The clinical features and potential mechanisms of cognitive disorders in peripheral autoimmune and inflammatory diseases.

According to a study from World Health Organization's Global Burden of Disease, mental and neurological disorders have accounted for 13% of global diseases in recent years and are on the rise. Neuropsychiatric conditions or neuroinflammatory disorders are linked by the presence of an exaggerated immune response both peripherally and in the central nervous system (CNS). Cognitive dysfunction (CD) encompasses a complex group of diseases and has frequently been described in the field of autoimmune diseases, especially in multiple non-CNS-related autoimmune diseases. Recent studies have provided various hypotheses regarding the occurrence of cognitive impairment in autoimmune diseases, including that abnormally activated immune cells can disrupt the integrity of the blood-brain barrier (BBB) to trigger a central neuroinflammatory response. When the BBB is intact, autoantibodies and pro-inflammatory molecules in peripheral circulation can enter the brain to activate microglia, inducing CNS inflammation and CD. However, the mechanisms explaining the association between the immune system and neural function and their contribution to diseases are uncertain. In this review, we used clinical statistics to illustrate the correlation between CD and autoimmune diseases that do not directly affect the CNS, summarized the clinical features and mechanisms by which autoimmune diseases trigger cognitive impairment, and explored existing knowledge regarding the link between CD and autoimmune diseases from the perspective of the field of neuroimmunology.

Molecular Characterization of an Isolate of Bean Common Mosaic Virus First Identified in Gardenia Using Metatranscriptome and Small RNA Sequencing.

Gardenia (Gardenia jasminoides) is a popular and economically vital plant known for its ornamental and medicinal properties. Despite its widespread cultivation, there has been no documentation of plant viruses on gardenia yet. In the present study, gardenia leaves exhibiting symptoms of plant viral diseases were sampled and sequenced by both metatranscriptome and small RNA sequencing. As a consequence, bean common mosaic virus (BCMV) was identified in gardenia for the first time and named BCMV-gardenia. The full genome sequence of BCMV-gardenia is 10,054 nucleotides (nt) in length (excluding the poly (A) at the 3' termini), encoding a large polyprotein of 3,222 amino acids. Sequence analysis showed that the N-termini of the polyprotein encoded by BCMV-gardenia is less conserved when compared to other BCMV isolates, whereas the C-termini is the most conserved. Maximum likelihood phylogenetic analysis showed that BCMV-gardenia was clustered closely with other BCMV isolates identified outside the leguminous plants. Our results indicated that the majority of BCMV-gardenia virus-derived small interfering RNAs (vsiRNAs) were 21 nt and 22 nt, with 21 nt being more abundant. The first nucleotide at the 5' termini of vsiRNAs derived from BCMV-gardenia preferred U and A. The ratio of vsiRNAs derived from sense (51.1%) and antisense (48.9%) strands is approaching, and the distribution of vsiRNAs along the viral genome is generally even, with some hot spots forming in local regions. Our findings could provide new insights into the diversity, evolution, and host expansion of BCMV and contribute to the prevention and treatment of this virus.

Complete genome sequence of a novel robigovirus infecting Mentha arvensis.

The complete genomic sequence of a novel robigovirus, provisionally named "Mentha arvensis robigovirus 1" (MARV1), was determined by combining next-generation sequencing (NGS), reverse transcription polymerase chain reaction (RT-PCR), and rapid amplification of cDNA ends (RACE) PCR. The complete genomic sequence of this new virus is 7617 nucleotides in length, excluding the 3' poly(A) tail. The MARV1 genome encodes a putative replicase, "triple gene block" proteins, and a coat protein. Phylogenetic analysis demonstrated that MARV1 is a member of the genus Robigovirus, with closest relationships to African oil palm ringspot virus (AOPRV). Furthermore, MARV1-derived small interfering RNAs (siRNAs) showed typical patterns of plant-virus-derived siRNAs produced by the host antiviral RNA interference pathway. This is the first report of a plant virus of the genus Robigovirus in M. arvensis.

The outcomes of aortic arch repair between open surgical repair and debranching endovascular hybrid surgical repair: A systematic review and meta-analysis.

BACKGROUND: At present, open surgical aortic arch repair (OAR) and debranching hybrid surgical aortic arch repair (HAR) serve as significant therapeutic approaches for aortic arch aneurysm or dissection. It remains unclear which technique is preferable. Our study aimed to compare the short-term and long-term outcomes of these two procedures. METHODS: To identify comparison studies of debranching HAR and OAR, a systematic search of the PubMed, Embase, Web of Science, and Cochrane Library databases was performed from January 2002 to April 2022. This study was registered on PROSPERO (CRD42020218080). RESULTS: Sixteen publications (1316 patients), including six propensity score-matching (PSM) analysis papers, were included in this study. Compared with the HAR group, the patients who underwent OAR were younger (OAR vs HAR: 67.53 ± 12.81 vs 71.29 ± 11.0; P < .00001), had less coronary artery disease (OAR vs HAR: 22.45% vs 32.6%; P = .007), less chronic obstructive pulmonary disease (OAR vs HAR: 16.16% vs 23.92%; P = .001), lower rates of previous stroke (OAR vs HAR: 12.46% vs 18.02%; P = .05), and a lower EuroSCORE (European System for Cardiac Operative Risk Evaluation) score (OAR vs HAR: 6.27 ± 1.04 vs 6.9 ± 3.76; P < .00001). HAR was associated with less postoperative blood transfusion (OAR vs HAR: 12.23% vs 7.91%; P = .04), shorter length of intensive care unit stays (OAR vs HAR: 5.92 ± 7.58 days vs 4.02 ± 6.60 days; P < .00001) and hospital stays (OAR vs HAR: 21.59 ± 17.54 days vs 16.49 ± 18.45 days; P < .0001), lower incidence of reoperation for bleeding complications (OAR vs HAR: 8.07% vs 3.96%; P = .01), fewer postoperative pulmonary complication (OAR vs HAR: 14.75% vs 5.02%; P < .0001), and acute renal failure (OAR vs HAR: 7.54% vs 5.17%; P = .03). In the PSM subgroup, the rates of spinal cord ischemic (OAR vs HAR: 5.75% vs 11.49%; P = .02), stroke (OAR vs HAR: 5.1% vs 17.35%; P = .01), and permanent paraplegia (OAR vs HAR: 2.79% vs 6.08%; P = .006) were lower in the OAR group than that in the HAR group. Although there was no statistically significant difference in 1-year survival rates (HAR vs OAR: hazard ratio [HR]: 1.54; P = .10), the 3-year and 5-year survivals were significantly higher in the OAR group than that in the HAR group (HAR vs OAR: HR: 1.69; P = .01; HAR vs OAR: HR: 1.68; P = .01). In the PSM subgroup, the OAR group was also significantly superior to the HAR group in terms of 3-year and 5-year survivals (HAR vs OAR: HR: 1.73; P = .04; HAR vs OAR: HR: 1.67; P = .04). The reintervention rate in the HAR group was significantly higher than that in the OAR group (OAR vs HAR: 8.24% vs 16.01%; P = .01). The most common reintervention was postoperative bleeding (8.07%) in the OAR group and endoleak (9.67%) in the HAR group. CONCLUSIONS: Our meta-analysis revealed that debranching HAR was associated with fewer perioperative complications than the OAR group, except for postoperative permanent paraplegia, reintervention, and stroke events. The OAR group demonstrated better 3-year and 5-year survivals than the debranching HAR group. However, patients in the OAR group had fewer comorbid factors and were younger than those in the HAR group. High-quality studies and well-powered randomized trials are needed to further evaluate this evolving field.

Co-option of a non-retroviral endogenous viral element in planthoppers.

Non-retroviral endogenous viral elements (nrEVEs) are widely dispersed throughout the genomes of eukaryotes. Although nrEVEs are known to be involved in host antiviral immunity, it remains an open question whether they can be domesticated as functional proteins to serve cellular innovations in arthropods. In this study, we found that endogenous toti-like viral elements (ToEVEs) are ubiquitously integrated into the genomes of three planthopper species, with highly variable distributions and polymorphism levels in planthopper populations. Three ToEVEs display exon‒intron structures and active transcription, suggesting that they might have been domesticated by planthoppers. CRISPR/Cas9 experiments revealed that one ToEVE in Nilaparvata lugens, NlToEVE14, has been co-opted by its host and plays essential roles in planthopper development and fecundity. Large-scale analysis of ToEVEs in arthropod genomes indicated that the number of arthropod nrEVEs is currently underestimated and that they may contribute to the functional diversity of arthropod genes.

XAF1 prevents hyperproduction of type I interferon upon viral infection by targeting IRF7.

Interferon regulatory factor (IRF) 3 and IRF7 are master regulators of type I interferon (IFN-I)-dependent antiviral innate immunity. Upon viral infection, a positive feedback loop is formed, wherein IRF7 promotes further induction of IFN-I in the later stage. Thus, it is critical to maintain a suitably low level of IRF7 to avoid the hyperproduction of IFN-I. In this study, we find that early expression of IFN-I-dependent STAT1 promotes the expression of XAF1 and that XAF1 is associated specifically with IRF7 and inhibits the activity of XIAP. XAF1-knockout and XIAP-transgenic mice display resistance to viral infection, and this resistance is accompanied by increases in IFN-I production and IRF7 stability. Mechanistically, we find that the XAF1-XIAP axis controls the activity of KLHL22, an adaptor of the BTB-CUL3-RBX1 E3 ligase complex through a ubiquitin-dependent pathway. CUL3-KLHL22 directly targets IRF7 and catalyzes its K48-linked ubiquitination and proteasomal degradation. These findings reveal unexpected functions of the XAF1-XIAP axis and KLHL22 in the regulation of IRF7 stability and highlight an important target for antiviral innate immunity.

[Single-Center Experience of Treating Chronic Limb-Threatening Ischemia of Lower Limbs Combined with Diabetes].

Objective: To summarize our hospital's single-center experience of and reflections on the treatment of chronic limb-threatening ischemia (CLTI) of lower limbs combined with diabetes in the past 5 years. Methods: We retrospectively analyzed cases of lower limb CLTI combined with diabetes diagnosed at our hospital from March 2017 to June 2021. The baseline data, surgical information, and follow-up results of the patients were collected. The primary outcome indicator was the patency rate of lower limb target artery within 1 year post-op, and the secondary indicators were the reoperation rate within 1 year post-op and the amputation rate within 1 year post-op. Results: A total of 89 patients with lower limb CLTI combined with diabetes were included in the study. A total of 85 patients underwent percutaneous transluminal angioplasty and the operation of 7 patients ended in failure, with the operation success rate reaching 91.76% (78/85). Three patients underwent femoral popliteal artery bypass grafting with artificial blood vessels and one patient underwent iliac femoral artery bypass grafting with artificial blood vessels, with the success rate of the operations reachign 100% (4/4). Among 78 patients who successfully underwent percutaneous transluminal angioplasty, the median follow-up time was 33 months (13, 64). Two patients died within one year after operation, with the post-op one-year survival rate being 97.44% (76/78). The post-op 1-year reoperation rate was 19.23% (15/78), the 1-year target vascular patency rate (deaths not included) was 85.53% (65/76), and the 1-year amputation rate was 3.85% (3/78). Among the patients who underwent bypass surgery, the follow-up period was 13-48 months. No thrombosis in or re-occlusion of the artificial blood vessels were observed during the follow-up period, and the artificial blood vessels remained unoccluded. Conclusion: Transluminal angioplasty has a relatively ideal rate of postoperative vascular patency. In addition, it is a minimally invasive procedure involving low perioperative risks and is performed under local anesthesia. Therefore, it can be used as the preferred treatment for patients with CLTI. On the other hand, bypass surgery has good long-term patency rate, but it involves higher perioperative risks and the procedure is more invasive. Therefore, bypass surgery can be used as an alternative when transluminal angioplasty ends in failure.

Influence of different fluid environments on tactile perception and finger friction.

Human beings often explore and perceive the characteristics of objects by touching with their fingers. During this process, the contact pressure and shear stress acting on the skin also modulate the tactile sensation. The external environment is an important factor that influences tactile perception as well as the finger friction characteristics. The purpose of this study was to investigate the effects of fluid environments, such as air, deionized water (DW) and thickened water (TW), on perceived roughness and relevant friction behaviour during finger movement. Two studies were performed to analyse the effect of fluid environment as well as the influence of lubricant viscosity on finger tactile friction behaviour. Participants conducted perception and sliding friction tests with their index finger in air and submerged in DW and TW, respectively. Perception tests were performed using a pairwise comparison, scoring the perceived roughness difference between a reference sample and the test sample. The statistical analysis showed that there was no significant difference in the roughness perception between air and DW, while the sensitivity of perception reduced with increasing lubricant viscosity. An approximate calculation of the film thickness was combined with classical lubrication theory to investigate the relationship between perception and friction. In TW, the thick film formed between the finger and the polytetrafluoroethylene plate changed the contact of the asperities with the skin, thus changing the subjective judgement and friction.

Multiomics analyses reveal a critical role of selenium in controlling T cell differentiation in Crohn's disease.

Inflammatory bowel disease (IBD) mainly includes Crohn's disease (CD) and ulcerative colitis (UC). Immune disorders play an essential role in the pathogenesis of these two IBDs, but the differences in the immune microenvironment of the colon and their underlying mechanisms remain poorly investigated. Here we examined the immunological features and metabolic microenvironment of untreated individuals with IBD by multiomics analyses. Modulation of CD-specific metabolites, particularly reduced selenium, can obviously shape type 1 T helper (Th1) cell differentiation, which is specifically enriched in CD. Selenium supplementation suppressed the symptoms and onset of CD and Th1 cell differentiation via selenoprotein W (SELW)-mediated cellular reactive oxygen species scavenging. SELW promoted purine salvage pathways and inhibited one-carbon metabolism by recruiting an E3 ubiquitin ligase, tripartite motif-containing protein 21, which controlled the stability of serine hydroxymethyltransferase 2. Our work highlights selenium as an essential regulator of T cell responses and potential therapeutic targets in CD.

Substrate-specific recognition of IKKs mediated by USP16 facilitates autoimmune inflammation.

The classic NF-κB pathway plays crucial roles in various immune responses and inflammatory diseases. Its key kinase, IKKß, participates in a variety of pathological and physiological processes by selectively recognizing its downstream substrates, including p105, p65, and IκBα, but the specific mechanisms of these substrates are unclear. Hyperactivation of one of the substrates, p105, is closely related to the onset of inflammatory bowel disease (IBD) in Nfkb1-deficient mice. In this study, we found that IKKß ubiquitination on lysine-238 was substantially increased during inflammation. Using mass spectrometry, we identified USP16 as an essential regulator of the IKKß ubiquitination level that selectively affected p105 phosphorylation without directly affecting p65 or IκBα phosphorylation. Furthermore, USP16 was highly expressed in colon macrophages in patients with IBD, and myeloid-conditional USP16-knockout mice exhibited reduced IBD severity. Our study provides a new theoretical basis for IBD pathogenesis and targeted precision intervention therapy.

A double-edged sword of immuno-microenvironment in cardiac homeostasis and injury repair.

The response of immune cells in cardiac injury is divided into three continuous phases: inflammation, proliferation and maturation. The kinetics of the inflammatory and proliferation phases directly influence the tissue repair. In cardiac homeostasis, cardiac tissue resident macrophages (cTMs) phagocytose bacteria and apoptotic cells. Meanwhile, NK cells prevent the maturation and transport of inflammatory cells. After cardiac injury, cTMs phagocytose the dead cardiomyocytes (CMs), regulate the proliferation and angiogenesis of cardiac progenitor cells. NK cells prevent the cardiac fibrosis, and promote vascularization and angiogenesis. Type 1 macrophages trigger the cardioprotective responses and promote tissue fibrosis in the early stage. Reversely, type 2 macrophages promote cardiac remodeling and angiogenesis in the late stage. Circulating macrophages and neutrophils firstly lead to chronic inflammation by secreting proinflammatory cytokines, and then release anti-inflammatory cytokines and growth factors, which regulate cardiac remodeling. In this process, dendritic cells (DCs) mediate the regulation of monocyte and macrophage recruitment. Recruited eosinophils and Mast cells (MCs) release some mediators which contribute to coronary vasoconstriction, leukocyte recruitment, formation of new blood vessels, scar formation. In adaptive immunity, effector T cells, especially Th17 cells, lead to the pathogenesis of cardiac fibrosis, including the distal fibrosis and scar formation. CMs protectors, Treg cells, inhibit reduce the inflammatory response, then directly trigger the regeneration of local progenitor cell via IL-10. B cells reduce myocardial injury by preserving cardiac function during the resolution of inflammation.

Single-nucleotide methylation specifically represses type I interferon in antiviral innate immunity.

Frequent outbreaks of viruses have caused a serious threat to public health. Previous evidence has revealed that DNA methylation is correlated with viral infections, but its role in innate immunity remains poorly investigated. Additionally, DNA methylation inhibitors promote IFN-I by upregulating endogenous retrovirus; however, studies of intrinsically demethylated tumors do not support this conclusion. This study found that Uhrf1 deficiency in myeloid cells significantly upregulated Ifnb expression, increasing resistance to viral infection. We performed whole-genome bisulfite sequencing and found that a single-nucleotide methylation site in the Ifnb promoter region disrupted IRF3 recruitment. We used site-specific mutant knock-in mice and a region-specific demethylation tool to confirm that this methylated site plays a critical role in regulating Ifnb expression and antiviral responses. These findings provide essential insight into DNA methylation in the regulation of the innate antiviral immune response.

Ubiquitination modification: critical regulation of IRF family stability and activity.

Interferon regulatory factors (IRFs) play pivotal and critical roles in innate and adaptive immune responses; thus, precise and stringent regulation of the stability and activation of IRFs in physiological processes is necessary. The stability and activities of IRFs are directly or indirectly targeted by endogenous and exogenous proteins in an ubiquitin-dependent manner. However, few reviews have summarized how host E3 ligases/DUBs or viral proteins regulate IRF stability and activity. Additionally, with recent technological developments, details about the ubiquitination of IRFs have been continuously revealed. As knowledge of how these proteins function and interact with IRFs may facilitate a better understanding of the regulation of IRFs in immune responses or other biological processes, we summarized current studies on the direct ubiquitination of IRFs, with an emphasis on how these proteins interact with IRFs and affect their activities, which may provide exciting targets for drug development by regulating the functions of specific E3 ligases.

The essential functions of mitochondrial dynamics in immune cells.

Mitochondria are highly mobile organelles due to fission, fusion, transport, and mitophagy, and these processes are known as mitochondrial dynamics. Mitochondrial dynamics play an important role in energy production, cell division, cell differentiation, and cell death. In the past decade, numerous studies have revealed the importance of mitochondrial metabolism in immunity, and mitochondrial dynamics are essential for immune responses mediated by various cell types. In this review, we mainly discuss the role of mitochondrial dynamics in activation, differentiation, cytokine production, and the activity of related pathways in immune cells, particularly T cells, B cells, and other cells involved in the innate immune response.

Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior.

Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.

A methodology for identifying optimum vibration absorbers with a reaction mass.

Tuned mass dampers (TMDs), in which a reaction mass is attached to a structural system via a spring-parallel-damper connection, are commonly used in a wide range of applications to suppress deleterious vibrations. Recently, a mass-included absorber layout with an inerter element, termed the tuned mass damper inerter (TMDI), was introduced, showing significant performance benefits on vibration suppression. However, there are countless mass-included absorber layouts with springs, dampers and inerters, which could potentially provide more preferred dynamic properties. Currently, because there is no systematic methodology for accessing them, only an extremely limited number of mass-included absorber layouts have been investigated. This paper proposes an approach to identify optimum vibration absorbers with a reaction mass. Using this approach, a full class of absorber layouts with a reaction mass and a pre-determined number of inerters, dampers and springs connected in series and parallel, can be systematically investigated using generic Immittance-Function-Networks. The advan- tages of the proposed approach are demonstrated via a 3 d.f. structure example.

USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance.

Calcineurin acts as a calcium-activated phosphatase that dephosphorylates various substrates, including members of the nuclear factor of activated T cells (NFAT) family, to trigger their nuclear translocation and transcriptional activity. However, the detailed mechanism regulating the recruitment of NFATs to calcineurin remains poorly understood. Here, we report that calcineurin A (CNA), encoded by PPP3CB or PPP3CC, is constitutively ubiquitinated on lysine 327, and this polyubiquitin chain is rapidly removed by ubiquitin carboxyl-terminal hydrolase 16 (USP16) in response to intracellular calcium stimulation. The K29-linked ubiquitination of CNA impairs NFAT recruitment and transcription of NFAT-targeted genes. USP16 deficiency prevents calcium-triggered deubiquitination of CNA in a manner consistent with defective maintenance and proliferation of peripheral T cells. T cell-specific USP16 knockout mice exhibit reduced severity of experimental autoimmune encephalitis and inflammatory bowel disease. Our data reveal the physiological function of CNA ubiquitination and its deubiquitinase USP16 in peripheral T cells. Notably, our results highlight a critical mechanism for the regulation of calcineurin activity and a novel immunosuppressive drug target for the treatment of autoimmune diseases.

Effect of Clostridium butyricum supplementation on the development of intestinal flora and the immune system of neonatal mice.

The objective of the present study was to examine whether Clostridium butyricum supplementation has a role in the regulation of the intestinal flora and the development of the immune system of neonatal mice. A total of 30 pregnant BALB/c mice, including their offspring, were randomly divided into three groups: In the maternal intervention group (Ba), maternal mice were treated with Clostridium butyricum from birth until weaning at postnatal day 21 (PD21) followed by administration of saline to the offspring at PD21-28; in the offspring intervention group (Ab), breast-feeding maternal mice were supplemented with saline and offspring were directly supplemented with Clostridium butyricum from PD21-28; in the both maternal and offspring intervention group (Bb), both maternal mice and offspring were supplemented with Clostridium butyricum at PD 0-21 and at PD21-28. While mice in the control group were given the same volume of normal saline. Stool samples from the offspring were collected at PD14, -21 and -28 to observe the intestinal flora by colony counts of Enterococcus spp., Enterobacter spp., Bifidobacterium spp. and Lactobacillus spp. Detection of intestinal secreted immunoglobulin A (sIgA) levels and serum cytokine (interferon-γ, and interleukin-12, -4 and -10) levels in offspring was performed to evaluate the effect on their immune system. The results revealed that compared with the control group, offspring in the Ba group displayed significantly decreased stool colony counts of Enterococcus spp. (t=3.123, P<0.01) at PD14 and significantly decreased counts of Enterobacter spp. at PD14 and -21 (t=2.563, P<0.05 and t=2.292, P<0.05, respectively). Compared with the control group, the stool colony counts of Bifidobacterium spp. and Lactobacillus spp. were significantly increased in the Ba group at PD21 (t=3.085, P<0.01 and t=2.8508, P<0.05, respectively). The Ab group had significantly higher stool colony counts of Bifidobacterium spp. and Lactobacillus spp. at PD28, compared with the control group (Q=7.679, P<0.01 and Q=6.149, P<0.01, respectively). There were no significant differences identified in the sIgA levels of the intestinal fluid and serum cytokine levels between the control group and the intervention groups. In conclusion, Clostridium butyricum administered to breast-feeding maternal mice was able to regulate the intestinal flora balance in their offspring. However, due to insignificant effects on sIgA level and the associated cytokines, Clostridium butyricum had a limited influence on the balance of type 1 vs. type 2 T-helper cells. However, using Clostridium butyricum as an invention may be a safe method for improving the balance of intestinal flora and associated processes in offspring.

The earliest unequivocally modern humans in southern China.

The hominin record from southern Asia for the early Late Pleistocene epoch is scarce. Well-dated and well-preserved fossils older than ∼45,000 years that can be unequivocally attributed to Homo sapiens are lacking. Here we present evidence from the newly excavated Fuyan Cave in Daoxian (southern China). This site has provided 47 human teeth dated to more than 80,000 years old, and with an inferred maximum age of 120,000 years. The morphological and metric assessment of this sample supports its unequivocal assignment to H. sapiens. The Daoxian sample is more derived than any other anatomically modern humans, resembling middle-to-late Late Pleistocene specimens and even contemporary humans. Our study shows that fully modern morphologies were present in southern China 30,000-70,000 years earlier than in the Levant and Europe. Our data fill a chronological and geographical gap that is relevant for understanding when H. sapiens first appeared in southern Asia. The Daoxian teeth also support the hypothesis that during the same period, southern China was inhabited by more derived populations than central and northern China. This evidence is important for the study of dispersal routes of modern humans. Finally, our results are relevant to exploring the reasons for the relatively late entry of H. sapiens into Europe. Some studies have investigated how the competition with H. sapiens may have caused Neanderthals' extinction (see ref. 8 and references therein). Notably, although fully modern humans were already present in southern China at least as early as ∼80,000 years ago, there is no evidence that they entered Europe before ∼45,000 years ago. This could indicate that H. neanderthalensis was indeed an additional ecological barrier for modern humans, who could only enter Europe when the demise of Neanderthals had already started.