Pharmacological characterization and differential expression of NMDA receptor subunits in the chicken vestibular system during development.

Previous studies demonstrated that in vitro preparations of the isolated vestibular system of diverse animal species still exhibit stable resting electrical activity and mechanically evoked synaptic transmission between hair cells and primary afferent endings. However, there are no reports related to their neurodevelopment. Therefore, this research aimed to examine whether NMDA receptors mediate these electrical signals in an isolated preparation of the chicken vestibular system at three developmental stages, E15, E18, and E21. We found that the spontaneous and mechanically evoked discharges from primary afferents of the posterior semicircular canal were modulated by agonists NMDA and glycine, but not by the agonist d-serine applied near the synapses. Moreover, the individually applied by bath perfusion of three NMDA receptor antagonists (MK-801, ifenprodil, and 2-naphthoic acid) or high Mg2+ decreased the resting discharge rate, the NMDA response, and the discharge rate of mechanically evoked activity from these primary afferents. Furthermore, we found that the vestibular ganglion shows a stage-dependent increase in the expression of NMDA receptor subunits GluN1, GluN2 (A-C), and GluN3 (A-B), being greater at E21, except for GluN2D, which was inversely related to the developmental stage. However, in the crista ampullaris, the expression pattern remained constant throughout development. This could suggest the possible existence of presynaptic NMDA receptors. Our results highlight that although the NMDA receptors are functionally active at the early embryonic stages of the vestibular system, NMDA and glycine reach their mature functionality to increase NMDA responses close to hatching (E21).

Epidermal Growth Factor Potentiates Migration of MDA-MB 231 Breast Cancer Cells by Increasing NaV1.5 Channel Expression.

INTRODUCTION: Breast cancer is one of the leading causes of death worldwide and is the result of dysregulation of various signaling pathways in mammary epithelial cells. The mortality rate in patients suffering from breast cancer is high because the tumor cells have a prominent invasive capacity towards the surrounding tissues. Previous studies carried out in tumor cell models show that voltage-gated ion channels may be important molecular actors that contribute to the migratory and invasive capacity of the tumor cells. METHODS: In this study, by using an experimental strategy that combines cell and molecular biology assays with electrophysiological recording, we sought to determine whether the voltage-dependent sodium channel NaV1.5 regulates the migratory capacity of the human breast cancer cell line MDA-MB 231, when cells are maintained in the presence of epidermal growth factor (EGF), as an inductor of the epithelial-mesenchymal transition. RESULTS: Our data show that EGF stimulates the migratory capacity of MDA-MB 231 cells, by regulating the functional expression of NaV1.5 channels. Consistent with this, the stimulatory actions of the growth factor were prevented by the use of tetrodotoxin, an Na+ channel selective blocker, as well as by resveratrol, an antioxidant that can also affect Na+ channel activity. DISCUSSION: The understanding of molecular mechanisms, such as the EGF pathway in the progression of breast cancer is fundamental for the design of more effective therapeutic strategies for the disease.

Effect of mechanical tactile noise on amplitude of visual evoked potentials: multisensory stochastic resonance.

The present investigation documents the electrophysiological occurrence of multisensory stochastic resonance in the human visual pathway elicited by tactile noise. We define multisensory stochastic resonance of brain evoked potentials as the phenomenon in which an intermediate level of input noise of one sensory modality enhances the brain evoked response of another sensory modality. Here we examined this phenomenon in visual evoked potentials (VEPs) modulated by the addition of tactile noise. Specifically, we examined whether a particular level of mechanical Gaussian noise applied to the index finger can improve the amplitude of the VEP. We compared the amplitude of the positive P100 VEP component between zero noise (ZN), optimal noise (ON), and high mechanical noise (HN). The data disclosed an inverted U-like graph for all the subjects, thus demonstrating the occurrence of a multisensory stochastic resonance in the P100 VEP.

ADHD Adults Show Lower Interindividual Similarity in Ex-Gaussian Reaction Time Vectors for Congruent Stimuli Compared to Control Peers.

OBJECTIVE: Interindividual similarity refers to how similarly individuals respond when receiving the same stimulus or intervention. In this study, we aimed to examine interindividual similarity in adults with ADHD. METHOD: We used the cosine similarity index of ex-Gaussian reaction time (RT) vectors of mu, sigma, and tau parameters during a Stroop task. RESULTS: Our results demonstrate that the ADHD group exhibits a reduced interindividual similarity index in their ex-Gaussian RT vectors for congruent stimuli compared to the healthy control group. Importantly, we did not find significant differences in the interindividual similarity index to incongruent stimuli between both groups, thus suggesting that this reduced index was selective for congruent stimuli. CONCLUSION: Our findings highlight that ADHD adults exhibit more significant interindividual differences in cognitive functioning when processing congruent stimuli than healthy controls. These results provide new insights into the selective mechanisms underlying ADHD and may contribute to developing new targeted interventions for this disorder.

Excitatory actions of GABA in developing chick vestibular afferents: effects on resting electrical activity.

The aim of this study was to characterize the effect of γ-aminobutyric acid (GABA) in the resting multiunit activity of the vestibular afferents during development using the isolated inner ear of embryonic and postnatal chickens (E15-E21 and P5). GABA (10(-3) to 10(-5) M; n = 133) and muscimol (10(-3) M) elicited an increase in the frequency of the basal discharge of the vestibular afferents. We found that GABA action was dose-dependent and inversely related to animal age. Thus, the largest effect was observed in embryonic ages such as E15 and E17 and decreases in E21 and P5. The GABAA receptor antagonists, bicuculline (10(-5) M; n = 10) and picrotoxin (10(-4) M; n = 10), significantly decreased the excitatory action of GABA and muscimol (10(-3) M). Additionally, CNQX 10(-6) M, MCPG 10(-5) M and 7ClKyn 10(-5) M (n = 5) were co-applied by bath substitution (n = 5). Both the basal discharge and the GABA action significantly decreased in these experimental conditions. The chloride channel blocker 9-AC 0.5 mM produced an important reduction in the effect of GABA 10(-3) (n = 5) and 10(-4) M (n = 5). Thus, our results suggest an excitatory role of GABA in the resting activity of the vestibular afferents that can be explained by changes in the gradient of concentration of Cl(-) during development. We show for the first time that the magnitude of this GABA effect decreases at later stages of embryonic and early postnatal development. Taking into account the results with glutamatergic antagonists, we conclude that GABA has a presynaptic action but is not the neurotransmitter in the vestibular afferent synapses, although it could act as a facilitator of the spontaneous activity and may regulate glutamate release.

Absence of effects of contralateral group I muscle afferents on presynaptic inhibition of Ia terminals in humans and cats.

Crossed effects from group I afferents on reflex excitability and their mechanisms of action are not yet well understood. The current view is that the influence is weak and takes place indirectly via oligosynaptic pathways. We examined possible contralateral effects from group I afferents on presynaptic inhibition of Ia terminals in humans and cats. In resting and seated human subjects the soleus (SO) H-reflex was conditioned by an electrical stimulus to the ipsilateral common peroneal nerve (CPN) to assess the level of presynaptic inhibition (PSI_control). A brief conditioning vibratory stimulus was applied to the triceps surae tendon at the contralateral side (to activate preferentially Ia muscle afferents). The amplitude of the resulting H-reflex response (PSI_conditioned) was compared to the H-reflex under PSI_control, i.e., without the vibration. The interstimulus interval between the brief vibratory stimulus and the electrical shock to the CPN was -60 to 60 ms. The H-reflex conditioned by both stimuli did not differ from that conditioned exclusively by the ipsilateral CPN stimulation. In anesthetized cats, bilateral monosynaptic reflexes (MSRs) in the left and right L(7) ventral roots were recorded simultaneously. Conditioning stimulation applied to the contralateral group I posterior biceps and semitendinosus (PBSt) afferents at different time intervals (0-120 ms) did not have an effect on the ipsilateral gastrocnemius/soleus (GS) MSR. An additional experimental paradigm in the cat using contralateral tendon vibration, similar to that conducted in humans, was also performed. No significant differences between GS-MSRs conditioned by ipsilateral PBSt stimulus alone and those conditioned by both ipsilateral PBSt stimulus and contralateral tendon vibration were detected. The present results strongly suggest an absence of effects from contralateral group I fibers on the presynaptic mechanism of MSR modulation in relaxed humans and anesthetized cats.

Sensing magnetic flux density of artificial neurons with a MEMS device.

We describe a simple procedure to characterize a magnetic field sensor based on microelectromechanical systems (MEMS) technology, which exploits the Lorentz force principle. This sensor is designed to detect, in future applications, the spiking activity of neurons or muscle cells. This procedure is based on the well-known capability that a magnetic MEMS device can be used to sense a small magnetic flux density. In this work, an electronic neuron (FitzHugh-Nagumo) is used to generate controlled spike-like magnetic fields. We show that the magnetic flux density generated by the hardware of this neuron can be detected with a new MEMS magnetic field sensor. This microdevice has a compact resonant structure (700 × 600 × 5 µm) integrated by an array of silicon beams and p-type piezoresistive sensing elements, which need an easy fabrication process. The proposed microsensor has a resolution of 80 nT, a sensitivity of 1.2 V.T(-1), a resonant frequency of 13.87 kHz, low power consumption (2.05 mW), quality factor of 93 at atmospheric pressure, and requires a simple signal processing circuit. The importance of our study is twofold. First, because the artificial neuron can generate well-controlled magnetic flux density, we suggest it could be used to analyze the resolution and performance of different magnetic field sensors intended for neurobiological applications. Second, the introduced MEMS magnetic field sensor may be used as a prototype to develop new high-resolution biomedical microdevices to sense magnetic fields from cardiac tissue, nerves, spinal cord, or the brain.

OX40 agonists for cancer treatment: a patent review.

INTRODUCTION: OX40 is an immune checkpoint in cancer and its presence in cancer is a good prognosis, making it a highly relevant target for the development of new immunotherapies. AREAS COVERED: The patent literature reveals vital information on new trends in cancer therapies. The authors used the patent databases of the six major patent offices in the world: United States Patent and Trademark Office, European Patent Office, World Intellectual Property Organization, Japan Patent Office, State Office of Intellectual Property of China and Korean Intellectual Property Office, to generate a panorama of patents related to OX40 agonists. Specific patents have been grouped into innovative patents and adoption patents. EXPERT OPINION: An increasing trend in the development of OX40 agonists in cancer, particularly in the years 2018 and 2019. United States was the leader in generating patents, followed by China and England. Major pharmaceutical companies have at least one anti-OX40 agonist, MEDI6469 and MEDI-0562 (AstraZeneca), PF-04518600 (Pfizer), GSK3174998 (GlaxoSmithKline), BMS-986,178 (Bristol-Myers Squibb) and MOXR0916 (Roche), which represent 68% of clinical trials conducted with OX40 agonists.

Development of spontaneous activity and response properties of primary lagenar neurons in the chick.

Here, we report for the first time developmental changes in spontaneous activity and in response properties of single nerve fibers from the macular chick lagena. Such aspects are important in order to get insight into the functional role of the lagena which remains undetermined. For this purpose, we used intracellular and extracellular single-unit recording techniques in an isolated inner ear preparation from the chicken at ages E15 and P1. At E15, afferent fibers displayed a low irregular spontaneous discharge rate (41 +/- 14 spikes/s, CV = 1.17 +/- 0.1), which was replaced by regular high frequency spontaneous activity at P1 (CV = 0.48 +/- 0.8, 89 +/- 27 spikes/s). During the developmental period including E15, the percentage of silent neurons was 60% while that of P1 was 40%. The synaptic activity was higher at E15 than at P1. The action potential waveform generated at E15 had small amplitude and derivative depolarization, and consequently, a large duration in correlation with respect to action potential waveform at P1 (respectively: 53 +/- 2 vs. 65 +/- 3 mV, 60 +/- 11 vs. 109 +/- 20 mV/ms, 3.6 +/- 0.4 vs. 1.1 +/- 0.12 ms). In addition, we recognized two response dynamics to the injection of current steps: phasic, or rapidly adapting neurons and tonic, or slowly adapting neurons. Our results indicate similar developmental processes for the lagena as described for the vestibular system in other species, in agreement with the known morphological characteristics of this otholitic end organ. The presence of more than one subtype of afferent neuron also correlates with previous reports on vestibular afferents with analogous electrophysiological properties, strongly suggesting the vestibular nature of the lagena.

Bispecific anti-PD-1/LAG-3 antibodies for treatment of advanced or metastatic solid tumors: a patent evaluation of US2018326054.

INTRODUCTION: Due to the primary role of PD-1 and LAG-3 in regulating the immune response in tumors, there is a need to develop therapies focused on the inhibition of PD-1 and LAG-3 in order to improve the immune response in patients with cancer. The authors of US2018326054 patent propose a method to eradicate cancer by using bispecific anti-PD-1/LAG-3 antibodies. AREAS COVERED: The US2018326054 patent describes anti-PD-1/LAG3 antibodies, pharmaceutical composition that contains it, and their application for cancer treatment, particularly pancreatic carcinoma. Proof concept and preclinical results show anti-PD-1/LAG-3 bispecific antibodies bind and are internalized by CD4 + T cells thereby increasing their effector functions (release of Granzyme B and INF-γ) in the presence of tumor cells, and completely suppress tumors in a murine model. EXPERT OPINION: Anti-PD-1/LAG-3 bispecific antibodies of the US2018326054 patent are new in a general concept, but treatment data is only shown for pancreatic carcinoma. The results to be obtained in future clinical trials of safety and efficacy could conclude whether these bispecific anti-PD-1/LAG-3 antibodies will be useful in a cancer treatment scheme.

Noisy Light Augments the Na+ Current in Somatosensory Pyramidal Neurons of Optogenetic Transgenic Mice.

In previous reports, we developed a method to apply Brownian optogenetic noise-photostimulation (BONP, 470 nm) up to 0.67 mW on the barrel cortex of in vivo ChR2 transgenic mice. In such studies, we found that the BONP produces an increase in the evoked field potentials and the neuronal responses of pyramidal neurons induced by somatosensory mechanical stimulation. Here we extended such findings by examining whether the same type of BONP augments the Na+ current amplitude elicited by voltage-clamp ramps of dissociated pyramidal neurons from the somatosensory cortex of ChR2 transgenic and wild type mice. We found that in all neurons from the ChR2 transgenic mice, but none of the wild type mice, the peak amplitude of a TTX-sensitive Na+ current and its inverse of latency exhibited inverted U-like graphs as a function of the BONP level. It means that an intermediate level of BONP increases both the peak amplitude of the Na+ current and its inverse of latency. Our research suggests that the impact of BONP on the Na+ channels of pyramidal neurons could be associated with the observed augmentation-effects in our previous in vivo preparation. Moreover, it provides caution information for the use of an appropriate range of light intensity, <0.67 mW, which could avoid opto non-genetics (also termed "optonongenetic") related responses due to light-induced temperature changes.

Treatment of cancer with an anti-KIR antibody: a patent evaluation of US9879082 and US2018208652.

Introduction: KIR is an inhibitory receptor expressed by natural killer cells that suppress the immune response against tumor cells. There is a great need to discover and develop new therapies focused on inhibiting the action of KIR and consequently improving the immune response in the various types of cancer. Authors of US9879082 and US2018208652 patents propose a method to eradicate cancer that utilizes anti-KIR antibody.Areas covered: US9879082 and US2018208652 patents describe an anti-KIR antibody, a pharmaceutical composition that contains it, and their application for cancer treatment, particularly, multiple myeloma and acute myeloid leukemia. Anti-KIR antibody is used to a dosage of 0.0003-3 mg antibody/kg patient weight, and is suspended in an isotonic solution consisting of sodium phosphate, sucrose, NaCl, and polysorbate 80.Expert opinion: The results of the clinical trials only support trials regarding the pharmacokinetic, pharmacodynamic, safety, and tolerability. In addition, these results demonstrate that treatment with the anti-KIR antibody can induce an antitumor response in cancer patients.

The Hemodynamic Mass Action of a Central Pattern Generator.

The hemodynamic response is a neurovascular and metabolic process in which there is rapid delivery of blood flow to a neuronal tissue in response to neuronal activation. The functional magnetic resonance imaging (fMRI) and the functional near-infrared spectroscopy (fNIRS), for instance, are based on the physiological principles of such hemodynamic responses. Both techniques allow the mapping of active neuronal regions in which the neurovascular and metabolic events are occurring. However, although both techniques have revolutionized the neurosciences, they are mostly employed for neuroimaging of the human brain but not for the spinal cord during functional tasks. Moreover, little is known about other techniques measuring the hemodynamic response in the spinal cord. The purpose of the present study was to show for the first time that a simple optical system termed direct current photoplethysmography (DC-PPG) can be employed to detect hemodynamic responses of the spinal cord and the brainstem during the functional activation of the spinal central pattern generator (CPG). In particular, we positioned two DC-PPG systems directly on the brainstem and spinal cord during fictive scratching in the cat. The optical DC-PPG systems allowed the trial-by-trial recording of massive hemodynamic signals. We found that the "strength" of the flexor-plus-extensor motoneuron activities during motor episodes of fictive scratching was significantly correlated to the "strengths" of the brainstem and spinal DC-PPG signals. Because the DC-PPG was robustly detected in real-time, we claim that such a functional signal reflects the hemodynamic mass action of the brainstem and spinal cord associated with the CPG motor action. Our findings shed light on an unexplored hemodynamic observable of the spinal CPGs, providing a proof of concept that the DC-PPG can be used for the assessment of the integrity of the human CPGs.

Leptin increases L-type Ca2+ channel expression and GnRH-stimulated LH release in LbetaT2 gonadotropes.

Leptin, a mediator of long-term regulation of energy balance, has been implicated in the release of adenohypophyseal gonadotropins by regulating gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus. However, a direct effect of leptin on hormone release from gonadotropes remains virtually unexplored. In the current report, we assessed the long-term (48 h) actions of leptin on voltage-gated channel activity and luteinizing hormone (LH) production in mouse pituitary gonadotrope LbetaT2 cells. Electrophysiological recordings showed that leptin treatment significantly increased whole-cell patch-clamp Ba(2+) current through L-type Ca(2+) channels. Quantitative RT-PCR analysis revealed increased levels of L-type (alpha(1D)) Ca(2+) channel mRNA. Likewise, radioimmunoassays using specific antibodies provided evidence that leptin alone had no effect on LH release but did enhance GnRH-induced secretion of the hormone. Leptin had no apparent effects on LH gene transcription in absence of GnRH, as measured by transient transfection assays using a LH promoter-reporter gene and real-time RT-PCR. These observations suggest that leptin might affect LH release by acting directly on the gonadotropes, favoring hormone production by enhancing responsiveness to GnRH as a result of increased Ca(2+) channel expression.

Afterdischarges of Spinal Interneurons Following a Brief High-Frequency Stimulation of Ia Afferents in the Cat.

Spinal motoneurons exhibit sustained afterdischarges and plateau potentials following a brief high-frequency stimulation of Ia afferents. Also, there is evidence that spinal cord interneurons exhibit plateau potentials. However, to our knowledge, there are no reports about the possible afterdischarge behavior of lumbar spinal interneurons activated by Ia afferents. Given that there are spinal interneurons receiving monosynaptic inputs from Ia afferents, these cells could then be activated in parallel to motoneurons after repetitive muscle stretch. We explored this possibility in cats with a precollicular-postmammillary decerebration. We found that a brief high-frequency stimulation of Ia afferents produces afterdischarges that are highly correlated to a DC slow potential recorded at the cord dorsum. We conclude that in the cat spinal cord, not only the motoneurons but also the interneurons from the superficial and deep dorsal horn produce sustained afterdischarges, thus highlighting the importance of interneurons in the spinal neuronal circuitry. The significance of our finding is that it opens the possibility that the spinal cord interneurons activated by Ia afferents could also exhibit bistability, a relevant phenomenon well-characterized in the motoneurons.

Resetting the Respiratory Rhythm with a Spinal Central Pattern Generator.

There is evidence that a variety of central and afferent stimuli, including swallowing, can produce phase resetting in the respiratory rhythmicity. Also, there are reports about the intrinsic linkage between locomotion and respiration. However, little is known about the interaction between the central pattern generators (CPGs) for scratching and respiration. The present study aims to examine whether the activation of scratching CPG produces phase resetting of the respiratory rhythm. We employed decerebrate cats to apply brief tactile stimuli to the pinna during the inspiratory-expiratory transition. We observed that those stimuli to the pinna not eliciting fictive scratching did not reset the respiratory rhythm. However, when the pinna stimuli elicited fictive scratching, then the respiratory rhythm exhibited a significant phase resetting. We also found interneurons in the medulla oblongata exhibiting phase resetting related to scratching-CPG episodes. This second finding suggests that this type of resetting involves brainstem components of the respiratory CPG. These results shed new light on the resetting action from a spinal CPG on the respiratory rhythm.

Augmenting EEG-global-coherence with auditory and visual noise: Multisensory internal stochastic resonance.

The present investigation documents the electrophysiological occurrence of multisensory internal stochastic resonance (MISR) in the human electroencephalographic (EEG) coherence elicited by auditory and visual noise.We define MISR of EEG coherence as the phenomenon for which an intermediate level of input noise of a sensory modality enhances EEG coherence in response to another noisy sensory modality. Here, EEG coherence is computed by the global weighted coherence (GWC), modulated by quasi-Brownian noise. Specifically, we examined whether a particular level of auditory noise together with constant visual noise (experimental condition 1) and a specified level of visual noise together with constant auditory noise (experimental condition 2), improves EEG's GWC. We compared GWC between ongoing EEG basal activity (BA), zero noise (ZN), optimal noise (ON), and high noise (HN).The data disclosed an intermediate level of input noise that enhances the GWC for the majority of the subjects, thus demonstrating for the first time the occurrence of multisensory internal stochastic resonance (SR) in visuoauditory processing within the central nervous system.

Computing the center of mass for traveling alpha waves in the human brain.

The phenomenon of traveling waves of the brain is an intriguing area of research, and its mechanisms and neurobiological bases have been unknown since the 1950s. The present study offers a new method to compute traveling alpha waves using the center of mass algorithm. Electroencephalographic alpha waves are oscillations with a characteristic frequency range and reactivity to closed eyes. Several lines of evidence derived from qualitative observations suggest that the alpha waves represent a spreading wave process with specific trajectories in the human brain. We found that during a certain alpha wave peak recorded with 30 electrodes the trajectory starts and ends in distinct regions of the brain, mostly frontal-occipital, frontal-frontal, or occipital-frontal, but the position of the trajectory at the time in which the maximal positivity of the alpha wave occurs has a definite position near the central regions. Thus we observed that the trajectory always crossed around the central zones, traveling from one region to another region of the brain. A similar trajectory pattern was observed for different alpha wave peaks in one alpha burst, and in different subjects, with a mean velocity of 2.1+/-0.29 m/s. We found that all our results were clear and reproducible in all of the subjects. To our knowledge, the present method documents the first explicit description of a spreading wave process with a singular pattern in the human brain in terms of the center of mass algorithm.

Effects of auditory noise on the psychophysical detection of visual signals: cross-modal stochastic resonance.

Harper [D.W. Harper, Signal detection analysis of effect of white noise intensity on sensitivity to visual flicker, Percept. Mot. Skills 48 (1979) 791-798] demonstrated that the visual flicker sensitivity was an inverted U-like function of the intensity of different levels of auditory noise from 50 to 90dB (SPL), without concomitant changes in the response bias. The aim of the present study was to extend these observations in the context of the stochastic resonance, a counterintuitive phenomenon in which a particular level of noise enhances the response of a nonlinear system to a weak input signal. We show psychophysical evidence in a yes-no paradigm for the existence of a stochastic resonance-like phenomenon in the auditory-visual interactions. We show that the detection of a weak visual signal was an inverted U-like function of the intensity of different levels of auditory noise. Nevertheless, for a strong visual signal the auditory noise acts in detriment of the ability of visual detection. Our results suggest that auditory noise could be employed in vision rehabilitation interventions in order to improve the detection of weak visual signals.