Ocr-mediated suppression of BrxX unveils a phage counter-defense mechanism.

The burgeoning crisis of antibiotic resistance has directed attention to bacteriophages as natural antibacterial agents capable of circumventing bacterial defenses. Central to this are the bacterial defense mechanisms, such as the BREX system, which utilizes the methyltransferase BrxX to protect against phage infection. This study presents the first in vitro characterization of BrxX from Escherichia coli, revealing its substrate-specific recognition and catalytic activity. We demonstrate that BrxX exhibits nonspecific DNA binding but selectively methylates adenine within specific motifs. Kinetic analysis indicates a potential regulation of BrxX by the concentration of its co-substrate, S-adenosylmethionine, and suggests a role for other BREX components in modulating BrxX activity. Furthermore, we elucidate the molecular mechanism by which the T7 phage protein Ocr (Overcoming classical restriction) inhibits BrxX. Despite low sequence homology between BrxX from different bacterial species, Ocr effectively suppresses BrxX's enzymatic activity through high-affinity binding. Cryo-electron microscopy and biophysical analyses reveal that Ocr, a DNA mimic, forms a stable complex with BrxX, highlighting a conserved interaction interface across diverse BrxX variants. Our findings provide insights into the strategic counteraction by phages against bacterial defense systems and offer a foundational understanding of the complex interplay between phages and their bacterial hosts, with implications for the development of phage therapy to combat antibiotic resistance.

ACKR1+ Endothelial Cells Mediate Leukocyte Infiltration and Synergize with SFRP2/ASPN+ Fibroblasts to Promote Skin Fibrosis in Systemic Sclerosis.

BACKGROUND: Skin fibrosis is the most typical pathological manifestation of systemic sclerosis (SSc) and localized scleroderma (LS) with unclear etiology and few effective treatments. Though excessive collagen secretion by fibroblasts is the primary cause of skin fibrosis, many lines of evidence suggested that vascular damage was the initiating event and various cell types along with fibroblasts worked together to contribute to the pathogenesis of skin fibrosis. OBJECTIVES: We sought to explore the relationships between vascular endothelial cell lesions and immune cell infiltration, along with the cell-cell interactions among various cell types within the fibrotic skin ecosystem. METHODS: Single-cell RNA-seq (10x Genomics) was performed on skin biopsies of 3 healthy donors and 7 SSc patients in Chinese. The additional 3 localized scleroderma patients' data from NCBI database (GSE160536) were integrated by Harmony. CellChat package (v1.5.0) was applied to analyze cell communication network. Transwell assay and subcutaneous bleomycin (BLM) injection in mice were used to explore the role of ACKR1 on immune cell infiltration. Milo single-cell western blot was applied to show the activation of fibroblast subclusters. RESULTS: A total of 62,295 cells were obtained and subpopulations of stromal and immune cells were identified. Interaction network analysis revealed that multiple chemokines secreted by macrophages, pericytes, and pro-inflammatory fibroblasts could bind with Duffy antigen/receptor for chemokines (ACKR1), which is highly expressed on ACKR1+ endothelial cells of lesion skin. Transwell assay revealed that over-expressed ACKR1 in HUVEC facilitated leukocyte infiltration under the treatment of IL8. The BLM mice showed enhanced ACKR1 expression, massive immune cell infiltration, and fibrosis in skin, which could be attenuated by ACKR1 inhibition. Furthermore, infiltrated macrophages with TGFB1 or PDGFB high production could activate SFRP2/ASPN+ fibroblasts to contribute to excessive accumulation of extracellular matrix (ECM), and the SOX4-ASPN axis plays an important role in the TGF-ß signaling cascade and the etiology of skin fibrosis. CONCLUSIONS: Our results reveal that highly expressed ACKR1 in endothelial cells of fibrotic skin tissue promotes immune cell infiltration, and SFRP2/ASPN+ fibroblasts synergize to exacerbate skin fibrosis.

Effectiveness of immediate implant placement into defective sockets in the esthetic zone: A systematic review and meta-analysis.

STATEMENT OF PROBLEM: A defective socket is common after tooth extraction in the esthetic zone, but whether an implant can be immediately placed in a defective socket is unclear. PURPOSE: The purpose of this systematic review and meta-analysis was to summarize relevant studies within the last 20 years on implant survival and changes in soft and hard tissues after immediate implant placement in esthetic areas with socket defects. MATERIAL AND METHODS: A search was conducted for the relevant studies in the PubMed/Medline, the Cochrane Library, Web of Science, and Embase databases from January 2000 to March 2022. The literature review, data retrieval, and judgment whether the included studies had a risk of bias were handled independently by 2 reviewers, and a single-arm meta-analysis was performed using a statistical software program. RESULTS: A total of 23 studies evaluating the immediate implant placement of 630 implants (9 studies without a flap and 14 studies with a flap) were included. A 98.1% implant survival rate (95% confidence interval (CI): 96.2%, 100.0%) was determined. Marginal bone loss (MBL) at 6, 12, and ≥24 months were 1.03 mm (95%CI: 1.02, 1.03), 0.72 mm (0.72, 0.73), and 1.15 mm (1.14, 1.16). Gingival recession at 12 months was 0.25 mm (95%CI: 0.17, 0.33). The pink esthetic score (PES) were 12.34 (95%CI: 12.16, 12.52) at 12 months and 12.58 (12.39, 12.76) at ≥24 months. CONCLUSIONS: Current evidence shows that immediate implant placement into defective sockets in esthetic areas is feasible. Immediate implant placement can have a relatively good therapeutic effect in terms of implant survival rate, MBL, gingival recession, and PES.

Exploiting the synergistic antibacterial activity of shikimic acid and ceftiofur against methicillin-resistant Staphylococcus aureus.

Efforts to curtail the escalating health threat posed by methicillin-resistant Staphylococcus aureus (MRSA), a formidable superbug, necessitate the development of innovative treatment strategies. Leveraging potential compounds from natural sources in tandem with antibiotics has emerged as a promising approach against MRSA. These strategies should enhance the antibiotic efficacy, reduce dosage and toxicity, and bypass MRSA resistance. In this study, we used a checkerboard assay to illustrate the significant synergistic anti-MRSA effect of shikimic acid (SA), a naturally occurring compound, and ceftiofur (CF). Time-kill curves further revealed that a combination of 1/4 of the minimum inhibitory concentration (MIC) of SA and 1/8 MIC of the sodium CF eradicated MRSA within 2 h, with no noticeable toxicity observed with these concentrations. In vivo experiments confirmed that this combination therapy demonstrated robust antimicrobial activity against MRSA-induced bacteremia in mice, significantly reducing bacterial loads in the kidneys, liver, and spleen, attenuating inflammatory cell infiltration, and alleviating pathological damage. This study not only offers a compelling strategy, capitalizing on the synergistic potential of SA and CF, to rapidly address antibiotic resistance but also contributes significantly to the refinement of antimicrobial therapeutic strategies.

TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis.

OBJECTIVES: Innate immunity significantly contributes to systemic sclerosis (SSc) pathogenesis. TLR8 is an important innate immune mediator that is implicated in autoimmunity and fibrosis. However, the expression, mechanism of action, and pathogenic role of TLR8 in SSc remain unclear. The aim of this study was to explore the roles and underlying mechanisms of TLR8 in SSc. METHODS: The expression of TLR8 was analyzed based on a public dataset and then verified in skin tissues and skin fibroblasts of SSc patients. The role of TLR8 in inflammation and fibrosis was investigated using a TLR8-overexpression vector, activator (VTX-2337), inhibitor (cu-cpt-8m), and TLR8 siRNA in skin fibroblasts. The pathogenic role of TLR8 in skin inflammation and fibrosis was further validated in a bleomycin (BLM)-induced mouse skin inflammation and fibrosis model. RESULTS: TLR8 levels were significantly elevated in SSc skin tissues and myofibroblasts, along with significant activation of the TLR8 pathway. In vitro studies showed that overexpression or activation of TLR8 by a recombinant plasmid or VTX-2337 upregulated IL-6, IL-1ß, COL I, COL III, and α-SMA in skin fibroblasts. Consistently, both TLR8-siRNA and cu-cpt-8m reversed the phenotypes observed in TLR8-activating fibroblasts. Mechanistically, TLR8 induces skin fibrosis and inflammation in a manner dependent on the MAPK, NF-κB, and SMAD2/3 pathways. Subcutaneous injection of cu-cpt-8m significantly alleviated BLM-induced skin inflammation and fibrosis in vivo. CONCLUSION: TLR8 might be a promising therapeutic target to improve the treatment strategy for SSc skin inflammation and fibrosis.

An optimal method for quantifying the facial sebum level and characterizing facial sebum features.

BACKGROUND: Evidence suggests that sebum content is important in skin disorders such as acne. However, sebum levels change depending on the external environment, and quantifying skin sebum levels is challenging. Here, we propose an optimal method for quantifying the facial sebum level. MATERIALS AND METHODS: Four hundred and sixty participants (160 males and 300 females) aged 20-40 were enrolled in this study. A Sebumeter SM 810 was used to measure the sebum level at five facial locations: the forehead, the chin, the left cheek, the right cheek, and the nose. The participants were divided into two groups; one group underwent a one-time measurement (n = 390, male: female = 120: 270), and the other underwent three consecutive measurements (n = 70, male: female = 40: 30). The casual sebum level (CSL) was measured in all patients after a 30-min acclimatization; subsequently, the sebum removal process was conducted, followed by a resting period of 1 h to determine the sebum excretion rate (SER). Spearman's correlation analysis and the Wilcoxon signed-rank test were used to compare the sebum level consistency and differences between the groups. RESULTS: Although three consecutive measurements better reflected the sebum content, the one-time measurement also represented the relative sebum level. One hour after sebum removal, the sebum level recovered to 70%-90%; thus, this method was applicable for use in SER quantification. Of the five testing points, the sebum content was highest in the nose and lowest in the cheeks (both left and right). In addition, the cheeks were the most stable sites in terms of testing points, testing times, and CSL/SER values. A one-time measurement of the CSL could represent the SER 1 h after the sebum removal. In our cohort, the sebum level of males with oily skin was decreased at age 32-35, and that of males with non-oily skin increased at 28-35. The opposite trend was observed in female participants. CONCLUSION: Sebum measurement methods were assessed, including testing times, indices (interval of time) and sites in a conditioned external environment. A one-time measurement of the CSL 1 h after sebum removal was sufficient to determine the sebum level and SER, and the cheeks are recommended as the testing site. Sex and skin type differences were observed in sebum level changes with age.

Self-Supporting Mn-RuO2 Nanoarrays for Stable Oxygen Evolution Reaction in Acid.

Currently, the process of an acidic oxygen evolution reaction (OER) necessitates the use of Iridium dioxygen (IrO2), which is both expensive and incredibly scarce on Earth. Ruthenium dioxygen (RuO2) offers high activity for acidic OERs and presents a potential substitution for IrO2. Nevertheless, its practical application is hindered by its relatively poor stability. In this study, we have developed Mn-doped RuO2 (Mn-RuO2) nanoarrays that are anchored on a titanium (Ti) mesh utilizing a two-step methodology involving the preparation of MnO2 nanoarrays followed by a subsequent Ru exchange and annealing process. By precisely optimizing the annealing temperature, we have managed to attain a remarkably low overpotential of 217 mV at 10 mA cm-2 in a 0.5 M H2SO4 solution. The enhanced catalytic activity of our Mn-RuO2 nanoarrays can be attributed to the electronic modification brought about by the high exposure of active sites, Mn dopant, efficient mass transfer, as well as the efficient transfer of electrons between the Ti mesh and the catalyst arrays. Furthermore, these self-supported Mn-RuO2 nanoarrays demonstrated excellent long-term stability throughout a chronoamperometry test lasting for 100 h, with no discernible changes observed in the Ru chemical states.

Insights into male androgenetic alopecia using comparative transcriptome profiling: hypoxia-inducible factor-1 and Wnt/ß-catenin signalling pathways.

BACKGROUND: The key pathophysiological changes in androgenetic alopecia (AGA) are limited to hair follicles (HFs) in frontal and vertex regions, sparing the occipital region. OBJECTIVES: To identify biological differences among HF subpopulations. METHODS: Paired vertex and occipital HFs from 10 male donors with AGA were collected for RNA sequencing assay. Furthermore, HF and cell experiments were conducted on the identified key genes to reveal their roles in AGA. RESULTS: Transcriptome profiles revealed that 506 mRNAs, 55 microRNAs and 127 long noncoding RNAs were differentially expressed in the AGA vertex HFs. Pathway analysis of mRNAs and microRNAs revealed involvement of the hypoxia-inducible factor (HIF)-1, Wnt/ß-catenin, and focal adhesion pathways. Differential expression of HIF-1 prolyl hydroxylase enzymes (EGLN1, EGLN3) and Wnt/ß-catenin pathway inhibitors (SERPINF1, SFRP2) was experimentally validated. In vitro studies revealed that reduction of EGLN1, EGLN3, SERPINF1 and SFRP2 stimulated proliferation of dermal papilla cells. Ex vivo HF studies showed that downregulation of EGLN1, EGLN3 and SERPINF1 promoted HF growth, postponed HF catagen transition, and prolonged the anagen stage, suggesting that these genes may be potentially utilized as therapeutic targets for AGA. CONCLUSIONS: We characterized key transcriptome changes in male AGA HFs, and found that HIF-1 pathway-related genes (EGLN1, EGLN3) and Wnt pathway inhibitors (SERPINF1, SFRP2) may play important roles in AGA. What is already known about this topic? Multiple differentially expressed genes and signalling pathways have been found between hair follicles (HFs) in the balding area (frontal and vertex regions) and nonbalding area (occipital region) of individuals with androgenetic alopecia (AGA). A whole-transcriptome atlas of the vertex and occipital region is lacking. What does this study add? We identified a number of differentially expressed genes and pathways between balding vertex and nonbalding occipital AGA HFs by using whole-transcriptome analyses. We identified pathways not previously reported in AGA, such as the hypoxia-inducible factor (HIF)-1 signalling pathway. We verified that HIF-1 pathway-related genes (EGLN1, EGLN3) and Wnt pathway inhibitors (PEDF, SFRP2) played important roles in dermal papilla cell activity, hair growth and the hair cycle. What is the translational message? The EGLN1, EGLN3, SERPINF1 and SFRP2 genes may be potentially utilized as therapeutic targets for AGA.

Advanced single-cell pooled CRISPR screening identifies C19orf53 required for cell proliferation based on mTORC1 regulators.

Multiplexed single-cell CRISPR screening has accelerated the systematic dissection of biological discoveries; however, the efficiency of CRISPR-based gene knockout has inherent limitations. Here, we present DoNick-seq, an advanced method for facilitating gene knockout and reducing off-target activity. We re-engineered two popular plasmid constructs suitable for use in pooled CRISPR screening of the single-cell transcriptome. We then used DoNick-seq to probe mTORC1 regulators and obtain genomic perturbation and transcriptome profiles from the same cell. Thus, DoNick-seq enabled us to simultaneously evaluate multiple gene interactions and the effect of amino acid depletion. By analyzing more than 20,000 cells from two cell lines, DoNick-seq efficiently identified gene targets, cell numbers, and cellular profiles. Our data also revealed the characteristics of mTORC1 negative and positive regulators, thereby shedding new insights into the mechanisms regulating cell growth and inhibition. We demonstrate that mTORC1 hyperactivation exhausts cellular free amino acids via increased proliferation ability. Furthermore, DoNick-seq identified the gene C19orf53, which mediates excessive cell proliferation, resulting in metabolic imbalance, and greatly enhances oxidative stress in response to toxins. Thus, our findings suggest that DoNick-seq facilitates high-throughput functional dissection of complex cellular responses at the single-cell level and increases the accuracy of CRISPR single-cell transcriptomics.

Clinical efficacy of microwave in the treatment of axillary osmidrosis and primary hyperhidrosis.

Axillary osmidrosis (AO) and primary hyperhidrosis (PH) are common diseases, but there are still difficulties in treatment. Microwave therapy may become a new method. In order to evaluate long-time efficacy of patients with AO or PH treated by microwave and to discuss possible mechanism of microwave therapy by combining results of clinical and pathological, the study was carried out. Ten AO or PH patients with moderate or severe level were selected as subjects, and each subject received microwave treatment of bilateral armpits. The follow-up period lasted 2 years, and the changes of perspiration and odor were evaluated in subjective and objective ways. Each subject took skin biopsy in the treatment area before and after treatment or each follow-up. Hematoxylin-eosin and immunohistochemical staining were performed. Both subjective and objective index reflected the significant improvement of AO and PH after treatment (p < 0.05). Dermatology life quality index score decreased by 10.4 ± 4.6 (p < 0.05). The number of apocrine glands decreased significantly after treatment, and most of them changed from secretory phase to quiescent phase. In conclusion, microwave therapy can destroy apocrine sweat glands, reduce number of functional glands, so as to improve symptoms of AO and PH and elevate quality of life, which is safe, effective, and stable.

Theoretical analysis of a 60 W solar-pumped single crystal fiber laser.

In order to improve the output power of solar-pumped single-crystal fiber (SCF) lasers, we propose a novel solar concentrating system, to the best of our knowledge, consisting of a parabolic mirror, a 3D compound parabolic concentrator, and a hollow-core reflector. By ray tracing with TracePro, the influence of the fiber's diameter and the hollow reflector's shape on the solar absorption efficiency is theoretically investigated. A typical Nd:YAG SCF with a core diameter of 1 mm, length of 150 mm, and doping concentration of 1 at.% is selected for a simulation of laser operation. The output characteristics of the laser are analyzed by solving the rate equation and power transmission equation; the maximum output power and solar-to-laser conversion efficiency are 60.62 W and 4.64%, respectively. The thermal effects of the laser are simulated by Comsol software. When the input solar power is 1307.4 W, the temperature decreases sharply first and then saturates along the SCF fiber, with the maximum value of 69.18°C at the input fiber end. This concentrating system can effectively overcome the limitation of end-launching solar power into SCFs and has great potential in improving the output power of solar fiber lasers.

Inhibition of ER stress-activated JNK pathway attenuates TNF-α-induced inflammatory response in bone marrow mesenchymal stem cells.

Bone marrow mesenchymal stem cells (BMMSCs) are characterized by their pluripotent differentiation and self-renewal capability and have been widely applied in regenerative medicine, gene therapy, and tissue repair. However, inflammatory response after BMMSCs transplantation was found to impair the osteogenic differentiation of BMMSCs. Thus, understanding the mechanisms underlying inflammation response will benefit the clinical use of BMMSCs. In this study, using a cell model of TNF-α-induced inflammatory response, we found that TNF-α treatment greatly elevated intracellular oxidative stress and induced endoplasmic reticulum (ER) stress by elevating the expression levels of ER sensors, such as PERK, ATF6 and IRE1A. Oxidative stress and ER stress formed a feedback loop to mediate TNF-α-induced inflammation response in BMMSCs. Moreover, c-Jun N-terminal kinase (JNK) signal pathway that coupled to the ER stress was significantly activated by increasing its phosphorylation upon TNF-α treatment. Importantly, pharmacological inhibition of ER stress effectively eliminated the phosphorylation of JNK and attenuated the TNF-α-induced inflammation response. In conclusion, our results indicated that TNF-α induced oxidative and ER stress, thereby leading to JNK activation, and generating inflammation response in BMMSCs. This pathway underlying TNF-α-induced inflammation response may provide new strategies to improve BMMSCs osteogenesis and other inflammation-associated bone diseases.

Exploring the Expression Differences Between Professionals and Laypeople Toward the COVID-19 Vaccine: Text Mining Approach.

BACKGROUND: COVID-19 is still rampant all over the world. Until now, the COVID-19 vaccine is the most promising measure to subdue contagion and achieve herd immunity. However, public vaccination intention is suboptimal. A clear division lies between medical professionals and laypeople. While most professionals eagerly promote the vaccination campaign, some laypeople exude suspicion, hesitancy, and even opposition toward COVID-19 vaccines. OBJECTIVE: This study aims to employ a text mining approach to examine expression differences and thematic disparities between the professionals and laypeople within the COVID-19 vaccine context. METHODS: We collected 3196 answers under 65 filtered questions concerning the COVID-19 vaccine from the China-based question and answer forum Zhihu. The questions were classified into 5 categories depending on their contents and description: adverse reactions, vaccination, vaccine effectiveness, social implications of vaccine, and vaccine development. Respondents were also manually coded into two groups: professional and laypeople. Automated text analysis was performed to calculate fundamental expression characteristics of the 2 groups, including answer length, attitude distribution, and high-frequency words. Furthermore, structural topic modeling (STM), as a cutting-edge branch in the topic modeling family, was used to extract topics under each question category, and thematic disparities were evaluated between the 2 groups. RESULTS: Laypeople are more prevailing in the COVID-19 vaccine-related discussion. Regarding differences in expression characteristics, the professionals posted longer answers and showed a conservative stance toward vaccine effectiveness than did laypeople. Laypeople mentioned countries more frequently, while professionals were inclined to raise medical jargon. STM discloses prominent topics under each question category. Statistical analysis revealed that laypeople preferred the "safety of Chinese-made vaccine" topic and other vaccine-related issues in other countries. However, the professionals paid more attention to medical principles and professional standards underlying the COVID-19 vaccine. With respect to topics associated with the social implications of vaccines, the 2 groups showed no significant difference. CONCLUSIONS: Our findings indicate that laypeople and professionals share some common grounds but also hold divergent focuses toward the COVID-19 vaccine issue. These incongruities can be summarized as "qualitatively different" in perspective rather than "quantitatively different" in scientific knowledge. Among those questions closely associated with medical expertise, the "qualitatively different" characteristic is quite conspicuous. This study boosts the current understanding of how the public perceives the COVID-19 vaccine, in a more nuanced way. Web-based question and answer forums are a bonanza for examining perception discrepancies among various identities. STM further exhibits unique strengths over the traditional topic modeling method in statistically testing the topic preference of diverse groups. Public health practitioners should be keenly aware of the cognitive differences between professionals and laypeople, and pay special attention to the topics with significant inconsistency across groups to build consensus and promote vaccination effectively.

Widely separated optical Kerr parametric oscillation in AlN microrings.

Here, we report $ {\chi ^{(3)}} $χ(3)-based optical parametric oscillation (OPO) with widely separated signal-idler frequencies from crystalline aluminum nitride microrings pumped at $ 2\,\,\unicode{x00B5}{\rm m} $2µm. By tailoring the width of the microring, OPO reaching toward the telecom and mid-infrared bands with a frequency separation of 64.2 THz is achieved. While dispersion engineering through changing the microring width is capable of shifting the OPO sideband by $ \gt {9}\;{\rm THz}$>9THz, the OPO frequency can also be agilely tuned in the ranges of 1 and 0.1 THz, respectively, by shifting the pump wavelength and controlling the chip's temperature. At high pump powers, the OPO sidebands further evolve into localized frequency comb lines. Such large-frequency-shift OPO with flexible wavelength tunability will lead to enhanced chip-scale light sources.

Distinct Function of Estrogen Receptors in the Rodent Anterior Cingulate Cortex in Pain-related Aversion.

BACKGROUND: Brain-derived estrogen is implicated in pain-related aversion; however, which estrogen receptors mediate this effect remains unclear. This study hypothesized that the different estrogen receptors in the rostral anterior cingulate cortex play distinct roles in pain-related aversion. METHODS: Formalin-induced conditioned place avoidance and place escape/avoidance paradigms were used to evaluate pain-related aversion in rodents. Immunohistochemistry and Western blotting were used to detect estrogen receptor expression. Patch-clamp recordings were used to examine N-methyl-D-aspartate-mediated excitatory postsynaptic currents in rostral anterior cingulate cortex slices. RESULTS: The administration of the estrogen receptor-ß antagonist 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP) or the G protein-coupled estrogen receptor-1 antagonist (3aS*,4R*,9bR*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15) but not the estrogen receptor-α antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP) into the rostral anterior cingulate cortex blocked pain-related aversion in rats (avoidance score, mean ± SD: 1,3-bis [4-hydroxyphenyl]-4-methyl-5-(4-[2-piperidinylethoxy] phenol)-1H-pyrazole dihydrochloride (MPP): 47.0 ± 18.9%, 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP): -7.4 ± 20.6%, and [3aS*,4R*,9bR*]-4-[6-bromo-1,3-benzodioxol-5-yl]-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15): -4.6 ± 17.0% vs. vehicle: 46.5 ± 12.2%; n = 7 to 9; P < 0.0001). Consistently, estrogen receptor-ß knockdown but not estrogen receptor-α knockdown by short-hairpin RNA also inhibited pain-related aversion in mice (avoidance score, mean ± SD: estrogen receptor-α-short-hairpin RNA: 26.0 ± 7.1% and estrogen receptor-ß-short-hairpin RNA: 6.3 ± 13.4% vs. control short-hairpin RNA: 29.1 ± 9.1%; n = 7 to 10; P < 0.0001). Furthermore, the direct administration of the estrogen receptor-ß agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN) or the G protein-coupled estrogen receptor-1 agonist (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1) into the rostral anterior cingulate cortex resulted in conditioned place avoidance (avoidance score, mean ± SD: 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN): 35.3 ± 9.5% and (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1): 43.5 ± 22.8% vs. vehicle: 0.3 ± 14.9%; n = 8; P < 0.0001) but did not affect mechanical or thermal sensitivity. The activation of the estrogen receptor-ß/protein kinase A or G protein-coupled estrogen receptor-1/protein kinase B pathway elicited the long-term potentiation of N-methyl-D-aspartate-mediated excitatory postsynaptic currents. CONCLUSIONS: These findings indicate that estrogen receptor-ß and G protein-coupled estrogen receptor-1 but not estrogen receptor-α in the rostral anterior cingulate cortex contribute to pain-related aversion by modulating N-methyl-D-aspartate receptor-mediated excitatory synaptic transmission.

The impact of emotional expressions on children's trust judgments.

Research on the development of selective trust has shown that young children do not indiscriminately trust all potential informants. They are likely to seek and endorse information from individuals who have proven competent or benign in the past. However, research on trust among adults raises the possibility that children might also be influenced by the emotions expressed by potential informants. In particular, they might trust individuals expressing more positive emotion. Indeed, young children's trust in particular informants based on their past behaviour might be undermined by their currently expressed emotions. To examine this possibility, we tested the selective trust of fifty 4- and 5-year-olds in two steps. We first confirmed that children are likely to invest more trust in individuals expressing more positive emotion. We then showed that even if children have already formed an impression of two potential informants based on their behavioural record, their choices about whose claims to trust are markedly influenced by the degree of positive emotion currently expressed by the two informants. By implication, the facial emotions expressed by potential informants can undermine young children's selective trust based on the behavioural record of those informants.

The Regulatory Role of MeAIB in Protein Metabolism and the mTOR Signaling Pathway in Porcine Enterocytes.

Amino acid transporters play an important role in cell growth and metabolism. MeAIB, a transporter-selective substrate, often represses the adaptive regulation of sodium-coupled neutral amino acid transporter 2 (SNAT2), which may act as a receptor and regulate cellular amino acid contents, therefore modulating cellular downstream signaling. The aim of this study was to investigate the effects of MeAIB to SNAT2 on cell proliferation, protein turnover, and the mammalian target of rapamycin (mTOR) signaling pathway in porcine enterocytes. Intestinal porcine epithelial cells (IPEC)-J2 cells were cultured in a high-glucose Dulbecco's modified Eagle's (DMEM-H) medium with 0 or 5 mmoL/L System A amino acid analogue (MeAIB) for 48 h. Cells were collected for analysis of proliferation, cell cycle, protein synthesis and degradation, intracellular free amino acids, and the expression of key genes involved in the mTOR signaling pathway. The results showed that SNAT2 inhibition by MeAIB depleted intracellular concentrations of not only SNAT2 amino acid substrates but also of indispensable amino acids (methionine and leucine), and suppressed cell proliferation and impaired protein synthesis. MeAIB inhibited mTOR phosphorylation, which might be involved in three translation regulators, EIF4EBP1, IGFBP3, and DDIT4 from PCR array analysis of the 84 genes related to the mTOR signaling pathway. These results suggest that SNAT2 inhibition treated with MeAIB plays an important role in regulating protein synthesis and mTOR signaling, and provide some information to further clarify its roles in the absorption of amino acids and signal transduction in the porcine small intestine.

Composite Nd:YAG-SiC-bonding laser with orthogonal-linear-polarization output.

We report a multiple-gain-element Nd:YAG laser where the gain media (three pieces of slab crystal) are alternately bonded to two optical quality 4H-SiC wafers. Such composite gain configuration can efficiently remove waste heat from the gain medium, preventing thermal lensing and heat-induced birefringence/distortion under high power laser operation. Through near Brewster's angles incidence designing and polarization discrimination, two orthogonally linearly polarized (P and S polarized) laser beams are generated simultaneously from different parts of the same system. Based on a T = 3% output coupler, this continuous wave laser produces maximum power of 5.34 W (0.83 W) with a slope efficiency of 21.1% (3.6%) for the S (P) polarized laser beam. At the 5-W level, the S polarized beam has a beam quality of M2~1.2. The wavelengths of these two perpendicularly polarized laser beams differ about 0.6 nm (1063.7 and 1064.3 nm). Polarized output behavior dependent on the output-coupler transmission is also studied, and it is found that increasing the transmission leads to steady growth of the P polarized laser beam; when a T = 1.3% output coupler is adopted, more than 99% of the output is the S polarized beam. The highest total output power is 6.75 W obtained with the T = 1.3% output coupler, corresponding to slope efficiency of 25.7%. This composite laser scheme, bonding multiple gain media with high-thermal-conductivity materials, opens a new avenue for high-power high-beam-quality solid-state lasers with multiple-polarization output beams.

[Molecular mechanisms of NMDA receptor-MAPK-CREB pathway underlying the involvement of the anterior cingulate cortex in pain-related aversion].

The pain experience includes a sensory-discriminative component and an emotional-affective component. The great progress in the genetic, molecular, cellular and systemic levels on the study of the sensory dimension of pain has been made. However, the study of the emotional components of pain is relatively backward. A line of clinic observations indicates that chronic pain and pain-related negative emotion affect the physical and mental health of patients. This review summarizes the main progress from our and other laboratories regarding the affective component of pain, elaborates the neuronal mechanisms of pain-related aversive emotion in the anterior cingulate cortex (ACC), especially the critical role of NMDA receptors and ERK-CREB pathway. A variety of regulatory molecules, such as synapse associated protein SIP30 and estrogen contribute to pain-related aversive emotion via facilitating presynaptic glutamate release and postsynaptic NMDA receptor-mediated synaptic transmission. The far-reaching effects of pain-related negative emotion on patients with chronic pain are emphasized.

Developing carbon-nitride nanosheets for mode-locking ytterbium fiber lasers.

Graphitic carbon nitrides (CNs) have appeared as a new type of photocatalyst for water splitting, but their optical properties (e.g., nonlinear absorption), to the best of our knowledge, have been seldom explored. Here, we report the saturable absorption effects of novel 2D carbon-nitride-type nanosheets and use them as saturable absorbers to passively mode-lock Yb-doped fiber lasers. The CN-based saturable absorber is manufactured by solution coating of 2D CN nanosheets on a gold mirror and has a modulation depth and saturation intensity of 12.5% and 7.5 MW/cm2, respectively. Two different output couplers are employed to construct ring laser cavities. With the 10% coupler, the mode-locked fiber laser produces pulses with duration of ∼310 ps, average power of 1.24 mW, and repetition rate of 7.65 MHz. The laser spectrum is centered at 1066 nm with a bandwidth of 2.4 nm. Increasing the coupling ratio to 50% improves the output power to 2.58 mW but at the same time broadens the pulse width to 420 ps. As a new kind of 2D material with strong saturable absorption, CN nanosheets will open a new way for novel photonic and optoelectronic devices.