Central Nervous System Activity Research Articles

MRNA editing of kainate receptor subunits: what do we know so far?

Kainate receptors (KARs) are considered one of the key modulators of synaptic activity in the mammalian central nervous system. These receptors were discovered more than 30 years ago, but their role in brain functioning remains unclear due to some peculiarities. One such feature of these receptors is the editing of pre-mRNAs encoding GluK1 and GluK2 subunits. Despite the long history of studying this phenomenon, numerous questions remain unanswered. This review summarizes the current data about the mechanism and role of pre-mRNA editing of KAR subunits in the mammalian brain and proposes a perspective of future investigations.

Dual Orexin Receptor Antagonist Attenuates Increases in IOP, ICP, and Translaminar Pressure Difference After Stimulation of the Hypothalamus in Rats.

PurposeIntraocular pressure (IOP) remains the only modifiable risk factor for glaucoma progression. Our previous discovery that stimulation of nuclei within the hypothalamus can modulate IOP, intracranial pressure (ICP), and translaminar pressure difference (TLPD) fluctuations led us to investigate this pathway further. Our purpose was to determine the role of orexin neurons, primarily located in the dorsomedial hypothalamus (DMH) and perifornical (PeF) regions of the hypothalamus, in modulating these pressures.MethodsSprague Dawley rats were pretreated systemically with a dual orexin receptor antagonist (DORA-12) at 30 mg/Kg (n = 8), 10 mg/Kg (n = 8), or vehicle control (n = 8). The IOP, ICP, heart rate (HR), and mean arterial pressure (MAP) were recorded prior to and following excitation of the DMH/PeF using microinjection of the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline methiodide (BMI).ResultsAdministration of the DORA at 30 mg/Kg significantly attenuated peak IOP by 5.2 ± 3.6 mm Hg (P = 0.007). During the peak response period (8–40 minutes), the area under the curve (AUC) for the 30 mg/Kg DORA cohort was significantly lower than the control cohort during the same period (P = 0.04). IOP responses for peak AUC versus DORA dose, from 0 to 30 mg/Kg, were linear (R2 = 0.18, P = 0.04). The ICP responses during the peak response period (4–16 minutes) versus DORA dose were also linear (R2 = 0.24, P = 0.014). Pretreatment with DORA significantly decreased AUC for the TLPD following stimulation of the DMH/PeF (10 mg/kg, P = 0.045 and 30 mg/kg, P = 0.015).ConclusionsDORAs have the potential to attenuate asynchronous changes in IOP and in ICP and to lessen the extent of TLPDs that may result from central nervous system (CNS) activation.

Abuse Potential of Cathinones in Humans: A Systematic Review.

Introduction and objective: Assessing the abuse potential of new substances with central nervous system activity is essential for preventing possible risks of misuse and addiction. The same methodology is recommended for the evaluation of the abuse potential of recreational drugs. This systematic review aims to assess the pharmacological effects related to the abuse potential and pharmacokinetics of cathinones, which are evaluated in both experimental and prospective observational studies in humans. Materials and Methods: A systematic search of the published literature was conducted to retrieve studies that had administered cathinone, mephedrone, methylone, and diethylpropion to evaluate their acute pharmacological effects related to abuse potential. Results: The search yielded 583 results, 18 of which were included to assess the abuse potential of cathinone (n = 5), mephedrone (n = 7), methylone (n = 1), and diethylpropion (n = 5). All four substances induce stimulant and euphorigenic effects that resemble those of amphetamines and MDMA, and their different intensities may be associated with varying levels of abuse potential. Conclusions: Cathinone, mephedrone, methylone, and diethylpropion induce a range of desirable and reinforcing effects that may, to some extent, result in abuse potential. Further investigation is needed to minimize and prevent their impact on society and public health.

Abstract PD4-05: Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases (BCBM)

Abstract Purpose: Up to half of patients (pts) with HER2+ metastatic breast cancer (MBC) will develop BCBM. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) with demonstrated efficacy in previously treated pts with HER2+ MBC. However, few pts with stable/treated brain metastases, and no pts with active (untreated or progressive) brain metastases, were included in completed clinical trials of T-DXd. Thus, central nervous system (CNS) efficacy of T-DXd is not well-characterized. Methods: We tested T-DXd in orthotopic pt BCBM-derived xenograft (PDX) models of HER2+, and HER2-low, BCBMs. To further validate T-DXd single agent CNS activity, we described clinical outcomes of T-DXd in a multi-institutional retrospective cohort of 16 patients with BCBM. Consecutive pts who initiated T-DXd between 1 Jan 2020 - 1 Nov 2020 (Duke) or 1 Jan 2020 - 15 June 2020 (Dana-Farber Cancer Institute) were included. Data cut-off date was 31 Dec 2020. CNS response was measured by via central radiology review at each participating institution. Up to 5 CNS target lesions were included. CNS partial response (PR) required >30% reduction in sum of CNS target lesions. Results: Treatment with 10 mg/kg T-DXd significantly prolonged survival in HER2+ BCBM PDX models DFBM-354 (67 vs 154 days, p=0.0018) and DFBM-355 (78 vs 156 days, p=0.0067) vs. vehicle control. We then tested TDX-d in a HER2 low BCBM PDX model (IHC 2+/FISH ratio <2) and found that c.f. vehicle, TDX-d significantly prolonged survival (72 v 141 days, p = 0.02). Finally, we treated DFBM-355 with trastuzumab emtansine (T-DM1) to generate resistance followed by treatment with T-DXd. We found that c.f. vehicle or continued T-DM1, T-DXd significantly prolonged survival in a T-DM1 resistant BCBM PDX model (63 vs 99 vs 215 days, p=0.01). In the retrospective cohort, median age was 44 (33-69 years). 15/16 pts had confirmed HER2 IHC 3+ or FISH-positive primary or metastatic tissue. 9/16 (56%) pts had either progressive or untreated HER2+ BCBMs on initiation of T-DXd. Median number of prior metastatic therapies was 4 (0-10). 14/16 (88%) had received previous T-DM1; 11/16 (69%) had received previous HER2-targeted tyrosine kinase inhibitor. Median time from previous CNS radiation was 15.1 months (1.3 - 45.2). At the time of data cutoff, 7 pts remained on T-DXd. Median number of cycles was 7 (2-17+). Responses are shown in Table 1. The overall intracranial clinical benefit rate (CR/PR or stable disease) was 75%, including 89% (8/9) of those with progressive or untreated BCBM at baseline. Conclusions: In a multi-institution cohort of 16 pts with HER2+ BCBMs treated with T-DXd, we find preliminary evidence of CNS efficacy, including in pts with progressive or untreated BCBMs. Additional pt data and further follow up will be presented at the meeting. Using BCBM PDX models we find that T-DXd prolongs survival in untreated HER2+ BCBM PDX models as well as in T-DM1 treated models. We also demonstrate efficacy of T-DXd in a HER2 low BCBM PDX model. Together, these data suggest that T-DXd has intracranial efficacy against HER2+ BCBMs. Prospective clinical trials in this pt population are warranted. Table 1.Best CNS Response of study cohortOverall population (n=16)Pts with progressive or untreated CNS disease at baseline (N=9)Pts with stable/treated CNS disease at baseline (N=7)Complete response (CR)0 (0)00 (0)Partial response (PR)10 (63)6 (67)#4 (57)+Stable disease (SD)2 (13)2 (22)0 (0)Progressive disease (PD)1 (6)0 (0)1 (14)No measurable CNS disease at baseline2 (13)0 (0)2 (29)Lost to follow-up1 (6)1 (11)0 (0).#Among these 6 pts, interval between most recent radiation and T-DXd initiation was 14.3 months, 12.4 months, 17 months, 18.2 months, and 8.2 months (one pt was radiation-naïve). +Among these 4 pts, interval between most recent radiation and T-DXd initiation was 19.1 months, 15.1 months, 1.5 months, and 16.9 months, respectively. Citation Format: Sheheryar Kabraji, Jing Ni, Sarah Sammons, Amanda ED Van Swearingen, Yanzhi Wang, Alyssa M Pereslete, Liangge Hsu, Chris Lascola, Heather Moore, Melissa Hughes, Akshara S Raghavendra, Maria Gule-Monroe, Rashmi K Murthy, Eric P Winer, Carey K Anders, Jean J Zhao, Nancy U Lin. Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases (BCBM) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-05.

Effects of Dapagliflozin and Combination Therapy With Exenatide on Food-Cue Induced Brain Activation in Patients With Type 2 Diabetes.

ContextSodium-glucose cotransporter-2 inhibitors (SGLT2i) cause less weight loss than expected based on urinary calorie excretion. This may be explained by SGLT2i-induced alterations in central reward and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists are associated with reduced appetite and body weight, mediated by direct and indirect central nervous system (CNS) effects.ObjectiveWe investigated the separate and combined effects of dapagliflozin and exenatide on the CNS in participants with obesity and type 2 diabetes.MethodsThis was a 16-week, double-blind, randomized, placebo-controlled trial. Obese participants with type 2 diabetes (n = 64, age 63.5 ± 0.9 years, BMI 31.7 ± 0.6 kg/m2) were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice daily 10 µg with dapagliflozin-matched placebo, dapagliflozin and exenatide, or double placebo. Using functional MRI, the effects of treatments on CNS responses to viewing food pictures were assessed after 10 days and 16 weeks of treatment.ResultsAfter 10 days, dapagliflozin increased, whereas exenatide decreased CNS activation in the left putamen. Combination therapy had no effect on responses to food pictures. After 16 weeks, no changes in CNS activation were observed with dapagliflozin, but CNS activation was reduced with dapagliflozin-exenatide in right amygdala.ConclusionThe early increase in CNS activation with dapagliflozin may contribute to the discrepancy between observed and expected weight loss. In combination therapy, exenatide blunted the increased CNS activation observed with dapagliflozin. These findings provide further insights into the weight-lowering mechanisms of SGLT2i and GLP-1 receptor agonists.

Binding studies of dopamine HCl drug with the mixed {sodium bis(2-ethylhexyl) sulfosuccinate + sodium dodecylsulfate} micelles: Physicochemical, spectroscopic, calorimetric and computational approach

Taking into consideration the importance of dopamine HCl as neurotransmitter in controlling central nervous system activities, the studies of binding interactions of dopamine HCl drug with micellar system (imitator of biomembranes) have been conducted by utilizing experimental as well as computational techniques. The systematic knowledge of physicochemical, spectroscopic and calorimetric properties is helpful to understand the physiological actions of biologically active additives in the living organisms. Therefore, mixed aggregation behavior of sodium bis(2-ethylhexyl) sulfosuccinate, AOT and sodium dodecylsulfate, SDS has been explored at diverse mole fractions of AOT, αAOT = 0.25, 0.39 and 0.50 in (1, 2 and 3) × 10−3 mol kg−1 dopamine HCl(aq) solutions by employing different techniques. From conductivity studies, the thermodynamic parameters (∆G°m, ∆H°m and ∆S°m), the molecular interaction parameter (βint) and the excess Gibbs free energy of micellization (∆Gmex) were ascertained at T = (298.15, 308.15, and 318.15) K. Isentropic compressibility (κs), partial specific volume (φv) and partial specific isentropic compressibility (φκ) parameters were computed from the density and sound velocity studies. Binding constant (Kb) and standard Gibbs free energy of binding (∆Gbο) have been evaluated from UV–visible absorption studies for dopamine HCl(aq) solutions at all the studied mole fractions of surfactant mixtures. Through dynamic light scattering (DLS) measurements, the hydrodynamic diameters (Dh) of mixed micellar aggregates have been acquired. Isothermal titration calorimetric (ITC) studies were executed to obtain the values of partitioning constant / binding constant (K), standard molar enthalpy of binding (ΔrHᴼ), standard molar entropy of binding (ΔrSᴼ), and stoichiometry of partitioning / binding (n) of drug with micellar system. Through density functional theory (DFT) calculations, the band gap between HOMO and LUMO for the dopamine-HCl bound mixed micelle system, and interactive features have been obtained. Aforementioned studies favor the supremacy of hydrophilic-hydrophilic / ionic and electrostatic interactions causing the binding among the hydrophilic / ionic groups of dopamine HCl (−OH, H+, Cl−), AOT (–SO3−, –OCO, Na+), and SDS (–OSO3−, Na+).

Potential of flavonoids as anti-Alzheimer’s agents: bench to bedside

Developing therapies for neurodegenerative diseases are challenging because of the presence of blood-brain barrier and Alzheimer being one of the commonest and uprising neurodegenerative disorders possess the need for developing novel therapies. Alzheimer's is attributed to be the sixth leading cause of death in the USA and the number of cases is estimated to be increased from 58 million in 2021 to 88 million by 2050. Natural drugs have benefits of being cost-effective, widely available, fewer side effects, and immuno-booster can be useful in managing Alzheimer. Flavonoids can slow the neuronal degeneration as they have shown activity in central nervous system and are able to cross the blood-brain barrier. These can be easily extracted from fruits, vegetable, and plants. In Alzheimer disease, flavonoids scavenges the reactive oxygen species and reduces the production of amyloid beta protein. Agents from sub-classes of flavonoids such as flavanones, flavanols, flavones, flavonols, anthocyanins, and isoflavones having pharmacological action in treating Alzheimer disease are discussed in this review.

Adenosine Receptors in Neuropsychiatric Disorders: Fine Regulators of Neurotransmission and Potential Therapeutic Targets.

Adenosine exerts an important role in the modulation of central nervous system (CNS) activity. Through the interaction with four G-protein coupled receptor (GPCR) subtypes, adenosine subtly regulates neurotransmission, interfering with the dopaminergic, glutamatergic, noradrenergic, serotoninergic, and endocannabinoid systems. The inhibitory and facilitating actions of adenosine on neurotransmission are mainly mediated by A1 and A2A adenosine receptors (ARs), respectively. Given their role in the CNS, ARs are promising therapeutic targets for neuropsychiatric disorders where altered neurotransmission represents the most likely etiological hypothesis. Activating or blocking ARs with specific pharmacological agents could therefore restore the balance of altered neurotransmitter systems, providing the rationale for the potential treatment of these highly debilitating conditions. In this review, we summarize and discuss the most relevant studies concerning AR modulation in psychotic and mood disorders such as schizophrenia, bipolar disorders, depression, and anxiety, as well as neurodevelopment disorders such as autism spectrum disorder (ASD), fragile X syndrome (FXS), attention-deficit hyperactivity disorder (ADHD), and neuropsychiatric aspects of neurodegenerative disorders.

Effects of Resistance Training on Skin Temperature and Its Relationship with Central Nervous System (CNS) Activation.

The aim of this work was to relate the activation of the sympathetic and parasympathetic nervous systems with the skin temperature (Tsk) of the lower limbs after a resistance training exercise. Under controlled conditions, the average Tsk in the areas of the anterior and posterior thighs, knees and legs was obtained with a thermal imager and the parasympathetic and sympathetic activation was registered with an Omegawave® device on 20 healthy and trained male volunteers (25.39 ± 8.21 years) before exercise, immediately after standard resistance training (3 exercises (2 quadriceps + 1 hamstrings) × 4 sets × 10 repetitions (70% 1RM), 90-sec recovery) and after 20 min of recovery. The results showed a significant effect of exercise and recovery on Tsk in all regions of interest (ROIs) considered (p < 0.05) and strong inverse relationships between sympathetic and parasympathetic activation values. Significant results were found for the total variation of Tsk (p < 0.05) with highly positive values for subjects with lower sympathetic activation and almost null or even negative values for those with higher sympathetic activation. Sympathetic activity was a significant predictor of total Tsk variation in the anterior thigh, posterior thigh and anterior knee but not in the posterior knee, anterior leg, and posterior leg. Baseline Tsk was a significant predictor of total Tsk variation the all ROIs except in the posterior knee. Tsk measured by thermography could be used to estimate the level of participation of muscle areas in exercise and registering the level of sympathetic activation before exercise could be interesting in predicting the athlete’s physiological response to strength training.

Neuromuscular Control Modelling of Human Perturbed Posture Through Piecewise Affine Autoregressive With Exogenous Input Models.

In this study, the neuromuscular control modeling of the perturbed human upright stance is assessed through piecewise affine autoregressive with exogenous input (PWARX) models. Ten healthy subjects underwent an experimental protocol where visual deprivation and cognitive load are applied to evaluate whether PWARX can be used for modeling the role of the central nervous system (CNS) in balance maintenance in different conditions. Balance maintenance is modeled as a single-link inverted pendulum; and kinematic, dynamic, and electromyography (EMG) data are used to fit the PWARX models of the CNS activity. Models are trained on 70% and tested on the 30% of unseen data belonging to the remaining dataset. The models are able to capture which factors the CNS is subjected to, showing a fitting accuracy higher than 90% for each experimental condition. The models present a switch between two different control dynamics, coherent with the physiological response to a sudden balance perturbation and mirrored by the data-driven lag selection for data time series. The outcomes of this study indicate that hybrid postural control policies, yet investigated for unperturbed stance, could be an appropriate motor control paradigm when balance maintenance undergoes external disruption.

Sepsis-Exacerbated Brain Dysfunction After Intracerebral Hemorrhage.

Sepsis susceptibility is significantly increased in patients with intracerebral hemorrhage (ICH), owing to immunosuppression and intestinal microbiota dysbiosis. To date, ICH with sepsis occurrence is still difficult for clinicians to deal with, and the mortality, as well as long-term cognitive disability, is still increasing. Actually, intracerebral hemorrhage and sepsis are mutually exacerbated via similar pathophysiological mechanisms, mainly consisting of systemic inflammation and circulatory dysfunction. The main consequence of these two processes is neural dysfunction and multiple organ damages, notably, via oxidative stress and neurotoxic mediation under the mediation of central nervous system activation and blood-brain barrier disruption. Besides, the comorbidity-induced multiple organ damages will produce numerous damage-associated molecular patterns and consequently exacerbate the severity of the disease. At present, the prospective views are about operating artificial restriction for the peripheral immune system and achieving cross-tolerance among organs via altering immune cell composition to reduce inflammatory damage.

Safe and Effective Cynomolgus Monkey GLP-Tox Study with Repetitive Intrathecal Application of a TGFBR2 Targeting LNA-Gapmer Antisense Oligonucleotide as Treatment Candidate for Neurodegenerative Disorders.

The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGFβ system to represent a potential pathogenic participant in disease progression, of amyotrophic lateral sclerosis (ALS) in particular, by generating and promoting a disequilibrium of neurodegenerative and neuroregenerative processes. The novel human/primate specific LNA Gapmer Antisense Oligonucleotide “NVP-13”, targeting TGFBR2, effectively reduced its expression and lowered TGFβ signal transduction in vitro and in vivo, paralleled by boosting neurogenic niche activity in human neuronal progenitor cells and nonhuman primate central nervous system. Here, we investigated NVP-13 in vivo pharmacology, safety, and tolerability following repeated intrathecal injections in nonhuman primate cynomolgus monkeys for 13 weeks in a GLP-toxicology study approach. NVP-13 was administered intrathecally with 1, 2, or 4 mg NVP-13/animal within 3 months on days 1, 15, 29, 43, 57, 71, and 85 in the initial 13 weeks. We were able to demonstrate an excellent local and systemic tolerability, and no adverse events in physiological, hematological, clinical chemistry, and microscopic findings in female and male Cynomolgus Monkeys. Under the conditions of this study, the no observed adverse effect level (NOAEL) is at least 4 mg/animal NVP-13.

Jatrorrhizine: A Review of Sources, Pharmacology, Pharmacokinetics and Toxicity.

Jatrorrhizine, an isoquinoline alkaloid, is a bioactive metabolite in common medicinal plants, such as Berberis vernae Schneid., Tinospora sagittata (Oliv.) Gagnep. and Coptis chinensis Franch. These plants have been used for centuries in traditional medicine for their wide-ranging pharmacological properties. This review emphasizes the latest and comprehensive information on the sources, pharmacology, pharmacokinetics and toxicity of jatrorrhizine. Studies on this alkaloid were collected from scientific internet databases, including the Web of Science, PubMed, ScienceDirect, Google Scholar, Elsevier, Springer, Wiley Online Library and Europe PMC and CNKI, using a combination of keywords involving “jatrorrhizine”, “sources”, “pharmacology,” “pharmacokinetics,” and “toxicology”. Jatrorrhizine exhibits anti-diabetic, antimicrobial, antiprotozoal, anticancer, anti-obesity and hypolipidemic properties, along with central nervous system activities and other beneficial activity. Studies of jatrorrhizine have laid the foundation for its application to the treatment of various diseases, but some issues still exist. Further investigations might emphasize 1) specific curative mechanisms of jatrorrhizine and clinical utility, 2) application prospect in the treatment of metabolic disorders, 3) comprehensive investigations of the toxicity mechanisms and 4) interactions of jatrorrhizine with other pharmaceuticals and development of derivatives.

Ponesimod inhibits astrocyte-mediated neuroinflammation and protects against cingulum demyelination via S1P1 -selective modulation.

Ponesimod is a sphingosine 1‐phosphate (S1P) receptor (S1PR) modulator that was recently approved for treating relapsing forms of multiple sclerosis (MS). Three other FDA‐approved S1PR modulators for MS—fingolimod, siponimod, and ozanimod—share peripheral immunological effects via common S1P1 interactions, yet ponesimod may access distinct central nervous system (CNS) mechanisms through its selectivity for the S1P1 receptor. Here, ponesimod was examined for S1PR internalization and binding, human astrocyte signaling and single‐cell RNA‐seq (scRNA‐seq) gene expression, and in vivo using murine cuprizone‐mediated demyelination. Studies confirmed ponesimod’s selectivity for S1P1 without comparable engagement to the other S1PR subtypes (S1P2,3,4,5). Ponesimod showed pharmacological properties of acute agonism followed by chronic functional antagonism of S1P1. A major locus of S1P1 expression in the CNS is on astrocytes, and scRNA‐seq of primary human astrocytes exposed to ponesimod identified a gene ontology relationship of reduced neuroinflammation and reduction in known astrocyte disease‐related genes including those of immediate early astrocytes that have been strongly associated with disease progression in MS animal models. Remarkably, ponesimod prevented cuprizone‐induced demyelination selectively in the cingulum, but not in the corpus callosum. These data support the CNS activities of ponesimod through S1P1, including protective, and likely selective, effects against demyelination in a major connection pathway of the brain, the limbic fibers of the cingulum, lesions of which have been associated with several neurologic impairments including MS fatigue.

Neuroinflammation in the pathogenesis of central neuropathic pain

The problem of chronic pain is a significant question of nowadays medicine due to its high prevalence and treatment ineffectiveness in most cases. It has been proved by means of neuroimaging methods that chronic pain is always associated with glial activation in central nervous system, leading to the disturbance of glial cells participation in the eregulation of neuron microenvironment and neurotransmitter exchange. As a result, interneuronal communication in nociceptive pathways is interrupted and pathological neuroplasticity processes develop, causing the formation of pathological circuits, selfregilated by means of positive feedback. Thus, intervention that is directed to neuroinflammation suppression can by pathogeneticaly approved and effective method to treat chronic pain. In this review basic mechanisms of the inflammation initiation and maintaining in central nervous system in chronic pain are considered, pathological self-regulated circuits with neurons and immune cells are described and current chronic pain medications with antiinflammatiry and antinociceptive properties are listed.

An Auto-Weighting Incremental Random Vector Functional Link Network for EEG-Based Driving Fatigue Detection

Recently, Electroencephalogram (EEG) has been receiving increasing attention in driving fatigue attention because it is generated by the neural activities of central nervous system and has been regarded as the gold standard to measure fatigue. However, most existing studies for EEG-based driving fatigue detection have some common limitations such as 1) using the batch learning mode and no incremental updating ability, 2) converting continuous fatigue indices into discrete levels which deviates far from the essence of fatigue detection, and 3) neglecting considering the different contributions of EEG feature dimensions in fatigue expression. To handle these problems, we propose an Auto-Weighting Incremental Random Vector Functional Link network (AWIRVFL) model for EEG-based driving fatigue detection, which simultaneously implements online regression prediction and incremental learning. Moreover, an auto-weighting variable is introduced to adaptively and quantitatively explore the importance of different feature dimensions. A novel optimization algorithm is proposed to solve the AWIRVFL objective function. Experiments were conducted on the SEED-VIG and sustained-attention driving task (SADT) data sets to validate the performance of AWIRVFL and the results demonstrated that AWIRVFL greatly outperforms the state-of-the-arts in terms of the two regression evaluation metrics, RMSE and MAPE. Moreover, the quantitative feature importance values are obtained.

Ideal sequencing in Stage IV epidermal growth factor receptor mutant Non-Small-Cell Lung Cancer.

Evidence from several studies has shown improved progression-free survival (PFS) with first- or second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) compared with chemotherapy for advanced NSCLC patients. But resistance to first or second-generation TKI therapies after 9 to 12 months of treatment initiation is a concern. Osimertinib is a third-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFRm (epidermal growth factor receptor mutated) and EGFR T790M and has demonstrated efficacy in NSCLC central nervous system (CNS) metastases. Trials have reported significantly longer PFS and higher median duration of response with osimertinib compared with first-generation EGFR-TKIs (erlotinib, gefitinib) and chemotherapy, respectively. And relatively lower rates of discontinuation due to adverse events (AEs). Significant improvement in overall survival was also observed when used as first-line treatment. Because EGFR-mutated tumors are highly dependent on EGFR signaling, optimal sequence of available TKIs - erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib - is necessary. The sequencing of EGFR-TKIs has changed over the past decade and depends on factors such as expected efficacy, CNS activity, tolerability, and options available after progression. Third-generation TKI may be the preferred first-line treatment because patients may not opt for or die before the start of second-line therapy, and it is difficult to predict which patients will eventually develop T790M mutation. The favorable tolerability profile alongside a longer time to disease progression makes osimertinib a preferred first-line treatment. Though clinical practice guidelines do not provide clear consensus on the most preferred EGFR-TKI, recent updates recommend osimertinib as a first-line treatment for advanced NSCLC patients. Also, improved patient selection incorporating clinical and molecular characteristics will help translate to better survival outcomes and improved quality of life. This review aims to determine the optimal sequence of administration of the EGFR-TKIs considering toxicity, quality of life, and survival outcomes among advanced NSCLC patients.

Assessment of melatonin-alpha adrenergic receptor complexes by molecular docking analysis.

The pineal melatonin (N-acetyl-5-methoxytryptamine) is a molecule associated in a way or another with probably all physiological systems, aiming to fulfil its functional integrative roles in central nervous system activity, sleep and wakefulness cycles, energy metabolism and thermoregulation, immune, reproductive, endocrine, cardiovascular, respiratory and excretory systems. Within this context, the present study aimed to assess in silico the formation of complexes between ligand melatonin and other potential receptor proteins by molecular docking analyses. The main steps established in this experimental procedure were: a) search and selection of the 3D structure of the melatonin from DrugBank; b) search and selection of 3D structures of other target receptor proteins using STRING, protein BLAST and database PDB; and c) formation of the complexes between melatonin and receptors selected using AutoDock4.0 server by molecular docking analyses. High reliability score and significant similarity were only identified between type 1B melatonin and alpha-2A adrenergic receptor. Thus, molecular docking assays were carried out using ligand melatonin and crystallographic structures of the alpha-2A adrenergic receptor coupled to an antagonist (ID PDB 6kux) and a partial agonist (ID PDB 6kuy) available in the database PDB. Binding energy values of -6.79 and -6.98 kcal/mol and structural stability by non-covalent intermolecular interactions were predicted during the formation of complexes between melatonin and alpha-2A adrenergic receptor 6kux and 6kuy, respectively. In this way, the findings described in current study may indicate strong interactions between melatonin and adrenoceptors, suggesting its possible partial agonist effect on the activation of the alfa-2A adrenergic receptor.

Traditional Chinese Medicine Fulonggan (Terra Flava Usta) Improves the Clinical Syndrome and Comorbidity of Regressive Autism: A Case Report

The occurrence of regressive autism is closely related to the disturbance of immunity and intestinal microbiota. The intestinal microbiota plays an important role in maintaining the balance of the human immune system, and also regulated central nervous system activity. Soil is a micro-ecological environment that contains the majority of all known microbial species. The number of species found in human feces is around 1/10 times of that found in soil. Therefore, soil can be considered as the microbial “seed bank”. Our previous research indicated that everyday living environments are too clean, which, combined with the lack of contact with soil, results in the loss of a large number of microorganisms, and eating soil increased the gut microbial diversity and immune function in mice. As a special soil, Fulonggan (Terra Flava Usta) is a safe traditional Chinese medicine that has been used in the clinic for 1500 years. Here we report a case of 4.5-year-old male regressive autism with comorbidities of food allergy, allergic rhinitis, and constipation. Fulonggan was used to treat for 12 months from the age of 52 months to 63 months. For the first month of taking Fulonggan, he was also receiving the allergy medicine Singulair (montelukast). The constipation disappeared 5 days after taking Fulonggan, the allergic rhinitis disappeared 4 months later, and the food allergy disappeared after the treatment was stopped. Furthermore, the language skills, social skills, and mood were obviously better according to the Gesell Developmental Scale–Chinese Revised Version and Autism Behavior Checklist. At present, the child has returned to kindergarten. This report proposes a new method for the treatments of regressive autism and comorbidities including food allergy, allergic rhinitis, and constipation. The therapeutic method is effective and safe, and worth to be an alternative for regressive autism or allergy diseases.

The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of central nervous system activity with repeated dosing.

Activation of cannabinoid receptor type 1 (CB 1 ) produces analgesia in a variety of preclinical models of pain; however, engagement of central CB 1 receptors is accompanied by unwanted side effects, such as psychoactivity, tolerance, and dependence. Therefore, some efforts to develop novel analgesics have focused on targeting peripheral CB 1 receptors to circumvent central CB 1 -related side effects. In the present study, we evaluated the effects of acute and repeated dosing with the peripherally selective CB 1 -preferring agonist CB-13 on nociception and central CB 1 -related phenotypes in a model of inflammatory pain in mice. We also evaluated cellular mechanisms underlying CB-13-induced antinociception in vitro using cultured mouse dorsal root ganglion neurons. CB-13 reduced inflammation-induced mechanical allodynia in male and female mice in a peripheral CB 1 -receptor-dependent manner and relieved inflammatory thermal hyperalgesia. In cultured mouse dorsal root ganglion neurons, CB-13 reduced TRPV1 sensitization and neuronal hyperexcitability induced by the inflammatory mediator prostaglandin E 2 , providing potential mechanistic explanations for the analgesic actions of peripheral CB 1 receptor activation. With acute dosing, phenotypes associated with central CB 1 receptor activation occurred only at a dose of CB-13 approximately 10-fold the ED 50 for reducing allodynia. Strikingly, repeated dosing resulted in both analgesic tolerance and CB 1 receptor dependence, even at a dose that did not produce central CB 1 -receptor-mediated phenotypes on acute dosing. This suggests that repeated CB-13 dosing leads to increased CNS exposure and unwanted engagement of central CB 1 receptors. Thus, caution is warranted regarding therapeutic use of CB-13 with the goal of avoiding CNS side effects. Nonetheless, the clear analgesic effect of acute peripheral CB 1 receptor activation suggests that peripherally restricted cannabinoids are a viable target for novel analgesic development.