Miracle-dz/UniFAR-FTUs huggingface dataset:
Selectivity for Three-Dimensional Shape and Grasping-Related Activity in the Macaque Ventral Premotor Cortex

Anatomical studies indicate that area F5 in the macaque ventral premotor cortex consists of three different sectors. One of these is F5a in the posterior bank of the inferior arcuate sulcus, but no functional characterization of F5a at the single-cell level exists. We investigated the neuronal selectivity for three-dimensional (3D) shape and grasping activity in F5a. In contrast to neighboring regions F5p and 45B, the great majority of F5a neurons showed selectivity for disparity-defined curved surfaces, and most neurons preserved this selectivity across positions in depth, indicating higher-order disparity selectivity. Thus, as predicted by monkey fMRI data, F5a neurons showed robust 3D-shape selectivity in the absence of a motor response. To investigate the relationship between disparity selectivity and grasping activity, we recorded from 3D-shape-selective F5a neurons during a visually guided grasping task and during grasping in the dark. F5a neurons encoding the depth profile of curved surfaces frequently responded during grasping of real-world objects in the light, but not in the dark, whereas nearby neurons were also active in the dark. The presence of 3D-shape-selective and “visual-dominant” neurons demonstrates that the F5a sector is distinct from neighboring regions of ventral premotor cortex, in line with recent anatomical connectivity studies.
Indirect costs and workplace productivity loss associated with non-Hodgkin lymphoma

Abstract The objective of this study was to examine indirect costs and workplace productivity loss (defined as an aggregate measure of absenteeism, short-term disability, and long-term disability days) associated with non-Hodgkin lymphoma (NHL) from a societal perspective in a commercially insured working-age United States population. The MarketScan® Commercial Claims and Encounters and Health and Productivity Management Databases (2007–2013) were used in this study, with controls matched 3:1 to NHL patients. In comparison to controls, NHL patients incurred significantly more workplace productivity loss (31.99 days; 95% CI: 25.24 days, 38.73 days; p < 0.001) and associated indirect costs ($6302.34; 95% CI: $4973.40, $7631.28; p < 0.001) in the 12-month post-diagnosis period when adjusting for covariates. NHL contributes significantly to losses in workplace productivity and higher associated indirect costs.
The Same Core Rhythm Generator Underlies Different Rhythmic Motor Patterns

Rhythmically active motor circuits can generate different activity patterns in response to different inputs. In most systems, however, it is not known whether the same neurons generate the underlying rhythm for each different pattern. Thus far, information regarding the degree of conservation of rhythm generator neurons is limited to a few pacemaker-driven circuits, in most of which the core rhythm generator is unchanged across different output patterns. We are addressing this issue in the network-driven, gastric mill (chewing) circuit in the crab stomatogastric nervous system. We first establish that distinct gastric mill motor patterns are triggered by separate stimulation of two extrinsic input pathways, the ventral cardiac neurons (VCNs) and postoesophageal commissure (POC) neurons. A prominent feature that distinguishes these gastric mill motor patterns is the LG (lateral gastric) protractor motor neuron activity pattern, which is tonic during the VCN rhythm and exhibits fast rhythmic bursting during the POC rhythm. These two motor patterns also differed in their cycle period and some motor neuron phase relationships, duty cycles, and burst durations. Despite the POC and VCN motor patterns being distinct, rhythm generation during each motor pattern required the activity of the same two, reciprocally inhibitory gastric mill neurons [LG, Int1 (interneuron 1)]. Specifically, reversibly hyperpolarizing LG or Int1, but no other gastric mill neuron, delayed the start of the next gastric mill cycle until after the imposed hyperpolarization. Thus, the same circuit neurons can comprise the core rhythm generator during different versions of a network-driven rhythmic motor pattern.
Lineage specification in the fly nervous system and evolutionary implications

Over the last decades, it has become clear that glia are multifunctional and plastic cells endowed with key regulatory roles. They control the response to developmental and/or pathological signals, thereby affecting neural proliferation, remodeling, survival, and regeneration. It is, therefore, important to understand the biology of these cells and the molecular mechanisms controlling their development/activity. The fly community has made major breakthroughs by characterizing the bases of gliogenesis and function. Here we describe the regulation and the role of the fly glial determinant. Then, we discuss the impact of the determinant in cell plasticity and differentiation. Finally, we address the conservation of this pathway across evolution.
Distinct Cell- and Layer-Specific Expression Patterns and Independent Regulation of Kv2 Channel Subtypes in Cortical Pyramidal Neurons

The Kv2 family of voltage-gated potassium channel α subunits, comprising Kv2.1 and Kv2.2, mediate the bulk of the neuronal delayed rectifier K+ current in many mammalian central neurons. Kv2.1 exhibits robust expression across many neuron types and is unique in its conditional role in modulating intrinsic excitability through changes in its phosphorylation state, which affect Kv2.1 expression, localization, and function. Much less is known of the highly related Kv2.2 subunit, especially in forebrain neurons. Here, through combined use of cortical layer markers and transgenic mouse lines, we show that Kv2.1 and Kv2.2 are localized to functionally distinct cortical cell types. Kv2.1 expression is consistently high throughout all cortical layers, especially in layer (L) 5b pyramidal neurons, whereas Kv2.2 expression is primarily limited to neurons in L2 and L5a. In addition, L4 of primary somatosensory cortex is strikingly devoid of Kv2.2 immunolabeling. The restricted pattern of Kv2.2 expression persists in Kv2.1-KO mice, suggesting distinct cell- and layer-specific functions for these two highly related Kv2 subunits. Analyses of endogenous Kv2.2 in cortical neurons in situ and recombinant Kv2.2 expressed in heterologous cells reveal that Kv2.2 is largely refractory to stimuli that trigger robust, phosphorylation-dependent changes in Kv2.1 clustering and function. Immunocytochemistry and voltage-clamp recordings from outside-out macropatches reveal distinct cellular expression patterns for Kv2.1 and Kv2.2 in intratelencephalic and pyramidal tract neurons of L5, indicating circuit-specific requirements for these Kv2 paralogs. Together, these results support distinct roles for these two Kv2 channel family members in mammalian cortex. SIGNIFICANCE STATEMENT Neurons within the neocortex are arranged in a laminar architecture and contribute to the input, processing, and/or output of sensory and motor signals in a cell- and layer-specific manner. Neurons of different cortical layers express diverse populations of ion channels and possess distinct intrinsic membrane properties. Here, we show that the Kv2 family members Kv2.1 and Kv2.2 are expressed in distinct cortical layers and pyramidal cell types associated with specific corticostriatal pathways. We find that Kv2.1 and Kv2.2 exhibit distinct responses to acute phosphorylation-dependent regulation in brain neurons in situ and in heterologous cells in vitro. These results identify a molecular mechanism that contributes to heterogeneity in cortical neuron ion channel function and regulation.
Protein Kinase C Mediates the Synergistic Interaction Between Agonists Acting at α2-Adrenergic and Delta-Opioid Receptors in Spinal Cord

Coactivation of spinal α2-adrenergic receptors (ARs) and opioid receptors produces antinociceptive synergy. Antinociceptive synergy between intrathecally administered α2AR and opioid agonists is well documented, but the mechanism underlying this synergy remains unclear. The delta-opioid receptor (DOP) and the α2AARs are coexpressed on the terminals of primary afferent fibers in the spinal cord where they may mediate this phenomenon. We evaluated the ability of the DOP-selective agonist deltorphin II (DELT), the α2AR agonist clonidine (CLON) or their combination to inhibit calcitonin gene-related peptide (CGRP) release from spinal cord slices. We then examined the possible underlying signaling mechanisms involved through coadministration of inhibitors of phospholipase C (PLC), protein kinase C (PKC) or protein kinase A (PKA). Potassium-evoked depolarization of spinal cord slices caused concentration-dependent release of CGRP. Coadministration of DELT and CLON inhibited the release of CGRP in a synergistic manner as confirmed statistically by isobolograpic analysis. Synergy was dependent on the activation of PLC and PKC, but not PKA, whereas the effect of agonist administration alone was only dependent on PLC. The importance of these findings was confirmed in vivo, using a thermal nociceptive test, demonstrating the PKC dependence of CLON-DELT antinociceptive synergy in mice. That inhibition of CGRP release by the combination was maintained in the presence of tetrodotoxin in spinal cord slices suggests that synergy does not rely on interneuronal signaling and may occur within single subcellular compartments. The present study reveals a novel signaling pathway underlying the synergistic analgesic interaction between DOP and α2AR agonists in the spinal cord.
Different Brain Circuitries Mediating Controllable and Uncontrollable Pain

Uncontrollable, compared with controllable, painful stimulation can lead to increased pain perception and activation in pain-processing brain regions, but it is currently unknown which brain areas mediate this effect. When pain is controllable, the lateral prefrontal cortex (PFC) seems to inhibit pain processing, although it is unclear how this is achieved. Using fMRI in healthy volunteers, we examined brain activation during controllable and uncontrollable stimulation to answer these questions. In the controllable task, participants self-adjusted temperatures applied to their hand of pain or warm intensities to provoke a constant sensation. In the uncontrollable task, the temperature time courses of the controllable task were replayed (yoked control) and participants rated their sensation continuously. During controllable pain trials, participants significantly downregulated the temperature to keep their sensation constant. Despite receiving the identical nociceptive input, intensity ratings increased during the uncontrollable pain trials. This additional sensitization was mirrored in increased activation of pain-processing regions such as insula, anterior cingulate cortex, and thalamus. Further, increased connectivity between the anterior insula and medial PFC (mPFC) in the uncontrollable and increased negative connectivity between dorsolateral PFC (dlPFC) and insula in the controllable task were observed. This suggests a pain-facilitating role of the mPFC during uncontrollable pain and a pain-inhibiting role of the dlPFC during controllable pain, both exerting their respective effects via the anterior insula. These results elucidate neural mechanisms of context-dependent pain modulation and their relation to subjective perception. SIGNIFICANCE STATEMENT Pain control is of uttermost importance and stimulus controllability is an important way to achieve endogenous pain modulation. Here, we show differential effects of controllability and uncontrollability on pain perception and cerebral pain processing. When pain was controllable, the dorsolateral prefrontal cortex downregulated pain-evoked activation in important pain-processing regions. In contrast, sensitization during uncontrollable pain was mediated by increased connectivity of the medial prefrontal cortex with the anterior insula and other pain-processing regions. These novel insights into cerebral pain modulation by stimulus controllability have the potential to improve treatment approaches in pain patients.
Efficient Encoding of Vocalizations in the Auditory Midbrain

An important question in sensory neuroscience is what coding strategies and mechanisms are used by the brain to detect and discriminate among behaviorally relevant stimuli. There is evidence that sensory systems migrate from a distributed and redundant encoding strategy at the periphery to a more heterogeneous encoding in cortical structures. It has been hypothesized that heterogeneity is an efficient encoding strategy that minimizes the redundancy of the neural code and maximizes information throughput. Evidence of this mechanism has been documented in cortical structures. In this study, we examined whether heterogeneous encoding of complex sounds contributes to efficient encoding in the auditory midbrain by characterizing neural responses to behaviorally relevant vocalizations in the mouse inferior colliculus (IC). We independently manipulated the frequency, amplitude, duration, and harmonic structure of the vocalizations to create a suite of modified vocalizations. Based on measures of both spike rate and timing, we characterized the heterogeneity of neural responses to the natural vocalizations and their perturbed variants. Using information theoretic measures, we found that heterogeneous response properties of IC neurons contribute to efficient encoding of behaviorally relevant vocalizations.
Myotube-derived exosomal miRNAs downregulate Sirtuin1 in myoblasts during muscle cell differentiation

It has recently been established that exosomes can mediate intercellular cross-talk under normal and pathological conditions through the transfer of specific miRNAs. As muscle cells secrete exosomes, we addressed the question of whether skeletal muscle (SkM) exosomes contained specific miRNAs, and whether they could act as “endocrine signals” during myogenesis. We compared the miRNA repertoires found in exosomes released from C2C12 myoblasts and myotubes and found that 171 and 182 miRNAs were exported into exosomes from myoblasts and myotubes, respectively. Interestingly, some miRNAs were expressed at higher levels in exosomes than in their donor cells and vice versa, indicating a selectivity in the incorporation of miRNAs into exosomes. Moreover miRNAs from C2C12 exosomes were regulated during myogenesis. The predicted target genes of regulated exosomal miRNAs are mainly involved in the control of important signaling pathways for muscle cell differentiation (e.g., Wnt signaling pathway). We demonstrated that exosomes from myotubes can transfer small RNAs (C. elegans miRNAs and siRNA) into myoblasts. Moreover, we present evidence that exosome miRNAs secreted by myotubes are functionally able to silence Sirt1 in myoblasts. As Sirt1 regulates muscle gene expression and differentiation, our results show that myotube–exosome miRNAs could contribute to the commitment of myoblasts in the process of differentiation. Until now, myokines in muscle cell secretome provided a conceptual basis for communication between muscles. Here, we show that miRNA exosomal transfer would be a powerful means by which gene expression is orchestrated to regulate SkM metabolic homeostasis.
Honey Bee Thermal/Chemical Sensor, AmHsTRPA, Reveals Neofunctionalization and Loss of Transient Receptor Potential Channel Genes

Insects are relatively small heterothermic animals, thus they are highly susceptible to changes in ambient temperature. However, a group of honey bees is able to maintain the brood nest temperature between 32°C and 36°C by either cooling or heating the nest. Nevertheless, how honey bees sense the ambient temperature is not known. We identified a honey bee Hymenoptera-specific transient receptor potential A (HsTRPA) channel (AmHsTRPA), which is activated by heat with an apparent threshold temperature of 34°C and insect antifeedants such as camphor in vitro. AmHsTRPA is expressed in the antennal flagellum, and ablation of the antennal flagella and injection of AmHsTRPA inhibitors impair warmth avoidance of honey bees. Gustatory responses of honey bees to sucrose are suppressed by noxious heat and insect antifeedants, but are relieved in the presence of AmHsTRPA inhibitors. These results suggest that AmHsTRPA may function as a thermal/chemical sensor in vivo. As shown previously, Hymenoptera has lost the ancient chemical sensor TRPA1; however, AmHsTRPA is able to complement the function of Drosophila melanogaster TRPA1. These results demonstrate that HsTRPA, originally arisen by the duplication of Water witch, has acquired thermal- and chemical-responsive properties, which has resulted in the loss of ancient TRPA1. Thus, this is an example of neofunctionalization of the duplicated ion channel gene followed by the loss of the functionally equivalent ancient gene.
Direct Recording of Dendrodendritic Excitation in the Olfactory Bulb: Divergent Properties of Local and External Glutamatergic Inputs Govern Synaptic Integration in Granule Cells

The olfactory bulb contains excitatory principal cells (mitral and tufted cells) that project to cortical targets as well as inhibitory interneurons. How the local circuitry in this region facilitates odor-specific output is not known, but previous work suggests that GABAergic granule cells plays an important role, especially during fine odor discrimination. Principal cells interact with granule cells through reciprocal dendrodendritic connections that are poorly understood. While many studies examined the GABAergic output side of these reciprocal connections, little is known about how granule cells are excited. Only two previous studies reported monosynaptically coupled mitral/granule cell connections and neither attempted to determine the fundamental properties of these synapses. Using dual intracellular recordings and a custom-built loose-patch amplifier, we have recorded unitary granule cell EPSPs evoked in response to mitral cell action potentials in rat (both sexes) brain slices. We find that the unitary dendrodendritic input is relatively weak with highly variable release probability and short-term depression. In contrast with the weak dendrodendritic input, the facilitating cortical input to granule cells is more powerful and less variable. Our computational simulations suggest that dendrodendritic synaptic properties prevent individual principal cells from strongly depolarizing granule cells, which likely discharge in response to either concerted activity among a large proportion of inputs or coactivation of a smaller subset of local dendrodendritic inputs with coincidence excitation from olfactory cortex. This dual-pathway requirement likely enables the sparse mitral/granule cell interconnections to develop highly odor-specific responses that facilitate fine olfactory discrimination. SIGNIFICANCE STATEMENT The olfactory bulb plays a central role in converting broad, highly overlapping, sensory input patterns into odor-selective population responses. How this occurs is not known, but experimental and theoretical studies suggest that local inhibition often plays a central role. Very little is known about how the most common local interneuron subtype, the granule cell, is excited during odor processing beyond the unusual anatomical arraignment of the interconnections (reciprocal dendrodendritic synapses). Using paired recordings and two-photon imaging, we determined the properties of the primary input to granule cells for the first time and show that these connections bias interneurons to fire in response to spiking in large populations of principal cells rather than a small group of highly active cells.
Does malnutrition affect survival in cirrhosis?

A total of 1,053 cirrhotic patients were included in a prospective study to determine whether malnutrition is a risk factor for mortality in cirrhotic patients. Child‐Pugh classification as well as clinical and biochemical variables were used to assess the severity of cirrhosis. Nutritional status was evaluated both by anthropometric and clinical measurements. Patients were defined as malnourished when midarm muscle area (MAMA) and/or midarm fat area (MAFA) were below the 5th percentile of an age‐ and sex‐matched population. During follow‐up, 419 patients died. The estimated survival rate was 82.7% at 1 year, 65.1% at 3 years, and 50.7% at 5 years. The presence of muscle depletion and/or of a steep reduction in fat deposits was associated with a higher risk of mortality (midarm muscle area, < 5th percentile, relative risk = 1.79; midarm fat area, < 5th percentile, relative risk = 1.35). When patients were stratified according to the Child‐Pugh classification, cumulative survival was lower in patients with a reduction in muscle mass in Child‐Pugh classes A and B (log rank: P = .027; P = .022, respectively) but not in class C. Conversely, a significant reduction in adipose tissue deposits appeared to have no independent impact on survival in any Child‐Pugh class. When examined using a multivariate Cox proportional hazard analysis, age, sex, bilirubin, cholinesterase, ascites, and esophageal varices were selected, whereas the parameters of nutritional status were not. This suggests that malnutrition, while strongly associated with the deterioration of liver function, cannot be considered an independent risk factor for mortality in a general population of cirrhotic patients.
Representation of Functional Category in the Monkey Prefrontal Cortex and Its Rule-Dependent Use for Behavioral Selection

Humans, monkeys, and other animals are considered to have the cognitive ability to use functional categories—that is, stimulus groups based on functional equivalence independent of physical properties. To investigate the underlying neural mechanisms of the use of functional categories, we recorded single-unit activity in the prefrontal cortex of monkeys performing a behavioral task in which the rule-dependent usage of functional category was needed to select an appropriate response. We found a neural correlate of functional categories on the single-neuron level and found that category information is coded independently of other task-relevant information such as rule and contingency information. Analysis of the time course of the information activation suggested that contingency information used for action selection is derived by integrating incoming category information with rule information maintained throughout a session. Such neural computation can be considered as the neural background of flexible behavioral control based on category and rule. SIGNIFICANCE STATEMENT Perceptual categories are based on perceptual similarity, whereas functional categories are based on functional equivalence independently of their physical properties. The neural background of perceptual categories has been investigated in a number of studies, but that of functional categories has been investigated in only a few. In the present study, we found neural correlates of functional categories on the single-neuron level. Further analysis suggested that functional category information and rule information is integrated within the prefrontal cortex to derive contingency information necessary for action selection. This study has shown how the brain uses the category to select an action appropriate to the behavioral context.