Causal structure learning from time series: Large regression coefficients may predict causal links better in practice than small p-values

In this article, we describe the algorithms for causal structure learning from time series data that won the Causality 4 Climate competition at the Conference on Neural Information Processing Systems 2019 (NeurIPS). We examine how our combination of established ideas achieves competitive performance on semi-realistic and realistic time series data exhibiting common challenges in real-world Earth sciences data. In particular, we discuss a) a rationale for leveraging linear methods to identify causal links in non-linear systems, b) a simulation-backed explanation as to why large regression coefficients may predict causal links better in practice than small p-values and thus why normalising the data may sometimes hinder causal structure learning. For benchmark usage, we detail the algorithms here and provide implementations at https://github.com/sweichwald/tidybench . We propose the presented competition-proven methods for baseline benchmark comparisons to guide the development of novel algorithms for structure learning from time series

Predominant Spastic Paraparesis Associated With the D178N Mutation in PRNP

Here we report on a 70-year-old female presenting with an unusual progressive syndrome with fatal outcome. The predominant features in this case were spastic paraparesis, cognitive decline and respiratory failure. Relatives affected with a similar syndrome were previously diagnosed with lipofuscinosis. However, whole-genome sequencing (WGS) in our case did not reveal any pathogenic variants in genes associated with lipofuscinosis, but instead detected the known D178 variant in PRNP. The course of disease was rapid despite the presence of methione at codon 129 in the mutated and valine in the healthy allele of PRNP. Typical neuropathological abnormalities for familial fatal insomnia (FFI) were found, Western blot analysis suggested a type 2B prion protein isoform. The serendipitous diagnosis obtained with WGS illustrates a role for the method in elusive cases

Human ISL1+ ventricular progenitors self-assemble into an in vivo functional heart patch and preserve cardiac function post infarction

The generation of human pluripotent stem cell (hPSC)-derived ventricular progenitors and their assembly into a 3-dimensional in vivo functional ventricular heart patch has remained an elusive goal. Herein, we report the generation of an enriched pool of hPSC-derived ventricular progenitors (HVPs), which can expand, differentiate, self-assemble, and mature into a functional ventricular patch in vivo without the aid of any gel or matrix. We documented a specific temporal window, in which the HVPs will engraft in vivo. On day 6 of differentiation, HVPs were enriched by depleting cells positive for pluripotency marker TRA-1-60 with magnetic-activated cell sorting (MACS), and 3 million sorted cells were sub-capsularly transplanted onto kidneys of NSG mice where, after 2 months, they formed a 7 mm x 3 mm x 4 mm myocardial patch resembling the ventricular wall. The graft acquired several features of maturation: expression of ventricular marker (MLC2v), desmosomes, appearance of T-tubule-like structures, and electrophysiological action potential signature consistent with maturation, all this in a non-cardiac environment. We further demonstrated that HVPs transplanted into un-injured hearts of NSG mice remain viable for up to 8 months. Moreover, transplantation of 2 million HVPs largely preserved myocardial contractile function following myocardial infarction. Taken together, our study reaffirms the promising idea of using progenitor cells for regenerative therapy.ERC AdG743225Swedish Research Council Distinguished Professor Grant Dnr 541-2013-8351The Knut and Alice Wallenberg Foundation (KAW Dnr 2013.0028)Horizon 2020 research and innovation programme grant agreement No 647714Publishe

Immune recognition molecules in synaptic plasticity and regeneration of spinal motoneurons

This thesis is based on the emerging concept that pattern recognition molecules, originally characterized in the immune system, may be expressed and used by neurons to mediate non-immune functions. In line with this concept, the major histocompatibility complex (MHC) class I and certain complements proteins have been implicated in synaptic plasticity in the developing visual system. In Paper I, we studied the expression of MHC class I mRNAs and proteins in normal and axotomized spinal mouse motoneurons. Two mRNAs encoding classical MHC class I molecules (H2-Kb and H2-Db) were moderately expressed in uninjured motoneuron cell bodies. After a peripheral nerve lesion, both mRNAs were strongly up-regulated by axotomized motoneurons and surrounding glial cells. Using a MHC class I antibody with affinity for H2-Db, we observed moderate immunoreactivity (IR) in the cell bodies of a subpopulation of uninjured spinal motoneurons. After a peripheral nerve lesion, H2-Db IR was strongly increased in activated microglia. In contrast to the in situ hybridization results, the H2-Db IR remained unchanged in axotomized motoneuron cell bodies. We then further investigated the in vivo motoneuron expression of H2-Db in the periphery. H2-Db IR was detected in a subpopulation of axons in the sciatic nerve and at the presynaptic side of the neuromuscular junction (NMJ) in hind limb muscles. When studying mice deficient in classical MHC class I (Kb-/-Db-/-), we observed abnormal dynamic changes in NMJ density during muscle reinnervation and delayed motor recovery after a sciatic nerve crush (SNC). During the reinnervation phase, Kb-/-Db-/- mice also displayed an attenuated proliferation of terminal Schwann cells at NMJs compared to wild-type mice (WT). Interestingly, we found expression of the paired immunoglobulin receptor B in dissociated Schwann cells and histological sections from the sciatic nerve. In order to investigate the role of MHC class I proteins in central motoneuron plasticity, we studied synaptic elimination from axotomized motoneuron cell bodies at the ultrastructural level in Paper II. In contrast to a previous publication by Shatz et al. 2000, axotomized motoneurons in mice lacking functional MHC class I (TAP1-/- and beta2m-/-) displayed an increased synaptic elimination compared to WT mice. Moreover, in beta2m-/- mice the remaining terminals were randomly dispersed along the cytoplasmic membrane in difference to WT animals where they were tightly clustered. When analyzing the types of synaptic terminals that were retracted in the beta2m-/- mice, we found a preferential loss of inhibitory terminals. In parallel, axonal regeneration appeared to be hampered in the absence of functional MHC class I molecules. Since complement-deficient animals (C1q-/- and C3-/-) are shown to display a phenotype resembling that of MHC class I-deficient mice regarding synaptic plasticity in the visual system, we investigated the role for complement proteins in adult motoneuron plasticity in Paper III. In accordance with a previous study by Steven et al. 2007, C3-/- deficient animals displayed a diminished reduction in synapse density and covering of axotomized motoneurons. The histological expression pattern of C1q and C3 in the spinal cord was somewhat hard to interpret. We found a clear up-regulation of complement mRNA and protein in the axotomized sciatic motor pool, but we have so far failed to determine the subcellular localization with certainty. Nonetheless, we found complement IR in close association with the motoneuron surface and with presynaptic terminals on proximal dendrites and with surrounding glial cells. In addition, C3-/- animals recovered motor function more rapidly after a SNC. In conclusion, we have investigated and found evidence of new roles for classical immune molecules in motoneurons with regard to synaptic plasticity and regeneration. The subcellular expression and signaling pathways remain to be described before specific functions and sites of action for these molecules can be determined. Further studies of neuronal immune molecules will be important in order to gain insight into the mechanisms of cellular interaction between different types of neurons or glial cells

The Role of BDNF in Experimental and Clinical Traumatic Brain Injury

Traumatic brain injury is one of the leading causes of mortality and morbidity in the world with no current pharmacological treatment. The role of BDNF in neural repair and regeneration is well established and has also been the focus of TBI research. Here, we review experimental animal models assessing BDNF expression following injury as well as clinical studies in humans including the role of BDNF polymorphism in TBI. There is a large heterogeneity in experimental setups and hence the results with different regional and temporal changes in BDNF expression. Several studies have also assessed different interventions to affect the BDNF expression following injury. Clinical studies highlight the importance of BDNF polymorphism in the outcome and indicate a protective role of BDNF polymorphism following injury. Considering the possibility of affecting the BDNF pathway with available substances, we discuss future studies using transgenic mice as well as iPSC in order to understand the underlying mechanism of BDNF polymorphism in TBI and develop a possible pharmacological treatment

The Extent of Synaptic Stripping of Motoneurons after Axotomy Is Not Correlated to Activation of Surrounding Glia or Downregulation of Postsynaptic Adhesion Molecules

Synapse elimination in the adult central nervous system can be modelled by axotomy of spinal motoneurons which triggers removal of synapses from the cell surface of lesioned motoneurons by processes that remain elusive. Proposed candidate mechanisms are removal of synapses by reactive microglia and astrocytes, based on the remarkable activation of these cell types in the vicinity of motoneurons following axon lesion, and/or decreased expression of synaptic adhesion molecules in lesioned motoneurons. In the present study, we investigated glia activation and adhesion molecule expression in motoneurons in two mouse strains with deviant patterns of synapse elimination following axotomy. Mice deficient in complement protein C3 display a markedly reduced loss of synapses from axotomized motoneurons, whereas mice with impaired function of major histocompatibility complex (MHC) class Ia display an augmented degree of stripping after axotomy. Activation of microglia and astrocytes was assessed by semiquantative immunohistochemistry for Iba 1 (microglia) and GFAP (astrocytes), while expression of synaptic adhesion molecules was determined by in situ hybridization. In spite of the fact that the two mouse strains display very different degrees of synapse elimination, no differences in terms of glial activation or in the downregulation of the studied adhesion molecules (SynCAM1, neuroligin-2,-3 and netrin G-2 ligand) could be detected. We conclude that neither glia activation nor downregulation of synaptic adhesion molecules are correlated to the different extent of the synaptic stripping in the two studied strains. Instead the magnitude of the stripping event is most likely a consequence of a precise molecular signaling, which at least in part is mediated by immune molecules

The Extent of Synaptic Stripping of Motoneurons after Axotomy Is Not Correlated to Activation of Surrounding Glia or Downregulation of Postsynaptic Adhesion Molecules

Synapse elimination in the adult central nervous system can be modelled by axotomy of spinal motoneurons which triggers removal of synapses from the cell surface of lesioned motoneurons by processes that remain elusive. Proposed candidate mechanisms are removal of synapses by reactive microglia and astrocytes, based on the remarkable activation of these cell types in the vicinity of motoneurons following axon lesion, and/or decreased expression of synaptic adhesion molecules in lesioned motoneurons. In the present study, we investigated glia activation and adhesion molecule expression in motoneurons in two mouse strains with deviant patterns of synapse elimination following axotomy. Mice deficient in complement protein C3 display a markedly reduced loss of synapses from axotomized motoneurons, whereas mice with impaired function of major histocompatibility complex (MHC) class Ia display an augmented degree of stripping after axotomy. Activation of microglia and astrocytes was assessed by semiquantative immunohistochemistry for Iba 1 (microglia) and GFAP (astrocytes), while expression of synaptic adhesion molecules was determined by in situ hybridization. In spite of the fact that the two mouse strains display very different degrees of synapse elimination, no differences in terms of glial activation or in the downregulation of the studied adhesion molecules (SynCAM1, neuroligin-2,-3 and netrin G-2 ligand) could be detected. We conclude that neither glia activation nor downregulation of synaptic adhesion molecules are correlated to the different extent of the synaptic stripping in the two studied strains. Instead the magnitude of the stripping event is most likely a consequence of a precise molecular signaling, which at least in part is mediated by immune molecules

No difference in mRNA signal of SynCAM1, NLG-2, -3 and NGL-2 between WT (first column), C3^−/− (second column) and K^b−/−D^b−/− mice (third column) one week after sciatic nerve lesion.

<p>ISH signal for SynCAM1 (first row), NLG-2 (second row), NLG-3 (third row) and NGL-2 (fourth row) mRNAs could be seen over motoneuron cell bodies visualized with bisbenzemide in the dorsal part of the ventral horn of the spinal cord. mRNA expression of all studied adhesion molecules decreased after axotomy but no difference was seen between the different mouse lines (quantified in right column ). Error bars indicate SEM, one-way ANOVA with Bonferroni’s multiple comparison test. Five animals were studied in each group. Scale bar = 50 µm.</p

No difference in astrocyte activation as measured by GFAP IR between WT, C3^−/− and K^b−/−D^b−/− mice one week after sciatic nerve lesion.

<p>Immunoreactivity for GFAP was measured in the sciatic motoneuron pool for WT mice (first row), C3^−/− (second row) and K^b−/−D^b−/− mice (third row). Ipsilateral (IL, second column) to contralateral (CL, first column) ratio of semiquantative measurements was quantified in the third column. In WT mice, GFAP IR IL/CL ratio was increased to 1.99 and 1.85 of the value on the control side in the two studied sets of experiment. In C3^−/− mice the corresponding increase in IL/CL ratio was 1.84, and in K^b−/−D^b−/− mice 2.04. Insets showing 50× magnification micrographs of GFAP IR around individual motoneurons. Six animals were studied in each group. Error bars indicate SEM, unpaired t-test. Scale bar = 50 µm.</p

No difference in microglia activation as measured by Iba1 IR between WT, C3^−/− and K^b−/−D^b−/− mice one week after sciatic nerve lesion.

<p>Immunoreactivity for Iba1 was measured in the sciatic motoneuron pool in WT (first row), C3^−/− (second row) and K^b−/−D^b−/− mice (third row). Ipsilateral (IL, second column) to contralateral (CL, first column) ratio of semiquantative measurements was quantified in the third column. In WT mice, Iba1 IR IL/CL ratio was increased to 5.22 and 5.21 of the value on the control side in the two studied sets of experiment. In C3^−/− mice the corresponding increase in IL/CL ratio was 5.05, and in K^b−/−D^b−/−5.39. Insets indicate 50× magnification micrographs of Iba1 IR around individual motoneurons. Six animals were studied in each group. Error bars indicate SEM, unpaired t-test. Scale bar = 50 µm.</p