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Objective: Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the world. The proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) E670G polymorphism has been reported to be associated with variability in levels of low density lipoprotein cholesterol, a risk factor for CAD. However, the relationship between PCSK9 E670G and CAD is still not fully elucidated., Methods: A total of 225 patients and 189 control subjects were recruited in this study. DNA was extracted from peripheral blood samples and was genotyped by mass array method. In addition, we also conducted a meta-analysis of case-control studies to elucidate the relationship of CAD and polymorphism., Results: The GG genotype of PCSK9 E670G was associated with a higher risk of CAD [odds ratio (OR) 2.994, 95% confidence interval (CI): 1.174-7.631], even adjusting for risk factors (OR 2.794, 95% CI: 1.215-7.460). Logistic regression analysis showed that the dominant genetic model increased the CAD risk (OR 2.313, 95% CI: 1.070-6.983) after adjusting the confounding factors. Meta-analysis results of 13 studies revealed that PCSK9 E670G polymorphism was correlated with CAD risk under different genetic models., Conclusion: Our results demonstrated that PCSK9 E670G genotype was associated with a high risk of CAD.

Developing efficient oxygen evolution reaction (OER) electrocatalysts can greatly advance the commercialization of proton exchange membrane (PEM) water electrolysis. However, the unclear and disputed reaction mechanism and structure-activity relationship of OER pose significant obstacles. Herein, the active site and intermediate for OER on AuIr nanoalloys are simultaneously identified and correlated with the activity, through the integration of in situ shell-isolated nanoparticle-enhanced Raman spectroscopy and X-ray absorption spectroscopy. The AuIr nanoalloys display excellent OER performance with an overpotential of only 246 mV to achieve 10 mA cm -2 and long-term stability under strong acidic conditions. Direct spectroscopic evidence demonstrates that * OO adsorbed on IrO x sites is the key intermediate for OER, and it is generated through the O-O coupling of adsorbed oxygen species directly from water, providing clear support for the adsorbate evolution mechanism. Moreover, the Raman information of the * OO intermediate can serve as a universal "in situ descriptor" that can be obtained both experimentally and theoretically to accelerate the catalyst design. It unveils that weakening the interactions of * OO on the catalysts and facilitating its desorption would boost the OER performance. This work deepens the mechanistic understandings on OER and provides insightful guidance for the design of more efficient OER catalysts., (© 2023 Wiley‐VCH GmbH.)

Intermetallic compounds are emerging as promising oxygen reduction reaction (ORR) catalysts for fuel cells due to their typically higher activity and durability compared to disordered alloys. However, the preparation of intermetallic catalysts often requires high-temperature annealing, which unfortunately leads to adverse sintering of the metal nanoparticles. Herein, we develop a scalable site-selective sulfur anchoring strategy that effectively suppresses alloy sintering, ensuring the formation of efficient intermetallic electrocatalysts with small sizes and high ordering degrees. The alloy-support interactions are precisely modulated by selectively modifying the alloy-support interfaces with oxidized sulfur species, thus simultaneously blocking both the nanoparticle migration and Oswald ripening pathways for sintering. Using this strategy, sub-5 nm PtCo intermetallic electrocatalysts enclosed by two atomic layers of Pt shells have been successfully prepared even at a metal loading higher than 30 wt%. The intermetallic catalysts exhibit excellent ORR performances in both rotating disk electrode and membrane electrode assembly conditions with a mass activity of 1.28 A mg Pt -1 at 0.9 V (vs. RHE) and a power density of 1.0 W cm -2 at a current density of 1.5 A cm -2 . The improved performances result from the enhanced Pt-Co electronic interactions and compressive surface strain generated by the highly ordering structure, while the atomic Pt shells prevent the dissolution of Co under highly acidic conditions. This work provides new insights to inhibit the sintering of nanoalloys and would promote the scalable synthesis and applications of platinum-based intermetallic catalysts., 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 Inc. All rights reserved.)

Full-length Bruton's tyrosine kinase (BTK) has been refractory to structural analysis. The nearest full-length structure of BTK to date consists of the autoinhibited SH3-SH2-kinase core. Precisely how the BTK N-terminal domains (the Pleckstrin homology/Tec homology [PHTH] domain and proline-rich regions [PRR] contain linker) contribute to BTK regulation remains unclear. We have produced crystals of full-length BTK for the first time but despite efforts to stabilize the autoinhibited state, the diffraction data still reveal only the SH3-SH2-kinase core with no electron density visible for the PHTH-PRR segment. Cryo-electron microscopy (cryoEM) data of full-length BTK, on the other hand, provide the first view of the PHTH domain within full-length BTK. CryoEM reconstructions support conformational heterogeneity in the PHTH-PRR region wherein the globular PHTH domain adopts a range of states arrayed around the autoinhibited SH3-SH2-kinase core. On the way to activation, disassembly of the SH3-SH2-kinase core opens a new autoinhibitory site on the kinase domain for PHTH domain binding that is ultimately released upon interaction of PHTH with phosphatidylinositol (3,4,5)-trisphosphate. Membrane-induced dimerization activates BTK and we present here a crystal structure of an activation loop swapped BTK kinase domain dimer that likely represents the conformational state leading to trans-autophosphorylation. Together, these data provide the first structural elucidation of full-length BTK and allow a deeper understanding of allosteric control over the BTK kinase domain during distinct stages of activation., Competing Interests: DL, LK, PJ, TW, JE No competing interests declared, AA Senior editor, eLife, (© 2023, Lin et al.)

Bruton's Tyrosine Kinase (BTK) is a nonreceptor tyrosine kinase that belongs to the TEC family. Mutations in the BTK gene cause X-linked agammaglobulinemia (XLA) leading to an arrest in B-cell development. BTK is also a drug target for B-cell lymphomas that rely on an intact B-cell receptor signaling cascade for survival. All FDA approved drugs for BTK target the ATP binding site of the catalytic kinase domain, leading to potential adverse events due to off-target inhibition. In addition, acquired resistance mutations occur in a subset of patients, rendering available BTK inhibitors ineffective. Therefore, allosteric sites on BTK should be explored for drug development to target BTK more specifically and in combination with active site inhibitors. Virtual screening against nonactive site pockets and in vitro experiments resulted in a series of small molecules that bind to BTK outside of the active site. We characterized these compounds using biochemical and biophysical techniques and narrowed our focus to compound "C2". C2 activates full-length BTK and smaller multidomain BTK fragments but not the isolated kinase domain, consistent with an allosteric mode of action. Kinetic experiments reveal a C2-mediated decrease in K m and an increase in k cat leading to an overall increase in the catalytic efficiency of BTK. C2 is also capable of activating the BTK XLA mutants. These proof-of-principle data reveal that BTK can be targeted allosterically with small molecules, providing an alternative to active site BTK inhibitors.

Palladium-based nanocatalysts play an important role in catalyzing the cathode oxygen reduction reaction (ORR) for fuel cells working under alkaline conditions, but the performance still needs to be improved to meet the requirements for large-scale applications. Herein, Au@Pd core-shell nanowires have been developed by coating Pd atomic layers on ultrafine gold nanowires and display outstanding electrocatalytic performance towards alkaline ORR. It is found that Pd overlayers with atomic thickness can be coated on 3 nm Au nanowires under CO atmosphere and completely cover the surfaces. The obtained ultrafine Au@Pd nanowires exhibit an electrochemical active area (ECSA) of 68.5 m 2 /g and a mass activity of 0.91 A/mg (at 0.9 V vs. RHE), which is around 3.1 and 15.2 times higher than that of commercial Pd/C. The activity loss of the ultrafine Au@Pd nanowire after 10,000 cycles of accelerated degradation tests is only ∼20 %, demonstrating its much better stability compared to commercial Pd/C. Further characterizations combined with density functional theory (DFT) calculations demonstrate that the electronic interactions between Pd atomic layers and underlying Au can increase the electronic density of Pd and promote the efficient activation of oxygen, thus leading to the improved ORR performance., 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 © 2023 Elsevier Inc. All rights reserved.)

Intermittent fasting (IF) has been shown to reduce cardiovascular risk factors in both animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction. However, the underlying molecular mechanisms behind these effects remain unclear. To shed light on the molecular and cellular adaptations of the heart to IF, we conducted comprehensive system-wide analyses of the proteome, phosphoproteome, and transcriptome, followed by functional analysis. Using advanced mass spectrometry, we profiled the proteome and phosphoproteome of heart tissues obtained from mice that were maintained on daily 12- or 16 hr fasting, every-other-day fasting, or ad libitum control feeding regimens for 6 months. We also performed RNA sequencing to evaluate whether the observed molecular responses to IF occur at the transcriptional or post-transcriptional levels. Our analyses revealed that IF significantly affected pathways that regulate cyclic GMP signaling, lipid and amino acid metabolism, cell adhesion, cell death, and inflammation. Furthermore, we found that the impact of IF on different metabolic processes varied depending on the length of the fasting regimen. Short IF regimens showed a higher correlation of pathway alteration, while longer IF regimens had an inverse correlation of metabolic processes such as fatty acid oxidation and immune processes. Additionally, functional echocardiographic analyses demonstrated that IF enhances stress-induced cardiac performance. Our systematic multi-omics study provides a molecular framework for understanding how IF impacts the heart's function and its vulnerability to injury and disease., Competing Interests: TA, AA, EL, SS, LP, VR, YC, YC, JK, JK, HS, DH, CR, DF, DM, GN, SB, KM, MG, GD, CS, BK, RS, MM, DJ, JG No competing interests declared, (© 2023, Arumugam, Alli-Shaik et al.)

Retinal injury after blunt ocular trauma may directly affect prognosis and lead to vision loss. To investigate the pathological changes and molecular mechanisms involved in retinal injury after blunt ocular trauma, we established a weight drop injury model of blunt ocular trauma in male Beagle dogs. Hematoxylin-eosin staining, immunofluorescence staining, western blotting, and TUNEL assays were performed to investigate retinal injury within 14 days after blunt ocular trauma. Compared with the control group, the thicknesses of the inner and outer nuclear layers, as well as the number of retinal ganglion cells, gradually decreased within 14 days after injury. The number of bipolar cells in the inner nuclear layer began to decrease 1 day after injury, while the numbers of cholinergic and amacrine cells in the inner nuclear layer did not decrease until 7 days after injury. Moreover, retinal cell necroptosis increased with time after injury; it progressed from the ganglion cell layer to the outer nuclear layer. Visual electrophysiological findings indicated that visual impairment began on the first day after injury and worsened over time. Additionally, blunt ocular trauma induced nerve regeneration and Müller glial hyperplasia; it also resulted in the recruitment of microglia to the retina and polarization of those microglia to the M1 phenotype. These findings suggest that necroptosis plays an important role in exacerbating retinal injury after blunt ocular trauma via gliosis and neuroinflammation. Such a role has important implications for the development of therapeutic strategies., Competing Interests: None

Objective: This study was undertaken to identify magnetic resonance imaging (MRI) biomarkers that differentiate migraine from cluster headache patients and imaging features that are shared., Methods: Clinical, functional, and structural MRI data were obtained from 20 migraineurs, 20 cluster headache patients, and 15 healthy controls. Support vector machine algorithms and a stepwise removal process were used to discriminate headache patients from controls, and subgroups of patients. Regional between-group differences and association between imaging features and patients' clinical characteristics were also investigated., Results: The accuracy for classifying headache patients from controls was 80%. The classification accuracy for discrimination between migraine and controls was 89%, and for cluster headache and controls it was 98%. For distinguishing cluster headache from migraine patients, the MRI classifier yielded an accuracy of 78%, whereas MRI-clinical combined classification model achieved an accuracy of 99%. Bilateral hypothalamic and periaqueductal gray (PAG) functional networks were the most important MRI features in classifying migraine and cluster headache patients from controls. The left thalamic network was the most discriminative MRI feature in classifying migraine from cluster headache patients. Compared to migraine, cluster headache patients showed decreased functional interaction between the left thalamus and cortical areas mediating interoception and sensory integration. The presence of restlessness was the most important clinical feature in discriminating the two groups of patients., Interpretation: Functional biomarkers, including the hypothalamic and PAG networks, are shared by migraine and cluster headache patients. The thalamocortical pathway may be the neural substrate that differentiates migraine from cluster headache attacks with their distinct clinical features. ANN NEUROL 2023;93:729-742., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

In 1995, a committee of the International Headache Society developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Cluster Headache. These have not been revised. With the emergence of new medications, neuromodulation devices and trial designs, an updated version of the International Headache Society Guidelines for Controlled Clinical Trials in Cluster Headache is warranted. Given the scarcity of evidence-based data for cluster headache therapies, the update is largely consensus-based, but takes into account lessons learned from recent trials and demands by patients. It is intended to apply to both drug and neuromodulation treatments, with specific proposals for the latter when needed. The primary objective is to propose a template for designing high quality, state-of-the-art, controlled clinical trials of acute and preventive treatments in episodic and chronic cluster headache. The recommendations should not be regarded as dogma and alternative solutions to particular methodological problems should be explored in the future and scientifically validated.

Intermittent fasting (IF) remains the most effective intervention to achieve robust anti-aging effects and attenuation of age-related diseases in various species. Epigenetic modifications mediate the biological effects of several environmental factors on gene expression; however, no information is available on the effects of IF on the epigenome. Here, we first found that IF for 3 months caused modulation of H3K9 trimethylation (H3K9me 3 ) in the cerebellum, which in turn orchestrated a plethora of transcriptomic changes involved in robust metabolic switching processes commonly observed during IF. Second, a portion of both the epigenomic and transcriptomic modulations induced by IF was remarkably preserved for at least 3 months post-IF refeeding, indicating that memory of IF-induced epigenetic changes was maintained. Notably, though, we found that termination of IF resulted in a loss of H3K9me 3 regulation of the transcriptome. Collectively, our study characterizes the novel effects of IF on the epigenetic-transcriptomic axis, which controls myriad metabolic processes. The comprehensive analyses undertaken in this study reveal a molecular framework for understanding how IF impacts the metabolo-epigenetic axis of the brain and will serve as a valuable resource for future research., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

Trigeminal autonomic cephalalgias (TACs) are discrete primary headache disorders, characterized by severe unilateral head pain, typically trigeminal distribution, with ipsilateral cranial autonomic symptoms. The conditions within this group are hemicrania continua, cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing and short-lasting unilateral neuralgiform headache with autonomic symptoms. Several advances have been made in understanding the pathogenesis and evolving treatment options in TACs. This review will outline the advances and updates in each TAC., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme. All rights reserved.)

Objective: To compare the clinical phenotype of patients with chronic migraine (CM) to patients with new daily persistent headache of the chronic migraine subtype (NDPH-CM)., Methods: A study was conducted of CM (n = 257) and NDPH-CM (n = 76) from a tertiary headache center in the UK, and in the US of patients with daily CM (n = 60) and NDPH-CM (n = 22)., Results: From the UK cohort, the age of first headache onset was lower in CM (mean ± SD: 16 ± 12 years) than in NDPH-CM (mean ± SD: 23 ± 14 years; p < 0.001). There was a greater number of associated migrainous symptoms in CM compared to NDPH-CM (median and interquartile range: 6, 5-8 vs. 5, 4-7; p < 0.001). A family history of headache was more common in CM compared to NDPH-CM (82%, 202/248, vs. 53%, 31/59; p < 0.001). In the US cohort there were no differences. Osmophobia (B = -1.08; p = 0.002) and older age at presentation to the clinic (B = -0.06; p = 0.001) were negative predictors of NDPH-CM., Conclusion: NDPH-CM is relatively less migrainous than CM in the UK cohort. Family history of headache is less common in NDPH-CM, with negative predictors for NDPH-CM including osmophobia and older age of presentation to the clinic. More work is required to understand the chronic migraine phenotype of new daily persistent headache., (© 2022 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Purpose: To study the effect of intraocular pressure (IOP) on refractive outcomes after deep anterior lamellar keratoplasty (DALK)., Methods: This retrospective study included eyes which underwent DALK. DALK technique involved either modified Anwar big-bubble if possible or manual anterior lamellar dissection. Our main outcome measures are postoperative IOP and refractive outcomes at postoperative week and months 1, 3, 6, and 12., Results: Fifty-nine eyes of 59 patients were included. DALK was performed for optical (93.2%) and tectonic (6.8%) purposes. 76.3% of the patients had keratoconus. Anwar's big-bubble technique was successful in 30 cases. Linear mixed-model was used to analyze the effect of the highest postoperative IOP measured prior to measurement of postoperative cylinder. Patients with greater maximum postoperative IOP measured had worse postoperative cylinder ( P = 0.015) and spherical equivalent ( P = 0.012). Those with IOP more than 21 mmHg had worse postoperative cylinder ( P = 0.050) and spherical equivalent ( P = 0.054). The method of DALK and presence of suture removal were not shown to statistically affect postoperative cylinder., Conclusion: Our study shows a positive correlation between postoperative IOP and worse spherical equivalent and cylinder post-DALK, emphasizing the need for good IOP control with IOP-lowering medication(s)., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Current Ophthalmology.)

Precise control and accurate understanding of the ordering degree of bimetallic nanocatalysts (BNs) are challenging yet crucial to acquire advanced materials for the oxygen reduction reaction (ORR). AuCu BNs with various ordering degrees were synthesized to evaluate the influence of ordering degree on the ORR at a molecular level using in situ Raman spectroscopy. The activity of AuCu BNs was improved by over 2 times after a disorder-to-order transition, making the performance of highly ordered AuCu BNs exceed that of benchmark Pt/C. Direct Raman spectroscopic evidence of key intermediate (*OH) demonstrates that the active site is the combination site of Au and Cu. Moreover, two distinct *OH species are observed on the ordered and disordered structure, and the ordered site is more beneficial for ORR due to its lower affinity to *OH. This work deepens the understanding on the important role of ordering degree on BNs and enables the design of improved catalysts., (© 2022 Wiley-VCH GmbH.)

Inflammation plays an important role during sepsis, and excessive inflammation can result in organ damage, chronic inflammation, fibrosis, and scarring. The study aimed to investigate the specific mechanism of emodin by constructing in vivo and in vitro septic lung injury models via inhibition and reduction of NF-kB and high mobility group box 1 (HMGB1) pathways. A cecal ligation and puncture (CLP) model was built for adult male Sprague-Dawley rats. Concentrations of TNF-α, IL-1β, and IL-6 in bronchoalveolar lavage fluid were determined using commercially available ELISA kits. Hematoxylin and eosin staining was used for the right lung inferior lobes. Myeloperoxidase (MPO) activity of the lung tissue was detected by using the MPO kit. Murine alveolar epithelial cell line (MLE-12) cells were used for flow cytometry and Western blot to analyze the apoptosis rate and protein expression. Emodin significantly decreased CLP-induced cell apoptosis, upregulated expression of sirtuin 1 (SIRT1), and inhibited p-p65/p65 and HMGB1. In lipopolysaccharide (LPS) treated cell model, emodin treatment markedly decreased LPS-induced release of IL-1, IL-6, and tumor necrosis factor (TNF)-α, inhibited LPS-induced cell apoptosis and suppressed protein levels of P-P65/P65 and HMGB1. However, science of SIRT1 reversed the above effects by treatment of emodin. In summarize, this study found that emodin can alleviate sepsis-induced lung injury in vivo and in vitro through regulation of SIRT1., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Aim: To explore the effects of laser-activated remote phosphors (LARP) on visual function in guinea pigs., Methods: Electroretinogram (ERG) of guinea pigs were observed after LARP irradiation at different frequencies and irradiation times. We evaluated the expression of rhodopsin, β-catenin, connexin36, calretinin, and calbindin in the retina of guinea pigs and measured the density of photoreceptor cells after high-frequency LARP irradiation., Results: After LARP irradiation, the ERG results showed that the amplitude of the dark-adapted 3.0 b-wave of the model eye was lower than that of the control eye after high-frequency irradiation ( P <0.05). The expression of rhodopsin, β-catenin, connexin36, calretinin, and calbindin in the retina of guinea pig declined., Conclusion: There is frequency cumulative damage effect on the retina that relates to LARP illumination frequency. This has significance for staff visual protection policies under LARP lighting conditions., (International Journal of Ophthalmology Press.)

Background: Cluster headache is a rare, strictly unilateral, severe episodic primary headache disorder. Due to the unpredictable and episodic nature of the attacks, nitroglycerin has been used to trigger attacks for research purposes to further our understanding of cluster headache pathophysiology., Objectives: We aimed to identify regions of significant cerebral blood flow (CBF) changes during nitroglycerin triggered cluster headache attacks, using MRI with arterial spin labelling (ASL)., Methods: Thirty-three subjects aged 18-60 years with episodic and chronic cluster headache were recruited and attended an open clinical screening visit without scanning to receive an intravenous nitroglycerin infusion (0.5 μg/kg/min over 20 min). Those for whom nitroglycerin successfully triggered a cluster headache attack, were invited to attend two subsequent scanning visits. They received either single-blinded intravenous nitroglycerin (0.5 μg/kg/min) or an equivalent volume of single-blinded intravenous 0.9% sodium chloride over a 20-minute infusion. Whole-brain CBF maps were acquired using a 3 Tesla MRI scanner pre-infusion and post-infusion. As cluster headache is a rare condition and purely unilateral disorder, an analysis strategy to ensure all the image data corresponded to symptomatology in the same hemisphere, without losing coherence across the group, was adopted. This consisted of spatially normalising all CBF maps to a standard symmetric reference template before flipping the images about the anterior-posterior axis for those CBF maps of subjects who experienced their headache in the right hemisphere. This procedure has been employed in previous studies and generated a group data set with expected features on the left hemisphere only., Results: Twenty-two subjects successfully responded to the nitroglycerin infusion and experienced triggered cluster headache attacks. A total of 20 subjects completed the placebo scanning visit, 20 completed the nitroglycerin scanning visit, and 18 subjects had completed both the nitroglycerin and placebo scanning visits. In a whole-brain analysis, we identified regions of significantly elevated CBF in the medial frontal gyrus, superior frontal gyrus, inferior frontal gyrus and cingulate gyrus, ipsilateral to attack side, in CBF maps acquired during cluster headache attack; compared with data from the placebo session. We also identified significantly reduced CBF in the precuneus, cuneus, superior parietal lobe and occipital lobe contralateral to the attack side. Of particular interest to this field of investigation, both the hypothalamus and ipsilateral ventral pons showed higher CBF in a separate region of interest analysis., Conclusion: Our data demonstrate that severe cluster headache leads to significant increases in regional cerebral perfusion, likely to reflect changes in neuronal activity in several regions of the brain, including the hypothalamus and the ventral pons. These data contribute to our understanding of cluster headache pathophysiology; and suggest that non-invasive ASL technology may be valuable in future mechanistic studies of this debilitating condition., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The bioactive alkaloids identified from Cortex Phellodendri (CP) were highly effective in treating rats with benign prostatic hyperplasia (BPH). Specifically, lipoxygenase-5 (LOX-5) and cyclooxygenase-2 (COX-2) were identified as two primary targets for alleviating inflammation in BPH rats. However, it remains unknown whether the alkaloid components in CP can interact with the two target proteins., Purpose: To further identify bioactive alkaloids targeting LOX/COX pathways., Methods: An affinity-ultrafiltration mass spectrometry approach was employed to screen dual-target LOX-5/COX-2 ligands from alkaloid extract. The structures of bioactive alkaloids were characterized by high-resolution Fourier transform ion cyclotron resonance mass spectrometry. To understand the molecular mechanisms underlying the effects of bioactive alkaloids, the expression levels of LOX-5 and COX-2 in BPH model rats were investigated at both protein and mRNA levels. The LOX-5/COX-2 enzymes activity experiments and molecular docking analysis were performed to fully evaluate the interactions between bioactive alkaloids and LOX-5/COX-2., Results: After comprehensive analysis, the results showed that bioactive alkaloids could suppress the expression of LOX-5 and COX-2 simultaneously to exert an anti-inflammatory effect on the progression of BPH. In addition, the screened protoberberine, demethyleneberberine was found to exhibit prominent inhibitory activities against both LOX-5 and COX-2 enzymes, palmatine and berberine with moderate inhibitory activities. Molecular docking analysis confirmed that demethyleneberberine could interact well with LOX-5/COX-2., Conclusion: This study is the first to explore the inhibitory effects of bioactive alkaloids from CP on LOX-5 and COX-2 activities in BPH rats. Our findings demonstrate that the bioactive alkaloids from CP can ameliorate BPH via dual LOX-5/COX-2 pathways, which serves as an efficient approach for the discovery of novel drug leads from natural products with reduced side effects., (Copyright © 2021. Published by Elsevier GmbH.)

Abstract: In south China, traditional herbal medicines have been widely used as functional foods or dietary supplements for daily health care. Many plant-derived chemical substances with biological activity are inadvertently ingested by collegiate athletes daily through canton-style herbal tea or herbal slow-cooked soup. In the view of the complexity of herbal ingredients, it is still no full survey reported for the sports risk of plant-derived sports doping. This research is firstly a descriptive statistical analysis. Collegiate athletes with different socio-economic characteristics from medical colleges in 3 different regions in China participated in the questionnaire survey. Three survey forms, including the oral interview, email inquiry, handing out and recovering the questionnaires in live, were developed and performed by researchers. It was first found that collegiate athletes resorted to some traditional herbal materials to protect their health care that there were regional differences (P < .01). Collegiate athletes with Health Fitness and Traditional Wushu as their sports expertise showed a higher frequency of recognition or ingestion in the use of traditional herbal materials (P < .01), while their different living types and cuisine preferences did not seem to be associated with the ingestion frequency of traditional herbal materials. In addition, in the view of the significant differences in the use of herbal preparations to relieve sports stress among young athletes in different regions (P < .01), the findings strongly suggested that athletes should strictly control their use of various herbal preparations during sports training and competition, including herbal wines, herbal oils, topical plasters, analgesic tablets., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: To investigate therapeutic effects of traditional Chinese medicine formulations, Hexuemingmu (HXMM) on laser-induced choroidal neovascularization (CNV) and follow-up effect in mice., Methods: C57BL/6 mice of 8-week-old were used and CNV was induced with 577 nm laser photocoagulation. Animals were randomly divided into groups and different doses of HXMM were administered daily. One, four, and eight weeks after the intervention, the electroretinogram (ERG), fundus fluorescence angiography, choroidal flat mount and immunofluorescence staining were preformed to evaluate the function and CNV formation. The expression levels of angiogenic proteins were determined by Western blotting and immunofluorescence staining. An analysis of variance and Kruskal-Wallis test were used to test the differences among the groups., Results: The results showed that HXMM effectively increased amplitude of ERG of mice ( P <0.05), alleviated fundus CNV leakage ( P <0.05), and reduced the area of neovascularization and the expression of angiogenic proteins ( P <0.05) after laser-induced CNV., Conclusion: HXMM can protect the retinal function of mice after laser-induced CNV, and inhibit the CNV development., (International Journal of Ophthalmology Press.)

Understanding the fundamental insights of oxygen activation and reaction at metal-oxide interfaces is of significant importance yet remains a major challenge due to the difficulty in in situ characterization of active oxygen species. Herein, the activation and reaction of molecular oxygen during CO oxidation at platinum-ceria interfaces has been in situ explored using surface-enhanced Raman spectroscopy (SERS) via a borrowing strategy, and different active oxygen species and their evolution during CO oxidation at platinum-ceria interfaces have been directly observed. In situ Raman spectroscopic evidence with isotopic exchange experiments demonstrate that oxygen is efficiently dissociated to chemisorbed O on Pt and lattice Ce-O species simultaneously at interfacial Ce 3+ defect sites under CO oxidation, leading to a much higher activity at platinum-ceria interfaces compared to that at Pt alone. Further in situ time-resolved SERS studies and density functional theory simulations reveal a more efficient molecular pathway through the reaction between adsorbed CO and chemisorbed Pt-O species transferred from the interfaces. This work deepens the fundamental understandings on oxygen activation and CO oxidation at metal-oxide interfaces and offers a sensitive technique for the in situ characterization of oxygen species under working conditions.

Aim: To explore whether the retinal neovascularization (NV) in a genetic mutant mice model could be ameliorated in an inherited retinitis pigmentosa (RP) mouse, which would help to elucidate the possible mechanism and prevention of retinal NV diseases in clinic., Methods: The Vldlr -/- mice, the genetic mutant mouse model of retinal NV caused by the homozygous mutation of Vldlr gene, with the rd1 mice, the inherited RP mouse caused by homozygous mutation of Pde6b gene were bred. Intercrossing of the above two mice led to the birth of the F1 hybrids, further inbreeding of which gave birth to the F2 offspring. The ocular genotypes and phenotypes of the mice from all generations were examined, with the F2 offspring grouped according to the genotypes., Results: The rd1 mice exhibited the RP phenotype of outer retinal degeneration and loss of retinal function. The Vldlr -/- mice exhibited the phenotype of retinal NV obviously shown by the fundus fluorescein angiography. The F1 hydrides, with the heterozygote genotype, exhibited no phenotypes of RP or retinal NV. The F2 offspring with homozygous genotypes were grouped into four subgroups. They were the F2-I mice with the wild-type Pde6b and Vldlr genes ( Pde6b +/+ - Vldlr +/+ ), which had normal ocular phenotypes; the F2-II mice with homozygous mutant Vldlr gene ( Pde6b +/+ - Vldlr -/- ), which exhibited the retinal NV phenotype; the F2-III mice with homozygous mutant Pde6b gene ( Pde6b -/- - Vldlr +/+ ), which exhibited the RP phenotype. Specifically, the F2-IV mice with homozygous mutant Vldlr and Pde6b gene ( Pde6b -/- - Vldlr -/- ) showed only the RP phenotype, without the signs of retinal NV., Conclusion: The retinal NV can be inhibited by the RP phenotype, which implies the role of a hyperoxic state in treating retinal NV diseases., (International Journal of Ophthalmology Press.)

Background: Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way., Methods: A single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms., Results: Thirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects ( U  = 15, z = -2.399, p  = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit., Conclusion: Intravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.

Cluster headache is a debilitating primary headache disorder that affects approximately 0.1% of the population worldwide. Cluster headache attacks involve severe unilateral pain in the trigeminal distribution together with ipsilateral cranial autonomic features and a sense of agitation. Acute treatments are available and are effective in just over half of the patients. Until recently, preventive medications were borrowed from non-headache indications, so management of cluster headache is challenging. However, as our understanding of cluster headache pathophysiology has evolved on the basis of key bench and neuroimaging studies, crucial neuropeptides and brain structures have been identified as emerging treatment targets. In this Review, we provide an overview of what is known about the pathophysiology of cluster headache and discuss the existing treatment options and their mechanisms of action. Existing acute treatments include triptans and high-flow oxygen, interim treatment options include corticosteroids in oral form or for greater occipital nerve block, and preventive treatments include verapamil, lithium, melatonin and topiramate. We also consider emerging treatment options, including calcitonin gene-related peptide antibodies, non-invasive vagus nerve stimulation, sphenopalatine ganglion stimulation and somatostatin receptor agonists, discuss how evidence from trials of these emerging treatments provides insights into the pathophysiology of cluster headache and highlight areas for future research.

Background: Modulation of the arachidonic acid (AA) cascade via 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) represent the two major pathways for treatments of inflammation and pain. The design and development of inhibitors targeting both 5-LOX and COX-2 has gained increasing popularity. As evidenced, 5-LOX and COX-2 dual targeted inhibitors have recently emerged as the front runners of anti-inflammatory drugs with improved efficacy and reduced side effects. Natural products represent a rich resource for the discovery of dual targeted 5-LOX and COX-2 inhibitors. By combining affinity ultrafiltration and high-performance liquid chromatography-mass spectrometry (AUF-LC-MS), an efficient method was developed to identify spirostanol glycosides and furostanol glycosides as the 5-LOX/COX-2 dual inhibitors from saponins extract of Anemarrhenae Rhizoma (SEAR)., Methods: A highly efficient method by combining affinity ultrafiltration and high-performance liquid chromatography-mass spectrometry (AUF-LC-MS) was first developed to screen and characterize the 5-LOX/COX-2 dual targeted inhibitors from SEAR. The structures of compounds in the ultrafiltrate were characterized by high resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). In addition, in vitro 5-LOX/COX-2 inhibition assays and their dual expression in vivo were performed to confirm the inhibitory activities of the compounds screened by AUF-LC-MS. Molecular docking studies with the corresponding binding energy were obtained which fit nicely to both 5-LOX and COX-2 protein cavities and in agreement with our affinity studies., Results: A total of 5 compounds, timosaponin A-II, timosaponin A-III, timosaponin B-II, timosaponin B-III and anemarrhenasaponin I, were identified as potential 5-LOX/COX-2 dual targeted inhibitors with specific binding values > 1.5 and IC 50 ≤ 6.07 μM., Conclusion: The present work demonstrated that spirostanol glycoside and furostanol glycoside were identified as two novel classes of dual inhibitors of 5-LOX/COX-2 enzymes by employing a highly efficient screening method of AUF-LC-MS. These natural products represent a novel class of anti-inflammatory agents with the potential of improved efficacy and reduced side effects., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier GmbH.)

The spillover of hydrogen species and its role in tuning the activity and selectivity in catalytic hydrogenation have been investigated in situ using surface-enhanced Raman spectroscopy (SERS) with 10 nm spatial resolution through the precise fabrication of Au/TiO 2 /Pt sandwich nanostructures. In situ SERS study reveals that hydrogen species can efficiently spillover at Pt-TiO 2 -Au interfaces, and the ultimate spillover distance on TiO 2 is about 50 nm. Combining kinetic isotope experiments and density functional theory calculations, it is found that the hydrogen spillover proceeds via the water-assisted cleavage and formation of surface hydrogen-oxygen bond. More importantly, the selectivity in the hydrogenation of the nitro or isocyanide group is manipulated by controlling the hydrogen spillover. This work provides molecular insights to deepen the understanding of hydrogen activation and boosts the design of active and selective catalysts for hydrogenation., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: Peroxisome proliferator-activated receptor γ ( PPARγ ) plays a key role in glucose, which is a ligand-mediated transcription factor. The lipid homeostasis often serves as a pharmacological target for new drug discovery and development., Materials and Methods: In the research, we synthesized a series of piperine derivatives and then used a fluorescence polarization-based PPARγ ligand screening assay to evaluate the agonistic activity of PPARγ . Then, we cultured human normal hepatocytes, which were treated with 100μM compounds 2a, 2t or 3d . Then, the levels of PPARγ gene were determined so as to show whether the compounds could activate or inhibit the expression of PPARγ ., Results: A total of 30 piperine derivatives were synthesized and evaluated. Compound 2a was identified as a potential PPARγ agonist with IC 50 at 2.43 μM, which is 2 times more potent than the positive control rosiglitazone with IC 50 at 5.61μM. The human hepatocytes cells were cultured and treated with compounds 2a , 2t or 3d as described in the "Materials and Methods" section. We found that compounds 2a, 2t and 3d could activate PPARγ by 11.8, 1.9 and 7.0 times compared with the "blank", with compound 2a activation being the most significant. Molecular docking studies indicated that the piperine derivative 2a stably interacts with the amino acid residues of the PPARγ complex active site, which is consistent with the results of the in vitro PPARγ ligand screening assay., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Wang et al.)

Anther indehiscence is an important form of functional male sterility that can facilitate the production of hybrid seed; however, the molecular mechanisms of anther indehiscence-based male sterility have not been thoroughly explored in eggplant ( Solanum melongena L.). Here, we used two-dimensional gel electrophoresis to compare the protein profiles in the anthers of normally developing (F142) and anther indehiscent (S16) S. melongena plants. Four differentially expressed proteins were identified using matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry. Of these proteins, the transcript accumulation of the eggplant CORONATINE INSENSITIVE1 ( SmCOI1 ) was significantly downregulated in S16 relative to F142. Phylogenetic analysis showed that SmCOI1 has high amino acid sequence similarity and clustered into the same subgroup as its homologs in other members of the Solanaceae . Subcellular localization analysis showed that SmCOI1 localized to the nucleus. Moreover, reverse-transcription quantitative PCR revealed that the jasmonic acid pathway genes SmJAZ1 and SmOPR3 are upregulated in F142 relative to S16. Protein-protein interaction studies identified a direct interaction between SmCOI1 and SmOPR3, but SmCOI1 failed to interact with SmJAZ1. These findings shed light on the regulatory mechanisms of anther dehiscence in eggplant., (© 2020 The Japanese Society for Plant Cell and Molecular Biology.)

Introduction: Intermittent fasting (IF) has been suggested to have neuroprotective effects through the activation of multiple signaling pathways. Rodents fasted intermittently exhibit enhanced hippocampal neurogenesis and long-term potentiation (LTP) at hippocampal synapses compared with sedentary animals fed an ad libitum (AL) diet. However, the underlying mechanisms have not been studied. In this study, we evaluated the mechanistic gap in understanding IF-induced neurogenesis., Methods: We evaluated the impact of 3 months of IF (12, 16, and 24 hr of food deprivation on a daily basis) on hippocampal neurogenesis in C57BL/6NTac mice using immunoblot analysis., Results: Three-month IF significantly increased activation of the Notch signaling pathway (Notch 1, NICD1, and HES5), neurotrophic factor BDNF, and downstream cellular transcription factor, cAMP response element-binding protein (p-CREB). The expression of postsynaptic marker, PSD95, and neuronal stem cell marker, Nestin, was also increased in the hippocampus in response to 3-month IF., Conclusions: These findings suggest that IF may increase hippocampal neurogenesis involving the Notch 1 pathway., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Background: Migraine is a common disabling neurological disorder where attacks have been recognized to consist of more than headache. The premonitory, headache, and postdromal phases are the various phases of the migraine cycle, where aura can occur before, during, or after the onset of pain. Migraine is also associated with photosensitivity and cranial autonomic symptoms, which includes lacrimation, conjunctival injection, periorbital edema, ptosis, nasal congestion, and rhinorrhoea. This review will present the current understanding of migraine pathophysiology and the relationship to the observed symptoms., Evidence Acquisition: The literature was reviewed with specific focus on clinical, neurophysiological, functional imaging, and preclinical studies in migraine including the studies on the role of calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP)., Results: The phases of the migraine cycle have been delineated by several studies. The observations of clinical symptoms help develop hypotheses of the key structures involved and the biochemical and neuronal pathways through which the effects are mediated. Preclinical studies and functional imaging studies have provided evidence for the role of multiple cortical areas, the diencephalon, especially the hypothalamus, and certain brainstem nuclei in the modulation of nociceptive processing, symptoms of the premonitory phase, aura, and photophobia. CGRP and PACAP have been found to be involved in nociceptive modulation and through exploration of CGRP mechanisms, new successful treatments have been developed., Conclusions: Migraine is a complex neural disorder and is important to understand when seeing patients who present to neuro-ophthalmology, especially with the successful translation from preclinical and clinical research leading to successful advances in migraine management.

In the first part of our review, we extensively discuss the different variants of dietary restriction (DR) regimens, as well as its corresponding mechanism(s) and subsequent effects. We also provide a detailed analysis of the different epigenetic mechanisms based on current knowledge. We postulate that DR may represent an environmental intervention that can modulate the epigenomic profile of an individual. It is highly plausible that epigenetic regulation by DR may help explain the asymmetric manifestation of DR effects in different individuals. Additionally, epigenetic modifications via DR may lead to epigenetic programming, providing protection against age-associated diseases, which in turn could lead to reduced morbidity and increased lifespan. In the second part of the review, we summarize recent findings that highlight the epigenomic axis of DR, which provides a better understanding of the mechanisms by which its numerous health benefits are achieved., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cluster headache is a neurological disorder that presents with unilateral severe headache associated with ipsilateral cranial autonomic symptoms. Cluster headache attacks often occur more than once a day, and typically manifesting in bouts. It has a point prevalence of 1 in 1000 and is the most common trigeminal autonomic cephalalgia. This article aims to guide general neurologists to an accurate diagnosis and practical management options for cluster headache patients., Competing Interests: Competing interests: PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, and personal fees from Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc., Biohaven Pharmaceuticals Inc., Dr Reddy's Laboratories, Electrocore LLC, eNeura, Impel Neuropharma, MundiPharma, Novartis, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Filamentous bulking could commonly influence effluent water quality in sewage treatment plants. Existing technologies are slowly effective, time consuming, and poorly adaptable. For now, enhancing organics substrates (COD) and dissolved oxygen (DO) concentration, adding FeCl 3 into the reactor, and maintaining alternant aeration conditions are common methods to control filamentous bulking, but the effects of coupling techniques on the control of bulking are rarely reported. In this study, the filamentous bulking resulting from unintentionally erupted Candidatus Saccharibacteria was controlled by FeCl 3 coupled with biochemical methods, which transforming step-feed A/O processes to the SBR process in the emergency by increasing DO to (7.45±0.49) mg·L -1 during aeration, enhancing COD to (332.73±106.06) mg·L -1 , and adding FeCl 3 into the reactor to set the starting concentration to 120 mg·L -1 . As the results showed, FeCl 3 coupled with the biochemical method quickly counteracted the bulking sludge mainly composed of Candidatus Saccharibacteria caused by unknown reason, while the Sludge Volume Index dropped from 274 mL·g -1 to 56 mL·g -1 within 14 days. The relative abundance of Candidatus Saccharibacteria decreased from 97.64% to 32.67% at the genus level because FeCl 3 coupled with the biochemical method inhibited growth of Candidatus Saccharibacteria . Meanwhile, effluents of both COD and PO 4 3- -P met the effluent requirements of the I-A discharge standard in China and removal efficiency of NH 4 + -N increased from 65.33% to 74.65%. The results showed that FeCl 3 coupled with the biochemical method exhibited good performance in the control of bulking caused by unknown reasons.

Scope: Intermittent fasting (IF) has been extensively reported to promote improved energy homeostasis and metabolic switching. While IF may be a plausible strategy to ameliorate the epidemiological burden of disease in many societies, our understanding of the underlying molecular mechanisms behind such effects is still lacking. The present study has sought to investigate the relationship between IF and changes in gene expression. We focused on the liver, which is highly sensitive to metabolic changes due to energy status. Mice were randomly assigned to ad libitum feeding or IF for 16 hours per day or for 24 hours on alternate days for 3 months, after which genome-wide transcriptome analysis of the liver was performed using RNA sequencing. Our findings revealed that IF caused robust transcriptomic changes in the liver that led to a complex array of metabolic changes. We also observed that the IF regimen produced distinct profiles of transcriptomic changes, highlighting the significance of temporally different periods of energy restriction. Our results suggest that IF can regulate metabolism via transcriptomic mechanisms and provide insight into how genetic interactions within the liver might lead to the numerous metabolic benefits of IF., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

The SRC, Abelson murine leukemia viral oncogene homolog 1, TEC and C-terminal SRC Kinase families of non-receptor tyrosine kinases (collectively the Src module kinases) mediate an array of cellular signaling processes and are therapeutic targets in many disease states. Crystal structures of Src modules kinases provide valuable insights into the regulatory mechanisms that control activation and generate a framework from which drug discovery can advance. The conformational ensembles visited by these multidomain kinases in solution are also key features of the regulatory machinery controlling catalytic activity. Measurement of dynamic motions within kinases substantially augments information derived from crystal structures. In this review, we focus on a body of work that has transformed our understanding of non-receptor tyrosine kinase regulation from a static view to one that incorporates how fluctuations in conformational ensembles and dynamic motions influence activation status. Regulatory dynamic networks are often shared across and between kinase families while specific dynamic behavior distinguishes unique regulatory mechanisms for select kinases. Moreover, intrinsically dynamic regions of kinases likely play important regulatory roles that have only been partially explored. Since there is clear precedence that kinase inhibitors can exploit specific dynamic features, continued efforts to define conformational ensembles and dynamic allostery will be key to combating drug resistance and devising alternate treatments for kinase-associated diseases., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Orofacial pain may have a variety of causes and offers a significant clinical challenge for its diagnosis and management., Objective: To assess the headache disorders presenting in a tertiary multidisciplinary orofacial pain clinic, after dental causes have been excluded., Methods: Clinic letters from the initial consultation and subsequent follow up reviews of the 142 patients, who were seen in the tertiary Multidisciplinary Orofacial Pain clinic between January 2015 until January 2018 were reviewed as a clinical audit., Results: The most common diagnoses were possible trigeminal autonomic cephalalgia (n = 62, 44%), migraine (n = 38, 27%) and painful post-traumatic trigeminal neuropathy (n = 17, 12%). The most common trigeminal autonomic cephalalgia diagnosis was hemicrania continua (n = 13, 9%), which is higher than the reported prevalence in neurology and headache clinics., Conclusion: This study demonstrates the importance of a multidisciplinary approach to diagnosing complex orofacial pain patients and the importance of awareness of primary headache disorders, in particular trigeminal autonomic cephalalgias, thereby reducing unnecessary diagnostic delays or procedures.

Pueraria lobata is one of the most important medicinal herbs used traditionally in China. According to Shanghan Lun ( Treatise on Exogenous Febrile Disease ), it has been used traditionally to relieve body heat, eye soring, dry mouth, headache associated with high blood pressure, and stiff neck problems. Modern studies in the 1970s revealed that isoflavonoids extracted from P. lobata were the bioactive components of an herbal remedy namely Yufeng Ningxin Tablets for the treatment of patients after stroke. This article reviews recent application of P. lobota in the treatment of diabetics and in reducing alcohol drinking. In view of its low toxicity profile, P. lobota stands an excellent chance to be developed as a phytomedicine for treating human diseases., Competing Interests: Conflict of interest The authors declare no conflict of interest

Brassica juncea is an important vegetable and condiment crop widely grown in Asia, and the yield and quality of its product organs are affected by flowering time. AGAMOUS-LIKE18-1 (AGL18-1) belongs to a member of MADS-domain transcription factors, which play vital roles in flowering time control, but the biological role of AGL18-1 in B. juncea ( BjuAGL18-1 ) has not been thoroughly revealed in flowering regulatory network. In this study, BjuAGL18-1 expressed highly in inflorescence and flower, but slightly in root, stem and leaf. The sense and anti-sense transgenic lines of BjuAGL18-1 were generated and showed that BjuAGL18-1 functioned as a flowering inhibitor and depressed growth of lateral branching. During the vegetative phase, BjuAGL18-1 induced another flowering repressor AGAMOUS-LIKE15 ( BjuAGL15 ) but inhibited the flowering signal integrator of SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 ( BjuSOC1 ) in Brassica juncea . Whereas, during the flower developmental phase, both SOC1 and AGAMOUS-LIKE24 ( AGL24 ) were down-regulated by BjuAGL18-1 . By contrast, AGL15 was promoted by BjuAGL18-1 , while SHORT VEGETATIVE PHASE ( SVP ) was independent of BjuAGL18-1 . Additionally, HISTONE DEACETYLASE 9 ( HDA9 ) was highly induced by BjuAGL18-1 . These results will provide valuable information for clarifying the molecular mechanism of BjuAGL18-1 in mediating flowering time., (© 2018 The Japanese Society for Plant Cell and Molecular Biology.)

Despite extensive research, treatments for clinical stroke are still limited only to the administration of tissue plasminogen activator and the recent introduction of mechanical thrombectomy, which can be used in only a limited proportion of patients due to time constraints. A plethora of inflammatory events occur during stroke, arising in part due to the body's immune response to brain injury. Neuroinflammation contributes significantly to neuronal cell death and the development of functional impairment and death in stroke patients. Therefore, elucidating the molecular and cellular mechanisms underlying inflammatory damage following stroke injury will be essential for the development of useful therapies. Research findings increasingly point to the likelihood that epigenetic mechanisms play a role in the pathophysiology of stroke. Epigenetics involves the differential regulation of gene expression, including those involved in brain inflammation and remodelling after stroke. Hence, it is conceivable that epigenetic mechanisms may contribute to differential interindividual vulnerability and injury responses to cerebral ischaemia. In this review, we summarize recent findings on the emerging role of epigenetics in the regulation of neuroinflammation in stroke. We also discuss potential epigenetic targets that may be assessed for the development of stroke therapies., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Cluster headache is a primary headache disorder affecting up to 0.1% of the population. Patients suffer from cluster headache attacks lasting from 15 to 180 min up to 8 times a day. The attacks are characterized by the severe unilateral pain mainly in the first division of the trigeminal nerve, with associated prominent unilateral cranial autonomic symptoms and a sense of agitation and restlessness during the attacks. The male-to-female ratio is approximately 2.5:1. Experimental, clinical, and neuroimaging studies have advanced our understanding of the pathogenesis of cluster headache. The pathophysiology involves activation of the trigeminovascular complex and the trigeminal-autonomic reflex and accounts for the unilateral severe headache, the prominent ipsilateral cranial autonomic symptoms. In addition, the circadian and circannual rhythmicity unique to this condition is postulated to involve the hypothalamus and suprachiasmatic nucleus. Although the clinical features are distinct, it may be misdiagnosed, with patients often presenting to the otolaryngologist or dentist with symptoms. The prognosis of cluster headache remains difficult to predict. Patients with episodic cluster headache can shift to chronic cluster headache and vice versa. Longitudinally, cluster headache tends to remit with age with less frequent bouts and more prolonged periods of remission in between bouts., Competing Interests: Peter James Goadsby reports grants and personal fees from Allergan, Amgen, and Eli-Lilly and Company; personal fees from Akita Biomedical, Alder Biopharmaceuticals, Avanir Pharma, Cipla Ltd., Dr Reddy's Laboratories, eNeura, Electrocore LLC, Novartis, Pfizer Inc., Quest Diagnostics Scion, Teva Pharmaceuticals, Trigemina Inc., Scion; personal fees from MedicoLegal work, Journal Watch, Up-to-Date, Massachusetts Medical Society, Oxford University Press; and in addition, Dr. Goadsby has a patent Magnetic stimulation for headache assigned, without fee, to eNeura.

The term trigeminal autonomic cephalalgias (TACs) encompasses four primary headache disorders - cluster headache, paroxysmal hemicrania (PH), hemicrania continua (HC), short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)/short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). All of these except HC are characterized by short-lasting headaches. HC is characterized by a continuous unilateral headache that waxes and wanes in its intensity without complete resolution. It is included in the TACs group given the overlap in the activation of the posterior hypothalamic grey, and the shared clinical feature of unilateral head pain with ipsilateral cranial autonomic symptoms. The present review gives an overview of the nosologic evolution, diagnosis, and management of TACs., Competing Interests: P.J. Goadsby reports personal fees from Allergan, Amgen, and Eli-Lilly and Company; and personal fees from Akita Biomedical, Alder Biopharmaceuticals, Cipla Ltd, Dr. Reddy's Laboratories, eNeura, Electrocore LLC, Novartis, Pfizer Inc, Quest Diagnostics, Scion, Teva Pharmaceuticals, Trigemina Inc., Scion; and personal fees from MedicoLegal work, Journal Watch, Up-to-Date, Massachusetts Medical Society, Oxford University Press; and in addition, Dr. Goadsby has a patent Magnetic stimulation for headache assigned, without fee, to eNeura.

Trigeminal autonomic cephalalgia (TAC) encompasses 4 unique primary headache types: cluster headache, paroxysmal hemicrania, hemicrania continua, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms. They are grouped on the basis of their shared clinical features of unilateral headache of varying durations and ipsilateral cranial autonomic symptoms. The shared clinical features reflect the underlying activation of the trigeminal-autonomic reflex. The treatment for TACs has been limited and not specific to the underlying pathogenesis. There is a proportion of patients who are refractory or intolerant to the current standard medical treatment. From instrumental bench work research and neuroimaging studies, there are new therapeutic targets identified in TACs. Treatment has become more targeted and aimed towards the pathogenesis of the conditions. The therapeutic targets range from the macroscopic and structural level down to the molecular and receptor level. The structural targets for surgical and noninvasive neuromodulation include central neuromodulation targets: posterior hypothalamus and, high cervical nerves, and peripheral neuromodulation targets: occipital nerves, sphenopalatine ganglion, and vagus nerve. In this review, we will also discuss the neuropeptide and molecular targets, in particular, calcitonin gene-related peptide, somatostatin, transient receptor potential vanilloid-1 receptor, nitric oxide, melatonin, orexin, pituitary adenylate cyclase-activating polypeptide, and glutamate.

Migraine is a common and disabling neurological disorder, with a significant socioeconomic burden. Its pathophysiology involves abnormalities in complex neuronal networks, interacting at different levels of the central and peripheral nervous system, resulting in the constellation of symptoms characteristic of a migraine attack. Management of migraine is individualised and often necessitates the commencement of preventive medication. Recent advancements in the understanding of the neurobiology of migraine have begun to account for some parts of the symptomatology, which has led to the development of novel target-based therapies that may revolutionise how migraine is treated in the future. This review will explore recent advances in the understanding of migraine pathophysiology, and pharmacotherapeutic developments for migraine prevention, with particular emphasis on novel treatments targeted at the calcitonin gene-related peptide (CGRP) pathway.

Background: Single-pulse transcranial magnetic stimulation (sTMS) is an emerging neuromodulation method reported to be useful in migraine. Despite a low propensity for side effects, some concern with its use in patients with cardiac pacemakers has been expressed., Case: We present a patient with chronic migraine with a cardiac pacemaker, who had tried unsuccessfully several migraine preventives with either poor efficacy or tolerability. With involvement of the cardiology team, we tested the effect of sTMS on her pacemaker and found it to be a safe and effective option for her., Conclusion: Having regard to the risk/benefit ratio of sTMS, its use in patients with disabling migraine in the presence of a cardiac pacemaker can be carefully evaluated and may represent a useful therapeutic option., (© 2018 American Headache Society.)

Multi-protein complexes, termed "inflammasomes," are known to contribute to neuronal cell death and brain injury following ischemic stroke. Ischemic stroke increases the expression and activation of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) Pyrin domain containing 1 and 3 (NLRP1 and NLRP3) inflammasome proteins and both interleukin (IL)-1β and IL-18 in neurons. In this study, we provide evidence that activation of either the NF-κB and MAPK signaling pathways was partly responsible for inducing the expression and activation of NLRP1 and NLRP3 inflammasome proteins and that these effects can be attenuated using pharmacological inhibitors of these two pathways in neurons and brain tissue under in vitro and in vivo ischemic conditions, respectively. Moreover, these findings provided supporting evidence that treatment with intravenous immunoglobulin (IVIg) preparation can reduce activation of the NF-κB and MAPK signaling pathways resulting in decreased expression and activation of NLRP1 and NLRP3 inflammasomes, as well as increasing expression of anti-apoptotic proteins, Bcl-2 and Bcl-xL, in primary cortical neurons and/or cerebral tissue under in vitro and in vivo ischemic conditions. In summary, these results provide compelling evidence that both the NF-κB and MAPK signaling pathways play a pivotal role in regulating the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons and brain tissue under ischemic conditions. In addition, treatment with IVIg preparation decreased the activation of the NF-κB and MAPK signaling pathways, and thus attenuated the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons under ischemic conditions. Hence, these findings suggest that therapeutic interventions that target inflammasome activation in neurons may provide new opportunities in the future treatment of ischemic stroke.