Testosterone does not mediate the correlation between dietary inflammation and serum klotho levels among males: insights from NHANES database.

Introduction: Serum Klotho (S-Klotho) is a transmembrane protein holds pivotal roles in anti-aging. The Dietary Inflammation Index (DII), a meticulously dietary tool, quantifies the inflammatory potential of an individual's diet. The existing research strongly suggests that a low DII diet plays a significant role in delaying aging and reducing aging-related symptoms in males. Testosterone could potentially act as a mediating intermediary between DII and S-Klotho. However, this aspect remains unexplored. This study aims to investigate the potential causal link of testosterone between DII and S-Klotho in males. Methods: We utilized data from National Health and Nutrition Examination Survey (NHANES) which focused on male participants from 2013-2016. Mediation analyses were used to investigate the effects of testosterone (TT), free testosterone (FT), and free androgen index (FAI) on the DII-S-Klotho relationship, using three modes adjusting for covariates. Results: Mediation analysis unveiled a significant inverse correlation between DII and S-Klotho levels (model 1: c = -14.78, p = 0.046). The interaction between DII and S-Klotho was modulated by TT in model 1 (ab = -1.36; 95% CI: -5.59, -0.55; p = 0.008), but lost significance after adjustments (model 2: ab = -0.39; 95% CI: -4.15, 1.66; p = 0.378; model 3: ab = -0.59; 95% CI: -4.08, 2.15; p = 0.442). For FT, the mediating impact was not statistically significant (model 1: ab = 0.43; 95% CI: -0.51, 5.44; p = 0.188; model 2: ab = 0.72; 95% CI: -0.26, 5.91; p = 0.136; model 3: ab = 0.84; 95% CI: -0.02, 8.06; p = 0.056). Conversely, FAI consistently influenced the DII-S-Klotho relationship (model 1: ab = 2.39; 95% CI: 0.69, 9.42; p = 0.002), maintaining significance after adjustments (model 2: ab = 3.2; 95% CI: 0.98, 11.72; p = 0.004; model 3: ab = 3.15; 95% CI: 0.89, 14.51; p = 0.026). Discussion: This study observed no mediating influence of TT or FT on the correlation between DII and S-Klotho after covariate control. Remarkably, FAI continued to significantly mediate the DII-S-Klotho connection even following covariate adjustment, although its significance in males warrants careful consideration.

Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

The Mechanism of Oxymatrine Targeting miR-27a-3p/PPAR-γ Signaling Pathway through m6A Modification to Regulate the Influence on Hemangioma Stem Cells on Propranolol Resistance.

OBJECTIVE: The proliferation and migration of hemangioma stem cells (HemSCs) induced apoptosis and adipose differentiation as well as increased the sensitivity of HemSCs to propranolol (PPNL). MiR-27a-3p negatively controlled the peroxisome-proliferator-activated receptor γ (PPAR-γ) level, counteracting the effect of PPAR-γ on HemSC progression and PPNL resistance. OMT accelerated HemSC progression and adipocyte differentiation via modulating the miR-27a-3p/PPAR-γ axis, inhibiting HemSC resistance to PPNL. In tumor-forming experiments, OMT exhibited a dose-dependent inhibitory effect on the volume of IH PPNL-resistant tumors, which was partially dependent on the regulation of m6A methylation transfer enzyme METTL3 and the miR-27a-3p/PPAR-γ axis, thereby inducing apoptosis. CONCLUSIONS: We conclude that OMT regulates IH and influences PPNL resistance via targeting the miR-27a-3p/PPAR-γ signaling pathway through m6A modification.

Development and validation of a fully automatic tissue delineation model for brain metastasis using a deep neural network.

Background: Stereotactic radiosurgery (SRS) treatment planning requires accurate delineation of brain metastases, a task that can be tedious and time-consuming. Although studies have explored the use of convolutional neural networks (CNNs) in magnetic resonance imaging (MRI) for automatic brain metastases delineation, none of these studies have performed clinical evaluation, raising concerns about clinical applicability. This study aimed to develop an artificial intelligence (AI) tool for the automatic delineation of single brain metastasis that could be integrated into clinical practice. Methods: Data from 426 patients with postcontrast T1-weighted MRIs who underwent SRS between March 2007 and August 2019 were retrospectively collected and divided into training, validation, and testing cohorts of 299, 42, and 85 patients, respectively. Two Gamma Knife (GK) surgeons contoured the brain metastases as the ground truth. A novel 2.5D CNN network was developed for single brain metastasis delineation. The mean Dice similarity coefficient (DSC) and average surface distance (ASD) were used to assess the performance of this method. Results: The mean DSC and ASD values were 88.34%±5.00% and 0.35±0.21 mm, respectively, for the contours generated with the AI tool based on the testing set. The DSC measure of the AI tool's performance was dependent on metastatic shape, reinforcement shape, and the existence of peritumoral edema (all P values <0.05). The clinical experts' subjective assessments showed that 415 out of 572 slices (72.6%) in the testing cohort were acceptable for clinical usage without revision. The average time spent editing an AI-generated contour compared with time spent with manual contouring was 74 vs. 196 seconds, respectively (P<0.01). Conclusions: The contours delineated with the AI tool for single brain metastasis were in close agreement with the ground truth. The developed AI tool can effectively reduce contouring time and aid in GK treatment planning of single brain metastasis in clinical practice.

Are the lists of questionable journals reasonable: A case study of early warning journal lists.

The use of lists of questionable journals as a means to ensure research quality and integrity is the subject of an ongoing debate due to their ambiguous criteria. To assess the reasonableness of these lists from a typological perspective, we examined how effectively they reflect differences in bibliometric attributes among distinct groups and whether these differences are consistent. Using the Early Warning Journal Lists from the National Science Library of the Chinese Academy of Sciences as a case study, we categorized listed journals by warning levels and publication years. Our findings indicate potential inconsistencies in the criteria used for assigning warning levels, as we observed varying degrees of differences (or their absence) among groups across different key academic indicators. Notably, when it comes to citation metrics like journal impact factor and journal citation indicator, it appears that these criteria may not have been considered for grouping, although this lack of clarity from the creators is apparent. This underscores the importance of conducting more scientific and thorough evaluations of lists of questionable journals, along with a greater emphasis on sharing precise standards and data. Our study also provides recommendations for future iterations of such lists by different institutions.

Metabolic modulation of mitochondrial mass during CD4+ T cell activation.

Mitochondrial biogenesis initiates within hours of T cell receptor (TCR) engagement and is critical for T cell activation, function, and survival; yet, how metabolic programs support mitochondrial biogenesis during TCR signaling is not fully understood. Here, we performed a multiplexed metabolic chemical screen in CD4+ T lymphocytes to identify modulators of metabolism that impact mitochondrial mass during early T cell activation. Treatment of T cells with pyrvinium pamoate early during their activation blocks an increase in mitochondrial mass and results in reduced proliferation, skewed CD4+ T cell differentiation, and reduced cytokine production. Furthermore, administration of pyrvinium pamoate at the time of induction of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis in mice, prevented the onset of clinical disease. Thus, modulation of mitochondrial biogenesis may provide a therapeutic strategy for modulating T cell immune responses.

A Novel IncX Plasmid Mediates High-Level Oxytetracycline and Streptomycin Resistance in Erwinia amylovora from Commercial Pear Orchards in California.

Isolates of the fire blight pathogen Erwinia amylovora with high-level resistance to oxytetracycline (minimal inhibitory concentration [MIC] > 100 µg/ml) and to streptomycin (MIC > 100 µg/ml) were recovered from four commercial pear orchards in California between 2018 and 2020. The two representative oxytetracycline- and streptomycin-resistant (OxyTcR-SmR) strains 32-10 and 33-1 were as virulent as the antibiotic susceptible strain 13-1 in causing blossom blight of pear and were recovered more than 50% of the time 7 days after co-inoculation to pear flowers with strain 13-1. In the field, inoculation of strain 32-10 to pear flowers that were pretreated with oxytetracycline at 200 µg/ml did not reduce disease compared with an untreated control. Four OxyTcR-SmR strains were subjected to draft genome sequencing to identify the genetic determinants of antibiotic resistance and their location. A 43.6-kb IncX plasmid, designated pX11-7, was detected in each of the four strains, and this plasmid encoded the tetracycline-resistance gene tetB and the streptomycin-resistance gene pair strAB within a large putatively mobile genetic element consisting of the transposon Tn10 that had inserted within the streptomycin-resistance transposon Tn6082. We also determined that pX11-7 was conjugative and was transferred at a rate that was 104 to 105 higher into an E. amylovora strain isolated in California compared with an E. amylovora strain that was isolated in Michigan. The occurrence of high levels of resistance to both oxytetracycline and streptomycin in E. amylovora strains from commercial pear orchards in California significantly limits the options for blossom blight management in these locations.

Identification of an important QTL for seed oil content in soybean.

Seed oil content is one of the most important quantitative traits in soybean (Glycine max) breeding. Here, we constructed a high-density single nucleotide polymorphism linkage map using two genetically similar parents, Heinong 84 and Kenfeng 17, that differ dramatically in their seed oil contents, and performed quantitative trait loci (QTL) mapping of seed oil content in a recombinant inbred line (RIL) population derived from their cross. We detected five QTL related to seed oil content distributed on five chromosomes. The QTL for seed oil content explained over 10% of the phenotypic variation over two years. This QTL was mapped to an interval containing 20 candidate genes, including a previously reported gene, soybean RING Finger 1a (RNF1a) encoding an E3 ubiquitin ligase. Notably, two short sequences were inserted in the GmRNF1a coding region of KF 17 compared to that of HN 84, resulting in a longer protein variant in KF 17. Our results thus provide information for uncovering the genetic mechanisms determining seed oil content in soybean, as well as identifying an additional QTL and highlighting GmRNF1a as candidate gene for modulating seed oil content in soybean. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01384-2.

Identification of priority pollutants and key factors affecting environmental risks of lead­zinc mine tailing sites.

Lead­zinc mine tailing sites are widely distributed in China. Tailing sites with different hydrological settings tend to have different susceptibilities toward pollution and hence different priority pollutants and environmental risks. This paper aims to identify priority pollutants and key factors influencing environmental risks of lead­zinc mine tailing sites with different types of hydrological settings. A database with detailed information on hydrological settings, pollution, etc. of 24 typical lead­zinc mine tailing sites in China was built. A rapid classification method of hydrological settings was proposed considering the groundwater recharge and migration of pollutants in the aquifer. Priority pollutants in leach liquor of tailings, soil, and groundwater of sites were identified using the osculating value method. The key factors affecting environmental risks of lead­zinc mine tailing sites were identified using the random forest algorithm. Four types of hydrological settings were classified. Pb/Zn/As/Cd/Sb, Fe/Pb/As/Co/Cd, and nitrate/iodide/As/Pb/Cd are identified as priority pollutants of leach liquor, soil, and groundwater, respectively. The lithology of the surface soil media, slope, and groundwater depth were identified as the top 3 key factors that affect the environmental risks of sites. Priority pollutants and key factors identified in this study can provide benchmarks for the risk management of lead­zinc mine tailing sites.

Human health risk assessment for contaminated sites: A retrospective review.

Soil contamination is a serious global hazard as contaminants can migrate to the human body through the soil, water, air, and food, threatening human health. Human Health Risk Assessment (HHRA) is a commonly used method for estimating the magnitude and probability of adverse health effects in humans that may be exposed to contaminants in contaminated environmental media in the present or future. Such estimations have improved for decades with various risk assessment frameworks and well-established models. However, the existing literature does not provide a comprehensive overview of the methods and models of HHRA that are needed to grasp the current status of HHRA and future research directions. Thus, this paper aims to systematically review the HHRA approaches and models, particularly those related to contaminated sites from peer-reviewed literature and guidelines. The approaches and models focus on methods used in hazard identification, toxicity databases in dose-response assessment, approaches and fate and transport models in exposure assessment, risk characterization, and uncertainty characterization. The features and applicability of the most commonly used HHRA tools are also described. The future research trend for HHRA for contaminated sites is also forecasted. The transition from animal experiments to new methods in risk identification, the integration and update and sharing of existing toxicity databases, the integration of human biomonitoring into the risk assessment process, and the integration of migration and transformation models and risk assessment are the way forward for risk assessment in the future. This review provides readers with an overall understanding of HHRA and a grasp of its developmental direction.

A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma.

Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pyrimidine biosynthesis pathway. A clinical stage inhibitor of DHODH (rate-limiting enzyme in the de novo pathway) diminishes uridine-5'-phosphate (UMP) pools, generates DNA damage, and induces apoptosis through suppression of replication forks-an "on-target" effect, as shown by uridine rescue. Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in the brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs.

Comparative analyses of six complete chloroplast genomes from the genus Cupressus and Juniperus (Cupressaceae).

Cupressaceae is a conifer family distributed around the world. Cupressus and Juniperus are the main genera of the Cupressaceae family and have important medicinal value. This leads to confusion between Cupressus and Juniperus due to similar morphologies. Here, the complete cp genomes of two Cupressus (C. duclouxiana and C. funebri) and four Juniperus (J. chinensis, J. gaussenii J. pingii and J. procumbens) were sequenced. The results revealed that the length of the cp genomes ranged from 126,996 bp to 129,959 bp, with 119 genes comprising 82 protein-coding genes, 33 transfer RNAs and 4 ribosomal RNAs. All chloroplast genomes of Cupressus and Juniperus lost whole IR regions, which is consistent with gymnosperm cp genome studies. In addition, the number of SSRs per species ranged from 54 to 73 and was dominated by mononucleotide repeats. In the six cp genomes of Cupressus and Juniperus, five highly divergent regions, including accD, accD-rpl2, ycf1, ycf2 and rrn23-rrn4.5, can be used as DNA barcodes of interspecific relationships and potential genetic markers. We compared the gene selection pressures (C. chengiana as reference species), and 6 genes underwent positive selection, the majority of which were related to photosynthesis. Phylogenetic results showed that the monophyly of Cupressus and Juniperus supported most bootstrap support. Cupressus funebris and J. chinensis were resolved to be early diverging species within Cupressus and Juniperus, and the two genera were sister groups to each other. This research revealed a new understanding of the structural pluralism and phylogenetic relationships of Cupressaceae cp genomes. These results will facilitate comprehension of the complexity and diversity of conifer cp genomes.

Comparative Analysis of the Complete Chloroplast Genomes of Eight Ficus Species and Insights into the Phylogenetic Relationships of Ficus.

The genus Ficus is an evergreen plant, the most numerous species in the family Moraceae, and is often used as a food and pharmacy source. The phylogenetic relationships of the genus Ficus have been debated for many years due to the overlapping phenotypic characters and morphological similarities between the genera. In this study, the eight Ficus species (Ficus altissima, Ficus auriculata, Ficus benjamina, Ficus curtipes, Ficus heteromorpha, Ficus lyrata, Ficus microcarpa, and Ficus virens) complete chloroplast (cp) genomes were successfully sequenced and phylogenetic analyses were made with other Ficus species. The result showed that the eight Ficus cp genomes ranged from 160,333 bp (F. heteromorpha) to 160,772 bp (F. curtipes), with a typical quadripartite structure. It was found that the eight Ficus cp genomes had similar genome structures, containing 127 unique genes. The cp genomes of the eight Ficus species contained 89−104 SSR loci, which were dominated by mono-nucleotides repeats. Moreover, we identified eight hypervariable regions (trnS-GCU_trnG-UCC, trnT-GGU_psbD, trnV-UAC_trnM-CAU, clpP_psbB, ndhF_trnL-UAG, trnL-UAG_ccsA, ndhD_psaC, and ycf1). Phylogenetic analyses have shown that the subgenus Ficus and subgenus Synoecia exhibit close affinities and based on the results, we prefer to merge the subgenus Synoecia into the subgenus Ficus. At the same time, new insights into the subgeneric classification of the Ficus macrophylla were provided. Overall, these results provide useful data for further studies on the molecular identification, phylogeny, species identification and population genetics of speciation in the Ficus genus.

Improving the voltage tolerance of perovskite light-emitting diodes via a charge-generation layer.

A high electrical field is necessary to achieve a high brightness for halide perovskite light-emitting diodes (PeLEDs). Charge accumulation in the perovskite film becomes more serious under a high electrical field owing to the imbalanced charge injection in PeLEDs. Concomitantly, the perovskite film will suffer from a higher electrical field increased by the accumulated-charge-induced local electrical field, dramatically accelerating the ion migration and degradation of PeLEDs. Here we construct a voltage-dependent hole injection structure consisting of a ZnO/poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) bilayer, which can properly adjust the hole injection according to the driving electrical field, matching with the injected electrons. As a result, the ZnO/PEDOT:PSS-containing PeLED can be operated under higher driving voltage with a higher peak brightness of 18920 cd/m2, which is 84% higher than the reference device based on a PEDOT:PSS single layer. Moreover, the ZnO/PEDOT:PSS-containing PeLED delivers a much higher power efficiency than the reference device under high driving voltages.

Nerve-stem cell crosstalk in skin regeneration and diseases.

Skin is the interface between the external environment and our body systems. It receives extensive innervation from the peripheral nervous system (PNS), which enables the skin to sense and respond to various stimuli such as touch and temperature. Recent studies have revealed unanticipated functions of cutaneous nerves in orchestrating stem cell behaviors and tissue regeneration. Diverse types of nerve fibers interact closely with different stem cell populations in the skin, specifying a nerve-derived niche for stem cell regulation. Here, we review recent discoveries on the nerve-stem cell crosstalk from tissue morphogenesis to regeneration and diseases, highlighting a key role of peripheral nerves in coupling stem cell activities with fluctuations from the inner body and the external world.

Comparison of genetic diversity between ancient and common populations of Docynia delavayi (Franch.) Schneid.

Docynia delavayi (Franch.) Schneid. (D. delavayi), is a wild fruit tree which combines edible, medicinal, ecological and ornamental uses. In this study, ancient and common populations of D. delavayi were examined for genetic diversity and structure using SSR markers. As a result, a total of 136 alleles were detected at 18 SSR loci, with the mean of 7.56 alleles. The value of Na, Ne, I, He and Nm of the ancient populations were lower than those of the common populations except for Ho and Fst. It indicates that the genetic diversity of the common populations is higher than that in ancient populations. The genetic differences between ancient populations were slightly greater than those between common populations, which demonstrated less gene flow between ancient populations. According to the analysis of molecular variance (AMOVA), the genetic variation within the common population was greater than that in the ancient population, indicating that there was a higher genetic diversity within the common population. Also, the clustering heatmap results are partially consistent with the principal coordinate analysis (PCoA) results. Moreover, the mantel test showed an extremely significant correlation between genetic and geography distance (r = 0.214, p < 0.0001). Based on this work, we proposed strategies for protecting, which offers a theoretical basis for their effective utilization and conservation of D. delavayi ancient tree resources.

Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination.

Nonalcoholic fatty liver disease (NAFLD) is a global health concern with no approved drugs. High-protein dietary intervention is currently the most effective treatment. However, its underlying mechanism is unknown. Here, using Drosophila oenocytes, the specialized hepatocyte-like cells, we find that dietary essential amino acids ameliorate hepatic steatosis by inducing polyubiquitination of Plin2, a lipid droplet-stabilizing protein. Leucine and isoleucine, two branched-chain essential amino acids, strongly bind to and activate the E3 ubiquitin ligase Ubr1, targeting Plin2 for degradation. We further show that the amino acid-induced Ubr1 activity is necessary to prevent steatosis in mouse livers and cultured human hepatocytes, providing molecular insight into the anti-NAFLD effects of dietary protein/amino acids. Importantly, split-intein-mediated trans-splicing expression of constitutively active UBR2, an Ubr1 family member, significantly ameliorates obesity-induced and high fat diet-induced hepatic steatosis in mice. Together, our results highlight activation of Ubr1 family proteins as a promising strategy in NAFLD treatment.

In-Orchard Population Dynamics of Erwinia amylovora on Apple Flower Stigmas.

Populations of the fire blight pathogen Erwinia amylovora Ea110 on apple flower stigmas were tracked over the course of apple bloom in field studies conducted between 2016 and 2019. In 18 of 23 experiments, flower stigmas inoculated on the first day of opening were found to harbor large (106 to 107 cells per flower) populations of E. amylovora when assessed 3 to 5 days postinoculation. However, populations inoculated on stigmas of flowers that were already open for 3 days did not reach 106 cells per flower, and populations inoculated on stigmas of flowers that were already open for 5 days never exceeded 104 cells per flower. During this study, ≥10-fold increases in E. amylovora stigma populations in a 24-h time period (termed population surges) were observed on 34.8, 20.0, and 4.0% of possible days on 1-, 3-, and 5-day-open flowers, respectively. Population surges occurred on days with average temperatures as high as 24.5 and as low as 6.1°C. Experiments incorporating more frequent sampling during days and overnight revealed that many population surges occurred between 10:00 p.m. and 2:00 a.m. A Pearson's correlation analysis of weather parameters occurring during surge events indicated that population surges were significantly associated with situations in which overnight temperatures increased or remained constant, in which wind speed decreased, and in which relative humidity increased. This study refines our knowledge of E. amylovora population dynamics and further indicates that E. amylovora is able to infect flowers during exposure to colder field temperatures than previously reported.

Soil heavy metal pollution of industrial legacies in China and health risk assessment.

Rapid urbanization in China has brought about large-scale factory relocation. Severe environmental ecological and human health risks are caused by a large number of contaminated legacies left in the city. To comprehensively review the pollution and assess the health risk of industrial legacies in China, a total of 625 polluted industrial legacies were compiled by document retrieval. Legacies are mainly located in the southwest of China, the North China Plain, Yangtze River Basin, Yangtze River Delta, and Pearl River Delta with a mean operation time of 35 years, and legacies of chemical manufacturing take the biggest proportion of all sites. Health risk assessments considering the uncertainty of exposure and toxic factors reveal that the soil heavy metal pollution in China is serious, with Pb, Cd, Zn, Ni, and As as dominant pollutants. Legacies of chemical manufacturing, ferrous metal processing, non-ferrous metal processing, and mines should be priority controlled for their large number and serious risks. Children are the most vulnerable people with more serious non-carcinogenic and carcinogenic risks, while males are slightly surpassed by females. Insights for better risk management of legacies are provided based on the comprehensive assessment of pollution and human health risk in this study.

Protein modifications in Hedgehog signaling: Cross talk and feedback regulation confer divergent Hedgehog signaling activity.

The complexity of the Hedgehog (Hh) signaling cascade has increased over the course of evolution; however, it does not suffice to accommodate the dynamic yet robust requirements of differential Hh signaling activity needed for embryonic development and adult homeostatic maintenance. One solution to solve this dilemma is to apply multiple forms of post-translational modifications (PTMs) to the core Hh signaling components, modulating their abundance, localization, and signaling activity. This review summarizes various forms of protein modifications utilized to regulate Hh signaling, with a special emphasis on crosstalk between different forms of PTMs and their feedback regulation by Hh signaling.