Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways. However, direct ...assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific cell types. We found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism. Moreover, our results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism. These findings suggest that molecular changes in upper-layer cortical circuits are linked to behavioral manifestations of autism.
Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and ...neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions.
Glioblastoma is a devastating form of brain cancer. To identify aspects of tumor heterogeneity that may illuminate drivers of tumor invasion, we created a glioblastoma tumor cell atlas with ...single-cell transcriptomics of cancer cells mapped onto a reference framework of the developing and adult human brain. We find that multiple GSC subtypes exist within a single tumor. Within these GSCs, we identify an invasive cell population similar to outer radial glia (oRG), a fetal cell type that expands the stem cell niche in normal human cortex. Using live time-lapse imaging of primary resected tumors, we discover that tumor-derived oRG-like cells undergo characteristic mitotic somal translocation behavior previously only observed in human development, suggesting a reactivation of developmental programs. In addition, we show that PTPRZ1 mediates both mitotic somal translocation and glioblastoma tumor invasion. These data suggest that the presence of heterogeneous GSCs may underlie glioblastoma’s rapid progression and invasion.
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•Glioblastoma tumors have heterogenous cell and cancer stem cell composition•Glioblastomas re-activate a developmental cell type, outer radial glia•These outer radial glia undergo mitotic somal translocation mediated by PTPRZ1•Outer radial glia in glioblastoma promote tumor invasion through PTPRZ1
Kriegstein and colleagues use single-cell RNA sequencing to create a tumor atlas of primary glioblastoma tumors. One interesting population they identify is the outer radial glia-like cell, a cell type found during normal cortical development that undergoes a characteristic mitotic somal translocation “jump-and-divide.” In tumors, these cells may promote invasive behavior.
We report a method for sensing analytes in tear-fluid using commercial contact lenses (CLs) as sample collectors for subsequent analysis with a cost-effective and field-portable reader. In this study ...we quantify lysozyme, the most prevalent protein in tear fluid, non-specifically bound to CLs worn by human participants. Our mobile reader uses time-lapse imaging to capture an increasing fluorescent signal in a standard well-plate, the rate-of-change of which is used to indirectly infer lysozyme concentration through the use of a standard curve. We empirically determined the best-suited CL material for our sampling procedure and assay, and subsequently monitored the lysozyme levels of nine healthy human participants over a two-week period. Of these participants who were regular CL wearers (6 out of 9), we observed an increase in lysozyme levels from 6.89 ± 2.02 μg mL
−1
to 10.72 ± 3.22 μg mL
−1
(mean ± SD) when inducing an instance of digital eye-strain by asking them to play a game on their mobile-phones during the CL wear-duration. We also observed a lower mean lysozyme concentration (2.43 ± 1.66 μg mL
−1
) in a patient cohort with dry eye disease (DED) as compared to the average monitoring level of healthy (no DED) human participants (6.89 ± 2.02 μg mL
−1
). Taken together, this study demonstrates tear-fluid analysis with simple and non-invasive sampling steps along with a rapid, easy-to-use, and cost-effective measurement system, ultimately indicating physiological differences in human participants. We believe this method could be used in future tear-fluid studies, even supporting multiplexed detection of a panel of tear biomarkers toward improved diagnostics and prognostics as well as personalized mobile-health applications.
A rapid and cost-effective method for monitoring proteins in tear-fluid is reported, which enables biomarker monitoring using contact lenses toward personalized mobile-health applications.
We demonstrate a novel electrowetting liquid combination using a room temperature ionic liquid (RTIL) and a nonpolar liquid, 1-phenyl-1-cyclohexene (PCH) suitable for focus-tunable 3-photon ...microscopy. We show that both liquids have over 90% transmission at 1300 nm over a 1.1 mm pathlength and an index of refraction contrast of 0.123. A lens using these liquids can be tuned from a contact angle of 133 to 48° with applied voltages of 0 and 60 V, respectively. Finally, a three-photon imaging system including an RTIL electrowetting lens was used to image a mouse brain slice. Axial scans taken with an electrowetting lens show excellent agreement with images acquired using a mechanically scanned objective.
The cochlear aqueduct (CA) connects the scala tympani to the subarachnoid space and is thought to assist in pressure regulation of perilymph in normal ears, however, its role and variation in inner ...ear pathology, such as in superior canal dehiscence syndrome (SCDS), is unknown. This retrospective radiographic investigation compared CA measurements and classification, as measured on flat-panel computerized tomography, among three groups of ears: controls, n = 64; anatomic superior canal dehiscence without symptoms (SCD), n = 28; and SCDS, n = 64. We found that in a multinomial logistic regression adjusted for age, sex, and BMI, an increase in CA length by 1 mm was associated with a lower odds for being in the SCDS group vs. control (Odds ratio 0.760 p = 0.005). Hierarchical clustering of continuous CA measures revealed a cluster with small CAs and a cluster with large CAs. Another multinomial logistic regression adjusted for the aforementioned clinical covariates showed an odds ratio of 2.97 for SCDS in the small CA cluster as compared to the large (p = 0.004). Further, no significant association was observed between SCDS symptomatology—vestibular and/or auditory symptoms—and CA structure in SCDS ears. The findings of this study lend support to the hypothesis that SCDS has a congenital etiology.
Recently, Bächinger et al. developed a software that measures the angle between the vestibular aqueduct proximal to the vestibule and the distal vestibular aqueduct on computed tomography (CT) scans ...and found differences in the vestibular aqueduct angle between the hypoplastic and degenerative categories of Meniere’s disease (MD). Hypoplastic radiological findings were associated with the development of bilateral MD and hypoplastic changes were not found outside of fetal temporal bones and individuals with MD. The purpose of this study is to examine how the software developed by Bächinger et al. performs when applied to a large dataset of adult patients with varied otologic diagnoses. Adult patients who underwent high resolution flat panel CT scans without intravenous contrast (n = 301) were retrospectively reviewed. Measurements of the angle of the vestibular aqueduct were made using the previously developed software tool. The tool could be applied to measure the vestibular aqueduct angle in most CT scans of the temporal bones (n = 572 ears, 95%). While the majority of ears fell within the normal range of <120 degrees (n = 462, 80%), fourteen ears (2.3%) in 13 patients were found to have vestibular aqueduct angles that meet criteria for hypoplastic MD (>140 degrees). Only one of the 13 patients had a diagnosis of MD and not in the ear in the hypoplastic category. An inconsistent pattern of other otologic diagnoses were found among the 13 individuals meeting criteria for hypoplastic MD. Although prior reports indicate the software has prognostic value in individuals with MD, these results suggest that the software may have lower positive predictive value when applied to a large population of individuals with varied otologic diagnoses.
Cortical organoids are self-organizing three-dimensional cultures that model features of the developing human cerebral cortex
. However, the fidelity of organoid models remains unclear
. Here we ...analyse the transcriptomes of individual primary human cortical cells from different developmental periods and cortical areas. We find that cortical development is characterized by progenitor maturation trajectories, the emergence of diverse cell subtypes and areal specification of newborn neurons. By contrast, organoids contain broad cell classes, but do not recapitulate distinct cellular subtype identities and appropriate progenitor maturation. Although the molecular signatures of cortical areas emerge in organoid neurons, they are not spatially segregated. Organoids also ectopically activate cellular stress pathways, which impairs cell-type specification. However, organoid stress and subtype defects are alleviated by transplantation into the mouse cortex. Together, these datasets and analytical tools provide a framework for evaluating and improving the accuracy of cortical organoids as models of human brain development.
Objective
This narrative review examines how speculative belief that the autonomic nervous system causes Meniere's Disease (MD) led otolaryngologists to adopt invasive surgical procedures and medical ...treatments still offered today.
Data Sources
Google Scholar, PubMed.
Review Methods
A comprehensive literature review (1860–2022) was performed using the terms “Meniere AND (sympathetic OR sympathectomy OR vasomotor OR cervical ganglion),” returning 5360 items. All s were briefly reviewed, relevant publications selected for further study, and key articles discussed by all authors. As it became clear that betahistine was related to the historical narrative, an additional search was performed using “Betahistine AND Meniere AND (vasomotor OR sympathetic OR sympathectomy OR cervical ganglion OR autonomic),” which yielded 336 results.
Results
In the 19th and 20th centuries, growing knowledge of human anatomy led the scientific community to speculate that autonomic dysregulation caused many medical conditions. Excessive sympathetic mediated vasomotor changes were thought to cause hypertension, ischemia, and tissue damage. Clinicians applied the hypothesis to MD, assigning the sympathetic nervous system responsible for vertigo secondary to paroxysmal vasospasm and for hearing loss to poor cochlear nutrition. Despite limited animal experiments and isolated clinical observations, otolaryngologists performed sympathectomies, and, in the 1970s, replaced the procedure with betahistine as an alternative medical treatment.
Conclusion
Premature excitement about a plausible hypothesis led to unnecessary and unwarranted operations. Despite absent evidence of sympathetic overactivation in MD, surgeons eagerly adopted sympathectomies, and later betahistine. Rigorous evaluation of the validity of these treatment practices is needed.
Level of Evidence
5 Laryngoscope, 134:535–542, 2024
As knowledge of human anatomy and the autonomic system advanced over the late 19th and early 20th centuries, theories of autonomic dysregulation were applied to a broad range of conditions including Meniere's Disease, a vestibular disorder whose etiology is poorly understood. The aim of this manuscript is to examine how speculative belief in the autonomic system as the cause of Meniere's led to the adoption of invasive surgical procedures and medical treatment that are still prescribed today.
The need for students to learn science, technology, engineering, and mathematics (STEM) has increased steadily, while student motivation in this area continues to fall behind. We investigated the ...effects of science utility value intervention in increasing the science motivation (i.e., interest in science, appreciation of the role of science in future careers, and intention to engage in science-related activities) of Korean 5th and 6th graders. The usefulness of science for attaining the personal and communal goals inherent to various non-STEM careers was emphasized and internalized through classroom activities including postcard writing. At the end of the semester, students in the experimental group (n = 219) perceived greater personal and communal utility in science than those from the control group (n = 197). This enhanced perception of science utility led to greater interest, a higher likelihood of cognitively connecting science to future careers, and the willingness to engage in scientific activities.
•Utility value intervention was implemented in elementary school classrooms.•The usefulness of science literacy in popular non-STEM careers was emphasized.•Students wrote about the usefulness of science for various jobs and communal goals.•Intervention enhanced the personal and communal utility value of science.•Intervention improved the willingness to engage in science-related activities.
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