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Bisphenol A (BPA) is a widespread environmental endocrine disruptor (EED) that can cause various environmental and health issues by inducing oxidative stress. The c-Jun N-terminal kinase (JNK) signaling pathway plays a crucial role in oxidative stress-mediated cellular damage. Although folic acid (FA) has demonstrated antioxidant properties, its potential protective effects against BPA-induced developmental and neurotoxicity, as well as the mechanisms involved in the JNK signaling pathway, are still not completely understood. Zebrafish embryos were exposed to different concentrations of BPA ranging from 20 to 40 µM, with or without treatment of 50 µM FA, starting at 6 hours post-fertilization (hpf). Various parameters such as hatchability, survival rate, body length, and heart rate were measured and analyzed. Transcriptome sequencing was conducted to study the changes in gene expression. Oxidative stress markers, including reactive oxygen species (ROS), lipid peroxidation (LPO), hydrogen peroxide (H2O2), and catalase (CAT) activity, were assessed. The expression of proteins related to the mitogen-activated protein kinase (MAPK)/JNK pathway was analyzed using western blot. Neurodevelopmental and apoptotic outcomes were evaluated through behavioral tests, immunofluorescence and RT-qPCR examinations. The study found that exposure to BPA led to a decrease in hatchability, survival, body length, heart rate, total antioxidant capacity and promoted apoptosis in zebrafish larvae. However, supplementation with FA was able to alleviate these negative effects. BPA exposure increased levels of ROS, LPO, and H2O2, while decreasing CAT activity in zebrafish larvae. Treatment with FA effectively reduced BPA-induced oxidative stress and restored antioxidant defense systems. Moreover, KEGG pathway enrichment analysis revealed that the MAPK signaling pathway was the most enriched signaling pathway. Further studies revealed that BPA activated the JNK signaling pathway, while FA suppressed this activation. Additionally, FA significantly improved BPA-induced neurobehavioral deficits and protected against neurocytological alterations. Our findings demonstrate that FA effectively protects against BPA-induced developmental and neurotoxic effects in zebrafish by suppressing oxidative stress and inhibiting the JNK signaling pathway. This study provides new strategies and insights for preventing BPA-induced developmental and neurotoxicity in aquatic organisms.

Abstract Tuberculosis (TB) remains the second leading cause of death from a single infectious agent and long-term medication could lead to antituberculosis drug-induced liver injury (ATB-DILI). We established a prospective longitudinal cohort of ATB-DILI with multiple timepoint blood sampling and used untargeted metabolomics to analyze the metabolic profiles of 107 plasma samples from healthy controls and newly diagnosed TB patients who either developed ATB-DILI within 2 months of anti-TB treatment (ATB-DILI subjects) or completed their treatment without any adverse drug reaction (ATB-Ctrl subjects). The untargeted metabolome revealed that 77 metabolites (of 895 total) were significantly changed with ATB-DILI progression. Among them, levels of multiple fatty acids and bile acids significantly increased over time in ATB-DILI subjects. Meanwhile, metabolites of the same class were highly correlated with each other and pathway analysis indicated both fatty acids metabolism and bile acids metabolism were up-regulated with ATB-DILI progression. The targeted metabolome further validated that 5 fatty acids had prediction capability at the early stage of the disease and 6 bile acids had a better diagnostic performance when ATB-DILI occurred. These findings provide evidence indicating that fatty acids metabolism and bile acids metabolism play a vital role during ATB-DILI progression. Our report adds a dynamic perspective better to understand the pathological process of ATB-DILI in clinical settings.

PurposeTo report a case of steroid-resistant nephrotic syndrome caused by a LAMB2 gene mutation, examine the associated literature, outline the clinical and genetic features of Pierson syndrome, and deepen the clinical comprehension of this condition.MethodThe study involved retrospective summary and analysis of the clinical presentations, genetic mutation features, and prognosis of one case involving a LAMB2 gene mutation. PubMed, Medline, Web of Science, CNKI, and Wanfang databases were searched to gather and summarize information on the pathological phenotypes and genotypic alterations associated with LAMB2 mutations.ResultA 9-month-old infant presented with edema and massive proteinuria, along with horizontal nystagmus and miosis, manifesting clinically as steroid-resistant nephrotic syndrome. Ocular symptoms prompted both a kidney biopsy and genetic testing. The biopsy revealed minimal change disease, while genetic testing identified compound heterozygous mutations in the LAMB2 gene: c.1405C > T (p.R469X) and c.1066 T > A (p.C356S), inherited from the father and mother, respectively. These mutations were determined to be novel. The diagnosis was confirmed as a LAMB2 gene mutation. A literature review of 26 cases with LAMB2 mutations indicated these typically presented as steroid-resistant or congenital nephrotic syndrome, with 14 cases also displaying ocular symptoms. Among the 18 cases undergoing kidney biopsy, findings included focal segmental glomerulosclerosis in 10 cases, minimal change disease in 4 cases, diffuse mesangial sclerosis in 2 cases, IgM nephropathy in 1 case, and mesangial proliferation in 1 case. Electron microscopy in 10 cases showed basement membrane splitting. Genetic analysis revealed 15 cases with compound heterozygous mutations, 5 with homozygous mutations, 3 with heterozygous mutations, 2 with frame-shift mutations, and 1 with a truncating mutation. 16 out of the 26 reported cases progressed to end-stage kidney disease.ConclusionMutations in the LAMB2 gene primarily manifest as steroid-resistant or congenital nephrotic syndrome, often accompanied by ocular abnormalities, suggesting a strong likelihood of this disease. The results of genetic testing offer a foundational basis for clinical diagnosis. The identification of a new mutation site in this case expands the known spectrum of mutations in the LAMB2 gene. Unfortunately, the prognosis associated with this condition is generally poor.

Abstract Objectives Juvenile dermatomyositis (JDM) is a chronic autoimmune disease. Some patients remain in an active state even though they were administrated with a combination of corticosteroid and methotrexate. Existing research has suggested that interferon and Janus kinase played an important role in pathogenesis. Existing research has suggested the efficacy of JAK inhibitors (JAKi). Our retrospective study aimed to investigate the efficacy of tofacitinib in refractory JDM patients. Methods A total of eighty-eight patients in China who had been diagnosed with JDM and subjected to tofacitinib therapy for over 3 months were retrospectively analyzed. Skin and muscle manifestations were assessed using the Cutaneous Assessment Tool-binary method (CAT-BM), Childhood Myositis Assessment Scale (CMAS), and kinase. Pulmonary function was assessed using a high-resolution CT (computerized tomography) scan and pulmonary symptoms. All patients were subjected to regular follow-up, and core measures were assessed every 3 months after initiation. Furthermore, the data were analyzed using the Wilcoxon single test, Mann–Whitney U test, and chi-square test. Results Compared with the baseline data, skin and muscle manifestations were found significantly improved during the respective follow-up visit. At the most recent follow-up, nearly 50% of patients achieved a clinical complete response and six patients received tofacitinib monotherapy. Sixty percent of patients suffering from interstitial lung disease well recovered on high-resolution CT. Seventy-five percent of patients showed a reduction in the size or number of calcinosis, and 25% of patients showed completely resolved calcinosis. Conclusion In this study, the result suggested that tofacitinib therapy exerted a certain effect on skin manifestations, muscle manifestations, interstitial lung disease (ILD), calcinosis, as well as downgrade of medication. In-depth research should be conducted to focus on the correlation between the pathogenesis of JDM and JAKi.

Abstract Background WDR35 variants are known to cause a rare autosomal recessive disorder-Cranioectodermal dysplasia (CED). The CED patients are commonly present with facial dysmorphisms (frontal bossing and low-set ears), sagittal craniosynostosis, growth retardation, dolichocephaly, skeletal deformities (brachydactyly, terminal hypoplasia of the fingers and narrow thorax), ectodermal abnormalities (sparse hair, and finger/toe nail dysplasia), nephronophthisis, retinal dystrophy and hepatic fibrosis. Diagnosis of CED can be difficult because it presents with high genetic heterogeneity. However, our understanding of the phenotype of CED caused by WDR35 variants could be more explicit, and the correlation between genotype and phenotype needs further improvement. Case presentation We report a case of the first Chinses patient of CED caused by WDR35 variants, a 3-year-and-3-month-old patient, who was admitted to our hospital with frontal bossing, growth retardation, low set ears, dolichocephaly, sparse hair, and small limbs, abnormal renal function, and moderate anemia. The child showed a novel phenotype of the ectopic testis except for presenting typical CED characteristics, and he was identified with novel compound heterozygous WDR35 variants (c.2590 C > T, p.Gln864* and c.2408_2416del, p.Asn803_Ala805del; NM_001006657). He was given iron succinate and erythropoietin to improve anemia and to inhibit repeated metabolic acidosis and hyperkalemia through acid correction, diuretic, and potassium-lowering treatments. The parents refused to accept renal replacement therapy for their child and were discharged voluntarily. Conclusions This is the first reported case of the WDR35 variants that can lead to CED and ectopic testis, which is also the first Chinese patient associated with WDR35 variants. This study expands our understanding of genotype-phenotype association in patients with WDR35 variants and provides genetic counseling for prevention and intervention in this genetic disorder. Neonatal carriers should be followed up for kidney and CED-related diseases to detect warning signs.

Abstract Background BAT1706 is a proposed biosimilar of bevacizumab, a vascular endothelial growth factor A (VEGF-A)-targeting biologic used to treat several different cancers, including metastatic colorectal cancer. A comprehensive physicochemical and functional similarity assessment is a key component of demonstrating biosimilarity between a reference biologic and a proposed biosimilar. Here we report the physicochemical and functional similarity of BAT1706 and reference bevacizumab sourced from both the United States (US-bevacizumab) and the European Union (EU-bevacizumab). Method A large range of product attributes, including primary and higher order structure, post-translational modifications, purity, stability, and potency, were characterized for BAT1706 and EU/US-bevacizumab using sensitive state-of-the-art analytical techniques. Up to 18 lots of US- and 29 lots of EU-bevacizumab, and 10 unique drug substance lots of BAT1706, were assessed. Result BAT1706 was shown to have an identical amino acid sequence and an indistinguishable higher-order structure compared with EU/US-bevacizumab. BAT1706 and EU/US-bevacizumab also exhibited similar post-translational modifications, glycan profiles, and charge variants. Potency, assessed using a wide range of bioassays, was also shown to be comparable between BAT1706 and EU/US-bevacizumab, with statistical equivalence demonstrated for VEGF-A binding and neutralizing activity. Conclusion Overall, this extensive comparability exercise demonstrated BAT1706 to match EU/US-bevacizumab in terms of all physicochemical and functional attributes assessed.

A new dimeric C-glycoside polyketide chrysomycin F (1), along with four new monomeric compounds, chrysomycins G (2), H (3), I (4), J (5), as well as three known analogues, chrysomycins A (6), B (7), and C (8), were isolated and characterised from a strain of Streptomyces sp. obtained from a sediment sample collected from the South China Sea. Their structures were determined by detailed spectroscopic analysis. Chrysomycin F contains two diastereomers, whose structures were further elucidated by a biomimetic [2 + 2] photodimerisation of chrysomycin A. Chrysomycins B and C showed potent anti-tuberculosis activity against both wild-type Mycobacterium tuberculosis and a number of clinically isolated MDR M. tuberculosis strains.

OX40 (CD134), a member of the TNF receptor superfamily, is a widely studied costimulatory immune checkpoint. Several OX40 agonistic antibodies are in the clinical stage for cancer treatment, among which PF-04518600 is the leader and currently in phase II trial. It has been recognized that one potential mode of action for anti-OX40 antibodies is the deletion of intratumoral Tregs. Thus, a novel human anti-OX40 antibody, BAT6026, was generated with enhanced antibody dependent cellular cytotoxicity (ADCC) via fucose deletion to strengthen its Treg depletion activity. This characteristic of BAT6026 differentiates it from other previously reported anti-OX40 antibodies in the field of tumor therapy. The affinity of BT6026 to OX40 was 0.28nM, approximately 8 times stronger than that of PF-04518600. BAT6026 effectively competed for the binding of ligand OX40L to OX40, whereas PF-04518600 only partially competed. Moreover, compared to PF-04518600, BAT6026 activated T cells more effectively when clustered by FcγRs engagement and stimulated SEB-pretreated PBMCs to secrete IL-2 cytokines in vitro. In addition, BAT6026 demonstrated stronger anti-tumor activity than PF-04518600 in an OX40-humanized mouse MC38 tumor model. BAT6026 also showed a significantly synergistic effect on tumor inhibition when combined treatment with PD-1 antibody. Analysis of tumor-infiltrating T cells revealed that BAT6026 treatment significantly reduced Treg cells and increased CD8+ T cells in tumor. Preclinical safety assessment in non-human primates demonstrated a good safety profile for BAT6026. Together these data warrant further development of BAT6026 into clinical trials for patients with cancer.

Tumor hypoxia is the most common feature of radioresistance to the radiotherapy (RT) of lung cancer and results in poor clinical outcomes. High-linear energy transfer (LET) radiation is a novel RT technique to overcome this problem. However, a limited number of studies have been elucidated on the underlying mechanism(s) of RIBE and RISBE in cancer cells exposed to high-LET radiation under hypoxia. Here, we developed a new method to investigate the RIBE and RISBE under hypoxia using the SPICE-QST proton microbeams and a layered tissue co-culture system. Normal lung fibroblast (WI-38) and lung cancer (A549) cells were exposed in the range of 06 Gy of proton microbeams, wherein only ~0.04–0.15% of the cells were traversed by protons. Subsequently, primary bystander A549 cells were co-cultured with secondary bystander A549 cells in the presence or absence of a GJIC and NO inhibitor using co-culture systems. Studies show that there are differences in RIBE in A549 and WI-38 primary bystander cells under normoxia and hypoxia. Interestingly, treatment with a GJIC inhibitor showed an increase in the toxicity of primary bystander WI-38 cells but a decrease in A549 cells under hypoxia. Our results also show the induction of RISBE in secondary bystander A549 cells under hypoxia, where GJIC and NO inhibitors reduced the stressful effects on secondary bystander A549 cells. Together, these preliminary results, for the first time, represented the involvement of intercellular communications through GJIC in propagation of RIBE and RISBE in hypoxic cancer cells.

To study the profiles and relationships of terpenoids and phytohormones in leaves of red-flesh citrus, we examined four red-flesh mutants that accumulate lycopene in the fruit and their corresponding wild types. We compared their contents of monoterpenoid and sesquiterpenoid volatiles, triterpenoid limonoid aglycones, and tetraterpenoid carotenoids. The types and concentrations of these terpenoids in the leaves varied among genotypes, and the leaf terpenoid profiles differed between red-flesh mutants and their wild types. However, lycopene was not detected in citrus leaves of all eight varieties, including the four mutants. According to phytohormone accumulation in the leaves, the citrus varieties could be classified into a low-phytohormone group (‘Red Anliu’ sweet orange, ‘Anliu’ sweet orange, and ‘Cara Cara’ navel orange), a high-phytohormone group (‘Seike’ navel orange), and a high-jasmonic acid group (‘Red-flesh Guanxi’ pummelo, ‘Guanxi’ pummelo, ‘Chuhong’ pummelo, and ‘Feicui’ pummelo). The contents of terpenoid volatiles were very low in leaves of ‘Red-flesh Guanxi’ and ‘Guanxi’ pummelo; therefore, they are ideal materials for verifying the functions of genes related to terpenoid volatiles in overexpression analyses. Sesquiterpenoid volatiles were positively correlated with phytohormones of abscisic acid, jasmonic acid, and salicylic acid. Taken together, lycopene was undetected in the leaves of red-flesh citrus mutants with abundant lycopene in their juice sacs, which suggested a tissue-specific accumulation pattern of lycopene in citrus red-flesh mutants. Furthermore, leaf volatile profiles could be suitable to develop fingerprint chromatograms of citrus resources, since leaf volatile profiles were dominated by several compounds that varied among genotypes in their combinations and concentrations.

Cardiovascular diseases (CVD), with high morbidity and mortality, seriously affect people’s life and social development. Clinically, reperfusion therapy is typically used to treat ischemic cardiomyopathy, such as severe coronary heart disease and acute myocardial infarction. However, reperfusion therapy can lead to myocardial ischemia reperfusion injury (MIRI), which can affect the prognosis of patients. Studying the mechanisms of MIRI can help us improve the treatment of MIRI. The pathological process of MIRI involves many mechanisms such as ferroptosis and mitophagy. Ferroptosis can exacerbate MIRI, and regulation of mitophagy can alleviate MIRI. Both ferroptosis and mitophagy are closely related to ROS, but there is no clear understanding of the relationship between ferroptosis and mitophagy. In this review, we analyzed the relationship between ferroptosis and mitophagy according to the role of mTOR, NLPR3 and HIF. In addition, simultaneous regulation of mitophagy and ferroptosis may be superior to single therapy for MIRI. We summarized potential drugs that can regulate mitophagy and/or ferroptosis, hoping to provide reference for the development of drugs and methods for MIRI treatment.

The interior atmosphere of storage facilities is very important for maintaining fruit quality and delaying senescence, so it's of significance to determine the volatile profiles in this environment for the postharvest industry. However, volatile profiles inside fruit storage facilities have been rarely reported. To study the volatile profiles of the atmosphere inside fruit storage facilities, a method comprising Monotrap™ adsorbent and GC–MS analysis in the study was developed and tested. Based on that, the volatile profiles in the atmosphere inside fruit storage facilities at four locations in Shaanxi Province were monitored. Altogether thirty-six volatiles were detected, and most of them were identified as esters. An analysis of the similarities of volatile profiles showed that the three storage rooms at each location clustered together. The storage rooms at two locations in Baoji had the most similar volatile profiles, and both were similar to that at Xianyang, but different from that at Yan'an, which were consistent with their geographic distributions. On the basis of a principal component analysis, heatmap dendrogram, and correlation matrix analysis, these compounds clustered into five groups. Compounds in Group 1, which were abundant in the storage room at Yan'an, were branched-chain esters, whereas the compounds in the other four groups were mainly straight-chain esters which were abundant in the storage rooms at Xianyang and Baoji. The difference among volatile profiles inside fruit storage facilities at four locations might be caused by ultraviolet radiation. In this study, we demonstrated the Monotrap™ adsorbent and GC–MS analysis were an efficient method for volatile compounds detection inside fruit storage facilities.

Lipid phosphate phosphatases (LPPs) are a key enzyme in the production and degradation of phosphatidic acid (PA), which plays an important role in plant growth, development, stress resistance and plant hormone response. Thus far, little is known about the LPP family genes in kiwifruit (Actinidia spp.). According to this study, 7 members in the AcLPP family were identified from the whole genome of kiwifruit, the subcellular localization predictions were mainly on the plasma membrane. Chromosomal localization analysis showed that the AcLPP genes were unevenly distributed on 5 chromosomes, it was determined to have undergone strong purifying selection pressure. There were 5 duplicate gene pairs and all underwent segmental duplication events. The LPP genes of kiwifruit were conserved when compared with other plants, especially in terms of evolutionary relationships, conserved motifs, protein sequences, and gene structures. Cis-regulatory elements mainly included hormone response elements and abiotic response elements. Functional annotation of GO revealed that AcLPP genes were closely related to phosphatase/hydrolase activity, phosphorus metabolism and dephosphorylation. AcLPP genes family were predicted to be targets of miRNA. Transcript level analysis revealed that the AcLPP family played diverse functions in different tissues and during growth, development, and postharvest storage stages. qPCR analysis showed that the members of AcLPP gene family might be regulated by ETH, ABA, GA3, and IAA hormone signals. The family members were regulated by the stress of salt stress, osmotic stress, cold stress, and heat stress. These results would provide a basis and reference for studying the agricultural characteristics of kiwifruit and improving its stress resistance.

Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage kidney disease (ESKD) in children and young adults. For approximately 30% of children with SRNS results from a genetic cause. In this study, genotype-phenotype correlations in a cohort of 283 pediatric patients with SRNS or early-onset NS (nephrotic syndrome presenting within the first year of life) from 23 major pediatric nephrology centers in China were analyzed. All patients were performed with next-generation sequencing and Sanger sequencing. The overall mutation detection rate was 37.5% (106 of 283 patients). WT1 was the most frequently detected mutation, followed by NPHS1, NPHS2, and ADCK4, and these four major causative genes (WT1, NPHS1, NPHS2, and ADCK4) account for 73.6% of patients with monogenic SRNS. Thirteen of 106 individuals (12.3%) carried mutations in ADCK4 that function within the coenzyme Q10 biosynthesis pathway. In the higher frequently ADCK4-related SRNS, two mutations, c.737G>A (p.S246N) and c.748G>C (p.D250H), were the most prevalent. Our study provides not only definitive diagnosis but also facilitate available targeted treatment for SRNS, and prediction of prognosis and renal outcome. Our indications for genetic testing are patients with FSGS, initial SRNS, cases of positive family history or those with extra-renal manifestations.

Citrus yellow vein clearing virus (CYVCV) is the causal agent of yellow vein clearing disease, a significant and devastating disease of most citrus species including lemon and sour orange. CYVCV, a single-strand positive-sense RNA virus containing six ORFs (Open Reading Frames), represents a new species in the genus Mandarivirus of the Alphaflexiviridae family. The virus can cause particularly serious damage, resulting in reduced tree vigor, lower yields, and decreased marketability of fruit production, and it has been found in India, Turkey, Pakistan, China and Iran. Here we described the geographical distribution of the virus, its transmission mode by grafting, mechanical inoculation, and insects, as well as currently available techniques for detection. In addition, we also discussed practical measures aimed at controlling the disease and provided theoretical guidance to prevent the acquisition and spread of the disease that is a significant step toward ensuring the health of the citrus industry.

ABSTRACT Aquaporins, integral membrane proteins widely distributed in organisms, facilitate the transport of water, glycerol, and other small uncharged solutes across cellular membranes and play important physiological roles in eukaryotes. However, characterizations and physiological functions of the prokaryotic aquaporins remain largely unknown. Here, we report that Streptococcus pneumoniae (pneumococcus) AqpC (Pn-AqpC), representing a new aquaporin subfamily possessing a distinct substrate-selective channel, functions as an oxygen porin by facilitating oxygen movement across the cell membrane and contributes significantly to pneumococcal virulence. The use of a phosphorescent oxygen probe showed that Pn-AqpC facilitates oxygen permeation into pneumococcal and Pn-AqpC-expressing yeast cells. Reconstituting Pn-AqpC into liposomes prepared with pneumococcal and Escherichia coli cellular membranes further verified that Pn-AqpC transports O2 but not water or glycerol. Alanine substitution showed that Pro232 in the substrate channel is key for Pn-AqpC in O2 transport. The deletion of Pn-aqpC significantly reduced H2O2 production and resistance to H2O2 and NO of pneumococci, whereas low-H2O2 treatment helped the ΔPn-aqpC mutant resist higher levels of H2O2 and even NO, indicating that Pn-AqpC-facilitated O2 permeation contributes to pneumococcal resistance to H2O2 and NO. Remarkably, the lack of Pn-aqpC alleviated cell autolysis, thus reducing pneumolysin (Ply) release and decreasing the hemolysis of pneumococci. Accordingly, the ΔPn-aqpC mutant markedly reduced survival in macrophages, decreased damage to macrophages, and significantly reduced lethality in mice. Therefore, the oxygen porin Pn-AqpC, through modulating H2O2 production and pneumolysin release, the two major pneumococcal virulence factors, controls the virulence of pneumococcus. Pn-AqpC orthologs are widely distributed in various pneumococcal serotypes, highlighting that the oxygen porin is important for pneumococcal pathogenicity. IMPORTANCE Pneumococcus is the leading cause of community-acquired pneumonia, bacteremia, and meningitis. This work reports that a novel aquaporin subfamily represented by pneumococcal Pn-AqpC functions as an oxygen porin facilitating O2 influx into cells. Importantly, by mediating O2 influx, Pn-AqpC controls the production and release of H2O2 and Ply, the two major pneumococcal virulence factors. Moreover, by enhancing endogenous H2O2 production, Pn-AqpC significantly increases pneumococcal resistance to H2O2 and even NO, the major bactericidal chemical produced by macrophages. Consequently, the deletion of Pn-aqpC markedly decreased pneumococcal survival in macrophages and reduced damage to macrophages. Accordingly, the ΔPn-aqpC mutant displays significantly attenuated virulence in a murine pneumonia model. Given that Pn-AqpC orthologs are widely distributed in all pneumococcal serotypes, this new subfamily of aquaporins is identified as novel virulence-related proteins.

Radioadaptive response (RAR) describes a phenomenon in a variety of in vitro and in vivo systems that a low-dose of priming ionizing radiation (IR) reduces detrimental effects of a subsequent challenge IR at higher doses. Among in vivo investigations, studies using the mouse RAR model (Yonezawa Effect) showed that RAR could significantly extenuate high-dose IR-induced detrimental effects such as decrease of hematopoietic stem cells and progenitor cells, acute radiation hematopoietic syndrome, genotoxicity and genomic instability. Meanwhile, it has been demonstrated that diet intervention has a great impact on health, and dietary restriction shows beneficial effects on numerous diseases in animal models. In this work, by using the mouse RAR model and mild dietary restriction (MDR), we confirmed that combination of RAR and MDR could more efficiently reduce radiogenotoxic damage without significant change of the RAR phenotype. These findings suggested that MDR may share some common pathways with RAR to activate mechanisms consequently resulting in suppression of genotoxicity. As MDR could also increase resistance to chemotherapy and radiotherapy in normal cells, we propose that combination of MDR, RAR, and other cancer treatments (i.e., chemotherapy and radiotherapy) represent a potential strategy to increase the treatment efficacy and prevent IR risk in humans.

Abstract Background Psoriasis is a chronic inflammatory dermatosis with complex genetic basis supported by family investigation. Renal involvement in psoriasis is sparsely studied and its pathogenesis is still unclear. Methods and Results We describe the case of a 7‐year‐old boy presented new onset of nephropathy two weeks after a flare‐up of psoriasis. His mother had a long history of psoriasis without abnormal urinalysis records. The case showed non‐nephrotic range proteinuria, microscopic hematuria without any other abnormal results including renal function, complement cascade, and ultrasound. Renal pathological demonstrated the diagnosis of C3 glomerulonephritis (C3GN) showing mesangial proliferative glomerulonephritis with C3 staining only, effacement of podocyte process and intramembranous electron dense deposit by electric microscopy. Parent‐child trio WES performed to screening the common variants of psoriasis susceptibility locus and also the rare variants associated with C3GN. We identified a missense single nucleotide polymorphism of CARD14 (*607211, rs34367357, p.Val585Ile) carried by the proband and his mother. Meta‐analysis proved the association of rs34367357 and psoriasis (p = 0.006, OR = 1.23). A hemizygouse mutation of CLCN5 (*300008, c.1904A＞G,p.Asn635Ser) was identified for diagnosis of Dent disease (*300009). Conclusion The case highlights the genetic study is necessary to facilitate disease differentiation in new onset of nephropathy with psoriasis in children.

Application of green fluorescent protein (GFP) in a variety of biosystems as a unique bioindicator or biomarker has revolutionized biological research and made groundbreaking achievements, while increasing evidence has shown alterations in biological properties and physiological functions of the cells and animals overexpressing transgenic GFP. In this work, response to total body irradiation (TBI) was comparatively studied in GFP transgenic C57BL/6-Tg (CAG-EGFP) mice and C57BL/6 N wild type mice. It was demonstrated that GFP transgenic mice were more sensitive to radiation-induced bone marrow death, and no adaptive response could be induced. In the nucleated bone marrow cells of GFP transgenic mice exposed to a middle dose, there was a significant increase in both the percentage of cells expressing pro-apoptotic gene Bax and apoptotic cell death. While in wild type cells, lower expression of pro-apoptotic gene Bax and higher expression of anti-apoptotic gene Bcl-2, and significant lower induction of apoptosis were observed compared to GFP transgenic cells. Results suggest that presence of GFP could alter response to TBI at whole body, cellular and molecular levels in mice. These findings indicate that there could be a major influence on the interpretation of the results obtained in GFP transgenic mice.

Abstract Background Mutations in COQ8B (*615567) as a defect of coenzyme Q10 (CoQ10) cause steroid resistant nephrotic syndrome (SRNS). Methods To define the clinical course and prognosis of COQ8B nephropathy, we retrospectively assessed the genotype and phenotype in patients with COQ8B mutations from Chinese Children Genetic Kidney Disease Database. We performed the comparing study of renal outcome following CoQ10 treatment and renal transplantation between early genetic detection and delayed genetic detection group. Results We identified 20 (5.8%) patients with biallelic mutations of COQ8B screening for patients with SRNS, non‐nephrotic proteinuria, or chronic kidney disease (CKD) of unknown origin. Patients with COQ8B mutations showed a largely renal‐limited phenotype presenting with proteinuria and/or advanced CKD at the time of diagnosis. Renal biopsy uniformly showed focal segmental glomerulosclerosis. Proteinuria was decreased, whereas the renal function was preserved in five patients following CoQ10 administration combined with angiotensin‐converting enzyme (ACE) inhibitor. The renal survival analysis disclosed a significantly better outcome in early genetic detection group than in delayed genetic detection group (Kaplan–Meier plot and log rank test, p = .037). Seven patients underwent deceased donor renal transplantation without recurrence of proteinuria or graft failure. Blood pressure showed decreased significantly during 6 to 12 months post transplantation. Conclusions COQ8B mutations are one of the most common causes of adolescent‐onset proteinuria and/or CKD of unknown etiology in the Chinese children. Early detection of COQ8B nephropathy following CoQ10 supplementation combined with ACE inhibitor could slow the progression of renal dysfunction. Renal transplantation in patients with COQ8B nephropathy showed no recurrence of proteinuria.

Humans are exposed to both psychological stress (PS) and radiation in some scenarios such as manned deep-space missions. It is of great concern to verify possible enhanced deleterious effects from such concurrent exposure. Pioneer studies showed that chronic restraint-induced PS (CRIPS) could attenuate Trp53 functions and increase gamma-ray-induced carcinogenesis in Trp53-heterozygous mice while CRIPS did not significantly modify the effects on X-ray-induced hematopoietic toxicity in Trp53 wild-type mice. As high-linear energy transfer (LET) radiation is the most important component of space radiation in causing biological effects, we further investigated the effects of CRIPS on high-LET iron-particle radiation (Fe)-induced hematopoietic toxicity in Trp53-heterozygous mice. The results showed that CRIPS alone could hardly induce significant alteration in hematological parameters (peripheral hemogram and micronucleated erythrocytes in bone marrow) while concurrent exposure caused elevated genotoxicity measured as micronucleus incidence in erythrocytes. Particularly, exposure to either CRISP or Fe-particle radiation at a low dose (0.1 Gy) did not induce a marked increase in the micronucleus incidence; however, concurrent exposure caused a significantly higher increase in the micronucleus incidence. These findings indicated that CRIPS could enhance the deleterious effects of high-LET radiation, particularly at a low dose, on the hematopoietic toxicity in Trp53-heterozygous mice.

Kiwifruit black spot disease has become increasingly widespread in many ‘CuiXiang’ kiwifruit plantings regions. This research was aimed at the pathogenic microorganisms of black spot of the ‘CuiXiang’ cultivar. Physiological, morphological and transcriptional characteristics between black spot fruit and healthy fruits were evaluated. Then, it applied a high-throughput internal transcribed spacer (ITS) sequencing to analyze the black spot disease microbial community. The cell structure showed that mycelium was attached to the surface of the kiwifruit through black spot, and that consequently the mitochondria were damaged, starch particles were reduced, and shelf life was shortened. Transcriptome revealed that different genes in kiwifruit with black spot disease were involved in cell wall modification, pathogen perception, and signal transduction. ITS sequencing results described the disease-causing fungi and found that the microbial diversity of black spot-diseased fruit was lower than that of healthy fruit. We predict that candidate pathogenic fungi Cladosporium cladosporioides, Diaporthe phaseolorum, Alternaria alternata, and Trichothecium roseum may cause black spot. This study was to explore the pathogenic fungal community of ‘CuiXiang’ kiwifruit black spot disease and to provide essential information for field prevention.

A transplanted organ is usually rejected without any major immunosuppressive treatment because of vigorous alloimmune responsiveness. However, continuous global immunosuppression may cause severe side effects, including nephrotoxicity, tumors, and infections. Therefore, it is necessary to seek novel immunosuppressive agents, especially natural ingredients that may provide sufficient efficacy in immunosuppression with minimal side effects. Shikonin is a bioactive naphthoquinone pigment, an ingredient originally extracted from the root of Lithospermum erythrorhizon. Previous studies have shown that shikonin regulates immunity and exerts anti-inflammatory effects. In particular, it can ameliorate arthritis in animal models. However, it is unclear whether shikonin inhibits alloimmunity or allograft rejection. In this study and for the first time, we demonstrated that shikonin significantly prolonged the survival of skin allografts in wild-type mice. Shikonin increased the frequencies of CD4+Foxp3+ regulatory T cells (Tregs) post-transplantation and induced CD4+Foxp3+ Tregs in vitro as well. Importantly, depleting the Tregs abrogated the extension of skin allograft survival induced by shikonin. It also decreased the frequencies of CD8+CD44highCD62Llow effector T cells and CD11c+CD80+/CD11c+CD86+ mature DCs after transplantation. Moreover, we found that shikonin inhibited the proliferation of T cells in vitro and suppressed their mTOR signaling. It also reduced the gene expression of pro-inflammatory cytokines, including IFNγ, IL-6, TNFα, and IL-17A, while increasing the gene expression of anti-inflammatory mediators IL-10, TGF-β1, and indoleamine-2, 3-dioxygenase (IDO) in skin allografts. Further, shikonin downregulated IDO protein expression in skin allografts and DCs in vitro. Taken together, shikonin inhibits allograft rejection via upregulating CD4+Foxp3+ Tregs. Thus, shikonin is a novel immunosuppressant that could be potentially used in clinical transplantation.

Radiotherapy (RT) treats cancer effectively with high doses of ionizing radiation (IR) to killing cancer cells and shrinking tumors while bearing the risk of developing different side effects, including secondary cancer, which is most concerning for long-term health consequences. Genomic instability (GI) is a characteristic of most cancer cells, and IR-induced GI can manifest as delayed homologous recombination (HR). Radioadaptive response (RAR) is capable of reducing genotoxicity, cell transformation, mutation, and carcinogenesis, but the rational evidence describing its contributions to the reduction of radiation risk, in particular, carcinogenesis, remains fragmented. In this work, to investigate the impact of RAR on high-dose, IR-induced GI measured as delayed HR, the frequency of recombinant cells was comparatively studied under RAR-inducible and -uninducible conditions in the nucleated cells in hematopoietic tissues (bone marrow and spleen) using the Rosa26 Direct Repeat-green fluorescent protein (RaDR-GFP) homozygote mice. Results demonstrated that the frequency of recombinant cells was significantly lower in hematopoietic tissues under RAR-inducible condition. These findings suggest that reduction in delayed HR may be at least a part of the mechanisms underlying decreased carcinogenesis by RAR, and application of RAR would contribute to a more rigorous and scientifically grounded system of radiation protection in RT.

A transplanted organ is always rejected in the absence of any immunosuppressive treatment due to vigorous alloimmunity. However, continuously global immunosuppression with a conventional immunosuppressant may result in severe side effects, including nephrotoxicity, tumors and infections. Tregs have been widely used to inhibit allograft rejection, especially in animal models. However, it's well accepted that administration of Tregs alone is not satisfactory in immune-competent wild-type animals. Therefore, it's imperative to promote Treg therapies under the cover of other approaches, including costimulatory blockade. In the present study, we demonstrated that administration of in vitro-expanded CD8+CD122+PD-1+ Tregs synergized with costimulatory blockade of CD40/CD154, but not B7/CD28, to prolong skin allograft survival in wild-type mice and to reduce cellular infiltration in skin allografts as well. Treg treatment and blockade of CD40/CD154, but not B7/CD28, also exhibited an additive effect on suppression of T cell proliferation in vitro and pro-inflammatory cytokine expression in skin allografts. Importantly, blocking B7/CD28, but not CD40/CD154, costimulation decreased the number of transferred CD8+CD122+PD-1+ Tregs and their expression of IL-10 in recipient mice. Furthermore, it's B7/CD28, but not CD40/CD154, costimulatory blockade that dramatically reduced IL-10 production by CD8+CD122+PD-1+ Tregs in vitro, suggesting that B7/CD28, but not CD40/CD154, costimulation is critical for their production of IL-10. Indeed, infusion of IL-10-deficient CD8+CD122+PD-1+ Tregs failed to synergize with anti-CD154 Ab treatment to further prolong allograft survival. Our data may explain why blocking B7/CD28 costimulatory pathway does not boost IL-10-dependent Treg suppression of alloimmunity. Thus, these findings could be implicated in clinical organ transplantation.

The existence of radiation-induced adaptive response (AR) was reported in varied biosystems. In mice, the first in vivo AR model was established using X-rays as both the priming and the challenge doses and rescue of bone marrow death as the end point. The underlying mechanism was due to the priming radiation-induced resistance in the blood-forming tissues. In a series of investigations, we further demonstrated the existence of AR using different types of ionizing radiation (IR) including low linear energy transfer (LET) X-rays and high LET heavy ion. In this article, we validated hematopoietic stem cells/hematopoietic progenitor cells (HSCs/HPCs) measured as endogenous colony-forming units-spleen (CFU-S) under AR inducible and uninducible conditions using combination of different types of IR. We confirmed the consistency of increased CFU-S number change with the AR inducible condition. These findings suggest that AR in mice induced by different types of IR would share at least in part a common underlying mechanism, the priming IR-induced resistance in the blood-forming tissues, which would lead to a protective effect on the HSCs/HPCs and play an important role in rescuing the animals from bone marrow death. These findings provide a new insight into the mechanistic study on AR in vivo.

Fruits of kiwifruit cultivars (Actinidia chinensis and A. deliciosa) generally have green or yellow flesh when ripe. A small number of genotypes have red flesh but this coloration is usually restricted to the inner pericarp. Three kiwifruit cultivars having red (‘Hongyang’), or yellow (‘Jinnong-2’), or green (‘Hayward’) flesh were investigated for their color characteristics and pigment contents during development and ripening. The results show the yellow of the ‘Jinnong-2’ fruit is due to the combined effects of chlorophyll degradation and of beta-carotene accumulation. The red inner pericarps of ‘Hongyang’ fruit are due to anthocyanin accumulation. Expression differences of the pathway genes in the inner pericarps of the three different kiwifruits suggest that stay-green (SGR) controls the degradation of chlorophylls, while lycopene beta-cyclase (LCY-β) controls the biosynthesis of beta-carotene. The abundance of anthocyanin in the inner pericarps of the ‘Hongyang’ fruit is the results of high expressions of UDP flavonoid glycosyltransferases (UFGT). At the same time, expressions of anthocyanin transcription factors show that AcMYBF110 expression parallels changes in anthocyanin concentration, so seems to be a key R2R3 MYB, regulating anthocyanin biosynthesis. Further, transient color assays reveal that AcMYBF110 can autonomously induce anthocyanin accumulation in Nicotiana tabacum leaves by activating the transcription of dihydroflavonol 4-reductase (NtDFR), anthocyanidin synthase (NtANS) and NtUFGT. For basic helix-loop-helix proteins (bHLHs) and WD-repeat proteins (WD40s), expression differences show these may depend on AcMYBF110 forming a MYB-bHLH-WD40 complex to regulate anthocyanin biosynthesis, instead of it having a direct involvement.

In citrus color mutants, the levels of carotenoid constituents and other secondary metabolites are different in their corresponding wild types. Terpenoids are closely related to coloration, bitterness, and flavor. In this study, terpenoid profiles and hormones in citrus fruits of two red-flesh mutants—Red Anliu orange and Red-flesh Guanxi pummelo—and their corresponding wild types were investigated using GC/MS, HPLC, and LC-MS/MS. Results showed that Red Anliu orange (high in carotenoids) and Anliu orange (low in carotenoids) accumulated low levels of limonoid aglycones but high levels of monoterpenoids; conversely, Red-flesh Guanxi pummelo (high in carotenoids) and Guanxi pummelo (deficient in carotenoids) accumulated high levels of limonoid aglycones but low levels of monoterpenoids. However, isopentenyl diphosphate was present at similar levels. A correlation analysis indicated that jasmonic and salicylic acids might play important roles in regulating terpenoid biosynthesis. Additionally, the similarities of carotenoid and volatile profiles between each mutant and its corresponding wild type were greater than those between the two mutants or the two wild types. The flux balance of terpenoid metabolism in citrus fruit tends toward stability among various citrus genera that have different terpenoid profiles. Bud mutations could influence metabolite profiles of citrus fruit to a limited extent.

Six new diketopiperazines, (±)-7,8-epoxy-brevianamide Q ((±)-1), (±)-8-hydroxy-brevianamide R ((±)-2), and (±)-8-epihydroxy-brevianamide R ((±)-3), together with four known compounds, (±)-brevianamide R ((±)-4), versicolorin B (5) and averufin (6), were isolated from a marine-derived fungus strain Aspergillus versicolor MF180151, which was recovered from a sediment sample collected from the Bohai Sea, China. The chemical structures were established by 1D- and 2D-NMR spectra and HR-ESI-MS. 1 is the first sample of brevianamides with an epoxy moiety. Their bioactivities were evaluated against Candida albicans, Bacillus subtilis, Staphylococcus aureus, methicillin-resistant S. aureus, Pseudomonas aeruginosa, and Bacillus Calmette-Guérin. Compounds 1−4 showed no activities against the pathogens, and compounds 5 and 6 showed moderate activities against S. aureus and methicillin-resistant S. aureus.

Volatile profiles yielded from gas chromatography-mass spectrometry (GC-MS) analysis provide abundant information not only for metabolism-related research, but also for chemotaxonomy. To study the chemotaxonomy of Mangshanyegan, its volatile profiles of fruit and leaf and those of 29 other genotypes of Citrus, Poncirus, and Fortunella were subjected to phylogenetic analyses. Results showed that 145 identified (including 64 tentatively identified) and 15 unidentified volatile compounds were detected from their peel oils. The phylogenetic analysis of peel oils based on hierarchical cluster analysis (HCA) demonstrated a good agreement with the Swingle taxonomy system, in which the three genera of Citrus, Poncirus, and Fortunella were almost completely separated. As to Citrus, HCA indicated that Citrophorum, Cephalocitrus, and Sinocitrus fell into three subgroups, respectively. Also, it revealed that Mangshanyegan contain volatile compounds similar to those from pummelo, though it is genetically believed to be a mandarin. These results were further supported by the principal component analysis of the peel oils and the HCA results of volatile profiles of leaves in the study.