Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury.

Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.

Selective Vulnerability of GABAergic Inhibitory Interneurons to Bilirubin Neurotoxicity in the Neonatal Brain.

Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here we report that bilirubin (BIL)-dependent cell death in auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel mediated current (Ih), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca2+-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, Ih and death, compromising audition at young adult stage in HCN1+/+, but not in HCN1-/- genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca2+ overload, neuronal death and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.Significance Statement This study demonstrated that bilirubin preferentially targets GABAergic interneurons where it facilitates not only gating of HCN1 channels but also targeting of intracellular HCN1 to plasma membrane in calcium-dependent manner, resulting in neuronal hyperexcitability, injury and sensory dysfunction. These findings implicate HCN1 channel not only as a potential driver for auditory abnormalities in neonatal patients with bilirubin encephalopathy, but also potential intervention target for clinical management of neurological impairments associated with severe jaundice. Selective vulnerability of interneurons to neurotoxicity may be of general significance for understanding other forms of brain injury.

Isolation of a Novel QTL, qSCM4, Associated with Strong Culm Affects Lodging Resistance and Panicle Branch Number in Rice.

Rice breeders are now developing new varieties with semi-high or even high plant height to further increase the grain yield, and the problem of lodging has re-appeared. We identified a major quantitative trait locus (QTL), qSCM4, for resistance to lodging by using an F2 segregant population and a recombinant self-incompatible line population from the cross between Shennong265 (SN265) and Lijiangxintuanheigu (LTH) after multiple years and multiple environments. Then, the residual heterozygous derived segregant population which consisted of 1781 individual plants, and the BC3F2 segregant population which consisted of 3216 individual plants, were used to shorten the physical interval of qSCM4 to 58.5 kb including 11 genes. DNA sequencing revealed the most likely candidate gene for qSCM4 was Os04g0615000, which encoded a functional protein with structural domains of serine and cysteine. There were 13 DNA sequence changes in LTH compared to SN265 in this gene, including a fragment deletion, two base changes in the 3' UTR region, six base changes in the exons, and four base changes in the introns. A near-isogenic line carrying qSCM4 showed that it improved the lodging resistance through increasing stem thickness by 25.3% and increasing stem folding resistance by 20.3%. Furthermore, it was also discovered that qSCM4 enhanced the primary branch per panicle by 16.7%, secondary branch by per panicle 9.9%, and grain number per panicle by 14.7%. All the above results will give us a valuable genetic resource for concurrently boosting culm strength and lodging resistance, and they will also provide a basis for further research on the lodging resistance mechanism of rice.

Simultaneous partial nitrification, denitrification, and phosphorus removal in sequencing batch reactors via controlled reduced aeration and short-term sludge retention time decrease.

Simultaneous bio-treatment processes of organic carbon (C)-, nitrogen (N)-, and phosphorus (P)-containing wastewater are challenged by insufficient carbon sources in the effluent. In the present study, two parallel anaerobic/aerobic sequencing batch reactors (R-1 and R-2) treating low C/N (≤4) wastewater were employed using different partial nitrification start-up strategies, controlled reduced aeration, and decreased sludge retention time. Advanced removal efficiencies for NH4+-N (≥96%), total nitrogen (TN, ≥86%), PO43--P (≥95%), and CODintra (≥91%) were realized, with TN and PO43--P effluent concentrations of 10.0 ± 3.5 and 0.11 ± 0.3 mg/L in R-1 and 9.28 ± 4.0 and 0.11 ± 0.1 mg/L in R-2, respectively. Higher nitrite accumulation rate (nearly 100%) and TN (121.1 ± 0.7 mg TN/g VSS·d) and P (12.5 ± 0.6 mg PO43--P/g VSS·d) removal loadings were obtained in R-2 by a thorough elimination of nitrite-oxidizing bacteria. Moreover, different microbial structures and nutrient removal pathways were identified. Denitrifying glycogen-accumulating organisms (Candidatus Competibacter) and phosphorus-accumulating organisms (PAOs) (Tetrasphaera) removed N and P with partial nitrification-endogenous denitrification pathways and aerobic P removal in R-1. In R-2, aerobic denitrifying bacteria (Psychrobacter) and PAOs ensured N and P removal through the partial nitrification-aerobic denitrification and aerobic P removal pathways. Compared to R-1, R-2 offers greater efficiency, convenience, and scope to further reduce carbon-source demand.

Association between the circulating superoxide dismutase and obstructive sleep apnea: a meta-analysis.

PURPOSE: Although it has been reported that superoxide dismutase (SOD) is related to obstructive sleep apnea (OSA), the results are controversial. In addition, the effects of the continuous positive airway pressure (CPAP) treatment on SOD levels are also inconsistent. The primary purpose of the present meta-analysis is to determine the relationship between the circulating SOD levels and OSA. METHODS: The studies included in this meta-analysis were selected from the PubMed, Embase, Cochrane Library, and Scopus databases. Two researchers independently reviewed the studies. Data analysis was performed using Stata 15.1. The overall effects were measured using the standardized mean difference (SMD) with a 95% confidence interval (CI). A random-effects model or a fixed-effects model was used, depending on the heterogeneity of the studies. RESULTS: A total of 14 studies were included, comprising 1240 patients and 457 controls. The results showed that the circulating SOD levels of the patients with OSA were significantly lower than that of the control group (SMD = - 1.645, 95% CI = - 2.279 to - 1.011, P < 0.001). We also studied changes in the circulating SOD levels in patients with OSA after the CPAP treatment. No significant difference was observed in the circulating SOD levels after the CPAP treatment (SMD = - 0.028, 95% CI = - 0.218 to 0.162, P = 0.772). CONCLUSION: The results suggested that patients with OSA have reduced levels of SOD and were related to disease severity. The results also indicated that circulating SOD levels may be a reliable marker for detecting systemic oxidative stress in patients with OSA. However, the circulating SOD levels were not affected by the short-term (4-12 weeks) CPAP treatment. Therefore, further large-scale, well-designed randomized controlled trials with a longer CPAP therapy (more than 6 months preferably) and good adherence to the treatment are needed to investigate this issue.

Effects of Continuous Positive Airway Pressure on Cell Adhesion Molecules in Patients with Obstructive Sleep Apnea: A Meta-Analysis.

PURPOSE: Previous studies have confirmed that patients with obstructive sleep apnea (OSA) have higher systemic inflammatory markers, including intercellular adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1(VCAM-1), and E-selectin compared to control subjects. However, the effects of continuous positive airway pressure (CPAP) therapy on circulating levels of ICAM-1, VCAM-1, and E-selectin in OSA patients remain inconsistent. Therefore, the primary purpose of the present meta-analysis is to estimate the effect of CPAP therapy on these cell adhesion molecules (CAMs) in patients with OSA. METHODS: The PubMed, Scopus, Embase, and Cochrane Library databases were searched. The overall effects were measured by the standardized mean difference (SMD) with a 95% confidence interval (CI). A random effects model or a fixed-effects model was used, depending on the heterogeneity of the studies. RESULTS: A total of 11 studies were included, comprising 650 OSA patients. The pooled results showed that CPAP therapy significantly decreased ICAM-1 (SMD = - 0.283, 95% CI - 0.464 to - 0.101, p = 0.002) and E-selectin levels (SMD = - 0.349, 95% CI - 0.566 to - 0.133, p = 0.002). In contrast, there was no significant improvement of VCAM-1 levels after CPAP treatment (SMD = - 0.160, 95% CI - 0.641 to 0.320, p = 0.513). CONCLUSIONS: Our meta-analysis demonstrated that CPAP treatment significantly decreased the circulating levels of ICAM-1 and E-selectin in OSA patients. Thus, ICAM-1 and E-selectin may be effective markers to evaluate CPAP therapy for reducing OSA cardiovascular risk in clinical practice.

Evidence for role of acid-sensing ion channel 1a in chronic rhinosinusitis with nasal polyps.

PURPOSE: A variety of inflammatory cells are infiltrated histologically in sinonasal mucosa of chronic rhinosinusitis with nasal polyps (CRSwNP), especially CRSwNP with asthma. Acid-sensing ion channel 1a (ASIC1a) is essential in the process of sensing acidification and triggering inflammation. Whereas, its role and mechanism in CRSwNP remain uncertain. The present study aimed to explore the roles and mechanism of ASIC1a in the pathogenesis of CRSwNP. METHODS: Nasal secretions from control subjects, patients with CRSwNP with or without asthma were collected for measuring pH values. Western blotting, real-time PCR and immunohistochemistry (IHC) were employed to assess ASIC1a expression in nasal tissue samples from included subjects. The co-localization of ASIC1a with inflammatory cells was evaluated by immunofluorescence staining. Then, dispersed nasal polyp cells (DNPCs) were cultured under acidified condition (pH 6.0), with or without ASIC1a inhibitor amiloride. Western blotting, real-time PCR, LDH activity kit, and ELISA were performed to assess the effects and mechanisms of stimulators on the cells. RESULTS: The pH values were significantly lower in the nasal secretions from patients with CRSwNP with asthma. Significant upregulation of ASIC1a protein, mRNA levels, and positive cells was found in CRSwNP with asthma. ASIC1a was detected in a variety of inflammatory cells. In cultured DNPCs, significant alterations of ASIC1a levels, LDH activity, HIF-1α levels, and inflammatory cytokines were found under acidified condition (pH 6.0), but were prevented by amiloride. CONCLUSION: Upregulation of ASIC1a might be essential in the process of sensing acidification and triggering inflammatory response via enhancing HIF-1α expression and LDH activity to activate inflammatory cells in the pathogenesis of CRSwNP, especially in CRSwNP with asthma.

Delayed Diagnosis and Treatment of Cerebrospinal Fluid Leakage in Current Practice.

As delayed diagnosis and treatment of cerebrospinal fluid (CSF) leakage are common in current practice, this study was performed to determine associated factors and discuss appropriate strategies to deal with these problems. A retrospective analysis of all cases of CSF leakage in our hospital from 2007 to 2018, including 41 patients with CSF rhinorrhea and 5 with CSF otorhinorrhea, was performed. Symptoms, associated diseases, misdiagnoses, history of skull base repair surgical, previous medical costs, and number of hospital visits before visiting our institution were reviewed. The diagnoses, surgical reconstruction methods, and prognoses of the patients were analyzed. In 18 patients, CSF leakage was spontaneous, in 14 the cause was trauma, and in the remaining 14 the origin was iatrogenic. Twelve patients had been misdiagnosed with allergic rhinitis, rhinosinusitis, or otitis media. Twelve cases had intracranial infection and 14 suffered airway infection. Six had undergone unsuccessful craniotomy, endonasal endoscopic surgery, or ear surgery for treatment of CSF leakage before visiting our institute. This resulted in an average of 5.13 ±â€Š1.32 referrals and medical costs of up to 20,795.7 ±â€Š4553.80 RMB. The success rate was 97.83% after repairing CSF fistulae in our hospital. The septal floor flap (SFF) method (based on ethmoidal arteries) to treat CSF rhinorrhea showed a success rate of 100% in 12 patients. Therefore, early localization, clinical diagnosis, and appropriate repair surgery can avoid the occurrence of delayed events. Pedicled flaps, including SFF, are recommended to manage challenging CSF rhinorrhea.

Tanshinone IIA alleviates lipopolysaccharide-induced acute lung injury by downregulating TRPM7 and pro-inflammatory factors.

The study aimed to investigate the role of Tanshinone IIA (Tan IIA) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in its regulation of TRPM7. Wistar male rats were randomly divided into the normal saline (NS), LPS, knockout (KO) + LPS, low-dose Tan IIA (Tan-L), middle-dose Tan IIA (Tan-M), high-dose Tan IIA (Tan-H) and KO + high-dose Tan IIA (KO + Tan-H) groups. The level of tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, TRPM7 protein expression, current density-voltage curve and Ca2+ concentration were detected through ELISA, Western blotting, electrophysiological experiment and a calcium-imaging technique, respectively. The rats in the KO + LPS, Tan-L, Tan-M, Tan-H and KO + Tan-H groups all displayed lower levels of TNF-α, IL-1ß and IL-6 than the LPS group. Rats in the KO + Tan-H group exhibited lower levels of NF-α, IL-1ß and IL-6 than rats in the Tan-H group. Elevated levels of TRPM7 protein expression in the LPS and Tan groups were detected in comparison with the NS group. However, TRPM7 protein expression in Tan-M and Tan-H groups was notably lower than in that of the LPS group. In comparison with the NS group, the LPS and Tan groups had a greater PIMs cell density and a higher concentration of Ca2+ . Contrary results were observed in the KO + LPS, Tan-H and KO + Tan-H groups. Tan IIA decreases calcium influx in PIMs and inhibits pro-inflammatory factors which provide an alleviatory effect in regards to LPS-induced ALI by suppressing TRPM7 expression.

Photodegradation of Moxifloxacin Hydrochloride Solutions under Visible Light Irradiation: Identification of Products and the Effect of pH on their Formation.

The photodegradation study is essential for the phototoxicity assessment of fluoroquinolones. Various LC-MS techniques and ultraviolet (UV) lamp irradiation conditions have been used for the identification of their photodegradation products. In this study, visible light (400-760 nm) lamp irradiation was selected for the photodegradation of moxifloxacin (MOXI) hydrochloride solutions. Two photodegradation products were identified by LC-MS/MS at first, but one product could not be speculated from the mass spectrum and any known degradation mechanisms. To obtain an adequate amount for the structure elucidation, this unknown product was isolated by recrystallization and semi-preparative HPLC. Then, its structure was further identified by 1H-NMR, 13C-NMR, and 2D-NMR. Based on spectral data, this new photodegradation product was unambiguously named as 7-[3-(3-aminopropyl)-1H-pyrrol-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which was formed through the open of hexahydroxy N-containing heterocycle and the formation of two alkene bonds in pyrrole ring. The effects of solution pH value on the formation of photodegradation products were compared. Their production was minimum at pH 5.0 and maximum at pH 7.0. Because MOXI hydrochloride has been used extensively in clinical practice and visible light is the most possible light source that pharmaceutical products are exposed to, our study is important for the quality control of MOXI liquid preparations.

Comparison of Pathogen Eradication Rate and Safety of Anti-Bacterial Agents for Bronchitis: A Network Meta-Analysis.

A large number of population in both developing and developed countries are affected by bronchitis, among all the factors, bacterial infection was considered as a critical cause of acute exacerbations of chronic bronchitis. Although several anti-bacterial agents were proved to have the effect of alleviating bronchitis, their relative efficacies and potential side effects remained not clear. We are keen to compare the pathogen eradication rate and safety of anti-bacterial agents for bronchitis. Relevant studies were searched in multiple sources and data were extracted from eligible studies. Then conventional meta-analysis and network meta-analysis (NMA) were conducted to determine the relative efficacy and safety of bronchitis medications. The efficacy of bronchitis medications was determined by using the outcome of pathogen eradication, including total pathogen eradication, pathogen eradication of Haemophilus influenzae, pathogen eradication of Moraxella catarrhalis, and pathogen eradication of Streptococcus pneumoniae. In addition, safety was assessed by using the outcome of adverse effects and diarrhoea. A 27 RCTs with 9,414 participants were included in the study. Among the medications, gatifloxacin and moxifloxacin exhibited better performance than clarithromycin with respect to pathogen eradication of H. influenzae (OR = 21.37, CI: 1.22-541.28; OR = 7.43, CI: 1.79-30.50). Clarithromycin, gemifloxacin, levofloxacin, moxifloxacin, and telithromycin appeared to be more preferable than amoxicillin + clavulanate and azithromycin with respect to diarrhoea (all OR <1). The surface under the cumulative ranking curve (SUCRA) results suggested that gemifloxacin and levofloxacin had a relatively high ranking in total pathogen eradication, whereas amoxicillin + clavulanate and azithromycin exhibited relatively lower ranking with respect to adverse effects and diarrhoea. Gemifloxacin and levofloxacin are more preferable than others for lowering respiratory tract inflammation and infections considering their balanced performance between pathogen eradication and adverse effects. J. Cell. Biochem. 118: 3171-3183, 2017. © 2017 Wiley Periodicals, Inc.

Network meta-analysis of migraine disorder treatment by NSAIDs and triptans.

BACKGROUND: Migraine is a neurological disorder resulting in large socioeconomic burden. This network meta-analysis (NMA) is designed to compare the relative efficacy and tolerability of non-steroidal anti-inflammatory agents (NSAIDs) and triptans. METHODS: We conducted systematic searches in database PubMed and Embase. Treatment effectiveness was compared by synthesizing direct and indirect evidences using NMA. The surface under curve ranking area (SUCRA) was created to rank those interventions. RESULTS: Eletriptan and rizatriptan are superior to sumatriptan, zolmitriptan, almotriptan, ibuprofen and aspirin with respect to pain-relief. When analyzing 2 h-nausea-absence, rizatriptan has a better efficacy than sumatriptan, while other treatments indicate no distinctive difference compared with placebo. Furthermore, sumatriptan demonstrates a higher incidence of all-adverse-event compared with diclofenac-potassium, ibuprofen and almotriptan. CONCLUSION: This study suggests that eletriptan may be the most suitable therapy for migraine from a comprehensive point of view. In the meantime ibuprofen may also be a good choice for its excellent tolerability. Multi-component medication also attracts attention and may be a promising avenue for the next generation of migraine treatment.

New insights on the role of the insular cortex and habenula in OSA.

PURPOSE: Abnormal structure or function in the central nervous system (CNS) can also affect obstructive sleep apnea (OSA). Because human afferent and motor pathways that regulate apnea are still poorly understood, it is not possible to modify the behavior of motor neurons to control airway function. The purpose of this article is to clear the central control mechanism of genioglossus (GG) and to discuss how altered activity in the limbic system and its related structures might affect OSA development, in order to provide help for the treatment of this disease. METHODS: Functional magnetic resonance imaging (fMRI) data from previous studies on OSA-related brain damage in human beings plus the data from clinical and animal experiments are summarized. These articles are overviewed to discuss the roles of the limbic system-the insular cortex (Ic), the habenula (Hb), and CNS-in the pathogenesis and mechanisms of OSA. RESULTS: The Ic, which relays signals through the Hb, may play a role in OSA because activating the Ic causes the Hb to suppress activity of the raphe nucleus (RN), resulting in lower levels of 5-hydroxytryptamine (5-HT) that decreases the muscle tone of the GG. This leads to airway collapse. CONCLUSIONS: The Ic may be an important region in the development of OSA. Altered activity in the limbic system and its related structures could also be associated with OSA.

The lateral habenular nucleus mediates signal transduction from the insular cortex in OSA rats.

PURPOSE: The insular cortex (Ic) and habenular nuclei (Hb) of the limbic system are associated with human and animal dyspnea by regulating 5-hydroxytryptamine (5-HT) release in the raphe nuclei (RN). However, the Hb are composed of the medial habenular nucleus (MHb) and the lateral habenular nucleus (LHb). Therefore, it is still unclear whether the Ic signal is conducted through the MHb or LHb. This study aimed to investigate the role of the Hb and Ic in obstructive sleep apnea syndrome (OSA) and the functional relationship between these two structures. METHODS: We monitored multiple indicators, including the respiration movement curve, neuronal activity in the MHb and LHb, and arterial blood gas, when stimulating the anterior Ic of Wistar rats. We compared the results with the control group (stimulating the surrounding cortex). RESULTS: Electrical stimulation of the Ic in the rat brain caused respiratory disturbances, apnea, reduced blood pH, and aggravated base deficit (more negative base excess value) compared to control animals (p < 0.05). It also reduced the spontaneous firing of the MHb neurons but increased that of the LHb neurons. Electrical stimulation of the Ic induces apnea in rats in a similar manner to human OSA. The Ic and the Hb are functionally linked. Stimulation of the Ic inhibits the MHb, but activates the LHb. It induces OSA-like symptoms by enhancing LHb-mediated inhibition of the RN. CONCLUSIONS: This study illustrates the mechanism by which an animal model of OSA is created by stimulating the Ic and promotes understanding of OSA pathogenesis.

The efficacy and safety of immune-checkpoint inhibitors plus chemotherapy versus chemotherapy for non-small cell lung cancer: An updated systematic review and meta-analysis.

BACKGROUND: Immune-checkpoint inhibitors(ICIs) combined with chemotherapy are emerging as an effective first-line treatment in advanced non-small cell lung cancer (NSCLC); however, reports on the magnitude of effectiveness and safety are conflicting. METHODS: Relevant articles published before February 2022 were searched in PubMed, Embase, and the Cochrane Library. The study included all randomized controlled trials that evaluated ICIs with chemotherapy versus chemotherapy for the treatment of NSCLC. Among the outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs). RESULTS: Our meta-analysis included a total of 12 studies. Overall analysis indicated that ICIs plus chemotherapy could significantly improve OS (HR = 0.79; 95% CI: 0.74-0.84; I2 = 44.4%, P = 0.055), PFS (HR = 0.62; 95% CI: 0.59-0.67; I2 = 75.3%, P = 0.000), and ORR (RR = 1.48; 95% CI: 1.27-1.73; I2 = 79.0%, P = 0.000) when compared to chemotherapy treatments. Subgroup analysis showed that PD-1/PD-L1 inhibitors combined with chemotherapy significantly improved OS, PFS, and ORR when compared with chemotherapy with decreased grade 1-2 TRAEs. In addition, female patients with nonsquamous histology might receive more OS benefit from ICIs plus chemotherapy when compared to chemotherapy alone. Despite the fact that CTLA-4 inhibitors combined with chemotherapy increased PFS, there were no benefits gained in OS nor ORR. When PD-L1/CTLA-4 inhibitors were added to chemotherapy, the risk of grade 3-5 adverse events increased whereas PD-1 inhibitors did not. CONCLUSIONS: ICIs plus chemotherapy, compared with chemotherapy, were associated with significantly improved PFS, ORR, and OS in NSCLC therapy. However, PD-L1/CTLA-4 inhibitors plus chemotherapy could increase the risk of grade 3-5 adverse events, but not PD-1 inhibitors plus chemotherapy.

Coupling coordination and spatiotemporal dynamic evolution of the water-energy-food-land (WEFL) nexus in the Yangtze River Economic Belt, China.

The interrelationship between regional water, energy, food, and land systems is extremely complex. Hence, accurately assessing the coupling coordination relationship and identifying the influential factors of the water-energy-food-land nexus (WEFL nexus) are of utmost importance. This study proposes a novel analytical framework and evaluation index system for exploring interactions across the WEFL nexus. The comprehensive benefit evaluation index (CBEI), coupling coordination degree (CCD) model, and obstacle factor diagnosis model are integrated to assess and analyze the coupling coordination relationship and spatiotemporal dynamic evolution of the WEFL nexus in the Yangtze River Economic Belt (YREB) from 2006 to 2020. The results indicated that (1) the CBEI and CCD generally increased from 0.23 to 0.79 and 0.45 to 0.88, respectively, revealing the upward trend of the coordination development levels of the WEFL nexus in the YREB. (2) The lower reaches achieved a relatively higher coordination development degree than the upper and middle reaches of the YREB. (3) The findings of obstacle factors reveal that agricultural non-point source pollution control, waterlogging disaster prevention, industrial solid waste efficient treatment, and urban water-saving are the essential fields that need to be improved in YREB's future development. This study helps to understand the complex interrelation of the WEFL nexus at different spatial-temporal scales and provides a novel framework that can be used as an evaluation system and policy insights for a region's integrated resources, environmental management, and green sustainable development.

Effect of Lianhua Qingwen capsules on the positive rate of COVID-19 close contacts: A retrospective analysis of a large-scale population-based cohort study.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is still spreading worldwide. COVID-19 close contact is a key point of this epidemic. However, no medication is now available for close contact. This study aims to evaluate the beneficial effect and safety of the Lianhua Qingwen capsule (LHQW) on COVID-19 close contacts via a large, retrospective cohort study. METHODS: A total of 25,002 close contacts from 199 quarantine sites in Changchun, Jilin, who underwent medical observation, were included. The information about these close contacts were collected for further epidemiological research. Moreover, subjects were divided into an exposure group (LHQW group, oral, 4 capsules/time, t.i.d.; 18,579 subjects) and a non-exposure group (control group; 6,423 subjects). Inverse probability of treatment weighting (IPTW) with propensity score was employed to evaluate the positive rate of the SARS-CoV-2 nucleic acid test in nasal and throat swabs confirmed by polymerase chain reaction (PCR). RESULTS: A total of 22,975 subjects were included in the analysis, 17,286 cases in the LHQW group and 5,689 cases in the control group. The positive rate of nucleic acid testing in the LHQW group was 5.12%, and that in the control group was 9.70% before the adjustment of IPTW of the propensity score; the difference between the two groups was -4.58% (95% CI -5.44- -3.77%, p <  0.001). After adjusting IPTW, the positive rate of nucleic acid testing in the LHQW group and the control group was 5.10% and 9.80%, respectively; the difference between the two groups was -4.70% (95% CI -5.18- -4.23, p < 0.001). The conclusions before and after the IPTW adjustment were consistent. No test drug-related adverse reactions were observed during the study period. CONCLUSION: LHQW has a beneficial effect and safety on the close contacts of SARS-CoV-2 who are under medical observation at the quarantine sites and can be used as an optional drug for those close contacts.

Bilirubin gates the TRPM2 channel as a direct agonist to exacerbate ischemic brain damage.

Stroke prognosis is negatively associated with an elevation of serum bilirubin, but how bilirubin worsens outcomes remains mysterious. We report that post-, but not pre-, stroke bilirubin levels among inpatients scale with infarct volume. In mouse models, bilirubin increases neuronal excitability and ischemic infarct, whereas ischemic insults induce the release of endogenous bilirubin, all of which are attenuated by knockout of the TRPM2 channel or its antagonist A23. Independent of canonical TRPM2 intracellular agonists, bilirubin and its metabolic derivatives gate the channel opening, whereas A23 antagonizes it by binding to the same cavity. Knocking in a loss of binding point mutation for bilirubin, TRPM2-D1066A, effectively antagonizes ischemic neurotoxicity in mice. These findings suggest a vicious cycle of stroke injury in which initial ischemic insults trigger the release of endogenous bilirubin from injured cells, which potentially acts as a volume neurotransmitter to activate TRPM2 channels, aggravating Ca2+-dependent brain injury.

Injection of L-glutamate into the insular cortex produces sleep apnea and serotonin reduction in rats.

PURPOSE: Obstructive sleep apnea (OSA) is primarily characterized by repetitive episodes of complete or partial obstruction of airflow during sleep. The neuronal and cellular mechanisms underlying this process are not fully understood, although the focus of some studies is on putative serotonin (5-HT) mechanisms, and serotonergic therapy may be beneficial to OSA patients. This study aimed to demonstrate possible changes in 5-HT associated with induction of OSA in a rat model. METHODS: Apnea was induced in rats by injection of L-glutamate (L-Glu) into the insular cortex. We examined changes in: (1) simultaneous genioglossus and diaphragm EMG activity; and (2) peripheral and cerebral levels of 5-HT, by histology. RESULTS: Injection of L-glutamate (L-Glu) into the insular cortex induced apnea in the rats. L-Glu stimulation of the insular cortex also produced significant reductions in plasma 5-HT levels and the expression of 5-HT in the brainstem. In addition, lower activity was observed in the GG and a higher activity was observed in the diaphragm, as compared to controls. CONCLUSION: Data indicate that L-Glu stimulation of the insular cortex simulates the electrical activity of the genioglossus muscle and diaphragm in sleep apnea, and contributes to reduced peripheral and cerebral 5-HT levels in rats. The results of our study suggest that 5-HT may play a role in the pathogenesis of OSA.

Mal-effects of obstructive sleep apnea on the heart.

OBJECTIVE: This study aims to examine the impact of chronic intermittent hypoxia on hearts in patients with obstructive sleep apnea (OSA). METHODS: Two hundred twenty patients were divided into groups based on (1) severity of the disease, (2) years of disease history, and (3) with or without secondary hypertension. All subjects underwent blood pressure measurements, polysomnogram monitoring, and cardiac Doppler ultrasound examinations. RESULTS: The left ventricular ejection fraction (LVEF), fractional shortening (FS), and the ratio of early to late diastolic filling (E/A) in patients with severe OSA were lower than in those with moderate OSA and in healthy controls. The inner diameters of the main pulmonary artery (inD of MPA), the inner diameters of the right cardiac ventricle (inD of RV), and the thickness of anterior wall of the right ventricle (TAW of RV) were increased in patients with severe OSA compared to those with moderate disease and worsened as a function of time with disease. The tissue Doppler imaging-derived Tei index and pulmonary artery systolic pressure were also increased along with the severity of OSA. LVEF and FS in patients who had suffered from OSA for >10 years were decreased compared with those suffering from OSA for a shorter time. LVEF and FS in patients with secondary hypertension were decreased significantly relative to non-hypertensive OSA patients and healthy controls. E/A was decreased in OSA patients whether they had secondary hypertension or not. CONCLUSION: OSA affected the left ventricular diastolic function in the early stage of the disease. Extended exposure to OSA resulted in left ventricular dysfunction with increased hypertension. Right ventricle dysfunction and abnormalities became more severe as the disease progressed.