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Colchicine is a widely prescribed anti-inflammatory drug for the treatment of gout, familial Mediterranean fever and pericarditis, but its narrow therapeutic window presents a significant risk of severe toxicity. Despite its clinical relevance, the molecular mechanisms underlying colchicine's pharmacological effects and associated toxicity and explored potential therapeutic interventions to mitigate its adverse effects. We showed the colchicine's impact on cellular morphology in human umbilical vein endothelial cells (HUVEC) and HeLa cells including cell rounding and detachment following 24 h of exposure that revealed pronounced cytotoxic effects. We then established a large-scale screening model to identify small molecules capable of reversing colchicine-induced cellular toxicity, and identified MLN4924, an inhibitor of the Cullin-RING E3 ligase (CRL) system, as a promising candidate for mitigating colchicine-induced cellular injury. Through a comprehensive multi-omics approach including transcriptomics, proteomics, phosphoproteomics and ubiquitinomics, we systematically characterized the molecular perturbations caused by colchicine and delineated the protective mechanisms of MLN4924. We found that MLN4924 exerted its protective effects by modulating critical cellular pathways, specifically preventing the dysregulation of cell cycle progression, mitotic disruption and microtubule destabilization triggered by colchicine. Furthermore, proteomic and phosphoproteomic analyses revealed significant alterations in kinase signaling networks, with combined inhibition of CDK1 and PAK1 emerging as an effective strategy to counteract colchicine-induced cellular dysfunction. These results not only provide a detailed molecular characterization of colchicine toxicity but also identify key therapeutic targets, laying the groundwork for the development of targeted interventions to mitigate colchicine-induced adverse effects in clinical practice., Competing Interests: Competing interests: The patent application (ZL 2021 1 0280667.1) was filed by Min-jia Tan, Bin Liu, and Lin-hui Zhai for the novel application of MLN4924 in alleviating colchicine poisoning. All the authors in this project declare that they have no competing interests., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Influenza A virus (IAV) is a widespread pathogen that poses a significant threat to human health, causing pandemics with high mortality and pathogenicity. Given the emergence of increasingly drug-resistant strains of IAV, currently available antiviral drugs have been reported to be inadequate to meet clinical demands. Therefore, continuous exploration of safe, effective and broad-spectrum antiviral medications is urgently required. Here, we found that the small molecule compound J1 exhibited low toxicity both in vitro and in vivo. Moreover, J1 exhibits broad-spectrum antiviral activity against enveloped viruses, including IAV, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human coronavirus OC43 (HCoV-OC43), herpes simplex virus type 1 (HSV-1) and HSV-2. In this study, we explored the inhibitory effects and mechanism of action of J1 on IAV in vivo and in vitro. The results showed that J1 inhibited infection by IAV strains, including H1N1, H7N9, H5N1 and H3N2, as well as by oseltamivir-resistant strains. Mechanistic studies have shown that J1 blocks IAV infection mainly through specific interactions with the influenza virus hemagglutinin HA2 subunit, thereby blocking membrane fusion. BALB/c mice were used to establish a model of acute lung injury (ALI) induced by IAV. Treatment with J1 increased survival rates and reduced viral titers, lung index and lung inflammatory damage in virus-infected mice. In conclusion, J1 possesses significant anti-IAV effects in vitro and in vivo, providing insights into the development of broad-spectrum antivirals against future pandemics., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

This cross-sectional survey aims to determine whether cotinine exposure would enhance the relationship between blood manganese (Mn) and non-alcoholic fatty liver disease (NAFLD) in children using the NHANES database. Restricted cubic spline (RCS) and logistic regression analyses were adopted to determine the potential relationship. Besides, we tested the robustness of the results by performing trend tests and subgroup analyses. The study finally enrolled 866 children aged 18 years and below. Blood Mn was linearly linked to NAFLD and the risk of NAFLD was increased with the blood Mn elevation (P < 0.05). There was a notable relationship between blood Mn and NAFLD in crude model 1, which was still significant upon adjustment of all the identified covariates (all P < 0.05). Under Mn exposure, the cotinine-exposed group had a higher risk of NAFLD than the cotinine-unexposed group. In conclusion, blood Mn level is an independent risk factor for pediatric NAFLD, and cotinine exposure can enhance this relationship to some degree. Therefore, reducing cotinine exposure may alleviate detrimental consequences related to exposure to heavy metals in children., (© 2024. The Author(s).)

Aiming at the shortcomings of the BP neural network in practical applications, such as easy to fall into local extremum and slow convergence speed, we optimized the initial weights and thresholds of the BP neural network using the particle swarm optimization (PSO). Additionally, cloud computing service, web technology, cloud database and numerical simulation were integrated to construct an intelligent feedback analysis cloud program for underground engineering safety monitoring based on the PSO-BP algorithm. The program could conveniently, quickly, and intelligently carry out numerical analysis of underground engineering and dynamic feedback analysis of surrounding rock parameters. The program was applied to the cloud inversion analysis of the surrounding rock parameters for the underground powerhouse of the Shuangjiangkou Hydropower Station. The calculated displacement simulated with the back-analyzed parameters matches the measured displacement very well. The posterior variance evaluation shows that the posterior error ratio is 0.045 and the small error probability is 0.999. The evaluation results indicate that the intelligent feedback analysis cloud program has high accuracy and can be applied to engineering practice., (© 2024. The Author(s).)

Accurate indel calling plays an important role in precision medicine. A benchmarking indel set is essential for thoroughly evaluating the indel calling performance of bioinformatics pipelines. A reference sample with a set of known-positive variants was developed in the FDA-led Sequencing Quality Control Phase 2 (SEQC2) project, but the known indels in the known-positive set were limited. This project sought to provide an enriched set of known indels that would be more translationally relevant by focusing on additional cancer related regions. A thorough manual review process completed by 42 reviewers, two advisors, and a judging panel of three researchers significantly enriched the known indel set by an additional 516 indels. The extended benchmarking indel set has a large range of variant allele frequencies (VAFs), with 87% of them having a VAF below 20% in reference Sample A. The reference Sample A and the indel set can be used for comprehensive benchmarking of indel calling across a wider range of VAF values in the lower range. Indel length was also variable, but the majority were under 10 base pairs (bps). Most of the indels were within coding regions, with the remainder in the gene regulatory regions. Although high confidence can be derived from the robust study design and meticulous human review, this extensive indel set has not undergone orthogonal validation. The extended benchmarking indel set, along with the indels in the previously published known-positive set, was the truth set used to benchmark indel calling pipelines in a community challenge hosted on the precisionFDA platform. This benchmarking indel set and reference samples can be utilized for a comprehensive evaluation of indel calling pipelines. Additionally, the insights and solutions obtained during the manual review process can aid in improving the performance of these pipelines., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Neurologically isolated ocular motor nerve palsies often present a management dilemma. Neuroimaging is more likely to be offered to patients <50 years without coexisting ischaemic risk factors as their risk of sinister underlying causes is thought to be higher. However, populations are rapidly ageing and advanced neuroimaging is now more widely available. We thus investigated the incidence of abnormal neuroimaging outcomes in the traditionally low-risk older patient group., Methods: This is a retrospective cohort study of 353 patients presenting with isolated ocular motor nerve palsies to a tertiary neuro-ophthalmology service in Singapore over a four-year (2015 to 2019) period. Clinical data was obtained through manual review of case records. Common aetiologies, age-based differences in prevalence of causes and abnormal neuroimaging outcomes were statistically analysed., Results: Abnormal neuroimaging outcomes were significantly greater in the younger cohort only when age segregation was performed at 60 years of age. In a multivariate analysis, acute onset rather than ischaemic risk factors were independently predictive of normal neuroimaging outcomes. After adjusting for prior cancer risk and clinical bias from presumed ischaemic palsies, abnormal neuroimaging outcomes were seen in 14.1% ≥ 50 yrs, 10.9% ≥ 60 yrs and 15.1% ≥ 70 yrs., Conclusions: In patients presenting with isolated ocular motor nerve palsies, acute onset may be a more reliable indicator of an ischaemic palsy rather than advanced age or presence of ischaemic risk factors. If onset is not acute, neuroimaging should be considered irrespective of age and coexisting ischaemic risk factors., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Cervicogenic headache is an often observed secondary headache in clinical settings, with patients who endure prolonged and persistent pain being particularly susceptible to mood changes. Currently, the Mulligan is one of the effective methods for CEH. However, there is a lack of evaluation about the strength and frequency of headaches, as well as the assessment of pain-induced emotions, in individuals with CEH using this particular procedure. Herein, we aimed to evaluate the effectiveness of the Mulligan maneuver from a multidimensional perspective of pain intensity and mood. A total of forty patients diagnosed with CEH who satisfied the specified inclusion criteria were recruited and allocated randomly into two groups: the control group and the treatment group, with each group consisting of twenty cases. The control group received health education, while the treatment group received the Mulligan maneuver once daily over a course of 10 treatment sessions.The clinical outcome of patients with CEH in two groups was assessed using the Visual Analog Scale (VAS), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD). Resting-state functional magnetic resonance imaging was employed to examine variations in brain function activities between the two CEH groups. Brain regions showing differences were identified as regions of interest and subsequently correlated with clinical behavioral measures using Pearson's correlation analysis. The differences in VAS, HAMA and HAMD between the two groups of CEH patients were also statistically significant. The brain regions that showed differences in the ReHo scores between the two groups of CEH patients included the left cerebellum, the frontal gyrus, and the middle temporal gyrus. There was a positive correlation between the left frontal gyrus and VAS, HAMA and HAMD. The left middle temporal gyrus had a negative correlation with VAS, HAMA, and HAMD and the left cerebellum had a positive correlation with VAS correlation. The Mulligan maneuver may improve pain levels and have a moderating effect on pain-related negative emotions by regulating the function of relevant brain regions in CEH patients., (© 2023. The Author(s).)

Hippocampal neuronal damage may induce cognitive impairment. Neurotrophic tyrosine kinase receptor 1 (NTRK1) reportedly regulates neuronal damage, although the underlying mechanism remains unclear. The present study aimed to investigate the role of NTRK1 in mouse hippocampal neuronal damage and the specific mechanism. A mouse NTRK1-knockdown model was established and subjected to pre-treatment with BAY-3827, followed by a behavioral test, Nissl staining, and NeuN immunofluorescence (IF) staining to evaluate the cognitive impairment and hippocampal neuronal damage. Next, an in vitro analysis was conducted using the CCK-8 assay, TUNEL assay, NeuN IF staining, DCFH-DA staining, JC-1 staining, ATP content test, mRFP-eGFP-LC3 assay, and LC3-II IF staining to elucidate the effect of NTRK1 on mouse hippocampal neuronal activity, apoptosis, damage, mitochondrial function, and autophagy. Subsequently, rescue experiments were performed by subjecting the NTRK1-knockdown neurons to pre-treatment with O304 and Rapamycin. The AMPK/ULK1/FUNDC1 pathway activity and mitophagy were detected using western blotting (WB) analysis. Resultantly, in vivo analysis revealed that NTRK1 knockdown induced mouse cognitive impairment and hippocampal tissue damage, in addition to inactivating the AMPK/ULK1/FUNDC1 pathway activity and mitophagy in the hippocampal tissues of mice. The treatment with BAY-3827 exacerbated the mouse depressive-like behavior induced by NTRK1 knockdown. The results of in vitro analysis indicated that NTRK1 knockdown attenuated viability, NeuN expression, ATP production, mitochondrial membrane potential, and mitophagy, while enhancing apoptosis and ROS production in mouse hippocampal neurons. Conversely, pre-treatment with O304 and rapamycin abrogated the suppression of mitophagy and the promotion of neuronal damage induced upon NTRK1 silencing. Conclusively, NTRK1 knockdown induces mouse hippocampal neuronal damage through the suppression of mitophagy via inactivating the AMPK/ULK1/FUNDC1 pathway. This finding would provide insight leading to the development of novel strategies for the treatment of cognitive impairment induced due to hippocampal neuronal damage., (© 2023. The Author(s).)

An ongoing randomized, double-blind, controlled phase 2 trial was conducted to evaluate the safety and immunogenicity of a mosaic-type recombinant vaccine candidate, named NVSI-06-09, as a booster dose in subjects aged 18 years and older from the United Arab Emirates (UAE), who had administered two or three doses of inactivated vaccine BBIBP-CorV at least 6 months prior to enrollment. The participants were randomly assigned with 1:1 to receive a booster dose of NVSI-06-09 or BBIBP-CorV. The primary outcomes were immunogenicity and safety against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, and the exploratory outcome was cross-immunogenicity against other circulating strains. Between May 25 and 30, 2022, 516 adults received booster vaccination with 260 in NVSI-06-09 group and 256 in BBIBP-CorV group. Interim results showed a similar safety profile between two booster groups, with low incidence of adverse reactions of grade 1 or 2. For immunogenicity, by day 14 post-booster, the fold rises in neutralizing antibody geometric mean titers (GMTs) from baseline elicited by NVSI-06-09 were remarkably higher than those by BBIBP-CorV against the prototype strain (19.67 vs 4.47-fold), Omicron BA.1.1 (42.35 vs 3.78-fold), BA.2 (25.09 vs 2.91-fold), BA.4 (22.42 vs 2.69-fold), and BA.5 variants (27.06 vs 4.73-fold). Similarly, the neutralizing GMTs boosted by NVSI-06-09 against Beta and Delta variants were also 6.60-fold and 7.17-fold higher than those by BBIBP-CorV. Our findings indicated that a booster dose of NVSI-06-09 was well-tolerated and elicited broad-spectrum neutralizing responses against divergent SARS-CoV-2 variants, including Omicron and its sub-lineages., (© 2022. The Author(s).)

Canagliflozin is an antidiabetic medicine that inhibits sodium-glucose cotransporter 2 (SGLT2) in proximal tubules. Recently, it was reported to have several noncanonical effects other than SGLT2 inhibiting. However, the effects of canagliflozin on skeletal muscle regeneration remain largely unexplored. Thus, in vivo muscle contractile properties recovery in mice ischemic lower limbs following gliflozins treatment was evaluated. The C2C12 myoblast differentiation after gliflozins treatment was also assessed in vitro. As a result, both in vivo and in vitro data indicate that canagliflozin impairs intrinsic myogenic regeneration, thus hindering ischemic limb muscle contractile properties, fatigue resistance recovery, and tissue regeneration. Mitochondrial structure and activity are both disrupted by canagliflozin in myoblasts. Single-cell RNA sequencing of ischemic tibialis anterior reveals a decrease in leucyl-tRNA synthetase 2 (LARS2) in muscle stem cells attributable to canagliflozin. Further investigation explicates the noncanonical function of LARS2, which plays pivotal roles in regulating myoblast differentiation and muscle regeneration by affecting mitochondrial structure and activity. Enhanced expression of LARS2 restores the differentiation of canagliflozin-treated myoblasts, and accelerates ischemic skeletal muscle regeneration in canagliflozin-treated mice. Our data suggest that canagliflozin directly impairs ischemic skeletal muscle recovery in mice by downregulating LARS2 expression in muscle stem cells, and that LARS2 may be a promising therapeutic target for injured skeletal muscle regeneration., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The widespread occurrence of sulfate-reducing microorganisms (SRMs) in temporarily oxic/hypoxic aquatic environments indicates an intriguing possibility that SRMs can prevail in constantly oxic/hypoxic terrestrial sulfate-rich environments. However, little attention has been given to this possibility, leading to an incomplete understanding of microorganisms driving the terrestrial part of the global sulfur (S) cycle. In this study, genome-centric metagenomics and metatranscriptomics were employed to explore the diversity, metabolic potential, and gene expression profile of SRMs in a revegetated acidic mine wasteland under constantly oxic/hypoxic conditions. We recovered 16 medium- to high-quality metagenome-assembled genomes (MAGs) containing reductive dsrAB. Among them, 12 and four MAGs belonged to Acidobacteria and Deltaproteobacteria, respectively, harboring three new SRM genera. Comparative genomic analysis based on seven high-quality MAGs (completeness >90% and contamination <10%; including six acidobacterial and one deltaproteobacterial) and genomes of three additional cultured model species showed that Acidobacteria-related SRMs had more genes encoding glycoside hydrolases, oxygen-tolerant hydrogenases, and cytochrome c oxidases than Deltaproteobacteria-related SRMs. The opposite pattern was observed for genes encoding superoxide reductases and thioredoxin peroxidases. Using VirSorter, viral genome sequences were found in five of the 16 MAGs and in all three cultured model species. These prophages encoded enzymes involved in glycoside hydrolysis and antioxidation in their hosts. Moreover, metatranscriptomic analysis revealed that 15 of the 16 SRMs reported here were active in situ. An acidobacterial MAG containing a prophage dominated the SRM transcripts, expressing a large number of genes involved in its response to oxidative stress and competition for organic matter., (© 2022. The Author(s).)

The increased coronavirus disease 2019 (COVID-19) breakthrough cases pose the need of booster vaccination. We conducted a randomised, double-blinded, controlled, phase 2 trial to assess the immunogenicity and safety of the heterologous prime-boost vaccination with an inactivated COVID-19 vaccine (BBIBP-CorV) followed by a recombinant protein-based vaccine (NVSI-06-07), using homologous boost with BBIBP-CorV as control. Three groups of healthy adults (600 individuals per group) who had completed two-dose BBIBP-CorV vaccinations 1-3 months, 4-6 months and ≥6 months earlier, respectively, were randomly assigned in a 1:1 ratio to receive either NVSI-06-07 or BBIBP-CorV boost. Immunogenicity assays showed that in NVSI-06-07 groups, neutralizing antibody geometric mean titers (GMTs) against the prototype SARS-CoV-2 increased by 21.01-63.85 folds on day 28 after vaccination, whereas only 4.20-16.78 folds of increases were observed in control groups. For Omicron variant, the neutralizing antibody GMT elicited by homologous boost was 37.91 on day 14, however, a significantly higher neutralizing GMT of 292.53 was induced by heterologous booster. Similar results were obtained for other SARS-CoV-2 variants of concerns (VOCs), including Alpha, Beta and Delta. Both heterologous and homologous boosters have a good safety profile. Local and systemic adverse reactions were absent, mild or moderate in most participants, and the overall safety was quite similar between two booster schemes. Our findings indicated that NVSI-06-07 is safe and immunogenic as a heterologous booster in BBIBP-CorV recipients and was immunogenically superior to the homologous booster against not only SARS-CoV-2 prototype strain but also VOCs, including Omicron., (© 2022. The Author(s).)

Natural Killer T (NKT) cells and Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells that express semi-invariant αβ T cell receptors (TCRs) through which they recognise CD1d and MR1 molecules, respectively, in complex with specific ligands. These cells play important roles in health and disease in many organs, but their precise intra-organ location is not well established. Here, using CD1d and MR1 tetramer staining techniques, we describe the precise location of NKT and MAIT cells in lymphoid and peripheral organs. Within the thymus, NKT cells were concentrated in the medullary side of the corticomedullary junction. In spleen and lymph nodes, NKT cells were mainly localised within T cell zones, although following in vivo activation with the potent NKT-cell ligand α-GalCer, they expanded throughout the spleen. MAIT cells were clearly detectable in Vα19 TCR transgenic mice and were rare but detectable in lymphoid tissue of non-transgenic mice. In contrast to NKT cells, MAIT cells were more closely associated with the B cell zone and red pulp of the spleen. Accordingly, we have provided an extensive analysis of the in situ localisation of NKT and MAIT cells and suggest differences between the intra-organ location of these two cell types., (© 2022. The Author(s).)

Cardiac hypertrophy is a common adaptive response to a variety of stimuli, but prolonged hypertrophy leads to heart failure. Hence, discovery of agents treating cardiac hypertrophy is urgently needed. In the present study, we investigated the effects of QF84139, a newly synthesized pyrazine derivative, on cardiac hypertrophy and the underlying mechanisms. In neonatal rat cardiomyocytes (NRCMs), pretreatment with QF84139 (1-10 μM) concentration-dependently inhibited phenylephrine-induced hypertrophic responses characterized by fetal genes reactivation, increased ANP protein level and enlarged cardiomyocytes. In adult male mice, administration of QF84139 (5-90 mg·kg -1 ·d -1 , i.p., for 2 weeks) dose-dependently reversed transverse aortic constriction (TAC)-induced cardiac hypertrophy displayed by cardiomyocyte size, left ventricular mass, heart weights, and reactivation of fetal genes. We further revealed that QF84139 selectively activated the AMPK signaling pathway without affecting the phosphorylation of CaMKIIδ, ERK1/2, AKT, PKCε, and P38 kinases in phenylephrine-treated NRCMs and in the hearts of TAC-treated mice. In NRCMs, QF84139 did not show additive effects with metformin on the AMPK activation, whereas the anti-hypertrophic effect of QF84139 was abolished by an AMPK inhibitor Compound C or knockdown of AMPKα2. In AMPKα2-deficient mice, the anti-hypertrophic effect of QF84139 was also vanished. These results demonstrate that QF84139 attenuates the PE- and TAC-induced cardiac hypertrophy via activating the AMPK signaling. This structurally novel compound would be a promising lead compound for developing effective agents for the treatment of cardiac hypertrophy., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Epigallocatechin gallate (EGCG) has the effect to protect skin from ultraviolet B (UVB) induced damages, but it is unstable under ambient conditions, being susceptible to become brown in color. Gallocatechin gallate (GCG), an epimer counterpart of EGCG, is more stable chemically than EGCG. The potential effects of GCG against UVB-induced skin damages has not been available. The objective of this study was to investigate the protective effects of GCG against UVB-induced skin photodamages. GCG was topically applied on the skin of hairless mice at three dosage levels (LL, 12.5 mg/mL; ML 25 mg/mL; HL, 50 mg/mL), with EGCG and a commercially available baby sunscreen lotion SPF50 PA +++ as control. The mice were then irradiated by UVB (fluence rate 1.7 µmol/m 2 s) for 45 min. The treatments were carried out once a day for 6 consecutive days. Skin measurements and histological studies were performed at the end of experiment. The results show that GCG treatments at ML and HL levels inhibited the increase in levels of skin oil and pigmentation induced by UVB irradiation, and improved the skin elasticity and collagen fibers. GCG at ML and HL levels inhibited the formation of melanosomes and aberrations in mitochondria of UVB-irradiated skin in hairless mice. It is concluded that GCG protected skin from UVB-induced photodamages by improving skin elasticity and collagen fibers, and inhibiting aberrations in mitochondria and formation of melanosomes., (© 2022. The Author(s).)

Type 1 diabetes (T1D) is an autoimmune disease. Different factors, including genetics and viruses may contribute to T1D, but the causes of T1D are not fully known, and there is currently no cure. The advent of high-throughput technologies has revolutionized the field of medicine and biology, and analysis of multi-source data along with clinical information has brought a better understanding of the mechanisms behind disease pathogenesis. The aim of this work was the development of a data repository linking clinical information and interactome studies in T1D. To address this goal, we analyzed the electronic health records and online databases of genes, proteins, miRNAs, and pathways to have a global view of T1D. There were common comorbid diseases such as anemia, hypertension, vitreous diseases, renal diseases, and atherosclerosis in the phenotypic disease networks. In the protein-protein interaction network, CASP3 and TNF were date-hub proteins involved in several pathways. Moreover, CTNNB1, IGF1R, and STAT3 were hub proteins, whereas miR-155-5p, miR-34a-5p, miR-23-3p, and miR-20a-5p were hub miRNAs in the gene-miRNA interaction network. Multiple levels of information including genetic, protein, miRNA and clinical data resulted in multiple results, which suggests the complementarity of multiple sources. With the integration of multifaceted information, it will shed light on the mechanisms underlying T1D; the provided data and repository has utility in understanding phenotypic disease networks for the potential development of comorbidities in T1D patients as well as the clues for further research on T1D comorbidities., (© 2021. The Author(s).)

This study was to assess the effect of the predictive model for distinguishing clear cell RCC (ccRCC) from non-clear cell RCC (non-ccRCC) by establishing predictive radiomic models based on enhanced-computed tomography (CT) images of renal cell carcinoma (RCC). A total of 190 cases with RCC confirmed by pathology were retrospectively analyzed, with the patients being randomly divided into two groups, including the training set and testing set according to the ratio of 7:3. A total of 396 radiomic features were computationally obtained and analyzed with the Correlation between features, Univariate Logistics and Multivariate Logistics. Finally, 4 features were selected, and three machine models (Random Forest (RF), Support Vector Machine (SVM) and Logistic Regression (LR)) were established to discriminate RCC subtypes. The radiomics performance was compared with that of radiologist diagnosis. In the testing set, the RF model had an area under the curve (AUC) value of 0.909, a sensitivity of 0.956, and a specificity of 0.538. The SVM model had an AUC value of 0.841, a sensitivity of 1.0, and a specificity of 0.231, in the testing set. The LR model had an AUC value of 0.906, a sensitivity of 0.956, and a specificity of 0.692, in the testing set. The sensitivity and specificity of radiologist diagnosis to differentiate ccRCC from non-ccRCC were 0.850 and 0.581, respectively, with the AUC value of the radiologist diagnosis as 0.69. In conclusion, radiomics models based on CT imaging data show promise for augmenting radiological diagnosis in renal cancer, especially for differentiating ccRCC from non-ccRCC.

Tumor cells have long been recognized as a relative contraindication to hyperbaric oxygen treatment (HBOT) since HBOT might enhance progressive cancer growth. However, in an oxygen deficit condition, tumor cells are more progressive and can be metastatic. HBOT increasing in oxygen partial pressure may benefit tumor suppression. In this study, we investigated the effects of HBOT on solid tumors, such as lung cancer. Non-small cell human lung carcinoma A549-cell-transferred severe combined immunodeficiency mice (SCID) mice were selected as an in vivo model to detect the potential mechanism of HBOT in lung tumors. HBOT not only improved tumor hypoxia but also suppressed tumor growth in murine xenograft tumor models. Platelet endothelial cell adhesion molecule (PECAM-1/CD31) was significantly increased after HBOT. Immunostaining of cleaved caspase-3 was demonstrated and apoptotic tumor cells with nuclear debris were aggregated starting on the 14th-day after HBOT. In vitro, HBOT suppressed the growth of A549 cells in a time-dependent manner and immediately downregulated the expression of p53 protein after HBOT in A549 cells. Furthermore, HBOT-reduced p53 protein could be rescued by a proteasome degradation inhibitor, but not an autophagy inhibitor in A549 cells. Our results demonstrated that HBOT improved tissue angiogenesis, tumor hypoxia and increased tumor apoptosis to lung cancer cells in murine xenograft tumor models, through modifying the tumor hypoxic microenvironment. HBOT will merit further cancer therapy as an adjuvant treatment for solid tumors, such as lung cancer.

Herein, using data from the Korean Longitudinal Study of Aging (2006-2018), we evaluated denture use and chewing ability to determine the status of oral health in middle-aged adults who exercised regularly; further, we investigated the relationship of oral health with all-cause mortality. From the basic survey conducted in 2006, we interviewed 10,254 participants who were followed up until death. The participants were grouped based on regular exercise into REG (n = 3921) and non-REG (n = 6290) groups. The mortality rate was higher in the non-REG group than in the REG group (35.8% versus 26.9%; p < 0.001). The mortality rate was higher in denture users (versus non-denture users), non-drinkers (versus alcohol drinkers), and those on medical aid (versus national health insurance). The mortality rate was higher in participants with poor masticatory ability, lower education level, and poor subjective health perception (p < 0.001). Denture use and masticatory discomfort were not significant risk factors for mortality in the non-REG group (p > 0.05). In conclusion, masticatory discomfort was a risk factor for increased mortality in middle-aged Korean adults who exercised regularly, at least once a week. Thus, assessment of masticatory ability could be a useful indicator of life expectancy in middle-aged adults.

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 10 7 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95% CI -29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.

The challenge of decoding information about complex diseases hidden in huge number of single nucleotide polymorphism (SNP) genotypes is undertaken based on five dbGaP studies. Current genome-wide association studies have successfully identified many high-risk SNPs associated with diseases, but precise diagnostic models for complex diseases by these or more other SNP genotypes are still unavailable in the literature. We report that lung cancer, breast cancer and prostate cancer as the first three top cancers worldwide can be predicted precisely via 240-370 SNPs with accuracy up to 99% according to leave-one-out and 10-fold cross-validation. Our findings (1) confirm an early guess of Dr. Mitchell H. Gail that about 300 SNPs are needed to improve risk forecasts for breast cancer, (2) reveal an incredible fact that SNP genotypes may contain almost all information that one wants to know, and (3) show a hopeful possibility that complex diseases can be precisely diagnosed by means of SNP genotypes without using phenotypical features. In short words, information hidden in SNP genotypes can be extracted in efficient ways to make precise diagnoses for complex diseases.

Nature reserves play an extraordinarily important role in conserving animal populations and their habitats. However, landscape change and unreasonable zoning designations often render these protected areas inadequate. Therefore, regular evaluation of the efficacy of protected lands is critical for maintaining and improving management strategies. Using species distribution models and GAP analysis, we assessed the changes in suitable habitat for the Brown Eared-pheasant (Crossoptilon mantchuricum) in two Chinese nature reserves between 1995 and 2013. Our results showed that the habitat suitability of Brown Eared-pheasant has changed dramatically during this period, and fragmentation analyses showed an increase in concentration area and decrease in patch area. In particular, our findings show that the national nature reserves need to adjust their ranges to ensure the conservation of this flagship species. Our study further provides a new viewpoint for evaluating the efficacy of protected lands, particularly in highly urbanized regions where conservation goals must be balanced with changing landscapes.

Signaling elicited by the stem cell factors SOX2, OCT4, KLF4, and MYC not only mediates reprogramming of differentiated cells to pluripotency but has also been correlated with tumor malignancy. In this study, we found SOX2 expression signifies poor recurrence-free survival and correlates with advanced pathological grade in bladder cancer. SOX2 silencing attenuated bladder cancer cell growth, while its expression promoted cancer cell survival and proliferation. Under low-serum stress, SOX2 expression promoted AKT phosphorylation and bladder cancer cells' spheroid-forming capability. Furthermore, pharmacological inhibition of AKT phosphorylation, using MK2206, inhibited the SOX2-mediated spheroid formation of bladder cancer cells. Gene expression profiling showed that SOX2 expression, in turn, induced IGF2 expression, while SOX2 silencing inhibited IGF2 expression. Moreover, knocking down IGF2 and IGF1R diminished bladder cancer cell growth. Lastly, pharmacological inhibition of IGF1R, using linsitinib, also inhibited the SOX2-mediated spheroid formation of bladder cancer cells under low-serum stress. Our findings indicate the SOX2-IGF2 signaling affects the aggressiveness of bladder cancer cell growth. This signaling could be a promising biomarker and therapeutic target for bladder cancer intervention.

Mycobacterium tuberculosis (MTB) is commonly used as a model to study pathogenicity and multiple drug resistance in bacteria. These MTB characteristics are highly dependent on the evolution and phylogeography of the bacterium. In this paper, we describe 15 new genomes of multidrug-resistant MTB (MDRTB) from Malaysia. The assessments and annotations on the genome assemblies suggest that strain differences are due to lineages and horizontal gene transfer during the course of evolution. The genomes show mutations listed in current drug resistance databases and global MTB collections. This genome data will augment existing information available for comparative genomic studies to understand MTB drug resistance mechanisms and evolution.

The repeated measurements of heart rate variability (HRV) is more relevant than a single HRV measurement in predicting patient prognosis but is less addressed previously. This prospective study aimed to investigate the association between repeated measurements of HRV and long-term mortality in chronic hemodialysis patients. The 164 patients (65.0 ± 13.1 years; woman, 57.3%) were enrolled from June 1, 2010, to August 31, 2010, and received four HRV measurements (before and during the index hemodialysis session) after the enrollment. The baseline characteristic and clinical variables, including mortality, were documented. The joint modeling method and Cox regression were used for statistical analyses. After an 8-year follow-up, 79 patients expired, and 85 patients survived. We found that higher normalized high-frequency (nHF) (hazard ratio [HR] 1.033) as well as lower very-low-frequency (HR 0.990), Variance (HR 0.991), normalized low-frequency (HR 0.999, P = 0.006), and low-frequency/high-frequency ratio (HR 0.796) were independent predictors for cardiovascular mortality. Whereas the independent predictors for infection-associated mortality included higher nHF (HR 1.033) as well as higher age (HR 19.29) and lower serum albumin (HR 0.01, P = 0.001). (all P < 0.001 unless otherwise stated) In conclusion, HRV measurement predicts long-term mortality among hemodialysis patients.

Elucidation of the molecular mechanism related to the dedifferentiation and redifferentiation during tissue culture will be useful for optimizing regeneration system of tea plant. In this study, an integrated sRNAome and transcriptome analyses were carried out during phase changes of the stem explant culture. Among 198 miRNAs and 8001 predicted target genes, 178 differentially expressed miRNAs and 4264 potential targets were screened out from explants, primary calli, as well as regenerated roots and shoots. According to KEGG analysis of the potential targets, pathway of "aminoacyl-tRNA biosynthesis", "proteasome" and "glutathione metabolism" was of great significance during the dedifferentiation, and pathway of "porphyrin and chlorophyll metabolism", "mRNA surveillance pathway", "nucleotide excision repair" was indispensable for redifferentiation of the calli. Expression pattern of 12 miRNAs, including csn-micR390e, csn-miR156b-5p, csn-miR157d-5p, csn-miR156, csn-miR166a-3p, csn-miR166e, csn-miR167d, csn-miR393c-3p, csn-miR394, csn-miR396a-3p, csn-miR396 and csn-miR396e-3p, was validated by qRT-PCR among 57 differentially expressed phase-specific miRNAs. Validation also confirmed that regulatory module of csn-miR167d/ERF3, csn-miR156/SPB1, csn-miR166a-3p/ATHB15, csn-miR396/AIP15A, csn-miR157d-5p/GST and csn-miR393c-3p/ATG18b might play important roles in regulating the phase changes during tissue culture of stem explants.

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

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

Spermatogenesis is a differentiation process that requires dramatic changes to DNA architecture, a process governed in part by Transition Nuclear Proteins 1 and 2 (TNP1 and TNP2). Translation of Tnp1 and Tnp2 mRNAs is temporally disengaged from their transcription. We hypothesized that RNA regulatory proteins associate specifically with Tnp mRNAs to control the delayed timing of their translation. To identify potential regulatory proteins, we isolated endogenous mRNA/protein complexes from testis extract and identified by mass spectrometry proteins that associated with one or both Tnp transcripts. Five proteins showed strong association with Tnp transcripts but had low signal when Actin mRNA was isolated. We visualized the expression patterns in testis sections of the five proteins and found that each of the proteins was detected in germ cells at the appropriate stages to regulate Tnp RNA expression.

Haloarchaea utilize various microbial rhodopsins to harvest light energy or to mediate phototaxis in search of optimal environmental niches. To date, only the red light-sensing sensory rhodopsin I (SRI) and the blue light-sensing sensory rhodopsin II (SRII) have been shown to mediate positive and negative phototaxis, respectively. In this work, we demonstrated that a blue-green light-sensing (504 nm) sensory rhodopsin from Haloarcula marismortui, SRM, attenuated both positive and negative phototaxis through its sensing region. The H. marismortui genome encodes three sensory rhodopsins: SRI, SRII and SRM. Using spectroscopic assays, we first demonstrated the interaction between SRM and its cognate transducer, HtrM. We then transformed an SRM-HtrM fusion protein into Halobacterium salinarum, which contains only SRI and SRII, and observed that SRM-HtrM fusion protein decreased both positive and negative phototaxis of H. salinarum. Together, our results suggested a novel phototaxis signalling system in H. marismortui comprised of three sensory rhodopsins in which the phototactic response of SRI and SRII were attenuated by SRM.

Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. We examined if tumor tissue and circulating protein levels of all vascular endothelial growth factors (VEGFs) and VEGF receptors (VEGFRs) were synchronous and different in Taiwan patients with metastatic CRC (mCRC) vs. non-mCRC. We analyzed samples from 109 patients enrolled from 2005-2017, 50 with stages I/II and 59 with stages III/IV CRC. We found that VEGF-A, -B, -C, -D, placental growth factor (PlGF), VEGFR-1, VEGFR-2, and VEGFR-3 were higher in tumor tissues than non-tumor tissues. Metastatic patients had higher levels of circulating VEGFs and soluble VEGFRs (sVEGFRs) than healthy subjects, as well as higher VEGF-A, -B, -C, -D, and PlGF proteins in both tumor tissue and serum than non-metastatic patients. Protein levels of VEGF and VEGFR were mainly associated with the patient's age, tumor site, tumor size, tumor stage, and lymph node metastasis. Patients exhibiting high levels of VEGF, VEGFR, and sVEGFR had a shorter overall survival and disease-free survival than those with low levels. We conclude that synchronous changes in VEGF and VEGFR levels in CRC tissue and serum VEGF can discriminate between metastatic and non-metastatic subjects and high levels are associated with poor survival in CRC.

Tissue culture is very important for identifying the gene function of Camellia sinensis (L.) and exploiting novel germplasm through transgenic technology. Regeneration system of tea plant has been explored but not been well established since the molecular mechanism of tea plant regeneration is not clear yet. In this study, transcriptomic analysis was performed in the initial explants of tea plant and their dedifferentiated and redifferentiated tissues. A total of 93,607 unigenes were obtained through de novo assembly, and 7,193 differentially expressed genes (DEGs) were screened out from the 42,417 annotated unigenes. Much more DEGs were observed during phase transition rather than at growth stages of callus. Our KOG and KEGG analysis, and qPCR results confirmed that phase transition of tea plant was closely related to the mechanism that regulate expression of genes encoding the auxin- and cytokinin-responsive proteins, transcription factor MYB15 and ethylene-responsive transcription factor ERF RAP2-12. These findings provide a reliable foundation for elucidating the mechanism of the phase transition and may help to optimize the regeneration system by regulating the gene expression pattern.

Panel j was inadvertently labelled as panel k in the caption to Fig. 4. Similarly, 'Fig. 4k' should have been 'Fig. 4j' in the sentence beginning 'TNF-α-deficient gBT-I cells were…'. In addition, the surname of author Umaimainthan Palendira was misspelled 'Palendria'. These errors have been corrected online.

The immune system can suppress tumour development both by eliminating malignant cells and by preventing the outgrowth and spread of cancer cells that resist eradication 1 . Clinical and experimental data suggest that the latter mode of control-termed cancer-immune equilibrium 1 -can be maintained for prolonged periods of time, possibly up to several decades 2-4 . Although cancers most frequently originate in epithelial layers, the nature and spatiotemporal dynamics of immune responses that maintain cancer-immune equilibrium in these tissue compartments remain unclear. Here, using a mouse model of transplantable cutaneous melanoma 5 , we show that tissue-resident memory CD8 + T cells (T RM cells) promote a durable melanoma-immune equilibrium that is confined to the epidermal layer of the skin. A proportion of mice (~40%) transplanted with melanoma cells remained free of macroscopic skin lesions long after epicutaneous inoculation, and generation of tumour-specific epidermal CD69 + CD103 + T RM cells correlated with this spontaneous disease control. By contrast, mice deficient in T RM formation were more susceptible to tumour development. Despite being tumour - free at the macroscopic level, mice frequently harboured melanoma cells in the epidermal layer of the skin long after inoculation, and intravital imaging revealed that these cells were dynamically surveyed by T RM cells. Consistent with their role in melanoma surveillance, tumour-specific T RM cells that were generated before melanoma inoculation conferred profound protection from tumour development independently of recirculating T cells. Finally, depletion of T RM cells triggered tumour outgrowth in a proportion (~20%) of mice with occult melanomas, demonstrating that T RM cells can actively suppress cancer progression. Our results show that T RM cells have a fundamental role in the surveillance of subclinical melanomas in the skin by maintaining cancer-immune equilibrium. As such, they provide strong impetus for exploring these cells as targets of future anticancer immunotherapies.

Polarised light imaging microscopy, with the addition of a liquid crystal (LC) phase retarder, was used to determine the birefringence of silk fibres with high (∼1 μm) spatial resolution. The measurement was carried out with the silk fibres (the optical slow axis) and the slow axis of the LC-retarder set at parallel angles. The direct fit of the transmission data allowed for high fidelity determination of the birefringence Δn ≈ 1.63 × 10 -2 (with ∼2% uncertainty) of the brown silk fibre, (Antheraea pernyi) averaged over the wavelength range λ = (425-625) nm. By measuring retardance at four separate wavelengths, it was possible to determine the true value of the birefringence of a thicker sample when an optical path may include a large number of wavelengths. The numerical procedures and required hardware are described for the do-it-yourself assembly of the imaging polariscope at a fractional budget compared to commercial units.

Thioesters are key intermediates in biology, which often are generated from less energy-rich amide precursors. Staphylococcus aureus sortase A (SrtA) is an enzyme widely used in biotechnology for peptide ligation. The reaction proceeds in two steps, where the first step involves the conversion of an amide bond of substrate peptide into a thioester intermediate with the enzyme. Here we show that the free energy required for this step is matched by an about 30-fold increase in binding affinity of a calcium ion at the calcium binding site of SrtA, which is remote from the thioester bond. The magnitude of this allosteric effect highlights the importance of calcium for the activity of SrtA. The increase in calcium binding affinity upon binding of substrate not only achieves catalytic formation of an energy-rich intermediate in the absence of nucleotide triphosphates or any tight non-covalent enzyme-substrate interactions, but is also accompanied by accumulation of the labile thioester intermediate, which makes it directly observable in nuclear magnetic resonance (NMR) spectra.

Tea plant (Camellia sinensis) is a typical fluoride (F) hyperaccumulator enriching most F in old leaves. There is association between the risk of fluorosis and excessive consumption of teas prepared using the old leaves. It is meaningful to develop methods for controlling F levels in tea leaves. We generated a comprehensive RNA-seq dataset from tea plants grown at various F levels for different durations by hydroponics, aiming at providing information on mechanism of F metabolism in tea plant. Besides raw reads of the RNA-seq dataset, we present assembled unigenes and aligned unigenes with annotations versus the Gene Ontology (GO) databases, Kyoto Encyclopaedia of Genes and Genomes (KEGG) databases, and Nonredundant (Nr) protein databases with low e-values. 69,488 unigenes were obtained in total, in which 40,894 were given Nr annotations.

Podophyllotoxin is used as medical cream which is widely applied to genital warts and molluscum contagiosum. Although previous study showed that podophyllotoxin had minimal toxicity, it was forbidden to use during pregnancy since it might be toxic to the embryos. In present study we used mouse as the model and tried to examine whether podophyllotoxin exposure was toxic to oocyte maturation, which further affected embryo development. Our results showed that podophyllotoxin exposure inhibited mouse oocyte maturation, showing with the failure of polar body extrusion, and the inhibitory effects of podophyllotoxin on oocytes was dose-depended. Further studies showed that the meiotic spindle formation was disturbed, the chromosomes were misaligned and the fluorescence signal of microtubule was decreased, indicating that podophyllotoxin may affect microtubule dynamics for spindle organization. Moreover, the oocytes which reached metaphase II under podophyllotoxin exposure also showed aberrant spindle morphology and chromosome misalignment, and the embryos generated from these oocytes showed low developmental competence. We also found that the localization of p44/42 MAPK and gamma-tubulin was disrupted, which further confirmed the effects of podophyllotoxin on meiotic spindle formation. In all, our results indicated that podophyllotoxin exposure could affect mouse oocyte maturation by disturbing microtubule dynamics and meiotic spindle formation.

To acquire device-quality TiO x films usually needs high-temperature growth or additional post-thermal treatment. However, both processes make it very difficult to form the p-type TiO x even under oxygen-poor growth condition. With the aid of high energy generated by high power impulse magnetron sputtering (HIPIMS), a highly stable p-type TiO x film with good quality can be achieved. In this research, by varying the oxygen flow rate, p-type γ-TiO and n-type TiO 2 films were both prepared by HIPIMS. Furthermore, p- and n-type thin film transistors employing γ-TiO and TiO 2 as channel layers possess the field-effect carrier mobilities of 0.2 and 0.7 cm 2 /Vs, while their on/off current ratios are 1.7 × 10 4 and 2.5 × 10 5 , respectively. The first presented p-type γ-TiO TFT is a major breakthrough for fabricating the TiO x -based p-n combinational devices. Additionally, our work also confirms HIPIMS offers the possibility of growing both p- and n-type conductive oxides, significantly expanding the practical usage of this technique.

Lower back pain (LBP) is the most common disease in orthopedic clinics world-wide. A classic Fangji of traditional Chinese medicine, Duhuo Jisheng Decoction (DHJSD), has been proven clinically effective for LBP but its therapeutic mechanisms remain unclear. We hypothesized that DHJSD might relieve LBP through inhibiting the exaggerated proinflammatory cytokines and extracellular matrix (ECM) degradation. Thus, we studied the effects of DHJSD on stromal cell-derived factor-1 (SDF-1)-induced inflammation and ECM degradation in human nucleus pulposus cells (hNPCs). The primary hNPCs were isolated from either degenerated human intervertebral disc (HID) of LBP patients or normal HID of lumbar vertebral fracture patients, and cultured in vitro. The cells were treated with SDF-1 (10 ng/mL) and subsequently with different concentrations (100-500 μg/mL) of DHJSD for 24 h, respectively. We found that application of DHJSD significantly antagonized the SDF-1-induced production of proinflammatory cytokines and reduction of aggrecan and type II collagen in the hNPCs. DHJSD also markedly reduced the SDF-1-induced increase of CXCR4 and p-p65 and inhibited the nuclear translocation of p65 in the hNPCs. DHJSD, CXCR4-siRNA, and NF-κB inhibitor (BAY11-7082) caused the same inhibition of exaggerated proinflammatory cytokines in the SDF-1-treated hNPCs. These results provided compelling evidence that DHJSD may inhibit the generation of proinflammatory mediators and ECM degradation of HID through an orchestrated targeting at multiple molecules in the SDF-1/CXCR4/NF-κB pathway, thus offered novel mechanistic insights into the clinical effectiveness of DHJSD on LBP.

Anxiety is a frequent and serious complication of children and adolescents receiving dialysis. Low serum vitamin D levels have been associated with anxiety in non-pediatric patients. This study sought to examine the possible association between serum vitamin D levels and the presence of anxiety in children and adolescents with dialysis in China. A total of 156 pediatric patients who were on hemodialysis or peritoneal dialysis and 100 healthy controls were included in the current study. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured by using a competitive protein-binding assay. Anxiety was assessed by using the Chinese version of the Screen for Child Anxiety Related Emotional Disorders (SCARED, = 25 as cutoff). Among 156 patients, 110 had a current anxiety (70.5%) and 46 did not (29.5%). Serum levels of 25(OH)D were significantly lower in patients with anxiety than in normal controls (19.4 ± 10.3 vs. 38.6 ± 15.5 ng/ml, P < 0.001). Serum 25(OH)D levels (≤15.0 ng/ml) were independently associated with the existent of anxiety in children and adolescents receiving dialysis (OR 4.650, 95% CI 1.663-13.001, P = 0.003). Our research demonstrates that low serum levels of vitamin D are independently associated with anxiety among children and adolescents on dialysis, which needs to be confirmed in future experimental and clinical studies.

Mucoepidermoid carcinoma (MEC) arises in many glandular tissues and contributes to the most common malignant salivary gland cancers. MEC is specifically associated with a unique t(11;19) translocation and the resulting CRTC1-MAML2 fusion is a major oncogenic driver for MEC initiation and maintenance. However, the molecular basis underlying the CRTC1-MAML2 oncogenic functions remains elusive. Through gene expression profiling analysis, we observed that LINC00473, a long non-coding RNA (lncRNA), was the top down-regulated target in CRTC1-MAML2-depleted human MEC cells. LncRNAs belong to a new class of non-coding RNAs with emerging roles in tumorigenesis and progression, but remain poorly characterized. In this study, we investigated the role of LINC00473 in mediating CRTC1-MAML2 oncogenic activity in human MEC. We found that LINC00473 transcription was significantly induced in human CRTC1-MAML2-positive MEC cell lines and primary MEC tumors, and was tightly correlated with the CRTC1-MAML2 RNA level. LINC00473 induction was dependent on the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Depletion of LINC00473 significantly reduced the proliferation and survival of human MEC cells in vitro and blocked the in vivo tumor growth in a human MEC xenograft model. RNA in situ hybridization analysis demonstrated a predominantly nuclear localization pattern for LINC00473 in human MEC cells. Furthermore, gene expression profiling revealed that LINC00473 depletion resulted in differential expression of genes important in cancer cell growth and survival. LINC00473 likely regulates gene expression in part through its ability to bind to a cAMP signaling pathway component NONO, enhancing the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Our overall results demonstrate that LINC00473 is a downstream target and an important mediator of the CRTC1-MAML2 oncoprotein. Therefore, LINC00473 acts as a promising biomarker and therapeutic target for human CRTC1-MAML2-positive MECs.

Treatment of hypertension with thiazide diuretics may trigger hypokalemia, hyperglycemia, and hyperuricemia. Some studies suggest simultaneous potassium supplementation in hypertensive patients using thiazide diuretics. However, few clinical studies have reported the impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities in blood glucose and uric acid (UA) metabolisms. One hundred hypertensive patients meeting the inclusion criteria were equally randomized to two groups: IND group receiving indapamide (1.25-2.5 mg daily) alone, and IND/KCI group receiving IND (1.25-2.5 mg daily) plus potassium chloride (40 mmol daily), both for 24 weeks. At the end of 24-week follow-up, serum K + level in IND group decreased from 4.27 ± 0.28 to 3.98 ± 0.46 mmol/L (P < 0.001), and fasting plasma glucose (FPG) and UA increased from 5.11 ± 0.52 to 5.31 ± 0.57 mmol/L (P < 0.05), and from 0.404 ± 0.078 to 0.433 ± 0.072 mmol/L (P < 0.05), respectively. Serum K + level in IND/KCl group decreased from 4.27 ± 0.36 to 3.89 ± 0.28 mmol/L (P < 0.001), and FPB and UA increased from 5.10 ± 0.41 to 5.35 ± 0.55 mmol/L (P < 0.01), and from 0.391 ± 0.073 to 0.457 ± 0.128 mmol/L (P < 0.001), respectively. The difference value between the serum K + level and FPG before and after treatment was not statistically significant between the two groups. However, the difference value in UA in IND/KCl group was significantly higher than that in IND group (0.066 (95% confidence interval (CI): 0.041-0.090)  mmol/L vs. 0.029 (95% CI: 0.006-0.058) mmol/L, P < 0.05). The results showed that long-term routine potassium supplementation could not prevent or attenuate thiazide diuretic-induced abnormalities of glucose metabolism in hypertensive patients; rather, it may aggravate the UA metabolic abnormality.

The brown planthopper, Nilaparvata lugens, is an economically important pest on rice in Asia. Chemical control is still the most efficient primary way for rice planthopper control. However, due to the intensive use of insecticides to control this pest over many years, resistance to most of the classes of chemical insecticides has been reported. In this article, we report on the status of eight insecticides resistance in Nilaparvata lugens (Stål) collected from China over the period 2012-2016. All of the field populations collected in 2016 had developed extremely high resistance to imidacloprid, thiamethoxam, and buprofezin. Synergism tests showed that piperonyl butoxide (PBO) produced a high synergism of imidacloprid, thiamethoxam, and buprofezin effects in the three field populations, YA2016, HX2016, and YC2016. Functional studies using both double-strand RNA (dsRNA)-mediated knockdown in the expression of CYP6ER1 and transgenic expression of CYP6ER1 in Drosophila melanogaster showed that CYP6ER1 confers imidacloprid, thiamethoxam and buprofezin resistance. These results will be beneficial for effective insecticide resistance management strategies to prevent or delay the development of insecticide resistance in brown planthopper populations.

Stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most devastating diseases of wheat. Resistant cultivars are the preferred strategy to control the disease. Space-induced wheat mutant R39 has adult-plant resistance (APR) to Pst. Genetic analysis indicated that a single recessive gene, designated YrR39, was responsible for the APR of R39 to Pst. Bulked segregant analysis (BSA) combined with a SLAF sequencing (SLAF-seq) strategy was used to fine-map YrR39 to a 17.39 Mb segment on chromosome 4B. The region was confirmed by analysis with simple sequence repeat (SSR) markers. A total of 126 genes were annotated in the region and 21 genes with annotations associated with disease response were selected for further qRT-PCR analysis. The candidate gene Traes&#95;4BS&#95;C868349E1 (annotated as an F-box/LRR-repeat protein) was up-regulated after 12, 24, 48, and 96 hours post inoculation with Pst, suggesting it is likely involved in the resistance. The current study demonstrated that BSA combined with SLAF-seq for SNP discovery is an efficient approach for mapping and identifying candidate functional gene.

The brain has long been known to be the regulation center of itch, but the neuropathology of chronic itch, such as chronic spontaneous urticaria (CSU), remains unclear. Thus, we aimed to explore the brain areas involved in the pathophysiology of CSU in hopes that our results may provide valuable insights into the treatment of chronic itch conditions. 40 CSU patients and 40 healthy controls (HCs) were recruited. Urticaria activity scores 7 (UAS7) were collected to evaluate patient's clinical symptoms. Amplitude of low frequency fluctuations (ALFF), voxel-based morphometry (VBM), and seed-based resting-state functional connectivity (rs-FC) analysis were used to assess brain activity and related plasticity. Compared with HCs, CSU patients exhibited 1) higher ALFF values in the right ventral striatum / putamen, which were positively associated with clinical symptoms as measured by UAS7; 2) gray matter volume (GMV) increase in the right ventral striatum and putamen; and 3) decreased rs-FC between the right ventral striatum and the right occipital cortex and between the right putamen and the left precentral gyrus. Using multiple-modality brain imaging tools, we demonstrated the dysfunction of the striatum in CSU. Our results may provide valuable insights into the neuropathology and development of chronic itch.

The X-chromosome linked inhibitor of apoptosis (XIAP) is a multidomain metalloprotein involved in caspase inhibition and in copper homeostasis. It contains three zinc-binding baculoviral IAP repeats (BIR) domains, which are responsible for caspase interaction. Recently, it has been suggested that the BIR domains can bind copper, however high resolution data on such interaction is missing. Here we characterize by NMR the structural properties of BIR1 in solution, and the effects of its interaction with copper both in vitro and in physiological environments. BIR1 is dimeric in solution, consistent with the X-ray structure. Cysteine 12, located in the unfolded N-terminal region, has a remarkably low redox potential, and is prone to oxidation even in reducing physiological environments. Interaction of BIR1 with copper(II) results in the oxidation of cysteine 12, with the formation of either an intermolecular disulfide bond between two BIR1 molecules or a mixed disulfide bond with glutathione, whereas the zinc binding site is not affected by the interaction.

The prognostic value of anterior gradient-2 (AGR2) in tumours remains inconclusive. Here, we systematically reviewed the literature evidence and assessed the association between AGR2 expression and prognosis in solid tumours. The primary outcomes were overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS)/recurrence-free survival (RFS)/progression-free survival (PFS). All analyses were performed by STATA 12.0, with the hazard ratio (HR) or odds ratios (OR), and 95% confidence interval (CI) as the effect size estimate. A total of 20 studies containing 3285 cases were included. Pooled analyses revealed that AGR2 overexpression had an unfavourable impact on OS (HR 1.93, 95% CI 1.32-2.81) and time to tumour progression (TTP) (DFS/RFS/PFS) (HR 1.60 95% CI 1.06-2.40) in solid tumour patients. Subgroup analyses indicated that AGR2 overexpression in breast cancer patients was significantly associated with poor OS (HR 3.02, 95% CI 1.03-8.81) and TTP (HR 1.93, 95% CI 1.17-3.20). Excluding breast cancer, AGR2 overexpression was also found to have a significant correlation with poor OS in the remaining solid tumour patients (HR 1.51, 95% CI 1.04-2.19). Overall, AGR2 might be a potential biomarker to predict prognosis in solid tumour patients.