The “Haunt” project: An attempt to build a “haunted” room by manipulating complex electromagnetic fields and infrasound

Recent research has suggested that a number of environmental factors may be associated with a tendency for susceptible individuals to report mildly anomalous sensations typically associated with “haunted” locations, including a sense of presence, feeling dizzy, inexplicable smells, and so on. Factors that may be associated with such sensations include fluctuations in the electromagnetic field and the presence of infrasound. A review of such work is presented, followed by the results of the “Haunt” project in which an attempt was made to construct an artificial “haunted” room by systematically varying such environmental factors. Participants (N = 79) were required to spend 50 minutes in a specially constructed chamber, within which they were exposed to infrasound, complex electromagnetic fields, both or neither. They were informed in advance that during this period they might experience anomalous sensations and asked to record on a floor-plan their location at the time occurrence of any such sensations, along with a note of the time of occurrence and a brief description of the sensation. Upon completing the session in the experimental chamber, they were asked to complete three questionnaires. The first was an EXIT scale asking respondents to indicate whether or not they had experienced particular anomalous sensations. The second was the Australian Sheep-Goat Scale, a widely used measure of belief in and experience of the paranormal. The third was Persinger’s Personal Philosophy Inventory, although only the items that constitute the Temporal Lobe Signs Inventory (TLS) sub-scale were scored. These items deal with psychological experiences typically associated with temporal lobe epilepsy but normally distributed throughout the general population. Although many participants reported anomalous sensations of various kinds, the number reported was unrelated to experimental condition but was related to TLS scores. The most parsimonious explanation for our findings is in terms of suggestibility

Mendelian gene identification through mouse embryo viability screening.

BACKGROUND: The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. METHODS: Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid, or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes. We explored a gene similarity approach for novel gene discovery and investigated unsolved cases from the 100,000 Genomes Project. RESULTS: We found that genes in the early gestation lethal category have distinct characteristics and are enriched for genes linked with recessive forms of inherited metabolic disease. We identified several genes sharing multiple features with known biallelic forms of inborn errors of the metabolism and found signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes in patients recruited under this disease category. We highlight two novel gene candidates with phenotypic overlap between the patients and the mouse knockouts. CONCLUSIONS: Information on the developmental period at which embryonic lethality occurs in the knockout mouse may be used for novel disease gene discovery that helps to prioritise variants in unsolved rare disease cases

Altered gene expression profile in a mouse model of SCN8A encephalopathy

12 month embargo; Available online 9 November 2016SCN8A encephalopathy is a severe, early-onset epilepsy disorder resulting from de novo gain-of-function mutations in the voltage-gated sodium channel Na(v)1.6. To identify the effects of this disorder on mRNA expression, RNA-seq was performed on brain tissue from a knock-in mouse expressing the patient mutation p.Asn1768Asp (N1768D). RNA was isolated from forebrain, cerebellum, and brainstem both before and after seizure onset, and from age-matched wildtype littermates. Altered transcript profiles were observed only in forebrain and only after seizures. The abundance of 50 transcripts increased more than 3-fold and 15 transcripts decreased more than 3 fold after seizures. The elevated transcripts included two anti-convulsant neuropeptides and more than a dozen genes involved in reactive astrocytosis and response to neuronal damage. There was no change in the level of transcripts encoding other voltage-gated sodium, potassium or calcium channels. Reactive astrocytosis was observed in the hippocampus of mutant mice after seizures. There is considerable overlap between the genes affected in this genetic model of epilepsy and those altered by chemically induced seizures, traumatic brain injury, ischemia, and inflammation. The data support the view that gain-of-function mutations of SCN8A lead to pathogenic alterations in brain function contributing to encephalopathy.NIH [R01 NS34509]; Dravet Syndrome FoundationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Mapt deletion fails to rescue premature lethality in two models of sodium channel epilepsy

Deletion of Mapt, encoding the microtubuleâ binding protein Tau, prevents disease in multiple genetic models of hyperexcitability. To investigate whether the effect of Tau depletion is generalizable across multiple sodium channel geneâ linked models of epilepsy, we examined the Scn1bâ /â mouse model of Dravet syndrome, and the Scn8aN1768D/+ model of Early Infantile Epileptic Encephalopathy. Both models display severe seizures and early mortality. We found no prolongation of survival between Scn1bâ /â ,Mapt+/+, Scn1bâ /â ,Mapt+/â , or Scn1bâ /â ,Maptâ /â mice or between Scn8aN1768D/+,Mapt+/+, Scn8aN1768D/+,Mapt+/â , or Scn8aN1768D/+,Maptâ /â mice. Thus, the effect of Mapt deletion on mortality in epileptic encephalopathy models is gene specific and provides further mechanistic insight.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145566/1/acn3599.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145566/2/acn3599_am.pd

Altered gene expression profile in a mouse model of SCN8A encephalopathy

12 month embargo; Available online 9 November 2016SCN8A encephalopathy is a severe, early-onset epilepsy disorder resulting from de novo gain-of-function mutations in the voltage-gated sodium channel Na(v)1.6. To identify the effects of this disorder on mRNA expression, RNA-seq was performed on brain tissue from a knock-in mouse expressing the patient mutation p.Asn1768Asp (N1768D). RNA was isolated from forebrain, cerebellum, and brainstem both before and after seizure onset, and from age-matched wildtype littermates. Altered transcript profiles were observed only in forebrain and only after seizures. The abundance of 50 transcripts increased more than 3-fold and 15 transcripts decreased more than 3 fold after seizures. The elevated transcripts included two anti-convulsant neuropeptides and more than a dozen genes involved in reactive astrocytosis and response to neuronal damage. There was no change in the level of transcripts encoding other voltage-gated sodium, potassium or calcium channels. Reactive astrocytosis was observed in the hippocampus of mutant mice after seizures. There is considerable overlap between the genes affected in this genetic model of epilepsy and those altered by chemically induced seizures, traumatic brain injury, ischemia, and inflammation. The data support the view that gain-of-function mutations of SCN8A lead to pathogenic alterations in brain function contributing to encephalopathy.NIH [R01 NS34509]; Dravet Syndrome FoundationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models

Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation genomically humanized knockin mouse models, by replacing the mouse genomic region of Sod1, Tardbp (TDP-43), and Fus, with their human orthologs, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new standard of large knockin allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing. Extensive analysis shows that homozygous humanized animals only express human protein at endogenous levels. Characterization of humanized FUS animals showed that they are phenotypically normal throughout their lifespan. These humanized strains are vital for preclinical assessment of interventions and serve as templates for the addition of coding or non-coding human ALS/FTD mutations to dissect disease pathomechanisms, in a physiological context

Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease