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Emerson, R.

Publications and source records attributed to Emerson, R..

3 recordsLinked to original sources

Human interictal epileptiform discharges are traveling waves reflecting ictal self-organization

Interictal epileptiform discharges (IEDs), also known as interictal spikes, are large intermittent electrophysiological events observed between seizures in patients with epilepsy. Though they occur far more often than seizures, IEDs are less studied, and their relationship to seizures remains unclear. To better understand this relationship, we examined multi-day recordings of microelectrode arrays implanted in human epilepsy patients, allowing us to precisely observe the spatiotemporal propagation of IEDs, spontaneous seizures, and how they relate. These recordings showed that the majority of IEDs are traveling waves, traversing the same path as ictal discharges during seizures, and with a fixed direction relative to seizure propagation. Moreover, the majority of IEDs, like ictal discharges, were bidirectional, with one predominant and a second, less frequent antipodal direction. These results reveal a fundamental spatiotemporal similarity between IEDs and ictal discharges. These results also imply that most IEDs arise in brain tissue outside the site of seizure onset and propagate toward it, indicating that the propagation of IEDs provides useful information for localizing the seizure focus.

neuroscience

Massively Multiplexed Affinity Characterization of Therapeutic Antibodies Against SARS-CoV-2 Variants

Antibody therapies represent a valuable tool to reduce COVID-19 deaths and hospitalizations. Multiple antibody candidates have been granted emergency use authorization by the FDA and many more are in clinical trials. Most antibody therapies for COVID-19 are engineered to bind to the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein and disrupt its interaction with ACE2. Notably, several SARS-CoV-2 strains have accrued mutations throughout the RBD that improve ACE2 binding affinity, enhance viral transmission, and escape some existing antibody therapies. Here, we measure the binding affinity of 33 therapeutic antibodies against a large panel of SARS-CoV-2 variants and related strains of clinical significance to determine epitopic residues, determine which mutations result in loss of binding, and predict how future RBD variants may impact antibody efficacy. One-Sentence SummaryBy measuring protein binding in vitro, we identify which clinical antibodies retain binding to various mutant SARS-CoV-2 strains.

bioengineering

Vaginal squamous cell carcinoma develops in mice with Arid1a loss and gain of oncogenic Kras

Recent sequencing studies showed that loss-of-function mutations in ARID1A (AT-rich interactive domain 1a) were enriched in gynecologic malignancies. However, multiple mouse models with deletion of Arid1a did not exhibit gynecologic malignancy. Oncogenic KRAS mutations are a common finding in endometrial cancers. However, expression of oncogenic Kras (KrasG12D) in the uterus was not sufficient to develop endometrial cancer. These results suggest that both ARID1A deletion and oncogenic KRAS require additional hits before driving gynecologic malignancy. To determine the role of the combination effects of deletion of Arid1a and oncogenic Kras, Arid1aflox/flox mice were crossed to KrasLox-Stop-Lox-G12D/+ mice using progesterone receptor Cre (PgrCre/+). Survival studies, histology, and immunohistochemistry were used to characterize the phenotype. Hormone dependence was evaluated by ovarian hormone depletion and estradiol replacement. Arid1aflox/flox; KrasLox-Stop-Lox-G12D/+; PgrCre/+ (AKP) mice exhibited early euthanasia due to large vaginal tumors, which were invasive squamous cell carcinoma. Younger mice exhibited precancerous intraepithelial lesions that progressed to invasive squamous cell carcinoma with age. Immunohistochemistry supported the pathological diagnosis with abnormal expression and localization of cytokeratin 5, tumor protein P63, cyclin dependent kinase inhibitor 2A (CDKN2A or p16), and marker of proliferation Ki-67. Vaginal lesions in AKP mice were hormone dependent. Ovarian hormone deletion in AKP mice resulted in atrophic vaginal epithelium without evidence of vaginal tumors. Estradiol replacement in ovarian hormone depleted AKP mice resulted in lesions that resembled the squamous cell carcinoma in intact mice. AKP mice did not develop endometrial cancer. Arid1a deletion with KrasG12D expression drives invasive vaginal squamous cell carcinoma. This mouse can be used to study the transition from benign precursor lesions into invasive vaginal squamous cell carcinoma offering insights into progression.

cancer biology