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Urinary metabolomics is a useful non-invasive tool for large-scale screening of disease-related metabolites. However, no comprehensive urinary metabolomic analysis of vitiligo is presently available. To investigate the urine metabolic pattern of vitiligo patients, we conducted a combined cross-sectional and prospective self-control cohort study and an untargeted urinary metabolomic analysis. In the cross-sectional study, 295 vitiligo patients and 192 age‐ and sex‐matched controls were enrolled, and 71 differential metabolites between two groups were identified. Pathway enrichment analysis revealed that drug metabolism-cytochrome P450, biopterin metabolism, vitamin B9 (folate) metabolism, selenoamino acid metabolism, and methionine and cysteine metabolism showed significant enrichment in vitiligo patients compared with the status in healthy controls. In the self-control cohort, 46 active vitiligo patients were recruited to analyse the urinary metabolic signatures after treatment. All of these patients were asked to undertake follow-up visits every 2 months three times after first consulting and the disease stage was evaluated compared with that at the last visit. Folate metabolism, linoleate metabolism, leukotriene metabolism, alkaloid biosynthesis, and tyrosine metabolism were predicted to be involved in vitiligo activity. Our study is the first attempt to reveal urinary metabolic signatures of vitiligo patients and provides new insights into the metabolic mechanisms of vitiligo.

This study aimed to develop and validate a novel rabbit fixator made from a thermoplastic mask for awake imaging experiments. When heated in a hot-water bath at 65–70 °C for 2–5 min, the thermoplastic mask became soft and could be molded to fit over the entire body of an anesthetized rabbit (4 ml of 3% pentobarbital sodium solution by intramuscular injection). Twenty rabbits were randomly divided into fixator (n = 10) and anesthesia (n = 10) groups. The animals’ vital signs, stress hormones (cortisol and adrenaline), and subjective image quality scores for the computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) scanning were measured and compared. Phantom CT, MRI and PET studies were performed to assess the performance with and without the thermoplastic mask by using image agents at different concentrations or with different radioactivity. The respiration rate (RR), systolic blood pressure (SBP), diastolic blood pressure (DBP), peripheral capillary oxygen saturation (SpO2) and body temperature (T) decreased after anesthesia (all P P > 0.05). The heart rate (HR), cortisol and adrenaline did not significantly decrease after either anesthesia or fixation (all P > 0.05). The subjective image quality scores for the CT and MRI images of the head, thorax, liver, kidney, intestines and pelvis and the subjective image quality scores for the PET images did not significantly differ between the two groups (all P > 0.05). For all examined organs except the muscle, 18F-FDG metabolism was lower after fixation than after anesthesia, and was almost identical of liver between two groups. The phantom study showed that the CT values, standard uptake values and MR T2 signal values did not differ significantly with or without the mask (all P > 0.05). A novel rabbit fixator created using a thermoplastic mask could be used to obtain high-quality images for different imaging modalities in an awake and near-physiological state.

Orf is a highly contagious zoonotic disease of small ruminants caused by Parapoxvirus. Kisspeptin, encoded by the KISS1 gene with its cognate receptor GPR-54 is recognized as an upstream orchestrator in the hypothalamic-pituitary-gonadal axis. This study was designed to construct a DNA vaccine that produces a fused peptide composed of a major immunodominant protein of the orf virus (B2L) and kisspeptin-54, a neuropeptide with recognized roles in mammalian reproductive biology. The administration of this recombinant vaccine is shown to produce a significant antibody and cell-mediated immune response directed against B2L compared to the control group (p p

The Morris water maze (MWM) is widely used to evaluate rodent spatial learning and memory. However, current evaluation measures are not comprehensive because there is a wide distribution in the measured response. Utilizing the graph cognition hypothesis, we proposed four new deviation indices to evaluate cognitive function in the MWM that compared the optimal swim track to the actual track taken. These include the sum of the lateral deviation vectors, the sum of the offset angles, the sum of the correction vectors, and the sum of the lateral deviation vectors to the initial optimal route. We compared the four new deviation indices to the classically used escape latency measures in a vascular dementia model and demonstrated a higher consistency in the normal distribution between the vascular dementia group and the control rats. Further, the new measures displayed higher sensitivity and specificity compared to what escape latency displayed in the Monte Carlo simulation. From the receiver operating characteristic curve, the diagnostic values of the new deviation indices are higher than those of escape latency. Therefore, including these new evaluation indices in MWM experiments provided a more effective analysis of cognitive function compared to using escape latency.

The successful restoration of corneal innervation and function after a corneal injury is a clinically challenging issue. Structural and functional recovery after a nerve injury involves a complex series of steps in which microtubules play a key role. The aim of the current study was to investigate the effects of epothilone B (EpoB), a microtubule-stabilizing agent, on corneal innervation and the functional recovery of the corneal nerve in mice after corneal epithelial abrasion. The pretreatment of mice with EpoB has a remarkable effect on the stabilization of beta-III tubulin, as demonstrated by substantial increases in the visualization of beta-III tubulin, nerve beading, corneal reinnervation, and reaction to stimuli. Furthermore, a pharmacokinetic analysis showed that EpoB remains at a high concentration in the cornea and the trigeminal ganglion for at least 6 days after administration. In addition, the administration of EpoB at 24 hours after corneal abrasion has a marked therapeutic effect on nerve regrowth and functional recovery. In conclusion, EpoB treatment may have therapeutic utility for improving corneal reinnervation and restoring sensitivity following corneal injury.

Otitis media (OM) is a major cause of morbidity in pediatric and adult patients. This inflammatory condition is characterized by mucous cell hyperplasia that is thought to produce mucins from the middle ear mucosa. We are interested in the role of Notch signalling pathway in this inflammatory process. Using an acute otitis media (AOM) mouse model through injection of Streptococcus Pneumoniae into the middle ear, histopathologic examination and quantitative RT-PCR, acute inflammation with the thickness of mucosa, Goblet cell hyperplasia, and cilia loss were determined and gene expression related to the Notch signaling pathway were evaluated. Upregulation of the mucous cell markers, Argr2 and Muc5AC, and downregulation of the cilia cell marker, Foxj1 and Dnai2, were observed in AOM. In addition, genes encoding Notch receptors and ligands (Notch1, Notch2, Notch3, Notch4 and Dll1) and the Notch target genes (Hes1, Hes5, Hey1, NRARP) in AOM decreased significantly. The expression of the Notch1 and Jagged1 also showed down-regulation throughout the mouse middle ear epithelium. Taken together, this study suggests that downregulation of the Notch signaling pathway is involved in the mucosa hyperplasia during AOM.

To discover tumor-associated proteins in osteosarcoma, a quantitative proteomic analysis was performed to identify proteins that were differentially expressed between osteosarcoma and human osteoblastic cells. Through clinical screening and a functional evaluation, chromosome segregation 1-like (CSE1L) protein was found to be related to the growth of osteosarcoma cells. To date, little is known about the function and underlying mechanism of CSE1L in osteosarcoma. In the present study, we show that knockdown of CSE1L inhibits osteosarcoma growth in vitro and in vivo. By co-immunoprecipitation and RNA-seq analysis, CSE1L was found to interact with mutS homolog 6 (MSH6) and function as a positive regulator of MSH6 protein in osteosarcoma cells. A rescue study showed that decreased growth of osteosarcoma cells by CSE1L knockdown was reversed by MSH6 overexpression, indicating that the activity of CSE1L was an MSH6-dependent function. In addition, depletion of MSH6 hindered cellular proliferation in vitro and in vivo. Notably, CSE1L expression was correlated with MSH6 expression in tumor samples and was associated with poor prognosis in patients with osteosarcoma. Taken together, our results demonstrate that the CSE1L-MSH6 axis has an important role in osteosarcoma progression.

Sensory hair cells are coordinately oriented within each inner ear sensory organ to exhibit a particular form of planar cell polarity (PCP) necessary for mechanotransduction. However, the developmental events associated with establishing PCP in the vestibule are unclear, hindering data interpretation and employment of the vestibule for PCP studies. Herein, we investigated PCP of the mouse vestibular organs. We further characterised cell cycle exit, cell differentiation, and PCP establishment in the utricle. We found that hair cells formed first in the striolar and medial extrastriolar (MES) regions of the utricle at embryonic day 11.5 (E11.5), while cells in the lateral extrastriolar region (LES) mostly formed at E13.5. Cell differentiation was initiated in the striolar region, which expanded first toward the MES, then to the LES by E15.5. The polarity of hair cells was established at birth along a putative line of polarity reversal (LPR), lateral to the striolar region. Core PCP protein Vangl2 emerged in the cell boundaries since E11.5, while cell intrinsic polarity protein Gαi3 appeared at E12.5, then polarized to the bare zone of individual hair cell at E13.5. These findings provide a blueprint of the developmental events associated with establishing PCP in the utricle.

The mechanisms of corneal epithelial lesions and delayed wound repair, as well as their association with diabetes mellitus, are critical issues for clinical ophthalmologists. To test whether the diabetic condition alters the circadian rhythm in a mouse cornea and whether insulin can synchronise the corneal clock, we studied the effects of streptozotocin-induced diabetes on the mitosis of epithelial cells, the recruitment of leukocytes to the cornea, and the expression of main core clock genes (Clock, Bmal1, Per2, Cry1, and Rev-erbα) in the corneal epithelium. We also assessed the possible effect of insulin on these modifications. Diabetes downregulated Clock, Bmal1, and Per2 expression, upregulated Cry1 and Rev-erbα expression, reduced corneal epithelial mitosis, and increased leukocyte (neutrophils and γδ T-cells) recruitment to the cornea. Early treatments with insulin partially restored the altered rhythmicity in the diabetic cornea. In conclusion, insulin-dependent diabetes altered the normal rhythmicity of the cornea, and insulin administration had a beneficial effect on restoring normal rhythmicity in the diabetic cornea.

Bats, order Chiroptera, are one of the largest monophyletic clades in mammals. Based on morphology and behaviour bats were once differentiated into two suborders Megachiroptera and Microchiroptera Recently, researchers proposed alternative views of chiropteran classification (suborders Yinpterochiroptera and Yangochiroptera) based on morphological, molecular and fossil evidence. Since genome-scale data can significantly increase the number of informative characters for analysis, transcriptome RNA-seq data for 12 bat taxa were generated in an attempt to resolve bat subordinal relationships at the genome level. Phylogenetic reconstructions were conducted using up to 1470 orthologous genes and 634,288 aligned sites. We found strong support for the Yinpterochiroptera-Yangochiroptera classification. Next, we built expression distance matrices for each species and reconstructed gene expression trees. The tree is highly consistent with sequence-based phylogeny. We also examined the influence of taxa sampling on the performance of phylogenetic methods, and found that the topology is robust to sampling. Relaxed molecular clock estimates the divergence between Yinpterochiroptera and Yangochiroptera around 63 million years ago. The most recent common ancestor of Yinpterochiroptera, corresponding to the split between Rhinolophoidea and Pteropodidae (Old World Fruit bats), is estimated to have occurred 60 million years ago. Our work provided a valuable resource to further explore the evolutionary relationship within bats.

Growth differentiation factor-15 (GDF-15) has been implicated in ischemic brain injury and synapse development, but its involvement in modulating neuronal excitability and synaptic transmission remain poorly understood. In this study, we investigated the effects of GDF-15 on non-evoked miniature excitatory post-synaptic currents (mEPSCs) and neurotransmitter release in the medial prefrontal cortex (mPFC) in mice. Incubation of mPFC slices with GDF-15 for 60 min significantly increased the frequency of mEPSCs without effect on their amplitude. GDF-15 also significantly elevated presynaptic glutamate release, as shown by HPLC. These effects were blocked by dual TGF-β type I receptor (TβRI) and TGF-β type II receptor (TβRII) antagonists, but not by a TβRI antagonist alone. Meanwhile, GDF-15 enhanced pERK level and inhibition of MAPK/ERK activity attenuated the GDF-15-induced increases in mEPSC and glutamate release. Blocking T-type calcium channels reduced the GDF-15 induced up-regulation of synaptic transmission. Membrane-protein extraction and use of an intracellular protein-transport inhibitor showed that GDF-15 promoted CaV3.1 and CaV3.3 α-subunit expression by trafficking to the membrane. These results confirm previous findings in cerebellar granule neurons, in which GDF-15 induces its neurobiological effects via TβRII and activation of the ERK pathway, providing novel insights into the mechanism of GDF-15 function in cortical neurons.

Pathogen invasion triggers a number of cellular responses and alters the host transcriptome. Here we report that the type of changes to cellular transcriptome is related to the type of cellular functions affected by lytic infection of Herpes Simplex Virus type I in Human primary fibroblasts. Specifically, genes involved in stress responses and nuclear transport exhibited mostly changes in alternative polyadenylation (APA), cell cycle genes showed mostly alternative splicing (AS) changes, while genes in neurogenesis, rarely underwent these changes. Transcriptome wide, the infection resulted in 1,032 cases of AS, 161 incidences of APA, 1,827 events of isoform changes and up regulation of 596 genes and down regulations of 61 genes compared to uninfected cells. Thus, these findings provided important and specific links between cellular responses to HSV-1 infection and the type of alterations to the host transcriptome, highlighting important roles of RNA processing in virus-host interactions.

Discovery of variable lymphocyte receptors (VLRs) in agnathans (jawless fish) has brought the origin of adaptive immunity system (AIS) forward to 500 million years ago accompanying with the emergence of vertebrates. Previous findings indicated that amphioxus, a representative model organism of chordate, also possesses some homologs of the basic components of TCR/BCR-based AIS, but it remains unknown if there exist any components of VLR-based AIS in amphioxus. Bioinformatics analyses revealed the amphioxus Branchiostoma floridae encodes a group of putative VLR-like proteins. Here we reported the 1.79 Å crystal structure of Bf66946, which forms a crescent-shaped structure of five leucine-rich repeats (LRRs). Structural comparisons indicated that Bf66946 resembles the lamprey VLRC. Further electrostatic potential analyses showed a negatively-charged patch at the concave of LRR solenoid structure that might be responsible for antigen recognition. Site-directed mutagenesis combined with bacterial binding assays revealed that Bf66946 binds to the surface of Gram-positive bacteria Staphylococcus aureus and Streptococcus pneumonia via a couple of acidic residues at the concave. In addition, the closest homolog of Bf66946 is highly expressed in the potential immune organ gill of Branchiostoma belcheri. Altogether, our findings provide the first structural evidence for the emergence of VLR-like molecules in the basal chordates.

Vitamin D receptor (VDR) is highly expressed in human and mouse kidneys. Nevertheless, its functions remain obscure. This study investigated the effects of vitamin D3 (VitD3) pretreatment on renal inflammation during lipopolysaccharide (LPS)-induced acute kidney injury. Mice were intraperitoneally injected with LPS. In VitD3 + LPS group, mice were pretreated with VitD3 (25 μg/kg) at 48, 24 and 1 h before LPS injection. As expected, an obvious reduction of renal function and pathological damage was observed in LPS-treated mice. VitD3 pretreatment significantly alleviated LPS-induced reduction of renal function and pathological damage. Moreover, VitD3 pretreatment attenuated LPS-induced renal inflammatory cytokines, chemokines and adhesion molecules. In addition, pretreatment with 1,25(OH)2D3, the active form of VitD3, alleviated LPS-induced up-regulation of inflammatory cytokines and chemokines in human HK-2 cells, a renal tubular epithelial cell line, in a VDR-dependent manner. Further analysis showed that VitD3, which activated renal VDR, specifically repressed LPS-induced nuclear translocation of nuclear factor kappa B (NF-κB) p65 subunit in the renal tubules. LPS, which activated renal NF-κB, reciprocally suppressed renal VDR and its target gene. Moreover, VitD3 reinforced the physical interaction between renal VDR and NF-κB p65 subunit. These results provide a mechanistic explanation for VitD3-mediated anti-inflammatory activity during LPS-induced acute kidney injury.

Human dihydroorotate dehydrogenase (hDHODH) is an attractive therapeutic target for the treatment of rheumatoid arthritis, transplant rejection and other autoimmune diseases. Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range. Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo. Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold. This work not only elucidates promising scaffolds targeting hDHODH for the treatment of rheumatoid arthritis, but also demonstrates that the water-mediated hydrogen bond interaction is an important factor in molecular design and optimization.

Mutualistic ants can protect their partners from natural enemies in nature. Aenasius bambawalei is an important parasitoid of the the invasive mealybug Phenacoccus solenopsis. We hypothesized that mutualism between native ants and mealybugs would favor survival of mealybugs. To test this, we examined effects of tending by the native mutualistic ant Tapinoma melanocephalum on growth of P. solenopsis colonies on Chinese hibiscus, Hibiscus rosa-sinensis, in a field setting. Ant workers with access to honeydew of mealybugs lived much longer than those provisioned only with water in the laboratory and number of ant workers foraging increased significantly with growth of mealybug colonies in the field. In later observations, there were significant differences in densities of mealybugs between ant-tended and -excluded treatments. Survival rate of mealybugs experiencing parasitoid attack was significantly higher on ant-tended plants than on ant-excluded plants. When the parasitoid was excluded, there was no difference in survival rate of mealybugs between ant-tended and -excluded plants. In most cases, ants directly attacked the parasitoid, causing the parasitoid to take evasive action. We conclude that native ants such as T. melanocephalum have the potential to facilitate invasion and spread of P. solenopsis in China by providing them with protection from parasitoids.

The present study was designed to highlight the impact of seed priming with polyethylene glycol on physiological and molecular mechanism of two cultivars of Oryza sativa L. under different levels of zinc oxide nanorods (0, 250, 500 and 750 mg L−1). Plant growth parameters were significantly increased in seed priming with 30% PEG under nano-ZnO stress in both cultivars. Whereas, this increase was more prominent in cultivar Qian You No. 1 as compared to cultivar Zhu Liang You 06. Significant increase in photosynthetic pigment with PEG priming under stress. Antioxidant enzymes activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) as well as malondialdehyde (MDA) contents were significantly reduced with PEG priming under nano-ZnO stress. Gene expression analysis also suggested that expression of APXa, APXb, CATa, CATb, CATc, SOD1, SOD2 and SOD3 genes were down regulated with PEG priming as compared to non-primed seeds under stress. The ultrastructural analysis showed that leaf mesophyll and root cells were significantly damaged under nano-ZnO stress in both cultivars but the damage was prominent in Zhu Liang You 06. However, seed priming with PEG significantly alleviate the toxic effects of nano-ZnO stress and improved the cell structures of leaf and roots in both cultivars.

The crab-eating frog, Fejervarya cancrivora, is the only frog that lives near seas. It tolerates increased environmental concentrations of sodium, chloride and potassium partly by raising ion and urea levels in its blood plasma. The molecular mechanism of the adaptation remains rarely documented. Herein, we analyze transcriptomes of the crab-eating frog and its closely related saline-intolerant species, F. limnocharis, to explore the molecular basis of adaptations to such extreme environmental conditions. Analyses reveal the potential genetic mechanism underlying the adaptation to salinity for the crab-eating frog. Genes in categories associated with ion transport appear to have evolved rapidly in F. cancrivora. Both positively selected and differentially expressed genes exhibit enrichment in the GO category regulation of renal sodium excretion. In this category, the positively selected sites of ANPEP and AVPR2 encode CD13 and V2 receptors, respectively; they fall precisely on conserved domains. More differentially expressed rapidly evolved genes occur in the kidney of F. cancrivora than in F. limnocharis. Four genes involved in the regulation of body fluid levels show signs of positive selection and increased expression. Significant up-regulation occurs in several genes of F. cancrivora associated with renin-angiotensin system and aldosterone-regulated sodium reabsorption pathways, which relate to osmotic regulation.

Techniques for rapid design of dielectric materials with appropriate permittivity for many important technological applications are urgently needed. It is found that functional structure blocks (FSBs) are helpful in rational design of inorganic dielectrics with expected permittivity. To achieve this, coordination polyhedra are parameterized as FSBs and a simple empirical model to evaluate permittivity based on these FSB parameters is proposed. Using this model, a wide range of examples including ferroelectric, high/low permittivity materials are discussed, resulting in several candidate materials for experimental follow-up.

Environment enrichment (EE) has a variety of effects on brain structure and function. Brain-derived neurotrophic factor (BDNF) is essential for EE-induced hippocampal neurogenesis and memory enhancement. However, the intracellular pathway downstream of BDNF to modulate EE effects is poorly understood. Here we show that integrin-linked kinase (ILK) levels are elevated upon EE stimuli in a BDNF-dependent manner. Using ILK-shRNA (siILK) lentivirus, we demonstrate that knockdown of ILK impairs EE-promoted hippocampal neurogenesis and memory by increasing glycogen synthase kinase-3β (GSK3β) activity. Finally, overexpressing ILK in the hippocampus could rescue the neurogenesis and memory deficits in BDNF+/− mice. These results indicate that ILK is indispensable for BDNF-mediated hippocampal neurogenesis and memory enhancement upon EE stimuli via regulating GSK3β activity. This is a new insight of the precise mechanism in EE-enhanced memory processes and ILK is a potentially important therapeutic target that merits further study.

It is still debate of the relationship between the dietary protein consumption and risk of fracture. We searched Medline and Embase to assess the effects of dietary protein consumption on risk of fracture. Twelve prospective cohort studies with 407,104 participants were included, higher total protein consumption may be decrease 11% risk of hip fractures, with adj. RR of 0.89 (0.82, 0.97), no significant difference was found for total protein and risk of all fractures and limb fracture; for animal protein consumption and risk of all fractures and hip fracture, with adj.RR of 0.79 (032, 1.96) and 1.04 (0.70, 1.54); for vegetable protein consumption and risk of all fractures, hip fracture and limb fractures with adj.RR of 0.77 (0.52, 1.12), 1.00 (0.53, 1.91) and 0.94 (0.40, 2.22), the subgroup of vegetable protein consumption and risk of all fractures of postmenopausal women with adj.RR of 0.78(0.52,1.16). Dose-response meta-analysis the relationship of total/animal/vegetable protein and hip fracture was consistent to the results of forest plot, the line of total protein and hip fracture was below the Y = 1.0 line. This meta-analysis showed that total dietary protein consumption may be decrease the risk of hip fracture, but not for animal or vegetable protein.

A synthetic approach to stable enols was introduced and series of acyclic aliphatic solid enols were obtained and characterized. Relationship between the structure and the stability of these enols was discussed. Gaussian 09 calculations had been carried out to rationalize the stability of the enols. These enol structures were confirmed by 1H NMR, 13C NMR, MS, IR, partly by single crystal X-ray structure analysis and the protons exchange experiments. This work showed that very stable acyclic aliphatic enols can be synthesized efficiently without any purification.