Continuation of connecting orbits in 3D-ODEs: (I) Point-to-cycle connections

We propose new methods for the numerical continuation of point-to-cycle connecting orbits in 3-dimensional autonomous ODE's using projection boundary conditions. In our approach, the projection boundary conditions near the cycle are formulated using an eigenfunction of the associated adjoint variational equation, avoiding costly and numerically unstable computations of the monodromy matrix. The equations for the eigenfunction are included in the defining boundary-value problem, allowing a straightforward implementation in AUTO, in which only the standard features of the software are employed. Homotopy methods to find connecting orbits are discussed in general and illustrated with several examples, including the Lorenz equations. Complete AUTO demos, which can be easily adapted to any autonomous 3-dimensional ODE system, are freely available.Comment: 18 pages, 10 figure

Developmental Splicing Deregulation in Leukodystrophies Related to EIF2B Mutations

Leukodystrophies (LD) are rare inherited disorders that primarily affect the white matter (WM) of the central nervous system. The large heterogeneity of LD results from the diversity of the genetically determined defects that interfere with glial cells functions. Astrocytes have been identified as the primary target of LD with cystic myelin breakdown including those related to mutations in the ubiquitous translation initiation factor eIF2B. EIF2B is involved in global protein synthesis and its regulation under normal and stress conditions. Little is known about how eIF2B mutations have a major effect on WM. We performed a transcriptomic analysis using fibroblasts of 10 eIF2B-mutated patients with a severe phenotype and 10 age matched patients with other types of LD in comparison to control fibroblasts. ANOVA was used to identify genes that were statistically significantly differentially expressed at basal state and after ER-stress. The pattern of differentially expressed genes between basal state and ER-stress did not differ significantly among each of the three conditions. However, 70 genes were specifically differentially expressed in eIF2B-mutated fibroblasts whatever the stress conditions tested compared to controls, 96% being under-expressed. Most of these genes were involved in mRNA regulation and mitochondrial metabolism. The 13 most representative genes, including genes belonging to the Heterogeneous Nuclear Ribonucleoprotein (HNRNP) family, described as regulators of splicing events and stability of mRNA, were dysregulated during the development of eIF2B-mutated brains. HNRNPH1, F and C mRNA were over-expressed in foetus but under-expressed in children and adult brains. The abnormal regulation of HNRNP expression in the brain of eIF2B-mutated patients was concomitant with splicing dysregulation of the main genes involved in glial maturation such as PLP1 for oligodendrocytes and GFAP in astrocytes. These findings demonstrate a developmental deregulation of splicing events in glial cells that is related to abnormal production of HNRNP, in eIF2B-mutated brains

Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress

Cannabidiol (CBD) is the most abundant cannabinoid in Cannabis sativa that has no psychoactive properties. CBD has been approved to treat inflammation, pain and spasticity associated with multiple sclerosis (MS), of which demyelination and oligodendrocyte loss are hallmarks. Thus, we investigated the protective effects of CBD against the damage to oligodendrocyte progenitor cells (OPCs) mediated by the immune system. Doses of 1 μM CBD protect OPCs from oxidative stress by decreasing the production of reactive oxygen species. CBD also protects OPCs from apoptosis induced by LPS/IFNγ through the decrease of caspase 3 induction via mechanisms that do not involve CB1, CB2, TRPV1 or PPARγ receptors. Tunicamycin-induced OPC death was attenuated by CBD, suggesting a role of endoplasmic reticulum (ER) stress in the mode of action of CBD. This protection against ER stress-induced apoptosis was associated with reduced phosphorylation of eiF2α, one of the initiators of the ER stress pathway. Indeed, CBD diminished the phosphorylation of PKR and eiF2α induced by LPS/IFNγ. The pro-survival effects of CBD in OPCs were accompanied by decreases in the expression of ER apoptotic effectors (CHOP, Bax and caspase 12), and increased expression of the anti-apoptotic Bcl-2. These findings suggest that attenuation of the ER stress pathway is involved in the ‘oligoprotective' effects of CBD during inflammation

An anatomic gene expression atlas of the adult mouse brain

Studying gene expression provides a powerful means of understanding structure-function relationships in the nervous system. The availability of genome-scale in situ hybridization datasets enables new possibilities for understanding brain organization based on gene expression patterns. The Anatomic Gene Expression Atlas (AGEA) is a new relational atlas revealing the genetic architecture of the adult C57Bl/6J mouse brain based on spatial correlations across expression data for thousands of genes in the Allen Brain Atlas (ABA). The AGEA includes three discovery tools for examining neuroanatomical relationships and boundaries: (1) three-dimensional expression-based correlation maps, (2) a hierarchical transcriptome-based parcellation of the brain and (3) a facility to retrieve from the ABA specific genes showing enriched expression in local correlated domains. The utility of this atlas is illustrated by analysis of genetic organization in the thalamus, striatum and cerebral cortex. The AGEA is a publicly accessible online computational tool integrated with the ABA (http://mouse.brain-map.org/agea)

Changing behaviour 'more or less'-do theories of behaviour inform strategies for implementation and de-implementation? A critical interpretive synthesis

BACKGROUND: Implementing evidence-based care requires healthcare practitioners to do less of some things (de-implementation) and more of others (implementation). Variations in effectiveness of behaviour change interventions may result from failure to consider a distinction between approaches by which behaviour increases and decreases in frequency. The distinction is not well represented in methods for designing interventions. This review aimed to identify whether there is a theoretical rationale to support this distinction. METHODS: Using Critical Interpretative Synthesis, this conceptual review included papers from a broad range of fields (biology, psychology, education, business) likely to report approaches for increasing or decreasing behaviour. Articles were identified from databases using search terms related to theory and behaviour change. Articles reporting changes in frequency of behaviour and explicit use of theory were included. Data extracted were direction of behaviour change, how theory was operationalised, and theory-based recommendations for behaviour change. Analyses of extracted data were conducted iteratively and involved inductive coding and critical exploration of ideas and purposive sampling of additional papers to explore theoretical concepts in greater detail. RESULTS: Critical analysis of 66 papers and their theoretical sources identified three key findings: (1) 9 of the 15 behavioural theories identified do not distinguish between implementation and de-implementation (5 theories were applied to only implementation or de-implementation, not both); (2) a common strategy for decreasing frequency was substituting one behaviour with another. No theoretical basis for this strategy was articulated, nor were methods proposed for selecting appropriate substitute behaviours; (3) Operant Learning Theory makes an explicit distinction between techniques for increasing and decreasing frequency. DISCUSSION: Behavioural theories provide little insight into the distinction between implementation and de-implementation. Operant Learning Theory identified different strategies for implementation and de-implementation, but these strategies may not be acceptable in health systems. Additionally, if behaviour substitution is an approach for de-implementation, further investigation may inform methods or rationale for selecting the substitute behaviour

Peri-Pubertal Emergence of UNC-5 Homologue Expression by Dopamine Neurons in Rodents

Puberty is a critical period in mesocorticolimbic dopamine (DA) system development, particularly for the medial prefrontal cortex (mPFC) projection which achieves maturity in early adulthood. The guidance cue netrin-1 organizes neuronal networks by attracting or repelling cellular processes through DCC (deleted in colorectal cancer) and UNC-5 homologue (UNC5H) receptors, respectively. We have shown that variations in netrin-1 receptor levels lead to selective reorganization of mPFC DA circuitry, and changes in DA-related behaviors, in transgenic mice and in rats. Significantly, these effects are only observed after puberty, suggesting that netrin-1 mediated effects on DA systems vary across development. Here we report on the normal expression of DCC and UNC5H in the ventral tegmental area (VTA) by DA neurons from embryonic life to adulthood, in both mice and rats. We show a dramatic and enduring pubertal change in the ratio of DCC:UNC5H receptors, reflecting a shift toward predominant UNC5H function. This shift in DCC:UNC5H ratio coincides with the pubertal emergence of UNC5H expression by VTA DA neurons. Although the distribution of DCC and UNC5H by VTA DA neurons changes during puberty, the pattern of netrin-1 immunoreactivity in these cells does not. Together, our findings suggest that DCC:UNC5H ratios in DA neurons at critical periods may have important consequences for the organization and function of mesocorticolimbic DA systems

Rapid Reversal of Chondroitin Sulfate Proteoglycan Associated Staining in Subcompartments of Mouse Neostriatum during the Emergence of Behaviour

BACKGROUND: The neostriatum, the mouse homologue of the primate caudate/putamen, is the input nucleus for the basal ganglia, receiving both cortical and dopaminergic input to each of its sub-compartments, the striosomes and matrix. The coordinated activation of corticostriatal pathways is considered vital for motor and cognitive abilities, yet the mechanisms which underlie the generation of these circuits are unknown. The early and specific targeting of striatal subcompartments by both corticostriatal and nigrostriatal terminals suggests activity-independent mechanisms, such as axon guidance cues, may play a role in this process. Candidates include the chondroitin sulfate proteoglycan (CSPG) family of glycoproteins which have roles not only in axon guidance, but also in the maturation and stability of neural circuits where they are expressed in lattice-like perineuronal nets (PNNs). METHODOLOGY/PRINCIPAL FINDINGS: The expression of CSPG-associated structures and PNNs with respect to neostriatal subcompartments has been examined qualitatively and quantitatively using double-labelling for Wisteria floribunda agglutinin (WFA), and the mu-opioid receptor (muOR), a marker for striosomes, at six postnatal ages in mice. We find that at the earliest ages (postnatal day (P)4 and P10), WFA-positive clusters overlap preferentially with the striosome compartment. By P14, these clusters disappear. In contrast, PNNs were first seen at P10 and continued to increase in density and spread throughout the caudate/putamen with maturation. Remarkably, the PNNs overlap almost exclusively with the neostriatal matrix. CONCLUSIONS/SIGNIFICANCE: This is the first description of a reversal in the distribution of CSPG associated structures, as well as the emergence and maintenance of PNNs in specific subcompartments of the neostriatum. These results suggest diverse roles for CSPGs in the formation of functional corticostriatal and nigrostriatal connectivity within the striosome and matrix compartments of the developing caudate/putamen

Wastewater-Based Epidemiology: Global Collaborative to Maximize Contributions in the Fight against COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), a novel member of the Coronaviridae family, has been identified as the etiologic agent of an ongoing pandemic of severe pneumonia known as COVID-19. To date there have been millions of cases of COVID-19 diagnosed in 184 countries with case fatality rates ranging from 1.8% in Germany to 12.5% in Italy. Limited diagnostic testing capacity and asymptomatic and oligosymptomatic infections result in significant uncertainty in the estimated extent of SARS-CoV-2 infection. Recent reports have documented that infection with SARS-CoV-2 is accompanied by persistent shedding of virus RNA in feces in 27% to 89% of patients at densities from 0.8 to 7.5 log10 gene copies per gram. The presence of SARS-CoV-2 RNA in feces raises the potential to survey sewage for virus RNA to inform epidemiological monitoring of COVID-19, which we refer to as wastewater-based epidemiology (WBE), but is also known as environmental surveillance