Biology subjects

Manley, W.

Publications and source records attributed to Manley, W..

3 recordsLinked to original sources

bioRxiv2024

Interneurons that BiTE: Harnessing the migratory capacity of cortical inhibitory interneuron precursors to treat high-grade glioma

Glioblastoma has a poor prognosis with limited therapeutic options. To date, almost all therapeutic agents that showed promise in in vitro assays, preclinical trials, or even in early clinical trials have failed to make a substantial impact on the survival of patients with high-grade glioma. One major obstacle for small molecules, therapeutic proteins, or immune cells remains the blood brain barrier, which often prevents the efficient delivery of agents to the tumor. To address this delivery issue, we developed a cellular vector where implanted modified post-mitotic Migratory Cortical Inhibitory Interneuron Precursors (MCIPs) migrate to high-grade glioma by chemoattraction to locally secrete a therapeutic protein. The inhibitory interneurons of the cerebral cortex originate predominantly in the ventral/subcortical portion of the telencephalic neural tube. During fetal brain development, MCIP migration is guided over long distances by chemorepulsant and chemoattractant factors. Remarkably, several MCIP chemoattractant factors are also secreted by high-grade gliomas. Indeed, our in vitro and in vivo data show that MCIPs robustly migrate to the majority of glioblastoma cell lines evaluated. As a proof of principle, we modified the MCIPs to secrete bispecific T-cell engagers (BiTEs), linking the EGFR tumor antigen to CD3 on T-cells to create an adaptor molecule that induces an anti-tumor response of resident and supplied T-cells by bridging a tumor antigen and the T-cell receptor. We find that implanted BITE-secreting MCIPs significantly extended survival of mice injected with high-grade glioma. Therefore, we conclude that the use of MCIPs as a delivery vector for therapeutic agents could revolutionize the way we treat glioblastoma, as they allow for the local delivery of therapeutic agents in high concentrations, bypassing the need for these agents to cross the blood brain barrier while reducing the risk for systemic toxicities outside of the brain.

cancer biology↗

bioRxiv2023

Modeling Tick Populations: An Ecological Test Case forGradient Boosted Trees

General linear models have been the foundational statistical framework used to discover the ecological processes that explain the distribution and abundance of natural populations. Analyses of the rapidly expanding cache of environmental and ecological data, however, require advanced statistical methods to contend with complexities inherent to extremely large natural data sets. Modern machine learning frameworks such as gradient boosted trees efficiently identify complex ecological relationships in massive data sets, which are expected to result in accurate predictions of the distribution and abundance of organisms in nature. However, rigorous assessments of the theoretical advantages of these methodologies on natural data sets are rare. Here we compare the abilities of gradient boosted and linear models to identify environmental features that explain observed variations in the distribution and abundance of blacklegged tick (Ixodes scapularis) populations in a data set collected across New York State over a ten-year period. The gradient boosted and linear models use similar environmental features to explain tick demography, although the gradient boosted models found non-linear relationships and interactions that are difficult to anticipate and often impractical to identify with a linear modeling framework. Further, the gradient boosted models predicted the distribution and abundance of ticks in years and areas beyond the training data with much greater accuracy than their linear model counterparts. The flexible gradient boosting framework also permitted additional model types that provide practical advantages for tick surveillance and public health. The results highlight the potential of gradient boosted models to discover novel ecological phenomena affecting pathogen demography and as a powerful public health tool to mitigate disease risks.

ecology↗

bioRxiv2019

Enhanced maturation of fast-spiking interneurons driven by mTOR activation

The use of stem cell derived neurons for cell-based therapies is limited by a protracted maturation. We present a novel approach for accelerating the post-mitotic maturation of human stem cell derived interneurons via the activation of mTOR signaling. Lox sites were placed within PTEN, a key mTOR inhibitor, in a cortical interneuron (CIn) reporter line. Following directed differentiation and purification by FACS, the CIns were exposed to Cre-expressing lentivirus, then transplanted into mouse neocortex or plated onto cultured rat neocortex. Input synaptogenesis and dendritogenesis was greatly enhanced in the PTEN-deleted CIns. Whole-cell recording of the PTEN-deleted CIns in slices of transplanted neocortex revealed multiple indices of enhanced maturation. Finally, we observed similar effects using transient, doxycycline-inducible activation of AKT. We thus present an inducible, reversible approach for accelerating the maturation of human stem cell derived CIns, and to study the influences of this disease-related signaling system in human neurons.

neuroscience↗