In Silico Prediction of the Phosphorylation of NS3 as an Essential Mechanism for Dengue Virus Replication and the Antiviral Activity of Quercetin.

Dengue virus infection is a global health problem for which there have been challenges to obtaining a cure. Current vaccines and anti-viral drugs can only be narrowly applied in ongoing clinical trials. We employed computational methods based on structure-function relationships between human host kinases and viral nonstructural protein 3 (NS3) to understand viral replication inhibitors' therapeutic effect.

Cardiac Alternans Occurs through the Synergy of Voltage- and Calcium-Dependent Mechanisms.

Cardiac alternans is characterized by alternating weak and strong beats of the heart. This signaling at the cellular level may appear as alternating long and short action potentials (APs) that occur in synchrony with alternating large and small calcium transients, respectively. Previous studies have suggested that alternans manifests itself through either a voltage dependent mechanism based upon action potential restitution or as a calcium dependent mechanism based on refractoriness of calcium release.

Quantitative neuronal morphometry by supervised and unsupervised learning.

We present a protocol to characterize the morphological properties of individual neurons reconstructed from microscopic imaging. We first describe a simple procedure to extract relevant morphological features from digital tracings of neural arbors. Then, we provide detailed steps on classification, clustering, and statistical analysis of the traced cells based on morphological features.

Cellular anatomy of the mouse primary motor cortex.

An essential step toward understanding brain function is to establish a structural framework with cellular resolution on which multi-scale datasets spanning molecules, cells, circuits and systems can be integrated and interpreted. Here, as part of the collaborative Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-based anatomical description of one exemplar brain structure, the mouse primary motor cortex, upper limb area (MOp-ul). Using genetic and viral labelling, barcoded anatomy resolved by sequencing, single-neuron reconstruction, whole-brain imaging and cloud-based neuroinformatics tools, we delineated the MOp-ul in 3D and refined its sublaminar organization.

Schematic memory persistence and transience for efficient and robust continual learning.

Continual learning is considered a promising step toward next-generation Artificial Intelligence (AI), where deep neural networks (DNNs) make decisions by continuously learning a sequence of different tasks akin to human learning processes. It is still quite primitive, with existing works focusing primarily on avoiding (catastrophic) forgetting. However, since forgetting is inevitable given bounded memory and unbounded task loads, 'how to reasonably forget' is a problem continual learning must address in order to reduce the performance gap between AIs and humans, in terms of (1) memory efficiency, (2) generalizability, and (3) robustness when dealing with noisy data.

Effect of crista morphology on mitochondrial ATP output: A computational study.

Folding of the mitochondrial inner membrane (IM) into cristae greatly increases the ATP-generating surface area, , per unit volume but also creates diffusional bottlenecks that could limit reaction rates inside mitochondria. This study explores possible effects of inner membrane folding on mitochondrial ATP output, using a mathematical model for energy metabolism developed by the Jafri group and two- and three-dimensional spatial models for mitochondria, implemented on the Virtual Cell platform. Simulations demonstrate that cristae are micro-compartments functionally distinct from the cytosol.

Temporal pattern and synergy influence activity of ERK signaling pathways during L-LTP induction.

Long-lasting long-term potentiation (L-LTP) is a cellular mechanism of learning and memory storage. Studies have demonstrated a requirement for extracellular signal-regulated kinase (ERK) activation in L-LTP produced by a diversity of temporal stimulation patterns. Multiple signaling pathways converge to activate ERK, with different pathways being required for different stimulation patterns.

A Method for Estimating the Potential Synaptic Connections Between Axons and Dendrites From 2D Neuronal Images.

Computational neuroscience aims to model, reproduce, and predict network dynamics for different neuronal ensembles by distilling knowledge derived from electrophysiological and morphological evidence. However, analyses and simulations often remain critically limited by the sparsity of direct experimental constraints on essential parameters, such as electron microscopy and electrophysiology pair/multiple recording evidence of connectivity statistics. Notably, available data are particularly scarce regarding quantitative information on synaptic connections among identified neuronal types.

Formin 3 directs dendritic architecture via microtubule regulation and is required for somatosensory nociceptive behavior.

Dendrite shape impacts functional connectivity and is mediated by organization and dynamics of cytoskeletal fibers. Identifying the molecular factors that regulate dendritic cytoskeletal architecture is therefore important in understanding the mechanistic links between cytoskeletal organization and neuronal function. We identified Formin 3 (Form3) as an essential regulator of cytoskeletal architecture in nociceptive sensory neurons in Drosophila larvae.

Organization of the inputs and outputs of the mouse superior colliculus.

The superior colliculus (SC) receives diverse and robust cortical inputs to drive a range of cognitive and sensorimotor behaviors. However, it remains unclear how descending cortical input arising from higher-order associative areas coordinate with SC sensorimotor networks to influence its outputs. Here, we construct a comprehensive map of all cortico-tectal projections and identify four collicular zones with differential cortical inputs: medial (SC.

An imaging analysis protocol to trace, quantify, and model multi-signal neuron morphology.

We describe how to reconstruct and quantify multi-signal neuronal morphology, using the dendritic distributions of microtubules and F-actin in sensory neurons from fly larvae as examples. We then provide a detailed procedure to analyze channel-specific morphometrics from these enhanced reconstructions. To illustrate applications, we demonstrate how to run a cytoskeleton-constrained simulation of dendritic tree generation and explain its validation against experimental data.

BEAN: Interpretable and Efficient Learning With Biologically-Enhanced Artificial Neuronal Assembly Regularization.

Deep neural networks (DNNs) are known for extracting useful information from large amounts of data. However, the representations learned in DNNs are typically hard to interpret, especially in dense layers. One crucial issue of the classical DNN model such as multilayer perceptron (MLP) is that neurons in the same layer of DNNs are conditionally independent of each other, which makes co-training and emergence of higher modularity difficult.

X-ROS Signaling Depends on Length-Dependent Calcium Buffering by Troponin.

The stretching of a cardiomyocyte leads to the increased production of reactive oxygen species that increases ryanodine receptor open probability through a process termed X-ROS signaling. The stretching of the myocyte also increases the calcium affinity of myofilament Troponin C, which increases its calcium buffering capacity. Here, an integrative experimental and modeling study is pursued to explain the interplay of length-dependent changes in calcium buffering by troponin and stretch-activated X-ROS calcium signaling.

Efficient metadata mining of web-accessible neural morphologies.

Advancements in neuroscience research have led to steadily accelerating data production and sharing. The online community repository of neural reconstructions NeuroMorpho.Org grew from fewer than 1000 digitally traced neurons in 2006 to more than 140,000 cells today, including glia that now constitute 10.

Connectivity characterization of the mouse basolateral amygdalar complex.

The basolateral amygdalar complex (BLA) is implicated in behaviors ranging from fear acquisition to addiction. Optogenetic methods have enabled the association of circuit-specific functions to uniquely connected BLA cell types. Thus, a systematic and detailed connectivity profile of BLA projection neurons to inform granular, cell type-specific interrogations is warranted.

Evolution of water conservation in humans.

To sustain life, humans and other terrestrial animals must maintain a tight balance of water gain and water loss each day. However, the evolution of human water balance physiology is poorly understood due to the absence of comparative measures from other hominoids. While humans drink daily to maintain water balance, rainforest-living great apes typically obtain adequate water from their food and can go days or weeks without drinking.

A neuronal blueprint for directional mechanosensation in larval zebrafish.

Animals have a remarkable ability to use local cues to orient in space in the absence of a panoramic fixed reference frame. Here we use the mechanosensory lateral line in larval zebrafish to understand rheotaxis, an innate oriented swimming evoked by water currents. We generated a comprehensive light-microscopy cell-resolution projectome of lateralis afferent neurons (LANs) and used clustering techniques for morphological classification.

Highlights from the Era of Open Source Web-Based Tools.

High digital connectivity and a focus on reproducibility are contributing to an open science revolution in neuroscience. Repositories and platforms have emerged across the whole spectrum of subdisciplines, paving the way for a paradigm shift in the way we share, analyze, and reuse vast amounts of data collected across many laboratories. Here, we describe how open access web-based tools are changing the landscape and culture of neuroscience, highlighting six free resources that span subdisciplines from behavior to whole-brain mapping, circuits, neurons, and gene variants.

Comprehensive Estimates of Potential Synaptic Connections in Local Circuits of the Rodent Hippocampal Formation by Axonal-Dendritic Overlap.

A quantitative description of the hippocampal formation synaptic architecture is essential for understanding the neural mechanisms of episodic memory. Yet the existing knowledge of connectivity statistics between different neuron types in the rodent hippocampus only captures a mere 5% of this circuitry. We present a systematic pipeline to produce first-approximation estimates for most of the missing information.

Operations Research Methods for Estimating the Population Size of Neuron Types.

Understanding brain computation requires assembling a complete catalog of its architectural components. Although the brain is organized into several anatomical and functional regions, it is ultimately the neurons in every region that are responsible for cognition and behavior. Thus, classifying neuron types throughout the brain and quantifying the population sizes of distinct classes in different regions is a key subject of research in the neuroscience community.

Predicting Genetic Variation Severity Using Machine Learning to Interpret Molecular Simulations.

Distinct missense mutations in a specific gene have been associated with different diseases as well as differing severity of a disease. Current computational methods predict the potential pathogenicity of a missense variant but fail to differentiate between separate disease or severity phenotypes. We have developed a method to overcome this limitation by applying machine learning to features extracted from molecular dynamics simulations, creating a way to predict the effect of novel genetic variants in causing a disease, drug resistance, or another specific trait.

Neuropeptide S receptor gene Asn107 polymorphism in obese male individuals in Pakistan.

Neuropeptide S (NPS) is a naturally occurring appetite stimulant, associated with anxiety, stress, and excitement regulation. Neuropeptide S serves as a hypothalamic energy regulator that enhances food intake with a reduced level of satiety. NPS activates fat angiogenesis and the proliferation of new adipocytes in obesity.

Distinct Relations of Microtubules and Actin Filaments with Dendritic Architecture.

Microtubules (MTs) and F-actin (F-act) have long been recognized as key regulators of dendritic morphology. Nevertheless, precisely ascertaining their distinct influences on dendritic trees have been hampered until now by the lack of direct, arbor-wide cytoskeletal quantification. We pair live confocal imaging of fluorescently labeled dendritic arborization (da) neurons in Drosophila larvae with complete multi-signal neural tracing to separately measure MTs and F-act.