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Delivery of Large Gene Circuits In vivo Using an Engineered Baculovirus Vector for Multifactorial Control of Gene Expression
No full textMany of the viral vectors used for gene therapy are limited by the cargo size they can deliver into cells in tissue. As a result, most therapies being actively considered today tend to consist of monomodal expression of one or two genes. While this modality is undoubtedly effective for many applications, there remains advantages to being able to deliver more genetic cargo. A viral vector with an increased cargo capacity could allow room not only for more and larger therapeutic genes, but also regulatory elements that permit complex, multifactorial regulation of therapeutic gene expression. Here we use the insect-derived baculovirus capable of packaging and delivering >100 kb of transgene DNA as a vector for complex gene circuits that regulate and enhance in vivo gene therapy. Baculovirus has many advantages over other vectors: the ability to transduce a broad spectrum of mammalian cells, a large packaging capacity, no replication in mammalian cells, and a low toxicity in vivo. However, while baculovirus has been used as a gene therapy vector previously, its potential has been limited by its transient expression, as well as its susceptibility to inactivation by the complement system.
We then implemented a hierarchical cloning scheme for the rapid generation and prototyping of baculovirus vectors containing up to 10 different expression units. We then address several shortcomings of the baculovirus by pseudo-typing the AcMNPV baculovirus with two proteins, the Vesticular stromatitis virus protein G and a fusion protein consisting of several complement regulatory domains. This engineered vector has increased transduction and persistence in mouse liver, muscle, and brain tissue. To our knowledge, this is the first time systemic delivery of baculovirus has been shown to be an effective delivery route. Using this engineered virus, we screened a library of 24 variations of a tamoxifen inducible circuit in order to select the architecture with the highest dynamic range, up to a 67-fold increase over uninduced. Finally, we demonstrate two orthogonal small molecule inducible systems (grazoprevir and tamoxifen) delivered by baculovirus in vivo, both as separate viruses and as one complete circuit. Our findings demonstrate the usefulness of complex regulation for the gene therapy field, as well as the utility of the baculovirus as a therapeutic vector
Implementation and Use of the Neuromusculoskeletal Modeling Pipeline
No full textNeuromusculoskeletal injuries including osteoarthritis, stroke, spinal cord
injury, and traumatic brain injury affect roughly 19% of the U.S. adult population.
Standardized interventions have produced suboptimal functional outcomes due to
the unique treatment needs of each patient. Strides have been made to utilize
computational models to develop personalized treatments, but researchers and
clinicians have yet to cross the “valley of death” between fundamental research and
clinical usefulness. This article introduces the Neuromusculoskeletal Modeling
(NMSM) Pipeline, two MATLAB-based toolsets that add Model Personalization and
Treatment Optimization functionality to OpenSim. The two toolsets facilitate
computational design of individualized treatments for neuromusculoskeletal
impairments through the use of personalized neuromusculoskeletal models and
predictive simulation. The Model Personalization toolset contains four tools for
personalizing 1) joint structure models, 2) muscle-tendon models, 3) neural control
models, and 4) foot-ground contact models. The Treatment Optimization toolset
contains three tools for predicting and optimizing a patient’s functional outcome for
different treatment options using a patient’s personalized neuromusculoskeletal
model with direct collocation optimal control methods.
Two NMSM Pipeline use cases are presented. The first example is an
individual post-stroke with impaired walking function, where the goal is to predict
how the subject’s neural control could be changed to improve walking speed
without increasing metabolic cost. First the Model Personalization toolset was used
to develop a personalized neuromusculoskeletal model of the subject starting from a
generic OpenSim full-body model and experimental walking data (video motion
capture, ground reaction, and electromyography) collected from the subject at his
self-selected speed. Next the Treatment Optimization toolset was used with the
personalized model to predict how the subject could recruit existing muscle
synergies more effectively to reduce muscle activation disparities between the
paretic and non-paretic legs. The software predicted that the subject could increase
his walking speed by 60% without increasing his metabolic cost per unit time by
modifying the recruitment of his existing muscle synergies. This hypothetical
treatment demonstrates how NMSM Pipeline tools could allow researchers working
collaboratively with clinicians to develop personalized neuromusculoskeletal
models of individual patients and to perform predictive simulations for the purpose
of designing personalized treatments that maximize a patient’s post-treatment
functional outcome.
The second example is a novel personalized closed-chain kinematic shoulder
model creation process utilizing the first Model Personalization tool, Joint Model
Personalization. Commonly used kinematic shoulder models typically use
regression-based kinematics and open-chain constructions, these models can
produce low accuracy and anatomically impossible kinematics for many motions
and subjects. After creating synthetic marker data and a model compatible with the
NMSM Pipeline, joint parameters were automatically optimized to minimize the
error between modeled kinematics and experimental kinematics of eight motions.
The software produced a series of models with average marker distance errors
below 1 millimeter across all motions for the best 5 degree of freedom model. This
novel personalized closed-chain kinematic shoulder illustrates the ability of the
NMSM Pipeline to influence the field of neuromusculoskeletal modelin
Behavior Infractions and Subsequent Disciplinary Actions in Aldine ISD Schools
No full textThe purpose of this brief is to examine changes in school discipline rates in Aldine ISD from 2019-20 to 2022-23 and to explore how discipline practices varied by race/ethnicity and special education status in 2022-23
Housing Affordability and Instability
No full textThis snapshot looked at housing affordability and instability in the Houston area. Residents were asked how difficult it was in the past 12 months to afford housing costs, and if certain factors such as increasing rents or utility bills, contributed to the difficulty they experienced. Residents were also asked whether the challenges they faced had forced them to move in the past year
Houston Residents and Their Pets
No full textAccording to a recent nationwide poll, more than 87 million households have at least one pet, and in nearly all of them, pets are viewed as part of the family, providing companionship, emotional support, and opportunities for social interaction (Megna, 2024). The Houston metropolitan area ranked fourth in the country for share of households with dogs and eighth for cats in 2021 (Jordan, 2022). This brief takes a closer look at who has pets in Houston and Harris County, including further exploring the different types and number of pets people have, as well as the self-reported benefits that come with having them
89th Texas Legislative Session: Priorities and Policy Views
No full textThe Texas legislature’s 89th regular session commenced on January 14, 2025, and will run until June 2, 2025. During this 140-day legislative period, the state legislature will introduce and vote on bills, resolutions, and emergency matters. School vouchers, public school funding, water supply, and cannabis regulations are some of the key issues in this session. To evaluate public expectations for this legislative session and support for proposed policies, residents in Fort Bend, Harris, and Montgomery Counties who are part of the Greater Houston Community Panel were asked about their top priorities for state legislators and how strongly they support or oppose the proposed issues
Treadmill-IO: a novel multi-modal VR tool for studying learning of complex rodent behaviors
No full textTraditionally, spatial navigation in animal models in virtual reality (VR) settings has been studied primarily using visual cues. However, few studies have investigated VR navigation in environments promoting interactions between the auditory system and hippocampus. Here I present a novel multi-modal virtual reality system that can be defined by either visual, sound, or both stimuli that are modulated based on the animal’s real-time position. To examine how the hippocampus represents the visual and sound environment, I developed a hippocampus-depend task where animals are trained to lick for a reward on each lap in the reward zone. I report behavioral evidence that mice can learn to navigate in our sound VR task. Similarly, in the visual VR environment, I replaced the sound stimuli with different types of visual stimuli in the same location to preserve the spatial information for both types of VR environments and observed the same result. There has been an increasing volume of research that requires a large amount of resources used on high-throughput animal training in difficult tasks. Evidently, how to make informed decisions early in the training is important to any experimenter so that valuable resources and time are not wasted on animals that are not able to learn. Here I present possible parameters that could differentiate learners from non-learners, namely lick probability, lick selectivity, lick rate, percentage of valid laps, average speed, and lick latency. I observe that learners have a higher lick probability, and low lick latency while maintaining a high percentage of valid laps, on the other hand, non-learners exhibit low lick probability, and high lick latency with a low percentage of valid laps. During the transition of different maze-length environments, learners exhibit an increase in average speed while non-learners maintain or exhibit a decrease in speed. With combined information from these parameters, experimenters can now focus on using resources more efficiently thus contributing to a faster turnover for research
Surveilling Im/mobilities Under the Digital Security State: An Ethnography of CBP One™ Across the Extended Mexico-US Borderlands
No full textThe security state is expanding through digital border control and migration management. Based on twenty-eight months of ethnographic fieldwork in northern and central Mexico, I examine how the Mexico-US border becomes displaced across territorial and digital boundaries into various domains of social life along the migrant trail. Previous studies emphasize the political dimensions of surveillance within security states. By studying encounters between asylum-seeking migrants, humanitarian workers, US officials and software engineers acting under punitive asylum policies and digital innovation, my research interrogates how the sociotechnical development and implementation of CBP One™, a border-crossing smartphone app, generates bureaucratic, expressive and popular cultural forms that enforce and resist the transnational im/material bordering and surveillance practices of digital security states in the twenty-first century
Dataset
No full textThe file contains raw data of the paper.A work investigates multimode ultrastrong coupling between cavity modes of a three-dimensional photonic-crystal cavity and the cyclotron resonance of a Landau-quantized two-dimensional electron gas in gallium arsenide.1.
The Power of Hunger: Food and Slave Trading in Atlantic Africa, 1712–1807
No full textThe Power of Hunger provides a new perspective on the transatlantic slave trade during the long eighteenth century. Focusing on the leading human trafficking nation of the period, the British Empire, it shows how hunger shaped the trade and the ramifications thereof. In England, the business of feeding slave ships drew a diverse group of Britons into Atlantic commerce. This broader involvement in human trafficking raised incomes and contributed to the larger economic development of the Kingdom. At sea, the need to purchase foodstuffs in Africa helped dictate where and when British vessels conducted business. During the middle passage, enslavers intentionally subjected captives to hunger to serve the maxims of profit and power. In Africa, merchants and producers gainfully fed European slave ships through an intense commercialization of agriculture. The costs attending these benefits were great. Provision exports from Africa fostered food insecurity that perpetuated slavery and cultivated economic underdevelopment. Through a demonstration of the historical power of hunger, this dissertation informs readers how the slave trade functioned, whose interests it served, and how it fomented global inequities of today