Neuronal population activity in the olivocerebellum encodes the frequency of essential tremor in mice and patients.

Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the Grid2dupE3 mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.

Effects of Helicobacter pylori and Moluodan on the Wnt/ß-catenin signaling pathway in mice with precancerous gastric cancer lesions.

BACKGROUND: Helicobacter pylori (H. pylori) is the primary risk factor for gastric cancer (GC), the Wnt/ß-Catenin signaling pathway is closely linked to tumourigenesis. GC has a high mortality rate and treatment cost, and there are no drugs to prevent the progression of gastric precancerous lesions to GC. Therefore, it is necessary to find a novel drug that is inexpensive and preventive to against GC. AIM: To explore the effects of H. pylori and Moluodan on the Wnt/ß-Catenin signaling pathway and precancerous lesions of GC (PLGC). METHODS: Mice were divided into the control, N-methyl-N-nitrosourea (MNU), H. pylori + MNU, and Moluodan groups. We first created an H. pylori infection model in the H. pylori + MNU and Moluodan groups. A PLGC model was created in the remaining three groups except for the control group. Moluodan was fed to mice in the Moloudan group ad libitum. The general condition of mice were observed during the whole experiment period. Gastric tissues of mice were grossly and microscopically examined. Through quantitative real-time PCR (qRT-PCR) and Western blotting analysis, the expression of relevant genes were detected. RESULTS: Mice in the H. pylori + MNU group showed the worst performance in general condition, gastric tissue visual and microscopic observation, followed by the MNU group, Moluodan group and the control group. QRT-PCR and Western blotting analysis were used to detect the expression of relevant genes, the results showed that the H. pylori + MNU group had the highest expression, followed by the MNU group, Moluodan group and the control group. CONCLUSION: H. pylori can activate the Wnt/ß-catenin signaling pathway, thereby facilitating the development and progression of PLGC. Moluodan suppressed the activation of the Wnt/ß-catenin signaling pathway, thereby decreasing the progression of PLGC.

[Bifidobacterium bifidum TMC3115 Promotes Early Life Intestinal Microbiota Building to Alleviate Symptoms of Inflammatory Bowel Disease].

Objective: To investigate the effects of using Bifidobacterium bifidum TMC3115 in early life on intestinal microbiota and immune functions and the long-term impact on inflammatory bowel disease. Methods: Fourteen pregnant BALB/c mice were purchased and 84 newborn BALB/c mice were subsequently obtained. Then, the newborn mice were randomly assigned to a normal saline (NS) group and a TMC3115 group, given via oral gavage normal saline and TMC3115, respectively, at a daily volume of 0.2 mL for each mouse. About 42 mice were assigned to each group. The gavage was stopped after 3 weeks. At this point, half of the mice in each group were sacrificed, and then the remaining mice in each group were randomly divided into NS-water group, NS-DSS group, TMC3115-water group, and TMC3115-DSS group, with about 10 mice in each group. The mice were given regular feed until the end of week 6 when they were given 3% dextran sulphate sodium (DSS) ad libitum for 4 days to establish the enteritis model, while the non-modeling groups were given pure water ad libitum. The experiment ended after 6 weeks and 4 days. The weekly body mass changes of the mice were documented. The intestinal tissue at the end of the experiment and the fecal samples, spleen and serum of the mice at 3 weeks and at the end of the experiment were collected to determine the pathology scores of colonic inflammation, the composition of fecal gut microbiota, spleen organ index and the mass concentration of serum cytokines. Results: 1) At the end of the experiment, the inflammatory pathology score was significantly lower in the TMC3115-DSS group compared with that of the Saline-DSS group ( P<0.05), with less disruption of colonic crypt structures and other structures, less inflammatory infiltration, and more intact epithelial structures. 2) At 3 weeks, in comparison with those of the NS group, the relative abundance of Bifidobacteriumwas significantly higher in the feces of the TMC3115 ( P<0.05), the relative abundance of both Enterococcusand Staphylococcuswas lower ( P<0.05), the splenic organ index was significantly higher ( P<0.05), and interleukin (IL)-10 was significantly decreased ( P<0.05), while there was no significant change in IL-6 or TNF-α ( P>0.05). At the end of the experiment, in comparison with those of the NS-DSS group that undergone DSS induction, the TMC3115-DSS group had reduced relative abundance of Staphylococcus, Staphylococcus tumefaciens and Escherichia/ Shigellain the feces ( P<0.05), while the splenic organ index was significantly higher ( P<0.05), and there were no significant changes in IL-6 or TNF-α ( P>0.05). Conclusion: The use of TMC3115 in early life promotes the construction of gut microbiota in neonatal mice, thereby producing a long-term effect that alleviates colitis in mice, but the mechanisms involved are still not fully understood.

[Pollution Characteristics and Source Apportionment of Typical and Emerging Per- and Polyfluoroalkylated Substances in Tuojiang River Basin].

Forty-eight surface water samples were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in order to study the pollution characteristics and source apportionment of per- and polyfluoroalkylated substances (PFASs) in the Tuojiang River. The results showed that ΣPFASs in the Tuojiang River ranged from 12.5-3789 ng·L-1, and perfluorooctanoic acid (PFOA) was the predominant PFAS, with a concentration of 9.97-3764 ng·L-1 (73.6%-99.8%), suggesting that legacy PFASs were still the dominant PFASs in the Tuojiang River. The most frequently detected emerging PFASs was 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (F-53B), with a detection frequency of 100%, suggesting the wide use of F-53B in the Tuojiang River. Sodium 1H, 1H, 2H, 2H-perfluorooctane sulfonate (6:2 FTS) displayed the highest concentration among all emerging PFASs[nd-27.3 ng·L-1, mean:(9.12±7.70) ng·L-1], and the concentrations were at the higher levels compared to those in other rivers around the world. In addition, ΣPFASs showed the highest concentrations of ΣPFASs at the fluorochemical manufacturing park (FMP), followed by those in the Luzhou section (in the lower reaches of the Tuojiang River), indicating that the emission of FMP and human daily production activities were the main influencing factors of PFASs pollution in the Tuojiang River. The estimated flux of PFASs from the Tuojiang River to the Yangtze River was 353 kg·a-1, and PFOA displayed the greatest mass loading (348 kg·a-1), which could provide the basic data for controlling PFASs in the Tuojiang River.

Revision of the genus Homa Distant (Hemiptera: Cicadellidae: Typhlocybinae).

The leafhopper genus Homa Distant is revised. Four new species, H. osificata Xu, Dietrich Qin sp. nov., H. oretinia Xu, Dietrich Qin sp. nov., H. asilata Xu, Dietrich Qin sp. nov., and H. algulata Xu, Dietrich Qin sp. nov., are described from Thailand. H. haematoptilus (Kirkaldy) is redescribed based on specimens from the Oriental Region. All included species are illustrated and a key is provided to separate species for which males are known.

Cerebellar Oscillations in Familial and Sporadic Essential Tremor.

Enhanced cerebellar oscillations have recently been identified in essential tremor (ET) patients as a key pathophysiological change. Since ET is considered a heterogeneous group of diseases, we investigated whether cerebellar oscillations differ in ET subtypes (familial vs. sporadic). This study aims to determine cerebellar physiology in familial and sporadic ET. Using surface electroencephalogram, we studied cerebellar physiology in 40 ET cases (n = 22 familial and n = 18 sporadic) and 20 age-matched controls. Both familial and sporadic ET cases had an increase in the intensity of cerebellar oscillations when compared to controls. Interestingly, cerebellar oscillations correlated with tremor severity in familial ET but not in sporadic ET. Our study demonstrated that ET cases have enhanced cerebellar oscillations, and the different relationships between cerebellar oscillations and tremor severity in familial and sporadic ET suggest diverse cerebellar pathophysiology.

Two new empoascine leafhopper genera, Thaioasca and Mjolnirus, from Thailand (Hemiptera: Cicadellidae: Typhlocybinae), with a checklist of Empoascini in Thailand.

Two new microleafhopper genera of Empoascini, Thaioasca Wang, Xu Qin, gen. nov. and Mjolnirus Wang, Xu Qin, gen. nov., based on the type species, Thaioasca contaminata Wang, Xu Qin, sp. nov. and Mjolnirus mediolobus Wang, Xu Qin, sp. nov. are described from Thailand. Male habitus photos and illustrations of male genitalia of these two new species are given. A checklist of Empoascini from Thailand is also provided.

[Therapeutic effect of scalp acupuncture combined with rehabilitation training on balance dysfunction in children with spastic hemiplegia].

OBJECTIVE: To investigate the therapeutic effect of scalp acupuncture and rehabilitation training on balance dysfunction in children with spasmodic hemiplegia so as to provide the reference to the optimization of treatment scheme. METHODS: A total of 60 children with spastic hemiplegia were divided into a routine group and a scalp acupuncture group, 30 cases in each one according to random number table. In the routine group, the rehabilitation training was provided, including exercise training, balance training, spasmotherapy apparatus, electromyography biofeedback apparatus and orthoses. In the scalp acupuncture group, on the base of the treatment as the routine group, scalp acupuncture was supplemented at motor area, foot motor sensory area, equilibrium area and parietal temporal anterior oblique line. Separately, before the treatment, after 3 months treatment and after 6 months treatment, the dimension D and E of the gross motor function measure-88 (GMFM-88) and Berg balance scale (BBS) were adopted to evaluate balance related motor functions and equilibrium function. The differences in the above 3 indicators at different time stages were compared in children between the two groups. RESULTS: Compared with the score before the treatment, BBS score was obviously increased after 3 and 6 months treatment in the patients of the two groups respectively (P<0.05). The score in the dimension D and E after 6-month treatment was increased significantly as compared with the score before treatment and after 3-month treatment in the same group respectively (P<0.05). Compared with the routine group, the score of dimension D and E of GMFM-88 as well as BBS score were all increased obviously in the scalp acupuncture group after 3 and 6 months treatment (P<0.05). CONCLUSION: On the base of routine rehabilitation training, scalp acupuncture can improve balance function of children with spastic hemiplegia better.

Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology.

Essential tremor (ET) is one of the most common movement disorders and the prototypical disorder for abnormal rhythmic movements. However, the pathophysiology of tremor generation in ET remains unclear. Here, we used autoptic cerebral tissue from patients with ET, clinical data, and mouse models to report that synaptic pruning deficits of climbing fiber (CF)-to-Purkinje cell (PC) synapses, which are related to glutamate receptor delta 2 (GluRδ2) protein insufficiency, cause excessive cerebellar oscillations and might be responsible for tremor. The CF-PC synaptic pruning deficits were correlated with the reduction in GluRδ2 expression in the postmortem ET cerebellum. Mice with GluRδ2 insufficiency and CF-PC synaptic pruning deficits develop ET-like tremor that can be suppressed with viral rescue of GluRδ2 protein. Step-by-step optogenetic or pharmacological inhibition of neuronal firing, axonal activity, or synaptic vesicle release confirmed that the activity of the excessive CF-to-PC synapses is required for tremor generation. In vivo electrophysiology in mice showed that excessive cerebellar oscillatory activity is CF dependent and necessary for tremor and optogenetic-driven PC synchronization was sufficient to generate tremor in wild-type animals. Human validation by cerebellar electroencephalography confirmed that excessive cerebellar oscillations also exist in patients with ET. Our findings identify a pathophysiologic contribution to tremor at molecular (GluRδ2), structural (CF-to-PC synapses), physiological (cerebellar oscillations), and behavioral levels (kinetic tremor) that might have clinical applications for treating ET.

Subchronic Oral Toxicity Evaluation of Lanthanum: A 90-day, Repeated Dose Study in Rats.

OBJECTIVE: The present study was undertaken to evaluate the subchronic toxicity of lanthanum and to determine the no observed adverse effect level (NOAEL), which is a critical factor in the establishment of an acceptable dietary intake (ADI). METHODS: In accordance with the Organization for Economic Co-operation and Development (OECD) testing guidelines, lanthanum nitrate was administered once daily by gavage to Sprague-Dawley (SD) rats at dose levels of 0, 1.5, 6.0, 24.0, and 144.0 mg/kg body weight (BW) per day for 90 days, followed by a recovery period of 4 weeks in the 144.0 mg/kg BW per day and normal control groups. Outcome parameters were mortality, clinical symptoms, body and organ weights, serum chemistry, and food consumption, as well as ophthalmic, urinary, hematologic, and histopathologic indicators. The benchmark dose (BMD) approach was applied to estimate a point of departure for the hazard risk assessment of lanthanum. RESULTS: Significant decreases were found in the 144.0 mg/kg BW group in the growth index, including body weight, organ weights, and food consumption. This study suggests that the NOAEL of lanthanum nitrate is 24.0 mg/kg BW per day. Importantly, the 95% lower confidence value of the benchmark dose (BMDL) was estimated as 9.4 mg/kg BW per day in females and 19.3 mg/kg BW per day in males. CONCLUSION: The present subchronic oral exposure toxicity study may provide scientific data for the risk assessment of lanthanum and other rare earth elements (REEs).

Reversible preoperative renal dysfunction does not add to the risk of postoperative acute kidney injury after cardiac valve surgery.

OBJECTIVE: To evaluate the impact of the renal dysfunction (RD) type and change of postoperative cardiac function on the risk of developing acute kidney injury (AKI) in patients who underwent cardiac valve surgery. METHOD: Reversible renal dysfunction (RRD) was defined as preoperative RD in patients who had not been initially diagnosed with chronic kidney disease (CKD). Cardiac function improvement (CFI) was defined as postoperative left ventricular ejection function - preoperative left ventricular ejection function (ΔEF) >0%, and cardiac function not improved (CFNI) as ΔEF ≤0%. RESULTS: Of the 4,805 (94%) cardiac valve surgery patients, 301 (6%) were RD cases. The AKI incidence in the RRD group (n=252) was significantly lower than in the CKD group (n=49) (36.5% vs 63.3%, P=0.018). The AKI and renal replacement therapy incidences in the CFI group (n=174) were significantly lower than in the CFNI group (n=127) (33.9% vs 50.4%, P=0.004; 6.3% vs 13.4%, P=0.037). After adjustment for age, gender, and other confounding factors, CKD and CKD + CFNI were identified as independent risk factors for AKI in all patients after cardiac valve surgery. Multivariate logistic regression analysis showed that the risk factors for postoperative AKI in preoperative RD patients were age, gender (male), hypertension, diabetes, chronic heart failure, cardiopulmonary bypass time (every 1 min added), and intraoperative hypotension, while CFI after surgery could reduce the risk. CONCLUSION: For cardiac valve surgery patients, preoperative CKD was an independent risk factor for postoperative AKI, but RRD did not add to the risk. Improved postoperative cardiac function can significantly reduce the risk of postoperative AKI.

High-dose versus low-dose haemofiltration for the treatment of critically ill patients with acute kidney injury: an updated systematic review and meta-analysis.

OBJECTIVE: The purpose of this study was to perform a systematic review and meta-analysis to evaluate the effect of high-dose versus low-dose haemofiltration on the survival of critically ill patients with acute kidney injury (AKI). We hypothesised that high-dose treatments are not associated with a higher risk of mortality. DESIGN: Meta-analysis. SETTING: Randomised controlled trials and two-arm prospective and retrospective studies were included. PARTICIPANTS: Critically ill patients with AKI. INTERVENTIONS: Continuous renal replacement therapy. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes: 90-day mortality, intensive care unit (ICU) mortality, hospital mortality; secondary outcomes: length of ICU and hospital stay. RESULT: Eight studies including 2970 patients were included in the analysis. Pooled results showed no significant difference in the 90-mortality rate between patients treated with high-dose or low-dose haemofiltration (pooled OR=0.90, 95% CI 0.73 to 1.11, p=0.32). Findings were similar for ICU (pooled OR=1.12, 95% CI 0.94 to 1.34, p=0.21) and hospital mortality (pooled OR=1.03, 95% CI 0.81 to 1.30, p=0.84). Length of ICU and hospital stay were similar between high-dose and low-dose groups. Pooled results are not overly influenced by any one study, different cut-off points of prescribed dose or different cut-off points of delivered dose. Meta-regression analysis indicated that the results were not affected by the percentage of patients with sepsis or septic shock. CONCLUSION: High-dose and low-dose haemofiltration produce similar outcomes with respect to mortality and length of ICU and hospital stay in critically ill patients with AKI.This study was not registered at the time the data were collected and analysed. It has since been registered on 17 February 2017 at http://www.researchregistry.com/, registration number: reviewregistry211.

Subchronic toxicity study of yttrium nitrate by 90-day repeated oral exposure in rats.

Concerns regarding the adverse effects of long-term exposure to low levels of rare earth elements (REEs) from foods on human health have arisen in recent years. Nevertheless, no official acceptable daily intake (ADI) has yet been proposed for either total REEs or individual REE. In accordance with the Organization for Economic Co-operation and Development (OECD) testing guideline, the present study was undertaken to evaluate the subchronic toxicity of yttrium, a representative heavy REE with higher contaminated level in foods in China, to achieve a no observed adverse effect level (NOAEL) which is a critical basis for the establishment of an ADI. Yttrium nitrate was orally administered to rats at doses of 0, 10, 30 and 90 mg/kg/day for 90 days followed by a recovery period of 4 weeks. The following toxicity indices were measured: mortality, clinical signs, daily food consumption and weekly body weight; urinalysis, hematology, blood coagulation, clinical biochemistry and histopathology at the end of administration and recovery periods. No toxicologically significant changes were found in any yttrium-treated group as compared to the concurrent control group. Under the present experimental condition, the NOAEL in rats was thus set at 90 mg/kg for yttrium nitrate, i.e. 29.1 mg/kg for yttrium.

AMPK activator acadesine fails to alleviate isoniazid-caused mitochondrial instability in HepG2 cells.

Isoniazid (INH) is a first-line antituberculosis drug that is adversely associated with hepatotoxicity. Recently, impairment of mitochondrial homeostasis involved in this side effect has been noticed. Mitochondrial homeostasis is achieved by the balance between the generation of functional mitochondria by biogenesis and elimination of dysfunctional mitochondria by autophagy. AMP-activated protein kinase (AMPK) can maintain mitochondrial stability through positive control of these two processes. In this study, we showed that AMPK activator acadesine (AICAR) alleviated INH-caused impairment of mitochondrial biogenesis by activation of silent information regulator two ortholog 1 (SIRT1)-peroxisome proliferator-activated receptor γ coactivator 1α (PGC1 α) pathway in HepG2 cells. However, mitochondrial instability and apoptosis were caused by AICAR along with an unexpected decrease in INH-induced cytoprotective autophagy. Therefore, AICAR failed to alleviate INH-caused mitochondrial instability in HepG2 cells due to its inhibitory effect on autophagy induced by INH. Copyright © 2017 John Wiley & Sons, Ltd.

Silica nanoparticles and lead acetate co-exposure triggered synergistic cytotoxicity in A549 cells through potentiation of mitochondria-dependent apoptosis induction.

The adverse effects of PM2.5 are the results of combined toxicities of finer particles and their adsorbed toxic pollutants. Nevertheless, the combined toxicity of finer particles and air pollutants still remains unclear. The present study was therefore undertaken to investigate the combined cytotoxicity of silica nanoparticles (nano-SiO2, a typical atmospheric ultrafine particle) and lead acetate (Pb, a representative air pollutant) in A549 cells focusing on mitochondria-dependent apoptosis induction. The results showed that Pb exposure alone induced mitochondria-dependent apoptosis in A549 cells, as evidenced by increased apoptotic rate and Bax/Bcl-2 ratio, up-regulated caspases 3 and 9 expressions as well as decreased mitochondrial membrane potential. Non-cytotoxic concentration of nano-SiO2 exposure alone did not trigger apoptosis in A549 cells, but potentialized the apoptotic changes when co-exposure with Pb. Factorial analyses revealed synergistic interactions were responsible for the potentiation of joint apoptotic responses.

Metallothionein protects against isoniazid-induced liver injury through the inhibition of CYP2E1-dependent oxidative and nitrosative impairment in mice.

Oxidative stress mediated by hepatic CYP2E1 during isoniazid (INH) metabolism is considered responsible for INH hepatotoxicity. This study attempts to determine whether metallothionein (MT), a cysteine-rich antioxidant can protect against INH-induced liver injury by using a MT-I/II deficient mouse model (MT-/- mice). MT-/- mice and the corresponding wild-type mice received intragastric administrations of 0, 75, 150 and 300 mg/kg of INH for 15 days. The results showed that 150 and 300 mg/kg of INH induced liver injury in both types of mice, as evidenced by increased liver index and histopathological change of liver vacuolar degeneration. Increased hepatic MDA level and 3-NT expression, and decreased GSH content and SOD activity were also observed in both types of mice, indicating the involvement of oxidative and nitrosative stress. INH treatment upregulated hepatic CYP2E1 expression in both types of mice, and the severity of liver injury was in concert with the elevation of CYP2E1 expression. Comparative analyses revealed liver vacuolar degeneration and oxidative and nitrosative stress were more severe in MT-/- mice than wild-type mice, suggesting the hepatoprotection of MT against INH hepatotoxicity. Taken together, these findings clearly demonstrate that MT protects against INH-induced liver toxicity by ameliorating CYP2E1-dependent oxidative and nitrosative impairment.

Significance of perioperative goal-directed hemodynamic approach in preventing postoperative complications in patients after cardiac surgery: a meta-analysis and systematic review.

PURPOSE: Goal-directed hemodynamic therapy (GDT) is used to prevent hypoperfusion resulting from surgery. The objective of this study was to analyze the efficacy and importance of perioperative GDT. METHODS: PUBMED, MEDLINE, CENTRAL, and Google Scholar databases were searched until 17 June 2016 using the search terms: cardiac output, cardiac surgical procedures, hemodynamics, goal-directed therapy, and intraoperative. Randomized-controlled trials with pre-emptive hemodynamic intervention for cardiac surgical population versus standard hemodynamic therapy were included. RESULTS: Nine studies were included with a total of 1148 patients. The overall analysis revealed no significant difference in the all-cause mortality (pooled peto OR =0.58, 95%CI =0.27-1.525, p = 0.164), duration of mechanical ventilation (pooled difference in mean= -1.48, 95%CI= -3.24 to 0.28, p = 0.099), or length of intensive care unit (ICU) stay (pooled difference in mean= -9.10, 95%CI= -20.14 to 1.93, p = 0.106) between patients in the GDT and control groups. Patients in the GDP group were associated with shorter hospital stay than those in the control group (pooled difference in mean= -1.52, 95%CI= -2.31 to -0.73, p < 0.001). CONCLUSION: GDT reduces the length of hospital stay compared with the standard of care. Further studies are necessary to continually assess the benefit of GDT following major surgery. Key Messages The results of this analysis revealed no significant difference between cardiac surgery patients receiving goal-directed hemodynamic therapy (GDT) or conventional fluid therapy in terms of the all-cause mortality, duration of mechanical intervention, and length of ICU-stay. The length of hospital stay was significantly reduced in patients treated with GDT compare to conventional fluid therapy. GDT may have limited benefit in reducing mortality; however, the association to shorter length of hospital stay may suggest that better hemodynamic balance can facilitate postoperative recovery.

Neuronal firing patterns outweigh circuitry oscillations in parkinsonian motor control.

Neuronal oscillations at beta frequencies (20-50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinson's disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy.

Prepubertal exposure to an oestrogenic mycotoxin zearalenone induces central precocious puberty in immature female rats through the mechanism of premature activation of hypothalamic kisspeptin-GPR54 signaling.

Sporadic epidemics and several researches in rodents indicated that zearalenone (ZEA) and its metabolites, the prevailing oestrogenic mycotoxins in foodstuffs, were a triggering factor for true precocious puberty development in girls. Nevertheless, the neuroendocrine mechanism through which ZEA mycoestrogens advance puberty onset is not fully understood. To elucidate this issue, hypothalamic kisspeptin-G-protein coupled receptor-54 (GPR54) signaling pathway that regulates the onset of puberty was focused on in the present study. Immature female SD rats were given a daily intragastric administration of corn oil (vehicle control), 50 µg/kg body weight (bw) of 17ß-estradiol (E2, positive control), and 3 doses (0.2, 1 and 5 mg/kg bw) of ZEA for consecutive 5 days starting from postnatal day 15, respectively. Puberty onset was evaluated by detecting the physiological and hormonal responses, and hypothalamic kisspeptin-GPR54 pathway was determined to reveal the neuroendocrine mechanism. As the markers of puberty onset, vaginal opening was significantly accelerated and uterine weight was increased in both E2 and 5 mg/kg ZEA groups. Serum levels of follicle stimulating hormone, luteinizing hormone and estradiol were also markedly elevated by E2 and 5 mg/kg ZEA, which is compatible with the changes in peripheral reproductive organs. The mRNA and protein expressions of hypothalamic gonadotropin-releasing hormone (GnRH) were both obviously elevated by E2 and 5 mg/kg ZEA. GnRH expression changes occurred in parallel with increased expressions of hypothalamic Kiss1 and its receptor GPR54 at both mRNA and protein levels. Most of these changes were also noted in 1 mg/kg ZEA group, but none in 0.2 mg/kg group. Therefore, within the context of this study, the No Observed Adverse Effect Level (NOAEL) for ZEA in terms of oestrogenic activity and puberty-promoting effect in immature female rats was considered to be 0.2 mg/kg bw per day, and the Lowest Observed Adverse Effect Level (LOAEL) was 1 mg/kg bw per day. In conclusion, prepubertal exposure to dietary relevant levels of ZEA induced central precocious puberty in female rats by premature activation of hypothalamic kisspeptin-GPR54-GnRH signaling pathway, followed by the stimulation of gonadotropins release at an earlier age, resulting in the advancement of vaginal opening and enlargement of uterus at periphery.

Induction of protective autophagy against apoptosis in HepG2 cells by isoniazid independent of the p38 signaling pathway.

Isoniazid (INH), one of the first-line anti-tuberculosis drugs, is adversely associated with hepatotoxicity in the clinic. However, the detailed mechanism of this side effect is still unclear. The traditional theory that cytochrome P450 2E1 is involved in INH-induced hepatotoxicity remains controversial, therefore other mechanisms by which INH exerts hepatotoxicity need to be investigated. In the current study, we showed that in vitro treatment of human hepatocarcinoma HepG2 cells with INH induced caspase-dependent apoptosis through extrinsic and intrinsic pathways. It was characterized by the increased population of apoptotic cells using Annexin V/propidium iodide (PI) double staining by flow cytometry, and by the activation of caspases 8, 9, 3 and poly (ADP-ribose)-polymerase (PARP) proteins by western blotting. INH treatment also induced autophagy as shown by the upregulated levels of microtubule-associated protein 1 light chain 3-II (LC3-II), increased GFP-LC3 punctates, and elevated monodansylcadaverine (MDC) fluorescence intensity. The measurement of the autophagic flux using chloroquine (CQ) confirmed that INH stimulated autophagy but did not inhibit it by impairing lysosomal degradation. The blockage of autophagy with CQ exacerbated INH-induced apoptosis significantly. Further study showed that INH treatment down-regulated the protein phosphorylation of the mammalian target of rapamycin (mTOR), the key negative regulator of autophagy. In addition, INH induced p38 signaling activation. SB203580, a p38 inhibitor, effectively enhanced INH-induced apoptosis by increasing the cleavages of caspases 9, 3 and PARP, but did not affect autophagy. In summary, we firstly found that INH induced a protective autophagy which was associated with the inhibition of the mTOR pathway, and that INH induced p38 signaling activation to inhibit apoptosis by down-regulation of caspases 9, 3 and PARP pathways, but not that of autophagy. Thus, activation of autophagy and p38 signaling is presumably a therapeutic strategy for INH-induced hepatotoxicity.