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Ginseng (Panax ginseng C. A. Meyer) is a perennial plant with a long dormancy period. While some researchers employ gibberellin and other substances to stimulate premature germination, this method is limited to laboratory settings and cannot be applied to the field cultivation of ginseng. The mechanism underlying the germination of ginseng overwintering buds remains largely unexplored. Understanding the internal changes during the dormancy release process in the overwintering buds would facilitate the discovery of potential genes, metabolites, or regulatory pathways associated with it. In this study, we approximately determined the onset of dormancy release through morphological observations and investigated the process of dormancy release in ginseng overwintering buds using transcriptomic and metabolomic approaches. Our analyses revealed that the germination process of ginseng overwintering buds is regulated by multiple plant hormones, each acting at different times. Among these, abscisic acid (ABA) and gibberellic acid (GA) serve as classical signaling molecules regulating the dormancy process, while other hormones may promote the subsequent growth of overwintering buds. Additionally, metabolic pathways associated with arginine may be involved in the dormancy release process. Polyamines synthesized downstream may promote the growth of overwintering buds after dormancy release and participate in subsequent reproductive growth. This study provides insights into the germination process of ginseng overwintering buds at the molecular level and serves as a reference for further exploration of the detailed mechanism underlying ginseng overwintering germination in the future.

N6-Methyladenosine (m6A) is the most abundant modification in eukaryotic mRNA, and plays important biological functions via regulating RNA fate determination. Recent studies have shown that m6A modification plays a key role in hematologic malignancies, including acute myeloid leukemia. The current growth of epitranscriptomic research mainly benefits from technological progress in detecting RNA m6A modification in a transcriptome-wide manner. In this review, we first briefly summarize the latest advances in RNA m6A biology by focusing on writers, readers, and erasers of m6A modification, and describe the development of high-throughput methods for RNA m6A mapping. We further discuss the important roles of m6A modifiers in acute myeloid leukemia, and highlight the identification of potential inhibitors for AML treatment by targeting of m6A modifiers. Overall, this review provides a comprehensive summary of RNA m6A biology in acute myeloid leukemia.

Hematopoietic stem cells (HSC) maintain lifetime whole blood hematopoiesis through self-renewal and differentiation. In order to sustain HSC stemness, most HSC reside in a quiescence state, which is affected by diverse cellular stress and intracellular signal transduction. How HSC accommodate those challenges to preserve lifetime capacity remains elusive. Here we show that Pax transactivation domain-interacting protein (PTIP) is required for preserving HSC quiescence via regulating lysosomal activity. Using a genetic knockout mouse model to specifically delete Ptip in HSC, we find that loss of Ptip promotes HSC exiting quiescence, and results in functional exhaustion of HSC. Mechanistically, Ptip loss increases lysosomal degradative activity of HSC. Restraining lysosomal activity restores the quiescence and repopulation potency of Ptip-/- HSC. Additionally, PTIP interacts with SMAD2/3 and mediates transforming growth factor-β signaling-induced HSC quiescence. Overall, our work uncovers a key role of PTIP in sustaining HSC quiescence via regulating lysosomal activity.

Insecticide-based vector control measures play an important role in the prevention and control of insect-borne infectious diseases such as malaria; however, insecticide resistance has become a severe global problem for vector control. To date, the metabolic mechanism by which Anopheles sinensis, the most widely distributed malaria vector in China and Asia, detoxifies insecticides is not clear. In this study, the molecular metabolite changes in both the larval and adult stages of deltamethrin susceptible (DS) and deltamethrin-resistant (DR) An. sinensis mosquitoes were analysed by using liquid chromatography tandem mass spectrometry (LC-MS/MS) after exposure to deltamethrin. There were 127 differential metabolites in larval DR An. sinensis and 168 in adults. Five metabolites (glycerophosphocholine, deoxyguanosine, DL-methionine sulfoxide, D-myo-inositol-3-phosphate and N-acetyl-alpha-D-glucosamine1-phosphate) were downregulated in both DR larvae and adults, and one metabolite (aspartyl-glutamine) was upregulated, and the ratio of down- and up-regulation of these metabolites was 5:1. The differential metabolites between the DS and DR mosquitos were mainly classified into organic oxygen compounds, carboxylic acids and their derivatives, glycerophospholipids and purine nucleotides, and the common pathway enriched in both the larval and adult DR An. sinensis was glycerophospholipid metabolism. The findings of this study provide further mechanistic understanding of insecticide resistance in An. sinensis.

Dentinogenesis is a key process in tooth formation and is regulated by a series of pre- and post-transcriptional regulations. N6-methyl-adenosine (m6A), which is the most prevalent internal chemical modification that can be removed by the RNA demethylase AlkB homolog H5 (ALKBH5), has recently been reported to be involved in several biological processes. However, the exact function of ALKBH5-mediated m6A modification in tooth development remains unclear. Here, we showed that Alkbh5 was expressed in pre-odontoblasts, polarizing odontoblasts, and secretory odontoblasts. Alkbh5 overexpression in the mouse dental papilla cell line mDPC6T promoted odontoblastic differentiation. Conditional knockout of Alkbh5 in Dmp1-expressing odontoblasts led to a decrease in number of odontoblasts and increased pre-dentin formation. Mechanistically, RNA sequencing and m6A sequencing of Alkbh5-overexpressing mDPC6T cells revealed that Alkbh5 promoted odontoblast differentiation by prolonging the half-life of Runx2 transcripts in an m6A-dependent manner and by activating the phosphatidylinositol 3-kinase/protein kinase B pathway. Notably, the loss of Alkbh5 expression in odontoblasts impaired tertiary dentin formation in vivo. These results suggested that the RNA demethylase ALKBH5 plays a role in dentinogenesis.

ReS2-based heterostructures, which involve the coupling of a narrow band-gap semiconductor ReS2 with other wide band-gap semiconductors, have shown promising performance in energy conversion and environmental pollution protection in recent years. This review focuses on the preparation methods, encompassing hydrothermal, chemical vapor deposition, and exfoliation techniques, as well as achievements in correlated applications of ReS2-based heterostructures, including type-I, type-II heterostructures, and Z-scheme heterostructures for hydrogen evolution, reduction of CO2, and degradation of pollutants. We believe that this review provides an overview of the most recent advances to guide further research and development of ReS2-based heterostructures for photocatalysis.

N6-methyladenosine (m6A) is a commonly modification of mammalian mRNAs and plays key roles in various cellular processes. Emerging evidence reveals the importance of RNA m6A modification in maintaining stem cell function in normal hematopoiesis and leukemogenesis. In this review, we first briefly summarize the latest advances in RNA m6A biology, and further highlight the roles of m6A writers, readers and erasers in normal hematopoiesis and acute myeloid leukemia. Moreover, we also discuss the mechanisms of these m6A modifiers in preserving the function of hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs), as well as potential strategies for targeting m6A modification related pathways. Overall, we provide a comprehensive summary and our insights into the field of RNA m6A in normal hematopoiesis and leukemia pathogenesis.

Abstract Diabetes is associated with impaired wound healing, which may be caused primarily by a deficiency in dendritic epidermal T cells (DETCs). In the epidermis, IL-15, IGF-1, and mTOR are known to regulate the maintenance of DETCs; however, it is unclear how these molecules may intersect to regulate DETC homeostasis in diabetes. Here, we show that the reduction of DETCs in the epidermis of diabetic mice is caused by altered homeostasis mediated by a reduction in IL-15 levels. Both impaired mTOR activation and reduction of IL-15 in the epidermis play important roles in DETC homeostasis. Moreover, IGF-1 drives keratinocytes to produce IL-15. The activation of IL-15 is dependent on mTOR, and conversely, mTOR regulates IGF-1 production in DETC, in a classic feedback regulatory loop. Our data suggest that in the setting of diabetes, reduced IGF-1, impaired mTOR pathway activation and reduced IL-15 in the epidermis function coordinately to promote altered DETC homeostasis and delayed skin wound closure.

Backgroud/Aims: The effects of rapamycin (RPM) on wound healing have been previously studied. However, reciprocal contradictory data have been reported, and the underlying mechanism remains unclear. This study aims to uncover differential role of RPM in regulation of wound healing and explore the possible mechanism. Methods: C57BL/6J mice and epidermal cells were treated with different doses of RPM. The wound re-epithelialization was observed by hematoxylin and eosin (HE) staining. The expression of IL-15 and IGF-1 were detected by immunohistochemistry and quantitative real-time PCR. Epidermal cell survival was determined by CCK-8 assays. Moreover, the mTORC1 and mTORC2 pathway were examined by western blot analysis. Results: This study showed that differential doses of RPM could lead to separate consequences in epidermis. Histological analyses showed that low-dose RPM promoted wound healing, and enhanced the expression of IL-15 and IGF-1. Furthermore, western blot analysis showed that the effect of low-dose RPM in epidermis were not through mTORC1 pathway. Instead, activation of the Akt/mTORC2 pathway was involved in low-dose RPM-induced IL-15 and IGF-1 production in epidermis, while high-dose RPM inhibited the expression of IL-15 and IGF-1 and the activity of mTORC1 and mTORC2 pathway. Conclusion: This study for the first time demonstrated that RPM-mediated wound healing was dose-dependent.

Wound healing is a complex and dynamic process that progresses through the distinct phases of hemostasis, inflammation, proliferation, and remodeling. Both inflammation and re-epithelialization, in which skin γδ T cells are heavily involved, are required for efficient skin wound healing. Dendritic epidermal T cells (DETCs), which reside in murine epidermis, are activated to secrete epidermal cell growth factors, such as IGF-1 and KGF-1/2, to promote re-epithelialization after skin injury. Epidermal IL-15 is not only required for DETC homeostasis in the intact epidermis but it also facilitates the activation and IGF-1 production of DETC after skin injury. Further, the epidermal expression of IL-15 and IGF-1 constitutes a feedback regulatory loop to promote wound repair. Dermis-resident Vγ4 T cells infiltrate into the epidermis at the wound edges through the CCR6-CCL20 pathway after skin injury and provide a major source of IL-17A, which enhances the production of IL-1β and IL-23 in the epidermis to form a positive feedback loop for the initiation and amplification of local inflammation at the early stages of wound healing. IL-1β and IL-23 suppress the production of IGF-1 by DETCs and, therefore, impede wound healing. A functional loop may exist among Vγ4 T cells, epidermal cells, and DETCs to regulate wound repair.

Dendritic epidermal T cells (DETCs) and dermal Vγ4 T cells engage in wound re-epithelialization and skin inflammation. However, it remains unknown whether a functional link between Vγ4 T cell pro-inflammation and DETC pro-healing exists to affect the outcome of skin wound closure. Here, we revealed that Vγ4 T cell-derived IL-17A inhibited IGF-1 production by DETCs to delay skin wound healing. Epidermal IL-1β and IL-23 were required for Vγ4 T cells to suppress IGF-1 production by DETCs after skin injury. Moreover, we clarified that IL-1β rather than IL-23 played a more important role in inhibiting IGF-1 production by DETCs in an NF-κB-dependent manner. Together, these findings suggested a mechanistic link between Vγ4 T cell-derived IL-17A, epidermal IL-1β/IL-23, DETC-derived IGF-1, and wound-healing responses in the skin.

Altered homeostasis and dysfunction of dendritic epidermal T cells (DETCs) contribute to abnormal diabetic wound healing. IL-15 plays important roles in survival and activation of T lymphocytes. Recently, reduction of epidermal IL-15 has been reported as an important mechanism for abnormal DETC homeostasis in streptozotocin -induced diabetic animals. However, the role of IL-15 in impaired diabetic wound healing remains unknown. Here, we found that, through rescuing the insufficient activation of DETCs, IL-15 increased IGF-1 production by DETCs and thereby promoted diabetic skin wound repair. Regulation of IGF-1 in DETCs by IL-15 was partly dependent on the mTOR pathway. In addition, expression of IL-15 and IGF-1 were positively correlated in wounded epidermis. Together, our data indicated that IL-15 enhanced IGF-1 production by DETCs to promoting diabetic wound repair, suggesting IL-15 as a potential therapeutic agent for managing diabetic wound healing.

Abstract Background Frailty, defined as a phenotype of decreased physiological reserves and diminished ability to respond to stressors, has been linked to the development of chronic diseases. Epidemiological evidence connecting frailty to non‐alcoholic fatty liver disease (NAFLD) and cirrhosis risks remain sparse. We aimed to assess the longitudinal associations of frailty with the risks of severe NAFLD and cirrhosis in middle‐aged to older adults and further explore the modification role of genetic risk on these associations. Methods This study included a total of 398 386 participants from the UK Biobank. Incident cases of severe NAFLD and cirrhosis were ascertained through linked hospital records and death registries. Frailty status was assessed by a modified version of the frailty phenotype, encompassing five key components: weight loss, tiredness, physical activity, gait speed, and grip strength. Participants were classified as pre‐frailty if they met one or two of these criteria, and as frailty if they met three or more. Genetic predisposition to NAFLD and cirrhosis was estimated by genetic risk score (GRS) and further categorized into high, intermediate, and low genetic risk levels according to tertiles of GRSs. Cox proportional hazards regression model was employed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for their associations. Results The mean (standard deviation) age of the study population was 56.6 (8.03) years. 214 408 (53.8%) of the participants was female; 14 924 (3.75%) of participants met the criteria for frailty, 170 498 (42.8%) for pre‐frailty, and 212 964 (53.5%) for non‐frailty. Over a median follow‐up of 12.0 years, we documented 4439 incident severe NAFLD and 3323 incident cirrhosis cases, respectively. Compared with non‐frailty, both pre‐frailty (HR: 1.50; 95% CI: 1.40–1.60) and frailty (HR: 1.98; 95% CI: 1.77–2.21) were associated with increased risk of NAFLD. Similar associations were observed for cirrhosis, the corresponding HRs (95% CIs) for non‐frailty, pre‐frailty, and frailty were 1.00 (reference), 1.29 (1.20, 1.38), and 1.90 (1.66, 2.18). Such associations were consistent across all genetic risk levels, with no observed interactions between frailty and GRSs (all P for interactions ≥0.10). Compared with participants with frailty and a low level of genetic risk, the greatest risk increasement in developing severe NAFLD (HR: 3.36; 95% CI: 2.83–3.99) and cirrhosis (HR: 2.81; 95% CI: 2.29–3.44) was both observed in those with frailty and a high level of genetic risk. Conclusions Our findings indicate that frailty is a significant predictor of severe NAFLD and cirrhosis, irrespective of genetic predisposition.

Background: Chronic respiratory diseases (CRDs) are among the top three causes of human mortality. The relationship between modifiable environmental risk factor of noise and risk of mortality in CRDs is unclear. We investigated the longitudinal association between environmental noise exposure and cause-specific mortality in individuals with CRDs, considering the modifying effect of air pollution. Methods: Residential noise exposure was modelled using Common Noise Assessment Methods in Europe. Information on death causes were acquired from death registry data. Cox proportional-hazards models were used to estimate effect sizes. Results: Among 41,222 participants selected from UK Biobank with CRDs in baseline, a total of 3618 death cases occurred during an average follow-up of 12 years with mortality density of 7.16 per 1000 person years. Exposure with highest noise level (> percentile 90) were associated with 22 % (Hazard ratio [HR] = 1.22, 95 % confidence interval [CI]: 1.05, 1.42), 71 % (HR = 1.71, 95 % CI: 1.14, 2.56), and 84 % (HR = 1.84, 95 % CI: 1.10, 3.07) increased risks for all-cause, respiratory disease (RD)-cause, and COPD-cause mortalities, separately. Both multiplicative and additive interactions was found between air pollution and noise with the risk of RD-cause mortality. Participants with high air pollution and noise exposure were associated with a 101 % (HR = 2.01, 95 % CI: 1.10, 3.66) increased risk of RD-cause mortality. Conclusion: It is imperative to mitigate noise exposure as a preventive measure against incident mortality in individuals with CRDs.

The aim of this study is to investigate the characteristics of the intraseasonal oscillation (ISO) with a 10–30-day cycle over mid-high-latitude Eurasia during boreal summer. The leading mode of this ISO is determined using an extended empirical orthogonal function analysis. Through a phase composite analysis, it is observed that a southeastward-propagating wave train with a quasi-barotropic structure is present in Eurasia. The dynamical mechanism and energy conversion affecting its propagation are also analyzed. The negative (positive) temperature tendency appears in the southeastern part of the temperature anomaly in the lower troposphere (upper troposphere), resulting in further southeastward displacement of the temperature perturbation. A diagnosis of temperature tendency shows that the main cause of the southeastward movement is the advection of anomalous temperature by the mean zonal wind. The energy conversion analysis reveals that by converting kinetic energy and potential energy, the ISO perturbation acquires energy from the summertime mean flow during its southeastward movement.

BackgroundHousehold solid fuel have been associated with changes of handgrip strength (HGS). However, no study has explored the longitudinal associations between household solid fuel use and HGS. Thus, the aim of our cohort study was to investigate the longitudinal associations between household fuel use and HGS.MethodsThe study was based on the China Health and Retirement Longitudinal Study. A handheld dynamometer was used to measure HGS. Household fuel use statuses were collected using questionnaires. Analyses of covariance were performed to examine the associations between household fuel use and HGS.ResultsThe study included 9,382 participants during a 4-year follow-up. The participants who used solid fuel for cooking had more decreases of HGS than those who used clean fuel (P < 0.0001). The least square means (95% CIs) of changes of HGS for participants who used solid fuel and those who used clean fuel for cooking were −1.67 (−2.15, −1.19) and−2.27 (−2.75, −1.79), respectively. The association between fuel use for heating and HGS was non-significant (P = 0.63). The interaction terms of sex to cooking fuel (P = 0.04) and smoking to cooking fuel (P < 0.001) were significant; men and participants who had ever smoked had higher decreases in HGS.ConclusionUsing household solid fuel for cooking but not heating was associated with more decreases in HGS. Proper ventilation and clean fuel should be promoted for public health.

BackgroundIn China, mental health of frontline medical staff might be influenced by clinicians' ability to handle the outbreak of coronavirus disease 2019 (COVID-19). Few studies to-date have addressed the association between clinicians' competencies and mental health in this context. This cross-sectional study was to examine the prevalence of mental health symptoms among frontline medical staff that fought against the COVID-19 outbreak, and explore the associations between their competencies, and separate and concurrent depressive and anxiety symptoms.MethodsA total of 623 frontline medical staff was included in this study. Competencies, depressive symptoms, and anxiety symptoms were assessed using a self-reported short form of the Chinese clinical physicians' competency model, Patient Health Questionnaire-9, and Generalized Anxiety Disorder-7 questionnaire, respectively. Logistic regression models were used to evaluate the associations between one SD increase in competency scores and the prevalence of mental health problems.ResultsThe prevalence of depressive, anxiety, and comorbid depressive and anxiety symptoms was 40.93, 31.78, and 26.00%, respectively. Among the medical staff with higher total competency scores, the prevalence of depressive [odds ratios (ORs) = 0.67, 95% confidence intervals (CIs): 0.55–0.81], anxiety (OR = 0.68, 95% CI: 0.56–0.83), and comorbid anxiety and depressive symptoms (OR = 0.69, 95% CI: 0.55–0.83) was lower than among their lower-scoring counterparts. Subgroup analyses stratified by core competency scores revealed similar associations as the main analyses.ConclusionThe present findings highlight the association between high core competency scores and lower prevalence of depressive, anxiety, and comorbid anxiety and depressive symptoms.

Medical imaging provides a powerful tool for medical diagnosis. In the process of computer-aided diagnosis and treatment of liver cancer based on medical imaging, accurate segmentation of liver region from abdominal CT images is an important step. However, due to defects of liver tissue and limitations of CT imaging procession, the gray level of liver region in CT image is heterogeneous, and the boundary between the liver and those of adjacent tissues and organs is blurred, which makes the liver segmentation an extremely difficult task. In this study, aiming at solving the problem of low segmentation accuracy of the original 3D U-Net network, an improved network based on the three-dimensional (3D) U-Net, is proposed. Moreover, in order to solve the problem of insufficient training data caused by the difficulty of acquiring labeled 3D data, an improved 3D U-Net network is embedded into the framework of generative adversarial networks (GAN), which establishes a semi-supervised 3D liver segmentation optimization algorithm. Finally, considering the problem of poor quality of 3D abdominal fake images generated by utilizing random noise as input, deep convolutional neural networks (DCNN) based on feature restoration method is designed to generate more realistic fake images. By testing the proposed algorithm on the LiTS-2017 and KiTS19 dataset, experimental results show that the proposed semi-supervised 3D liver segmentation method can greatly improve the segmentation performance of liver, with a Dice score of 0.9424 outperforming other methods.

Purpose: This study aimed to determine the longitudinal association between hand grip strength (HGS) and the development of non-alcoholic fatty liver disease (NAFLD) in adults.Design: A cohort study.Methods: This study was conducted in a general Chinese population (n = 14,154) from 2013–2018. NAFLD was diagnosed by liver ultrasonography during evaluating alcohol consumption. The associations between the HGS and NAFLD were assessed using a multivariable Cox proportional hazards regression model.Results: During the study period with a mean follow-up duration of 3.20 years, 2,452 participants developed NAFLD. The risk of NAFLD decreased progressively with increasing HGS in both men and women (P for trend

The aim is to comprehensively and accurately assess potential relationships between single nucleotide polymorphisms (SNP) and lung cancer (LC) risk by summarizing the evidence in systematic reviews and meta-analyses. This umbrella review was registered with the PROSPERO international prospective register of systematic reviews under registration number CRD42020204685. The PubMed, Web of Science, and Embase databases were searched to identify eligible systematic reviews and meta-analyses from inception to August 14, 2020. The evaluation of cumulative evidence was conducted for associations with nominally statistical significance based on the Venice criteria and false positive report probability (FPRP). This umbrella review finally included 120 articles of a total of 190 SNP. The median number of studies and sample size included in the meta-analyses were five (range, 3–52) and 4 389 (range, 354–256 490), respectively. A total of 85 SNP (in 218 genetic models) were nominally statistically associated with LC risk. Based on the Venice criteria and FPRP, 13 SNP (in 22 genetic models), 47 SNP (in 99 genetic models), and 55 SNP (in 94 genetic models) had strong, moderate, and weak cumulative evidence of associations with LC risk, respectively. In conclusion, this umbrella review indicated that only 13 SNP (of 11 genes and one miRNA) were strongly correlated to LC risk. These findings can serve as a general and helpful reference for further genetic studies.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common liver injury. We performed this umbrella review of meta-analyses to summarize the evidence on the associations of nutritional, lifestyle, and metabolic factors with NAFLD.Methods: We searched the PubMed, Embase, and Web of Science databases from inception until July 2, 2020, to identify meta-analyses of observational studies which explored the associations of nutritional, lifestyle, and metabolic factors with NAFLD. Evidence levels were assessed using summary effect sizes, 95% prediction intervals, between-study heterogeneity, evidence of small-study effects, and evidence of excess significance bias for each meta-analysis. (No. of PROSPERO, CRD42020200124).Results: Twenty two risk or protective factors from 10 published meta-analyses were included and studied. Three risk factors (sugar-sweetened beverage consumption, serum fetuin-A, and waist circumference) with highly suggestive levels of evidence and three risk factors (soft drink consumption, former smoking, and body mass index) with suggestive levels of evidence were identified. Only two protective factors (physical activity and serum vitamin D level [among adults in Western countries]) with suggestive levels of evidence were identified. Furthermore, other six risk factors and two protective factors with weak levels of evidence were identified.Conclusions: We found varying levels of evidence of associations of nutritional, lifestyle, and metabolic factors and NAFLD. The results suggest that nutritional and lifestyle management should be considered as a major primary preventive strategy for NAFLD. Moreover, considering the low quality of included meta-analyses and limited area of research topics, future high-quality original studies and meta-analyses should be performed to study these associations.