Integrating mineral elements and metabolite features to distinguish Lotus seeds from different geographic origins.

The characteristics of lotus seeds (LS) are influenced by variety and environment. However, it remains unknown the difference of metabolites and elements of LS from different origins. In this study, an accurate quantification method (97-107 %) for 20 mineral elements in LS was developed, and a metabolomic method was established to identify a total of 323 metabolites in LS. Mineral composition analysis revealed significant variations in the mineral element contents among LS samples from seven geographical regions. LS were rich in potassium (14,710 mg/kg), manganese (67.19 mg/kg), with a low level of sodium (210 mg/kg). A total of 10 mineral elements and 117 metabolites (p < 0.05 and VIP > 1) were identified as the potential geographical markers of LS by integration analysis. The linear discriminant analysis model showed high prediction accuracy. This study provides strong experimental evidence to maintain the authenticity and quality of LS in the food industry.

Genetic history and biological adaptive landscape of the Tujia people inferred from shared haplotypes and alleles.

BACKGROUND: High-quality genomic datasets from under-representative populations are essential for population genetic analysis and medical relevance. Although the Tujia are the most populous ethnic minority in southwestern China, previous genetic studies have been fragmented and only partially reveal their genetic diversity landscape. The understanding of their fine-scale genetic structure and potentially differentiated biological adaptive features remains nascent. OBJECTIVES: This study aims to explore the demographic history and genetic architecture related to the natural selection of the Tujia people, focusing on a meta-Tujia population from the central regions of the Yangtze River Basin. RESULTS: Population genetic analyses conducted on the meta-Tujia people indicate that they occupy an intermediate position in the East Asian North-South genetic cline. A close genetic affinity was identified between the Tujia people and neighboring Sinitic-speaking populations. Admixture models suggest that the Tujia can be modeled as a mixture of northern and southern ancestries. Estimates of f3/f4 statistics confirmed the presence of ancestral links to ancient Yellow River Basin millet farmers and the BaBanQinCen-related groups. Furthermore, population-specific natural selection signatures were explored, revealing highly differentiated functional variants between the Tujia and southern indigenous populations, including genes associated with hair morphology (e.g., EDAR) and skin pigmentation (e.g., SLC24A5). Additionally, both shared and unique selection signatures were identified among ethnically diverse but geographically adjacent populations, highlighting their extensive admixture and the biological adaptations introduced by this admixture. CONCLUSIONS: The study unveils significant population movements and genetic admixture among the Tujia and other ethno-linguistically diverse East Asian groups, elucidating the differentiated adaptation processes across geographically diverse populations from the current genetic landscape.

Correction: Highly stable color-tunable organic long-persistent luminescence from a single-component exciplex copolymer for in vitro antibacterial.

[This corrects the article DOI: 10.1039/D4SC02839B.].

Highly stable color-tunable organic long-persistent luminescence from a single-component exciplex copolymer for in vitro antibacterial.

Developing exciplex-based organic long-persistent luminescence (OLPL) materials with high stability is very important but remains a formidable challenge in a single-component system. Here, we report a facile strategy to achieve highly stable OLPL in an amorphous exciplex copolymer system via through-space charge transfer (TSCT). The copolymer composed of electron donor and acceptor units can not only exhibit effective TSCT for intra/intermolecular exciplex emission but also construct a rigid environment to isolate oxygen and suppress non-radiative decay, thereby enabling stable exciplex-based OLPL emission with color-tunable feature for more than 100 h under ambient conditions. These single-component OLPL copolymers demonstrate robust antibacterial activity against Escherichia coli under visible light irradiation. These results provide a solid example to exploit highly stable exciplex-based OLPL in polymers, shedding light on how the TSCT mechanism may potentially contribute to OLPL in a single-component molecular system and broadening the scope of OLPL applications.

Multiple Human Population Movements and Cultural Dispersal Events Shaped the Landscape of Chinese Paternal Heritage.

Large-scale genomic projects and ancient DNA innovations have ushered in a new paradigm for exploring human evolutionary history. However, the genetic legacy of spatiotemporally diverse ancient Eurasians within Chinese paternal lineages remains unresolved. Here, we report an integrated Y-chromosome genomic database encompassing 15,563 individuals from both modern and ancient Eurasians, including 919 newly reported individuals, to investigate the Chinese paternal genomic diversity. The high-resolution, time-stamped phylogeny reveals multiple diversification events and extensive expansions in the early and middle Neolithic. We identify four major ancient population movements, each associated with technological innovations that have shaped the Chinese paternal landscape. First, the expansion of early East Asians and millet farmers from the Yellow River Basin predominantly carrying O2/D subclades significantly influenced the formation of the Sino-Tibetan people and facilitated the permanent settlement of the Tibetan Plateau. Second, the dispersal of rice farmers from the Yangtze River Valley carrying O1 and certain O2 sublineages reshapes the genetic makeup of southern Han Chinese, as well as the Tai-Kadai, Austronesian, Hmong-Mien, and Austroasiatic people. Third, the Neolithic Siberian Q/C paternal lineages originated and proliferated among hunter-gatherers on the Mongolian Plateau and the Amur River Basin, leaving a significant imprint on the gene pools of northern China. Fourth, the J/G/R paternal lineages derived from western Eurasia, which were initially spread by Yamnaya-related steppe pastoralists, maintain their presence primarily in northwestern China. Overall, our research provides comprehensive genetic evidence elucidating the significant impact of interactions with culturally distinct ancient Eurasians on the patterns of paternal diversity in modern Chinese populations.

Population genetic admixture and evolutionary history in the Shandong Peninsula inferred from integrative modern and ancient genomic resources.

BACKGROUND: Ancient northern East Asians (ANEA) from the Yellow River region, who pioneered millet cultivation, play a crucial role in understanding the origins of ethnolinguistically diverse populations in modern China and the entire landscape of deep genetic structure and variation discovery in modern East Asians. However, the direct links between ANEA and geographically proximate modern populations, as well as the biological adaptive processes involved, remain poorly understood. RESULTS: Here, we generated genome-wide SNP data for 264 individuals from geographically different Han populations in Shandong. An integrated genomic resource encompassing both modern and ancient East Asians was compiled to examine fine-scale population admixture scenarios and adaptive traits. The reconstruction of demographic history and hierarchical clustering patterns revealed that individuals from the Shandong Peninsula share a close genetic affinity with ANEA, indicating long-term genetic continuity and mobility in the lower Yellow River basin since the early Neolithic period. Biological adaptive signatures, including those related to immune and metabolic pathways, were identified through analyses of haplotype homozygosity and allele frequency spectra. These signatures are linked to complex traits such as height and body mass index, which may be associated with adaptations to cold environments, dietary practices, and pathogen exposure. Additionally, allele frequency trajectories over time and a haplotype network of two highly differentiated genes, ABCC11 and SLC10A1, were delineated. These genes, which are associated with axillary odor and bilirubin metabolism, respectively, illustrate how local adaptations can influence the diversification of traits in East Asians. CONCLUSIONS: Our findings provide a comprehensive genomic dataset that elucidates the fine-scale genetic history and evolutionary trajectory of natural selection signals and disease susceptibility in Han Chinese populations. This study serves as a paradigm for integrating spatiotemporally diverse ancient genomes in the era of population genomic medicine.

TLR9 promotes monocytic myeloid-derived suppressor cell induction during JEV infection.

Myeloid-derived suppressor cells (MDSCs) are a group of heterologous populations of immature bone marrow cells consisting of progenitor cells of macrophages, dendritic cells and granulocytes. Recent studies have revealed that the accumulation of MDSCs in the mouse spleen plays a pivotal role in suppressing the immune response following JEV infection. However, the mechanisms by which JEV induces MDSCs are poorly understood. Here, it was found that JEV infection induces mitochondrial damage and the release of mitochondrial DNA (mtDNA), which further leads to the activation of TLR9. TLR9 deficiency decreases the M-MDSCs population and their suppressive function both in vitro and in vivo. Moreover, the increase of MHCⅡ expression on antigen-presenting cells and CD28 expression on T cells in TLR9-/- mice was positively correlated with M-MDSCs reduction. Accordingly, the survival rate of TLR9-/- mice dramatically increased after JEV infection. These findings reveal the connections of mitochondrial damage and TLR9 activation to the induction of M-MDSCs during JEV infection.

Malaria resistance-related biological adaptation and complex evolutionary footprints inferred from one integrative Tai-Kadai-related genomic resource.

Pathogen‒host adaptative interactions and complex population demographical processes, including admixture, drift, and Darwen selection, have considerably shaped the Neolithic-to-Modern Western Eurasian population structure and genetic susceptibility to modern human diseases. However, the genetic footprints of evolutionary events in East Asia remain unknown due to the underrepresentation of genomic diversity and the design of large-scale population studies. We reported one aggregated database of genome-wide SNP variations from 796 Tai-Kadai (TK) genomes, including that of Bouyei first reported here, to explore the genetic history, population structure, and biological adaptative features of TK people from southern China and Southeast Asia. We found geography-related population substructure among TK people using the state-of-the-art population genetic structure reconstruction techniques based on the allele frequency spectrum and haplotype-resolved phased fragments. We found that the northern TK people from Guizhou harbored one TK-dominant ancestry maximized in the Bouyei people, and the southern TK people from Thailand were more influenced by Southeast Asians and indigenous people. We reconstructed fitted admixture models and demographic graphs, which showed that TK people received gene flow from ancient southern rice farmer-related lineages related to the Hmong-Mien and Austroasiatic people and from northern millet farmers associated with the Sino-Tibetan people. Biological adaptation focused on our identified unique TK lineages related to Bouyei, which showed many adaptive signatures conferring Malaria resistance and low-rate lipid metabolism. Further gene enrichment, the allele frequency distribution of derived alleles, and their correlation with the incidence of Malaria further confirmed that CR1 played an essential role in the resistance of Malaria in the ancient "Baiyue" tribes.

Coupling of Perinuclear Actin Cap and Nuclear Mechanics in Regulating Flow-Induced Yap Spatiotemporal Nucleocytoplasmic Transport.

Mechanical forces, including flow shear stress, govern fundamental cellular processes by modulating nucleocytoplasmic transport of transcription factors like Yes-associated Protein (YAP). However, the underlying mechanical mechanism remains elusive. In this study, it is reported that unidirectional flow induces biphasic YAP transport with initial nuclear import, followed by nuclear export as actin cap formation and nuclear stiffening. Conversely, pathological oscillatory flow induces slight actin cap formation, nuclear softening, and sustained YAP nuclear localization. To elucidate the disparately YAP spatiotemporal distribution, a 3D mechanochemical model is developed, which integrates flow sensing, cytoskeleton organization, nucleus mechanotransduction, and YAP transport. The results unveiled that despite the significant localized nuclear stress imposed by the actin cap, its inherent stiffness counteracts the dispersed contractile stress exerted by conventional fibers on the nuclear membrane. Moreover, alterations in nuclear stiffness synergistically regulate nuclear deformation, thereby governing YAP transport. Furthermore, by expanding the single-cell model to a collective vertex framework, it is revealed that the irregularities in actin cap formation within individual cells have the potential to induce topological defects and spatially heterogeneous YAP distribution in the cellular monolayer. This work unveils a unified mechanism of flow-induced nucleocytoplasmic transport, providing a linkage between transcription factor localization and mechanical stimulation.

Distinguished biological adaptation architecture aggravated population differentiation of Tibeto-Burman-speaking people.

Tibeto-Burman (TB) people have endeavored to adapt to the hypoxic, cold, and high-UV high-altitude environments in the Tibetan Plateau and complex disease exposures in lowland rainforests since the late Paleolithic period. However, the full landscape of genetic history and biological adaptation of geographically diverse TB-speaking people, as well as their interaction mechanism, remain unknown. Here, we generate a whole-genome meta-database of 500 individuals from 39 TB-speaking populations and present a comprehensive landscape of genetic diversity, admixture history, and differentiated adaptative features of geographically different TB-speaking people. We identify genetic differentiation related to geography and language among TB-speaking people, consistent with their differentiated admixture process with incoming or indigenous ancestral source populations. A robust genetic connection between the Tibetan-Yi corridor and the ancient Yellow River people supports their Northern China origin hypothesis. We finally report substructure-related differentiated biological adaptative signatures between highland Tibetans and Loloish speakers. Adaptative signatures associated with the physical pigmentation (EDAR and SLC24A5) and metabolism (ALDH9A1) are identified in Loloish people, which differed from the high-altitude adaptative genetic architecture in Tibetan. TB-related genomic resources provide new insights into the genetic basis of biological adaptation and better reference for the anthropologically informed sampling design in biomedical and genomic cohort research.

Deciphering Cell-Cell Interactions with Integrative Single-Cell Secretion Profiling.

Cell-cell interactions are the fundamental behaviors to regulate cellular activities. A comprehensive evaluation of intercellular interactions requires direct profiling of various signaling behaviors simultaneously at the single-cell level, which remains lacking. Herein, an integrative single-cell secretion analysis platform is presented to profile different secreted factors (four proteins, three extracellular vesicles (EV) phenotypes), spatial distances, and migration information (distances and direction) simultaneously from high-throughput paired single cells using an antibody-barcode microchip. Applying the platform to analyze the tumor-stromal and tumor-immune interactions with the human oral squamous cell carcinoma (OSCC) cell lines and primary OSCC cells reveals that the initial distances between cells would determine their migratory distances and direction to approach stable organization. The cell-cell in close proximity enhances protein secretions while attenuating EV secretions. Migration has a more profound correlation with protein secretions than EV secretions, in which absolute migration distance affects protein secretions significantly but not the direction. These findings highlight the significance of spatial organization in regulating cell signaling behaviors and demonstrate that the integrative single-cell secretion profiling platform is well-suited for a comprehensive dissection of intercellular communication and interactions, providing new avenues for understanding cell-cell interaction biology and how different signaling behaviors coordinate within the tumor microenvironment.

Spatial barcoding-enabled highly multiplexed immunoassay with digital microfluidics.

Digital microfluidics (DMF), facilitating independent manipulation of microliter samples, provides an ideal platform for immunoassay detection; however, suffering limited multiplexity. To address the need, herein we described a digital microfluidics (DMF) platform that realizes spatial barcoding on the Teflon-coated indium tin oxide (ITO) glass side to fulfill highly multiplexed immunoassay (10+) with low-volume samples (∼4 µL) in parallel, representing the highest multiplexing recorded to date for DMF-actuated immunoassay. Planar-based spatial immobilization of multiple capture antibodies was realized on a Teflon-coated ITO glass side, which was then used as the top plate of the DMF device. Droplets containing analytes, secondary antibodies, and fluorescent signaling reporters with low volume, which were electrically manipulated by our DMF control system, were shuttled sequentially along the working electrodes to complete the immuno-reaction. Evaluation of platform performance with recombinant proteins showed excellent sensitivity and reproducibility. To test the feasibility of our platform in analyzing multiplex biomarkers of the immune response, we used lipopolysaccharide-stimulated macrophages as a model system for protein secretion dynamics studies. As a result, temporal profiling of pro-inflammatory cytokine secretion dynamics was obtained. The spatial barcoding strategy presented here is easy-to-operate to enable a more comprehensive evaluation of protein abundance from biological samples, paving the way for new opportunities to realize multiplexity-associated applications with the DMF platform.

Hydrogel Loaded with VEGF/TFEB-Engineered Extracellular Vesicles for Rescuing Critical Limb Ischemia by a Dual-Pathway Activation Strategy.

Critical limb ischemia (CLI) is the most severe clinical manifestation of peripheral arterial disease, which causes many amputations and deaths. Conventional treatment strategies for CLI (e.g., stent implantation and vascular surgery) bring surgical risk, which are not suitable for each patient. Extracellular vesicles (EVs) can be a potential solution for CLI. Herein, vascular endothelial growth factor (VEGF; i.e., a crucial molecule related to angiogenesis) and transcription factor EB (TFEB; i.e., a pivotal regulator of autophagy) are chosen as the target gene to improve the bioactivity of EVs derived from endothelial cells. The VEGF/TFEB-engineered EVs (Engineered-EVs) are fabricated by genetically engineering the parent cells, and their versatile functions are confirmed using three cell models (human umbilical vein endothelial cells, myoblast, and monocytes). Injectable thermal-responsive hydrogel are then combined with Engineered-EVs to combat CLI. These results reveal that the hydrogel can enhance the stability of Engineered-EVs in vivo and release EVs at different temperatures. Moreover, the results of animal studies indicate that Engineered-EV/Hydrogel can significantly improve neovascularization, attenuate muscle injury, and recover limb function after CLI. Finally, mechanistic studies shed light on the therapeutic effect of Engineered-EV/Hydrogel due to the activated VEGF/VEGFR pathway and autophagy-lysosomal pathway.

Delivery of Nitric Oxide in the Cardiovascular System: Implications for Clinical Diagnosis and Therapy.

Nitric oxide (NO) is a key molecule in cardiovascular homeostasis and its abnormal delivery is highly associated with the occurrence and development of cardiovascular disease (CVD). The assessment and manipulation of NO delivery is crucial to the diagnosis and therapy of CVD, such as endothelial dysfunction, atherosclerotic progression, pulmonary hypertension, and cardiovascular manifestations of coronavirus (COVID-19). However, due to the low concentration and fast reaction characteristics of NO in the cardiovascular system, clinical applications centered on NO delivery are challenging. In this tutorial review, we first summarized the methods to estimate the in vivo NO delivery process, based on computational modeling and flow-mediated dilation, to assess endothelial function and vulnerability of atherosclerotic plaque. Then, emerging bioimaging technologies that have the potential to experimentally measure arterial NO concentration were discussed, including Raman spectroscopy and electrochemical sensors. In addition to diagnostic methods, therapies aimed at controlling NO delivery to regulate CVD were reviewed, including the NO release platform to treat endothelial dysfunction and atherosclerosis and inhaled NO therapy to treat pulmonary hypertension and COVID-19. Two potential methods to improve the effectiveness of existing NO therapy were also discussed, including the combination of NO release platform and computational modeling, and stem cell therapy, which currently remains at the laboratory stage but has clinical potential for the treatment of CVD.

Microfluidic Model to Mimic Initial Event of Neovascularization.

Neovascularization is usually initialized from an existing normal vasculature and the biomechanical microenvironment of endothelial cells (ECs) in the initial stage varies dramatically from the following process of neovascularization. Although there are plenty of models to simulate different stages of neovascularization, an in vitro 3D model that capitulates the initial process of neovascularization under the corresponding stimulations of normal vasculature microenvironments is still lacking. Here, we reconstructed an in vitro 3D model that mimics the initial event of neovascularization (MIEN). The MIEN model contains a microfluidic sprouting chip and an automatic control, highly efficient circulation system. A functional, perfusable microchannel coated with endothelium was formed and the process of sprouting was simulated in the microfluidic sprouting chip. The initially physiological microenvironment of neovascularization was recapitulated with the microfluidic control system, by which ECs would be exposed to high luminal shear stress, physiological transendothelial flow, and various vascular endothelial growth factor (VEGF) distributions simultaneously. The MIEN model can be readily applied to the study of neovascularization mechanism and holds a potential promise as a low-cost platform for drug screening and toxicology applications.

Single-Cell Secretion Analysis in the Engineered Tumor Microenvironment Reveals Differential Modulation of Macrophage Immune Responses.

It is increasingly recognized that the cellular microenvironment plays critical roles in regulating the fate and physiology of cells. Despite recent advancements in single-cell analysis technologies, engineering and integration of the microenvironment for single-cell analysis platforms remain limited. Here, we report a single-cell cytokine secretion analysis platform that integrated both the three-dimensional cell culture and the primary oral squamous cell carcinoma tumor cell co-culture to provide both physical and physiological cues for single cells to be analyzed. We apply the platform to investigate the immune responses of human macrophages stimulated with the ligand of toll-like receptor 4 lipopolysaccharide. Notably, we observe the differential modulation effect in cytokine secretions by the tumor microenvironment, in which antitumor cytokine TNF-a secretion was attenuated, and protumor cytokine IL-6 would increase. The differential modulation effect is conserved from cell line-derived macrophages to primary macrophages derived from healthy donors. Immunofluorescence staining further reveals that ∼50% of macrophage cells could be polarized from M1 to the M2 phenotype within 12 h in the engineered tumor microenvironment. This work demonstrates the significance of the cell microenvironment toward single-cell analysis, which could help to evaluate how immune cells will respond in the complex microenvironment more accurately.

Flow shear stress controls the initiation of neovascularization via heparan sulfate proteoglycans within a biomimetic microfluidic model.

Endothelial cells (ECs) in vivo are subjected to three forms of shear stress induced by luminal blood flow, transendothelial flow and interstitial flow simultaneously. It is controversial that shear stress, especially the component induced by luminal flow, was thought to inhibit the initialization of angiogenesis and trigger arteriogenesis. Here, we combined microfabrication techniques and delicate numerical simulations to reconstruct the initial physiological microenvironment of neovascularization in vitro, where ECs experience high luminal shear stress, physiological transendothelial flow and various vascular endothelial growth factor (VEGF) distributions simultaneously. With the biomimetic microfluidic model, cell alignment and endothelial sprouting assays were carried out. We found that luminal shear stress inhibits endothelial sprouting and tubule formation in a dose-dependent manner. Although a high concentration of VEGF increases EC sprouting, neither a positive nor a negative VEGF gradient additionally affects the degree of sprouting, and luminal shear stress significantly attenuates neovascularization even in the presence of VEGF. Heparinase was used to selectively degrade the heparan sulfate proteoglycan (HSPG) coating on ECs and messenger RNA profiles in ECs were analyzed. It turned out that HSPGs could act as a mechanosensor to sense the change of fluid shear stress, modulate multiple EC gene expressions, and hence affect neovascularization. In summary, distraction from the stabilized state, such as decreased luminal shear stress, increased VEGF and the destructed mechanotransduction of HSPGs would induce the initiation of neovascularization. Our study highlights the key role of the magnitude and forms of shear stress in neovascularization.

Author Correction: Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease.

Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; however, the underlying molecular mechanism remains elusive. Here, we uncover Sh2b1 in leptin receptor (LepR) neurons as a critical component of a SNS/brown adipose tissue (BAT)/thermogenesis axis. LepR neuron-specific deletion of Sh2b1 abrogates leptin-stimulated sympathetic nerve activation and impairs BAT thermogenic programs, leading to reduced core body temperature and cold intolerance. The adipose SNS degenerates progressively in mutant mice after 8 weeks of age. Adult-onset ablation of Sh2b1 in the mediobasal hypothalamus also impairs the SNS/BAT/thermogenesis axis; conversely, hypothalamic overexpression of human SH2B1 has the opposite effects. Mice with either LepR neuron-specific or adult-onset, hypothalamus-specific ablation of Sh2b1 develop obesity, insulin resistance, and liver steatosis. In contrast, hypothalamic overexpression of SH2B1 protects against high fat diet-induced obesity and metabolic syndromes. Our results unravel an unrecognized LepR neuron Sh2b1/SNS/BAT/thermogenesis axis that combats obesity and metabolic disease.

The pharmaceutical multi-activity of metallofullerenol invigorates cancer therapy.

Currently, cancer continues to afflict humanity. The direct destruction and killing of tumor cells by surgery, radiation and chemotherapy gives rise to many side effects and compromised efficacy. Encouragingly, the rapid development of nanotechnology offers attractive opportunities to revolutionize the current situation of cancer therapy. Metallofullerenol Gd@C82(OH)22, in contrast to chemotherapeutics that directly kill tumor cells, demonstrates anti-tumor behavior with high efficiency and low toxicity by modulating the tumor microenvironment. Furthermore, Gd@C82(OH)22 has been recently reported to specifically target cancer stem cells. In this review, we give a concise introduction to the development of the fullerene family and then report the anti-tumor activity of Gd@C82(OH)22 based on its unique physicochemical characteristics, followed by a comprehensive summary of the anti-tumor biological mechanisms which target different components of the tumor microenvironment as well as the biodistribution and toxicity of Gd@C82(OH)22. Finally, we describe Gd@C82(OH)22 as a "particulate medicine" to highlight its distinctions from conventional "molecular medicine", with considerable emphasis on the advantages of nanomedicine. The in-depth investigation of Gd@C82(OH)22 undoubtedly provides a constructive reference for the development of other nanomedicines, especially in the fullerene family. The application of nanotechnology in the medical field definitely provides a promising and favorable future for improving the current status of cancer therapy.