Multi-omics and 3D-imaging reveal bone heterogeneity and unique calvaria cells in neuroinflammation

The meninges of the brain are an important component of neuroinflammatory response. Diverse immune cells move from the calvaria marrow into the dura mater via recently discovered skull-meninges connections (SMCs). However, how the calvaria bone marrow is different from the other bones and whether and how it contributes to human diseases remain unknown. Using multi-omics approaches and whole mouse transparency we reveal that bone marrow cells are highly heterogeneous across the mouse body. The calvaria harbors the most distinct molecular signature with hundreds of differentially expressed genes and proteins. Acute brain injury induces skull-specific alterations including increased calvaria cell numbers. Moreover, TSPO-positron-emission-tomography imaging of stroke, multiple sclerosis and neurodegenerative disease patients demonstrate disease-associated uptake patterns in the human skull, mirroring the underlying brain inflammation. Our study indicates that the calvaria is more than a physical barrier, and its immune cells may present new ways to control brain pathologies.

Are push and pull factors for entrepreneurship and brain drain same? Perception of students and professionals

Brain drain has gained attention since past few decades, this phenomenon is very apparent in Pakistan as number of people applying for immigration is increasing day by day. Although there are many measures that can be taken to reduce the process, however the best one in current local scenario is developing a safe and sound entrepreneurial niche. This study aims to provide causes of brain drain and preventive measures for this. Secondary aim of the study is to identify opinion of respondents about significance for using self-employment opportunities as solution for slowing the process of brain drain. Third this study will try to examine the relationship between factors causing brain drain and barriers preventing self-employment as career choice. Sample of the study was divided into two strata. First group consisted of 25 respondents from five high-notch professions including medicine and engineering. Second part of the sample was 20 students from doctoral (PhD), masters, medicine and engineering classes. A self developed instrumentwas be used to collect data. It is a semi-structured interview schedule for taking responses of first two segments of sample. Data was analyzed by using thematic analysis to achieve objectives of the study. It is evident that factors that are causing brain drain are almost same as those serving as barrier for adopting entrepreneurship as career choice. The officials can control brain drain by establishing entrepreneurial niche.

Transmission of amyloid-beta and tau pathologies is associated with cognitive impairments in a primate

Amyloid-β (Aβ) pathology transmission has been described in patients following iatrogenic exposure to compounds contaminated with Aβ proteins. It can induce cerebral Aβ angiopathy resulting in brain hemorrhages and devastating clinical impacts. Iatrogenic transmission of tau pathology is also suspected but not experimentally proven. In both scenarios, lesions were detected several decades after the putatively triggering medico-surgical act. There is however little information regarding the cognitive repercussions in individuals who do not develop cerebral hemorrhages. In the current study, we inoculated the posterior cingulate cortex and underlying corpus callosum of young adult primates (Microcebus murinus) with either Alzheimer’s disease or control brain extracts. This led to widespread Aβ and tau pathologies in all of the Alzheimer-inoculated animals following a 21-month-long incubation period (n = 12) whereas none of the control brain extract-inoculated animals developed such lesions (n = 6). Aβ deposition affected almost all cortical regions. Tau pathology was also detected in Aβ-deposit-free regions distant from the inoculation sites (e.g. in the entorhinal cortex), while some regions adjacent, but not connected, to the inoculation sites were spared (e.g. the occipital cortex). Alzheimer-inoculated animals developed cognitive deficits and cerebral atrophy compared to controls. These pathologies were induced using two different batches of Alzheimer brain extracts. This is the first experimental demonstration that tau can be transmitted by human brain extracts inoculations in a primate. We also showed for the first time that the transmission of widespread Aβ and tau pathologies can be associated with cognitive decline. Our results thus reinforce the need to organize a systematic monitoring of individuals who underwent procedures associated with a risk of Aβ and tau iatrogenic transmission. They also provide support for Alzheimer brain-inoculated primates as relevant models of Alzheimer pathology.

Neuroscience meets cancer: networks and neuronal input to brain tumors

The nervous system with its complex organizational features and functions is well-known for its impressive ability to process information and drive countless biological processes. It has come to the surprise of many that the nervous system can also be intimately involved in an unwelcome area of human life: the initiation and progression of cancer. For brain tumors, the parallels to neurodevelopment and nervous system function can be found on multiple levels. First, cancer cells of incurable gliomas interconnect with long cellular extensions to a large communicating multicellular network. Second, indirect and direct neuronal input can generate, activate, and control brain tumor growth. Third, it is becoming increasingly clear that those features not only drive brain tumor progression but also the notorious resistance of these tumors against standard antitumor therapies. Remarkably, these recent insights have already generated novel ideas for better antitumor therapies.

Src and Memory: A Study of Filial Imprinting and Predispositions in the Domestic Chick

Visual imprinting is a learning process whereby young animals come to prefer a visual stimulus after exposure to it (training). The available evidence indicates that the intermediate medial mesopallium (IMM) in the domestic chick forebrain is a site of memory formation during visual imprinting. We have studied the role of Src, an important non-receptor tyrosine kinase, in memory formation. Amounts of total Src (Total-Src) and its two phosphorylated forms, tyrosine-416 (activated, 416P-Src) and tyrosine-527 (inhibited, 527P-Src), were measured 1 and 24 h after training in the IMM and in a control brain region, the posterior pole of nidopallium (PPN). One hour after training, in the left IMM, we observed a positive correlation between the amount of 527P-Src and learning strength that was attributable to learning, and there was also a positive correlation between 416P-Src and learning strength that was attributable to a predisposition to learn readily. Twenty-four hours after training, the amount of Total-Src increased with learning strength in both the left and right IMM, and amount of 527P-Src increased with learning strength only in the left IMM; both correlations were attributable to learning. A further, negative, correlation between learning strength and 416P-Src/Total-Src in the left IMM reflected a predisposition to learn. No learning-related changes were found in the PPN control region. We suggest that there are two pools of Src; one of them in an active state and reflecting a predisposition to learn, and the second one in an inhibited condition, which increases as a result of learning. These two pools may represent two or more signaling pathways, namely, one pathway downstream of Src activated by tyrosine-416 phosphorylation and another upstream of Src, keeping the enzyme in an inactivated state via phosphorylation of tyrosine-527.

Hydrolysis of a second Asp-Pro site at the N-terminus of NOTCH3 in inherited vascular dementia

Cerebrovascular pathology at the biochemical level has been informed by the study of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a vascular disorder caused by NOTCH3 mutations. Previous work in CADASIL described N-terminal proteolysis of NOTCH3 generated by specific non-enzymatic cleavage of the first Asp-Pro sequence of the protein. Here, we investigated whether the second Asp-Pro peptide bond (residues 121–122) of NOTCH3 is cleaved in CADASIL. Monospecific antibodies were generated that recognize the neo-epitope predicted to be generated by cleavage after Asp121. These antibodies were used to localize cleavage events at Asp121 in post-mortem CADASIL and control brain tissue and to investigate factors that regulate cleavage at Asp121. We report that cleavage at Asp121 occurs at a high level in the arterial media of CADASIL cerebral arteries. Leptomeningeal arteries demonstrated substantially more cleavage product than penetrating arteries in the white matter, and control vessels harbored only a small amount of cleaved NOTCH3. Proteolysis at Asp121 occurred in purified preparations of NOTCH3 ectodomain, was increased by acidic pH and reductive conditions, and required native protein conformation for cleavage. Increasing the concentration of NOTCH3 EGF-like domain protein elevated the level of proteolysis. On the other hand, several polyanionic chemicals potently blocked cleavage at Asp121. These studies demonstrate that the NOTCH3 protein in CADASIL is cleaved in multiple locations at labile Asp-Pro peptide bonds. As such, chronic brain vascular disease, like other neurodegenerative conditions, features proteolysis of pathological proteins at multiple sites which may generate small pathological peptides.

Quantitative Peptidomics of Mouse Brain After Infection With Cyst-Forming Toxoplasma gondii

Toxoplasma gondii is an obligate intracellular parasite capable of establishing persistent infection within the host brain and inducing severe neuropathology. Peptides are important native molecules responsible for a wide range of biological functions within the central nervous system. However, peptidome profiling in host brain during T. gondii infection has never been investigated. Using a label-free peptidomics approach (LC–MS/MS), we identified a total of 2,735 endogenous peptides from acutely infected, chronically infected and control brain samples following T. gondii infection. Quantitative analysis revealed 478 and 344 significantly differentially expressed peptides (DEPs) in the acute and chronic infection stages, respectively. Functional analysis of DEPs by Gene Ontology suggested these DEPs mainly originated from cell part and took part in cellular process. We also identified three novel neuropeptides derived from the precursor protein cholecystokinin. These results demonstrated the usefulness of quantitative peptidomics in determining bioactive peptides and elucidating their functions in the regulation of behavior modification during T. gondii infection.

Cryo-EM structure of alpha-synuclein fibrils amplified by PMCA from PD and MSA patient brains

Synucleinopathies are neurodegenerative diseases related to the aggregation of the protein alpha-synuclein (aSyn). Among these diseases, Parkinson disease (PD) and multiple system atrophy (MSA) are most prevalent. aSyn can readily form different fibrillar polymorphs, if exposed to an air-water interface or by templating with pre-existing fibrils. We here report the structures of three fibrillar polymorphs that were obtained after seeding monomeric aSyn with PD and MSA patients brain homogenates using protein misfolding cyclic amplification (PMCA). Seeding with a control brain homogenate did not produce fibrils, and seeding with other in vitro generated fibrillar polymorphs as a control faithfully produced polymorphs of a different type. The here determined fibril structures from PD and MSA brain tissue represent new folds, which partly resemble that of previously reported in vitro generated fibrils from Y39 phosphorylated aSyn protein. The relevance of these fibrils for synucleinopathies in humans remains to be further investigated.

Stopping vs Resting state during motor imagery paradigm

Current non-invasive Brain Machine interfaces commonly rely on the decoding of sustained motor imagery activity (MI). This approach enables a user to control brain-actuated devices by triggering predetermined motor actions. One major drawback of such strategy is that users are not trained to stop their actions. Indeed, the termination process involved in BMI is poorly understood with most of the studies assuming that the end of an MI action is similar to the resting state. Here we hypothesize that the process of stopping MI (MI termination) and resting state are two different processes that should be decoded independently due to the exhibition of different neural pattens. We compared the detection of both states transitions of an imagined movement, i.e. rest-to-movement (onset) and movement-to-rest (offset). Our results shows that both decoders show significant differences in term of performances and latency (N=17 Subjects) with the offset decoder able to detect faster and better MI termination. While studying this difference, we found that the offset decoder is primarily based on the use of features in Beta band which appears earlier. Based on this finding, we also proposed a Random Forrest based decoder which enable to distinguish three classes (MI, MI termination and REST).