Genome-wide CRISPR/Cas9 library screen identifies C16orf62 as a host dependency factor for porcine deltacoronavirus infection.

ABSTRACTPorcine deltacoronavirus (PDCoV) is an emerging pathogen that can cause severe diarrhea and high mortality in suckling piglets. Moreover, evidence of PDCoV infection in humans has raised concerns regarding potential public health risks. To identify potential therapeutic targets for PDCoV, we performed a genome-wide CRISPR/Cas9 library screening to find key host factors important to PDCoV infection. Several host genes in this screen were enriched, including ANPEP, which encodes the PDCoV receptor aminopeptidase N (APN). Furthermore, we discovered C16orf62, also known as the VPS35 endosomal protein sorting factor like (VPS35L), as an important host factor required for PDCoV infection. C16orf62 is an important component of the multiprotein retriever complex involved in protein recycling in the endosomal compartment and its gene knockout led to a remarkable decrease in the binding and internalization of PDCoV into host cells. While we did not find evidence for direct interaction between C16orf62 and the viral s (spike) protein, C16orf62 gene knockout was shown to downregulate APN expression at the cell surface. This study marks the first instance of a genome-wide CRISPR/Cas9-based screen tailored for PDCoV, revealing C16orf62 as a host factor required for PDCoV replication. These insights may provide promising avenues for the development of antiviral drugs against PDCoV infection.

Assessing ecological responses of exposure to the pyrethroid insecticide lambda-cyhalothrin in sub-tropical freshwater ecosystems.

Pyrethroid insecticides are widely detected in aquatic ecosystems due to their extensive use in agriculture and horticulture, which could pose a potential risk to aquatic non-target organisms. While previous ecotoxicological studies have been conducted mainly with standard tests and local species under temperate conditions, scarce information is available on the effects of pyrethroid insecticides on communities and ecosystems under (sub-)tropical conditions. A single application of lambda-cyhalothrin at concentrations of 0, 9, 30, and 100 ng/L was evaluated in outdoor mesocosms under sub-tropical conditions. Lambda-cyhalothrin was found to dissipate rapidly in the water column, with only 11 % and 7 % of the remaining dose measured at 1 and 3 days after application, respectively. Lambda-cyhalothrin concentrations disappeared considerably faster from the water compartment compared to temperate conditions. Consistent decreases in abundance were observed for Lecane lunaris at the medium and higher treatments (NOEC = 9 ng/L) and at the highest treatment (NOEC = 30 ng/L) for Keratella tropica. On the contrary, two taxa belonging to Cladocera (i.e., Ceriodaphnia sp. and Diaphanosoma sp.) showed the most prominent increase in abundance related to the lambda-cyhalothrin treatments. At the community level, a consistent no observed effect concentrations (NOECs) of 9 ng/L could be calculated for the zooplankton community. A marginal significant overall treatment related effect was observed for the macroinvertebrate community. The results of species sensitivity distribution (SSD) analysis based on results of acute toxicity experiments conducted alongside the mesocosm experiment and obtained from the literature indicated that macroinvertebrates from temperate regions may be generally more sensitive than their counterparts in (sub-)tropical regions. Overall, these findings suggest that environmentally relevant concentrations of the pyrethroid insecticide lambda-cyhalothrin may lead to different ecological outcomes in freshwater ecosystems in the (sub-)tropics relative to temperate regions.

[Testis-sparing microsurgery for benign testis tumor: A report of 16 cases].

OBJECTIVE: To investigate the safety and clinical effect of testis-sparing microsurgery (TSMS) in the treatment of benign testis tumor (BTT). METHODS: We retrospectively analyzed the clinical data on 16 cases of BTT treated in the Department of Andrology of the Affiliated Hospital of Qingdao University from October 2020 to February 2023. The median age of the patients was 23 years. All the tumors were unilateral, 7 in the left and 9 in the right side, with a median diameter of 1.85 cm (1.0－3.5 cm). The patients all underwent color Doppler flow imaging (CDFI), MRI, semen analysis and examination of serum T, alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG) and lactate dehydrogenase (LDH), followed by TSMS. The boundaries between the tumors and normal testis tissue were accurately identified under the microscope, and the tumors and the adjacent normal testis tissue 2 mm from their margins were excised completely. Bipolar coagulation forceps were used for wound hemostasis to maximally preserve the normal testis tissue. The resected specimens were subjected to fast frozen pathology intraoperatively, and the patients were followed up for 14－40 months by regular scrotal CDFI, MRI and examinations of serum T and semen parameters. RESULTS: The levels of serum T, AFP, HCG and LDH and semen parameters were all within the normal range preoperatively. TSMS were successfully completed in all the cases, and all were pathologically confirmed as BTT according to the latest edition of WHO Classification of Tumors: Urinary and Male Genital Tumors. CDFI showed normal blood supply within the testis tissue at 1 month after surgery. No signs of intra-testicular tumor residue, recurrence or metastasis, nor significant changes in the levels of serum T, AFP, HCG or LDH or semen parameters were observed during the follow-up as compared with the baseline. Natural conception was achieved in 2 cases at 16 and 18 months respectively after surgery. CONCLUSION: BTT can be differentially diagnosed by CDFI and MRI before surgery and confirmed by histopathology. TSMS can achieve complete excision of the tumor, maximal sparing of the normal testis tissue and thereby effective preservation of male fertility.

Molecular characteristics of patients with colorectal signet-ring cell carcinoma with different ABO blood groups.

Background: Colorectal signet-ring cell carcinoma (SRCC) is a rare subtype of malignant adenocarcinoma, accounting for approximately 1 % of colorectal cancer (CRC) cases. Its biomarkers and molecular characteristics remain controversial, and there are no specific therapeutic targets or strategies for its clinical treatment. Methods: A retrospective study was conducted between January 2010 and December 2021. 1058 colorectal cancer cases from the Sun Yat-sen University Cancer Center and 489 cases from the Tumor Genome Atlas Project were included in the analysis, of which 64 were SRCC. Data extraction included patient demographics, blood types and risk factors, including clinical variables and genomics (either a 19-gene panel NGS or 1021-gene panel NGS). Univariate analyses were performed to identify factors significantly associated with overall survival. Results: The blood groups of 27 (42.2 %), 18 (28.1 %), 12 (18.8 %), and seven (10.9 %) patients were classified as O, A, B, and AB, respectively. We found that O was a unique blood group characterized by a low frequency of KRAS mutations, a high frequency of heterozygosity at each HLA class I locus, and a high tumor mutational burden (TMB). Patients in blood group A with high-frequency KRAS mutations and those in blood group B with anemia and metabolic abnormalities required targeted treatment. Furthermore, genetic alterations in SRCC differed from those in adenocarcinoma and mucinous adenocarcinoma. Conclusions: Our study revealed genomic changes in SRCC patients across different blood groups, which could advance the understanding and precise treatment of colorectal SRCC.

Unveiling the impact of airways: A comparative analysis of oropharyngeal and nasopharyngeal airways in painless fiberoptic bronchoscopy.

Background: This study compared the efficacy of oropharyngeal airways (OA) and nasopharyngeal airways (NA) in maintaining oxygenation during painless fiberoptic bronchoscopy (PFB) in patients sedated with remimazolam besylate. Methods: Two hundred and fifty-two patients were randomized to the OA or NA group. Remimazolam besylate was used for anesthesia induction and maintenance in both groups. We measured and recorded several physiological parameters, including mean arterial pressure, heart rate and oxygen saturation (SpO2), at various time points: before anesthesia (T1), after anesthesia induction (T2), immediately after the bronchoscope reached the trachea (T3), during the procedure (T4), and 5 min after transfer to the post-anesthesia care unit (T5). The incidence and frequency of hypoxemia, minimum SpO2 during the procedure and patient awakening time after flumazenil administration were also recorded. Additionally, the relationship between minimum SpO2 and body mass index (BMI) was investigated. Results: Patients in the NA group experienced a higher incidence of hypoxemia compared to the OA group. Patients in the OA group maintained higher SpO2 levels at T3 and had a higher minimum SpO2 during the procedure than the NA group. Furthermore, a significant negative correlation was observed between minimum SpO2 and BMI. Following flumazenil anesthesia reversal, nearly 97 % of patients awakened within 1 min. Conclusions: This study suggests that OA may provide a better safety profile than NA by preserving respiratory function during PFB.

Plant growth promoting endophyte modulates soil ecological characteristics during the enhancement process of cadmium phytoremediation.

Endophyte assisted phytoremediation of cadmium (Cd) contaminated soil represents a promising strategy. However, the precise soil ecological regulatory mechanisms by which endophyte enhance the Cd phytoextraction remain unclear. Here, we employed the plant growth promoting endophyte (PGPE) Pseudomonas sp. E3, which has been validated to effectively enhance Cd extraction in Solanum nigrum L., to investigate its regulatory mechanism on soil ecology. The results demonstrated that while PGPE inoculation resulted in minimal alterations to the physicochemical properties of the bulk soil, it led to a notable increase in acid phosphatase activity by 17.86% and urease activity by 24.85% in the rhizosphere soil. This, in turn, significantly raised the available nitrogen and phosphorus contents by 16.93% and 21.27%, respectively, in the rhizosphere soil. Additionally, PGPE inoculation effectively replenished the bioavailable fractions of Fe and Cd, which had been depleted due to root uptake. Importantly, the inoculation specifically augmented the abundance of biomarkers p_Patescibacteria, f_Saccharimonadales, and g_Saccharimonadales in the rhizosphere soil. These biomarkers exhibited a significant positive correlation with the available nutrient and metal element contents. Moreover, the co-occurrence network analysis demonstrated that the inoculation resulted in a simplified bacterial community network, which may have facilitated community synergism by displacing bacteria with a negative association. This regulation appears to occur independently of PGPE colonization. Overall, our findings suggested that PGPE also exerts a regulatory influence on soil ecological features, significantly aiding hyperaccumulators in nutrient acquisition and heavy metal accumulation.

An Unsupervised Error Detection Methodology for Detecting Mislabels in Healthcare Analytics.

Medical datasets may be imbalanced and contain errors due to subjective test results and clinical variability. The poor quality of original data affects classification accuracy and reliability. Hence, detecting abnormal samples in the dataset can help clinicians make better decisions. In this study, we propose an unsupervised error detection method using patterns discovered by the Pattern Discovery and Disentanglement (PDD) model, developed in our earlier work. Applied to the large data, the eICU Collaborative Research Database for sepsis risk assessment, the proposed algorithm can effectively discover statistically significant association patterns, generate an interpretable knowledge base for interpretability, cluster samples in an unsupervised learning manner, and detect abnormal samples from the dataset. As shown in the experimental result, our method outperformed K-Means by 38% on the full dataset and 47% on the reduced dataset for unsupervised clustering. Multiple supervised classifiers improve accuracy by an average of 4% after removing abnormal samples by the proposed error detection approach. Therefore, the proposed algorithm provides a robust and practical solution for unsupervised clustering and error detection in healthcare data.

Simplified coherent chaotic optical secure communication scheme based on the Kramers-Kronig receiver.

Enhancing physical layer encryption in fiber-optic networks remains a challenging yet vital task. In this Letter, we propose a simplified coherent chaotic secure optical communication scheme based on the Kramers-Kronig (KK) receiver. This scheme incorporates a semiconductor laser with a phase-conjugated optical feedback serving as a common chaotic source, and its chaotic output is directly injected into the two slave lasers arranged separately at the transmitter and receiver end to achieve high-quality synchronization of chaotic signals, with a corresponding chaotic bandwidth of 30.6 GHz. By virtue of the common-signal-induced broad chaotic synchronization, a proof-of-principle demonstration is successfully conducted. It involves the secure transmission of a 20 Gbaud 16-level quadrature amplitude modulation (16QAM) signal over a 50 km standard single-mode fiber (SSMF) link. At the receiver end, we deploy a KK receiver to reconstruct the field of the optical signal and hence enable signal compensation and recovery with offline digital signal processing (DSP). This method simplifies device requirements in the current chaotic coherent optical secure communication, offering a cost-effective mode and promising path for advancing physical layer encryption in inter-data center communications.

Photonic deep residual time-delay reservoir computing.

Time-delay reservoir computing (TDRC) represents a simplified variant of recurrent neural networks, employing a nonlinear node with a feedback mechanism to construct virtual nodes. The capabilities of TDRC can be enhanced by transitioning to a deep architecture. In this work, we propose a novel photonic deep residual TDRC (DR-TDRC) with augmented capabilities. The additional time delay added to the residual structure enables DR-TDRC superior to traditional deep structures across various benchmark tasks, especially in memory capability and almost an order of magnitude improvement in nonlinear channel equalization. Additionally, a specifically designed clipping algorithm is utilized to counteract the damage of redundant layers in deep structures, enabling the extension of the deep TDRC to dozens rather than just a few layers, with higher performance. We experimentally demonstrate the proof-of-concept with a 4-layer DR-TDRC containing 960 interrelated neurons (240 neurons per layer), based on four injection-locked distributed feedback lasers. We confirm the potential for scalable deep RC with elevated performance. Our results provide a feasible approach for expanding deep photonic computing to satisfy the boosting demand for artificial intelligence.

SERS biosensors based on catalytic hairpin self-assembly and hybridization chain reaction cascade signal amplification strategies for ultrasensitive microRNA-21 detection.

A highly sensitive surface-enhanced Raman scattering (SERS) biosensor has been developed for the detection of microRNA-21 (miR-21) using an isothermal enzyme-free cascade amplification method involving catalytic hairpin assembly (CHA) and hybridization chain reaction (HCR). The CHA reaction is triggered by the target miR-21, which causes hairpin DNA (C1 and C2) to self-assemble into CHA products. After AgNPs@Capture captures the resulting CHA product, the HCR reaction is started, forming long-stranded DNA on the surface of AgNPs. A strong SERS signal is generated due to the presence of a large amount of the Raman reporter methylene blue (MB) in the vicinity of the SERS "hot spot" on the surface of AgNPs. The monitoring of the SERS signal changes of MB allows for the highly sensitive and specific detection of miR-21. In optimal conditions, the biosensor exhibits a satisfactory linear range and a low detection limit for miR-21 of 42.3 fM. Additionally, this SERS biosensor shows outstanding selectivity and reproducibility. The application of this methodology to clinical blood samples allows for the differentiation of cancer patients from healthy controls. As a result, the CHA-HCR amplification strategy used in this SERS biosensor could be a useful tool for miRNA detection and early cancer screening.

Entropy drives the ligand recognition in G-protein-coupled receptor subtypes.

Achieving ligand subtype selectivity within highly homologous subtypes of G-protein-coupled receptor (GPCR) is critical yet challenging for GPCR drug discovery, primarily due to the unclear mechanism underlying ligand subtype selectivity, which hampers the rational design of subtype-selective ligands. Herein, we disclose an unusual molecular mechanism of entropy-driven ligand recognition in cannabinoid (CB) receptor subtypes, revealed through atomic-level molecular dynamics simulations, cryoelectron microscopy structure, and mutagenesis experiments. This mechanism is attributed to the distinct conformational dynamics of the receptor's orthosteric pocket, leading to variations in ligand binding entropy and consequently, differential binding affinities, which culminate in specific ligand recognition. We experimentally validated this mechanism and leveraged it to design ligands with enhanced or ablated subtype selectivity. One such ligand demonstrated favorable pharmacokinetic properties and significant efficacy in rodent inflammatory analgesic models. More importantly, it is precisely due to the high subtype selectivity obtained based on this mechanism that this ligand does not show addictive properties in animal models. Our findings elucidate the unconventional role of entropy in CB receptor subtype selectivity and suggest a strategy for rational design of ligands to achieve entropy-driven subtype selectivity for many pharmaceutically important GPCRs.

[Value of calprotectin S100 A8/A9 in predicting the severity of Mycoplasma pneumoniae pneumonia in children]. / 钙卫蛋白S100 A8/A9å¯¹è‚ºç‚Žæ”¯åŽŸä½“è‚ºç‚Žæ‚£å„¿ç— æƒ ä¸¥é‡ç¨‹åº¦çš„é¢„æµ‹ä»·å€¼.

OBJECTIVES: To investigate the role of calprotectin S100 A8/A9 complex in evaluating the condition of children with severe Mycoplasma pneumoniae pneumonia (SMPP). METHODS: A prospective study was conducted among 136 children with Mycoplasma pneumoniae pneumonia (MPP) and 30 healthy controls. According to the severity of the condition, the children with MPP were divided into mild subgroup (40 children) and SMPP subgroup (96 children). The levels of S100 A8/A9 complex and related inflammatory factors were compared between the MPP group and the healthy control group, as well as between the two subgroups of MPP. The role of S100 A8/A9 in assessing the severity of MPP was explored. RESULTS: The MPP group had a significantly higher level of S100 A8/A9 than the healthy control group, with a significantly greater increase in the SMPP subgroup (P<0.05). The multivariate logistic regression analysis showed that the increases in serum C reactive protein (CRP) and S100A8/A9 were closely associated with SMPP (P<0.05). The receiver operating characteristic (ROC) curve analysis showed that the combined measurement of serum S100 A8/A9 and CRP had an area under the ROC curve of 0.904 in predicting SMPP, which was significantly higher than the AUC of S100 A8/A9 or CRP alone (P<0.05), with a specificity of 0.718 and a sensitivity of 0.952. CONCLUSIONS: S100 A8/A9 is closely associated with the severity of MPP, and the combination of S100 A8/A9 with CRP is more advantageous for assessing the severity of MPP in children.

Rapid discrimination of African swine fever virus nucleic acid and virions using BenzoNuclease.

African swine fever (ASF) is an acute and severe infectious disease caused by the African Swine Fever Virus (ASFV). ASFV exhibits significant resistance and stability in the environment, which, coupled with its double-stranded DNA and large genome, predisposes it to contaminate laboratory samples. This characteristic can lead to false-positive results in swine farm settings even days after disinfection, as detectable through polymerase chain reaction (PCR) or real-time fluorescent quantitative PCR (qPCR) assays. To meet the demand for efficient clinical methods capable of discriminating between ASFV nucleic acid and ASFV virions, this study aims to ascertain the efficacy of the nuclease "BenzoNuclease" in distinguishing ASFV nucleic acid (ASFV-DNA) from ASFV virions. BenzoNuclease is a versatile nucleic acid enzyme with the capacity to degrade nearly all forms of DNA and RNA. Initially, this research established a highly sensitive general PCR detection method for ASFV. Subsequently, a positive control was constructed using the M13 bacteriophage to substitute for active ASFV, facilitating the development of an improved qPCR method. It is important to note that common disinfectants have the potential to deactivate BenzoNuclease. However, in an environment simulating actual production applications, residual disinfectants do not interfere with the enzymatic efficacy of BenzoNuclease, thus not affecting the detection capabilities of this method. Positive clinical samples from pig farms, upon testing with the improved method, revealed that three samples were positive, indicating the presence of viral particles, while the remaining samples were negative, indicating the presence of nucleic acids. This provides an additional new option for sample testing in pig farms.

Pharmacogenomic Polygenic Model of Clopidogrel Predicts Recurrent Ischemic Events in Chinese Patients With Coronary Artery Disease.

PURPOSE: Patients with coronary artery disease (CAD) need to take antiplatelet drugs regularly in order to prevent thrombosis; however, there is existing inter-individual variability in drug response. Pharmacogenomic studies indicate that drug response may also be influenced by genetic variants, and multiple genetic variants may work together. We assumed that patients carrying more risk alleles might have a worse clopidogrel drug response and that a polygenic model integrated different single variants might have the potential to explain clopidogrel drug response variability better. We aimed to investigate whether the polygenic model could be used to predict clopidogrel drug response. METHODS: A total of 935 CAD patients were enrolled in the study. We investigated the association between 19 clopidogrel-related single-nucleotide polymorphisms (SNPs) and the incidence of recurrent ischemic events. Additionally, a polygenic model was constructed to assess the risk of ischemic events. FINDINGS: There were only 2 SNPs of CYP2C8 gene (rs1934980 and rs17110453) that were nominally associated with incidence of recurrent ischemic events. We constructed a polygenic model integrated with 6 clopidogrel-related SNPs. When compared with patients carrying 6 or fewer risk alleles, patients with 7 or more risk alleles had a higher risk of ischemic events (hazard ratio = 1.87; P = 0.04). IMPLICATIONS: The polygenetic model may be useful for clopidogrel drug response prediction in patients with CAD.

Characterizing the aggregated encoding method utilizing bursts activated by a VCSEL-neuron with a feedback structure.

The rapid advancement of photonic technologies has facilitated the development of photonic neurons that emulate neuronal functionalities akin to those observed in the human brain. Neuronal bursts frequently occur in behaviors where information is encoded and transmitted. Here, we present the demonstration of the bursting response activated by an artificial photonic neuron. This neuron utilizes a single vertical-cavity surface-emitting laser (VCSEL) and encodes multiple stimuli effectively by varying the spike count during a burst based on the polarization competition in the VCSEL. By virtue of the modulated optical injection in the VCSEL employed to trigger the spiking response, we activate bursts output in the VCSEL with a feedback structure in this scheme. The bursting response activated by the VCSEL-neuron exhibits neural signal characteristics, promising an excitation threshold and the refractory period. Significantly, this marks the inaugural implementation of a controllable integrated encoding scheme predicated on bursts within photonic neurons. There are two remarkable merits; on the one hand, the interspike interval of bursts is distinctly diminished, amounting to merely one twenty-fourth compared to that observed in optoelectronic oscillators. Moreover, the interspike period of bursts is about 70.8% shorter than the period of spikes activated by a VCSEL neuron without optical feedback. Our results may shed light on the analogy between optical and biological neurons and open the door to fast burst encoding-based optical systems with a speed several orders of magnitude faster than their biological counterparts.

Enhanced extreme events in three cascade-coupled semiconductor lasers.

Extreme events (EEs) are rare and unpredictable, as have been observed in nature. Up to now, manipulating EEs has remained a challenge. Here, we experimentally observe the enhancement of EEs in a three cascade-coupled semiconductor laser system. Specifically, a continuous-wave optical injection semiconductor laser acts as the chaotic source with rare EEs, which is subsequently injected into a second laser for increasing the number of EEs. Interestingly, we find that the number and region size of EEs can be further enhanced by sequentially injecting into a third laser, i.e., a cascade-injection structure. Our experimental observations are in good agreement with the numerical results, which indicate that EEs can be significantly enhanced in wide injection parameter space due to the cascade-injection effect. Furthermore, our simulations show that the evoluation of the regions with enhanced EEs may be associated with the noise considered.

Case report: Multiple organ failure caused by Japanese spotted fever.

A 71-year-old male had disseminated multiple organ dysfunction syndrome (MODS). Following treatment with cefotaxime and piperacillin-tazobactam, his symptoms have worsened instead. Multiple organ failure caused by Japanese Spotted Fever (JSF) was diagnosed based on metagenomic next-generation sequencing (mNGS), we rapidly treated the patient with doxycycline. Thereafter, his symptoms gradually improved. In this report, we emphasized the importance of rapid microbial diagnostic tools and the early use of tetracyclines for the treatment of JSF.

Conjoint analysis of physio-biochemical, transcriptomic, and metabolomic reveals the response characteristics of solanum nigrum L. to cadmium stress.

Cadmium (Cd) is a nonessential element in plants and has adverse effects on the growth and development of plants. However, the molecular mechanisms of Cd phytotoxicity, tolerance and accumulation in hyperaccumulators Solanum nigrum L. has not been well understood. Here, physiology, transcriptome, and metabolome analyses were conducted to investigate the influence on the S. nigrum under 0, 25, 50, 75 and 100 µM Cd concentrations for 7 days. Pot experiments demonstrated that compared with the control, Cd treatment significantly inhibited the biomass, promoted the Cd accumulation and translocation, and disturbed the balance of mineral nutrient metabolism in S. nigrum, particularly at 100 µM Cd level. Moreover, the photosynthetic pigments contents were severely decreased, while the content of total protein, proline, malondialdehyde (MDA), H2O2, and antioxidant enzyme activities generally increased first and then slightly declined with increasing Cd concentrations, in both leaves and roots. Furthermore, combined with the previous transcriptomic data, numerous crucial coding-genes related to mineral nutrients and Cd ion transport, and the antioxidant enzymes biosynthesis were identified, and their expression pattern was regulated under different Cd stress. Simultaneously, metabolomic analyses revealed that Cd treatment significantly changed the expression level of many metabolites related to amino acid, lipid, carbohydrate, and nucleotide metabolism. Metabolic pathway analysis also showed that S. nigrum roots activated some differentially expressed metabolites (DEMs) involved in energy metabolism, which may enhance the energy supply for detoxification. Importantly, central common metabolism pathways of DEGs and DEMs, including the "TCA cycle", "glutathione metabolic pathway" and "glyoxylate and dicarboxylate metabolism" were screened using conjoint transcriptomics and metabolomics analysis. Our results provide some novel evidences on the physiological and molecular mechanisms of Cd tolerance in hyperaccumulator S. nigrum plants.

IL-38 Aggravates Atopic Dermatitis via Facilitating Migration of Langerhans cells.

Atopic dermatitis (AD) is a common inflammation skin disease that involves dysregulated interplay between immune cells and keratinocytes. Interleukin-38 (IL-38), a poorly characterized IL-1 family cytokine, its role and mechanism in the pathogenesis of AD is elusive. Here, we show that IL-38 is mainly secreted by epidermal keratinocytes and highly expressed in the skin and downregulated in AD lesions. We generated IL-38 keratinocyte-specific knockout mice (K14Cre/+-IL-38f/f ) and induced AD models by 2,4-dinitrofluorobenzene (DNFB). Unexpectedly, after treatment with DNFB, K14Cre/+-IL-38f/f mice were less susceptible to cutaneous inflammation of AD. Moreover, keratinocyte-specific deletion of IL-38 suppressed the migration of Langerhans cells (LCs) into lymph nodes which results in disturbed differentiation of CD4+T cells and decreased the infiltration of immune cells into AD lesions. LCs are a type of dendritic cell that reside specifically in the epidermis and regulate immune responses. We developed LC-like cells in vitro from mouse bone marrow (BM) and treated with recombined IL-38. The results show that IL-38 depended on IL-36R, activated the phosphorylated expression of IRAK4 and NF-κB P65 and upregulated the expression of CCR7 to promoting the migration of LCs, nevertheless, the upregulation disappeared with the addition of IL-36 receptor antagonist (IL-36RA), IRAK4 or NF-κB P65 inhibitor. Furthermore, after treatment with IRAK4 inhibitors, the experimental AD phenotypes were alleviated and so IRAK4 is considered a promising target for the treatment of inflammatory diseases. Overall, our findings indicated a potential pathway that IL-38 depends on IL-36R, leading to LCs migration to promote AD by upregulating CCR7 via IRAK4/NF-κB and implied the prevention and treatment of AD, supporting potential clinical utilization of IRAK4 inhibitors in AD treatment.