Disparate Functions Research Articles

A metabolic function of the hippocampal sharp wave-ripple.

The hippocampus has previously been implicated in both cognitive and endocrine functions1-15. We simultaneously measured electrophysiological activity from the hippocampus and interstitial glucose concentrations in the body of freely behaving rats to identify an activity pattern that may link these disparate functions of the hippocampus. Here we report that clusters of sharp wave-ripples recorded from the hippocampus reliably predicted a decrease in peripheral glucose concentrations within about 10min. This correlation was not dependent on circadian, ultradian or meal-triggered fluctuations, could be mimicked with optogenetically induced ripples in the hippocampus (but not in the parietal cortex) and was attenuated to chance levels by pharmacogenetically suppressing activity of the lateral septum, which is the major conduit between the hippocampus and thehypothalamus. Our findings demonstrate that a function of the sharp wave-ripple is to modulate peripheral glucose homeostasis, and offer a mechanism for the link between sleep disruption and blood glucose dysregulation in type2 diabetes16-18.

Exploring partial intrinsic and extrinsic symmetry in 3D medical imaging.

We present a novel methodology to detect imperfect bilateral symmetry in CT of human anatomy. In this paper, the structurally symmetric nature of the pelvic bone is explored and is used to provide interventional image augmentation for treatment of unilateral fractures in patients with traumatic injuries. The mathematical basis of our solution is based on the incorporation of attributes and characteristics that satisfy the properties of intrinsic and extrinsic symmetry and are robust to outliers. In the first step, feature points that satisfy intrinsic symmetry are automatically detected in the Möbius space defined on the CT data. These features are then pruned via a two-stage RANSAC to attain correspondences that satisfy also the extrinsic symmetry. Then, a disparity function based on Tukey's biweight robust estimator is introduced and minimized to identify a symmetry plane parametrization that yields maximum contralateral similarity. Finally, a novel regularization term is introduced to enhance similarity between bone density histograms across the partial symmetry plane, relying on the important biological observation that, even if injured, the dislocated bone segments remain within the body. Our extensive evaluations on various cases of common fracture types demonstrate the validity of the novel concepts and the accuracy of the proposed method.

Neurophysiology of embodied mental rotation: Event‐related potentials in a mental rotation task with human bodies as compared to alphanumeric stimuli

The present study examines if the neural signature of information processing in mental rotation tasks is moderated by stimulus characteristics (e.g., body-related vs. non-body-related stimuli). In the present experiment, stimulus sets of human figures (back view; left vs. right arm abduction) and alphanumeric characters ('R'; normal vs. mirrored view) were scrutinized with event-related potentials (ERPs) in the electroencephalography (EEG). Participants had to judge parity between an upright (0° orientation) and a comparison stimulus (stimulus disparity; 0°, 45°, 90°, 135° or 180°). There was a main effect of stimulus disparity for the behavioural (response time and error rates), as well as for the neural data (rotation-related negativity, RRN). The interaction of stimulus disparity and stimulus type was significant for the RRN, but not for the response time. Lower RRN amplitudes for letters indicate a more pronounced use of alternative processes (e.g., memory retrieval), which seems to be reflected in higher N350 amplitudes. Moreover, the increase of the RRN amplitude and the increase in response time as a function of disparity were positively correlated. Task differences were evident for several ERP components (i.e., N150, P150 and N250), being independent of disparity, which might reflect differences in early and late object cognition prior to the mental rotation process itself. This might be associated with the task-dependent activation of embodied cognition processes in mental rotation tasks.

Designing Regulation Across Organizations: Assessing the Functions and Dimensions of Governance

AbstractIn recent years, regulation scholars and policymakers have increasingly turned their attention to the role of inter‐governmental organizational design in effective governance. The existing literature on regulatory design has provided important insights into the advantages and disadvantages of alternative structural options. This article synthesizes and builds on that literature by describing a novel framework for characterizing, analyzing, and structuring authority across public institutions. Drawing on examples from a range of jurisdictions, it highlights the value of this framework in identifying the values tradeoffs that should drive policymakers' decisions to choose among competing structural alternatives. The framework is founded on two important points. First, inter‐governmental allocations of authority can be structured along three different dimensions. Failing to appreciate the existence of, and differences among, these dimensions can prompt misassessments of the reasons for existing regulatory failures and selection of structural allocations that do not suit the problems intended to be addressed. Second, allocations of authority can, and in many cases should, vary for disparate governmental functions. Differential functional allocations of authority can minimize obstacles to needed structural reforms and tailor inter‐governmental relations in ways that best promote chosen regulatory values, such as efficiency, effectiveness, and accountability, as well as how allocational choices may and perhaps should vary depending on the governmental function being performed. Finally, the article suggests how future regulation and governance scholarship can harness this emerging framework to help build a body of empirical evidence upon which policymakers can draw in future regulatory design endeavors.

Optimal receive beamforming in spatial antenna diversity system using evolutionary genetic algorithm

Frequent packet loss and power inadequacy are the major issues in wireless fading networks owing to the deep fading effects and inefficient resource utilization caused by unoriented information forwarding mechanisms. Diversity techniques are potentially employed in wireless communication systems to combat the impact of fading and reinforce the desired service level guarantees for data transmission. In this work, we employ spatial diversity and antenna beamforming methods to significantly improve the signal quality performance of wireless networks and enhance the reliability by decreasing the bit error probability. A constrained optimization problem is formulated for alleviating the net noise power integrated with the adaptive beamforming vector and ameliorated channel state information. For this, the evolutionary genetic algorithm scheme is iteratively implemented for evaluating the optimal solution of the proposed optimization problem. The influence of various selection functions in the application of genetic algorithm is investigated for effective heuristic modeling design and searching through the feasible solution space. Through extensive simulation results, several crucial network parameters characterizing the proficiency of wireless communications including the noise power, signal-to-noise ratio (SNR), bit error rate (BER) are estimated and analyzed for varying number of antennas deployed at the receiver node. Furthermore, the performance of the proposed genetic algorithm based optimization technique is compared with the existing models using the key channel quality metrics of achievable SNR, BER, and model computational complexity. • Spatial diversity and receive beamforming techniques can be jointly implemented. • This optimization model achieves enhanced signal quality and reliability performance. • Evolutionary genetic algorithm solves the problem using intelligent heuristic design. • Disparate selection functions exhibit different iterative complexity for optimization. • Simulation is used to show the improved noise power, SNR, BER with evolving antennas.

Immunology and microbiology: how do they affect social cognition and emotion recognition?

Social interactions profoundly influence animals' life. The quality of social interactions and many everyday life decisions are determined by a proper perception, processing and reaction to others' emotions. Notably, alterations in these social processes characterize a number of neurodevelopmental disorders, including autism spectrum disorders and schizophrenia. Increasing evidences support an implication of immune system vulnerability and inflammatory processes in disparate behavioral functions and the aforementioned neurodevelopmental disorders. In this review, we show a possible unifying view on how immune responses, within and outside the brain, and the communication between the immune system and brain responses might influence emotion recognition and related social responses. In particular, we highlight the importance of combining genetics, immunology and microbiology factors in understanding social behaviors. We underline the importance of better disentangling the whole machinery between brain-immune system interactions to better address the complexity of social processes.

B cells modulate the expression of MHC-II on cardiac CCR2− macrophages

The uninjured murine heart contains a heterogeneous population of macrophages with disparate ontogenies and functions. These macrophages are often associated with blood vessels and can be subclassified based on the expression of CC chemokine receptor 2 (CCR2) and major histocompatibility complex class II (MHC-II). The biological cues that modulate these macrophage pool subpopulations have not been completely identified. It has been recently shown that a sub-population of circulating naïve B cells adheres to the myocardial microvasculature. We hypothesized that B cells might modulate the phenotype of myocardial macrophages. To test this hypothesis, we analyzed both the relative location of B cells and macrophages in myocardial histological section and the prevalence of myocardial macrophage subsets in hearts from B cell–deficient mice (μMT) and mice depleted of B cells through administration of an anti-CD20 antibody. We found that B cells pause in the microvasculature in proximity of macrophages and modulate the number of myocardial CCR2−MHC-IIhigh cells. Through in vitro studies we found that this is likely the result of a paracrine effect of B cells on the expression of MHC-II in CCR2− cells. These results reveal an unexpected relationship between B cells and resident macrophages and, highlighting a direct intramyocardial effect of circulating B cells, challenge the currently held belief that naïve recirculating B lymphocytes merely shuttle between lymphoid stations.

Dynamics of global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain

Efforts to understand genetic variability involved in an individual's susceptibility to chronic pain support a role for upstream regulation by epigenetic mechanisms. To examine the transcriptomic and epigenetic basis of chronic pain that resides in the peripheral nervous system, we used RNA-seq and ATAC-seq of the rat dorsal root ganglion (DRG) to identify novel molecular pathways associated with pain hypersensitivity in two well-studied persistent pain models induced by Chronic Constriction Injury (CCI) of the sciatic nerve and intra-plantar injection of Complete Freund's Adjuvant (CFA) in rats. Our RNA-seq studies identify a variety of biological process related to synapse organization, membrane potential, transmembrane transport, and ion binding. Interestingly, genes that encode transcriptional regulators were disproportionately downregulated in both models. Our ATAC-seq data provide a comprehensive map of changes in chromatin accessibility in the DRG. A total of 1123 regions showed changes in chromatin accessibility in one or both models when compared to the naive and 31 shared differentially accessible regions (DAR)s. Functional annotation of the DARs identified disparate molecular functions enriched for each pain model which suggests that chromatin structure may be altered differently following sciatic nerve injury and hind paw inflammation. Motif analysis identified 17 DNA sequences known to bind transcription factors in the CCI DARs and 33 in the CFA DARs. Two motifs were significantly enriched in both models. Our improved understanding of the changes in chromatin accessibility that occur in chronic pain states may identify regulatory that play a central role in changing gene expression in the DRG. F32NR015728 (KES), KL2 TR003108 (KES), NS110598 (YG), NS117761 (YG), Johns Hopkins Blaustein Pain Research Fund (SDT).

63438 Differential chromatin accessibility at dorsal root ganglia enhancers is associated with nerve injury

ABSTRACT IMPACT: Our improved understanding of the changes in chromatin accessibility that occur in persistent pain states may identify regulatory genomic elements that play essential roles in modulating gene expression in the DRG. OBJECTIVES/GOALS: Efforts to understand genetic variability involved in an individual’s susceptibility to persistent pain support a role for upstream regulation by epigenetic mechanisms. Our objective was to examine the transcriptomic and epigenetic basis of persistent pain following nerve injury. METHODS/STUDY POPULATION: We used a multiomic approach to identify novel molecular pathways associated with nerve injury-induced pain hypersensitivity. Adult Sprague Dawley rats were randomized to Chronic Constriction Injury (CCI) to the sciatic nerve or no treatment (naive). The ipsilateral L4-L6 dorsal root ganglia (DRG)s were removed on Day 14 and used for ChIP-seq for H3K4me1, ATAC-seq, and RNA-seq. We assessed for differential chromatin accessibility, transcription factor motifs, and enrichment for biological processes in chromatin accessible regions associated with cis-regulatory regions identified by ATAC-seq and H3K4me1 enrichment. Luciferase assays determined the functional significance of these sequences. RESULTS/ANTICIPATED RESULTS: We identified 58,446 genomic regions where H3K4me1 enrichment overlapped with chromatin accessibility. Differential analysis identified 2145 of these 58,446 regions that had changes in accessibility after CCI. The majority of these regions were located in introns or intergenic regions. Functional annotation of the differentially accessible regions identified disparate molecular functions enriched following nerve injury which suggests that altered chromatin structure plays a role in the development of mechanical hypersensitivity. Motif analysis identified specific transcription factor families whose binding sequences were enriched in regions of increased or decreased accessibility. Luciferase assays showed significant enhancement or repression of gene transcription. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our data provides a comprehensive map of chromatin accessibility changes in the DRG after CCI and emphasizes the importance of chromatin structure in the development and maintenance of chronic pain.

Data-sharing markets for integrating IoT data processing functionalities

The recent evolution of the Internet of Things into a cyber-physical reality has spawned various challenges from a data management perspective. In addition, IoT platform designers are faced with another set of questions. How can platforms be extended to smoothly integrate new data management functionalities? Currently, data processing related tasks are typically realized by manually developed code and functions which creates difficulties in maintenance and growth. Hence we need to explore other approaches to integration for IoT platforms. In this paper we cover both these aspects: (1) we explore several emerging data management challenges, and (2) we propose an IoT platform integration model that can combine disparate functionalities under one roof. For the first, we focus on the following challenges: sensor data quality, privacy in data streams, machine learning model management, and resource-aware data management. For the second, we propose an information-integration model for IoT platforms. The model revolves around the concept of a Data-Sharing Market where data management functionalities can share and exchange information about their data with other functionalities. In addition, data-sharing markets themselves can be combined into networks of markets where information flows from one market to another, which creates a web of information exchange about data resources. To motivate this work we present a use-case application in smart cities.

Dynamics of Global Gene Expression and Chromatin Accessibility of the Peripheral Nervous System in Animal Models of Persistent Pain

Efforts to understand genetic variability involved in an individuals susceptibility to chronic pain support a role for upstream regulation by epigenetic mechanisms. To examine the transcriptomic and epigenetic basis of chronic pain that resides in the peripheral nervous system, we used RNA-seq and ATAC-seq of the rat dorsal root ganglion (DRG) to identify novel molecular pathways associated with pain hypersensitivity in two well-studied persistent pain models induced by Chronic Constriction Injury (CCI) of the sciatic nerve and intra-plantar injection of Complete Freunds Adjuvant (CFA) in rats. Our RNA-seq studies identify a variety of biological process related to synapse organization, membrane potential, transmembrane transport, and ion binding. Interestingly, genes that encode transcriptional regulators were disproportionately downregulated in both models. Our ATAC-seq data provide a comprehensive map of chromatin accessibility changes in the DRG. A total of 1123 regions showed changes in chromatin accessibility in one or both models when compared to the naive and 31 shared differentially accessible regions (DAR)s. Functional annotation of the DARs identified disparate molecular functions enriched for each pain model which suggests that chromatin structure may be altered differently following sciatic nerve injury and hind paw inflammation. Motif analysis identified 17 DNA sequences known to bind transcription factors in the CCI DARs and 33 in the CFA DARs. Two motifs were significantly enriched in both models. Our improved understanding of the changes in chromatin accessibility that occur in chronic pain states may identify regulatory genomic elements that play essential roles in modulating gene expression in the DRG.

The missing linker: emerging trends for H1 variant-specific functions.

Major advances in the chromatin and epigenetics fields have uncovered the importance of core histones, histone variants and their post-translational modifications (PTMs) in modulating chromatin structure. However, an acutely understudied related feature of chromatin structure is the role of linker histone H1. Previous assumptions of the functional redundancy of the 11 nonallelic H1 variants are contrasted by their strong evolutionary conservation, variability in their potential PTMs, and increased reports of their disparate functions, sub-nuclear localizations and unique expression patterns in different cell types. The commonly accepted notion that histone H1 functions solely in chromatin compaction and transcription repression is now being challenged by work from multiple groups. These studies highlight histone H1 variants as underappreciated facets of chromatin dynamics that function independently in various chromatin-based processes. In this review, we present notable findings involving the individual somatic H1 variants of which there are seven, underscoring their particular contributions to distinctly significant chromatin-related processes.

Transplantation of an obesity-associated human gut microbiota to mice induces vascular dysfunction and glucose intolerance

ABSTRACT Recent preclinical data suggest that alterations in the gut microbiota may be an important factor linking obesity to vascular dysfunction, an early sign of cardiovascular disease. The purpose of this study was to begin translation of these preclinical data by examining whether vascular phenotypes in humans are transmissible through the gut microbiota. We hypothesized that germ-free mice colonized with gut microbiota from obese individuals would display diminished vascular function compared to germ-free mice receiving microbiota from lean individuals. We transplanted fecal material from obese and lean age-and sex-matched participants with disparate vascular function to germ-free mice. Using Principle Component Analysis, the microbiota of colonized mice separated by donor group along the first principle component, accounting for between 70–93% of the total variability in the dataset. The microbiota of mice receiving transplants from lean individuals was also characterized by increased alpha diversity, as well as increased relative abundance of potentially beneficial bacteria, including Bifidobacterium, Lactobacillus, and Bacteroides ovatis. Endothelium-dependent dilation, aortic pulse wave velocity and glucose tolerance were significantly altered in mice receiving microbiota from the obese donor relative to those receiving microbiota from the lean donor or those remaining germ-free. These data indicate that the obesity-associated human gut microbiota is sufficient to alter the vascular phenotype in germ-free mice in the absence of differences in body weight or dietary manipulation, and provide justification for future clinical trials to test the efficacy of microbiota-targeted therapies in the prevention or treatment of cardiovascular disease.

Impaired autophagy: The collateral damage of lysosomal storage disorders.

Lysosomal storage disorders (LSDs), which number over fifty, are monogenically inherited and caused by mutations in genes encoding proteins that are involved in lysosomal function. Lack of the functional protein results in storage of a distinctive material within the lysosomes, which for years was thought to determine the pathophysiology of the disorder. However, our current view posits that the primary storage material disrupts the normal role of the lysosome in the autophagic pathway resulting in the secondary storage of autophagic debris. It is this “collateral damage” which is common to the LSDs but nonetheless intricately nuanced in each. We have selected five LSDs resulting from defective proteins that govern widely different lysosomal functions including glycogen degradation (Pompe), lysosomal transport (Cystinosis), lysosomal trafficking (Danon), glycolipid degradation (Gaucher) and an unidentified function (Batten) and argue that despite the disparate functions, these proteins, when mutant, all impair the autophagic process uniquely.

A Tale of Two Emotions: The Diverging Salience and Health Consequences of Calmness and Excitement in Old Age

Using two studies, we examined the late life prevalence and health consequences of discrete positive emotions posited to motivate rest and recovery (calmness) or pursuit of novelty and stimulation (excitement). Study 1 assessed the salience of these discrete emotions in older adults (n=73, Mage=73) relative to younger adults (n=73, Mage=23) over a one-week period. Multilevel models showed that older (vs. younger) adults reported higher calmness and lower excitement. Study 2 examined the longitudinal health consequences of calmness and excitement in old age (n=336, Mage=75), as moderated by perceived control. Multilevel growth models showed that calmness, but not excitement, buffered against 10-year declines in psychological well-being (perceived stress, depressive symptoms) and physical health (physical symptoms, chronic conditions) for older adults with low perceived control. Results suggest that positive emotions with disparate motivational functions become more (calmness) or less (excitement) salient and have diverging implications for health in old age.

The Ubiquitin Ligase TRAIP: Double-Edged Sword at the Replisome.

In preparation for cell division, the genome must be copied with high fidelity. However, replisomes often encounter obstacles, including bulky DNA lesions caused by reactive metabolites and chemotherapeutics, as well as stable nucleoprotein complexes. Here, we discuss recent advances in our understanding of TRAIP, a replisome-associated E3 ubiquitin ligase that is mutated in microcephalic primordial dwarfism. In interphase, TRAIP helps replisomes overcome DNA interstrand crosslinks and DNA-protein crosslinks, whereas in mitosis it triggers disassembly of all replisomes that remain on chromatin. We describe a model to explain how TRAIP performs these disparate functions and how they help maintain genome integrity.

The Study of Perceptual Eye Position Examination and Visual Perceptual Training in Postoperative Intermittent Exotropes

The aim of this study was to investigate perceptual eye position (PEP) and to evaluate the effect of dichoptic visual perceptual training in postoperative intermittent exotropia [X(T)]. We enrolled 30 non-strabismus children (control group) and 54 postoperative X(T) children [divided into training group (33 patients) and non-training group (21 patients)]. All subjects received measurements of PEP, and the postoperative X(T) children were measured both in the third postoperative day and the third postoperative month. All patients in training group received 3-month dichoptic visual perceptual training based on a unique virtual reality platform. The results showed that the postoperative X(T) children with normal eye position still had an abnormal PEP. After a period of visual perceptual training, the PEP pixels in postoperative children dramatically decreased. The results revealed that PEP could evaluate fixation disparity and binocular visual function perceptively and precisely, and the dichoptic visual perceptive training may rebuild binocular visual function.

Perceptual enhancement of suprathreshold luminance modulation in stereoscopic patterns.

Previous studies have shown that the binocular summation of luminance contrast signals depends on the parameters involved in stereopsis when the luminance contrast is at the detection threshold. However, less attention has been paid to the perception of luminance modulation in stereoscopic patterns at suprathreshold contrast. To address this issue, we determined the contrast of stereoscopic patterns at the perceptual match to a standard contrast as a function of binocular disparity. The matched contrast was close to the standard contrast at 0 degrees disparity, but decreased as disparity deviated from 0 degrees, suggesting that sufficient disparity perceptually enhances luminance contrast. The reduction of matched contrast was more evident for uncrossed disparities than for crossed disparities, which almost disappeared when the contrast was near the threshold and also occurred when vertical disparity was introduced. We argue that the perceptual enhancement of the luminance contrast is due to the weaker interocular suppression for stimuli with large disparities.

Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics, and Oncogenesis - Part 2: Acetate and ACSS2 in Health and Disease.

Acetate, the shortest chain fatty acid, has been implicated in providing health benefits whether it is derived from the diet or is generated from microbial fermentation of fiber in the gut. These health benefits range widely from improved cardiac function to enhanced red blood cell generation and memory formation. Understanding how acetate could influence so many disparate biological functions is now an area of intensive research. Protein acetylation is one of the most common post-translational modifications and increased systemic acetate strongly drives protein acetylation. By virtue of acetylation impacting the activity of virtually every class of protein, acetate driven alterations in signaling and gene transcription have been associated with several common human diseases, including cancer. In part 2 of this review, we will focus on some of the roles that acetate plays in health and human disease. The acetate-activating enzyme acyl-CoA short-chain synthetase family member 2 (ACSS2) will be a major part of that focus due to its role in targeted protein acetylation reactions that can regulate central metabolism and stress responses. ACSS2 is the only known enzyme that can recycle acetate derived from deacetylation reactions in the cytoplasm and nucleus of cells, including both protein and metabolite deacetylation reactions. As such, ACSS2 can recycle acetate derived from histone deacetylase reactions as well as protein deacetylation reactions mediated by sirtuins, among many others. Notably, ACSS2 can activate acetate released from acetylated metabolites including N-acetylaspartate (NAA), the most concentrated acetylated metabolite in the human brain. NAA has been associated with the metabolic reprograming of cancer cells, where ACSS2 also plays a role. Here, we discuss the context-specific roles that acetate can play in health and disease.

Molecular Logic of Prokaryotic Surface Layer Structures.

Most prokaryotic cells are encased in a surface layer (S-layer) consisting of a paracrystalline array of repeating lattice-forming proteins. S-layer proteins populate a vast and diverse sequence space, performing disparate functions in prokaryotic cells, including cellular defense, cell-shape maintenance, and regulation of import and export of materials. This article highlights recent advances in the understanding of S-layer structure and assembly, made possible by rapidly evolving structural and cell biology methods. We underscore shared assembly principles revealed by recent work and discuss a common molecular framework that may be used to understand the structural organization of S-layer proteins across bacteria and archaea.