bioRxiv Subject Collection: Neuroscience's Journal
[Most Recent Entries]
[Calendar View]
Wednesday, March 20th, 2024
| Time |
Event |
| 2:35a |
The role of rat prelimbic cortex in decision making
The frontal cortex plays a critical role in decision-making. One specific frontal area, the anterior cingulate cortex, has been identified as crucial for setting a threshold for how much evidence is needed before a choice is made (Domenech & Dreher, 2010). Threshold is a key concept in drift diffusion models, a popular framework used to understand decision-making processes. Here, we investigated the role of the prelimbic cortex, part of the rodent cingulate cortex, in decision making. Male and female rats learned to choose between stimuli associated with high and low value rewards. Females learned faster, were more selective in their responses, and integrated information about the stimuli more quickly. By contrast, males learned more slowly and showed a decrease in their decision thresholds during choice learning. Inactivating the prelimbic cortex in female and male rats sped up decision making without affecting choice accuracy. Drift diffusion modeling found selective effects of prelimbic cortex inactivation on the decision threshold, which was reduced with increasing doses of the GABA-A agonist muscimol. Stimulating the prelimbic cortex through mu opioid receptors slowed the animals' choice latencies and increased the decision threshold. These findings provide the first causal evidence that the prelimbic cortex directly influences decision processes. Additionally, they suggest possible sex-based differences in early choice learning. | | 2:35a |
Multi-Site Investigation of Gut Microbiota in CDKL5 Deficiency Disorder Mouse Models: Targeting Dysbiosis to Improve Neurological Outcomes
Background: Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder (CDD) is a rare X-linked developmental encephalopathy caused by pathogenic variants of the CDKL5 gene. In addition to a diverse range of neurological symptoms, CDD patients frequently manifest gastrointestinal (GI) issues and subclinical immune dysregulation. This comorbidity suggests a potential association with the intestinal microbiota, prompting an investigation into whether gut dysbiosis contributes to the severity of both GI and neurological symptoms. Methods: We examined the gut microbiota composition in two CDKL5 null (KO) mouse models in males at three different developmental stages: postnatal day (P) 25 and P32 during youth, and P70 during adulthood. Results: Changes in diversity and composition were observed, particularly during juvenile ages, suggesting a potential gut microbiota dysbiosis in the CDD mouse models. To further understand the role of the gut microbiota in CDD, we administered an antibiotic cocktail to the mice and conducted functional and behavioral assessments. Remarkably, significant improvement in visual cortical responses and reductions in hyperactive behavior were observed. To shed light on the cellular mechanisms we focused on microglia. Alterations in specific aspects of microglia morphology, indicative of activation state and surveillance of the microenvironment, were observed in CDKL5 KO mice and ameliorated by antibiotic administration. Conclusions: Our findings highlight the potential impact of modifications in the intestinal microbiota on the severity of CDD symptoms, expanding our understanding beyond GI disturbances to encompass influences on neurological outcomes. This cross-border study provides valuable insights into the intricate interplay between gut microbiota and neurodevelopmental disorders. | | 9:20a |
deepGOLSA: Goal-directed planning with subgoal reduction models human brain activity
Goal-directed planning presents a challenge for classical Reinforcement Learning (RL) algorithms due to the vastness of combinatorial state and goal spaces. Humans and animals adapt to complex environments especially with diverse, non-stationary objectives, often employing intermediate goals for long-horizon tasks. Here we propose a novel method for effectively deriving subgoals from arbitrary and distant original goals, called the deep Goal Oriented Learning and Selection of Action, or deepGOLSA model. Using a loop-removal technique, the method distills high-quality subgoals from a replay buffer, all without the need of prior environmental knowledge. This generalizable and scalable solution applies across different domains. Simulations show that the model can be integrated into existing RL frameworks like Deep Q Networks and Soft Actor-Critic models.DeepGOLSA accelerates performance in both discrete and continuous tasks, such as grid world navigation and robotic arm manipulation, relative to existing RL models. Moreover, the subgoal reduction mechanism, even without iterative training, outperforms its integrated deep RL counterparts when solving a navigation task. The goal reduction mechanism also models human problem-solving. Comparing the model's performance and activation with human behavior and fMRI data in a treasure hunting task, we found matching representational patterns between specific deepGOLSA model components and corresponding human brain areas, particularly the vmPFC and basal ganglia. The results suggest a new computational framework for examining goal-directed behaviors in humans. | | 9:20a |
Synapse specific and plasticity-regulated AMPAR mobility tunes synaptic integration
Synaptic responses adapt to fast repetitive inputs during bursts of neuronal network activity over timescales of milliseconds to seconds, either transiently facilitating or depressing. This high-frequency stimulus-dependent short-term synaptic plasticity (HF-STP) relies on a number of molecular processes that collectively endow synapses with filtering properties for information processing, optimized for the transmission of certain input frequencies and patterns in distinct circuits 1-3. Changes in HF-STP are traditionally thought to stem from changes in pre-synaptic transmitter release 1,2, but post-synaptic modifications in receptor biophysical properties or surface diffusion also regulate HF-STP 4-11. A major challenge in understanding synapse function is to decipher how pre- and post-synaptic mechanisms synergistically tune synaptic transmission efficacy during HF-STP, and to determine how neuronal activity modifies post-synaptic signal computation and integration to diversify neuronal circuit function. Here, taking advantage of new molecular tools to directly visualize glutamate release 12 and specifically manipulate the surface diffusion of endogenous AMPAR in intact circuits 13, we define the respective contributions of pre-synaptic glutamate release, AMPAR desensitization and surface mobility to frequency-dependent synaptic adaptation. We demonstrate that post-synaptic gain control and signal integration capacity in synaptic networks is influenced by synapse-specific differences in AMPAR desensitization and diffusion-trapping characteristics that are shaped by molecular signaling events recruited during LTP. | | 10:32a |
Causal Interactions between Phase- and Amplitude-Coupling in Cortical Networks
Phase coherence and amplitude correlations across brain regions are two main mechanisms of connectivity that govern brain dynamics at multiple scales. However, despite the increasing evidence that associates these mechanisms with brain functions and cognitive processes, the relationship between these different coupling modes is not well understood. Here, we study the causal relation between both types of functional coupling across multiple cortical areas. While most of the studies adopt a definition based on pairs of electrodes or regions of interest, we here employ a multichannel approach that provides us with a time-resolved definition of phase and amplitude coupling parameters. Using data recorded with a multichannel ECoG array from the ferret brain, we found that the transmission of information between both modes can be unidirectional or bidirectional, depending on the frequency band of the underlying signal. These results were reproduced in magnetoencephalography (MEG) data recorded during resting from the human brain. We show that this transmission of information occurs in a model of coupled oscillators and may represent a generic feature of a dynamical system. Together, our findings open the possibility of a general mechanism that may govern multi-scale interactions in brain dynamics. | | 11:47a |
The bidirectional role of GABAA and GABAB receptors during the differentiation process of neural precursor cells of thesubventricular zone
The intricate process of neuronal differentiation integrates multiple signals to induce transcriptional, morphological, and electrophysiological changes that reshape the properties of neural precursor cells during their maturation and migration process. An increasing number of neurotransmitters and biomolecules have been identified that serve as molecular signals that trigger and guide this process. In this sense, taurine, a sulfur-containing, non-essential amino acid widely expressed in the mammal brain, modulates the neuronal differentiation process. In this study, we describe the effect of taurine acting via the ionotropic GABAA receptor and the metabotropic GABAB receptor on the neuronal differentiation and electrophysiological properties of precursor cells derived from the subventricular zone of the mouse brain. Taurine stimulates the number of neurites and favors the dendritic complexity of the neural precursor cells, accompanied by changes in the somatic input resistance and the strength of inward and outward membranal currents. At the pharmacological level, the blockade of GABAA receptors inhibits these effects, whereas the stimulation of GABAB receptors has no positive effects on the taurine-mediated differentiation process. Strikingly, the blockade of the GABAB receptor with CGP533737 stimulates neurite outgrowth, dendritic complexity, and membranal current kinetics of neural precursor cells. The effects of taurine on the differentiation process involve Ca2+ mobilization and the activation of intracellular signaling cascades since chelation of intracellular calcium with BAPTA-AM, and inhibition of the CaMKII, ERK1/2, and Src kinase inhibits the neurite outgrowth of neural precursor cells of the subventricular zone. | | 2:31p |
Motor cortex directly excites the output nucleus of the basal ganglia, the substantia nigra pars reticulata.
Inhibitory neurons of the substantia nigra pars reticulata (SNr) serve as a primary output through which the basal ganglia regulate behaviour. Projections to the SNr from beyond the basal ganglia have also been identified anatomically. Using a virally-targeted optogenetic approach, combined with whole cell patch-clamp recordings of SNr neurons in acute brain slices, we show that projection neurons of the primary and secondary motor cortices (M1 and M2) make functional excitatory synapses with subpopulations of inhibitory SNr neurons. Furthermore, we demonstrate that photostimulation of these cortical axon terminals increases SNr neuron firing rate. To further investigate the spatial organisation of cortical input to SNr, we employed a transsynaptic viral-labelling approach to identify SNr neurons receiving monosynaptic input from M1 and M2. We found a topographical relationship between motor cortex and SNr, and identified downstream targets of cortical-recipient SNr subpopulations. These findings reveal functional pathways by which M1 and M2 can directly modulate basal ganglia output to different downstream targets. | | 7:30p |
NanoPlex: a universal strategy for fluorescence microscopy multiplexing using nanobodies with erasable signals
Fluorescence microscopy has long been a transformative technique in biological sciences. Nevertheless, most implementations are limited to a few targets, revealed using primary antibodies (1.Abs) and fluorescently conjugated secondary antibodies. Super-resolution techniques such as Exchange-PAINT and, more recently, SUM-PAINT have increased multiplexing capabilities, but they require specialized equipment, software, and knowledge. To enable multiplexing for any imaging technique in any laboratory, we developed NanoPlex, a streamlined method based on conventional 1.Abs revealed by engineered secondary nanobodies (2.Nbs) that allow to selectively erase the fluorescence signals. We developed three complementary signal removal strategies: OptoPlex (light-induced), EnzyPlex (enzymatic), and ChemiPlex (chemical). We showcase NanoPlex reaching 21 targets for 3D confocal analyses and 5-8 targets for dSTORM and STED super-resolution imaging. NanoPlex has the potential to revolutionize multi-target fluorescent imaging methods, potentially redefining the multiplexing capabilities of antibody-based assays. | | 8:47p |
Evaluating the position of the uncal apex as a predictor of episodic memory across the adult lifespan
Structural decline of the hippocampus occurs in heterogeneous patterns across its spatial extent, and is an important determinant of episodic memory dysfunction in aging. However, evidence indicate that the anatomical landmark uncal apex, used to demarcate anterior and posterior hippocampal subregions, changes position as the hippocampus atrophies. This emphasizes a risk of misclassifying gray matter into the incorrect subregion when using standard demarcation methods, contributing to over- and underestimation of age effects on anterior and posterior hippocampal volume. Yet, it remains unexplored whether inter-individual differences in uncal apex position predict episodic memory performance in itself. Here, we manually identified the uncal apex in anatomical MRI data from a healthy adult-lifespan sample (n=180; 20-79 years), assessed age differences in its position, and associations with word recollection performance. Increasing age was linked to a more anteriorly located uncal apex (retracting ~0.041 mm/year). Importantly, a more anterior uncal apex position was linked to lower memory performance. Whereas anterior hippocampal volume remained stable with increasing age, posterior volume displayed non-linear decline with an infliction point at approximately 45 years. Neither anterior nor posterior hippocampal volumes predicted memory performance, but the ratio of posterior to anterior volume showed a significant association with memory when taking the position of the uncal apex into account. These results indicate that uncal apex position may provide an estimate of hippocampal integrity sensitive to inter-individual differences in memory, independent of limitations associated with different segmentation methods. | | 8:47p |
Dedifferentiation of caudate-cortical connectivity is linked to reduced D1 dopamine receptor availability and poorer memory function in aging
Decreasing integrity of striato-cortical circuits has been highlighted as an important determinant of declines in flexible, higher-order cognition in older age. Here, leveraging multi-modal (fMRI, PET) neuroimaging data from a large adult lifespan sample, we demonstrate older age to be associated with less specific functional coupling between the caudate and cortical association networks. This age-related dedifferentiation of caudate-cortical connectivity was present during both rest and an active working memory task, and predicted poorer short and long-term memory performance with older age. Notably, reduced striatal and prefrontal dopamine D1-like receptor (D1DR) availability was associated with less specific caudate-cortical coupling across the lifespan and accounted for age-related variation in this measure. These findings highlight decreased dopaminergic neuromodulation as one factor contributing to differences in striato-cortical function, and memory performance, with older age. | | 8:47p |
Rapamycin Treatment Reduces Brain Pericyte Constriction in Ischemic Stroke
The contraction and subsequent death of brain pericytes may play a role in microvascular no-reflow following the re-opening of an occluded artery during ischemic stroke. Mammalian target of rapamycin (mTOR) inhibition has been shown to reduce motility/contractility of various cancer cell lines and reduce neuronal cell death in stroke. However, the effects of mTOR inhibition on brain pericyte contraction and death during ischemia have not yet been investigated. Cultured pericytes exposed to simulated ischemia for 12 hours in vitro contracted after less than 1 h, which was about 7h prior to cell death. Rapamycin significantly reduced the rate of pericyte contraction during ischemia, however, it did not have a significant effect on pericyte viability at any time point. Rapamycin appeared to reduce pericyte contraction through a RhoA-dependent pathway, independent of changes in intracellular calcium. Using a mouse model of middle cerebral artery occlusion, rapamycin significantly increased the diameter of capillaries underneath pericytes and increased the number of open capillaries 30 minutes following recanalization. Our findings suggest rapamycin may be a useful adjuvant therapeutic to reduce pericyte contraction and improve cerebral reperfusion post-stroke. | | 8:47p |
Incretin hormones and pharmacomimetics rapidly inhibit AgRP neuron activity to suppress appetite
Analogs of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have become mainstays of obesity and diabetes management. However, both the physiologic role of incretin hormones in the control of appetite and the pharmacologic mechanisms by which incretin-mimetic drugs suppress caloric intake remain incompletely understood. Hunger-promoting AgRP-expressing neurons are an important hypothalamic population that regulates food intake. Therefore, we set out to determine how incretins analogs affect their activity in vivo. Using fiber photometry, we observed that both GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) agonism acutely inhibit AgRP neuron activity in fasted mice and reduce the response of AgRP neurons to food. Moreover, optogenetic stimulation of AgRP neurons partially attenuated incretin-induced feeding suppression, suggesting that AgRP neuron inhibition is necessary for the full appetite-suppressing effects of incretin-based therapeutics. Finally, we found that GIP but not GLP-1 is necessary for nutrient-mediated AgRP neuron inhibition, representing a novel physiologic role for GIP in maintaining energy balance. Taken together, these findings reveal neural mechanisms underlying the efficacy of incretin-mimetic obesity therapies. Understanding these drugs' mechanisms of action is crucial for the development of next-generation obesity pharmacotherapies with an improved therapeutic profile. | | 8:47p |
Distinct Functional Roles of Narrow and Broadband High-Gamma Activities in Human Primary Somatosensory Cortex
In previous studies, higher (broadband) and lower (narrowband) components of high-gamma (HG) activity (approximately from 50 to 150 Hz) have different functions and origins in the primary visual cortex (V1). However, in the primary somatosensory cortex (S1), it is unknown whether those are similarly segregated. Furthermore, the origin and functional role of S1 HG activity still remain unclear. Here, we investigate their roles by measuring neural activity during vibrotactile and texture stimuli in humans. Also, to estimate their origins, S1 layer-specific HG activity was measured in rats during somatosensory stimulation. In the human experiment, with texture stimulation, the lower HG activity (LHG, 50-70 Hz) in S1 represents the intensity of the sustained mechanical stimulus. In the vibrotactile experiment, the higher HG (HHG, 70 -150 Hz) activity in S1 depended on the ratio of low and high mechanical frequencies with its pattern being a mixture of neural activity for low and high mechanical frequencies. Furthermore, 8 texture types could be classified using power values of HHG activity, while the classification using LHG activity showed poor performance. In the rat experiment, we found that both HHG and LHG activities are highest in the somatosensory input layer (layer IV), similar to previous visual cortex studies. Interestingly, analysis of spike-triggered LFP (stLFP) revealed significant HG oscillations during pressure stimulation with the stLFP HG power most significant in layer IV, suggesting that both LHG and HHG activities are closely related to the neuronal firing in layer IV. In summary, LHG activity represents the intensity of tactile sensation, while HHG activity represents the detail of the surface geometry of objects interacting with skin. Additionally, low and high mechanical frequencies are processed in parallel in S1. Finally, both HHG and LHG originated in layer IV of S1. | | 8:47p |
Ventral hippocampus mediates inter-trial responding in signaled active avoidance
The hippocampus has a central role in regulating contextual processes in memory. We have shown that pharmacological inactivation of ventral hippocampus (VH) attenuates the context-dependence of signaled active avoidance (SAA) in rats. Here, we explore whether the VH mediates intertrial responses (ITRs), which are putative unreinforced avoidance responses that occur between trials. First, we examined whether VH inactivation would affect ITRs. Male rats underwent SAA training and subsequently received intra-VH infusions of saline or muscimol before retrieval tests in the training context. Rats that received muscimol performed significantly fewer ITRs, but equivalent avoidance responses, compared to controls. Next, we asked whether chemogenetic VH activation would increase ITR vigor. In male and female rats expressing excitatory (hM3Dq) DREADDs, systemic CNO administration produced a robust ITR increase that was not due to nonspecific locomotor effects. Then, we examined whether chemogenetic VH activation potentiated ITRs in an alternate (non-training) test context and found it did. Finally, to determine if context-US associations mediate ITRs, we exposed rats to the training context for three days after SAA training to extinguish the context. Rats submitted to context extinction did not show a reliable decrease in ITRs during a retrieval test, suggesting that context-US associations are not responsible for ITRs. Collectively, these results reveal an important role for the VH in context-dependent ITRs during SAA. Further work is required to explore the neural circuits and associative basis for these responses, which may be underlie pathological avoidance that occurs in humans after threat has passed. | | 8:47p |
Multi-omics Identify Serotonin Transporter as a Promising Therapeutic Target for Essential Tremor
Essential tremor (ET) stands as one of the most prevalent cerebellar movement disorders. However, effective treatment remains elusive, largely due to a limited understanding of its molecular pathology. Harmaline-induced tremor in mouse is a well-established animal model for ET, while with enigmatic mechanism. The aim of this study was to get insight into the molecular intricacies underlying cerebellar dysfunction in harmaline-induced tremor. Combining LC-MS/MS and RNA-Seq analysis, we delved into the variation of the cerebellum between harmaline-induced tremor and the control ones. This comprehensive investigation revealed a profile of this mouse model from mRNA and protein level, highlighting 5194 correlated coding molecules, with 19 proving to be significant. Further KEGG enrichment analysis identified cerebellar serotonin transporter (SERT) as the key molecule in harmaline-induced tremor. The implications of this transcriptomic and proteomic exploration underscore the potential therapeutic value of targeting SERT as a novel treatment approach for ET. In general, our study unveils crucial insights that could pave the way for molecular target identification and effective therapeutic interventions for ET. | | 8:47p |
Development of a novel, non-invasive and whole brain biomarker of demyelination in a mouse model of multiple sclerosis
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), affecting 2.8 million people worldwide, that presents multiple features, one of which is demyelination. Although treatments exist to manage the condition, no cure has been found to stop the progression of neurodegeneration.
To develop new treatments and investigate the multiple systems impacted by MS, new imaging technologies are needed at the preclinical stage. Functional ultrasound imaging (fUS) has recently been demonstrated to robustly measure brain cerebral blood volume (CBV) dynamics as an indirect measure of neural activity. This study aimed at proposing a new biomarker of de- and/or re-myelination in a mouse model of MS induced by cuprizone. We demonstrate first that extended demyelination induces an increased hemodynamic response in the primary sensory cortex both spatially and temporally, which is consistent with fMRI data collected on MS patients. Second, using descriptors of the evoked hemodynamic response, we show that 3 of these descriptors allows the prediction of the level of myelin in the primary sensory cortex (p=5. 10-5) and the thalamus (p=6. 10-6). The development of such a non-invasive biomarker is crucial in the MS field as is provides an extremely useful tool for both disease follow-up and drug development.
RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSMultiple sclerosis (MS) is an autoimmune neurodegenerative disorder of the central nervous system. It is the most common cause of neurological disability in young adults, affecting approximately 2.8 million worldwide. While the field of studies in MS has been very active at identifying the neurobiological cellular and molecular mechanisms underlying MS progression, the number of new treatments has been very limited so far, due to several factors, such as the lack of robust and non-invasive biomarkers of myelin loss in longitudinal studies (measurements during the development of the disease). Unfortunately, quantification of myelin loss, (one of the key neurobiological markers of MS progression) is classically performed post-mortem on fixed tissues, preventing longitudinal studies. Longitudinal follow up of an indirect measure of myelin loss is possible, using magnetic resonance imaging. However, the small size of rodent brains poses a challenge for conventional imaging techniques, requiring the use of high field magnet to achieve the necessary sensitivity and resolution.
Added value of this studyIn this study, using a sensitive neuroimaging technique, we developed a simple, non-invasive, predictive biomarker able to quantify the individual amount of myelin content consistently and accurately in brain structures in mice.
Implications of all the available evidenceThe development of such a biomarker is extremely important for the MS field as it will accelerate the pre-clinical tests for drug efficacy. The benefits provided by our biomarker encompass: 1) Enhanced sensitivity in individually quantifying myelin content, providing a more comprehensive assessment across diverse brain regions 2) Speeding up the process of the discovery, by reducing the number of animals required per group and 3) It will also likely lead to new scientific outcomes, as many more structures will be studied (most teams and drug compagnies only study the demyelination at the level of the corpus callosum).
Finally, from a clinical perspective, given the brain alterations observed in this animal model closely mirror those observed in early stages in patients with MS, we anticipate our biomarker, with minimal additional refinements, to be readily applicable in clinical settings. | | 8:47p |
Ibudilast Protects Retinal Bipolar Cells from Excitotoxic Retinal Damage and Activates the mTOR Pathway
Ibudilast, an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE), has been recently shown to have neuroprotective effects in a variety of neurologic diseases. We utilize a chick excitotoxic retinal damage model to investigate ibudilasts potential to protect retinal neurons. Using single cell RNA-sequencing (scRNA-seq), we find that MIF, putative MIF receptors CD74 and CD44, and several PDEs are upregulated in different retinal cells during damage. Intravitreal ibudilast is well tolerated in the eye and causes no evidence of toxicity. Ibudilast effectively protects neurons in the inner nuclear layer from NMDA-induced cell death, restores retinal layer thickness on spectral domain optical coherence tomography, and preserves retinal neuron function, particularly for the ON bipolar cells, as assessed by electroretinography. PDE inhibition seems essential for ibudilasts neuroprotection, as AV1013, the analogue that lacks PDE inhibitor activity, is ineffective. scRNA-seq analysis reveals upregulation of multiple signaling pathways, including mTOR, in damaged Muller glia (MG) with ibudilast treatment compared to AV1013. Components of mTORC1 and mTORC2 are upregulated in both bipolar cells and MG with ibudilast. The mTOR inhibitor rapamycin blocked accumulation of pS6 but did not reduce TUNEL positive dying cells. Additionally, through ligand-receptor interaction analysis, crosstalk between bipolar cells and MG may be important for neuroprotection. We have identified several paracrine signaling pathways that are known to contribute to cell survival and neuroprotection and might play essential roles in ibudilast function. These findings highlight ibudilasts potential to protect inner retinal neurons during damage and show promise for future clinical translation.
Graphical AbstractO_ST_ABSMain PointsC_ST_ABS- Ibudilast, a MIF and PDE inhibitor, preserves the form and function of the retina, especially bipolar cells, during excitotoxic damage
- Ibudilast upregulates multiple signaling pathways, including mTOR, in damaged Muller glia and bipolar cells
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/585556v1_ufig1.gif" ALT="Figure 1">
View larger version (41K):
org.highwire.dtl.DTLVardef@1e6628eorg.highwire.dtl.DTLVardef@5086beorg.highwire.dtl.DTLVardef@be3692org.highwire.dtl.DTLVardef@1f0bd0f_HPS_FORMAT_FIGEXP M_FIG C_FIG |
|