Correction: Farnesyl pyrophosphate is a new danger signal inducing acute cell death.

[This corrects the article DOI: 10.1371/journal.pbio.3001134.].

Farnesyl pyrophosphate is a new danger signal inducing acute cell death.

Cell death is a vital event in life. Infections and injuries cause lytic cell death, which gives rise to danger signals that can further induce cell death, inflammation, and tissue damage. The mevalonate (MVA) pathway is an essential, highly conserved and dynamic metabolic pathway. Here, we discover that farnesyl pyrophosphate (FPP), a metabolic intermediate of the MVA pathway, functions as a newly identified danger signal to trigger acute cell death leading to neuron loss in stroke. Harboring both a hydrophobic 15-carbon isoprenyl chain and a heavily charged pyrophosphate head, FPP leads to acute cell death independent of its downstream metabolic pathways. Mechanistically, extracellular calcium influx and the cation channel transient receptor potential melastatin 2 (TRPM2) exhibit essential roles in FPP-induced cell death. FPP activates TRPM2 opening for ion influx. Furthermore, in terms of a mouse model constructing by middle cerebral artery occlusion (MCAO), FPP accumulates in the brain, which indicates the function of the FPP and TRPM2 danger signal axis in ischemic injury. Overall, our data have revealed a novel function of the MVA pathway intermediate metabolite FPP as a danger signal via transient receptor potential cation channels.

Development and evaluation of a program based on a generative pre-trained transformer model from a public natural language processing platform for efficiency enhancement in post-procedural quality control of esophageal endoscopic submucosal dissection.

BACKGROUND: Post-procedural quality control of endoscopic submucosal dissection (ESD) is emphasized in guidelines. However, this process can be tedious and time-consuming. Recently, a pre-training model called generative pre-trained transformer (GPT) on a public natural language processing platform has emerged and garnered significant attention, whose capabilities align well with the post-procedural quality control process and have the potential to streamline it. Therefore, we developed a simple program utilizing this platform and evaluated its performance. METHODS: Esophageal ESDs were retrospectively included. The manual quality control process was performed and act as reference standard. GPT's prompt was optimized through multiple iterations. A Python program was developed to automatically submit prompt with pathological report of each ESD procedure and collect quality control information provided by GPT. Its performance on quality control was evaluated with accuracy, precision, recall, and F-1 score. RESULTS: 165 cases were involved into the dataset, of which 5 were utilized as the prompt optimization dataset and 160 as the validation dataset. Definitive prompt was achieved through seven iterations. Time spent on the validation dataset by GPT was 13.47 ± 2.43 min. Accuracies of pathological diagnosis, invasion depth, horizontal margin, vertical margin, vascular invasion, and lymphatic invasion of the quality control program were (0.940, 0.952) (95% CI), (0.925, 0.945) (95% CI), 0.931, 1.0, and 1.0, respectively. Precisions were (0.965, 0.969) (95% CI), (0.934, 0.954) (95% CI), and 0.957 for pathological diagnosis, invasion depth, and horizontal margin, respectively. Recalls were (0.940, 0.952) (95% CI), (0.925, 0.945) (95% CI), and 0.931 for factors as mentioned, respectively. F1-score were (0.945, 0.957) (95% CI), (0.928, 0.948) (95% CI), and 0.941 for factors as mentioned, respectively. CONCLUSIONS: This quality control program was qualified of post-procedural quality control of esophageal ESDs. GPT can be easily applied to this quality control process and reduce workload of the endoscopists.

Migraine-like headache in subjects with isolated Lambl's excrescences: a case series and literature review.

AIM: Lambl's excrescences are mobile, thin, fibrinous connective tissue strands typically found on left-sided cardiac values. Migraine is positively associated with structural cardiac anomalies. However, it remains unclear whether Lambl's excrescences are associated with migraine. METHODS: Retrospective review of 182 inpatients with Lambl's excrescences confirmed by transesophageal echocardiogram in Chinese PLA General Hospital since January 2010. Among them, those with isolated Lambl's excrescences presented with migraine-like headache were included. We collected information on the demographics and clinical profiles of all participants, and performed follow-up visits. RESULTS: A total of 8 patients presented with migraine-like headache among 15 patients with isolated Lambl's excrescences. They included 2 men and 6 women, with an average age of 44.63 ± 12.24 years. Among these patients, 3 had visual aura, and 6 manifested infarct-like lesions on magnetic resonance imaging, of which 2 developed lesions after first visit. During follow-up, 4 patients suffering from intervention for Lambl's excrescences dramatically reduced headache recurrence compared to the other 4 patients only receiving migraine preventive medications. CONCLUSIONS: This study supports the hypothesis that microemboli from isolated Lambl's excrescences could cause migraine-like headache. And intervention for Lambl's excrescences may be crucial for preventing headache recurrence.

This study supports the hypothesis that microemboli from isolated Lambl's excrescences could cause migraine-like headache.The small sample size study fails to make management recommendations.

Unveiling the therapeutic potential of Dl-3-n-butylphthalide in NTG-induced migraine mouse: activating the Nrf2 pathway to alleviate oxidative stress and neuroinflammation.

BACKGROUND: Migraine stands as a prevalent primary headache disorder, with prior research highlighting the significant involvement of oxidative stress and inflammatory pathways in its pathogenesis and chronicity. Existing evidence indicates the capacity of Dl-3-n-butylphthalide (NBP) to mitigate oxidative stress and inflammation, thereby conferring neuroprotective benefits in many central nervous system diseases. However, the specific therapeutic implications of NBP in the context of migraine remain to be elucidated. METHODS: We established a C57BL/6 mouse model of chronic migraine (CM) using recurrent intraperitoneal injections of nitroglycerin (NTG, 10 mg/kg), and prophylactic treatment was simulated by administering NBP (30 mg/kg, 60 mg/kg, 120 mg/kg) by gavage prior to each NTG injection. Mechanical threshold was assessed using von Frey fibers, and photophobia and anxious behaviours were assessed using a light/dark box and elevated plus maze. Expression of c-Fos, calcitonin gene-related peptide (CGRP), Nucleus factor erythroid 2-related factor 2 (Nrf2) and related pathway proteins in the spinal trigeminal nucleus caudalis (SP5C) were detected by Western blotting (WB) or immunofluorescence (IF). The expression of IL-1ß, IL-6, TNF-α, Superoxide dismutase (SOD) and malondialdehyde (MDA) in SP5C and CGRP in plasma were detected by ELISA. A reactive oxygen species (ROS) probe was used to detect the expression of ROS in the SP5C. RESULTS: At the end of the modelling period, chronic migraine mice showed significantly reduced mechanical nociceptive thresholds, as well as photophobic and anxious behaviours. Pretreatment with NBP attenuated nociceptive sensitization, photophobia, and anxiety in the model mice, reduced expression levels of c-Fos and CGRP in the SP5C and activated Nrf2 and its downstream proteins HO-1 and NQO-1. By measuring the associated cytokines, we also found that NBP reduced levels of oxidative stress and inflammation. Most importantly, the therapeutic effect of NBP was significantly reduced after the administration of ML385 to inhibit Nrf2. CONCLUSIONS: Our data suggest that NBP may alleviate migraine by activating the Nrf2 pathway to reduce oxidative stress and inflammation in migraine mouse models, confirming that it may be a potential drug for the treatment of migraine.

The crucial role of locus coeruleus noradrenergic neurons in the interaction between acute sleep disturbance and headache.

BACKGROUND: Both epidemiological and clinical studies have indicated that headache and sleep disturbances share a complex relationship. Although headache and sleep share common neurophysiological and anatomical foundations, the mechanism underlying their interaction remains poorly understood. The structures of the diencephalon and brainstem, particularly the locus coeruleus (LC), are the primary sites where the sleep and headache pathways intersect. To better understand the intricate nature of the relationship between headache and sleep, our study focused on investigating the role and function of noradrenergic neurons in the LC during acute headache and acute sleep disturbance. METHOD: To explore the relationship between acute headache and acute sleep disturbance, we primarily employed nitroglycerin (NTG)-induced migraine-like headache and acute sleep deprivation (ASD) models. Initially, we conducted experiments to confirm that ASD enhances headache and that acute headache can lead to acute sleep disturbance. Subsequently, we examined the separate roles of the LC in sleep and headache. We observed the effects of drug-induced activation and inhibition and chemogenetic manipulation of LC noradrenergic neurons on ASD-induced headache facilitation and acute headache-related sleep disturbance. This approach enabled us to demonstrate the bidirectional function of LC noradrenergic neurons. RESULTS: Our findings indicate that ASD facilitated the development of NTG-induced migraine-like headache, while acute headache affected sleep quality. Furthermore, activating the LC reduced the headache threshold and increased sleep latency, whereas inhibiting the LC had the opposite effect. Additional investigations demonstrated that activating LC noradrenergic neurons further intensified pain facilitation from ASD, while inhibiting these neurons reduced this pain facilitation. Moreover, activating LC noradrenergic neurons exacerbated the impact of acute headache on sleep quality, while inhibiting them alleviated this influence. CONCLUSION: The LC serves as a significant anatomical and functional region in the interaction between acute sleep disturbance and acute headache. The involvement of LC noradrenergic neurons is pivotal in facilitating headache triggered by ASD and influencing the effects of headache on sleep quality.

Peptidase inhibitor (PI16) impairs bladder cancer metastasis by inhibiting NF-κB activation via disrupting multiple-site ubiquitination of NEMO.

BACKGROUND: Bladder cancer (BLCA) is a malignancy that frequently metastasizes and leads to poor patient prognosis. It is essential to understand the molecular mechanisms underlying the progression and metastasis of BLCA and identify potential biomarkers. METHODS: The expression of peptidase inhibitor 16 (PI16) was analysed using quantitative PCR, immunoblotting and immunohistochemistry assays. The functional roles of PI16 were evaluated using wound healing, transwell, and human umbilical vein endothelial cell tube formation assays, as well as in vivo tumour models. The effects of PI16 on nuclear factor κB (NF-κB) signalling activation were examined using luciferase reporter gene systems, immunoblotting and immunofluorescence assays. Co-immunoprecipitation was used to investigate the interaction of PI16 with annexin-A1 (ANXA1) and NEMO. RESULTS: PI16 expression was downregulated in bladder cancer tissues, and lower PI16 levels correlated with disease progression and poor survival in patients with BLCA. Overexpressing PI16 inhibited BLCA cell growth, motility, invasion and angiogenesis in vitro and in vivo, while silencing PI16 had the opposite effects. Mechanistically, PI16 inhibited the activation of the NF-κB pathway by interacting with ANXA1, which inhibited K63 and M1 ubiquitination of NEMO. CONCLUSIONS: These results indicate that PI16 functions as a tumour suppressor in BLCA by inhibiting tumour growth and metastasis. Additionally, PI16 may serve as a potential biomarker for metastatic BLCA.

RNAi-based silencing of proteasome 20S subunit alpha 2 affected the survival and development of Henosepilachna vigintioctopunctata.

Henosepilachna vigintioctopunctata is a notorious pest of solanaceous plants in Asia, which is mainly managed by chemical pesticides. RNA interference (RNAi) technique is considered to be a promising and effective alternative for pest control. In this study, we selected the proteasome 20S subunit alpha 2 (Prosα2) gene, a cellular protein involved in many proteins regulatory processes, to explore the RNAi efficiency in H. vigintioctopunctata. The obtained results confirmed the significant lethal effects of HvProsα2 silencing on the H. vigintioctopunctata 1st instar larvae at concentrations of 100, 50, and 5 ng/µL. Ingestion of the bacterially expressed dsHvProsα2 caused high mortality in both larvae and adults. Moreover, silencing of HvProsα2 resulted in feeding disorders, growth delay, and abnormal intestinal development of the larvae. Overall, HvProsα2 acts as an important regulator for the growth and development of H. vigintioctopunctata, and can serve as a candidate target gene for the RNAi-based control of H. vigintioctopunctata.

RNAi assays in the striped flea beetle (Phyllotreta striolata) suggest Psγ-COPI and PsArf1COPI as potential molecular targets for pest control.

Phyllotreta striolata (Fabricius), commonly known as the striped flea beetle (SFB), is a notorious insect pest that attacks Brassicaceae plants worldwide, leading to tremendous economic losses. RNA interference (RNAi) has been proposed as a promising strategy for sustainable and eco-friendly pest control. In this study, a total of nine housekeeping genes including PsVATPA, PsHSP90, PsEF1A, PsRPL6, PsRPS24, PsActin, PsTUBA, PsRPS18, and PsRPL4 were evaluated under four different conditions (organization, population, sex, and RNAi). PsEF1A and PsVATPA were identified as the best reference genes for RNAi bioassay. Furthermore, a total of 24 target genes were selected to investigate their RNAi effects in SFB adults with double-stranded RNAs (dsRNAs), five of them showed significant mortality (28.00% to 70.00%), namely Psα-COPI, Psß-COPI, PsRPS18, Psγ-COPI, and PsArf1COPI. We found that gene transcript levels of the two most lethal genes, Psγ-COPI and PsArf1COPI, were significantly decreased after treated with the target dsRNAs either by feeding or injection method. The findings from this study demonstrated that the introduction of dsRNAs via oral feedings or injection induces the RNAi-mediated silencing of target genes and can lead to insect mortality. Overall, the identified target genes can be explored in developing RNAi-based insecticides for SFB control.

Ovarian germ cell tumor/mastocytosis with KIT mutation: A unique clinicopathological entity.

Most tumors are sporadic and originated from somatic mutations. Some rare germline mutations cause familial tumors, often involving multiple tissues or organs. Tumors from somatic mosaicism during embryonic development are extremely rare. We describe here a pediatric patient who developed both an ovarian germ cell tumor and systemic mastocytosis. Targeted DNA next-generation sequencing analysis revealed similar genomic changes including the same KIT D816V mutation in both tissues, suggesting a common progenitor cancer cell. The KIT mutated cells are likely from early embryonic development during germ cell migration. A literature search found additional eight similar cases. These diseases are characterized by pediatric-onset, all-female, neoplastic proliferation in both gonad and bone marrow, and a common oncogenic cause, that is, KIT mutation, constituting a clinically and genetically homogenous disease entity. Importantly, the association of germ cell tumors with hematopoietic neoplasms suggests that the primordial germ cells are the primitive hematopoietic stem cells, a much-debated and unsettled question.

Proteomics profiling reveals mitochondrial damage in the thalamus in a mouse model of chronic migraine.

BACKGROUND: Migraine, a complex brain disorder, is regarded as a possible clinical manifestation of brain energy dysfunction. The trigeminovascular system is considered the basis for the pathogenesis of migraine, hence we depicted the proteomics profiling of key regions in this system, then focusing on protein alterations related to mitochondrial function. The aim of this study is to illustrate the role of mitochondria in migraine. METHODS: A mouse model of chronic migraine (CM) was established by repeated nitroglycerin (NTG) stimulation and evaluated by von-Frey filaments, a hot plate and a light-dark box. Differentially expressed proteins (DEPs) in some subcortical brain regions of the trigeminovascular system were screened through liquid chromatography-tandem mass spectrometry (LC‒MS/MS) to analyse the specificity of key signaling pathways in different brain regions. And then mitochondrial function, structure and dynamics were determined by qPCR, ELISA, and transmission electron microscope (TEM). Finally, the effect of mitochondrial intervention-Urolithin A (UA) on CM was investigated. RESULTS: Repeated NTG injection triggered photophobia, periorbital and hind paw allodynia in mice. The proteomics profiling of CM model showed that 529, 109, 163, 152 and 419 DEPs were identified in the thalamus, hypothalamus, periaqueductal grey (PAG), trigeminal ganglion (TG) and trigeminocervical complex (TCC), respectively. The most significant changes in the brain region-specific pathways pointed to thalamic mitochondrial impairment. NTG induced mitochondrial structural disruption, dysfunction and homeostatic dysregulation, which could be partially attenuated by UA intervention. CONCLUSION: Our findings highlight the involvement of mitochondrial damage in the thalamus in central sensitization of CM, which provides evidence of possible metabolic mechanisms in migraine pathophysiology.

Neuropeptide Y in the medial habenula alleviates migraine-like behaviors through the Y1 receptor.

BACKGROUND: Migraine is a highly disabling health burden with multiple symptoms; however, it remains undertreated because of an inadequate understanding of its neural mechanisms. Neuropeptide Y (NPY) has been demonstrated to be involved in the modulation of pain and emotion, and may play a role in migraine pathophysiology. Changes in NPY levels have been found in patients with migraine, but whether and how these changes contribute to migraine is unknown. Therefore, the purpose of this study was to investigate the role of NPY in migraine-like phenotypes. METHODS: Here, we used intraperitoneal injection of glyceryl trinitrate (GTN, 10 mg/kg) as a migraine mouse model, which was verified by light-aversive test, von Frey test, and elevated plus maze test. We then performed whole-brain imaging with NPY-GFP mice to explore the critical regions where NPY was changed by GTN treatment. Next, we microinjected NPY into the medial habenula (MHb), and further infused Y1 or Y2 receptor agonists into the MHb, respectively, to detect the effects of NPY in GTN-induced migraine-like behaviors. RESULTS: GTN effectively triggered allodynia, photophobia, and anxiety-like behaviors in mice. After that, we found a decreased level of GFP+ cells in the MHb of GTN-treated mice. Microinjection of NPY attenuated GTN-induced allodynia and anxiety without affecting photophobia. Furthermore, we found that activation of Y1-but not Y2-receptors attenuated GTN-induced allodynia and anxiety. CONCLUSIONS: Taken together, our data support that the NPY signaling in the MHb produces analgesic and anxiolytic effects through the Y1 receptor. These findings may provide new insights into novel therapeutic targets for the treatment of migraine.

SBSN drives bladder cancer metastasis via EGFR/SRC/STAT3 signalling.

BACKGROUND: Patients with metastatic bladder cancer have very poor prognosis and predictive biomarkers are urgently needed for early clinical detection and intervention. In this study, we evaluate the effect and mechanism of Suprabasin (SBSN) on bladder cancer metastasis. METHODS: A tissue array was used to detect SBSN expression by immunohistochemistry. A tumour-bearing mouse model was used for metastasis evaluation in vivo. Transwell and wound-healing assays were used for in vitro evaluation of migration and invasion. Comprehensive molecular screening was achieved by western blotting, immunofluorescence, luciferase reporter assay, and ELISA. RESULTS: SBSN was found markedly overexpressed in bladder cancer, and indicated poor prognosis of patients. SBSN promoted invasion and metastasis of bladder cancer cells both in vivo and in vitro. The secreted SBSN exhibited identical biological function and regulation in bladder cancer metastasis, and the interaction of secreted SBSN and EGFR could play an essential role in activating the signalling in which SBSN enhanced the phosphorylation of EGFR and SRC kinase, followed with phosphorylation and nuclear location of STAT3. CONCLUSIONS: Our findings highlight that SBSN, and secreted SBSN, promote bladder cancer metastasis through activation of EGFR/SRC/STAT3 pathway and identify SBSN as a potential diagnostic and therapeutic target for bladder cancer.

Extracellular vesicles from bone marrow stromal cells reduce the impact of stroke on glial cell activation and blood brain-barrier permeability via a putative miR-124/PRX1 signalling pathway.

Ischaemic stroke (IS) is a cerebrovascular disease caused by cerebral infarction and cerebral artery occlusion. In this study, we proposed that EVs from bone marrow stromal cells (BMSCs) could reduce the impact of stroke by reducing the resultant glial cell activation and blood-brain barrier (BBB) leak. We furthermore investigated some of the signalling mechanisms. The transient middle cerebral artery occlusion (t-MCAO) mouse model was established. The behavioural deficits and neuronal damage were verified using Bederson's scale and the 28-point neurological score. The area of cerebral infarction was detected. The expressions of astrocytes/microglia markers and BBB permeability were evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining. The internalization of EVs by astrocytes/microglia in the peripheral area was detected by fluorescence labelling. The expressions of astrocyte/microglia markers were measured by RT-qPCR. Levels of TNF-α and IL-1ß in microglia were detected by ELISA. BBB permeability was evaluated. The downstream target genes and pathway of miR-124 were analysed. Microglia/astrocytes were treated by oxygen-glucose deprivation reoxygenation (OGD/R). OGD/R microglia/astrocyte conditioned medium was used to culture bEnd.3 cells. The transendothelial electric resistance (TEER) of bEnd.3 cells was measured, and BBB permeability was characterized. Our results suggested that EVs from BMSCs can indeed reduce the extent of stroke-mediated damage and evidenced that these effects are mediated via expression of the non-coding RNA, miR-124 that may act via the peroxiredoxin 1 (PRX1). Our results provided further motivation to pursue the use of modified EVs as a treatment option for neurological diseases.

Predictive values of systemic inflammatory responses index in early neurological deterioration in patients with acute ischemic stroke.

BACKGROUND: Acute ischemic stroke (AIS) is the main cause of worldwide death and disability. Early neurological deterioration (END) can further increase the probability of death and disability in patients with ischemic stroke. Therefore, it is essential to find biomarkers to predict END early. Inflammatory response plays a crucial role in determining the course, outcome, and prognosis of END. Earlier studies focused on the relationship between routine hematological inflammatory markers and END, which limited the results. At present, relatively new and comprehensive markers of inflammatory response are relatively scarce. In this study, we investigate the predictive value of inflammatory markers in acute ischemic stroke cases for END which include systemic inflammatory response index (SIRI), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), neutrophil/lymphocyte ratio (NLR), and then to establish a nomogram model. METHODS: A total of 375 patients with AIS were analyzed who were admitted to the Second Affiliated Hospital of Harbin Medical University from September 2019 to June 2021. The associations between END and inflammatory markers were studied by employing the analysis of univariate. Following that, through regression models of the least absolute shrinkage and selection operator, the END risk model's feature selection was optimized. The development of the model of prediction was carried out by applying the multivariable logistic regression analysis. The calibration, discrimination, and clinical efficacy of the prediction model were studied via calibration plot, C-index, and decision curve analysis (DCA). The bootstrapping validation method was used for the evaluation of internal validation. RESULTS: We constructed a nomogram consisting of CRP, monocytes, NIHSS and SIRI. This model had desirable calibration and discrimination, with a C-index of 0.757 (95% confidence interval: 0.702-0.805). Interval validation could still achieve the higher C-index value of 0.747. When the risk threshold for END was greater than 13% but less than 84%, DCA proved to be clinically useful. CONCLUSIONS: Our research shows that SIRI can be used as a new predictor of END, as well as a monitor of treatment response. Compared with the traditional single inflammatory indicator, the integration of SIRI nomogram can predict the occurrence of END more objectively and reliably.

RNAi suppression of the nuclear receptor FTZ-F1 impaired ecdysis, pupation, and reproduction in the 28-spotted potato ladybeetle, Henosepilachna vigintioctopunctata.

Fushi-tarazu factor 1 (FTZF1) is an ecdysone-inducible transcription factor that plays a vital role during the metamorphosis in insects. In this study, we functionally characterized HvFTZ-F1 in H. vigintioctopunctata, a dreadful solanaceous crop pest, by using a dietary RNA interference technique. The HvFTZ-F1 expression levels were elevated in the 1st and 2nd-instars before molting and declined immediately after ecdysis. The HvFTZ-F1 silencing led to high mortality in the 1st instars, while the expression of the osmosis-regulative gene, HvAQPAn.G, was significantly increased in the 1st instars. HvFTZ-F1 silencing downregulated the Halloween and 20E-related genes, decreased the ecdysteroids titer, suppressed the expression of pigmentation-related genes, and reduced the catecholamines titer. In the 4th instars, HvFTZ-F1 silencing caused 100% mortality by arresting the development at the prepupal stage and preventing new abdominal cuticle formation. In the female adults, HvFTZ-F1 silencing caused an evident decrease in fecundity, prolonged the pre-oviposition period, reduced the number of eggs and hatching rate, severely atrophied the ovaries. Moreover, the 20E-related genes and the dopamine synthesis genes were suppressed in the dsHvFTZ-F1-treated females. Overall, our results revealed that HvFTZ-F1 regulates ecdysis, pupation, and reproduction in H. vigintioctopunctata, thereby could be a promising molecular target for the development of RNAi-based biopesticides to control H. vigintioctopunctata.

Repeated inflammatory dural stimulation-induced cephalic allodynia causes alteration of gut microbial composition in rats.

BACKGROUND: Gut microbial dysbiosis and gut-brain axis dysfunction have been implicated in the pathophysiology of migraine. However, it is unclear whether migraine-related cephalic allodynia could induce the alteration of gut microbial composition. METHODS: A classic migraine rat model was established by repeated dural infusions of inflammatory soup (IS). Periorbital mechanical threshold and nociception-related behaviors were used to evaluate IS-induced cephalic allodynia and the preventive effect of topiramate. The alterations in gut microbial composition and potential metabolic pathways were investigated based on the results of 16 S rRNA gene sequencing. Microbiota-related short-chain fatty acids and tryptophan metabolites were detected and quantified by mass spectrometry analysis. RESULTS: Repeated dural IS infusions induced cephalic allodynia (decreased mechanical threshold), migraine-like behaviors (increased immobility time and reduced moving distance), and microbial composition alteration, which were ameliorated by the treatment of topiramate. Decreased Lactobacillus was the most prominent biomarker genus in the IS-induced alteration of microbial composition. Additionally, IS infusions also enhanced metabolic pathways of the gut microbiota in butanoate, propanoate, and tryptophan, while the increased tryptophan-related metabolites indole-3-acetamide and tryptophol in feces could be the indicators. CONCLUSIONS: Inflammatory dural stimulation-induced cephalic allodynia causes the alterations of gut microbiota profile and microbial metabolic pathways.

LncRNA Snhg8 attenuates microglial inflammation response and blood-brain barrier damage in ischemic stroke through regulating miR-425-5p mediated SIRT1/NF-κB signaling.

Increasing studies have indicated that abnormal expressed long noncoding RNAs (lncRNAs) play a vital role in ischemic stroke. Small nucleolar RNA host gene 8 (Snhg8), a member of lncRNAs, has been found to induce neuronal apoptosis in chronic cerebral ischemia models. Here, we aim to explore the function and molecular mechanism of Snhg8 in modulating microglial inflammation as well as brain microvascular endothelial cell (BMEC) damage following ischemic injury. Our data suggested that Snhg8 was low-expressed in the brain tissues of mice that underwent middle cerebral artery occlusion (MCAO) surgery and oxygen-glucose deprivation (OGD)-treated primary microglia and BMECs. Gain- or loss-of function approaches found that Snhg8 upregulation not only attenuated ischemic induced inflammatory response in microglia but also relieved BMECs injury both in vitro and in vivo. Furthermore, we conducted a bioinformatics analysis to explore the underlying mechanism of Snhg8. The results indicated that Snhg8 served as a competitive endogenous RNA by sponging miR-425-5p, which was proved to promote microglial inflammation and BMECs injury by targeting sirtuin1 (SIRT1)-mediated nuclear factor-κB (NF-κB) pathway. Overall, these results revealed that the Snhg8/miR-425-5p/SIRT1/NF-κB axis plays a critical role in the regulation of cerebral ischemia-induced microglial inflammation and brain-blood barrier damage.

Toxicity of fluralaner against vegetable pests and its sublethal impact on a biocontrol predatory ladybeetle.

Fluralaner, a systemic pesticide, was originally registered with the US Food and Drug Administration in 2014 under the trade name Bravecto for flea treatment for pets. As a GABA antagonist, the footprint of fluralaner has expended beyond medical and veterinary pests in recent years. In this study, we examined the acute toxicity of fluralaner against three pests of Henosepilachna vigintioctopunctata, Megalurothrips usitatus, and Phyllotreta striolata in the Solanaceae, Fabaceae, and Cruciferae families, respectively, and the sublethal impact of fluralaner on Propylaea japonica, a widely distributed predatory ladybeetle. Based on LC50, fluralaner was effective against H. vigintioctopunctata (0.098 mg a.i. L-1 for the second instar larvae), M. usitatus (0.134 mg a.i. L-1 for adult females), and P. striolata (0.595 mg a.i. L-1 for adults). For P. japonica, however, fluralaner was substantially less effective (1.177 mg a.i. L-1 for the third instar larvae). Furthermore, the LC10 and LC30 of P. japonica were also consistently higher than the LC50 of the three pests. In addition, we did not observe any significant impacts of fluralaner at LC10 and LC30 on the life history traits, including body weight, developmental time, pre-oviposition period, and fecundity of P. japonica. Based on our results from acute toxicities and sublethal impacts, fluralaner is effective against vegetable pests, while potentially friendly to P. japonica when employed as a biological control agent.

A renal cell carcinoma with EWSR1-TFE3 fusion gene.

Both EWSR1 and TFE3 are well-known oncogenes. EWSR1 encodes an RNA-binding protein involved in multiple soft tissue tumors, including Ewing's sarcoma/peripheral neuroectodermal tumor, desmoplastic small round cell tumor, soft tissue clear cell sarcoma (malignant melanoma of soft parts), extraskeletal myxoid chondrosarcoma, and myxoid liposarcomas. TFE3 regulates both Golgi and lysosomal homeostasis and is rearranged in renal cell carcinoma (RCC), alveolar soft part sarcoma, epithelioid hemangioendothelioma, and perivascular epitheloid cell tumors (PEComas). In this report, we found a rare case of RCC with a fusion between 5' EWSR1 and 3' TFE3. The fusion product retained most functional motifs of TFE3. The oncogenic mechanism likely involves TFE3 overexpression through its juxtaposition with the regulatory elements of EWSR1 and its translocation to the nucleus, resulting in the deregulation of Golgi and lysosomal homeostasis. This is a second case of RCC containing EWSR1-TFE3 fusion.