Sensory neuron transient receptor potential vanilloid-1 channel regulates angiogenesis through CGRP in vivo.

Angiogenesis plays a key role in bone regeneration. The role of neurons of peripheral nerves involved in angiogenesis of bone defects needs to be explored. The transient receptor potential vanilloid 1 (TRPV1), a nociceptor of noxious stimuli, is expressed on sensory neurons. Apart from nociception, little is known about the role of sensory innervation in angiogenesis. Calcitonin gene-related peptide (CGRP), a neuropeptide secreted by sensory nerve terminals, has been associated with vascular regeneration. We characterized the reinnervation of vessels in bone repair and assessed the impact of TRPV1-CGRP signaling on early vascularization. We investigated the pro-angiogenic effect of neuronal TRPV1 in the mouse model of femur defect. Micro-CT analysis with Microfil® reagent perfusion demonstrated neuronal TRPV1 activation enhanced angiogenesis by increasing vessel volume, number, and thickness. Meanwhile, TRPV1 activation upregulated the mRNA and protein expression of vascular endothelial growth factor A (VEGF-A), cell adhesion molecule-1 (CD31), and CGRP. Immunostaining revealed the co-localization of TRPV1 and CGRP in dorsal root ganglia (DRG) sensory neurons. By affecting neuronal TRPV1 channels, the release of neuronal and local CGRP was controlled. We demonstrated that TRPV1 influenced on blood vessel development by promoting CGRP release from sensory nerve terminals. Our results showed that neuronal TRPV1 played a crucial role in regulating angiogenesis during bone repair and provided important clinical implications for the development of novel therapeutic approaches for angiogenesis.

Streptococcus salivarius K12 Alleviates Oral Mucositis in Patients Undergoing Radiotherapy for Malignant Head and Neck Tumors: A Randomized Controlled Trial.

PURPOSE: Oral mucositis (OM) is a common debilitating toxicity associated with radiotherapy (RT) for malignant head and neck tumors. This prospective, randomized, double-blind, placebo-controlled trial aimed to evaluate the efficacy and safety of Streptococcus salivarius K12 (SsK12) in reducing the incidence, duration, and severity of severe OM (SOM). METHODS: A total of 160 patients with malignant head and neck tumors undergoing definitive or postoperative adjuvant RT were randomly assigned (1:1) to receive SsK12 probiotic (n = 80) or placebo (n = 80) at West China Hospital, Sichuan University, Chengdu, China. Patients were instructed to suck SsK12 or placebo lozenges thrice daily from the initiation to the end of RT. OM was evaluated twice a week during RT and once a week thereafter for up to 8 weeks. The primary end point was the incidence of SOM. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. RESULTS: Baseline patient characteristics were similar in the SsK12 and placebo groups. The incidence of SOM was significantly lower in the SsK12 group as compared with the placebo group (36.6% v 54.2%; P = .0351). The duration (median, 0.0 days v 7.0 days; mean, 8.9 days v 18.3 days; P = .0084) and time to develop SOM (median, not estimable v 42.0 days; hazard ratio, 0.55 [95% CI, 0.34 to 0.89]; log-rank test: P = .0123) were also improved in the case of the SsK12 group. Adverse events were similar between the groups, and mild or moderate gastrointestinal reactions (flatulence or dyspepsia) associated with the lozenges were observed in two patients in the SsK12 group. High-throughput sequencing results indicated that SsK12 inhibited opportunistic pathogens and enriched oral commensals during RT. CONCLUSION: In this prospective, randomized clinical trial, SsK12 probiotic significantly reduced the incidence, onset, and duration of SOM with a good safety profile.

CLIP: accurate prediction of disordered linear interacting peptides from protein sequences using co-evolutionary information.

One of key features of intrinsically disordered regions (IDRs) is facilitation of protein-protein and protein-nucleic acids interactions. These disordered binding regions include molecular recognition features (MoRFs), short linear motifs (SLiMs) and longer binding domains. Vast majority of current predictors of disordered binding regions target MoRFs, with a handful of methods that predict SLiMs and disordered protein-binding domains. A new and broader class of disordered binding regions, linear interacting peptides (LIPs), was introduced recently and applied in the MobiDB resource. LIPs are segments in protein sequences that undergo disorder-to-order transition upon binding to a protein or a nucleic acid, and they cover MoRFs, SLiMs and disordered protein-binding domains. Although current predictors of MoRFs and disordered protein-binding regions could be used to identify some LIPs, there are no dedicated sequence-based predictors of LIPs. To this end, we introduce CLIP, a new predictor of LIPs that utilizes robust logistic regression model to combine three complementary types of inputs: co-evolutionary information derived from multiple sequence alignments, physicochemical profiles and disorder predictions. Ablation analysis suggests that the co-evolutionary information is particularly useful for this prediction and that combining the three inputs provides substantial improvements when compared to using these inputs individually. Comparative empirical assessments using low-similarity test datasets reveal that CLIP secures area under receiver operating characteristic curve (AUC) of 0.8 and substantially improves over the results produced by the closest current tools that predict MoRFs and disordered protein-binding regions. The webserver of CLIP is freely available at http://biomine.cs.vcu.edu/servers/CLIP/ and the standalone code can be downloaded from http://yanglab.qd.sdu.edu.cn/download/CLIP/.

Cognitive control is modulated by hierarchical complexity of task switching: An event-related potential study.

The study aimed to explore the effect of hierarchical complexity on task switching. The participants (n = 36) were asked to perform a magnitude or parity judgement on digits (1-9) in the hierarchical simple or complex block. In the simple block, participants made a numerical judgement on the presented digit (1-9) in each trial, whereas in the complex block, they had to first identify whether the digit in the current trial belonged to a predefined category (e.g., whether it was an even number), then perform a numerical judgement or not respond. The behavioural results revealed a significant interaction between hierarchical complexity and transition type (repeat vs. switch), with greater switch cost in the complex than in the simple block. Event-related potentials (ERPs) locked in the cue stage did not reveal this interaction, whereas the ERPs locked in the target stage revealed this interaction during the N2 and P3 time windows, with a larger switch negativity (switch minus repeat) in the complex than in the simple block. These findings demonstrate that an increase in hierarchical complexity triggers increased reactive control in the inhibition of the old task-set and reconfiguration of the new task-set during task switching.

Comparative study of B content and δ11 B in the enamel of isolated teeth from brothers in the same family.

RATIONALE: The quantity of boron (B) and its isotopic ratios in tooth can provide information on dietary habits and oral health of individuals. These metrics are gradually being used in stomatology, environmental science and geochemistry. METHODS: This study measured the B concentration and δ11 B in the enamel of isolated teeth from brothers in the same family living in high-B-exposure areas at different times using inductively coupled plasma mass spectrometry (ICP-MS) and multicollector ICP-MS. RESULTS: The results demonstrate that B content in tooth samples of two brothers is related to the time of shedding. The earlier the time of shedding, the lower is the B content in tooth. The B content increased from 20.5 µg/g of the central incisor (6-7 years old) of the younger brother to 50.4 µg/g of the second molar (10-12 years old). And B content for the elder brother increased from 28.7 to 58.3 µg/g at the same positions. In the same family, the diet and environmental input of B is basically similar, and the B exposure is basically the same every year. The annual growth rate of B for the younger brother in this experiment is about 4.98 µg/g per year and that for the elder brother is about 4.93 µg/g per year. The δ11 B of shed teeth at different times from the same person is basically similar, but different from person to person. The δ11 B of shed teeth from the elder brother varies from 15.5‰ to 17.9‰ and from the younger brother varies from 5.2‰ to 6.7‰. The δ11 B is quite different for the brothers in the same family who had the same food and environmental intake of B. CONCLUSIONS: The experimental data confirmed the relationship between the information of B (B content and δ11 B) in shed teeth and B exposure. They provided an experimental basis using modern human teeth to apply B-isotope paleo-environmental significance.

The effects and potential applications of concentrated growth factor in dentin-pulp complex regeneration.

The dentin-pulp complex is essential for the long-term integrity and viability of teeth but it is susceptible to damage caused by external factors. Because traditional approaches for preserving the dentin-pulp complex have various limitations, there is a need for novel methods for dentin-pulp complex reconstruction. The development of stem cell-based tissue engineering has given rise to the possibility of combining dental stem cells with a tissue-reparative microenvironment to promote dentin-pulp complex regeneration. Concentrated growth factor, a platelet concentrate, is a promising scaffold for the treatment of dentin-pulp complex disorders. Given its characteristics of autogenesis, convenience, usability, and biodegradability, concentrated growth factor has gained popularity in medical and dental fields for repairing bone defects and promoting soft-tissue healing. Numerous in vitro studies have demonstrated that concentrated growth factor can promote the proliferation and migration of dental stem cells. Here, we review the current state of knowledge on the effects of concentrated growth factor on stem cells and its potential applications in dentin-pulp complex regeneration.

A novel vertical aligned mesoporous silica coated nanohydroxyapatite particle as efficient dexamethasone carrier for potential application in osteogenesis.

Bone defect is a common problem and inducing osteoblasts differentiation is the key process for the regenerative repair. Recently, the mesoporous silica (MS) coated nanohydroxyapatite (nHA) particles (nHA-MS) has shown enhanced intrinsic potency for bone regeneration, whereas whether the osteogenesis potency can be further enhanced after drug delivery has not been investigated. In this study, the nHA-MS was fabricated by a novel biphase stratification growth way. The cytotoxicity in MC3T3-E1 was validated by MTT assay, apoptosis analysis and cell cycle examination. The cell uptake was observed by confocal laser scanning microscope and transmission electron microscope respectively. After adsorption with dexamethasone (DEX), the osteogenic differentiation was determined bothin vitroandin vivo. The synthesized nHA-MS showed a core-shell structure that the nanorod-like nHA was coated by a porous MS shell (∼5 nm pores diameter, ∼50 nm thickness). A dose-dependent cytotoxicity was observed and below 10 µg ml-1was a safe concentration. The nHA-MS also showed efficient cell uptake efficiency and more efficient in DEX loading and release. After DEX adsorption, the nanoparticles exhibited enhanced osteogenic induction in MC3T3-E1 and rat calvarial bone defect regeneration. In conclusion, the nHA-MS is a favorable platform for drug delivery to obtain more enhanced osteogenesis capabilities.

Effects of Drynaria Total Flavonoid on the Microstructure of the Mandible in Ovariectomized Rats.

BACKGROUND The aim of this study is to investigate the effects of Drynaria total flavonoids (DTF) on mandible microarchitecture, serum estrogen (E2), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL) levels in an ovariectomy-induced osteoporosis rat model. MATERIAL AND METHODS Thirty female Sprague-Dawley rats were divided into 5 groups (n=6 per group): sham surgery, ovariectomy (OVX), and low-dose, middle-dose, and high-dose DTF. Mandibular osteoporosis was induced by ovariectomy; an equal amount of ovary-sized fat tissue was removed from the sham group. The DTF-treated groups were given DTF gavage at different doses for 12 weeks; the sham and OVX groups were given saline. After the treatment phase, the effects of DTF on the microarchitecture of the mandible were evaluated by measuring bone density, maximum load, morphometric parameters, and histopathological alterations. Serum E2, OPG, and RANKL levels were measured. RESULTS The OVX group showed obvious osteoporosis in the mandible and decreased serum E2 levels and OPG/RANKL ratio. The low-dose group did not show significant improvement in mandibular microstructure. The middle-dose group showed significantly ameliorated osteoporosis. The high-dose group had further improvement in bone microstructures and increase of OPG/RANKL over the middle-dose group. Furthermore, ovariectomy significantly decreased serum E2, but DTF treatment failed to restore serum E2 levels. CONCLUSIONS Ovariectomy can cause significant bone loss in the rat mandible and a decrease in serum E2 and OPG/RANKL. DTF significantly improved the mandibular microstructure and restored OPG/RANKL balance, but it did not restore the decreased serum E2 concentration following ovariectomy.

Children prefer pattern over shape during complex categorization.

Numerous studies have shown that children tend to view objects with similar shapes as having the same category. However, these studies often adopt simple categorization tasks and ignore the perceptual dimension (e.g., surface pattern of objects) that likely attract children's attention. The purpose of this study was to test how children categorize when pattern competes against shape. In Experiment 1a children were presented with a target and several testing objects that shared the same shape, color, or texture as the target. The results indicated that children preferentially selected the shape-sharing objects. However, when the texture was replaced by pattern (Experiment 1b), there was no significant difference between shape and pattern choices. When shared features were intricately overlapped between different pairs of stimuli (Experiment 2), children preferentially chose objects that shared patterns over those that shared shapes. These findings are the first to reveal children's pattern preference in categorization, supporting the view that children's categorization is flexible.

Neural Dynamics of Cognitive Control in Various Types of Incongruence.

Conflict-control is a core function of cognitive control. Although numerous studies have considered cognitive control to be domain-general, the shared and distinct brain responses to different types of incongruence or conflict remain unclear. Using a hybrid flanker task, the present study explored the temporal dynamics of brain activation to three types of incongruence: flanker interference, rule-based response switch (rule-switch), and action-based response switch (response-alternation). The results showed that: (1) all three types of incongruence evoked larger N2 amplitudes than the congruent condition in the frontal region, with the N2 amplitudes and topographical distribution of the N2 effect differing between the different types of incongruence; and (2) in the P300 time window, the flanker interference condition yielded the most delayed P300 latency, whereas the rule-switch and response-alternation conditions yielded smaller P300 amplitudes with a longer interval from P300 peak to a keypress. These findings suggest that different types of incongruence are first monitored similarly by the cognitive control system and then resolved differently.

Effect of alprazolam on rat serum metabolic profiles.

We developed a serum metabolomic method by gas chromatography-mass spectrometry (GC-MS) to evaluate the effect of alprazolam in rats. The GC-MS with HP-5MS (0.25 µm × 30 m × 0.25 mm) mass was conducted in electron impact ionization (EI) mode with electron energy of 70 eV, and full-scan mode with m/z 50-550. The rats were randomly divided to four groups, three alprazolam-treated groups and a control group. The alprazolam-treated rats were given 5, 10 or 20 mg/kg (low, medium, high) of alprazolam by intragastric administration each day for 14 days. The serum samples were corrected on the seventh and fourteenth days for metabolomic study. The blood was collected for biochemical tests. Then liver and brain were rapidly isolated and immersed for pathological study. Compared with the control group, on the seventh and fourteen days, the levels of d-glucose, 9,12-octadecadienoic acid, butanoic acid, l-proline, d-mannose and malic acid had changed, indicating that alprazolam induced energy metabolism, fatty acid metabolism and amino acid metabolism perturbations in rats. There was no significant difference for alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, urea and uric acid between controls and alprazolam groups. According to the pathological results, alprazolam is not hepatotoxic. Metabolomics could distinguish different alprazolam doses in rats.

Strontium concentrations and isotope ratios in enamel of healthy and carious teeth in southern Shaanxi, China.

RATIONALE: As the trace element strontium (Sr) plays a significant role in dental health, it is important to determine the Sr concentration and isotope composition ((87)Sr/(86)Sr) of teeth and whether these values are related to caries formation, age and sex. METHODS: A total of 160 permanent teeth were collected from 7- to 79-year-old people from the southern Shaanxi area of China, including 100 healthy teeth and 60 carious teeth (men and women each accounted for half of the samples). The concentration and isotope composition of Sr elements in the dental enamel of the teeth were measured using inductively coupled plasma mass spectrometry (ICP-MS) and thermal ionization mass spectrometry (TIMS). RESULTS: A significantly lower Sr concentration was found in the enamel of the carious teeth than in that of the healthy teeth for individuals of varying ages and sex. The Sr concentration in human carious teeth ranged between 79.70 µg/g and 85.80 µg/g; while the Sr concentration in healthy teeth ranged between 128 µg/g and 156.77 µg/g. Our results also demonstrated that the (87)Sr/(86)Sr ratio did not appear to be affected by the caries formation, age or sex. The (87)Sr/(86)Sr ratio in the enamel of the healthy and carious teeth of individuals of varying ages and genders ranged between 0.710935 and 0.711037, which falls into the range of (87)Sr/(86)Sr ratios found in the local, naturally occurring water, soils and rocks. CONCLUSIONS: Sr plays a significant role in dental health, and there is a negative correlation between Sr and the occurrence of dental caries. The (87)Sr/(86)Sr ratio of teeth reflects the (87)Sr/(86)Sr ratio of the associated environment, and there is no significant relationship with the frequency of dental caries, age or sex.