Language Impairments in Epilepsy-Aphasia Syndromes

Authors:

Olivia Pan, Maria Maloney, Takao Hensch

Date Created:

2025-01-01

Course Title:

Professor:

Not specified

About Paper:

Epilepsy-aphasia syndromes (EAS) are a category of childhood then further analyzed to assess the amount of calls, transition seizures accompanied by language impairment. Individuals often probabilities between various call types, and overall organization outgrow the seizures, but the language impairments can be long (“grammar”) of the vocalizations. To induce oxidative stress, lasting. A mutation in the gene GRIN2A, which codes for the a dopamine re-uptake inhibitor, GBR 12909, will be further GluN2A subunit of the NMDA receptor, is commonly associated administered (10mg/kg, i.p.) to adult mice for ten days. USVs with EAS. Additionally, oxidative stress, the imbalance of reactiveare recorded before the GBR injections and then repeated after oxygen species (ROS) and antioxidants that results in cellular the injections for comparison. The results will demonstrate damage, may further exacerbate the effects of this mutation. To whether loss of GRIN2A itself impacts USVs and to what extent investigate the relationship between seizures, oxidative stress, oxidative stress in adulthood (a second “hit”) might aggravate any and language development, this project examined ultrasonic vocalization impairment, perhaps through a lower number of calls vocalizations (USVs). USVs are high frequency vocalizations or more disorganized “speech.” The next phase of this project produced by mice during social interactions. Our paradigm will be to chemically induce thalamo-cortical seizures in mice with specifically looked at USVs produced by male mice during pentylenetetrazol (PTZ) and investigate the impact of acute vs courtship behavior. USVs were recorded by placing a male mouse chronic seizure activity on USVs. Ultimately, this would inform in an arena with a female in estrus. The recordings were annotated whether GRIN2A mutation, additional oxidative stress, or simply by classifying each individual “syllable” into one of thirteen the presence of seizures drives language impairment in EAS. categories, using a deep learning network (DeepSqueak) program, Tumors in Waiting: How the Immune Microenvironment Delays or Drives Colorectal Cancer Giovanna Panetta, Pearl Lie, Nilay Sethi Harvard College | Cabot House | Molecular and Cellular Biology | 2028 The earliest steps of tumorigenesis don’t happen in isolation, theyare analyzed for expansion, immune infiltration, and molecular unfold within a living tissue shaped by inflammation, surveillance,changes. Multi-omic approaches, including RNA sequencing, and cellular crosstalk. In colorectal cancer (CRC), how the ATAC-seq, and CUT&RUN, characterize transcriptional and immune system responds to premalignant lesions may determine epigenomic alterations associated with immune pressure or its whether abnormal epithelium is eliminated, tolerated, or allowed absence. to progress. This study asks a simple but critical question: Which InitialresultssuggestthatthepresenceofcytotoxicTcellsandTh1- immune components are responsible for keeping early colorectal type signals plays a decisive role in constraining lesion outgrowth. neoplasia in check, and what happens when they’re absent? In their absence, premalignant cells persist and expand, acquiring To explore this, this study uses both the AOM/DSS inflammation- transcriptional and chromatin features that may support immune driven model and orthotopic transplantation of Apc-mutant evasion or altered differentiation. The immune microenvironment intestinal organoids into a range of immune-distinct mouse doesn’t just respond to transformation; it shapes the direction it hosts. These include: immunocompetent C57BL/6J mice (intact takes. immune system); TCRα knockout mice (deficient in αβ T cells); Future work will apply perturbation-based genetic screening to Rag2 knockout mice (lacking all mature B and T cells); T-bet identify epithelial-intrinsic regulators of immune engagement. knockout mice (impaired in Th1 responses and IFN-γ production); By clarifying how early lesions interact with their immune athymic Nude mice (unable to produce mature T cells due to thymic absence); and NSG mice (lacking functional B, T, environment, this study aims to uncover new opportunities for and NK cells, with severely compromised innate and adaptive immune-based interception of colorectal cancer before malignant transformation occurs. immunity). Lesion growth is tracked over time, and tissues Identifying Promising Genetic Markers Linked to Elevated Monocyte Distribution Width Sairam Pantham, Saeed Nazemidashtarjandi, Martin Yarmush Harvard College | Mather House | Chemical and Physical Biology | 2028 Monocyte distribution width (MDW) has emerged as a significant macrophages, another was treated with resolvin D2 (RvD2), a diagnostic and prognostic marker for inflammatory conditions, known anti-inflammatory regulator, and a third was treated with a reflecting the variability in size of monocytes in response to combination of LPS and RvD2. A fourth group was left untreated. inflammatory stimuli. Studies clearly document that MDW values Afterculturingthemonocytesfor48hours,anautomatedhemocyte of over 20.0, when combined with laboratory tests, can predict analyzer was used to measure the average MDW of each treatment sepsis, and that chronically high MDW values are closely linked to group. In addition, single-cell RNA sequencing (scRNA-seq) data inflammatoryconditionssuchasautoimmunedisorders. Thisstudy was collected and subsequently analyzed through the RNA library looks to understand the genetic expression profiles of monocyte Seurat. Results suggest that MDW was elevated in monocytes populations with high MDW and the differences compared to treated with LPS alone, with scRNA-seq analysis suggesting those of monocyte populations with low MDW identifies genetic that this population contains a relatively high proportion of markers linked to high MDW, potentially exposing targets for intermediate CD14++CD16+ monocytes. Differential expression drug development. To this end, monocytes were isolated from analysis indicates that markers such as SLAMF7, PLAC8, FFAR2, blood donated by a consenting patient at two separate time points, and MMP14 are significantly upregulated exclusively in cells yielding two total samples. In each sample, the monocytes treated with LPS alone, especially within intermediate monocyte were then separated into four groups. One group was treated subpopulations, serving as direct links to an elevated MDW withlipopolysaccharide(LPS),apro-inflammatorystimuluslinked phenotype and potential targets for designing and testing drugs for to the transition between monocytes and pro-inflammatory M1 inflammatory conditions. 122 Program for Research in Science and Engineering Desthiobiotin-NeutrAvidin Affinity Mediated Extraction of Extracellular Vesicles from Unprocessed Solutions Ian Park, David Walt Harvard College | Adams House | Biomedical Engineering | 2028 Extracellular vesicles (EVs) are nano-sized, secreted vesicles Validation using single-vesicle imaging successfully illustrated which can contain and transport cellular proteins, lipids, and both the specificity and efficiency of the method, where the nucleic acids. The role of EVs in cancer progression is capture efficiency of desthiobiotin proved similar to that of well-studied, and previous work in the lab has demonstrated biotin and the release efficiency far surpassed that of currently a correlation between progressive stages of breast cancer and comparable methods. High-throughput imaging techniques were EVs positively expressing the tetraspanin protein CD9. While used to calibrate environmental variables to produce the greatest such a link appears promising as a the target of diagnostic efficiency. This method will allow for more robust EV-diagnostic assays, current methods of EV extraction from blood and sera assays derived from patient samples. While this method has lack specificity and efficiency, limiting such capabilities. Here, significantly improved EV extraction capabilities, there are still we describe a novel method of EV extraction, without sample various future directions for this project. Additionally, pH- processing, by leveraging the competing interactions between sensitive forms of biotin, such as 2-iminobiotin, could potentially biotin- and desthiobiotin-NeutrAvidin on a PEGylated single-EV create an orthogonal diagnostic assay, whereas direct conjugation surface. The stronger binding interaction between NeutrAvidin of desthiobiotin on the PEGylated surface could allow for a and biotin outcompetes the interaction between NeutrAvidin and reusable method of EV extraction. desthiobiotin, thus releasing EVs conjugated to desthiobiotin.

Abstract:

Epilepsy-aphasia syndromes (EAS) are a category of childhood then further analyzed to assess the amount of calls, transition seizures accompanied by language impairment. Individuals often probabilities between various call types, and overall organization outgrow the seizures, but the language impairments can be long (“grammar”) of the vocalizations. To induce oxidative stress, lasting. A mutation in the gene GRIN2A, which codes for the a dopamine re-uptake inhibitor, GBR 12909, will be further GluN2A subunit of the NMDA receptor, is commonly associated administered (10mg/kg, i.p.) to adult mice for ten days. USVs with EAS. Additionally, oxidative stress, the imbalance of reactiveare recorded before the GBR injections and then repeated after oxygen species (ROS) and antioxidants that results in cellular the injections for comparison. The results will demonstrate damage, may further exacerbate the effects of this mutation. To whether loss of GRIN2A itself impacts USVs and to what extent investigate the relationship between seizures, oxidative stress, oxidative stress in adulthood (a second “hit”) might aggravate any and language development, this project examined ultrasonic vocalization impairment, perhaps through a lower number of calls vocalizations (USVs). USVs are high frequency vocalizations or more disorganized “speech.” The next phase of this project produced by mice during social interactions. Our paradigm will be to chemically induce thalamo-cortical seizures in mice with specifically looked at USVs produced by male mice during pentylenetetrazol (PTZ) and investigate the impact of acute vs courtship behavior. USVs were recorded by placing a male mouse chronic seizure activity on USVs. Ultimately, this would inform in an arena with a female in estrus. The recordings were annotated whether GRIN2A mutation, additional oxidative stress, or simply by classifying each individual “syllable” into one of thirteen the presence of seizures drives language impairment in EAS. categories, using a deep learning network (DeepSqueak) program, Tumors in Waiting: How the Immune Microenvironment Delays or Drives Colorectal Cancer Giovanna Panetta, Pearl Lie, Nilay Sethi Harvard College | Cabot House | Molecular and Cellular Biology | 2028 The earliest steps of tumorigenesis don’t happen in isolation, theyare analyzed for expansion, immune infiltration, and molecular unfold within a living tissue shaped by inflammation, surveillance,changes. Multi-omic approaches, including RNA sequencing, and cellular crosstalk. In colorectal cancer (CRC), how the ATAC-seq, and CUT&RUN, characterize transcriptional and immune system responds to premalignant lesions may determine epigenomic alterations associated with immune pressure or its whether abnormal epithelium is eliminated, tolerated, or allowed absence. to progress. This study asks a simple but critical question: Which InitialresultssuggestthatthepresenceofcytotoxicTcellsandTh1- immune components are responsible for keeping early colorectal type signals plays a decisive role in constraining lesion outgrowth. neoplasia in check, and what happens when they’re absent? In their absence, premalignant cells persist and expand, acquiring To explore this, this study uses both the AOM/DSS inflammation- transcriptional and chromatin features that may support immune driven model and orthotopic transplantation of Apc-mutant evasion or altered differentiation. The immune microenvironment intestinal organoids into a range of immune-distinct mouse doesn’t just respond to transformation; it shapes the direction it hosts. These include: immunocompetent C57BL/6J mice (intact takes. immune system); TCRα knockout mice (deficient in αβ T cells); Future work will apply perturbation-based genetic screening to Rag2 knockout mice (lacking all mature B and T cells); T-bet identify epithelial-intrinsic regulators of immune engagement. knockout mice (impaired in Th1 responses and IFN-γ production); By clarifying how early lesions interact with their immune athymic Nude mice (unable to produce mature T cells due to thymic absence); and NSG mice (lacking functional B, T, environment, this study aims to uncover new opportunities for and NK cells, with severely compromised innate and adaptive immune-based interception of colorectal cancer before malignant transformation occurs. immunity). Lesion growth is tracked over time, and tissues Identifying Promising Genetic Markers Linked to Elevated Monocyte Distribution Width Sairam Pantham, Saeed Nazemidashtarjandi, Martin Yarmush Harvard College | Mather House | Chemical and Physical Biology | 2028 Monocyte distribution width (MDW) has emerged as a significant macrophages, another was treated with resolvin D2 (RvD2), a diagnostic and prognostic marker for inflammatory conditions, known anti-inflammatory regulator, and a third was treated with a reflecting the variability in size of monocytes in response to combination of LPS and RvD2. A fourth group was left untreated. inflammatory stimuli. Studies clearly document that MDW values Afterculturingthemonocytesfor48hours,anautomatedhemocyte of over 20.0, when combined with laboratory tests, can predict analyzer was used to measure the average MDW of each treatment sepsis, and that chronically high MDW values are closely linked to group. In addition, single-cell RNA sequencing (scRNA-seq) data inflammatoryconditionssuchasautoimmunedisorders. Thisstudy was collected and subsequently analyzed through the RNA library looks to understand the genetic expression profiles of monocyte Seurat. Results suggest that MDW was elevated in monocytes populations with high MDW and the differences compared to treated with LPS alone, with scRNA-seq analysis suggesting those of monocyte populations with low MDW identifies genetic that this population contains a relatively high proportion of markers linked to high MDW, potentially exposing targets for intermediate CD14++CD16+ monocytes. Differential expression drug development. To this end, monocytes were isolated from analysis indicates that markers such as SLAMF7, PLAC8, FFAR2, blood donated by a consenting patient at two separate time points, and MMP14 are significantly upregulated exclusively in cells yielding two total samples. In each sample, the monocytes treated with LPS alone, especially within intermediate monocyte were then separated into four groups. One group was treated subpopulations, serving as direct links to an elevated MDW withlipopolysaccharide(LPS),apro-inflammatorystimuluslinked phenotype and potential targets for designing and testing drugs for to the transition between monocytes and pro-inflammatory M1 inflammatory conditions. 122 Program for Research in Science and Engineering Desthiobiotin-NeutrAvidin Affinity Mediated Extraction of Extracellular Vesicles from Unprocessed Solutions Ian Park, David Walt Harvard College | Adams House | Biomedical Engineering | 2028 Extracellular vesicles (EVs) are nano-sized, secreted vesicles Validation using single-vesicle imaging successfully illustrated which can contain and transport cellular proteins, lipids, and both the specificity and efficiency of the method, where the nucleic acids. The role of EVs in cancer progression is capture efficiency of desthiobiotin proved similar to that of well-studied, and previous work in the lab has demonstrated biotin and the release efficiency far surpassed that of currently a correlation between progressive stages of breast cancer and comparable methods. High-throughput imaging techniques were EVs positively expressing the tetraspanin protein CD9. While used to calibrate environmental variables to produce the greatest such a link appears promising as a the target of diagnostic efficiency. This method will allow for more robust EV-diagnostic assays, current methods of EV extraction from blood and sera assays derived from patient samples. While this method has lack specificity and efficiency, limiting such capabilities. Here, significantly improved EV extraction capabilities, there are still we describe a novel method of EV extraction, without sample various future directions for this project. Additionally, pH- processing, by leveraging the competing interactions between sensitive forms of biotin, such as 2-iminobiotin, could potentially biotin- and desthiobiotin-NeutrAvidin on a PEGylated single-EV create an orthogonal diagnostic assay, whereas direct conjugation surface. The stronger binding interaction between NeutrAvidin of desthiobiotin on the PEGylated surface could allow for a and biotin outcompetes the interaction between NeutrAvidin and reusable method of EV extraction. desthiobiotin, thus releasing EVs conjugated to desthiobiotin.

Source:

Harvard / Harvard College | Lowell House | Pyschology | 2027 / 2025

Topics:

immune, monocyte, mice, mdw, usvs, seizure, high, cell, desthiobiotin, language, impairment, oxidative

Co-authors:

@oliviapan357 , @mariamaloney358 , @takaohensch260