A conjugate vaccine strategy that induces protective immunity against arecoline.

Betel-quid chewing addiction is the leading cause of oral submucous fibrosis and oral cancer, resulting in significant socio-economic burdens. Vaccination may serve as a promising potential remedy to mitigate the abuse and combat accidental overdose of betel nut. Hapten design is the crucial factor to the development of arecoline vaccine that determines the efficacy of a candidate vaccine. Herein, we reported that two kinds of novel arecoline-based haptens were synthesized and conjugated to Bovine Serum Albumin (BSA) to generate immunogens, which generated antibodies with high affinity for arecoline but reduced binding for guvacoline and no affinity for arecaidine or guvacine. Notably, vaccination with Arec-N-BSA, which via the N-position on the tetrahydropyridine ring (tertiary amine group), led to a higher antibody affinity compared to Arec-CONH-BSA, blunted analgesia and attenuated hypothermia for arecoline.

Effect of age on postural performance and control strategies during changes in visual input and dual-tasking stances.

Background: With age, people begin to experience deterioration in standing balance, especially when sensory input is suddenly removed or added. Here, we sought to explore the effects of age on postural performance and postural control strategies. Methods: The convenience sample consisted of 15 young, 10 middle-aged, and 14 elderly healthy adults. They were instructed to stand with their feet together in four randomly administered conditions involving visual input removal/addition and single-/dual-tasking. Dual-tasking involved continuous subtraction by 3s. Results: Postural sway displacement in the two older groups seemed larger than that in the younger group; however, neither the main effect of group (F2, 36 = 1.152, p = .327) nor the group × time interaction effect (F4, 27 = 0.229, p = .922) was significant. Greater stiffness of the lower leg muscles was observed in the vision-addition condition than in the vision-removal condition in only the elderly group (t13 = -2.755, p = .016). The dual-tasking condition resulted in smaller sway displacement (F1, 36 = 7.690, p = .009) and greater muscle stiffness (F1, 36 = 5.495, p = .025). In the vision-removal condition, the increase in muscle stiffness due to dual-tasking was significantly larger in the middle-aged (t9 = -3.736, p = .005) and elderly groups (t13 = -2.512, p = .026). Conclusions: In healthy older individuals, age-related changes were observed in control strategies used to maintain standing balance upon changes in visual input. The dual-task paradigm induced the use of an ankle-stiffening strategy in middle-aged and elderly adults.

Inflammation and DKK1-induced AKT activation contribute to endothelial dysfunction following NR2F2 loss.

NR2F2 is expressed in endothelial cells (ECs) and Nr2f2 knockout produces lethal cardiovascular defects. In humans, reduced NR2F2 expression is associated with cardiovascular diseases including congenital heart disease and atherosclerosis. Here, NR2F2 silencing in human primary ECs led to inflammation, endothelial-to-mesenchymal transition (EndMT), proliferation, hypermigration, apoptosis-resistance, and increased production of reactive oxygen species. These changes were associated with STAT and AKT activation along with increased production of DKK1. Co-silencing DKK1 and NR2F2 prevented NR2F2-loss-induced STAT and AKT activation and reversed EndMT. Serum DKK1 concentrations were elevated in patients with pulmonary arterial hypertension (PAH) and DKK1 was secreted by ECs in response to in vitro loss of either BMPR2 or CAV1, which are genetic defects associated with the development of PAH. In human primary ECs, NR2F2 suppressed DKK1, whereas its loss conversely induced DKK1 and disrupted endothelial homeostasis, promoting phenotypic abnormalities associated with pathologic vascular remodeling. Activating NR2F2 or blocking DKK1 may be useful therapeutic targets for treating chronic vascular diseases associated with EC dysfunction.NEW & NOTEWORTHY NR2F2 loss in the endothelial lining of blood vessels is associated with cardiovascular disease. Here, NR2F2-silenced human endothelial cells were inflammatory, proliferative, hypermigratory, and apoptosis-resistant with increased oxidant stress and endothelial-to-mesenchymal transition. DKK1 was induced in NR2F2-silenced endothelial cells, while co-silencing NR2F2 and DKK1 prevented NR2F2-loss-associated abnormalities in endothelial signaling and phenotype. Activating NR2F2 or blocking DKK1 may be useful therapeutic targets for treating vascular diseases associated with endothelial dysfunction.

Ligand-gated mechanisms leading to ictogenesis in focal epileptic disorders.

We review here the neuronal mechanisms that cause seizures in focal epileptic disorders and, specifically, those involving limbic structures that are known to be implicated in human mesial temporal lobe epilepsy. In both epileptic patients and animal models, the initiation of focal seizures - which are most often characterized by a low-voltage fast onset EEG pattern - is presumably dependent on the synchronous firing of GABA-releasing interneurons that, by activating post-synaptic GABAA receptors, cause large increases in extracellular [K+] through the activation of the co-transporter KCC2. A similar mechanism may contribute to seizure maintenance; accordingly, inhibiting KCC2 activity transforms seizure activity into a continuous pattern of short-lasting epileptiform discharges. It has also been found that interactions between different areas of the limbic system modulate seizure occurrence by controlling extracellular [K+] homeostasis. In line with this view, low-frequency electrical or optogenetic activation of limbic networks restrain seizure generation, an effect that may also involve the activation of GABAB receptors and activity-dependent changes in epileptiform synchronization. Overall, these findings highlight the paradoxical role of GABAA signaling in both focal seizure generation and maintenance, emphasize the efficacy of low-frequency activation in abating seizures, and provide experimental evidence explaining the poor efficacy of antiepileptic drugs designed to augment GABAergic function in controlling seizures in focal epileptic disorders.

Plasma Cell-Free DNA Predicts Survival and Maps Specific Sources of Injury in Pulmonary Arterial Hypertension.

BACKGROUND: Cell-free DNA (cfDNA) is a noninvasive marker of cellular injury. Its significance in pulmonary arterial hypertension (PAH) is unknown. METHODS: Plasma cfDNA was measured in 2 PAH cohorts (A, n=48; B, n=161) and controls (n=48). Data were collected for REVEAL 2.0 (Registry to Evaluate Early and Long-Term PAH Disease Management) scores and outcome determinations. Patients were divided into the following REVEAL risk groups: low (≤6), medium (7-8), and high (≥9). Total cfDNA concentrations were compared among controls and PAH risk groups by 1-way analysis of variance. Log-rank tests compared survival between cfDNA tertiles and REVEAL risk groups. Areas under the receiver operating characteristic curve were estimated from logistic regression models. A sample subset from cohort B (n=96) and controls (n=16) underwent bisulfite sequencing followed by a deconvolution algorithm to map cell-specific cfDNA methylation patterns, with concentrations compared using t tests. RESULTS: In cohort A, median (interquartile range) age was 62 years (47-71), with 75% female, and median (interquartile range) REVEAL 2.0 was 6 (4-9). In cohort B, median (interquartile range) age was 59 years (49-71), with 69% female, and median (interquartile range) REVEAL 2.0 was 7 (6-9). In both cohorts, cfDNA concentrations differed among patients with PAH of varying REVEAL risk and controls (analysis of variance P≤0.002) and were greater in the high-risk compared with the low-risk category (P≤0.002). In cohort B, death or lung transplant occurred in 14 of 54, 23 of 53, and 35 of 54 patients in the lowest, middle, and highest cfDNA tertiles, respectively. cfDNA levels stratified as tertiles (log-rank: P=0.0001) and REVEAL risk groups (log-rank: P<0.0001) each predicted transplant-free survival. The addition of cfDNA to REVEAL improved discrimination (area under the receiver operating characteristic curve, 0.72-0.78; P=0.02). Compared with controls, methylation analysis in patients with PAH revealed increased cfDNA originating from erythrocyte progenitors, neutrophils, monocytes, adipocytes, natural killer cells, vascular endothelium, and cardiac myocytes (Bonferroni adjusted P<0.05). cfDNA concentrations derived from erythrocyte progenitor cells, cardiac myocytes, and vascular endothelium were greater in patients with PAH with high-risk versus low-risk REVEAL scores (P≤0.02). CONCLUSIONS: Circulating cfDNA is elevated in patients with PAH, correlates with disease severity, and predicts worse survival. Results from cfDNA methylation analyses in patients with PAH are consistent with prevailing paradigms of disease pathogenesis.

Regiodivergent Synthesis of Methylene and Methyl Ring-Fused Isoquinolinones: Base-Promoted Isomerization of N-Allyl Amides.

Methylene and methyl tricyclic isoquinolinones were selectively prepared using a palladium(II)-catalyzed aerobic aza-Wacker reaction, followed by a base- and temperature-controlled Heck reaction catalyzed by palladium(0). Exo- to endo-double-bond migration in isoquinolinones was achieved with 93-99% yields by treatment of the Heck products with Cs2CO3 in dimethyl sulfoxide (DMSO) at 150 °C. A probable mechanism for Cs2CO3-promoted olefin isomerization was proposed and examined using D-isotope labeling experiments. Finally, yuanamide, a 13-methyl-8-oxoprotoberberine alkaloid, was synthesized using the palladium-catalyzed aza-Wacker/Heck/migration sequence.

Mineralocorticoid receptor antagonist treatment of established pulmonary arterial hypertension improves interventricular dependence in the SU5416-hypoxia rat model.

Treatment with mineralocorticoid receptor (MR) antagonists beginning at the outset of disease, or early thereafter, prevents pulmonary vascular remodeling in preclinical models of pulmonary arterial hypertension (PAH). However, the efficacy of MR blockade in established disease, a more clinically relevant condition, remains unknown. Therefore, we investigated the effectiveness of two MR antagonists, eplerenone (EPL) and spironolactone (SPL), after the development of severe right ventricular (RV) dysfunction in the rat SU5416-hypoxia (SuHx) PAH model. Cardiac magnetic resonance imaging (MRI) in SuHx rats at the end of week 5, before study treatment, confirmed features of established disease including reduced RV ejection fraction and RV hypertrophy, pronounced septal flattening with impaired left ventricular filling and reduced cardiac index. Five weeks of treatment with either EPL or SPL improved left ventricular filling and prevented the further decline in cardiac index compared with placebo. Interventricular septal displacement was reduced by EPL whereas SPL effects were similar, but not significant. Although MR antagonists did not significantly reduce pulmonary artery pressure or vessel remodeling in SuHx rats with established disease, animals with higher drug levels had lower pulmonary pressures. Consistent with effects on cardiac function, EPL treatment tended to suppress MR and proinflammatory gene induction in the RV. In conclusion, MR antagonist treatment led to modest, but consistent beneficial effects on interventricular dependence after the onset of significant RV dysfunction in the SuHx PAH model. These results suggest that measures of RV structure and/or function may be useful endpoints in clinical trials of MR antagonists in patients with PAH.

Non/hypo-response to hepatitis B vaccination and influencing factors in HIV-infected patients in the context of different immunization schedules / 中华流行病学杂志

Objective: To study the non/hypo-response to hepatitis B vaccination in HIV-infected patients, identify the influencing factors and provide evidence for the development of hepatitis B prevention and control strategies and measures for special population. Methods: On the basis of the randomized controlled trial of 20 µg hepatitis B vaccine immunization at 0-1-6 month, 0-1-2-6 month and 60 µg hepatitis B vaccine immunization at 0-1-2-6 month, the HIV-infected patients who completed one-month follow-up after the full course vaccination were selected as study subjects. Quantification of antibody to hepatitis B surface antigen (anti-HBs) in serum samples was performed by using chemiluminescent microparticle immunoassay (CMIA) and demographic characteristics, disease history, HIV infection and treatment status of the study subjects were collected. Statistical analysis was conducted by χ2 test, t test, unconditional logistic regression and interaction analyses. Results: The non/hypo-response rates to hepatitis B vaccination were 34.65% (35/101), 24.49% (24/98) and 10.99% (10/91) in 20 µg group at 0-1-6 month or 0-1-2-6 month and 60 µg group at 0-1-2-6 month (P<0.001), respectively. Logistic regression analysis showed that after controlling for confounding factors, the risk for non/hypo-response was 0.22 times higher in HIV-infected patients receiving 60 µg hepatitis B vaccine at 0-1-2-6 month than in patients receiving 20 µg hepatitis B vaccine at 0-1-6 month (95%CI: 0.10-0.50), the risk for non/hypo-response was higher in men than in women (OR=3.65, 95%CI: 1.88-7.07), and the risk for non/hypo-response was 2.64 times higher in those without hepatitis B vaccination history than in those with hepatitis B vaccination history (95%CI: 1.10-6.32). Moreover, there were multiplicative interactions between immunization schedule and gender (OR=2.49, 95%CI: 1.24-5.00). Conclusion: The non/hypo-response rate to hepatitis B vaccination was significantly lower in HIV-infected patients receiving 60 µg hepatitis B vaccine at 0-1-2-6 month than in those receiving 20 µg hepatitis B vaccine at 0-1-6 month and 0-1-2-6 month. Gender, vaccination schedule and history of hepatitis B vaccination were the influencing factors of the non/hypo-response to hepatitis B vaccination. There was a multiplicative interaction between vaccination schedule and gender, and men receiving 20 µg hepatitis B vaccines had a higher risk for non/hypo-response to hepatitis B vaccination.

HIV infection status and related factors in men who have sex with men in sentinel surveillance in Shanxi province, 2010, 2015 and 2020 / 中华流行病学杂志

Objective: To understand the infection status of HIV and related factors in men who have sex with men (MSM) in Shanxi province in 2010, 2015 and 2020. Methods: According to the sentinel surveillance protocol, continuous cross-sectional survey were conducted to collect the information about basic characteristics, general demographic characteristics, AIDS knowledge awareness, high-risk sexual behavior, sexually transmitted diseases, intervention services and HIV infection rate of the MSM in Shanxi in 2010, 2015 and 2020. Results: In 2010, 2015 and 2020, a total of 2 708 MSM were included in this study. There were significant differences in HIV infection rate among three years (χ2=23.76, P<0.001) with an increasing trend with year (trend χ2 =17.34, P<0.001). The rates of anal sex, commercial sex and heterosexual behavior in the past 6 months were 77.62% (2 102/2 708), 5.91% (160/2 708) and 28.14% (762/2 708) respectively, and the rates of consistent use of condom were 52.52% (1 104/2 102), 63.13% (101/160) and 23.49%(179/762) respectively, and the rate of consistent condom use was low. Results from multivariate logistic regression analysis showed that different cities, having educational level of junior high school or below, being recruited through internet, voluntary counseling and testing, suffering from sexually transmitted diseases, occasional condom use in anal sex in the past 6 months were the correlative factors of HIV infection of MSM. Conclusions: The HIV infection rate of MSM in Shanxi increased year by year from 2010, 2015 to 2020. The HIV/AIDS-related risk behavior persisted, and the proportion of condomuse adherence was low, and the HIV detection rate was low in the MSM, so targeted and effective measures should be taken to promote the condom use adherence and regular HIV testing in MSM.

Modified hydrated sodium calcium aluminosilicate-supplemented diet protects porcine oocyte quality from zearalenone toxicity.

Zearalenone (ZEN) is one of the most common mycotoxins produced by fungus in contaminated feed. ZEN has multiple toxicities, including reproductive toxicity of domestic animals, particularly pigs. However, studies on the effects of ZEN on ovary/oocytes have been primarily based on in vitro experiments, and there is still no evidence from porcine in vivo models due to multiple limitations. Moreover, no report has investigated the effect of hydrated sodium calcium aluminosilicate (HSCAS) as a supplement on pig oocyte quality. In the present study, we fed pigs a 1.0 mg/kg ZEN-contaminated diet for 10 days. The results showed that pigs fed ZEN presented reduced oocyte-cumulus cell interactions, an increase in the number of denuded oocytes in ovaries, a decrease in the number of oocytes in each ovary, and an increase in the oocyte death rate. Oocytes from ZEN-exposed pigs exhibited a delayed cell cycle and abnormal cytoskeletal dynamics during meiotic maturation, which could be due to oxidative stress-induced autophagy. Moreover, we also show that supplementing the ZEN-contaminated diet with modified HSCAS effectively protected porcine oocyte quality. Taken together, our study provides in vivo data demonstrating the protective effects of HSCAS against ZEN toxicity in porcine oocytes.

Palladium-Catalyzed Stereoselective Aza-Wacker-Heck Cyclization: One-Pot Stepwise Strategy toward Tetracyclic Fused Heterocycles.

Palladium-catalyzed intramolecular tandem cyclization reactions were conducted for the synthesis of densely cis/cis-fused aza-tetracyclic structures. The process involved a palladium(II)-catalyzed aerobic aza-Wacker reaction, followed by a palladium(0)-catalyzed Heck reaction. The effects of the solvent and benzene substitution pattern on the one-pot, two-step cascade reaction were studied systematically, and a probable mechanism was proposed. Strained pentahydrobenzo[f]cyclopenta[hi]indolizin-6-one and racemic γ-lycorane can also be synthesized rapidly using this palladium-catalyzed aza-Wacker-Heck cyclization reaction.

[Phosphate Control Effect and Water Body Remediation of Magnesium Modified Reed Biochar].

Adding biochar from harvested reed to sediments is a new method to control the release of sedimentary phosphorus. Three types of Mg-modified biochars were prepared by pyrolysis of reed modified by magnesium chloride at 300, 450, and 600℃.The phosphate adsorption characteristics of the three types of biochars were analyzed by isothermal adsorption experiments. Biochar MBC-450 with good phosphate adsorption effects was selected as the material for the following experiments. Taking the sediment and overlying water of a campus river as the experimental object, we studied the adsorption of phosphate in overlying water and the control of sedimentary phosphorus by Mg-modified biochar under different dosage modes (mixing and covering). The concentration of DIP in the overlying water could be effectively reduced by biochar mixing and covering, and the accumulative phosphorus adsorption capacity increased by 17.3% (mixing) and 11.7% (covering) compared with that of the control. The control effect of sedimentary phosphorus by biochar mixing was more obvious; the DIP in sedimentary water decreased by 14.7%, 18.9%, and 35.36% from 0-2 cm to 4-6 cm compared with the control. The DIP in sedimentary water decreased by 33.3%, -28.2%, and 12.9% when covered with biochar. Compared with the control, the proportion of NH4 Cl-P in the sediment of 0-2 cm and 2-4 cm increased by 15% and 15% (mixing) and 12% and 2% (covering), respectively, while BD-P in TP decreased by 7% and 9% (mixing) and 6% and 3% (covering), respectively, and the Al-P in TP decreased by 7% and 6% (mixing) and 7% and -1% (covering), respectively. The other forms of phosphorus did not change significantly. Biochar mixing and covering can both improve the microbial activity in surface sediment, and biochar mixing can improve the microbial activity in deeper sediments more significantly.

[Adsorption Properties of Sludge-hydrochar for Methylene Blue].

A low-cost and efficient adsorbent, based on sewage sludge, was prepared by hydrothermal carbonization. The sludge-hydrochar was prepared at different temperatures (160, 190, 220, and 250℃) and different reaction times (1, 4, 8, and 16 h). It was applied to the adsorption of methylene blue (MB) in water. This study analyzed the structure and physicochemical properties of hydrochar by BET, FT-IR, and zero charge points. In addition, we investigated the optimum hydrothermal conditions for the preparation of adsorbents and adsorption properties for MB by experiments. Studies have shown that 190℃ and 4 h were the best hydrothermal conditions for the preparation of adsorbent (SS190-4). SS190-4 has the largest specific surface area (11.916 m2·g-1) and the best removal rate (96.44%) for methylene blue (MB). The adsorption of MB is more favorable when the solution is alkaline. The adsorption conforms to the Langmuir isotherm equation, and the maximum model adsorption capacity for MB is 400 mg·g-1. When the concentration of hydrochar is 0.5 g·L-1, it is more economical and reasonable. When there are coexisting ions in the solution, the adsorption capacity of hydrochar to MB is inhibited. The adsorption process of MB by hydrochar conforms to the quasi-secondary kinetic model, which is a spontaneous exothermic reaction.

[Phosphate Adsorption from Water on CaO2-loaded Magnetic Diatomite].

In this study,magnetic diatomite was used as a carrier to load calcium peroxide(CaO2) nanoparticles,fabricating a high efficiency phosphate adsorption and recovery composite material(MDCP).The micromorphology, inner structure,crystalline constituents and element composition of MDCP were characterized by SEM,EDX-mapping,XRD, XDS, and VSM,respectively.The adsorption isotherm data of MDCP exhibited good agreement with the Langmuir isotherm model. According to the Langmuir model,when T=20℃,the maximum monolayer phosphate adsorption capacities can reach 191.84mg·g-1 for MDCP. The isotherm and kinetics studies showed that MDCP has a regulating effect on the pH of the solution,which can maintain the pH of the solution at the level where adsorption of phosphate occurs on MDCP as a chemisorption process. pH plays a important role on the adsorption of phosphate by MDCP,the pH of effective adsorption ranges from 4 to 10,and the pH of the adsorbed solution can still be maintained in the range of 7 to 9.The MDCP exhibited a high selective adsorption for phosphate in the presence of anions,including Cl-, SO42-, CO32-, HCO32-, F-, and NO3-.The recovered MDCP could be desorbed by HCl solution,and after desorption, the phosphate removal rate of MDCP after re-loading CaO2 could still reach 70% of the initial adsorption.

KCC2 antagonism and gabaergic synchronization in the entorhinal cortex in the absence of ionotropic glutamatergic receptor signalling.

γ-Aminobutyric acid (GABA), which is released by interneurons, plays an active role in generating interictal epileptiform spikes during blockade of ionotropic glutamatergic signalling, but it remains unclear whether and how the K+-Cl- cotransporter 2 (KCC2) influences these paroxysmal events. Therefore, we employed tetrode recordings in the in vitro rat entorhinal cortex (EC) to analyze the effects of the KCC2 antagonist VU0463271 on 4-aminopyridine (4AP)-induced interictal spikes that were pharmacologically isolated by applying ionotropic glutamatergic receptor antagonists. After the addition of VU0463271, these interictal spikes continued to occur at similar rates as in control (i.e., during application of 4AP with ionotropic glutamatergic receptor antagonists) but were smaller and shorter. Despite the absence of ionotropic glutamatergic receptor signalling, both interneurons and principal cells increased their firing during interictal spikes. Moreover, we found that KCC2 antagonism increased interneuron firing but decreased principal cell firing during the interictal spike rising phase; in contrast, during the falling phase, interneuron firing decreased in the presence of VU0463271 while no change was observed in principal cell firing. Overall, our results show that KCC2 antagonism enhances interneuron excitability at the onset of interictal spikes generated by the EC neuronal networks during blockade of ionotropic glutamatergic transmission but disrupts later neuronal recruitment.

Interaction of Osteoarthritis and BMI on Leptin Promoter Methylation in Taiwanese Adults.

Leptin (LEP) regulates glucose metabolism and energy storage in the body. Osteoarthritis (OA) is associated with the upregulation of serum LEP. LEP promoter methylation is associated with obesity. So far, few studies have explored the association of BMI and OA with LEP methylation. We assessed the interaction between body mass index (BMI) and OA on LEP promoter methylation. Data of 1114 participants comprising 583 men and 558 women, aged 30-70 years were retrieved from the Taiwan Biobank Database (2008-2015). Osteoarthritis was self-reported and cases were those who reported having ever been clinically diagnosed with osteoarthritis. BMI was categorized into underweight, normal weight, overweight, and obesity. The mean LEP promoter methylation level in individuals with osteoarthritis was 0.5509 ± 0.00437 and 0.5375 ± 0.00101 in those without osteoarthritis. The interaction between osteoarthritis and BMI on LEP promoter methylation was significant (p-value = 0.0180). With normal BMI as the reference, the mean LEP promoter methylation level was significantly higher in obese osteoarthritic individuals (ß = 0.03696, p-value = 0.0187). However, there was no significant association between BMI and LEP promoter methylation in individuals without osteoarthritis, regardless of BMI. In conclusion, only obesity was significantly associated with LEP promoter methylation (higher levels) specifically in osteoarthritic patients.

[Research progress on relationship between urban greenspace distribution and the socioeconomic characteristics of residents]. / åŸŽå¸‚ç»¿åœ°æ ¼å±€ä¸Žå± æ°‘ç¤¾ä¼šç»æµŽç‰¹å¾å ³ç³»ç ”ç©¶è¿›å±•.

Urban greenspace, which serves as a place for residents to connect with nature and relax, provides important ecosystem services. Access to greenspace is often related to the socio-economic characteristics of residents, which received a lot attention from researchers and practitioners. Previous studies have mostly focused on single city to analyze the spatial relationship between greenspace distribution and residents' characteristics. We conducted a meta-analysis with global studies. The objectives were to classify findings from different cases and investigate the impacts from the location of research area, indicator and analytical method, and summarized major factors influen-cing the relationship between greenspace distribution and residents' characteristics. The results showed that more than half of the cases (58.2%) found that the socially advantaged population benefited more from greenspace. About a quarter cases (25.4%) revealed the opposite, that was, the disadvantaged population benefited more from greenspace. The remaining case studies (16.4%) did not find significant correlation between them. The studies reviewed here were diverse in terms of scale, indicator selection, and analytical method. Overall, we found no connection between finding and the choice of scale/indicator/analytical method. The reviewed case studies were mostly conducted in cities of western countries, which differed in their development trajectories and urban characteristics from cities in China. To understand association between urban greenspace and residents' characteristics in China, we urged to carry out more local studies, which would potentially provide scientific evidence for building sustainable cities during rapid urbanization.

Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy.

OBJECTIVE: To establish the effects induced by long-term, unilateral stimulation of parvalbumin (PV)-positive interneurons on seizures, interictal spikes, and high-frequency oscillations (80-500Hz) occurring after pilocarpine-induced status epilepticus (SE)-a proven model of mesial temporal lobe epilepsy (MTLE)-in transgenic mice expressing or not expressing ChR2. METHODS: PV-ChR2 (n = 6) and PV-Cre (n = 6) mice were treated with pilocarpine to induce SE. Three hours after SE onset, unilateral optogenetic stimulation (450nm, 25mW, 20-millisecond pulses delivered at 8Hz for 30 seconds every 2 minutes) of CA3 PV-positive interneurons was implemented for 14 continuous days in both groups. RESULTS: Rates of seizures (p < 0.01), interictal spikes (p < 0.001), and interictal spikes with fast ripples (250-500Hz) (p < 0.001) were lower in PV-ChR2 than in PV-Cre mice. Ripples (80-200Hz) occurring outside of interictal spikes had higher rates in the PV-ChR2 group (p < 0.01), whereas isolated fast ripples had lower rates (p < 0.01). However, seizure probability was higher during optogenetic stimulation in PV-ChR2 compared to PV-Cre animals (p < 0.05). INTERPRETATION: Our findings show that the unilateral activation of CA3 PV-positive interneurons exerts anti-ictogenic effects associated with decreased rates of interictal spikes and fast ripples in this MTLE model. However, PV-positive interneuron stimulation can paradoxically trigger seizures in epileptic animals, supporting the notion that γ-aminobutyric acid type A signaling can also initiate ictogenesis. ANN NEUROL 2019;86:714-728.

KCC2 antagonism increases neuronal network excitability but disrupts ictogenesis in vitro.

The potassium-chloride cotransporter 2 (KCC2) plays a role in epileptiform synchronization, but it remains unclear how it influences such a process. Here, we used tetrode recordings in the in vitro rat entorhinal cortex (EC) to analyze the effects of the KCC2 antagonist VU0463271 on 4-aminopyridine (4AP)-induced ictal and interictal activity. During 4AP application, ictal events were associated with significant increases in interneurons and principal cells activities. VU0463271 application transformed ictal discharges to shorter ictal-like events that were not accompanied by significant increases in interneuron or principal cell firing. Interictal events persisted during VU0463271 application at an accelerated frequency of occurrence with significant increases in interneuron and principal cell activity. Further analysis revealed that interneuron and principal cell firing rate during 4AP-induced interictal events were increased after VU0463271 application without changes in synchronicity. Overall, our results demonstrate that in the EC, KCC2 antagonism enhances both interneuron and principal cell excitability, while paradoxically decreasing the ability of neuronal networks to generate structured ictal events.NEW & NOTEWORTHY We are the first to use tetrode recordings in the entorhinal cortex to demonstrate that antagonizing potassium-chloride cotransporter 2 (KCC2) function abolishes ictal discharges and the associated, dynamic changes in single-unit firing in the in vitro 4-aminopyrine model of epileptiform synchronization. Interictal discharges were, however, shorter and more frequent during KCC2 antagonism, while the associated single-unit activity increased, suggesting augmented neuronal excitability. Our findings highlight the complex role of KCC2 in disease pathology.