Uncaria Rhynchophylla and hirsuteine as TRPV1 agonists inducing channel desensitization.

Ethnopharmacological Relevance: Uncaria rhynchophylla (UR) is recognized for its therapeutic applications in treating hypertension and inflammation. However, the specific molecular mechanisms how UR and its bioactive constituents modulate inflammatory pathways remain unknown. This study investigates the effects of UR extract and its constituent, hirsuteine (HST), on TRPV1 channel modulation which is related to hypertension and inflammation.

Tentonin 3 is a pore-forming subunit of a slow inactivation mechanosensitive channel.

Mechanically activating (MA) channels transduce numerous physiological functions. Tentonin 3/TMEM150C (TTN3) confers MA currents with slow inactivation kinetics in somato- and barosensory neurons. However, questions were raised about its role as a Piezo1 regulator and its potential as a channel pore.

Ion-Induced PIP2 Clustering with Martini3: Modification of Phosphate-Ion Interactions and Comparison with CHARMM36.

Phosphatidylinositol 4,5-bisphosphate (PIP) is a critical lipid for cellular signaling. The specific phosphorylation of the inositol ring controls protein binding as well as clustering behavior. Two popular models to describe ion-mediated clustering of PIP are Martini3 (M3) and CHARMM36 (C36).

Amplification of olfactory signals by Anoctamin 9 is important for mammalian olfaction.

Sensing smells of foods, prey, or predators determines animal survival. Olfactory sensory neurons in the olfactory epithelium (OE) detect odorants, where cAMP and Ca play a significant role in transducing odorant inputs to electrical activity. Here we show Anoctamin 9, a cation channel activated by cAMP/PKA pathway, is expressed in the OE and amplifies olfactory signals.

Neural Information Processing and Computations of Two-Input Synapses.

Information processing in artificial neural networks is largely dependent on the nature of neuron models. While commonly used models are designed for linear integration of synaptic inputs, accumulating experimental evidence suggests that biological neurons are capable of nonlinear computations for many converging synaptic inputs via homo- and heterosynaptic mechanisms. This nonlinear neuronal computation may play an important role in complex information processing at the neural circuit level.

Design principles of PI(4,5)P clustering under protein-free conditions: Specific cation effects and calcium-potassium synergy.

Phosphatidylinositol 4,5-bisphosphate (PIP2) clustering is a key component in cell signaling, yet little is known about the atomic-level features of this phenomenon. Network-theoretic analysis of multimicrosecond atomistic simulations of PIP2 containing asymmetric bilayers under protein-free conditions, presented here, reveals how design principles of PIP2 clustering are determined by the specific cation effects. Ca2+ generates large clusters (6% are pentamer or larger) by adding existing PIP2 dimers formed by strong O‒Ca2+‒O bridging interactions of unprotonated P4/P5 phosphates.

Differentiating amnestic from non-amnestic mild cognitive impairment subtypes using graph theoretical measures of electroencephalography.

The purpose of this study was to explore different patterns of functional networks between amnestic mild cognitive impairment (aMCI) and non-aMCI (naMCI) using electroencephalography (EEG) graph theoretical analysis. The data of 197 drug-naïve individuals who complained cognitive impairment were reviewed. Resting-state EEG data was acquired.

Lotus Seed Green Embryo Extract and a Purified Glycosyloxyflavone Constituent, Narcissoside, Activate TRPV1 Channels in Dorsal Root Ganglion Sensory Neurons.

Several studies have documented the broad-spectrum bioactivities of a lotus seed ( [PN]) green embryo extract. However, the specific bioactive components and associated molecular mechanisms remain largely unknown. This study aimed to identify the ion channel-activating mechanisms of PN extracts.

The structural aspects of neural dynamics and information flow.

Background: Neurons have specialized structures that facilitate information transfer using electrical and chemical signals. Within the perspective of neural computation, the neuronal structure is an important prerequisite for the versatile computational capabilities of neurons resulting from the integration of diverse synaptic input patterns, complex interactions among the passive and active dendritic local currents, and the interplay between dendrite and soma to generate action potential output. For this, characterization of the relationship between the structure and neuronal spike dynamics could provide essential information about the cellular-level mechanism supporting neural computations.

Characterization of multiscale logic operations in the neural circuits.

: Ever since the seminal work by McCulloch and Pitts, the theory of neural computation and its philosophical foundation known as 'computationalism' have been central to brain-inspired artificial intelligence (AI) technologies. The present study describes neural dynamics and neural coding approaches to understand the mechanisms of neural computation. The primary focus is to characterize the multiscale nature of logic computations in the brain, which might occur at a single neuron level, between neighboring neurons via synaptic transmission, and at the neural circuit level.

Drinking coffee enhances neurocognitive function by reorganizing brain functional connectivity.

The purpose of this study was to identify the mechanisms underlying effects of coffee on cognition in the context of brain networks. Here we investigated functional connectivity before and after drinking coffee using graph-theoretic analysis of electroencephalography (EEG). Twenty-one healthy adults voluntarily participated in this study.

Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function. SLC46A3 was localized to the lysosome where it modulated intracellular copper levels.

PLD2-PI(4,5)P2 interactions in fluid phase membranes: Structural modeling and molecular dynamics simulations.

Interaction of phospholipase D2 (PLD2) with phosphatidylinositol (4,5)-bisphosphate (PIP2) is regarded as the critical step of numerous physiological processes. Here we build a full-length model of human PLD2 (hPLD2) combining template-based and ab initio modeling techniques and use microsecond all-atom molecular dynamics (MD) simulations of the protein in contact with a complex membrane to determine hPLD2-PIP2 interactions. MD simulations reveal that the intermolecular interactions preferentially occur between specific PIP2 phosphate groups and hPLD2 residues; the most strongly interacting residues are arginine at the pbox consensus sequence (PX) and pleckstrin homology (PH) domain.

Computational modeling of the effects of autophagy on amyloid-β peptide levels.

Background: Autophagy is an evolutionarily conserved intracellular process that is used for delivering proteins and organelles to the lysosome for degradation. For decades, autophagy has been speculated to regulate amyloid-β peptide (Aβ) accumulation, which is involved in Alzheimer's disease (AD); however, specific autophagic effects on the Aβ kinetics only have begun to be explored.

Results: We develop a mathematical model for autophagy with respect to Aβ kinetics and perform simulations to understand the quantitative relationship between Aβ levels and autophagy activity.

Characterization of Specific Ion Effects on PI(4,5)P Clustering: Molecular Dynamics Simulations and Graph-Theoretic Analysis.

Numerous cellular functions mediated by phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P; PIP) involve clustering of the lipid as well as colocalization with other lipids. Although the cation-mediated electrostatic interaction is regarded as the primary clustering mechanism, the ion-specific nature of the intermolecular network formation makes it challenging to characterize the clusters. Here we use all-atom molecular dynamics (MD) simulations of PIP monolayers and graph-theoretic analysis to gain insight into the phenomenon.

Comparison of the umbrella sampling and the double decoupling method in binding free energy predictions for SAMPL6 octa-acid host-guest challenges.

We calculate the absolute binding free energies of tetra-methylated octa-acids host-guest systems as a part of the SAMPL6 blind challenge (receipt ID vq30p). We employed two different free energy simulation methods, i.e.

Force matching as a stepping stone to QM/MM CB[8] host/guest binding free energies: a SAMPL6 cautionary tale.

Use of quantum mechanical/molecular mechanical (QM/MM) methods in binding free energy calculations, particularly in the SAMPL challenge, often fail to achieve improvement over standard additive (MM) force fields. Frequently, the implementation is through use of reference potentials, or the so-called "indirect approach", and inherently relies on sufficient overlap existing between MM and QM/MM configurational spaces. This overlap is generally poor, particularly for the use of free energy perturbation to perform the MM to QM/MM free energy correction at the end states of interest (e.

Prediction of CB[8] host-guest binding free energies in SAMPL6 using the double-decoupling method.

This study reports the results of binding free energy calculations for CB[8] host-guest systems in the SAMPL6 blind challenge (receipt ID 3z83m). Force-field parameters were developed specific for each of host and guest molecules to improve configurational sampling. We used quantum mechanical (QM) implicit solvent calculations and QM force matching to determine non-bonded (partial atomic charges) and bonded terms, respectively.

Numerical study of entrainment of the human circadian system and recovery by light treatment.

Background: While the effects of light as a zeitgeber are well known, the way the effects are modulated by features of the sleep-wake system still remains to be studied in detail.

Methods: A mathematical model for disturbance and recovery of the human circadian system is presented. The model combines a circadian oscillator and a sleep-wake switch that includes the effects of orexin.

Graph-Theoretic Analysis of Monomethyl Phosphate Clustering in Ionic Solutions.

All-atom molecular dynamics simulations combined with graph-theoretic analysis reveal that clustering of monomethyl phosphate dianion (MMP) is strongly influenced by the types and combinations of cations in the aqueous solution. Although Ca promotes the formation of stable and large MMP clusters, K alone does not. Nonetheless, clusters are larger and their link lifetimes are longer in mixtures of K and Ca.

Autophagy mediates phase transitions from cell death to life.

Autophagy is a lysosomal degradation pathway, which is critical for maintaining normal cellular functions. Despite considerable advances in defining the specific molecular mechanism governing the autophagy pathway during the last decades, we are still far from understanding the underlying principle of the autophagy machinery and its complex role in human disease. As an alternative attempt to reinvigorate the search for the principle of the autophagy pathway, we in this study make use of the computer-aided analysis, complementing current molecular-level studies of autophagy.

Failure of Arm Movement Control in Stroke Patients, Characterized by Loss of Complexity.

We study the mechanism of human arm-posture control by means of nonlinear dynamics and quantitative time series analysis methods. Utilizing linear and nonlinear measures in combination, we find that pathological tremors emerge in patient dynamics and serve as a main feature discriminating between normal and patient groups. The deterministic structure accompanied with loss of complexity inherent in the tremor dynamics is also revealed.

Synaptotagmin-1 binds to PIP(2)-containing membrane but not to SNAREs at physiological ionic strength.

The Ca(2+) sensor synaptotagmin-1 is thought to trigger membrane fusion by binding to acidic membrane lipids and SNARE proteins. Previous work has shown that binding is mediated by electrostatic interactions that are sensitive to the ionic environment. However, the influence of divalent or polyvalent ions, at physiological concentrations, on synaptotagmin's binding to membranes or SNAREs has not been explored.