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Fold change (FC ≤ 1.5) list and GO enrichment analysis of probes affected by IHNV status.

OBJECTIVE. To assess whether HS severity is mirrored at the level of large-scale networks. METHODS. We studied preoperative high-resolution anatomical and diffusion-weighted MRI of 44 TLE patients with histopathological diagnosis of HS (n=25; TLE-HS) and isolated gliosis (n=19; TLE-G), and 25 healthy controls. Hippocampal measurements included surface-based subfield mapping of atrophy and T2 hyperintensity indexing cell loss and gliosis, respectively. Whole-brain connectomes were generated via diffusion tractography and examined using graph theory along with a novel network control theory paradigm which simulates functional dynamics from structural network data. RESULTS. Compared to controls, we observed markedly increased path length and decreased clustering in TLE-HS compared to controls, indicating lower global and local network efficiency, while TLE-G showed only subtle alterations. Similarly, network controllability was lower in TLE-HS only, suggesting limited range of functional dynamics. Hippocampal imaging markers were positively associated with macroscale network alterations, particularly in ipsilateral CA1-3. Systematic assessment across several networks revealed maximal changes in the hippocampal circuity. Findings were consistent when correcting for cortical thickness, suggesting independence from grey matter atrophy. CONCLUSIONS. Severe HS is associated with marked remodeling of connectome topology and structurally-governed functional dynamics in TLE, as opposed to isolated gliosis which has negligible effects. Cell loss, particularly in CA1-3, may exert a cascading effect on brain-wide connectomes, underlining coupled disease processes across multiple scales. Data_phen_conn_dryadPhenotypic information and mean connectome feature data for Bernhardt et al. (2019) Temporal lobe epilepsy: hippocampal pathology modulates white matter connectome topology and controllability. Neurology

Abstract Background Transcriptional repressor DREAM (downstream regulatory element antagonist modulator) is a Ca2+-binding protein that regulates Ca2+ homeostasis through gene regulation and protein-protein interactions. It has been shown that a dominant active form (daDREAM) is implicated in learning-related synaptic plasticity such as LTP and LTD in the hippocampus. Neuronal spines are reported to play important roles in plasticity and memory. However, the possible role of DREAM in spine plasticity has not been reported. Results Here we show that potentiating DREAM activity, by overexpressing daDREAM, reduced dendritic basal arborization and spine density in CA1 pyramidal neurons and increased spine density in dendrites in dentate gyrus granule cells. These microanatomical changes are accompanied by significant modifications in the expression of specific genes encoding the cytoskeletal proteins Arc, Formin 1 and Gelsolin in daDREAM hippocampus. Conclusions Our results strongly suggest that DREAM plays an important role in structural plasticity in the hippocampus.

Abstract Background Parkinson���s disease is a disabling neurodegenerative movement disorder characterized by dopaminergic neuron loss induced by ��-synuclein oligomers. There is an urgent need for disease-modifying therapies for Parkinson���s disease, but drug discovery is challenged by lack of in vivo models that recapitulate early stages of neurodegeneration. Invertebrate organisms, such as the nematode worm Caenorhabditis elegans, provide in vivo models of human disease processes that can be instrumental for initial pharmacological studies. Methods To identify early motor impairment of animals expressing ��-synuclein in dopaminergic neurons, we first used a custom-built tracking microscope that captures locomotion of single C. elegans with high spatial and temporal resolution. Next, we devised a method for semi-automated and blinded quantification of motor impairment for a population of simultaneously recorded animals with multi-worm tracking and custom image processing. We then used genetic and pharmacological methods to define the features of early motor dysfunction of ��-synuclein-expressing C. elegans. Finally, we applied the C. elegans model to a drug repurposing screen by combining it with an artificial intelligence platform and cell culture system to identify small molecules that inhibit ��-synuclein oligomers. Screen hits were validated using in vitro and in vivo mammalian models. Results We found a previously undescribed motor phenotype in transgenic ��-synuclein C. elegans that correlates with mutant or wild-type ��-synuclein protein levels and results from dopaminergic neuron dysfunction, but precedes neuronal loss. Together with artificial intelligence-driven in silico and in vitro screening, this C. elegans model identified five compounds that reduced motor dysfunction induced by ��-synuclein. Three of these compounds also decreased ��-synuclein oligomers in mammalian neurons, including rifabutin which has not been previously investigated for Parkinson���s disease. We found that treatment with rifabutin reduced nigrostriatal dopaminergic neurodegeneration due to ��-synuclein in a rat model. Conclusions We identified a C. elegans locomotor abnormality due to dopaminergic neuron dysfunction that models early ��-synuclein-mediated neurodegeneration. Our innovative approach applying this in vivo model to a multi-step drug repurposing screen, with artificial intelligence-driven in silico and in vitro methods, resulted in the discovery of at least one drug that may be repurposed as a disease-modifying therapy for Parkinson���s disease.

Additional file 10: Supplementary Figure 4. Transcript abundance in transcripts per million (tpm) as detected by sleuth from RNA-Seq for (A) Esrrb-203 (ENSMUST00000110204.8) and (B) Polr2a-201 (ENSMUST00000058470.15). (C) The relative quantity of Polr2a is decreased 1.24 -fold with postnatal stress alone, and 1.59-fold when mice were prenatally exposed to ethanol and postnatal stress, as detected by reverse transcription qPCR, open circles represent biological replicates not used in the RNA-Seq experiment, while closed circles represent samples included in the RNA-Seq experiment and serve as technical replicates. Transcript abundance in transcripts per million (tpm) using the kallisto-sleuth pipeline for all detected transcript variants of (D) Esrrb and (E) Polr2a. Esrrb-203 (ENSMUST00000110204.8) and Polr2a-201 (ENSMUST00000058470.15) are down-regulated following Ethanol + Stress as compared to controls and represent the largest protein-coding transcripts for each gene. (F) Polr2a is decreased 0.80-fold when mice were prenatally exposed to ethanol and postnatal stress, presented as normalized counts determined using the HISAT2-featureCounts-DESeq2 pipeline, *p < 0.05, **p < 0.01, ***q < 0.01. Note: We have included panels A-C from Fig. 3 to facilitate comparison.

Background: In our previous investigations of the role of the extracellular matrix (ECM) in promoting neurite growth we have observed that a permissive laminin (LN) substrate stimulates differential growth responses in subpopulations of mature dorsal root ganglion (DRG) neurons. DRG neurons expressing Trk and p75 receptors grow neurites on a LN substrate in the absence of neurotrophins, while isolectin B4-binding neurons (IB4+) do not display significant growth under the same conditions. We set out to determine whether there was an expression signature of the LN-induced neurite growth phenotype. Using a lectin binding protocol IB4+ neurons were isolated from dissociated DRG neurons, creating two groups - IB4+ and IB4-. A small-scale microarray approach was employed to screen the expression of a panel of ECM-associated genes following dissociation (t=0) and after 24 hr culture on LN (t=24LN). This was followed by qRT-PCR and immunocytochemistry of selected genes. Results: The microarray screen showed that 36 of the 144 genes on the arrays were consistently expressed by the neurons. The array analyses showed that six genes had lower expression in the IB4+ neurons compared to the IB4- cells at t=0 (CTSH, Icam1, Itgβ1, Lamb1, Plat, Spp1), and one gene was expressed at higher levels in the IB4+ cells (Plaur). qRT-PCR was carried out as an independent assessment of the array results. There were discrepancies between the two methods, with qRT-PCR confirming the differences in Lamb1, Plat and Plaur, and showing decreased expression of AdamTs1, FN, and Icam in the IB4+ cells at t=0. After 24 hr culture on LN, there were no significant differences detected by qRT-PCR between the IB4+ and IB4- cells. However, both groups showed upregulation of Itgβ1 and Plaur after 24 hr on LN, the IB4+ group also had increased Plat, and the IB4- cells showed decreased Lamb1, Icam1 and AdamTs1. Further, the array screen also detected a number of genes (not subjected to qRT-PCR) expressed similarly by both populations in relatively high levels but not detectably influenced by time in culture (Bsg, Cst3, Ctsb, Ctsd, Ctsl, Mmp14, Mmp19, Sparc. We carried out immunohistochemistry to confirm expression of proteins encoded by a number of these genes. Conclusions:Our results show that 1B4+ and IB4- neurons differ in the expression of several genes that are associated with responsiveness to the ECM prior to culturing (AdamTs1, FN, Icam1, Lamb1, Plat, Plaur). The data suggest that the genes expressed at higher levels in the IB4- neurons could contribute to the initial growth response of these cells in a permissive environment and could also represent a common injury response that subsequently promotes axon regeneration. The differential expression of several extracellular matrix molecules (FN, Lamb1, Icam) may suggest that the IB4- neurons are capable of maintaining /secreting their local extracellular environment which could aid in the regenerative process. Overall, these data provide new information on potential targets that could be manipulated to enhance axonal regeneration in the mature nervous system.

Additional file 6. BLAST against B. glabrata: A reciprocal BLAST search against the recently published transcriptome of twelve pooled Biomphalaria glabrata tissues [3].

Microglial cell morphology, phagocytosis, and mitochondrial alterations following stimulation with LPS. A–B: Microglial cell showing nuclear budding (arrowhead), a phenomenon suggestive of ongoing mitosis, and an accumulation of mitochondria with various alterations (m; inset). In particular, mitochondria partially to completely devoid of cristae and partially to completely devoid of a double external membrane can be seen. The adjacent microglial cell is representative of the most frequently observed morphological phenotype following treatment with LPS, showing several lipid vacuoles (v), similarly to what has been described previously. er = endoplasmic reticulum. C–D: microglial cell showing an accumulation of small mitochondria often devoid of cristae (inset). Budding from larger mitochondria can sometimes be seen (arrowhead). g = golgi apparatus. E–F: Microglial cell containing mitochondria of various sizes, from small to large, and often showing alteration (inset), as well as a large phagocytic inclusion (in). To be noted, only mitochondria showing alteration are annotated in the three insets. (TIF 18662 kb)