Glia cells are often viewed as support cells in the central nervous system, but recent discoveries highlight their importance in physiological functions and in neurological diseases. Central to this ...are leukodystrophies, a group of progressive, neurogenetic disease affecting white matter pathology. In this review, we take a closer look at multiple leukodystrophies, classified based on the primary glial cell type that is affected. While white matter diseases involve oligodendrocyte and myelin loss, we discuss how astrocytes and microglia are affected and impinge on oligodendrocyte, myelin and axonal pathology. We provide an overview of the leukodystrophies covering their hallmark features, clinical phenotypes, diverse molecular pathways, and potential therapeutics for clinical trials. Glial cells are gaining momentum as cellular therapeutic targets for treatment of demyelinating diseases such as leukodystrophies, currently with no treatment options. Here, we bring the much needed attention to role of glia in leukodystrophies, an integral step towards furthering disease comprehension, understanding mechanisms and developing future therapeutics.
Aberrant DNA methylation patterns in malignant cells allow insight into tumor evolution and development and can be used for disease classification. Here, we describe the genome-wide DNA methylation ...signatures of NPM-ALK-positive (ALK+) and NPM-ALK-negative (ALK−) anaplastic large-cell lymphoma (ALCL). We find that ALK+ and ALK− ALCL share common DNA methylation changes for genes involved in T cell differentiation and immune response, including TCR and CTLA-4, without an ALK-specific impact on tumor DNA methylation in gene promoters. Furthermore, we uncover a close relationship between global ALCL DNA methylation patterns and those in distinct thymic developmental stages and observe tumor-specific DNA hypomethylation in regulatory regions that are enriched for conserved transcription factor binding motifs such as AP1. Our results indicate similarity between ALCL tumor cells and thymic T cell subsets and a direct relationship between ALCL oncogenic signaling and DNA methylation through transcription factor induction and occupancy.
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•ALK+ and ALK− ALCL show highly similar genome-wide DNA methylation•ALCL tumor cells closely resemble undifferentiated thymic progenitor cells•Differentially methylated genes are implicated in major T cell functions•Oncogenic transcription factors produce epigenetic footprints
Using genome-wide DNA methylation profiling, Hassler et al. find that DNA methylation patterns in ALCL are related to specific thymic stages in T cell development, suggesting a thymic progenitor cell of origin. Moreover, comparison of ALK+ ALCL to ALK− ALCL indicates no ALK-specific impact on DNA methylation.
The human cerebral cortex is parcellated in hundreds of areas using neuroanatomy and imaging methods. Alternatively, cortical areas can be classified into few cortical types according to their degree ...of laminar differentiation. Cortical type analysis is based on the gradual and systematic variation of laminar features observed across the entire cerebral cortex in Nissl stained sections and has profound implications for understanding fundamental aspects of evolution, development, connections, function, and pathology of the cerebral cortex. In this protocol paper, we explain the general principles of cortical type analysis and provide tables with the fundamental features of laminar structure that are studied for this analysis. We apply cortical type analysis to the micrographs of the Atlas of the human cerebral cortex of von Economo and Koskinas and provide tables and maps with the areas of this Atlas and their corresponding cortical type. Finally, we correlate the cortical type maps with the T1w/T2w ratio from widely used reference magnetic resonance imaging scans. The analysis, tables and maps of the human cerebral cortex shown in this protocol paper can be used to predict patterns of connections between areas according to the principles of the Structural Model and determine their level in cortical hierarchies. Cortical types can also predict the spreading of abnormal proteins in neurodegenerative diseases to the level of cortical layers. In summary, cortical type analysis provides a theoretical and practical framework for directed studies of connectivity, synaptic plasticity, and selective vulnerability to neurologic and psychiatric diseases in the human neocortex.
A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide ...extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study.
Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case.
Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia.
We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.
Sixty years ago, Friedrich Sanides traced the origin of the tangential expansion of the primate neocortex to two ancestral anlagen in the allocortex of reptiles and mammals, and proposed the ...Hypothesis on the Dual Origin of the Neocortex. According to Sanides, paraolfactory and parahippocampal gradients of laminar elaboration expanded in evolution by addition of successive concentric rings of gradually different cortical types inside the allocortical ring. Rodents had fewer rings and primates had more rings in the inner part of the cortex. In the present article, we perform cortical type analysis of the neocortex of adult rats, Rhesus macaques, and humans to propose hypotheses on homology of cortical areas applying the principles of the Hypothesis on the Dual Origin of the Neocortex. We show that areas in the outer rings of the neocortex have comparable laminar elaboration in rats and primates, while most 6-layer eulaminate areas in the innermost rings of primate neocortex lack homologous counterparts in rats. We also represent the topological distribution of cortical types in simplified flat maps of the cerebral cortex of monotremes, rats, and primates. Finally, we propose an elaboration of the Hypothesis on the Dual Origin of the Neocortex in the context of modern studies of pallial patterning that integrates the specification of pallial sectors in development of vertebrate embryos. The updated version of the hypothesis of Sanides provides explanation for the emergence of cortical hierarchies in mammals and will guide future research in the phylogenetic origin of neocortical areas.
1. Bacterial endosymbionts play a fundamental role in insect ecology. Ants host a large diversity of bacterial symbionts, but comparably little is known about how the loss or reduction of symbionts ...affects ant fitness.
2. We investigated the effects of the rifampicin, a commonly used antibiotic, on colonies from several populations of the globally distributed tramp ant Cardiocondyla obscurior, which differ in their endosymbiont communities.
3. We found that rifampicin treatment negatively affected queen fecundity and colony productivity, even when there was a delay of 3 months between treatment and productivity assessment. In addition, the viability of sperm from males produced in rifampicin‐treated colonies was significantly reduced, pointing towards a trans‐generational effect of antibiotics on male ant fitness. As expected, rifampicin treatment also led to a significant decrease in the titres of Candidatus Westeberhardia cardiocondylae and Wolbachia sp., the main bacterial endosymbionts of this ant.
4. The negative effects of antibiotic exposure on ant and symbiont fitness were modulated by the presence and strain of symbiotic bacteria, revealing a complex relationship between the microbiome and ant fitness.
Treatment with the antibiotic rifampicin decreases endosymbiont densities and has strong negative effects on queen fecundity and colony productivity in a tramp ant.
Viability of sperm from males produced in rifampicin‐treated colonies is significantly reduced, pointing towards a trans‐generational effect of antibiotics on male ant fitness.
The degree to which rifampicin treatment affects the fitness of the ant host and its symbionts varies with population and the presence and genotype of symbiont strains.
Aicardi Goutières Syndrome (AGS) is an autoinflammatory disorder resulting in sustained interferon activation through defects in nucleic acid modification and sensing pathways. Thus, mRNA-based ...vaccination used against SARS-CoV-2, raise disease-specific safety concerns. To assess interferon signaling, we tested mRNA SARS-CoV-2 vaccines in AGS whole blood samples. Interferon activation is measured through quantitation of interferon signaling gene (ISG) expression and is increased in AGS patients. There was no increase in ISG scores from baseline following treatment with the nucleoside modified mRNA formulation compared to an increase with unmodified. A patient-family survey reported that the vaccines were well tolerated. These findings suggest that COVID vaccination using nucleoside-modified forms of mRNA vaccines are unlikely to directly stimulate ISG expression in response to mRNA internalization in AGS tissues. With continued community spread, we recommend vaccination using nucleoside-modified mRNA vaccines in this rare disease group in individuals for whom vaccines were previously well tolerated.
The cerebral cortex, the outer part of the brain that has expanded in humans, has layers whose differentiation varies within gradients. Along those gradients, we can define cortical types which range ...in number of layers and degrees of laminar differentiation. From least to most elaborate types there is an increase in the presence of granular layer IV, a shift in relative prominence of deep (layers V–VI) to superficial layers (layers II–III), and shift in location of large pyramidal neurons from deep (layers V–VI) to superficial layers (layers II–III), an increase in differentiation of deep layers (layers V–VI), and an increase in a defined boundary between layers I–II. According to this criteria, the following cortical types were defined: agranular, dysgranular, eulaminate I, and eulaminate II. In addition, primary areas in the cerebral cortex show distinct cortical features and are named koniocortices. Prior studies have shown that cortical types are related to epigenetics, synaptic plasticity, connections, pathologies, and evolution. Therefore, an algorithm to determine cortical type across areas in the human cortex will be a useful tool for the study of normal and pathological cortical networks. The Nissl stain, a standard histological staining method, was used in this study to observe differences in cortical type characteristics across the cerebral cortex. Qualitative analysis was performed on several cortical regions of an established neuroanatomical atlas, the prefrontal cortex of a post-mortem human, and the cerebral cortex of a rhesus macaque. Five laminar features were identified and used to group cortical regions into types, with less than 5% of disagreement amongst at least three experienced neuroanatomists. From these cortical type characteristics, an algorithm was created that can be used to systematically to determine cortical type throughout the cerebral cortex of humans and rhesus macaques. Additionally, quantitative analyses were performed in order to see if this cortical type classification could be an automated practice, that can be performed by individuals who are not experienced neuroanatomists. These quantitative measurements showed varying ability to classify cortical types; therefore, further studies will need to be performed in order to find the optimal quantitative measures of cortical type. A NMDS study was performed to summarize results of the various quantitative measurements, which showed an undisputable gradual trend of cortical types throughout the prefrontal cortex of the human brain. Overall, this study provides a cortical type classification algorithm that reliably and reproducibly identifies different cortical types in the cerebral cortex of human and rhesus macaque brains.
Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free ...breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.
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