Abstract Encoding of Categorical Decisions in Medial Superior Temporal and Lateral Intraparietal Cortices.

Categorization is an essential cognitive and perceptual process for decision-making and recognition. The posterior parietal cortex, particularly the lateral intraparietal (LIP) area has been suggested to transform visual feature encoding into abstract categorical representations. By contrast, areas closer to sensory input, such as the middle temporal (MT) area, encode stimulus features but not more abstract categorical information during categorization tasks. Here, we compare the contributions of the medial superior temporal (MST) and LIP areas in category computation by recording neuronal activity in both areas from two male rhesus macaques trained to perform a visual motion categorization task. MST is a core motion-processing region interconnected with MT and is often considered an intermediate processing stage between MT and LIP. We show that MST exhibits robust decision-correlated motion category encoding and working memory encoding similar to LIP, suggesting that MST plays a substantial role in cognitive computation, extending beyond its widely recognized role in visual motion processing.SIGNIFICANCE STATEMENT Categorization requires assigning incoming sensory stimuli into behaviorally relevant groups. Previous work found that parietal area LIP shows a strong encoding of the learned category membership of visual motion stimuli, while visual area MT shows strong direction tuning but not category tuning during a motion direction categorization task. Here we show that the medial superior temporal (MST) area, a visual motion-processing region interconnected with both LIP and MT, shows strong visual category encoding similar to that observed in LIP. This suggests that MST plays a greater role in abstract cognitive functions, extending beyond its well known role in visual motion processing.

Mechanistic models of PLC/PKC signaling implicate phosphatidic acid as a key amplifier of chemotactic gradient sensing.

Chemotaxis of fibroblasts and other mesenchymal cells is critical for embryonic development and wound healing. Fibroblast chemotaxis directed by a gradient of platelet-derived growth factor (PDGF) requires signaling through the phospholipase C (PLC)/protein kinase C (PKC) pathway. Diacylglycerol (DAG), the lipid product of PLC that activates conventional PKCs, is focally enriched at the up-gradient leading edge of fibroblasts responding to a shallow gradient of PDGF, signifying polarization. To explain the underlying mechanisms, we formulated reaction-diffusion models including as many as three putative feedback loops based on known biochemistry. These include the previously analyzed mechanism of substrate-buffering by myristoylated alanine-rich C kinase substrate (MARCKS) and two newly considered feedback loops involving the lipid, phosphatidic acid (PA). DAG kinases and phospholipase D, the enzymes that produce PA, are identified as key regulators in the models. Paradoxically, increasing DAG kinase activity can enhance the robustness of DAG/active PKC polarization with respect to chemoattractant concentration while decreasing their whole-cell levels. Finally, in simulations of wound invasion, efficient collective migration is achieved with thresholds for chemotaxis matching those of polarization in the reaction-diffusion models. This multi-scale modeling framework offers testable predictions to guide further study of signal transduction and cell behavior that affect mesenchymal chemotaxis.

A Reaction-Diffusion Model Explains Amplification of the PLC/PKC Pathway in Fibroblast Chemotaxis.

During the proliferative phase of cutaneous wound healing, dermal fibroblasts are recruited into the clotted wound by a concentration gradient of platelet-derived growth factor (PDGF), together with other spatial cues. Despite the importance of this chemotactic process, the mechanisms controlling the directed migration of slow-moving mesenchymal cells such as fibroblasts are not well understood. Here, we develop and analyze a reaction-diffusion model of phospholipase C/protein kinase C (PKC) signaling, which was recently identified as a requisite PDGF-gradient-sensing pathway, with the goal of identifying mechanisms that can amplify its sensitivity in the shallow external gradients typical of chemotaxis experiments. We show that phosphorylation of myristoylated alanine-rich C kinase substrate by membrane-localized PKC constitutes a positive feedback that is sufficient for local pathway amplification. The release of phosphorylated myristoylated alanine-rich C kinase substrate and its subsequent diffusion and dephosphorylation in the cytosol also serves to suppress the pathway in down-gradient regions of the cell. By itself, this mechanism only weakly amplifies signaling in a shallow PDGF gradient, but it synergizes with other feedback mechanisms to enhance amplification. This model offers a framework for a mechanistic understanding of phospholipase C/PKC signaling in chemotactic gradient sensing and can guide the design of experiments to assess the roles of putative feedback loops.

cAMP signaling mediates behavioral flexibility and consolidation of social status in Drosophila aggression.

Social rituals, such as male-male aggression in Drosophila, are often stereotyped and the component behavioral patterns modular. The likelihood of transition from one behavioral pattern to another is malleable by experience and confers flexibility to the behavioral repertoire. Experience-dependent modification of innate aggressive behavior in flies alters fighting strategies during fights and establishes dominant-subordinate relationships. Dominance hierarchies resulting from agonistic encounters are consolidated to longer-lasting, social-status-dependent behavioral modifications, resulting in a robust loser effect. We showed that cAMP dynamics regulated by the calcium-calmodulin-dependent adenylyl cyclase, Rut, and the cAMP phosphodiesterase, Dnc, but not the Amn gene product, in specific neuronal groups of the mushroom body and central complex, mediate behavioral plasticity necessary to establish dominant-subordinate relationships. rut and dnc mutant flies were unable to alter fighting strategies and establish dominance relationships during agonistic interactions. This real-time flexibility during a fight was independent of changes in aggression levels. Longer-term consolidation of social status in the form of a loser effect, however, required additional Amn-dependent inputs to cAMP signaling and involved a circuit-level association between the α/ß and γ neurons of the mushroom body. Our findings implicate cAMP signaling in mediating the plasticity of behavioral patterns in aggressive behavior and in the generation of a temporally stable memory trace that manifests as a loser effect.

Molecular mechanisms of cellular mechanosensing.

Mechanical forces direct a host of cellular and tissue processes. Although much emphasis has been placed on cell-adhesion complexes as force sensors, the forces must nevertheless be transmitted through the cortical cytoskeleton. Yet how the actin cortex senses and transmits forces and how cytoskeletal proteins interact in response to the forces is poorly understood. Here, by combining molecular and mechanical experimental perturbations with theoretical multiscale modelling, we decipher cortical mechanosensing from molecular to cellular scales. We show that forces are shared between myosin II and different actin crosslinkers, with myosin having potentiating or inhibitory effects on certain crosslinkers. Different types of cell deformation elicit distinct responses, with myosin and α-actinin responding to dilation, and filamin mainly reacting to shear. Our observations show that the accumulation kinetics of each protein may be explained by its molecular mechanisms, and that protein accumulation and the cell's viscoelastic state can explain cell contraction against mechanical load.

Separation anxiety: stress, tension and cytokinesis.

Cytokinesis, the physical separation of a mother cell into two daughter cells, progresses through a series of well-defined changes in morphology. These changes involve distinct biochemical and mechanical processes. Here, we review the mechanical features of cells during cytokinesis, discussing both the material properties as well as sources of stresses, both active and passive, which lead to the observed changes in morphology. We also describe a mechanosensory feedback control system that regulates protein localization and shape progression during cytokinesis.

The changing landscape in nephrology education in India.

Digital tools have revolutionized education in nephrology in India. All forms of in-person learning are moving online. Social media have taken over the world, with clinicians learning and promoting multidirectional education methods. E-learning is better equipped to keep up with the rapid pace of new knowledge generation and dissemination. The use of digital multimedia tools to enhance rapid learning is backed by science, viz., dual-coding theory. Digital tools such as Twitter, blogs, podcasts, YouTube, and Nephrology Simulator (NephSIM) have had an impact in facilitating nephrology education among medical professionals and the general public. Digital tools, such as NephMadness, have resulted in the gamification of nephrology learning. Social media usage by the nephrology community in India is growing at a rapid pace. Everyday Cases in Nephrology (#ECNeph), a monthly Twitter-based discussion focused on academically challenging clinical cases, has its origins in India. The Women in Nephrology, India (WIN-India) initiative is very active in facilitating digital education in India and has, in a short space of time, created phenomenal momentum. Furthermore, non-governmental organizations in India, such as the Kidney Warriors Foundation and the Multi Organ Harvesting Aid Network (MOHAN) Foundation, have successfully tapped into social media to educate and aid kidney disease patients. All technologies come with some drawbacks. Despite their acceptance and validation, digital tools have their own pitfalls. These relate to (1) accessibility and connectivity, (2) accuracy of the scientific information, (3) social media noise, and (4) patient privacy. All pitfalls of digital education can be addressed by avoiding excessive social media overload and adopting an appropriate peer-review process. It is advisable to seek written consent from patients whenever patient data are posted online, to avoid privacy issues.

Physiology of a Forgotten Electrolyte-Magnesium Disorders.

Magnesium (Mg2+) is the second most common intracellular cation and the fourth most abundant element on earth. However, Mg2+ is a frequently overlooked electrolyte and often not measured in patients. While hypomagnesemia is common in 15% of the general population, hypermagnesemia is typically only found in preeclamptic women after Mg2+ therapy and in patients with ESRD. Mild to moderate hypomagnesemia has been associated with hypertension, metabolic syndrome, type 2 diabetes mellitus, CKD, and cancer. Nutritional Mg2+ intake and enteral Mg2+ absorption are important for Mg2+ homeostasis, but the kidneys are the key regulators of Mg2+ homeostasis by limiting urinary excretion to less than 4% while the gastrointestinal tract loses over 50% of the Mg2+ intake in the feces. Here, we review the physiological relevance of Mg2+, the current knowledge of Mg2+ absorption in the kidneys and the gut, the different causes of hypomagnesemia, and a diagnostic approach on how to assess Mg2+ status. We highlight the latest discoveries of monogenetic conditions causing hypomagnesemia, which have enhanced our understanding of tubular Mg2+ absorption. We will also discuss external and iatrogenic causes of hypomagnesemia and advances in the treatment of hypomagnesemia.

Understanding the cooperative interaction between myosin II and actin cross-linkers mediated by actin filaments during mechanosensation.

Myosin II is a central mechanoenzyme in a wide range of cellular morphogenic processes. Its cellular localization is dependent not only on signal transduction pathways, but also on mechanical stress. We suggest that this stress-dependent distribution is the result of both the force-dependent binding to actin filaments and cooperative interactions between bound myosin heads. By assuming that the binding of myosin heads induces and/or stabilizes local conformational changes in the actin filaments that enhances myosin II binding locally, we successfully simulate the cooperative binding of myosin to actin observed experimentally. In addition, we can interpret the cooperative interactions between myosin and actin cross-linking proteins observed in cellular mechanosensation, provided that a similar mechanism operates among different proteins. Finally, we present a model that couples cooperative interactions to the assembly dynamics of myosin bipolar thick filaments and that accounts for the transient behaviors of the myosin II accumulation during mechanosensation. This mechanism is likely to be general for a range of myosin II-dependent cellular mechanosensory processes.

Similarity relations in visual search predict rapid visual categorization.

How do we perform rapid visual categorization?It is widely thought that categorization involves evaluating the similarity of an object to other category items, but the underlying features and similarity relations remain unknown. Here, we hypothesized that categorization performance is based on perceived similarity relations between items within and outside the category. To this end, we measured the categorization performance of human subjects on three diverse visual categories (animals, vehicles, and tools) and across three hierarchical levels (superordinate, basic, and subordinate levels among animals). For the same subjects, we measured their perceived pair-wise similarities between objects using a visual search task. Regardless of category and hierarchical level, we found that the time taken to categorize an object could be predicted using its similarity to members within and outside its category. We were able to account for several classic categorization phenomena, such as (a) the longer times required to reject category membership; (b) the longer times to categorize atypical objects; and (c) differences in performance across tasks and across hierarchical levels. These categorization times were also accounted for by a model that extracts coarse structure from an image. The striking agreement observed between categorization and visual search suggests that these two disparate tasks depend on a shared coarse object representation.

Interaction between neuronal encoding and population dynamics during categorization task switching in parietal cortex.

Primates excel at categorization, a cognitive process for assigning stimuli into behaviorally relevant groups. Categories are encoded in multiple brain areas and tasks, yet it remains unclear how neural encoding and dynamics support cognitive tasks with different demands. We recorded from parietal cortex during flexible switching between categorization tasks with distinct cognitive and motor demands and also studied recurrent neural networks (RNNs) trained on the same tasks. In the one-interval categorization task (OIC), monkeys rapidly reported their decisions with a saccade. In the delayed match-to-category (DMC) task, monkeys decided whether sequentially presented stimuli were categorical matches. Neuronal category encoding generalized across tasks, but categorical encoding was more binary-like in the DMC task and more graded in the OIC task. Furthermore, analysis of trained RNNs supports the hypothesis that binary-like encoding in DMC arises through compression of graded feature encoding by attractor dynamics underlying stimulus maintenance and/or comparison in working memory.

Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton.

To change shape, divide, form junctions, and migrate, cells reorganize their cytoskeletons in response to changing mechanical environments [1-4]. Actin cytoskeletal elements, including myosin II motors and actin crosslinkers, structurally remodel and activate signaling pathways in response to imposed stresses [5-9]. Recent studies demonstrate the importance of force-dependent structural rearrangement of α-catenin in adherens junctions [10] and vinculin's molecular clutch mechanism in focal adhesions [11]. However, the complete landscape of cytoskeletal mechanoresponsive proteins and the mechanisms by which these elements sense and respond to force remain to be elucidated. To find mechanosensitive elements in mammalian cells, we examined protein relocalization in response to controlled external stresses applied to individual cells. Here, we show that non-muscle myosin II, α-actinin, and filamin accumulate to mechanically stressed regions in cells from diverse lineages. Using reaction-diffusion models for force-sensitive binding, we successfully predicted which mammalian α-actinin and filamin paralogs would be mechanoaccumulative. Furthermore, a "Goldilocks zone" must exist for each protein where the actin-binding affinity must be optimal for accumulation. In addition, we leveraged genetic mutants to gain a molecular understanding of the mechanisms of α-actinin and filamin catch-bonding behavior. Two distinct modes of mechanoaccumulation can be observed: a fast, diffusion-based accumulation and a slower, myosin II-dependent cortical flow phase that acts on proteins with specific binding lifetimes. Finally, we uncovered cell-type- and cell-cycle-stage-specific control of the mechanosensation of myosin IIB, but not myosin IIA or IIC. Overall, these mechanoaccumulative mechanisms drive the cell's response to physical perturbation during proper tissue development and disease.

Cell shape regulation through mechanosensory feedback control.

Cells undergo controlled changes in morphology in response to intracellular and extracellular signals. These changes require a means for sensing and interpreting the signalling cues, for generating the forces that act on the cell's physical material, and a control system to regulate this process. Experiments on Dictyostelium amoebae have shown that force-generating proteins can localize in response to external mechanical perturbations. This mechanosensing, and the ensuing mechanical feedback, plays an important role in minimizing the effect of mechanical disturbances in the course of changes in cell shape, especially during cell division, and likely in other contexts, such as during three-dimensional migration. Owing to the complexity of the feedback system, which couples mechanical and biochemical signals involved in shape regulation, theoretical approaches can guide further investigation by providing insights that are difficult to decipher experimentally. Here, we present a computational model that explains the different mechanosensory and mechanoresponsive behaviours observed in Dictyostelium cells. The model features a multiscale description of myosin II bipolar thick filament assembly that includes cooperative and force-dependent myosin-actin binding, and identifies the feedback mechanisms hidden in the observed mechanoresponsive behaviours of Dictyostelium cells during micropipette aspiration experiments. These feedbacks provide a mechanistic explanation of cellular retraction and hence cell shape regulation.