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The gut microbiome plays pivotal roles in various physiological and pathological processes, with key metabolites including short chain fatty acids (SCFAs), bile acids (BAs), and tryptophan (TRP) derivatives gaining significant attention for their diverse physiological roles. However, quantifying these metabolites presents challenges due to structural similarity, low abundance, and inherent technical limitations in traditional detection methods. In this study, we developed a precise and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method utilizing a chemical isotope derivatization technique employing 4-(aminomethyl)-N,N-dimethylaniline-d 0 /d 6 (4-AND-d 0 /d 6 ) reagents to quantify 37 typical gut microbiome-derived metabolites. This method achieved an impressive 1500-fold enhancement in sensitivity for detecting metabolites, compared to methods using non-derivatized, intact molecules. Moreover, the quantitative accuracy of our chemical isotope derivatization strategy proved comparable to the stable isotope labeled internal standards (SIL-IS) method. Subsequently, we successfully applied this newly developed method to quantify target metabolites in plasma, brain, and fecal samples obtained from a neonatal hypoxic-ischemic encephalopathy (HIE) rat model. The aim was to identify crucial metabolites associated with the progression of HIE. Overall, our sensitive and reliable quantification method holds promise in elucidating the role of gut microbiome metabolites in the pathogenesis of various diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The gut barrier is essential for protection against pathogens and maintaining homeostasis. Macrophages are key players in the immune system, are indispensable for intestinal health, and contribute to immune defense and repair mechanisms. Understanding the multifaceted roles of macrophages can provide critical insights into maintaining and restoring gastrointestinal (GI) health. This review explores the essential role of macrophages in maintaining the gut barrier function and their contribution to post-inflammatory and post-infectious responses in the gut. Macrophages significantly contribute to gut barrier integrity through epithelial repair, immune modulation, and interactions with gut microbiota. They demonstrate active plasticity by switching phenotypes to resolve inflammation, facilitate tissue repair, and regulate microbial populations following an infection or inflammation. In addition, tissue-resident (M2) and infiltration (M1) macrophages convert to each other in gut problems such as IBS and IBD via major signaling pathways mediated by NF-κB, JAK/STAT, PI3K/AKT, MAPK, Toll-like receptors, and specific microRNAs such as miR-155, miR-29, miR-146a, and miR-199, which may be good targets for new therapeutic approaches. Future research should focus on elucidating the detailed molecular mechanisms and developing personalized therapeutic approaches to fully harness the potential of macrophages to maintain and restore intestinal permeability and gut health.

This study aimed to characterize the composition of intestinal and nasal microbiota in septic patients and identify potential microbial biomarkers for diagnosis. A total of 157 subjects, including 89 with sepsis, were enrolled from the affiliated hospital. Nasal swabs and fecal specimens were collected from septic and non-septic patients in the intensive care unit (ICU) and Department of Respiratory and Critical Care Medicine. DNA was extracted, and the V4 region of the 16S rRNA gene was amplified and sequenced using Illumina technology. Bioinformatics analysis, statistical processing, and machine learning techniques were employed to differentiate between septic and non-septic patients. The nasal microbiota of septic patients exhibited significantly lower community richness ( P = 0.002) and distinct compositions ( P = 0.001) compared to non-septic patients. Corynebacterium , Staphylococcus , Acinetobacter , and Pseudomonas were identified as enriched genera in the nasal microbiota of septic patients. The constructed machine learning model achieved an area under the curve (AUC) of 89.08, indicating its efficacy in differentiating septic and non-septic patients. Importantly, model validation demonstrated the effectiveness of the nasal microecological diagnosis prediction model with an AUC of 84.79, while the gut microecological diagnosis prediction model had poor predictive performance (AUC = 49.24). The nasal microbiota of ICU patients effectively distinguishes sepsis from non-septic cases and outperforms the gut microbiota. These findings have implications for the development of diagnostic strategies and advancements in critical care medicine.IMPORTANCEThe important clinical significance of this study is that it compared the intestinal and nasal microbiota of sepsis with non-sepsis patients and determined that the nasal microbiota is more effective than the intestinal microbiota in distinguishing patients with sepsis from those without sepsis, based on the difference in the lines of nasal specimens collected., Competing Interests: The authors declare no conflict of interest.

An estimated 694,550 United States service members were actively deployed to the Persian Gulf from 1990-1991. Many veterans who were deployed developed Persian Gulf War Syndrome along with chronic gastrointestinal symptoms after returning from the Persian Gulf. Our objective in this study was to determine the phenotypic expression of gastrointestinal symptom complexes in previously healthy veterans who had been stationed in the Persian Gulf. One hundred and four consecutive veterans (88 males, 16 females) who had previously been deployed in 1990-91 were evaluated for their bowel habits and gastrointestinal symptoms. A workup was completed to find identifiable causes of their symptoms and all veterans were asked to do a modified version of the Bowel Disease Questionnaire symptom survey. None of the veterans reported gastrointestinal symptoms before deployment. During deployment to the Persian Gulf: 22 veterans (21%) developed irritable bowel syndrome; 17 (16%) developed dyspepsia; 50 (48%) developed diarrhea; 11 (11%) developed bloating; and 4 (4%) developed constipation. The results of the current study suggest that the development of irritable bowel syndrome, dyspepsia, diarrhea, bloating, and constipation is frequently seen in deployed Gulf War Veterans and the gastrointestinal symptoms commonly persist upon returning home. These novel findings are very important for currently deployed veterans who are serving in the Middle East and are at a high risk of developing gastrointestinal disorders., Competing Interests: Conflicts of Interests The authors declare no conflicts of interest.

Adjusting the electronic state of noble metal catalysts on a nanoscale is crucial for optimizing the performance of nanocatalysts in many important environmental catalytic reactions, particularly in volatile organic compound (VOC) combustion. This study reports a novel strategy for optimizing Pt catalysts by modifying their electronic structure to enhance the electron density of Pt. The research illustrates the optimal 0.2Pt-0.3W/Fe 2 O 3 heterostructure with atomic-thick WO 3 layers as a bulking block to electronically modify supported Pt nanoparticles. Methods such as electron microscopy, X-ray photoelectron spectroscopy, and in situ Fourier transform infrared spectroscopy confirm Pt's electron-enriched state resulting from electron transfer from atomic-thick WO 3 . Testing for benzene oxidation revealed enhanced low-temperature activity with moderate tungsten incorporation. Kinetic and mechanistic analyses provide insights into how the enriched electron density benefits the activation of oxygen and the adsorption of benzene on Pt sites, thereby facilitating the oxidation reaction. This pioneering work on modifying the electronic structure of supported Pt nanocatalysts establishes an innovative catalyst design approach. The electronic structure-performance-dependent relationships presented in this study assist in the rational design of efficient VOC abatement catalysts, contributing to clean energy and environmental solutions.

Fulvic acid (FA) is a representative photosensitive dissolved organic matter (DOM) compound that occurs naturally in paddy soils. In this study, the effect of a FA + nitrate treatment (0, 4 and 8 mg/L FA + 20 mmol/L nitrate) on denitrification and As(III) immobilization in flooded paddy soils was assessed under dark and intermittently illuminated conditions (12 h light+12 h dark). The FA input stimulated denitrification in illuminated soils (~100 % of nitrate removal within 6 days) compared to dark conditions (~92 % nitrate removal after 6 days). Meanwhile, As(III) (initial concentration of 0.1 mmol/L) was nearly completely immobilized (~100 %) under illuminated conditions after 4 days for the FA + nitrate treatment compared to 90- 93 % retention in the dark. Denitrification and As immobilization were positively related to the FA dosage in the illuminated assays. The stronger denitrification in illuminated soils was ascribed to denitrifiers harvesting photoelectrons from photosensitive substrates/semiconducting minerals. FA addition also increased the activities of denitrifying enzymes (e.g., NAR, NIR and NOR) and the denitrification electron transport system by nearly 0.6-0.7 and 1.5-1.8 times that of the nitrate-alone treatment under illuminated and dark conditions, thereby fostering stronger denitrification. Upon irradiation, As(III) immobilization was not only stimulated by the interactions with the denitrification pathway whereby As(III) acts as an electron donor for denitrifiers, but was also modulated by Fe(III)/oxidative reactive species-derived photooxidation of As(III). Moreover, the FA + nitrate treatment promoted the enrichment of metal-oxidizing bacteria (e.g., Stenotrophomonas and Acidovorax) that are responsible for nitrate-dependent As(III)/Fe(II) oxidation. The results of this study enhance our understanding of interactions among the biogeochemical cycles of As, Fe, N and C, which are intricately linked by a biophotoelectrochemical pathway in flooded paddy soils., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Competing Interests: The authors declare no competing interests.

Volatile organic compounds such as benzene are hazardous air pollutants that require effective elimination. Noble metal-based catalysts exhibit high benzene combustion activity, but their prohibitive cost necessitates strategies to enhance utilization efficiency. This study investigates a Pt-Cu alloy catalyst for improved benzene combustion by preferentially exposing Pt active sites through Cu alloying. Aberration-corrected scanning transmission electron microscopy and X-ray spectroscopy characterize the nanoscale distribution and enrichment of Pt on the alloy surface. Kinetic measurements demonstrate substantially enhanced activity compared with Pt catalysts, attributed to increased Pt metallic site exposure rather than alteration of the reaction mechanism. In situ Fourier transform infrared (FTIR) spectroscopy reveals a higher abundance of terrace-like Pt sites in the alloy, beneficial for benzene adsorption. Partial pressure dependence analyses indicate competitive adsorption of benzene and O 2 , following Langmuir-Hinshelwood kinetics. These findings provide conceptual insights into tuning surface composition in bimetallic catalysts to optimize noble metal efficiency, with broad applicability for sustainable catalytic process advancement.

CO 2 , as a cheap and abundant renewable C1 resource, can be used to synthesize high value-added chemicals. In this paper, a series of bifunctional metallic niobium complexes were synthesized and their structures were characterized by IR, NMR and elemental analysis. All of these complexes have been proved to be efficient catalysts for the coupling reaction of CO 2 and epoxides to obtain cyclic carbonates under solvent- and co-catalyst-free conditions. By using CO 2 and propylene oxide as a model reaction, the optimal reaction conditions were systematically screened as: 100 °C, 1 MPa, 2 h, ratio of catalyst to alkylene oxide 1:100. Under the optimal reaction conditions, the bifunctional niobium catalysts can efficiently catalyze the coupling reaction with high yield and excellent selectivity (maximum yield of >99% at high pressure and 96.8% at atmospheric pressure). Moreover, this series of catalysts can also catalyze the coupling reaction at atmospheric pressure and most of them showed high conversion of epoxide. The catalysts have good substrate suitability and are also applicable to a variety of epoxides including diepoxides and good catalytic performances were achieved for producing the corresponding cyclic carbonates in most cases. Furthermore, the catalysts can be easily recovered by simple filtration and reused for at least five times without obvious loss of catalytic activity and selectivity. Kinetic studies were carried out preliminarily for the bifunctional niobium complexes with different halogen ions (3a(Cl - ), 3b(Br - ), 3c(I - )) and the formation activation energies ( E a ) of cyclic carbonates were obtained. The order of apparent activation energy E a is 3a (96.2 kJ/mol) > 3b (68.2 kJ/mol) > 3c (37.4 kJ/mol). Finally, a possible reaction mechanism is proposed.

Background & Aims: The etiology of abdominal pain in postinfectious, diarrhea-predominant irritable bowel syndrome (PI-IBS-D) is unknown, and few treatment options exist. Catechol-O-methyltransferase (COMT), an enzyme that inactivates and degrades biologically active catecholamines, plays an important role in numerous physiologic processes, including modulation of pain perception. Our objective was to determine the mechanism(s) of how decreased colonic COMT in PI-IBS-D patients contributes to the chronic abdominal pain phenotype after enteric infections., Methods: Colon neurons, epithelial cells, and macrophages were procured with laser capture microdissection from PI-IBS-D patients to evaluate cell-specific colonic COMT, microRNA-155 (miR-155), and tumor necrosis factor (TNF) α expression levels compared to recovered patients (infection cleared: did not develop PI-IBS-D) and control individuals. COMT -/- , colon-specific COMT -/- , and miR-155 -/- mice and human colonoids were used to model phenotypic expression of COMT in PI-IBS-D patients and to investigate signaling pathways linking abdominal pain. Citrobacter rodentium and trinitrobenzene sulfonic acid animal models were used to model postinflammatory changes seen in PI-IBS-D patients., Results: Colonic COMT levels were significantly decreased and correlated with increased visual analog scale abdominal pain ratings in PI-IBS-D patients compared to recovered patients and control individuals. Colonic miR-155 and TNF-α were increased in PI-IBS-D patients with diminished colonic COMT. COMT -/- mice had significantly increased expression of miR-155 and TNF-α in both colon tissues and dorsal root ganglia. Introduction of cV1q antibody (anti-TNF-α) into mice reversed visceral hypersensitivity after C rodentium and trinitrobenzene sulfonic acid., Conclusions: Decreased colonic COMT in PI-IBS-D patients drives abdominal pain phenotypes via the COMT/miR-155/TNF-α axis. These important findings will allow new treatment paradigms and more targeted and personalized medicine approaches for gastrointestinal disorders after enteric infections., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

A series of bifunctional Schiff base metal catalysts (Zn-NPClR, Zn-NPXH, and M-NPClH) with two quaternary ammonium groups were prepared for carbon dioxide (CO 2 ) and epoxide coupling reactions. The effects of the reaction variables on the catalytic activity were systematically investigated, and the optimal reaction conditions (120 °C, 1 MPa CO 2 , 3 h) were screened. The performances of different metal-centered catalysts were evaluated, and Co-NPClH showed excellent activity. This kind of bifunctional catalyst has a wide range of substrate applicability, excellent stability, and can be reused for more than five runs. A relatively high TOF could reach up to 1416 h -1 with Zn-NPClH as catalyst by adjusting reaction factors. In addition, the kinetic study of the coupling reaction catalyzed by three catalysts (Zn, Co, and Ni) was carried out to obtain the activation energy ( E a ) for the formation of cyclic carbonates. Finally, a possible mechanism for this cyclization reaction was proposed.

Objectives: This study aimed to evaluate the feasibility of reduced full-of-view synthetic high-b value diffusion-weighted images (rFOV-syDWIs) in the clinical application of cervical cancer based on image quality and diagnostic efficacy., Methods: We retrospectively evaluated the data of 35 patients with cervical cancer and 35 healthy volunteers from May to November 2021. All patients and volunteers underwent rFOV-DWI scans, including a 13b-protocol: b = 0, 25, 50, 75, 100, 150, 200, 400, 600, 800, 1000, 1200, and 1500 s/mm 2 and a 5b-protocol: b = 0, 100, 400, 800,1500 s/mm 2 . rFOV-syDWIs with b values of 1200 (rFOV-syDWI b=1200 ) and 1500 (rFOV-syDWI b=1500 ) were generated from two different multiple-b-value image datasets using a mono-exponential fitting algorithm. According to homoscedasticity and normality assessed by the Levene's test and Shapiro-Wilk test, the inter-modality differences of quantitative measurements were, respectively, examined by Wilcoxon signed-rank test or paired t test and the inter-group differences of ADC values were examined by independent t test or Mann-Whitney U test., Results: A higher inter-reader agreement between SNRs and CNRs was found in 13b-protocol and 5b-protocol rFOV-syDWI b=1200/1500 compared to 13b-protocol rFOV-sDWI b=1200/1500 (p < 0.05). AUC of 5b-protocol syADC mean,b=1200/1500 and syADC minimum,b=1200/1500 was equal or higher than that of 13b-protocol sADC mean,b=1200/1500 and sADC minimum,b=1200/1500 ., Conclusions: rFOV-syDWIs provide better lesion clarity and higher image quality than rFOV-sDWIs. 5b-protocol rFOV-syDWIs shorten scan time, and synthetic ADCs offer reliable diagnosis value as scanned 13b-protocol DWIs., (© 2023. The Author(s).)

Over 25% of veterans with Gulf War illness developed chronic gastrointestinal (GI) symptoms of unknown etiology after they returned from deployment to the Persian Gulf. To determine the prevalence of delayed gastric emptying and its association with autonomic dysfunction in returning Gulf War (GW) veterans with chronic GI symptoms, we prospectively studied 35 veterans who were deployed to the Persian Gulf and developed chronic nausea, vomiting, postprandial abdominal pain, and bloating during their tour of duty and 15 asymptomatic controls. All veterans underwent 5 standardized cardiovascular tests to assess autonomic function. Each test was scored from 0 (normal) to 5 (severe disease) and the mean was calculated. A composite score >1.5 was considered abnormal, with 5 representing severe autonomic dysfunction. A standardized gastric emptying test with a solid phase was performed in each veteran. A gastric retention of >50% at 100 minutes was considered abnormal. The composite autonomic score was 3.7 in veterans with GI symptoms (vs 1.3 in controls) (p<0.01). The mean solid phase retention at 100 minutes was 72.6% in the symptomatic veterans versus 24.6% in controls (p<0.001). Our results suggest that autonomic dysfunction and delayed gastric emptying are common in returning GW veterans with GI symptoms. Autonomic dysfunction was positively correlated with the severity of delayed gastric emptying and may account for the GI symptoms of nausea, vomiting, postprandial abdominal pain, and bloating. These new findings are important for an increasing number of veterans who are serving in the Persian Gulf and are at a high risk of developing GI disorders while deployed.

Ammonium, imidazole, or pyridinium functionalized β-cyclodextrins (β-CDs) were used as efficient one-component bifunctional catalysts for the coupling reaction of carbon dioxide (CO 2 ) and epoxide without the addition of solvent and metal. The influence of different catalysts and reaction parameters on the catalytic performance were examined in detail. Under optimal conditions, Im-CD1-I catalysts functionalized with imidazole groups were able to convert various epoxides into target products with high selectivity and good conversion rates. The one-component bifunctional catalysts can also be recovered easily by filtration and reused at least for five times with only slight decrease in catalytic performance. Finally, a possible process for hydroxyl group-assisted ring-opening of epoxide and functionalized group- induced activation of CO 2 was presented.

Transient receptor potential vanilloid 1 (TRPV1) is a promising target for developing antinociceptive agents. Here, we report the synthesis of N -indazole-4-aryl piperazine carboxamide analogues as TRPV1 modulators. The structure-activity relationship (SAR) reveals that substituting indazole at the 5-/6-position leads to TRPV1 agonism, whereas the 4- and 7-positions of indazole obtain mild antagonism and loss of activity, respectively. The whole-cell clamp patch assay shows that 28 is a potent and selective TRPV1 agonist and it relieves inflammatory and thermal pain by desensitizing the native TRPV1 current in the dorsal root ganglion (DRG) in mice. Additionally, site-directed mutagenesis combined with molecular docking shows an important hydrogen interaction between Arg557 and the indazole of 28 . Taken together, our findings provide insight into TRPV1 agonism-antagonism conversion based on the interaction between indazole and Arg557, which provides a strategy to obtain new TRPV1 agonists by structural modification of antagonists. Compound 28 may be used as a lead compound for further optimization.

Epigenetics is a process that alters gene activity or phenotype without any changes in the underlying DNA sequence or genotype. These biological changes may have deleterious effects and can lead to various human diseases. Ongoing research is continuing to illuminate the role of epigenetics in a variety of pathophysiologic processes. Several categories of epigenetic mechanisms have been studied including chromatin remodeling, DNA methylation, histone modification, and non-coding RNA mechanisms. These epigenetic changes can have a long-term effect on gene expression without any underlying changes in the DNA sequences. The underlying pathophysiology of disorders of brain-gut interaction and stress-induced visceral pain are not fully understood and the role of epigenetic mechanisms in these disorders are starting to be better understood. Current work is underway to determine how epigenetics plays a role in the neurobiology of patients with chronic visceral pain and heightened visceral nociception. More recently, both animal models and human studies have shown how epigenetic regulation modulates stress-induced visceral pain. While much more work is needed to fully delineate the mechanistic role of epigenetics in the neurobiology of chronic visceral nociception, the current study by Louwies et al., in Neurogastroenterology and Motility provides additional evidence supporting the involvement of epigenetic alterations in the central nucleus of the amygdala in stress-induced visceral hypersensitivity in rodents., (© 2022 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, predominantly expressed in a subset of peripheral sensory neurons for pain signaling. Topical application of agonist capsaicin for desensitizing TRPV1 currents has been approved for relief of chronic pain. However, the potent TRPV1 capsaicin is not ingestible and even topical capsaicin causes common side effects such as skin irritation, swelling, erythema and pruritus, suggesting that a mild TRPV1 agonist might be helpful for reducing side effects while reliving pain. In this study, we reported on a partial and selective TRPV1 agonist 4-(5-chloropyridin-2-yl)- N -(1 H -indazol-6-yl)piperazine-1-carboxamide named CPIPC that was modified based on targeting the residue Arg557, important for conversion between the channel antagonism and agonism. Whole-cell patch clamp recordings indicated a concentration-dependent activation of TRPV1 currents by CPIPC with an EC 50 of 1.56 ± 0.13 μM. The maximum efficacy of CPIPC (30 μM) was about 60% of saturated capsaicin (10 μM). Repetitive additions of CPIPC caused TRPV1 current desensitization in both TRPV1-expressing HEK293 cells and dorsal root ganglion (DRG) sensory neurons. Oral administration of CPIPC dose-dependently alleviated inflammatory pain in mice. Further site-directed mutagenesis combined with molecular docking revealed that residue Arg557 is critical for TRPV1 activation by CPIPC . Taken together, we identified a novel partial and selective TRPV1 agonist CPIPC that exhibits antinociceptive activity in mice.

Long non-coding RNAs (lncRNAs) have been confirmed to be connected with tumor proliferation, apoptosis, metastasis and recurrence. Previous studies have indicated that lncRNA calcium voltage-gated channel subunit α1 G (CACNA1G)-antisense 1 (AS1) can function as a pro-oncogene in several types of cancer. However, the specific role and mechanism of CACNA1G-AS1 have not been fully elucidated in human diffuse large B cell lymphoma (DLBCL). In the present study, CACNA1G-AS1 expression was verified in DLBCL tissues and cells by reverse transcription-quantitative PCR, and the relationship between CACNA1G-AS1 and microRNA (miR)-3160-5p was confirmed using luciferase reporter assays. After CACNA1G-AS1-knockdown and miR-3160-5p-overexpression, MTT, colony formation and flow cytometry assays were conducted to assess the changes in the cytotoxicity and apoptosis of OCI-Ly10 and SUDHL-4 cells. In addition, in vivo experiments were performed to determine the impact of CACNA1G-AS1-knockdown on tumor growth and apoptosis. It was revealed that CACNA1G-AS1 was highly expressed in DLBCL tissues and cells and that expression of CACNA1G-AS1 was associated with the clinical stage of DLBCL. Functionally, CACNA1G-AS1-knockdown was demonstrated to increase cytotoxicity and expedite apoptosis in DLBCL cells in vitro and in vivo . In addition, CACNA1G-AS1 could downregulate miR-3160-5p by targeting binding in DLBCL cells. Overexpression of miR-3160-5p had the same effects on the cytotoxicity and apoptosis of DLBCL cells as CACNA1G-AS1-knockdown. Overall, the present study revealed that CACNA1G-AS1-knockdown and miR-3160-5p-overexpression could prevent DLBCL carcinogenesis, which might provide novel therapeutic targets for DLBCL., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Zhou et al.)

A series of specific and potent fluorescent ligands were developed for labelling and visualizing Kv7.2/7.3 based molecular rotation restriction. Probes 21b and 24a were found to be safe and convenient tools to detect and visualize Kv7.2/7.3 in live cells and mouse brain tissue.

Five unprecedented chromone derivatives involving a 6/6/5/5/5/6 hexacyclic scaffold ( 1 , 2 ), 6/6/5/6/6/6/6 heptacyclic scaffold ( 3 ), and 6/6/6/5/5/6 hexacyclic scaffold ( 4 , 5 ) were obtained from the fungus Aspergillus deflectus NCC0415. Their structures were identified using comprehensive spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Except for 3 , the other compounds, especially the 6/6/6/5/5/6 hexacyclic derivatives ( 4 and 5 ), exhibited potent inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitory activities.

The extensive use of antibiotics for treating humans, animals, and plants has resulted in the contamination of aquatic environments, posing a potential threat to public health and aquatic life; hence, this topic is of great concern worldwide. Lakes are considered to be antibiotic-rich reservoirs because many of the antibiotics discharged from rivers enter lakes. Chaohu Lake is one of the top five freshwater lakes in China. This study aims to provide a current evaluation of the antibiotics present in the surface water of the Chaohu Lake basin. To this end, the occurrences of 18 antibiotics categorized into 5 different groups were investigated in the study area, and the impact of inflowing rivers on their distribution was assessed. The results showed that the concentrations of 14 antibiotics in water samples ranged from 0 to 892 ng/L, and that antibiotics were detected at most sampling sites. Among them, the Nanfeihe and Shiwulihe rivers, which are close to the city, contributed the most to antibiotic pollution, indicating the widespread occurrence of antibiotics in the study area. A risk assessment based on the risk quotient method indicated that ofloxacin, ciprofloxacin, sulfamethoxazole, erythromycin, and norfloxacin in the lake water posed a high ecological risk to algae, while sulfamethazine posed a high risk to plants (RQ >1)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Transient receptor potential ankyrin 1 (TRPA1) channel, as a nonselective ligand-gated cation channel robustly in dorsal root ganglion sensory neurons, is implicated in sensing noxious stimuli and nociceptive signaling. However, small-molecule tools targeting TRPA1 lack temporal and spatial resolution, limiting their use for validation of TRPA1 as a therapeutic target for pain. In our previous work, we found that 4,4'-(diazene-1,2-diyl)dianiline (AB1) is a photoswitchable TRPA1 agonist, but the poor water solubility and activity hinder its further development. Here, we report a series of specific and potent azobenzene-derived photoswitchable TRPA1 agonists (series 1 and 2) that enable optical control of the TRPA1 channel. Two representative compounds 1g and 2c can alleviate capsaicin-induced pain in the cheek model of mice through channel desensitization but not in TRPA1 knockout mice. Taken together, our findings demonstrate that photoswitchable TRPA1 agonists can be used as pharmacological tools for study of pain signaling.

Objective: The iridoid glycosides were extracted and separated from Osmanthus fragrans seeds, and the potential protective effect of Osmanthus fragrans seed extract on concanavalin A-induced immune liver injury in mice was studied. Methods: Osmanthus fragrans seeds were extracted by 95% ethanol reflux. Then, the iridoid glycosides were enriched by extraction refined through petroleum ether (60°C-90°C), ethyl acetate, and water-saturated n-butanol in sequence, so as to purify the n-butanol part ( Osmanthus fragrans seed's n-butanol extraction, OFSN) by macroporous resin. Specnuezhenide and Nuezhenoside G13 were used as the reference substances to determine the concentration of iridoid glycosides by HPLC. On this basis, a mouse immune liver injury model was established by tail intravenous concanavalin A (20 mg/kg); the contents of serum ALT, AST, IFN-γ, and TNF-α and the contents of liver tissue MDA and SOD were determined; the pathological changes of the liver by HE staining were observed; and the expression levels of p38MAPK and p-p38mapk in liver tissue were detected by WB. Results: The linearity, precision, repeatability, recovery, and stability of HPLC all met the requirements by validating with the methodology. The contents of Specnuezhenide and Nuezhenoside G13 in the n-butanol extracts were 39.20% and 39.88%, respectively. Actually, their contents can reach up to 82.56% and 87.9% after being purified by macroporous resin. The results of animal experiments show that OFSN could significantly reduce the liver and spleen index, reduce the ALT and AST contents in plasma and the MDA content in liver tissue, and then increase the SOD content. Besides, OFSN could also reduce the plasma IFN-γ and TNF-α levels. The HE staining result indicates that the pathological changes in the liver tissues of mice treated with OFSN are alleviated to different degrees while the WB result suggests that OFSN could significantly inhibit the expression of p-p38mapk. Conclusion: Osmanthus fragrans seeds are rich in iridoid glycosides, which has a good protective effect on mouse immune liver injury caused by concanavalin A. The mechanism may be related to inhibiting the phosphorylation of p38MAPK, inhibiting the release of inflammatory mediators, improving the antioxidant capacity of liver cells, and weakening the occurrence of lipid peroxidation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Xiao, Zhou, Diao, Zhang, Liu, Wang, Huang, Wu, Bai and Min.)

This study aimed to identify the prognostic factors in patients with Waldeyer's ring diffuse large B-cell lymphoma (WR-DLBCL), comparing the efficacy of radiotherapy (RT) for the WR-DLBCL patients in the pre-rituximab and rituximab eras. We conducted a retrospective analysis of 134 patients diagnosed with WR-DLBCL. Univariate and multivariate analyses were performed to identify the prognostic factors for WR-DLBCL. Then, we divided these patients into the rituximab plus chemotherapy group (R-chemotherapy) (n = 88) and chemotherapy group (n = 46), and the Kaplan-Meier and Cox regression model analyses were applied to investigate the treatment value of RT in both the groups. Multivariate analysis revealed international prognostic index (IPI) ≥ 3 and chemotherapy without rituximab as significant risk factors for the progression-free survival (PFS, IPI ≥ 3: p = 0.001; chemotherapy without rituximab: p = 0.002) and overall survival (OS, IPI ≥ 3, p < 0.001; chemotherapy without rituximab, p = 0.024). Rituximab combined with chemotherapy significantly improved PFS (p = 0.002) and OS (p = 0.006) in these patients. RT did not significantly contribute to the survival in the overall cohort analysis, whereas in the subgroup analysis, RT significantly improved the PFS (p = 0.025) and OS (p = 0.029) for the patients in the chemotherapy group, but not in the R-chemotherapy group. In conclusion, the WR-DLBCL patients could benefit from RT in the pre-rituximab era, whereas the addition of rituximab to chemotherapy significantly improved the survival of WR-DLBCL patients, and the clinical benefit of RT was reduced., (© 2021 John Wiley & Sons Ltd.)

For most signalized at-grade intersections, exclusive lanes for non-motorized vehicles have been applied to improve the level of service, capacity and safety of both motorized vehicles and non-motorized vehicles. However, because of various factors, riders of non-motorized vehicles have been observed using lanes for motorized vehicles instead of lanes for non-motorized vehicles, which usually negatively influences the performance of signalized intersections and sometimes may cause serious problems such as traffic congestion and accidents. The objective of this paper is to explore factors influencing the lane choice of riders of non-motorized vehicles at exit legs of signalized at-grade intersections and develop a prediction model for riders' lane choice. Data concerning the lane choice of riders of non-motorized vehicles and other impacting factors were collected at exit legs of four typical signalized at-grade intersections. Applying binary logistic regression, a probability prediction model was developed to explain how various factors influence the lane choice of riders of non-motorized vehicles. The prediction model indicates that female riders of non-motorized vehicles have a higher probability of choosing the lane for non-motorized vehicles than male riders. Compared with riders of non-motorized vehicles powered by electricity, riders of traditional man-powered bicycles are more likely to choose the lane for non-motorized vehicles. Right-turning riders of non-motorized vehicles are more likely to choose the lane for non-motorized vehicles than straight-going riders, who in turn, are more likely to choose the lane for non-motorized vehicles than left-turning riders. Decreasing the volume of non-motorized vehicles, increasing the volume of motorized vehicles, and widening the lane for non-motorized vehicles will increase the probability of the correct choice of lane for non-motorized vehicles. The predictions of the model are in good agreement with the observed facts. The model is meaningful for guidance on the design and management of signalized at-grade intersections.

Background: Objective: We examined the incidence of perioperative hypertensive crisis in robot-assisted retroperitoneal laparoscopic adrenalectomy., Methods: A consecutive series of 120 patients with adrenal tumours undergoing robot-assisted retroperitoneal laparoscopic adrenalectomy were included. Patients were divided into two groups: group A (hypertension group, 58 cases, mean age 43.59 years) and group B (normotension group, 62 cases, mean age 48.01 years). General anaesthesia was applied using endotracheal intubation and haemodynamic changes were closely monitored., Results: A total of nine (7.5%) hypertensive crisis cases were observed. After intravenous infusion of sodium nitroprusside, seven cases of them were quickly controlled and two cases experienced transient severe hypertension. The incidence of hypertensive crisis was 13.7% and 1.6% in groups A and B, respectively (p < 0.05)., Conclusion: These findings highlight the importance of strengthening the monitoring of anaesthesia and taking various measures to effectively control the blood pressure in robot-assisted retroperitoneal laparoscopic adrenalectomy, especially among hypertensive patients., (© 2020 John Wiley & Sons Ltd.)

Twelve new compounds, aspergorakhins A-L (1-12) coupled with one known xanthone leptosphaerin D (13), were isolated from the extract of soil-derived fungus Aspergillus gorakhpurensis F07ZB1707. Their structures were elucidated by spectroscopic data analysis including UV, IR, NMR, and HRESIMS. The absolute configurations of 5 and 8-11 were identified using ECD and OR calculations. All compounds were tested by enzyme inhibitory activity assay in vitro . Aspergorakhin A (1) showed selective activities against PTP1B and SHP1 over TCPTP with IC 50 values 0.57, 1.19, and 22.97 μM, respectively. Compounds 1 and 2 exhibited modest cytotoxicity against tumor cell lines A549, HeLa, Bel-7402, and SMMC-7721 with IC 50 values in the range of 6.75-83.4 μM., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

To improve the inevitable capacity fading issues faced by traditional submicron Si@C electrodes used as anode materials in LIBs, a flexible and conductive connection design is proposed and realized by a solid-state growth approach. In this construction, Si@C is entangled into in situ synthesized carbon nanotube-based network to form a highly connective Si@C/CNTs composite. The interwoven carbon-nanotubes having tight linkages with Si@C contribute to ensure the charge transfer pathway within Si@C particles and accommodate the volume expansion during cycling. The Co/N co-doping further facilitates the transportation of Li ions. As expected, the Si@C/CNT electrode shows improved conductivity and long-term cyclic stability with a high-capacity retention ratio of 80.7% after 500 cycles at 0.5 A g -1 . In this study, the flexible and conductive connection design realized by the in situ synthesis of CNTs can provide some reference to the improvement of alloy-type anode materials and not just Si-based anode materials for LIBs., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The ability of translated cellular proteins to perform their functions requires their proper folding after synthesis. The endoplasmic reticulum (ER) is responsible for coordinating protein folding and maturation. Infections, genetic mutations, environmental factors and many other conditions can lead to challenges to the ER known as ER stress. Altering ER homeostasis results in accumulation of misfolded or unfolded proteins. To eliminate this problem, a response is initiated by the cell called the unfolded protein response (UPR), which involves multiple signaling pathways. Prolonged ER stress or a dysregulated UPR can lead to premature apoptosis and an exaggerated inflammatory response. Following these discoveries, ER stress was shown to be related to several chronic diseases, such as diabetes mellitus, neurodegenerative disorders, fatty liver disease and inflammatory bowel disease that have not yet been clearly demonstrated pathophysiologically. Here, we review the field and present up-to-date information on the relationship between biological processing, ER stress, UPR, and several chronic diseases., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Thermosensitive transient receptor potential vanilloid 2 (thermoTRPV2) is a nonselective Ca 2+ -permeable cation channel broadly expressed, and is implicated in the pathology of diseases such as diabetes and pancreatitis. However, the physiological and pharmacological functions of TRPV2 channels have not been extensively investigated because of the absence of specific modulators. In this study, we report a pair of natural coumarin derivative enantiomers (-)-murraxocin (B304-1) and (+)-murraxocin (B304-2) from Murraya exotica for their selective inhibition of TRPV2 channels expressed in HEK293 cells and native TRPV2 currents in differentiated brown adipocytes. Whole-cell patch clamp recordings confirmed the enantiomers B304-1 and B304-2 could selectively inhibit the agonist mediated activation of TRPV2 current with IC 50 values of 22.2 ± 7.8 μM and 3.7 ± 0.7 μM, respectively. Molecular docking and site-directed mutagenesis revealed a key residue I600 of TRPV2 critical for the binding of the enantiomers. Furthermore, B304-1 and B304-2 significantly reversed TRPV2 agonist-induced inhibition of mouse brown adipocyte differentiation. Taken together, our identification of two natural coumarin enantiomers provides valuable tools and chemical leads for further elucidation of TRPV2 channel function, and pharmacological modulation of thermoTRPV2 in brown adipocytes may represent a new therapeutic strategy for treatment of energy imbalance or metabolic disorders., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Objective: To observe the effects of preoperative right stellate ganglion block on perioperative atrial fibrillation in patients undergoing lung lobectomy., Methods: Two hundred patients who underwent a scheduled lobectomy were randomly divided into the S and C groups. The S group was injected with 4mL of 0.2% ropivacaine under ultrasound guidance, and the C group did not receive stellate ganglion block. The patients underwent continuous ECG monitoring, and the incidences of atrial fibrillation and other types of arrhythmias were recorded from the start of surgery to 24hours after surgery., Results: The respective incidences of atrial fibrillation in the S group and the C group were 3% and 10% (p=0.045); other atrial arrhythmias were 20% and 38% (p=0.005); and ventricular arrhythmia were 28% and 39% (p=0.09)., Conclusions: The results of the study indicated that preoperative right stellate ganglion block can effectively reduce the incidence of intraoperative and postoperative atrial fibrillation., (Copyright © 2020 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.)

This study determined the potential of formic acid plus monolaurin (FA + ML) as an alternative to antibiotics in diet when piglets are challenged with ETEC. Piglets fed the FA + ML diet had lower fecal score and rectal temperature after the ETEC challenge. In addition, FA + ML supplementation induced lower plasma TNF-α, IL-6, and IL-1β concentration postchallenge, downregulated the mRNA expression of TNF-α, IL-1β, IL-6, and TLR4 in the ileum and TLR4 and CFTR in the jejunum. Phosphorylation levels of NF-κB p65 and MAPK p38 were reduced in the ileum of piglets fed FA + ML diet. Supplementation of FA + ML increased the relative abundance of genera Lactobacillus especially Lactobacillus amylovorus species and decreased the genus abundances of Actinobacillus , unidentified Enterobacteriaceae , Moraxella . Collectively, the combination of formic acid and monolaurin in diets have the potential to be an antibiotic alternative to mitigate inflammatory response in piglets challenged with ETEC.

Clustered regularly interspaced short palindromic repeats (CRISPR) are acquired immune system in bacteria and archaea. This system is used in site-directed gene editing. Recently, scientists discovered new CRISPR-associated (Cas) proteins, in which Cas12a-mediated gene editing can significantly reduce the off-target rate. In this article, we review CRISPR/Cas system's discovery of history, composition, classification, and working principle. The latest research progress of the CRISPR/Cas system, and its application in zebrafish are introduced.

Fluorescent probes have been used as effective methods for profiling proteins in biological systems because of their high selectivity, sensitivity, and temporal-spatial resolution. A specific fluorescent probe for understanding the function of the transient receptor potential ankyrin 1 (TRPA1) channel that is closely related with various diseases like persistent pain, respiratory, and chronic itch syndromes, however, is still lacking. Here, we report a "turn-on" fluorescent probe (A1CA) for visualizing TRPA1 channels in the plasma membrane of live cells based on a photochromic ligand derived from 4-(phenylazo)benzenamine. Evaluating the specificity and sensitivity of A1CA by electrophysiology and confocal imaging showed that the A1CA probe displays higher affinity and selectivity to TRPA1 channel versus all other ion channels including TRPV1, TRPV3, Nav1.4, Nav1.5, and hERG. Based on the supporting evidence, A1CA has great potential as a molecular imaging probe for high-throughput screening of novel TRPA1 agonists.

Human TRDMT1 is a transfer RNA (tRNA) methyltransferase for cytosine-5 methylation and has been suggested to be involved in the regulation of numerous developmental processes. However, little is known about the molecular mechanisms or their biological significance. In this study, we investigated the effects of CRISPR-based TRDMT1 knockdown on phenotypes, mRNA m5C modifications and gene expression changes in HEK293 cells. We found that knockdown of TRDMT1 significantly inhibited cell proliferation and migration but had no effect on clonogenic potential. The inhibitory effects could be attenuated by re-expression of TRDMT1 in HEK293 cells. RNA sequencing (RNA-Seq) and RNA bisulfite sequencing (RNA-BisSeq) were performed in TRDMT1 knockdown and wild-type HEK293 cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that the differentially expressed genes were associated with the cell cycle, RNA transport, and RNA degradation and were enriched in cancer and Notch signaling pathways. We also found that TRDMT1 knockdown could change mRNA methylation levels. For the first time, these findings clarify the role of TRDMT1 in regulating mRNA methylation and inhibiting the proliferation and migration of HEK293 cells. These results provide new insights into a new function of TRDMT1 and elucidate the molecular mechanisms of aberrant RNA m5C during tumorigenesis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Well over 700,000 United States military personnel participated in the Persian Gulf War in which they developed chronic health disorders of undetermined etiology. Up to 25% of Veterans had persistent and chronic gastrointestinal (GI) symptoms, which they suspected were related to their military service in the Gulf., Aim: The overall aim of the current study was to evaluate intestinal permeability in previously deployed Gulf War Veterans who developed chronic GI symptoms during their tour in the Persian Gulf., Methods: To accomplish this, we evaluated intestinal permeability (IP) using the urinary lactulose/mannitol test. Measurements of intestinal permeability were then correlated with mean ratings of daily abdominal pain, frequency of bowel movements, and consistency of bowel movements on the Bristol Stool Scale in all Veterans., Results: A total of 73 veterans had documented chronic GI symptoms (diarrhea, abdominal pain) and were included in the study. A total of 29/73 (39%) of veterans has increased IP and had a higher average daily stool frequency (P<0.05); increased liquid stools as indicated by a higher Bristol Stool Scale (P<0.01); and a higher mean M-VAS abdominal pain rating (P<0.01). Pearson correlation coefficients revealed that there was a positive correlation between increased IP and stool frequency, Bristol Stool Scale, and M-VAS abdominal pain rating., Conclusions: Our study demonstrates that deployed Gulf War Veterans with persistent GI symptoms commonly have increased intestinal permeability that potentiates the severity of abdominal pain, diarrhea, and stool consistency. These new findings in our study are important as they may lead to novel diagnostic biomarkers for returning Gulf War Veterans who suffer from chronic functional gastrointestinal disorders. These advances are also important for an increasing number of veterans who are now serving in the Persian Gulf and are at a high risk of developing these chronic pain disorders.

Background: More effective treatments are needed for patients with postinfectious, diarrhoea-predominant, irritable bowel syndrome (IBS-D). Accordingly, we conducted a randomised, double-blind, placebo-controlled, 8-week-long trial to assess the efficacy and safety of oral glutamine therapy in patients who developed IBS-D with increased intestinal permeability following an enteric infection., Methods: Eligible adults were randomised to glutamine (5 g/t.i.d.) or placebo for 8 weeks. The primary end point was a reduction of ≥50 points on the Irritable Bowel Syndrome Severity Scoring System (IBS-SS). Secondary endpoints included: raw IBS-SS scores, changes in daily bowel movement frequency, stool form (Bristol Stool Scale) and intestinal permeability., Results: Fifty-four glutamine and 52 placebo subjects completed the 8-week study. The primary endpoint occurred in 43 (79.6%) in the glutamine group and 3 (5.8%) in the placebo group (a 14-fold difference). Glutamine also reduced all secondary endpoint means: IBS-SS score at 8 weeks (301 vs 181, p<0.0001), daily bowel movement frequency (5.4 vs 2.9±1.0, p<0.0001), Bristol Stool Scale (6.5 vs 3.9, p<0.0001) and intestinal permeability (0.11 vs 0.05; p<0.0001). 'Intestinal hyperpermeability' (elevated urinary lactulose/mannitol ratios) was normalised in the glutamine but not the control group. Adverse events and rates of study-drug discontinuation were low and similar in the two groups. No serious adverse events were observed., Conclusions: In patients with IBS-D with intestinal hyperpermeability following an enteric infection, oral dietary glutamine supplements dramatically and safely reduced all major IBS-related endpoints. Large randomised clinical trials (RCTs) should now be done to validate these findings, assess quality of life benefits and explore pharmacological mechanisms., Trial Registration Number: NCT01414244; Results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

A highly sensitive fluorescent probe CBH based on solvatochromism and molecular rotation was designed and developed for imaging of hERG channels by employing a novel targeting group 4-benzylaniline. More importantly, CBH has the potential for the quantitative analysis of the hERG channels expressed in tumor cells.

This study aims to evaluate whether diets containing mixture of formic and propionic acid alone or supplemented with either capric acid or Bacillus Licheniformis can alleviate immune inflammatory response of piglets challenged with enterotoxigenic Escherichia coli (ETEC). A total of 30 weaning pigs were assigned to 5 diets, without additive (CON), with antibiotics (ATB), with 1% organic acid (OA; 64% formic and 25% propionic acid), with OA plus 0.2% capric acid (OA + CRA), and with OA plus 0.02% probiotic ( Bacillus Licheniformis ; OA + PB). After oral challenge with ETEC on day 10, the feces and plasma of all pigs were collected at different time points. Four additive treatments all decreased rectal temperature (RT) at 9 h and fecal scores (FS) at 24 h after challenge ( P < 0.05), while at 9 h after challenge, inclusion of OA induced a decrease of RT compared with OA + CRA and OA + PB ( P < 0.05). In plasma, concentration of interleukin (IL)-1 β was reduced with the addition of ATB and OA at 24 h and 48 h after challenge and it is lower in OA group than OA + CRA group at 24 h after challenge ( P < 0.05). Diets with ATB, OA, and OA + PB caused a decrease of the concentrations of IL-6 in plasma at 9 h after challenge ( P < 0.05). The four additives treated piglets showed decreased concentrations of plasma tumor necrosis factor- α and interferon- γ at 9 h and 24 h after challenge, respectively ( P < 0.05). In conclusion, OA supplementation alleviated the inflammatory response and reduced diarrhea incidence in piglets challenged with ETEC. However, no further improvements were observed when OA supplemented with CRA or probiotics.

The temperature-sensitive and calcium-permeable transient receptor potential vanilloid 3 (TRPV3) channel abundantly expressed in keratinocytes plays important functions in skin physiology. Dysfunctional gain-of-function TRPV3 gene mutations cause genetic Olmsted syndrome characterized by periorificial keratoderma, palmoplantar keratoderma, inflammation, and severe itching, which suggests that pharmacological inhibition of overactive TRPV3 function may be beneficial in treating pruritus or skin disorders. To test this hypothesis, we identified natural compound forsythoside B as a TRPV3 inhibitor through screening of human embryonic kidney 293 (HEK293) cells expressing human TRPV3 channels in a calcium fluorescent assay. Whole-cell patch-clamp recordings of HEK293 cells expressing TRPV3 confirmed that forsythoside B selectively inhibited the channel current activated by agonist 2-aminoethoxydiphenyl borate (50 µ M) in a dose-dependent fashion, with an IC 50 value of 6.7 ± 0.7 μ M. In vivo evaluation of scratching behavior demonstrated that pharmacological inhibition of TRPV3 by forsythoside B significantly attenuated acute itch induced by either the TRPV3 agonist carvacrol or the pruritogen histamine, as well as chronic itch induced by acetone-ether-water in a mouse model of dry skin. Furthermore, forsythoside B was able to prevent the death of HEK293 cells or native human immortalized nontumorigenic keratinocyte cells from human keratinocytes expressing a gain-of-function TRPV3 G573S mutant or in the presence of the TRPV3 agonist carvacrol. Taken together, our findings demonstrate the crucial role of TRPV3 in pruritus and keratinocyte toxicity; thus, specific inhibition of overactive TRPV3 by natural forsythoside B may possess therapeutic potential for treatment of chronic pruritus, skin allergy, or inflammation-related skin diseases., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

In critically ill patients, disruption of intestinal epithelial cell function occurs due to exposure of the epithelium to toxic internal and external inflammatory stimuli, which are key factors that trigger sepsis and multi-organ dysfunction syndrome (MODS). A greater understanding of how trauma and gut failure lead to sepsis and progression to MODS is much needed. In this issue of the JCI, Armacki and colleagues identify mechanisms by which thirty-eight-negative kinase 1 (TNK1) promotes the progression from intestinal apoptosis and gut failure to bacterial translocation, sepsis, and MODS. Moreover, the results of this study suggest TNK1 as a potential therapeutic target to prevent sepsis and MODS.

Introduction: Over 25% of Persian Gulf War (PGW) veterans with Gulf War Illness (GWI) (chronic health symptoms of undetermined etiology) developed gastrointestinal (GI) (diarrhea and abdominal pain) and other somatic symptoms., Objectives: Our study objective was to determine if veterans with GWI and GI symptoms exhibit heightened patterns of somatic pain perception (hypersensitivity) across nociceptive stimuli modalities., Methods: Participants were previously deployed GW Veterans with GWI and GI symptoms (n=53); veterans with GWI without GI symptom (n=47); and veteran controls (n=38). We determined pain thresholds for contact thermal, cold pressor, and ischemic stimuli., Results: Veterans with GWI and GI symptoms showed lower pain thresholds (P<0.001) for each stimulus. There was also overlap of somatic hypersensitivities among veterans with GI symptoms with 20% having hypersensitivity to all 3 somatic stimuli. Veterans with GWI and GI symptoms also showed a significant correlation between mechanical visual analog scale abdominal pain ratings and heat pain threshold, cold pressor threshold, and ischemic pain threshold/tolerance., Discussion: Our findings show that there is widespread somatic hypersensitivity in veterans with GWI/GI symptoms that is positively correlated with abdominal pain ratings. In addition, veterans with somatic hypersensitivity that overlap have the greatest number of extraintestinal symptoms. These findings may have a translational benefit: strategies for developing more effective therapeutic agents that can reduce and/or prevent somatic and GI symptoms in veterans deployed to future military conflicts.

Chronic pain conditions occurring in the lower abdomen and pelvis are common, often challenging to manage, and can negatively affect health-related quality of life. Methodological challenges in designing randomized clinical trials (RCTs) for these conditions likely contributes to the limited number of available treatments. The goal of this systematic review of RCTs of pharmacologic treatments for irritable bowel syndrome and 3 common chronic pelvic pain conditions are to: 1) summarize the primary end points and entry criteria, and 2) evaluate the clarity of reporting of important methodological details. In total, 127 RCTs were included in the analysis. The most common inclusion criteria were a minimum pain duration (81%), fulfilling an established diagnostic criteria (61%), and reporting a minimum pain intensity (42%). Primary end points were identified for only 57% of trials. These end points, summarized in this article, were highly variable. The results of this systematic review can be used to inform future research to optimize the entry criteria and outcome measures for pain conditions occurring in the lower abdomen and pelvis, to increase transparency in reporting to allow for proper interpretation of RCT results for clinical and policy applications, and to facilitate the aggregation of data in meta-analyses., Perspective: This article summarizes entry criteria and outcome measures and the clarity of reporting of these important design features in RCTs of irritable bowel syndrome and 3 common chronic pelvic pain conditions. These results can be used to improve design of future trials of these largely unaddressed pain conditions., (Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.)

Background: Milk protein is crucial for milk quality in sows and health of newborn piglets. Plasma amino acids (AA) in sows are important precursors for milk protein synthesis in the mammary gland. In order to study the regulation of AA transported in sow mammary glands and possible underlying mechanisms, we measured the expression of genes coding for milk proteins, AA transporter expressions, and plasma AA concentrations in sows at three different physiological stages (D-17, D1 and D17 of lactation), and then further investigated the regulation of AA transport across the cell membrane by adaptive mechanisms using pig mammary epithelial cells (PMEC) as an in vitro model. PMEC were cultured in DMEM:F12 with 4 amino acid concentrations (0 × AA complex, 1 × AA complex, 5 × AA complex, and 25 × AA complex). Classes of AA complexes evaluated in this study included neutral AAs ( L -Ala + L -Ser +  L -Cys), acidic AAs ( L -Asp, L -Glu) and neutral + basic AAs ( L -Ala + L -Ser +  L -Cys +  L -Lys)., Results: Our results indicated that mRNA expression of genes coding for milk protein (αs1-casein, αs2-casein, β-casein and κ-casein) increased significantly with the advance of physiological stage ( P  < 0.05), and plasma concentrations of most AAs including threonine, serine, glutamate, alanine, valine, cysteine, methionine, isoleucine and tyrosine were greater at D1 of lactation compared with D-17 and D17 of lactation ( P  < 0.05). Additionally, protein and gene expressions of AA transporters including excitatory AA transporter 3 (EAAT3), alanine/serine/cysteine/threonine transporter (ASCT1) and sodium-coupled neutral AA transporter 1 (SNAT2) were greater in lactating sow mammary glands compared with sow mammary glands in late pregnancy ( P  < 0.05). The mRNA expressions of SLC38A2 , SLC1A1, SLC6A14 increased significantly in the cell mediums supplemented with 5 × and 25 × of AA complexes compared with those cells cultured in DMEM/F12 cell medium ( P  < 0.05). The mRNA expressions of SLC38A, SLC1A4 , and SLC6A14 also increased in EBSS cell medium compared to DMEM/F12. However, only mRNA expression of SLC38A decreased when AA complex was added into EBSS ( P  < 0.05)., Conclusion: AA transportation was positively regulated in sow mammary glands with the advance of physiological stage from late pregnancy to peak of lactation and AA transporters in PMECs were adaptively regulated by changed AA concentrations., Competing Interests: The experiment was carried out according to Chinese guidelines for animal welfare and the National Institutes of Health guide for the care and use of Laboratory animals. All procedures related to animal feeding and surgeries were approved by the South China Agricultural University Animal Care and Use Committee.All authors read and approved the final manuscript.The authors declare that they have no competing interests.

In conjunction with the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership with the U.S. Food and Drug Administration and the American Pain Society, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society Pain Taxonomy (AAPT) initiative strove to develop the characteristics of a diagnostic system useful for clinical and research purposes across disciplines and types of chronic pain conditions. After the establishment of these characteristics, a working group of clinicians and clinical and basic scientists with expertise in abdominal, pelvic, and urogenital pain began generating core diagnostic criteria and defining the related extraintestinal somatic pain and other symptoms experienced by patients. Systematic diagnostic criteria for several common abdominal, pelvic, and urogenital pain conditions are in development. In this report, we present the proposed AAPT criteria for irritable bowel syndrome (IBS), the most common chronic, noncancer abdominal pain condition. A systematic review and synthesis was conducted to complement the Rome IV Diagnostic Criteria for IBS. Future efforts will subject these proposed AAPT criteria to systematic empirical evaluation of their feasibility, reliability, and validity. The AAPT IBS criteria are part of an evidence-based classification system that provides a consistent vocabulary regarding diagnostic criteria, common features, comorbidities, consequences, and putative mechanisms of the disorder. A similar approach is being applied to other chronic and often debilitating abdominal, pelvic, and urogenital pain conditions., Perspective: The AAPT's goal is to develop an evidence-based taxonomy for chronic pain on the basis of a consistently applied multidimensional framework, and encourage experts to apply this taxonomy to specific chronic pain conditions. In this report, the taxonomy is applied to IBS, a chronic abdominal pain condition., (Copyright © 2018. Published by Elsevier Inc.)

Objective: Many patients with irritable bowel syndrome IBS not only have abdominal pain but also may suffer from visceral hypersensitivity and heighted visceral nociception. Moreover, IBS has few effective therapeutic agents and mechanisms of disease are unclear. Our goals were to (i) identify microRNA (miRNA) expression, signalling and targets in human colon (controls; patients with IBS); (ii) verify in vitro, IBS-associated changes in miRNAs, especially miR-199, which is complementary to the transient receptor potential vanilloid type 1 (TRPV1) gene; and (iii) determine whether modulating the expression of miRNAs in vivo, especially miR-199, reverses associated changes and pathological hallmarks of visceral hypersensitivity via TRPV1 signalling., Design: We evaluated 45 patients with diarrhoea-predominant IBS (IBS-D) and 40 controls with (1) visceral pain severity score and (2) colonoscopy with biopsies. miRNA expression was evaluated in human colon following miRNA array analysis. Luciferase assays were done to confirm relationships between miR-199 and TRPV1 expression. A rat model of visceral hypersensitivity was used to study miR-199 and its target gene (TRPV1) expression in dorsal root ganglion (DRG) and colon in vivo., Results: Gut miR-199a/b expression in IBS-D was significantly decreased, which correlated directly with both increased visceral pain scores and TRPV1 expression. In vivo upregulation of miR-199a by intraperitoneal injection of lenti-miR-199a precursors decreased visceral hypersensitivity via diminished TRPV1 signalling., Conclusions: Decreased colonic miR-199a/b correlates with visceral pain in patients with IBS-D. Similarly, reduced miR-199a expression in rat DRG and colon tissue is associated with heightened visceral hypersensitivity. In vivo upregulation of miR-199a decreases visceral pain via inhibition of TRPV1 signalling. Thus, miR-199 precursors may be promising therapeutic candidates for the treatment in patients with visceral pain., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)