Moreover, the induction of kindling involves a simple non-invasive technique without the use of anesthesia. The protocol can be used for evaluation of both antiepileptic and antiepileptogenic agents.

Repeated exposure of 1.25 mM PTZ induced kindling in zebrafish, altering the brain neurotransmitter levels and gene expression. Inhibition of kindling induction and decrease in seizures in normal and kindled fish, respectively by VPA validated application of the model for preclinical testing of agents against epilepsy.

Repeated exposure of 1.25 mM PTZ induced kindling in zebrafish, altering the brain neurotransmitter levels and gene expression. Inhibition of kindling induction and decrease in seizures in normal and kindled fish, respectively by VPA validated application of the model for preclinical testing of agents against epilepsy.This study aimed to investigate the effect of keratinocyte growth factor (KGF) on the apoptosis, proliferation, damage repair, intercellular adhesion, and inflammatory cytokine release of cultured 16HBE 14o-bronchial ECs in vitro. Bronchial epithelial cells (ECs) from all subjects were obtained by bronchoscopic brushing. The expression levels of KGF and its receptor KGFR in collected cells were determined using RT-qPCR and Western blotting. The apoptosis and adhesion molecules expression by KGF administration were determined using flow cytometry and Western blotting. This occurred when 16HBE 14o-cell lines cultured and were exposed to interferon-γ (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in vitro. The role of KGF on proliferation and damage repair were analyzed using CCK-8, EdU and wound closure assays after 16HBE 14o-cells were scraped. The effect of KGF on the release of inflammation related cytokines by damaged ECs was measured using ELISA kits. Compared with healthy controls, the KGF and KGFR expression and apoptosis significantly increased in collected cells from asthma patients. In vitro, treatment of KGF may limit IFN-γ and TNF-α induced apoptosis by inhibiting apoptosis-associated markers in the TNF signaling pathway. Besides, KGF could limit the release of TSLP, IL-25 and IL-33 by damaged 16HBE 14o-cells. On the contrary, KGF could promote the intercellular adhesion and wound closure of cultured 16HBE 14o-cells via the increased expression level of intercellular junction proteins ICAM-1, β-catenin, E-cad, and Dsc3. In conclusion, KGF and KGFR may help bronchial ECs repair in asthma via the inhibition apoptosis of ECs while the promotion of proliferation and migration of ECs.Past research suggests that people’s beliefs about the malleability of their body weight influence their motivation to engage in healthful behaviors people who perceive their body weight as fixed (entity theorists) engage less in healthful behaviors than people who perceive their body weight as changeable (incremental theorists). Accordingly, current health interventions frequently aim at shifting entity theorists’ beliefs about the malleability of their body weight. Instead of trying to change these beliefs, we test whether the elicitation of pride from past achievements can serve as an intervention to promote healthful behaviors among entity theorists. In addition, we contrast the effect of pride recall among entity theorists with the effect among incremental theorists. Specifically, we find that entity theorists chose healthier behaviors upon the recall of pride related and unrelated to the health domain – the source of pride does not seem to matter. For incremental theorists, however, the source of pride does matter. While health-related pride led them to persist in making healthy food choices, health-unrelated pride instilled reward-seeking behavior among incremental theorists. Prompting health-related pride might be a viable motivational tool to promote healthy food choices, as it is beneficial for entity theorists without thwarting the motivation of incremental theorists.The purpose of this study is to examine consumers’ reactions to the introduction of nutrition and ingredient labelling for wine, a product that is so far still exempt from mandatory nutrition and ingredient labelling. It also analyses the effect of positive and negative information about the use of ingredients in wine on consumers’ choice. Representative samples for wine consumers from three distinctly different countries representing old and new wine markets (Australia, n = 745; Germany, n = 716; Italy, n = 715) completed a discrete choice experiment (DCE) with graphically simulated wine back labels. For each country, respondents were randomly allocated to a reference group and two different treatment conditions where they received newspaper-like information (positive, negative) before making choices. Results for the reference condition show that consumers across all three countries have a significant positive utility for detailed nutrition information. Instead, ingredient information only receives a positive utility in Italy, whereas German and Australian respondents do not receive utility from ingredient labelling. When consumers in the treatment group are confronted with negative media information the attribute importance of ingredients significantly increases across all three countries, clean labelled products without ingredients are preferred, and a significantly higher share of consumers in Germany and Italy prefer not to buy any wine. The treatment effect of positive media information on consumers’ wine choice is lower than that of negative information. The results of the study have implications for the pending new regulation of wine labelling and for communication strategies of the wine industry that should actively inform consumers about the necessity of ingredients in wine production.The recent outbreak of Coronavirus disease (COVID-19), first in Eastern Asia and then essentially across the world has been declared a pandemic by the WHO. COVID-19 is caused by a novel virus SARS-CoV2 (2019-nCoV), against which there is currently no vaccine available; and current antiviral therapies have failed, causing a very high mortality rate. Drug repurposing i.e. utilizing an approved drug for different indication, offers a time- and cost-efficient alternative for making new therapies available to patients. Although there are several reports presenting novel approaches to treat COVID-19, still an attentive review of previous scientific literature is essential to overcome their failure to exhibit efficacy. There is an urgent need to provide a comprehensive outlook toward utilizing drug repurposing as a tool for discovery of new therapies against COVID-19. In this article, we aim to provide a to-the-point review of current literature regarding efficacy of repurposed drugs against COVID-19 and other respiratory infections caused by coronaviruses. We have briefly discussed COVID-19 epidemiology, and then have discussed drug repurposing approaches and examples, specific to respiratory viruses. Limitations of utilization of repurposed drug molecules such as dosage regimen and associated challenges such as localized delivery in respiratory tract have also been discussed in detail.

To explore whether GOLPH3 regulated oxaliplatin (L-OHP) resistance of colon cancer cells via PI3K/AKT/mTOR pathway.

HCT116/L-OHP cells were divided into Blank, Control/GOLPH3 shRNA, BEZ235 (a PI3K/AKT/mTOR inhibitor), and GOLPH3+BEZ235 groups followed by the detection with MTT, soft agar colony formation, flow cytometry and TUNEL assays. Mice bearing HCT116/L-OHP xenografts were randomized into Control, L-OHP, NC/GOLPH3 shRNA, L-OHP+NC/GOLPH3 shRNA groups. The expressions of Ki67, Caspase-3, and PI3K/AKT/mTOR pathway proteins were examined by immunohistochemistry.

HCT116/L-OHP cells had increased GOLPH3 expression compared to HCT116 cells, which positively regulated PI3K/AKT/mTOR pathway in HCT116/L-OHP cells. BEZ235 declined IC50 of HCT116/L-OHP cells to L-OHP, decreased the expressions of ABCB1, ABCC1, ABCG2, ATP7A, ATP7B, MATE1, p-gp, MRP1 and BCRP, induced cell apoptosis, reduced cell proliferation, and arrested cells at G0/G1, which was reversed by GOLPH3 overexpression. L-OHP and GOLPH3 shRNA decreased tumor volume and reduced expression of Ki67 in tumor tissues with the increased Caspase-3. Meanwhile, the combined treatment had the better treatment effect.

GOLPH3 inhibition reduced proliferation and promoted apoptosis of HCT116/L-OHP cells, and also reversed the L-OHP resistance of HCT116/L-OHP, which may be associated with the suppression of P13K/AKT/mTOR pathway.

GOLPH3 inhibition reduced proliferation and promoted apoptosis of HCT116/L-OHP cells, and also reversed the L-OHP resistance of HCT116/L-OHP, which may be associated with the suppression of P13K/AKT/mTOR pathway.

Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies with a significant mortality rate. Despite the great advances in cancer treatment in the last few decades, effective treatment of CRC is still under challenge. One of the main problems associated with CRC treatment is the resistance of cancer cells to chemotherapy drugs.

Many studies have been carried out to identify CRC chemoresistance mechanisms, and shed light on the role of ATP-binding cassette transporters (ABC transporters), enzymes as thymidylate synthase, some signaling pathways, and cancer stem cells (CSC) in chemoresistance and failed CRC chemotherapies. Other studies have also been recently carried out to find solutions to overcome chemoresistance. Some of these studies have identified the role of miRNAs in chemoresistance of the CRC cells and the effective use of these micro-molecules to CRC treatment.

Considering the results of these studies, more focus on miRNAs likely leads to a proper solution to overcome CRC chemoresistance.

The current study has reviewed the related literature while discussing the efficacy of miRNAs as potential clinical tools for overcoming CRC chemoresistance and reviewing the most important chemoresistance mechanisms in CRC cells.

The current study has reviewed the related literature while discussing the efficacy of miRNAs as potential clinical tools for overcoming CRC chemoresistance and reviewing the most important chemoresistance mechanisms in CRC cells.Inflammation is a sophisticated biological tissue response to both extrinsic and intrinsic stimuli. Although the pathological aspects of inflammation are well appreciated, there are still rooms for understanding the physiological functions of the inflammation. Recent studies have focused on mechanisms, context and the role of physiological inflammation. Besides, there have been progress in the comprehension of commensal microbiota, immunometabolism, cancer and intracellular signaling events’ roles that impact on the regulation of inflammation. Despite the fact that inflammatory responses are vital through tissue damage, understanding the mechanisms to turn off the finished or unnecessary inflammation is crucial for restoring homeostasis. Inflammation seems to be a smart process that acts like two edges of a sword, meaning that it has both protective and deleterious consequences. Knowing both edges and the regulation processes will help the future understanding and therapy for various diseases.

Assessing patient fitness prior to high-risk operations is becoming increasingly vital in cardiothoracic surgery. Physical activity (PA) and frailty measures are powerful perioperative tools, albeit underused in clinical practice. This study aimed to assess the influence of patient frailty on PA post-surgery and other short-term outcomes.

Eighty patients undergoing a variety of cardiac surgical procedures (coronary revascularisation, valve repair/replacement, or combination) were recruited to participate. The Reported Edmonton Frailty Scale (REFS) was used to measure pre-operative frailty. As objective measures of PA, participants wore a wrist accelerometer device for 14 days prior to their operation and early in the post-operative period for 30 days.

A global reduction in PA was observed in the early post-operative period. Frailty was a significant predictor of reduced light (coef -2.23, 95% CI -4.21 – -0.25, p=0.028) and moderate activity (coef -1.85, 95% CI -2.99 – -0.70, p=0.002) post-operatively. Neither frailty nor pre-operative PA were predictors of post-operative composite complications. Both frailty (coef 0.134, 95% CI 0.106 – 0.162, p<0.001) and PA scores (p<0.05) were strong predictors of length of hospital stay (coef 1.76, 95% CI 0.003 – 3.524, p=0.05). Furthermore, patients who stayed in hospital longer were more likely to suffer early post-operative complications (stroke, renal failure, reoperation, pacemaker) if they were frail (p<0.0001) compared to non-frail patients (p=0.607).

This study highlights the predictive ability of objective frailty scoring and PA measurement for outcomes after cardiac surgery. This has important implications for surgical risk-stratification and personalized post-operative planning.

This study highlights the predictive ability of objective frailty scoring and PA measurement for outcomes after cardiac surgery. This has important implications for surgical risk-stratification and personalized post-operative planning.

Birth weight, preterm delivery, and size for gestational age are surrogate markers for development commonly used in congenital heart surgery. Understanding the associations of these variables with patient outcomes are of great importance.

We included all patients with hypoplastic left heart syndrome (HLHS) who underwent a Norwood procedure at a single institution from 1995-2018. Low birth weight was defined as less than 2.5 kilograms and preterm delivery occurred at less than 37 weeks gestation. Overall and conditional analyses were performed to evaluate for association with outcomes after the Norwood. Secondary analyses evaluated the association between development measures and post-operative length of stay (LOS) and ventilator duration.

In total 303 neonates (60% male) underwent the Norwood procedure and were followed for a median 3.9 years (IQR 0.5-10.4). Median birth weight was 3.1 kilograms (interquartile range [IQR] 2.8-3.4). Patients with low birth weight had decreased transplant-free survival compared to patients with a normal birth weight (HR 1.7, 95%CI 1.03-2.82, p=0.039). When conditioning on survival to second stage palliation, patients born small for gestational age had decreased transplant-free survival compared to patients born at appropriate size for gestational age (HR 2.8, 95%CI 1.31-6.09, p=0.008). Patients delivered preterm had longer hospital LOS (median 55 days vs 31 days, p=0.02) and more ventilator days compared to patients delivered at term (median 7 days vs 4 days, p=0.004).

Various development markers have differing prognostic importance for patients undergoing the Norwood procedure. Understanding these differences can help guide pre-operative decision-making and patient selection.

Various development markers have differing prognostic importance for patients undergoing the Norwood procedure. Understanding these differences can help guide pre-operative decision-making and patient selection.

Minimally invasive direct coronary artery bypass (MIDCAB) is a well-established low-impact surgical procedure for revascularization of left descending coronary artery with the left internal mammary artery. This work aims to evaluate safety, overall survival and freedom from major adverse cardio-cerebral events (MACCE) after 20 years of MIDCAB.

We retrospectively collected a series of 141 patients who underwent MIDCAB between 1997 and 2017 to assess long-term outcome. Therefore, we analysed 133 patients who consequently underwent revascularization of left descending coronary artery with left mammary artery via a full median sternotomy.

Actuarial survival rate at Kaplan-Meier curve was 100%, 95%, 90%, 83% and 70% at 1, 5, 10, 15 and 20 years, respectively. Freedom from MACCE, defined as myocardial infarction, stroke and cardiac death, was 97%, 90%, 79%, 75% and 61% at 1,5,10,15 and 20 years, respectively. At Cox multivariable analysis, age, cancer and chronic renal insufficiency have been found to be indes.Nose-to-brain delivery is an attractive route for direct drug delivery to the central nervous system (CNS), avoiding hepatic first-pass metabolism and solving blood-brain barrier passage issues. Therefore, the aim of the present study was the development of PLGA and PLGA/chitosan (chit) nanoparticles (NPs) with mucoadhesive properties, able to encapsulate ropinirole hydrochloride (RH), an anti-Parkinsonian dopaminergic agonist, and suitable to promote RH delivery across the nasal mucosa. NPs produced by nanoprecipitation showed spherical shape and a mean average size of 98.8 nm and 468.0 nm (PLGA and PLGA/chit, respectively). RH loaded PLGA/chit NPs showed a complete release of the drug in simulated nasal electrolyte solution (SNES) over the period of 24 h and increased the permeation of RH through sheep nasal mucosa by 3.22-fold in comparison to PLGA NPs. None of RH loaded NPs induced hemolysis in whole blood or the production of reactive oxygen species (ROS) in Raw 264.7 cells. On their turn, PLGA/chit NPs decreased cell viability of Raw 264.7 cells and Peripheral Blood Mononuclear Cells (PBMCs) in a concentration-dependent manner. These results revealed that, particularly PLGA/chit NPs, could be a valuable carrier for the delivery of RH to the CNS, opening a new path for Parkinson’s disease therapy.

Considering the pharmacological potential of solidagenone from Solidago chilensis, the present investigation was carried out to evaluate its antidepressant-like effect in mice with bacterial lipopolysaccharide (LPS)-induced depressive like behavior and its mode of action through the measurement of neuroinflammatory and oxidative markers.

In the prophylactic test, the mice were pretreated with solidagenone (1, 10 or 100 mg/kg, p.o) and after one hour received LPS. In therapeutic test, the mice received LPS and after 5 h were treated with solidagenone (1, 10 or 100 mg/kg, p.o). In both experimental approaches, the animals were submitted to OFT and to the TST after 6 and 24 h of the LPS administration, respectively. One hour after the TST the animals were euthanized, the blood was collected, the cortex was removed and biochemical analyzes were performed for measurement of the inflammatory and oxidative stress markers.

The LPS induced sickness- and depressive-like behaviors and increased the cortical activity of myeloperoxidase (MPO), as well as the IL-6 and TNF amount. Interestingly, the pretreatment with solidagenone at 100 mg/kg avoided the behavioral alterations in OFT. In the mice post treated with solidagenone, all tested doses of resulted in an antidepressant-like effect evidenced by the decrease in immobility time in the TST. This effect was accompanied by a decrease in the MPO activity and in the IL-6 and TNF levels in the cortex in parallel to the increase in catalase activity.

The solidagenone has a promissor antidepressant-like potential, which can result of its beneficial action in the neuroinflammation process and due its antioxidant capability at the central nervous system.

The solidagenone has a promissor antidepressant-like potential, which can result of its beneficial action in the neuroinflammation process and due its antioxidant capability at the central nervous system.Selective serotonin reuptake inhibitors are the first-line antidepressants for treating major depressive and post-traumatic stress disorders. These inhibitors directly bind to the serotonin transporter (SERT). Protein kinase C (PKC) is a key regulator of SERT functions as it can attenuate SERT activity through phosphorylation and its subsequent internalization. However, whether PKC-regulated SERT functions are involved in emotional impairment in a mouse model of stress remains unclear. Using a mouse model of swim-induced stress, we investigated whether the PKC-SERT system is involved in emotional impairment and tried to identify the PKC isoforms involved in this mechanism. Mice exposed to swim stress showed enhanced immobility and decreased social interaction times compared to those in swim stress-naive mice. Moreover, significant decreases in phosphorylated PKCβI and SERT levels were observed in the prefrontal cortex of stressed mice compared to those of swim stress-naive mice. No changes in levels of other phosphorylated PKC isoforms were observed between the two groups. Phorbol 12-myristate 13-acetate (a PKC activator) administration significantly attenuated enhanced immobility and decreased social interaction time in stressed mice and increased the serotonin turnover. Further, the PKC activator increased levels of phosphorylated PKCβI or SERT and decreased cell surface localization of SERT in stressed mice. Contrary to this, chelerythrine (a PKC inhibitor) administration exacerbated the immobility and sociality of mice exposed to mild stress. Our results suggest that PKCβI activation attenuates emotional impairment by suppressing SERT function in stressed mice. Thus, PKCβI may be a key target for the development of new treatment strategies for emotional impairment in stress-related disorders.Soluble amyloid beta (Aβ) is believed to contribute to cognitive deficits in the early stages of Alzheimer’s disease (AD). Increased soluble Aβ1-42 in the hippocampus is closely correlated with spatial learning and memory deficits in AD. Riluzole (RLZ), an FDA-approved drug for amyotrophic lateral sclerosis (ALS), has beneficial effects for AD. However, the mechanism underlying the effects remains unclear. In this study, its neuroprotective effect against soluble Aβ1-42-induced spatial cognitive deficits in rats was assessed. We found that intrahippocampal injection of soluble Aβ1-42 impaired spatial cognitive function and suppressed long-term potentiation (LTP) of the DG region, which was relevant to soluble Aβ1-42-induced shift of the hippocampal excitation/inhibition balance toward excitation. Interestingly, RLZ ameliorated Aβ1-42-induced behavioral and LTP impairments through rescuing the soluble Aβ1-42-induced excitation/inhibition imbalance. RLZ attenuated Aβ1-42-mediated facilitation of excitatory synaptic transmission by facilitating glutamate reuptake and decreasing presynaptic glutamate release. Meanwhile, RLZ attenuated the suppression of inhibitory synaptic transmission caused by Aβ1-42 by potentiating postsynaptic GABA receptor function. These results suggest that RLZ exerts a neuroprotective effect against soluble Aβ1-42-related spatial cognitive deficits through rescuing the excitation/inhibition imbalance, and it could be a potential therapy for AD.

Altered structural and functional brain networks have been extensively studied in major depressive disorder (MDD) patients. However, whether the differential connectivity patterns in the rich-club organization, assessed from structural brain network analyses, and the associated connections of these regions are particularly susceptible to depression remain unclear.

We acquired resting-state functional magnetic resonance imaging (R-fMRI) and diffusion tensor imaging (DTI) from 31 unmedicated MDD patients and 32 cognitively normal (CN) subjects and completed a series of neuropsychological tests. Rich-club organization, network properties, and coupling between structural and functional connectivity (SC-FC) were explored. Furthermore, whether these indices could potentially deliver effective clinical predictive value for MDD patients were examined.

The MDD patients showed disrupted structural rich-club organization and modularity, as well as a distinct correlation pattern between global efficiency and rich-club organization. Importantly, reduced SC-FC coupling, reflecting a decreased agreement in the integrity of the networks, was significantly associated with the strength of structural rich-club connections in the MDD patients. Furthermore, the disrupted structural rich-club organization, which was primarily located in the default mode network (DMN) and executive control network (ECN), emerged as a valuable indicator to distinguish between MDD and CN.

Findings of this study identified that the disrupted rich-club structural organization significantly influenced brain structural network modularity and integrity and could serve as a promising biological marker for the identification of MDD patients.

Findings of this study identified that the disrupted rich-club structural organization significantly influenced brain structural network modularity and integrity and could serve as a promising biological marker for the identification of MDD patients.Background Organic anion transporter 1 (OAT1) plays a vital role in avoiding the potential toxicity of various anionic drugs through the involvement of kidney elimination. We previously demonstrated that ubiquitin conjugation to OAT1 led to OAT1 internalization from cell surface, followed by degradation. Ubiquitination is a dynamic process, where deubiquitination is catalyzed by a class of ubiquitin-specific peptidases. Methods The role of ubiquitin-specific peptidase 8 (USP8) in hOAT1 function, expression and ubiquitination was assessed by conducting transporter uptake assay, biotinylation assay and ubiquitination assay. Results We demonstrated that USP8 overexpression in hOAT1-expressing cells led to an increased hOAT1 transporter activity and expression, which correlated well with a reduced hOAT1 ubiquitination. Such phenomenon was not observed in inactive USP8 mutant-transfected cells. In addition, the knockdown of endogenous USP8 by USP8-specific siRNA resulted in an increased hOAT1 ubiquitination, which correlated well with a decrease in hOAT1 expression and transport activity. Biotinylation experiments demonstrated that USP8-induced increase in hOAT1 expression and transport activity occurred through a deceleration of the rates of hOAT1 internalization and degradation. Conclusions These results indicated the regulatory role of USP8 in OAT1 function, expression, trafficking, and stability. General significance USP8 could be a new target for modulating OAT1-mediated drug transport.Phospholipase A2G6-associated neurodegeneration (PLAN) is a rare early-onset monogenic neurodegenerative movement disorder which targets the basal ganglia and other regions in the central and peripheral nervous system; presenting as a series of heterogenous subtypes in patients. We describe here a B6.C3-Pla2g6m1J/CxRwb mouse model of PLAN which presents with early-onset neurodegeneration at 90 days which is analogous of the disease progression that is observed in PLAN patients. Homozygous mice had a progressively worsening motor deficit, which presented as tremors starting at 65 days and progressed to severe motor dysfunction and increased falls on the wire hang test at 90 days. This motor deficit positively correlated with a reduction in tyrosine hydroxylase (TH) protein expression in dopaminergic neurons of the substantia nigra (SN) without any neuronal loss. Fluorescence imaging of Thy1-YFP revealed spheroid formation in the SN. The spheroids in homozygous mice strongly mirrors those observed in patients and were demonstrated to correlate strongly with the motor deficits as measured by the wire hang test. The appearance of spheroids preceded TH loss and increased spheroid numbers negatively correlated with TH expression. Perls/DAB staining revealed the presence of iron accumulation within the SN of mice. This mouse model captures many of the major hallmarks of PLAN including severe-early onset neurodegeneration, a motor deficit that correlates directly to TH levels, spheroid formation and iron accumulation within the basal ganglia. Thus, this mouse line is a useful tool for further research efforts to improve understanding of how these disease mechanisms give rise to the disease presentations seen in PLAN patients as well as to test novel therapies.Novel technologies using the intermediate-frequency magnetic field (IF-MF) in living environments are becoming popular with the advance in electricity utilization. However, the biological effects induced by the high-intensity and burst-type IF-MF exposure used in the wireless power transfer technologies for electric vehicles or medical devices, such as the magnetic stimulation techniques, are not well understood. Here, we developed an experimental platform using rats, that combined an 18 kHz, high-intensity (Max. 88 mT), Gaussian-shaped burst IF-MF exposure system with an in vivo extracellular recording system. In this paper, we aimed to report the qualitative differences in stimulus responses in the regions of the somatosensory cortex and peripheral nerve fibers that were induced by the IF-MF exposure to the rat spinal cord. We also report the modulation of the stimulus responses in the somatosensory cortex under anesthesia or waking states. Using this experimental platform, we succeeded in the detection of the motor evoked potentials or the neuronal activity in the somatosensory cortex that was induced by the IF-MF exposure to the spinal cord in rats. Compared to the state of anesthesia, the neuronal activities in the somatosensory cortex was enhanced during the waking state. On the other hand, these neuronal responses could not be confirmed by the IF-MF exposure-related coil sound only. Our experimental results indicated the basic knowledge of the biological responses and excitation mechanisms of the spinal cord stimulation by the IF-MF exposure.Proactive motor response inhibition is used to strategically restrain actions in preparation for stopping. In this study, we first examined the event related potential (ERP) elicited by low and high level of proactive response inhibition, as assessed by the stop-signal task. Corroborating previous studies, we found an increased amplitude of the contingent negative variation (CNV) in the high level of proactive inhibition. As the main goal of the present study, swLORETA was used to determine the neural generators characterising CNV differences between low and high levels of proactive inhibition. Results showed that the higher level of proactive inhibition involved numerous generators, including within the middle and medial frontal gyrus. Importantly, we observed that the lower level of proactive inhibition also involved a specific neural generator, within the frontopolar cortex. Altogether, present findings identified the specific brain sources of ERP signals involved in the later phase of motor preparation under low or high levels of proactive motor response inhibition.Diabetic ketoacidosis (DKA) has been associated with cognitive impairment and structural alterations in the brain. There is increased evidence supporting the role of neuroinflammation in causing these alterations. In the present study, using human microglial cell line (CHME-5), we aimed to investigate the effect of immunoglobulins (IG) on survival, activation, reactive oxygen species (ROS) and cytokine production of microglia exposed to ketone bodies. We demonstrated that high and low dose of ketone bodies induced a significant increase in ROS within 1 h after exposure to CHME-5 cells with upregulation in mitochondrial superoxide level 5 min after exposure suggestive of early and selective impairment of mitochondrial function. A significant and delayed increase of apoptosis of CHME-5 cells was observed 4 days after ketone bodies exposure. Cytokine expression reached a peak within 1 h and persisted for 3 days after exposure to ketone bodies. IG significantly reduced ROS and transiently suppressed cytokine expression of CHME-5 cells after exposure to ketone bodies. However, no effect of IG on apoptosis was observed. Overall, these results supported that ketone bodies induced microglia activation with early and selective impairment of mitochondrial function, increased cytokines expression and delayed increase in apoptosis. IG suppressed microglia activation and transiently inhibited cytokines expression without affecting apoptosis. These results warrant further experimental work on the role of microglia and potential benefit of IG in brain structural changes induced by DKA.Mild traumatic brain injury (mTBI) in early childhood is prevalent, and some children may be at risk for short- and long-term difficulties that could affect quality of life (QoL). Despite growing efforts to understand associations between potential risk factors and outcomes after injury, prognosis is elusive and lacks the inclusion of genetic variables which may convey additional predictive power. This study assessed which factors contribute to pediatric QoL 6 and 18 months post-recruitment in 159 participants (mTBI = 52; orthopedic injury [OI] = 43; typically developing controls [TDC] = 64) aged 18 to 60 months at the time of injury (M = 37.50, SD = 11.69). Family environment, injury characteristics, and child cognitive-behavioral functioning were assessed at 6 months via parent questionnaires and socio-cognitive assessment. QoL was determined using the Pediatric Quality of Life Inventory at both time points. Genetic information (Brain-derived neurotrophic factor [BDNF] genotype) was collected using saliva samples. Hierarchical regression analyses testing biological, family-environmental, injury and cognitive-behavioral factors revealed that the BDNF Val66Met polymorphism was a significant independent predictor of better QoL 6 months post-injury in the mTBI group. Lower parental distress significantly and independently predicted higher QoL 18 months after mTBI, and 6 months post-recruitment in the TDC group. At 18 months, models were non-significant for both control groups. Genetic factors involved in neuroplasticity may play an important role in recovery 6 months after mTBI and contribute to outcome via their interplay with environmental factors. Over time, family factors appear to become the primary determinants of post-mTBI outcome.This study examines how across-trial (average) and trial-by-trial (variability in) amplitude and latency of the N400 event-related potential (ERP) reflect temporal integration of pitch accent and beat gesture. Thirty native English speakers viewed videos of a talker producing sentences with beat gesture co-occurring with a pitch accented focus word (synchronous), beat gesture co-occurring with the onset of a subsequent non-focused word (asynchronous), or the absence of beat gesture (no beat). Across trials, increased amplitude and earlier latency were observed when beat gesture was temporally asynchronous with pitch accenting than when it was temporally synchronous with pitch accenting or absent. Moreover, temporal asynchrony of beat gesture relative to pitch accent increased trial-by-trial variability of N400 amplitude and latency and influenced the relationship between across-trial and trial-by-trial N400 latency. These results indicate that across-trial and trial-by-trial amplitude and latency of the N400 ERP reflect temporal integration of beat gesture and pitch accent during language comprehension, supporting extension of the integrated systems hypothesis of gesture-speech processing and neural noise theories to focus processing in typical adult populations.We investigated the effect of mild traumatic brain injury (mTBI) on the glymphatic pathway using contrast-enhanced magnetic resonance imaging (CE-MRI) and quantified with kinetic parameters obtained from an advanced two-compartment model. mTBI was induced in male Wistar rats using a closed head impact. Animals with and without mTBI (n = 7/group) underwent the identical MRI protocol 10-weeks post-injury, including T2-weighted imaging and 3D T1-weighted imaging with intra-cisterna magna injection of contrast agent (Gd-DTPA). The parameters of infusion rate, clearance rate and clearance time constant, characterizing the kinetic features of glymphatic tracer transport in a living brain, were quantified in multiple brain tissue regions. In the majority of examined regions, our quantification demonstrated significantly reduced infusion and clearance rates, and significantly increased clearance time constant in the mTBI animals compared to the healthy controls. These data indicate that mTBI induces chronic changes in influx and efflux of contrast agent and glymphatic pathway dysfunction. While the reduced efficiency of glymphatic function after mTBI was apparent in brain, regional evaluation revealed heterogeneous glymphatic effects of the mTBI in different anatomical regions. The suppression of glymphatic function, rather than the presence of focal lesions, indicates a persistent injury of the brain after mTBI. Thus, dynamic CE-MRI in conjunction with advanced kinetic analysis may offer a useful methodology for an objective assessment and confirmatory diagnosis of mTBI.

Despite the clinical effectiveness of transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), the comparability of these interventions in neurophysiological aspects have not been thoroughly investigated. Thus, we aimed to directly compare the electrophysiological effects of single-session tDCS and gamma-tACS in healthy subjects, matching the intervention protocol as closely as possible.

This was a randomized, double-blinded, and active-controlled study. Sixty healthy college students were enrolled in the study. Both tACS with, at 40Hz frequency, and tDCS have the same current intensity (2mA, 30min) within the same target area (right and left dorsolateral prefrontal cortex). Resting-state electroencephalography (EEG) was recorded before and after single-session stimulation.

Significant differences in theta, alpha, low-beta, and gamma frequencies were found between tDCS, tACS, and the sham groups. Low-beta source activity of the middle temporal gyrus was deced light on their potential clinical benefits and distinctive neuropathology in various clinical symptoms.

. The goal of the study was to test the effects of photobiomodulation therapy (PBMT) and intra-spinal injection of chondroitinase ABC (chABC) both alone and combined on pain induced by spinal cord injury (SCI) in rats.

SCI was induced by compression using an aneurysm clip. PBMT used a 660 nm laser starting at 30 minutes after SCI and then daily for 2 week, and at the end of 1-week ChABC was injected into the spinal cord. Allodynia (mechanical and cold), hyperalgesia (mechanical and thermal) and functional recovery were measured. Molecular levels of IL6, BDNF, GDNF and Gad65 were evaluated.

. Both ChABC, PBMT and the combination reduced allodynia and thermal hyperalgesia and improved functional recovery, but did not reduce mechanical hyperalgesia. Pain-related factors (BDNF and IL6) were decreased and anti-nociceptive factors (Gad65 and GDNF) were increased.

. Treatment of SCI by PBM is a non-invasive technique, and could be improved by ChABC injection to reduce neuropathic pain and improve movement.

. Treatment of SCI by PBM is a non-invasive technique, and could be improved by ChABC injection to reduce neuropathic pain and improve movement.During a range expansion, deleterious mutations can „surf” on the colonization front. The resultant decrease in fitness is known as expansion load. An Allee effect is known to reduce the loss of genetic diversity of expanding populations, by changing the nature of the expansion from „pulled” to „pushed”. We study the impact of an Allee effect on the formation of an expansion load with a new model, in which individuals have the genetic structure of a Muller’s ratchet. A key feature of Muller’s ratchet is that the population fatally accumulates deleterious mutations due to the stochastic loss of the fittest individuals, an event called a click of the ratchet. We observe fast clicks of the ratchet at the colonization front owing to small population size, followed by a slow fitness recovery due to migration of fit individuals from the bulk of the population, leading to a transient expansion load. For large population size, we are able to derive quantitative features of the expansion wave, such as the wave speed and the frequency of individuals carrying a given number of mutations. Using simulations, we show that the presence of an Allee effect reduces the rate at which clicks occur at the front, and thus reduces the expansion load.An inverse relationship between bone marrow (BM) adiposity and bone mass has been described in different physiological and pathological conditions, including osteoporosis (OP). In osteoporotic patients, lower bone mass density is indeed associated with higher BM fat content, suggesting a potential role for bone lipids in the OP pathogenesis. Nevertheless, some questions remain. Is that BM adiposity a cause or a consequence of the bone loss? What kinds of lipids are involved? Human data are somehow contradictories regarding bone lipid signature related to OP, and animal data are needed to support on one or another way the human observations. Bone lipid signature associated to OP needs to be clarified if we want to understand better their roles in OP. In that context, by using an ovariectomy-induced OP murine model and looking at lipids in two bone compartments BM and mineralized tissue (MT), our first challenge was to identify local lipid changes in relation to OP, in view to explore later the mechanisms by which those compounds could alter bone quality, particularly during the mineralization process. As the most striking data, long-term OP resulted in an accumulation of triglycerides, reduced levels of arachidonic and docosahexaenoic acids, an increase of stearoyl-CoA desaturase indices and a reduction of sphingomyelin in the MT, and potential consequences on bone properties and cell activities are discussed. The reader will appreciate that we are at an early stage of understanding the roles of lipids in the OP development and more investigations will be necessary.Low response to glucocorticoid (GC) predicts therapeutic failure in acute T lymphoblastic leukemia (T-ALL). The efficient and safe strategies are still required for the treatment of relapsed T-ALL. Our previous study revealed that tetrandrine induces apoptosis in human T lymphoblastoid leukemia cells possibly via activation of NF-κB. GCs are recognized as typical NF-κB inhibitors and are used for the treatment of T-ALL patients. In the present study, we examined whether methylprednisolone (MP) potentiates the cytotoxic effect of tetrandrine (TET) via NF-κB regulation by using human T lymphoblastoid leukemia MOLT-4 cells. WST-8 assay data showed that nM grade of MP increased cytotoxicity of TET against MOLT-4 cells in vitro. This effect seemed to be related to the potentiation of TET action by MP to induce apoptosis. Meanwhile, the combination also impeded the transition of cell cycle from G0/G1 phase to S phase. However, the regulation effect of this combination on cell cycle had no relationship with cyclin signaling pathway, since the drug-combination did not influence on the expression of cyclin A2/B1/D1 in MOLT-4 cells. On the other hand, the combination significantly inhibited the phosphorylation of NF-κB (p less then 0.01). These results suggest that nM grade of MP potentiates the cytotoxic effect of TET possibly via regulation of NF-κB activation and „G0/G1 to S” phase transition in human T lymphoblastoid leukemia MOLT-4 cells. Combination of TET and MP may provide a new therapeutic strategy for relapsed T-ALL.Postsynaptic Density Protein-95 (PSD-95) is a major scaffolding protein in the excitatory synapses in the brain and a critical regulator of synaptic maturation for NMDA and AMPA receptors. PSD-95 deficiency has been linked to cognitive and learning deficits implicated in neurodevelopmental disorders such as autism and schizophrenia. Previous studies have shown that PSD-95 deficiency causes a significant reduction in the excitatory response in the hippocampus. However, little is known about whether PSD-95 deficiency will affect gamma-aminobutyric acid (GABA)ergic inhibitory synapses. Using a PSD-95 transgenic mouse model (PSD-95+/-), we studied how PSD-95 deficiency affects GABAA receptor expression and function in the medial prefrontal cortex (mPFC) during adolescence. Our results showed a significant increase in the GABAA receptor subunit α1. Correspondingly, there are increases in the frequency and amplitude in spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons in the mPFC of PSD-95+/- mice, along with a significant increase in evoked IPSCs, leading to a dramatic shift in the excitatory-to-inhibitory balance in PSD-95 deficient mice. Furthermore, PSD-95 deficiency promotes inhibitory synapse function via upregulation and trafficking of NLGN2 and reduced GSK3β activity through tyr-216 phosphorylation. Our study provides novel insights on the effects of GABAergic transmission in the mPFC due to PSD-95 deficiency and its potential link with cognitive and learning deficits associated with neuropsychiatric disorders.The core (capsid) protein of hepatitis B virus (HBV) is the building block of nucleocapsids where viral DNA reverse transcriptional replication takes place and mediates virus-host cell interaction important for the persistence of HBV infection. The pleiotropic role of core protein (Cp) in HBV replication makes it an attractive target for antiviral therapies of chronic hepatitis B, a disease that affects more than 257 million people worldwide without a cure. Recent clinical studies indicate that core protein allosteric modulators (CpAMs) have a great promise as a key component of hepatitis B curative therapies. Particularly, it has been demonstrated that modulation of Cp dimer-dimer interactions by several chemical series of CpAMs not only inhibit nucleocapsid assembly and viral DNA replication, but also induce the disassembly of double-stranded DNA-containing nucleocapsids to prevent the synthesis of cccDNA. Moreover, the different chemotypes of CpAMs modulate Cp assembly by interaction with distinct amino acid residues at the HAP pocket between Cp dimer-dimer interfaces, which results in the assembly of Cp dimers into either non-capsid Cp polymers (type I CpAMs) or empty capsids with distinct physical property (type II CpAMs). The different CpAMs also differentially modulate Cp metabolism and subcellular distribution, which may impact cccDNA metabolism and host antiviral immune responses, the critical factors for the cure of chronic HBV infection. This review article highlights the recent research progress on the structure and function of core protein in HBV replication cycle, the mode of action of CpAMs, as well as the current status and perspectives on the discovery and development of core protein-targeting antivirals. This article forms part of a symposium in Antiviral Research on „Wide-ranging immune and direct-acting antiviral approaches to curing HBV and HDV infections.”The nuclear factor erythroid 2 related factor 2 (Nrf2) pathway upregulates key cellular defenses. Clinical trials are utilizing pharmacologic Nrf2 inducers such as bardoxolone methyl to treat chronic kidney disease, but Nrf2 activation has been linked to a paradoxical increase in; proteinuria. To understand this effect, we examined genetically engineered mice with elevated Nrf2 signaling due to reduced expression of the Nrf2 inhibitor, Kelch-like ECH-associated protein-1 (Keap1). These Keap1FA/FA mice lacked baseline proteinuria but exhibited increased; proteinuria in experimental models evoked by adriamycin, angiotensin II, or protein overload. After injury, Keap1FA/FA mice had increased glomerulosclerosis, nephrin disruption and shedding, podocyte injury, foot process effacement, and interstitial fibrosis. Keap1FA/FA mice also had higher daytime blood pressures and lower heart rates measured by radiotelemetry. Conversely, Nrf2 knockout mice were protected from proteinuria. We also examined the pharmacologic Nrf2 inducer CDDO-Im. Compared to angiotensin II alone, the combination of angiotensin II and CDDO-Im significantly increased proteinuria, a phenomenon not observed in Nrf2 knockout mice. This effect was not accompanied by additional increases in blood pressure. Finally, Nrf2 was found to be upregulated in the glomeruli of patients with focal segmental glomerulosclerosis, diabetic nephropathy, fibrillary glomerulonephritis, and membranous nephropathy. Thus, our studies demonstrate that Nrf2 induction in mice may exacerbate proteinuria in chronic kidney disease.Immunotactoid glomerulopathy (ITG) is a rare form of glomerulonephritis for which our understanding is limited to case reports and small case series. Herein we describe the clinical, pathologic, and outcome characteristics of 73 patients with ITG who typically presented with proteinuria, hematuria, and renal insufficiency. Hematologic disorders were present in 66% of patients, including lymphoma in 41% (mainly chronic lymphocytic leukemia/small lymphocytic lymphoma), monoclonal gammopathy in 20%, and multiple myeloma in 6%. Light microscopy revealed endocapillary proliferative (35%), membranoproliferative (29%) and membranous (29%) patterns of glomerular involvement. Electron microscopy revealed characteristic microtubular deposits with a diameter of 14-60 nm, hollow cores, frequent parallel alignment, and a predominant distribution outside of the lamina densa of the glomerular basement membrane. Importantly, immunofluorescence revealed IgG-dominant staining which was light chain and IgG subclass restricted in 67% of cases, indicating monoclonal composition. This finding was used to distinguish monoclonal and polyclonal variants of ITG. As compared to polyclonal, monoclonal ITG had a higher incidence of lymphoma (53% vs.11%), multiple myeloma (8% vs. 0), and monoclonal gammopathy (22% vs. 16%). Monoclonal ITG was more commonly treated with clone-directed therapy, which was associated with more frequent remission and less frequent end stage kidney disease. Thus, a third of ITG cases are polyclonal but a quarter of these cases are associated with hematologic conditions, underscoring the need for hematologic evaluation in all patients with ITG. Hence, based on these distinctions, ITG should be subclassified into monoclonal and polyclonal variants. Prognosis of ITG is good if the underlying hematologic condition is treated.During embryonic development in bilaterally symmetric organisms, correct midline crossing is important for the proper formation of functional neural circuits. The aberrant development of neural circuits can result in multiple neurodevelopmental disorders, including horizontal gaze palsy, congenital mirror movement disorder, and autism spectrum disorder. Thus, understanding the molecular mechanisms that regulate proper axon guidance at the midline can provide insights into the pathology of neurological disorders. The signaling mechanisms that regulate midline crossing have been extensively studied in the Drosophila ventral nerve cord and the mouse embryonic spinal cord. In this review, we discuss these axon guidance mechanisms, highlighting the most recent advances in the understanding of how commissural axons switch their responsiveness from attractants to repellents during midline crossing.