malignant tumors in the digestive system. We performed a two-sample Mendelian randomization analysis to explore the associations between 19 metabolism-related lifestyle and clinical risk factors and DSCs, including esophageal, gastric, colorectal, hepatocellular, biliary tract, and pancreatic cancer. The causal association was explored for all combinations of each risk factor and each DSC. We gathered information on the instrumental variables (IVs) from various sources and retrieved outcome information from Biobank Japan (BBJ). The data were all from studies of east Asian populations. Finally, 17,572 DSCs cases and 195,745 controls were included. Our analysis found that genetically predicted alcohol drinking was a strong indicator of gastric cancer (odds ratio (OR) = 0.95; 95% confidence interval (CI): 0.93-0.98) and hepatocellular carcinoma (OR = 1.11; 95% CI: 1.05-1.18), whereas coffee consumption had a potential protective effect on hepatocellular carcinoma (OR = 0.69; 95% CI: 0.53-0.90). Triglyceride was potentially associated with a decreased risk of biliary tract cancer (OR = 0.53; 95% CI: 0.34-0.81), and uric acid was associated with pancreatic cancer risk (OR = 0.59; 95% CI: 0.37-0.96). Metabolic syndrome (MetS) was associated with esophageal and gastric cancer. Additionally, there was no evidence for a causal association between other risk factors, including body mass index, waist circumference, waist-to-hip ratio, educational levels, lipoprotein cholesterol, total cholesterol, glycine, creatinine, gout, and Graves' disease, and DSCs. The leave-one-out analysis revealed that the single nucleotide polymorphism (SNP) rs671 from the ALDH2 gene has a disproportionately high contribution to the causal association between alcohol drinking and gastric cancer and hepatocellular carcinoma, as well as the association between coffee consumption and hepatocellular carcinoma. The present study revealed multiple metabolism-related lifestyle and clinical risk factors and a valuable SNP rs671 for DSCs, highlighting the significance of metabolic factors in both the prevention and treatment of DSCs.

Plantago asiatica L. polysaccharides: Physiochemical properties, structural characteristics, biological activity and application prospects: A review.

Plantago asiatica L. (PAL), a traditional herb, has been used in East Asia for thousands of years. In recent years, polysaccharides extracted from PAL have garnered increased attention due to their outstanding pharmacological and biological properties. Previous research has established that PAL-derived polysaccharides exhibit antioxidant, anti-inflammatory, antidiabetic, antitumor, antimicrobial, immune-regulatory, intestinal health-promoting, antiviral, and other effects. Nevertheless, a comprehensive summary of the research related to Plantago asiatica L. polysaccharides (PALP) has not been reported to date. In this paper, we review the methods for isolation and purification, physiochemical properties, structural features, and biological activities of PALP. To provide a foundation for research and application in the fields of medicine and food, this review also outlines the future development prospects of plantain polysaccharides.

Distribution of Hydrocarbons in the Snow Cover of Natural and Urbanized Landscapes in the South of the Far East, Russia.

This study analyzed total organic carbon (TOC), petroleum products (PP), suspended materials (SM), volatile aromatic hydrocarbons (toluene, o-xylene, etc.) and n-alkanes in the snow cover of Bol'shekhekhtsirsky, Zeysky state natural reserves and Khabarovsk, on 4, 5 and 9 stations in the south of the Russian Far East in March 2020. In Bol'shekhekhtsirsky reserve, the concentrations of TOC, PP, and SM in snow samples were in the range of 1.5-2.4, 0.06-0.11, and 11.4-1.9 mg/L, 1.4-1.9, 0.02-0.05, and 11-23 mg/L in Zeysky reserve, while in Khabarovsk were 1.7-23.7, 0.12-1.26, and 25-294 mg/L, respectively. In addition, the benzene, toluene, and o-xylene concentrations of snow samples ranges from not detected (ND) to 2.4, ND-3.1, and 1.1-2.7 µg/L in Khabarovsk, ND-1.3, ND-2.1, and ND-2.7 µg/L, respectively in Bol'shekhekhtsirsky reserve. Carbon preference index values of n-alkanes were consistent with anthropogenic sources for stations 7, 8 and 2 in Khabarovsk (Heat Power Plants 1, 2 and city roads). The snow of the Zeysky Reserve is not contaminated with organic pollutants, and can be used as a conditional background for the south of the Russian Far East.

Pollen Molecular Identification from a Long-Distance Migratory Insect, Spodoptera exigua, as Evidenced for Its Regional Pollination in Eastern Asia.

Understanding plant-insect interactions requires the uncovering of the host plant use of insect herbivores, but such information is scarce for most taxa, including nocturnal moth species, despite their vital role as herbivores and pollinators. In this study, we determined the plant species visited by an important moth species, Spodoptera exigua, by analyzing attached pollen on migratory individuals in Northeast China. Pollen grains were dislodged from 2334 S. exigua long-distance migrants captured between 2019 and 2021 on a small island in the center of the Bohai Strait, which serves as a seasonal migration pathway for this pest species, and 16.1% of the tested moths exhibited pollen contamination, primarily on the proboscis. Subsequently, 33 taxa from at least 23 plant families and 29 genera were identified using a combination of DNA barcoding and pollen morphology, primarily from the Angiosperm, Dicotyledoneae. Moreover, the sex, inter-annual, and seasonal differences in pollen adherence ratio and pollen taxa were revealed. Notably, compared to previously reported pollen types found on several other nocturnal moths, we found that almost all of the above 33 pollen taxa can be found in multiple nocturnal moth species, providing another important example of conspecific attraction. Additionally, we also discussed the indicative significance of the pollen present on the bodies of migratory individuals for determining their migratory route. Overall, by delineating the adult feeding and pollination behavior of S. exigua, we advanced our understanding of the interactions of the moths with their host plants, and its migration pattern, as well as facilitated the design of (area-wide) management strategies to preserve and optimize ecosystem services that they provide.

The west meets the east - A need for a renaissance in brain, behavior, and immunity research.

Psychoneuroimmunology (PNI)-the burgeoning concept in recent years, can potentially contribute to developing effective treatments for mental health disorders. Despite the advancement in the modern pharmacological approach for mental disorders, especially Western medicine attributed explicitly to interacting with a specific target has given rise to unmet needs, and treatment failure has led to the proliferation and exploration of traditional and alternative therapies. As research into these exciting under-explored traditional treatment approaches continues to evolve at an unprecedented pace, the need to gain vital insights into the potentiality and mechanism of action in neuropsychiatric disorders has resulted in the current Special Issue. This Special Issue is devoted to psychoneuroimmunology, focusing on introducing the recent advances with traditional and alternative medications in East Asia at the interface of immunology, neurosciences, molecular psychiatry and behavioural medicine neurosciences.

Juglans mandshurica Maximowicz as a traditional medicine: review of its phytochemistry and pharmacological activity in East Asia.

OBJECTIVES: The conducted search reveals that Juglans mandshurica Maximowicz, called Manchuria walnuts, had many local uses that can be categorized into cancer, dermatosis and acesodyne. KEY FINDINGS: Various metabolites including diarylheptanoids, naphthoquinones, and flavonoids (also their glycosides) were reported as bioactive metabolites. The isolated metabolites and extracts from J. mandshurica showed different biological activity including cytotoxicity, anti-inflammation, antimelanotic, anticomplement, anti-HIV, antimicrobial and anti-obesity activity. SUMMARY: It is indicated that this review will add value to more scientific research on J. mandshurica and enhance the increased interest in the sustainable commercialization of J. mandshurica. It also leads to the validation of unverified ethnobotanical claims. Future studies on J. mandshurica would be focused to establish the links between the pharmacological activity, bioactive metabolites, and traditional uses.

The efficacy, effectiveness, and safety of Kyung-ok-ko: A narrative review.

Kyung-ok-ko (KOK), a traditional medicinal formula in East Asia, has been recently studied across various fields. However, comprehensive reviews of clinical applications of KOK targeting clinical and experimental studies are lacking. Therefore, the application of KOK is being limited to the range of tonic medicines. To overcome this limitation, we aim to investigate the effectiveness, mechanism, and safety of KOK to obtain evidence regarding its effects in clinical applications. We searched for clinical and experimental articles in 11 databases (PubMed, Cochrane Library, Excerpta Medica dataBASE, China National Knowledge Infrastructure, Google Scholar, Research Information Sharing Service, Oriental Medicine Advanced Searching Integrated System, Koreanstudies Information Service System, Korean Medical Database, DBpia, and ScienceON). We selected 54 studies based on the inclusion criteria. Three clinical studies used KOK for a consumptive disease and health promotion. Fifty-one experimental studies reported the antioxidant activity, neuroprotective activity, anticancer effect, anti-inflammatory activity, immunological activity, growth promotion, impacts on cardiovascular system diseases, gastrointestinal system diseases, respiratory system diseases, and metabolic bone disease, hepatoprotective function, and antifatigue function of KOK, which were considered effective and safe in consumptive, chronic, metabolic, inflammatory, and immune diseases. We identified the effectiveness of KOK in the treatment of a wide range of diseases. However, further clinical studies are warranted in the future.

Health awareness and skilled birth attendance: An assessment of sustainable development goal 3.1 in south and south-east Asia.

BACKGROUND: The United Nation's Sustainable Development Goal 3.1 aims to reduce maternal mortality worldwide to 70 per 100,000 live births by 2030, which requires greater skilled birth attendant (SBA) coverage and increased health awareness. By evaluating relevant sociodemographic factors, this study aimed to identify different groups of women who lack health awareness and access to SBA services in eight selected low-and-middle-income countries (LMICs) of South and South-East Asia (SSEA), namely, Afghanistan, India, Indonesia, Myanmar, Nepal, Pakistan, Philippines, and Timor-Leste. METHODS: Nationally representative Demographic and Health Surveys (DHS) on women aged 15-49 years were analysed with a pooled sample of 95,521. Complex survey-adjusted logistic regression models were fitted to assess sociodemographic factors, SBA coverage, and health awareness. RESULTS: Women with higher health awareness were 44.4% (95% CI:1.32-1.58, p<0.001) more likely to access SBAs compared to the rest. Women and/or their partners with no or primary-level education, who were poorer, became young mothers (≤20 years), not involved in decision-making, or hardly exposed to media were less likely to seek SBAs and have higher health awareness. Women in rural areas with more children were also less likely to use SBAs. Timor-Leste, Afghanistan, Myanmar, and Nepal underperformed on SBA coverage amongst the selected LMICs of the SSEA region. CONCLUSION: Health education and mass-media-driven awareness could be an interventional avenue for LMICs to increase SBA coverage. Future studies comparing health policies within the SSEA region are required to identify reasons behind some nations' underperformance, while others are on track to achieve SDG 3.1.

Acupoint herbal patching for bronchitis: A systematic review and meta-analysis.

BACKGROUND: Acupoint herbal patching (AHP) has long been used to treat patients with bronchitis in East Asia. This review assessed the efficacy and safety of AHP as a treatment for bronchitis. METHODS: We performed a literature search using the 9 databases and included randomized controlled trials (RCTs) or quasi-RCTs that used AHP for bronchitis. The methodological quality of each RCT was assessed using the Cochrane Handbook version 5.3, the risk of bias tool, and Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Seven RCTs were included based on the inclusion criteria. All RCTs were published in China and had a high risk of bias. Three RCTs compared AHP with conventional drug therapy for the treatment of bronchitis. The meta-analysis also showed a significant improvement in treatment effectiveness (relative risk [RR] 1.28, 95% confidence interval [CI] 1.15, 1.42; P < .00001; I2 = 0%). Two RCTs investigated AHP combined with conventional drug therapy versus conventional drug therapy. The meta-analysis showed that AHP was significantly more effective than conventional therapy in terms of treatment effective rate (RR 1.16, 95% CI 1.03, 1.29; P = .01; I2 = 0%). Three RCTs reported adverse events, and none reported severe adverse events. CONCLUSIONS: AHP appears to be more effective than conventional drug therapy alone or a placebo. Furthermore, the AHP appears to be a safe treatment option. However, due to the small number of included trials and their poor methodological quality, future studies should include larger sample sizes and well-designed RCTs. TRIAL REGISTRATION NUMBER: PROSPERO: CRD 42018110380.

Effects of Dietary Iron Quantities and Sources on Lymantria dispar (Lepidoptera: Erebidae) Survival and Development.

Lymantria dispar L. is a serious invasive defoliator of broadleaf trees in both North America and Eurasia. When rearing L. dispar for research, the artificial diet must have a source of iron that is bioavailable and in the quantity needed to ensure normal development and survival. The standard iron supplement in L. dispar diet, amorphous ferric phosphate, is no longer commercially available, which motivated studies on alternative iron sources and concentrations. The responses of three L. dispar populations (including an L. dispar asiatica Vnukovskij population) to seven different iron doses were determined over two generations. The response to eight iron compounds and no added iron was also assessed over two generations for an L. dispar dispar population. The optimal levels of iron were 100, 150, and 198 mg/l of available iron for the New Jersey Standard Strain, a near-wild West Virginia population, and a near-wild Russian Far East population, respectively. All three populations showed symptoms of insufficient iron when reared on the lowest dose of iron and signs of excess iron at the highest two doses. All of the alternate iron sources evaluated provided adequate available iron, although three sources had some issues that may not make them the best options. These results reveal differences in nutritional requirements among different populations of L. dispar and verify the existence of viable replacement sources of iron for the standard amorphous ferric phosphate long used in L. dispar rearing.

A network pharmacology-based approach to explore mechanism of action of medicinal herbs for alopecia treatment.

Hair loss is one of the most common skin problems experienced by more than half of the world's population. In East Asia, medicinal herbs have been used widely in clinical practice to treat hair loss. Recent studies, including systematic literature reviews, indicate that medicinal herbs may demonstrate potential effects for hair loss treatment. In a previous study, we identified medical herbs used frequently for alopecia treatment. Herein, we explored the potential novel therapeutic mechanisms of 20 vital medicinal herbs for alopecia treatment that could distinguish them from known mechanisms of conventional drugs using network pharmacology analysis methods. We determined the herb-ingredient-target protein networks and ingredient-associated protein (gene)-associated pathway networks and calculated the weighted degree centrality to define the strength of the connections. Data showed that 20 vital medicinal herbs could exert therapeutic effects on alopecia mainly mediated via regulation of various target genes and proteins, including acetylcholinesterase (AChE), phospholipase A2 (PLA2) subtypes, ecto-5-nucleotidase (NTE5), folate receptor (FR), nicotinamide N-methyltransferase (NNMT), and quinolinate phosphoribosyltransferase (QPRT). Findings regarding target genes/proteins and pathways of medicinal herbs associated with alopecia treatment offer insights for further research to better understand the pathogenesis and therapeutic mechanism of medicinal herbs for alopecia treatment with traditional herbal medicine.

Regulating food labels in East Asia: A tale of two systems: Commentary on Negowetti et al. (2021).

The traditional role of food in promoting health and preventing illness is integral to many Asian cultures. This commentary provides a brief overview of health-related food products regulation in Asia. We cover regulations initiated to promote health and prevent chronic diseases and regulations of traditional medicine food products. We focus on specific regulations in Japan and Singapore that encourage the consumption of certain foods to promote population health and prevent chronic diseases. We also examine the complexity and difficulty of regulating traditional medicine food products in Malaysia and Singapore, where these products are important not just for health but also in promoting cultural traditions.

Facilitators of and barriers to providing high-quality midwifery education in South-East Asia-An integrative review.

BACKGROUND: With a diversity in midwifery education across the South-East Asia region, and with the knowledge about the lifesaving competency of the midwife profession, this study's aim is to describe facilitators of and barriers to providing high-quality midwifery education in South-East Asia. METHODS: Inspired by Whittemore and Knafl, we conducted a systematic integrative literature review including the five key stages of problem identification, literature search, data evaluation, data analysis, and presentation of results. The literature searches were conducted in October 2020 in the databases CINAHL, PubMed, and Scopus. A deductive data analysis based on global standards was performed. RESULTS: The search identified 1257 articles, 34 of which were included. Countries in South-East Asia did not fully comply with the ICM global standards. Midwifery education was not separated from that of nursing, and educators lacked formal qualifications in midwifery. Curriculum implementation in the clinical area was a key barrier to achieving learning outcomes. Higher academic education for midwifery educators and mentorship programs facilitated the pedagogic and assessment process, focusing on the abilities of critical thinking, reflection, and decision-making. CONCLUSIONS: Countries in South-East Asia still have a long way to go before they can provide high-quality midwifery education. The identified facilitators can lead to a difference in students' academic achievement and confidence in their clinical work. Coordinated actions will enable the progress in achieving competent midwives matching national health priorities. The findings highlight a need for more research on midwifery education in both theory and practice across the region.

Redefining health promotion to reach the unreached: opportunities for transformative change in South and South-East Asia.

The pandemic has exposed the vulnerability of our civilization and reinforced the importance of living in harmony with nature, not rampaging it in a conquering mode. South and South-East Asia have a vital role to play in achieving the global goal of 'Health for All' as the regions have a significantly large share of global income and multidimensional poor compared to other regions. Clearly, the progress in health and development outcomes of these regions cannot be achieved without addressing social determinants of health and ensuring active public participation. These regions must collectively address the social determinants of health following a realistic health promotion model. It is indeed a favourable time to look beyond the so-called predominantly reductionist biomedical model of health care to a more holistic model of health, that places humans and the environment at the centre, and emphasizes the importance of promoting health and wellbeing.

Phytoconstituents and Bioactivity of Plants of the Genus Spiraea L. (Rosaceae): A Review.

The genus Spiraea L. belongs to the Rosaceae Juss. family and includes more than 100 species distributed in the temperate zone and subtropical zone of the Northern Hemisphere at the center of species diversity in East Asia. Representatives of the genus are known as ornamental plants with many forms and varieties, are widely used in conventional medicine, and have a high resource potential. This review provides information on the diversity of phenolic compounds (flavonoids, phenolcarboxylic acids, and lignans), terpenoids, alkaloids, steroids, and other classes of secondary metabolites in the species of Spiraea worldwide. The article also presents little-known and hard-to-find data published in Russian concerning Spiraea phytochemistry. The biological activities of extracts and their fractions and of individual compounds having different types of biological activity (e.g., antioxidant, antibacterial, anti-inflammatory, and antifungal) are discussed. Data about biotechnological research on representatives of the genus Spiraea are presented too. The analysis of the literature showed that further chemical and pharmacological studies on Spiraea plants are quite promising.

What's the choice for goji: Lycium barbarum L. or L. chinense Mill.?

ETHNOPHARMACOLOGICAL RELEVANCE: For over one millennium, goji berries have been used traditionally as food and medicine in eastern Asia. In recent decades, it has become increasingly popular globally. However, the biocultural development of goji is poorly known. The botanical origin of goji is controversial: in many but not all modern regional or international quality standards, L. barbarum is accepted exclusively as the botanical origin of goji. AIM OF THE STUDY: Focusing on historical, biogeographical, botanical, phytochemical and pharmacological data, the overarching aim is to understand the biological origin of goji's historical uses, as well as whether the two species can be used interchangeably. MATERIALS AND METHODS: The taxonomic literature on L. barbarum and L. chinense were analysed, followed by a study of botanical specimens and fieldwork. Historical herbals and gazetteers were employed to define the historical producing areas and medical properties of goji. An identification of the species used in history was carried out. In a final step the phytochemical and pharmacological literature on the species was compared. RESULTS AND DISCUSSION: Due to their morphological similarity and different accessibility, fruits of both L. barbarum and L. chinense have been used interchangeably as food and medicine at least since 682 CE. While the fruit of L. barbarum was recognized to be superior in quality, the fruit of L. chinense was commonly used as an equivalent because of its easier accessibility. Cultivation of L. barbarum in China since 1960s improved its availability, which likely lead to its exclusive use as source of goji in China. The long-term safe use with no reported major safety concerns supports that these two species both are useful sources for medicinal Lycium. CONCLUSIONS: Medicinal plants had been used traditionally long before they were named in scientific nomenclature system. Therefore, the understanding of traditional herbal knowledge and the adequate use of those traditional medicines require a reliable identification based on archival records. This study developed an approach for the identification of species used historically, with an integrated analysis of specimens, historical herbals, and national gazetteers. Additionally, their different chemical profiles and pharmacological activities indicate that they should not be used interchangeably. Further scientific evidence is required for their safe and effective use.

Origin of ethnic groups, linguistic families, and civilizations in China viewed from the Y chromosome.

East Asia, geographically extending to the Pamir Plateau in the west, to the Himalayan Mountains in the southwest, to Lake Baikal in the north and to the South China Sea in the south, harbors a variety of people, cultures, and languages. To reconstruct the natural history of East Asians is a mission of multiple disciplines, including genetics, archaeology, linguistics, and ethnology. Geneticists confirm the recent African origin of modern East Asians. Anatomically modern humans arose in Africa and immigrated into East Asia via a southern route approximately 50,000 years ago. Following the end of the Last Glacial Maximum approximately 12,000 years ago, rice and millet were domesticated in the south and north of East Asia, respectively, which allowed human populations to expand and linguistic families and ethnic groups to develop. These Neolithic populations produced a strong relation between the present genetic structures and linguistic families. The expansion of the Hongshan people from northeastern China relocated most of the ethnic populations on a large scale approximately 5300 years ago. Most of the ethnic groups migrated to remote regions, producing genetic structure differences between the edge and center of East Asia. In central China, pronounced population admixture occurred and accelerated over time, which subsequently formed the Han Chinese population and eventually the Chinese civilization. Population migration between the north and the south throughout history has left a smooth gradient in north-south changes in genetic structure. Observation of the process of shaping the genetic structure of East Asians may help in understanding the global natural history of modern humans.

Cost-Effectiveness of Interventions to Improve Maternal, Newborn and Child Health Outcomes: A WHO-CHOICE Analysis for Eastern Sub-Saharan Africa and South-East Asia.

BACKGROUND: Information on cost-effectiveness allows policy-makers to evaluate if they are using currently available resources effectively and efficiently. Our objective is to examine the cost-effectiveness of health interventions to improve maternal, newborn and child health (MNCH) outcomes, to provide global evidence relative to the context of two geographic regions. METHODS: We consider interventions across the life course from adolescence to pregnancy and for children up to 5 years old. Interventions included are those that fall within the areas of immunization, child healthcare, nutrition, reproductive health, and maternal/newborn health, and for which it is possible to model impact on MNCH mortality outcomes using the Lives Saved Tool (LiST). Generalized cost-effectiveness analysis (GCEA) was used to derive average cost-effectiveness ratios (ACERs) for individual interventions and combinations (packages). Costs were assessed from the health system perspective and reported in international dollars. Health outcomes were estimated and reported as the gain in healthy life years (HLYs) due to the specific intervention or combination. The model was run for 2 regions: Eastern sub-Saharan Africa (SSA-E) and South-East Asia (SEA). RESULTS: The World Health Organization (WHO) recommended interventions to improve MNCH are generally considered cost-effective, with the majority of interventions demonstrating ACERs below I$100/HLY saved in the chosen settings (low-and middle-income countries [LMICs]). Best performing interventions are consistent across the two regions, and include family planning, neonatal resuscitation, management of pneumonia and neonatal infection, vitamin A supplementation, and measles vaccine. ACERs below I$100 can be found across all delivery platforms, from community to hospital level. The combination of interventions into packages (such as antenatal care) produces favorable ACERs. CONCLUSION: Within each region there are interventions which represent very good value for money. There are opportunities to gear investments towards high-impact interventions and packages for MNCH outcomes. Cost-effectiveness tools can be used at national level to inform investment cases and overall priority setting processes.

Genomic insights into population history and biological adaptation in Oceania.

The Pacific region is of major importance for addressing questions regarding human dispersals, interactions with archaic hominins and natural selection processes1. However, the demographic and adaptive history of Oceanian populations remains largely uncharacterized. Here we report high-coverage genomes of 317 individuals from 20 populations from the Pacific region. We find that the ancestors of Papuan-related ('Near Oceanian') groups underwent a strong bottleneck before the settlement of the region, and separated around 20,000-40,000 years ago. We infer that the East Asian ancestors of Pacific populations may have diverged from Taiwanese Indigenous peoples before the Neolithic expansion, which is thought to have started from Taiwan around 5,000 years ago2-4. Additionally, this dispersal was not followed by an immediate, single admixture event with Near Oceanian populations, but involved recurrent episodes of genetic interactions. Our analyses reveal marked differences in the proportion and nature of Denisovan heritage among Pacific groups, suggesting that independent interbreeding with highly structured archaic populations occurred. Furthermore, whereas introgression of Neanderthal genetic information facilitated the adaptation of modern humans related to multiple phenotypes (for example, metabolism, pigmentation and neuronal development), Denisovan introgression was primarily beneficial for immune-related functions. Finally, we report evidence of selective sweeps and polygenic adaptation associated with pathogen exposure and lipid metabolism in the Pacific region, increasing our understanding of the mechanisms of biological adaptation to island environments.

Initial Upper Palaeolithic humans in Europe had recent Neanderthal ancestry.

Modern humans appeared in Europe by at least 45,000 years ago1-5, but the extent of their interactions with Neanderthals, who disappeared by about 40,000 years ago6, and their relationship to the broader expansion of modern humans outside Africa are poorly understood. Here we present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria1,2. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artefact assemblage. Unlike two previously studied individuals of similar ages from Romania7 and Siberia8 who did not contribute detectably to later populations, these individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, we find that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common.