Scholarly Works, Institute for Critical Technology and Applied Science (ICTAS)

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Engineered live bacteria as disease detection and diagnosis tools
Tanniche, Imen; Behkam, Bahareh (2023-10-24)
Sensitive and minimally invasive medical diagnostics are essential to the early detection of diseases, monitoring their progression and response to treatment. Engineered bacteria as live sensors are being developed as a new class of biosensors for sensitive, robust, noninvasive, and in situ detection of disease onset at low cost. Akin to microrobotic systems, a combination of simple genetic rules, basic logic gates, and complex synthetic bioengineering principles are used to program bacterial vectors as living machines for detecting biomarkers of diseases, some of which cannot be detected with other sensing technologies. Bacterial whole-cell biosensors (BWCBs) can have wide-ranging functions from detection only, to detection and recording, to closed-loop detection-regulated treatment. In this review article, we first summarize the unique benefits of bacteria as living sensors. We then describe the different bacteria-based diagnosis approaches and provide examples of diagnosing various diseases and disorders. We also discuss the use of bacteria as imaging vectors for disease detection and image-guided surgery. We conclude by highlighting current challenges and opportunities for further exploration toward clinical translation of these bacteria-based systems.
Pulsed Electric Fields in Oncology: A Snapshot of Current Clinical Practices and Research Directions from the 4th World Congress of Electroporation
Campana, Luca G.; Daud, Adil; Lancellotti, Francesco; Arroyo, Julio P.; Davalos, Rafael V.; Di Prata, Claudia; Gehl, Julie (MDPI, 2023-06-25)
The 4th World Congress of Electroporation (Copenhagen, 9–13 October 2022) provided a unique opportunity to convene leading experts in pulsed electric fields (PEF). PEF-based therapies harness electric fields to produce therapeutically useful effects on cancers and represent a valuable option for a variety of patients. As such, irreversible electroporation (IRE), gene electrotransfer (GET), electrochemotherapy (ECT), calcium electroporation (Ca-EP), and tumour-treating fields (TTF) are on the rise. Still, their full therapeutic potential remains underappreciated, and the field faces fragmentation, as shown by parallel maturation and differences in the stages of development and regulatory approval worldwide. This narrative review provides a glimpse of PEF-based techniques, including key mechanisms, clinical indications, and advances in therapy; finally, it offers insights into current research directions. By highlighting a common ground, the authors aim to break silos, strengthen cross-functional collaboration, and pave the way to novel possibilities for intervention. Intriguingly, beyond their peculiar mechanism of action, PEF-based therapies share technical interconnections and multifaceted biological effects (e.g., vascular, immunological) worth exploiting in combinatorial strategies.
Atypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated with the Development of Post-Traumatic Epilepsy
Gudenschwager-Basso, Erwin Kristobal; Shandra, Oleksii; Volanth, Troy; Patel, Dipan C.; Kelly, Colin; Browning, Jack L.; Wei, Xiaoran; Harris, Elizabeth A.; Mahmutovic, Dzenis; Kaloss, Alexandra M.; Correa, Fernanda Guilhaume; Decker, Jeremy; Maharathi, Biswajit; Robel, Stefanie; Sontheimer, Harald; VandeVord, Pamela J.; Olsen, Michelle L.; Theus, Michelle H. (MDPI, 2023-04-25)
Background: Traumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under investigation. The dentate gyrus—a structure that is highly susceptible to injury—has been implicated in the evolution of seizure development. Methods: Utilizing the murine unilateral focal control cortical impact (CCI) injury, we evaluated seizure onset using 24/7 EEG video analysis at 2–4 months post-injury. Cellular changes in the dentate gyrus and hilus of the hippocampus were quantified by unbiased stereology and Imaris image analysis to evaluate Prox1-positive cell migration, astrocyte branching, and morphology, as well as neuronal loss at four months post-injury. Isolation of region-specific astrocytes and RNA-Seq were performed to determine differential gene expression in animals that developed post-traumatic epilepsy (PTE⁺) vs. those animals that did not (PTE⁻), which may be associated with epileptogenesis. Results: CCI injury resulted in 37% PTE incidence, which increased with injury severity and hippocampal damage. Histological assessments uncovered a significant loss of hilar interneurons that coincided with aberrant migration of Prox1-positive granule cells and reduced astroglial branching in PTE⁺ compared to PTE⁻ mice. We uniquely identified Cst3 as a PTE⁺-specific gene signature in astrocytes across all brain regions, which showed increased astroglial expression in the PTE⁺ hilus. Conclusions: These findings suggest that epileptogenesis may emerge following TBI due to distinct aberrant cellular remodeling events and key molecular changes in the dentate gyrus of the hippocampus.
The gut microbiome of wild American marten in the Upper Peninsula of Michigan
Lafferty, Diana J. R.; McKenney, Erin A.; Gillman, Sierra J.; Kailing, Chris D.; Walimaa, Myles C.; Kailing, Macy J.; Roell, Brian J. (Public Library of Science, 2022-11)
Carnivores are ecologically important and sensitive to habitat loss and anthropogenic disruption. Here we measured trophic level and gut bacterial composition as proxies of carnivore ecological status across the Upper Peninsula, Michigan, for wild American marten (Martes americana; hereafter marten). In contrast to studies that have focused on omnivorous and herbivorous species, we find that marten, like other carnivore species without a cecum, are dominated by Firmicutes (52.35%) and Proteobacteria (45.31%) but lack Bacteroidetes. Additionally, a majority of the 12 major bacterial genera (occurring at >= 1%) are known hydrogen producers, suggesting these taxa may contribute to host energy requirements through fermentative production of acetate. Our study suggests that live trapping and harvest methods yield similar marten gut microbiome data. In addition, preserving undisturbed forest likely impacts marten ecology by measurably increasing marten trophic level and altering the gut microbiome. Our study underscores the utility of the gut microbiome as a tool to monitor the ecological status of wild carnivore populations.
Determination of Hydrophobic Dispersive Surface Free Energy of Activated Carbon Fibers Measured by Inverse Gas Chromatographic Technique
Lee, Seul-Yi; Kim, Yeong-Hun; Mahajan, Roop L.; Park, Soo-Jin (MDPI, 2023-03-20)
Activated carbon fibers (ACFs) as one of the most important porous carbon materials are widely used in many applications that involve rapid adsorption and low-pressure loss, including air purification, water treatment, and electrochemical applications. For designing such fibers for the adsorption bed in gas and aqueous phases, in-depth comprehension of the surface components is crucial. However, achieving reliable values remains a major challenge due to the high adsorption affinity of ACFs. To overcome this problem, we propose a novel approach to determine London dispersive components (γSL) of the surface free energy of ACFs by inverse gas chromatography (IGC) technique at an infinite dilution. Our data reveal the γSL values at 298 K for bare carbon fibers (CFs) and the ACFs to be 97 and 260–285 mJ·m⁻², respectively, which lie in the regime of secondary bonding of physical adsorption. Our analysis indicates that these are impacted by micropores and defects on the carbon surfaces. Comparing the γSL obtained by the traditional Gray’s method, our method is concluded as the most accurate and reliable value for the hydrophobic dispersive surface component of porous carbonaceous materials. As such, it could serve as a valuable tool in designing interface engineering in adsorption-related applications.
Laboratory evaluation of climbing helmets: assessment of linear acceleration
Begonia, Mark T.; Rowson, Bethany M.; Scicli, Blake; Goff, John Eric (IOP Publishing, 2023-03-01)
This study utilized a guided free-fall drop tower and standard test headform to measure the peak linear acceleration (PLA) generated by different climbing helmet models that were impacted at various speeds (2-6 m s(-1)) and locations (top, front, rear, side). Wide-ranging impact performance was observed for the climbing helmet models selected. Helmets that produced lower PLAs were composed of protective materials, such as expanded polystyrene (EPS) or expanded polypropylene, which were integrated throughout multiple helmet regions including the front, rear and side. Climbing helmets that produced the highest PLAs consisted of a chinstrap, a suspension system, an acrylontrile butadiene styrene (ABS) outer shell, and an EPS inner layer, which was applied only to the top location. Variation in impact protection was attributed not only to helmet model but also impact location. Although head acceleration measurements were fairly similar between helmet models at the top location, impacts to the front, rear, and side led to larger changes in PLA. A 300 g cutoff for PLA was chosen due to its use as a pass/fail threshold in other helmet safety standards, and because it represents a high risk of severe head injury. All seven helmet models had the lowest acceleration values at the top location with PLAs below 300 g at speeds as high as 6 m s(-1). Impact performance varied more substantially at the front, rear, and side locations, with some models generating PLAs above 300 g at speeds as low as 3 m s(-1). These differences in impact performance represent opportunities for improved helmet design to better protect climbers across a broader range of impact scenarios in the event of a fall or other collision. An understanding of how current climbing helmets attenuate head acceleration could allow manufacturers to enhance next-generation models with innovative and more robust safety features including smart materials.
Histotripsy Ablation of Bone Tumors: Feasibility Study in Excised Canine Osteosarcoma Tumors
Arnold, Lauren; Hendricks-Wenger, Alissa; Coutermarsh-Ott, Sheryl; Gannon, Jessica; Hay, Alayna N.; Dervisis, Nikolaos G.; Klahn, Shawna L.; Allen, Irving C.; Tuohy, Joanne L.; Vlaisavljevich, Eli (Elsevier, 2021-12)
Osteosarcoma (OS) is a primary bone tumor affecting both dogs and humans. Histotripsy is a non-thermal, non-invasive focused ultrasound method using controlled acoustic cavitation to mechanically disintegrate tissue. In this study, we investigated the feasibility of treating primary OS tumors with histotripsy using a 500-kHz transducer on excised canine OS samples harvested after surgery at the Veterinary Teaching Hospital at Virginia Tech. Samples were embedded in gelatin tissue phantoms and treated with the 500-kHz histotripsy system using one- or two-cycle pulses at a pulse repetition frequency of 250 Hz and a dosage of 4000 pulses/point. Separate experiments also assessed histotripsy effects on normal canine bone and nerve using the same pulsing parameters. After treatment, histopathological evaluation of the samples was completed. To determine the feasibility of treating OS through intact skin/soft tissue, additional histotripsy experiments assessed OS with overlying tissues. Generation of bubble clouds was achieved at the focus in all tumor samples at peak negative pressures of 26.2 ± 4.5 MPa. Histopathology revealed effective cell ablation in treated areas for OS tumors, with no evidence of cell death or tissue damage in normal tissues. Treatment through tissue/skin resulted in generation of well-confined bubble clouds and ablation zones inside OS tumors. Results illustrate the feasibility of treating OS tumors with histotripsy. CORRIGENDUM: The authors regret that errors were present in the above article. The legend for Figure 5 on page 3441 should read “Fig. 5. Normal, healthy, non-neoplastic bone was excised from amputated canine limbs and subjected to histology. No histological differences were noted between untreated (a: magnification 4 x, b: magnification 40 x) and treated samples (c: magnification 4 x, d: magnification 40 x).” Also, the final section heading on page 3439 should read “Histotripsy ablation of ex vivo bone and nerve specimens.” Finally, the reference after the last complete sentence on page 3437 is incomplete and should read “Focal pressure waveforms for the 500-kHz transducer were measured using a custom-built fiberoptic hydrophone (FOPH) in degassed water at the focal point of each transducer (Parsons et al. 2006).” The authors would like to apologise for any inconvenience caused.
Highly porous gold supraparticles as surface-enhanced Raman spectroscopy (SERS) substrates for sensitive detection of environmental contaminants
Kang, Seju; Wang, Wei; Rahman, Asifur; Nam, Wonil; Zhou, Wei; Vikesland, Peter J. (Royal Society of Chemistry, 2022-11-15)
Surface-enhanced Raman spectroscopy (SERS) has great potential as an analytical technique for environmental analyses. In this study, we fabricated highly porous gold (Au) supraparticles (i.e., ∼100 μm diameter agglomerates of primary nano-sized particles) and evaluated their applicability as SERS substrates for the sensitive detection of environmental contaminants. Facile supraparticle fabrication was achieved by evaporating a droplet containing an Au and polystyrene (PS) nanoparticle mixture on a superamphiphobic nanofilament substrate. Porous Au supraparticles were obtained through the removal of the PS phase by calcination at 500 °C. The porosity of the Au supraparticles was readily adjusted by varying the volumetric ratios of Au and PS nanoparticles. Six environmental contaminants (malachite green isothiocyanate, rhodamine B, benzenethiol, atrazine, adenine, and gene segment) were successfully adsorbed to the porous Au supraparticles, and their distinct SERS spectra were obtained. The observed linear dependence of the characteristic Raman peak intensity for each environmental contaminant on its aqueous concentration reveals the quantitative SERS detection capability by porous Au supraparticles. The limit of detection (LOD) for the six environmental contaminants ranged from ∼10 nM to ∼10 μM, which depends on analyte affinity to the porous Au supraparticles and analyte intrinsic Raman cross-sections. The porous Au supraparticles enabled multiplex SERS detection and maintained comparable SERS detection sensitivity in wastewater influent. Overall, we envision that the Au supraparticles can potentially serve as practical and sensitive SERS devices for environmental analysis applications.
Histotripsy Ablation in Preclinical Animal Models of Cancer and Spontaneous Tumors in Veterinary Patients: A Review
Hendricks-Wenger, Alissa; Arnold, Lauren; Gannon, Jessica; Simon, Alex; Singh, Neha; Sheppard, Hannah; Nagai-Singer, Margaret A.; Imran, Khan Mohammed; Lee, Kiho; Clark-Deener, Sherrie; Byron, Christopher R.; Edwards, Michael R.; Larson, Martha M.; Rossmeisl, John H. Jr.; Coutermarsh-Ott, Sheryl; Eden, Kristin; Dervisis, Nikolaos G.; Klahn, Shawna L.; Tuohy, Joanne L.; Allen, Irving C.; Vlaisavljevich, Eli (IEEE, 2021-09-03)
New therapeutic strategies are direly needed in the fight against cancer. Over the last decade, several tumor ablation strategies have emerged as stand-alone or combination therapies. Histotripsy is the first completely noninvasive, nonthermal, and nonionizing tumor ablation method. Histotripsy can produce consistent and rapid ablations, even near critical structures. Additional benefits include real-time image guidance, high precision, and the ability to treat tumors of any predetermined size and shape. Unfortunately, the lack of clinically and physiologically relevant preclinical cancer models is often a significant limitation with all focal tumor ablation strategies. The majority of studies testing histotripsy for cancer treatment have focused on small animal models, which have been critical in moving this field forward and will continue to be essential for providing mechanistic insight. While these small animal models have notable translational value, there are significant limitations in terms of scale and anatomical relevance. To address these limitations, a diverse range of large animal models and spontaneous tumor studies in veterinary patients have emerged to complement existing rodent models. These models and veterinary patients are excellent at providing realistic avenues for developing and testing histotripsy devices and techniques designed for future use in human patients. Here, we provide a review of animal models used in preclinical histotripsy studies and compare histotripsy ablation in these models using a series of original case reports across a broad spectrum of preclinical animal models and spontaneous tumors in veterinary patients.
Particle-mediated Histotripsy for the Targeted Treatment of Intraluminal Biofilms in Catheter-based Medical Devices
Childers, Christopher; Edsall, Connor; Mehochko, Isabelle; Mustafa, Waleed; Yuksel Durmaz, Yasemin; Klibanov, Alexander L.; Rao, Jayasimha; Vlaisavljevich, Eli (American Association for the Advancement of Science (AAAS), 2022-08-09)
Objective: This paper is an initial work towards developing particle-mediated histotripsy (PMH) as a novel method of treating catheter-based medical device (CBMD) intraluminal biofilms. Impact Statement: CBMDs commonly become infected with bacterial biofilms leading to medical device failure, infection, and adverse patient outcomes. Introduction: Histotripsy is a noninvasive focused ultrasound ablation method that was recently proposed as a novel method to remove intraluminal biofilms. Here, we explore the potential of combining histotripsy with acoustically active particles to develop a PMH approach that can noninvasively remove biofilms without the need for high acoustic pressures or real-time image guidance for targeting. Methods: Histotripsy cavitation thresholds in catheters containing either gas-filled microbubbles (MBs) or fluid-filled nanocones (NCs) were determined. The ability of these particles to sustain cavitation over multiple ultrasound pulses was tested after a series of histotripsy exposures. Next, the ability of PMH to generate selective intraluminal cavitation without generating extraluminal cavitation was tested. Finally, the biofilm ablation and bactericidal capabilities of PMH were tested using both MBs and NCs. Results: PMH significantly reduced the histotripsy cavitation threshold, allowing for selective luminal cavitation for both MBs and NCs. Results further showed PMH successfully removed intraluminal biofilms in Tygon catheters. Finally, results from bactericidal experiments showed minimal reduction in bacteria viability. Conclusion: The results of this study demonstrate the potential for PMH to provide a new modality for removing bacterial biofilms from CBMDs and suggest that additional work is warranted to develop histotripsy and PMH for treatment of CBMD intraluminal biofilms.
A Study on Electron Acceptor of Carbonaceous Materials for Highly Efficient Hydrogen Uptakes
Lee, Seul-Yi; Park, Ji-Hye; Heo, Young-Jung; Lee, Eun-Sang; Park, Soo-Jin (MDPI, 2021-12)
Significant efforts have been directed toward the identification of carbonaceous materials that can be utilized for hydrogen uptake in order to develop on-board automotive systems with a gravimetric capacity of 5.5 wt.%, thus meeting the U.S. Department of Energy technical targets. However, the capacity of hydrogen storage is limited by the weak interaction between hydrogen molecules and the carbon surface. Cigarette butts, which are the most abundant form of primary plastic waste, remain an intractable environmental pollution problem. To transform this source of waste into a valuable adsorbent for hydrogen uptake, we prepared several forms of oxygen-rich cigarette butt-derived porous carbon (CGB-AC, with the activation temperature range of 600 and 900 & DEG;C). Our experimental investigation revealed that the specific surface area increased from 600 to 700 & DEG;C and then decreased as the temperature rose to 900 & DEG;C. In contrast, the oxygen contents gradually decreased with increasing activation temperature. CGB-AC700 had the highest H-2 excess uptake (QExcess) of 8.54 wt.% at 77 K and 20 bar, which was much higher than that of porous carbon reported in the previous studies. We found that the dynamic interaction between the porosity and the oxygen content determined the hydrogen storage capacity. The underlying mechanisms proposed in the present study would be useful in the design of efficient hydrogen storage because they explain the interaction between positive carbonaceous materials and negative hydrogen molecules in quadrupole orbitals.
High intensity focused ultrasound for the treatment of solid tumors: a pilot study in canine cancer patients
Carroll, Jennifer; Coutermarsh-Ott, Sheryl; Klahn, Shawna L.; Tuohy, Joanne L.; Barry, Sabrina L.; Allen, Irving C.; Hay, Alayna N.; Ruth, Jeffrey; Dervisis, Nikolaos G. (Taylor & Francis, 2022-01)
Purpose: To investigate the safety, feasibility, and outcomes of High-Intensity Focused Ultrasound (HIFU) for the treatment of solid tumors in a spontaneous canine cancer model. Methods: Dogs diagnosed with subcutaneous solid tumors were recruited, staged and pretreatment biopsies were obtained. A single HIFU treatment was delivered to result in partial tumor ablation using a commercially available HIFU unit. Tumors were resected 3-6 days post HIFU and samples obtained for histopathology and immunohistochemistry. Total RNA was isolated from paired pre and post treated FFPE tumor samples, and quantitative gene expression analysis was performed using the nCounter Canine IO Panel. Results: A total of 20 dogs diagnosed with solid tumors were recruited and treated in the study. Tumors treated included Soft Tissue Sarcoma (n = 15), Mast Cell Tumor (n = 3), Osteosarcoma (n = 1), and Thyroid Carcinoma (n = 1). HIFU was well tolerated with only 1 dog experiencing a clinically significant adverse event. Pathology confirmed the presence of complete tissue ablation at the HIFU targeted site and immunohistochemistry indicated immune cell infiltration at the treated/untreated tumor border. Quantitative gene expression analysis indicated that 28 genes associated with T-cell activation were differentially expressed post-HIFU. Conclusions: HIFU appears to be safe and feasible for the treatment of subcutaneous canine solid tumors, resulting in ablation of the targeted tissue. HIFU induced immunostimulatory changes, highlighting the canine cancer patient as an attractive model for studying the effects of focal ablation therapies on the tumor microenvironment.
An Emergency Powered Air-Purifying Respirator From Local Materials and its Efficacy Against Aerosolized Nanoparticles
Kessel, Jeff; Saevig, Christopher S.; Hill, W. Cary; Kessel, Benjamin; Hull, Matthew S. (Sage Publications Inc, 2022-03)
We describe an approach used by a rural healthcare provider to convert surgical helmets into emergency powered air-purifying respirators (PAPRs) at the onset of the COVID-19 pandemic. The approach uses common materials and efficacy was demonstrated against aerosols measuring 7 nm to 25 mu m in diameter.
Exploration of Novel Pathways Underlying Irreversible Electroporation Induced Anti-Tumor Immunity in Pancreatic Cancer
Imran, Khan Mohammad; Nagai-Singer, Margaret A.; Brock, Rebecca M.; Alinezhadbalalami, Nastaran; Davalos, Rafael V.; Allen, Irving C. (Frontiers, 2022-03-18)
Advancements in medical sciences and technologies have significantly improved the survival of many cancers; however, pancreatic cancer remains a deadly diagnosis. This malignancy is often diagnosed late in the disease when metastases have already occurred. Additionally, the location of the pancreas near vital organs limits surgical candidacy, the tumor's immunosuppressive environment limits immunotherapy success, and it is highly resistant to radiation and chemotherapy. Hence, clinicians and patients alike need a treatment paradigm that reduces primary tumor burden, activates systemic anti-tumor immunity, and reverses the local immunosuppressive microenvironment to eventually clear distant metastases. Irreversible electroporation (IRE), a novel non-thermal tumor ablation technique, applies high-voltage ultra-short pulses to permeabilize targeted cell membranes and induce cell death. Progression with IRE technology and an array of research studies have shown that beyond tumor debulking, IRE can induce anti-tumor immune responses possibly through tumor neo-antigen release. However, the success of IRE treatment (i.e. full ablation and tumor recurrence) is variable. We believe that IRE treatment induces IFN gamma expression, which then modulates immune checkpoint molecules and thus leads to tumor recurrence. This indicates a co-therapeutic use of IRE and immune checkpoint inhibitors as a promising treatment for pancreatic cancer patients. Here, we review the well-defined and speculated pathways involved in the immunostimulatory effects of IRE treatment for pancreatic cancer, as well as the regulatory pathways that may negate these anti-tumor responses. By defining these underlying mechanisms, future studies may identify improvements to systemic immune system engagement following local tumor ablation with IRE and beyond.
Transcriptional Interference Regulates the Evolutionary Development of Speech
Mortlock, Douglas P.; Fang, Zhi-Ming; Chandler, Kelly J.; Hou, Yue; Bickford, Lissett R.; de Bock, Charles E.; Eapen, Valsamma; Clarke, Raymond A. (MDPI, 2022-07-04)
The human capacity to speak is fundamental to our advanced intellectual, technological and social development. Yet so very little is known regarding the evolutionary genetics of speech or its relationship with the broader aspects of evolutionary development in primates. In this study, we describe a large family with evolutionary retrograde development of the larynx and wrist. The family presented with severe speech impairment and incremental retrograde elongations of the pisiform in the wrist that limited wrist rotation from 180° to 90° as in primitive primates. To our surprise, we found that a previously unknown primate-specific gene TOSPEAK had been disrupted in the family. TOSPEAK emerged de novo in an ancestor of extant primates across a 540 kb region of the genome with a pre-existing highly conserved long-range laryngeal enhancer for a neighbouring bone morphogenetic protein gene GDF6. We used transgenic mouse modelling to identify two additional GDF6 long-range enhancers within TOSPEAK that regulate GDF6 expression in the wrist. Disruption of TOSPEAK in the affected family blocked the transcription of TOSPEAK across the 3 GDF6 enhancers in association with a reduction in GDF6 expression and retrograde development of the larynx and wrist. Furthermore, we describe how TOSPEAK developed a human-specific promoter through the expansion of a penta-nucleotide direct repeat that first emerged de novo in the promoter of TOSPEAK in gibbon. This repeat subsequently expanded incrementally in higher hominids to form an overlapping series of Sp1/KLF transcription factor consensus binding sites in human that correlated with incremental increases in the promoter strength of TOSPEAK with human having the strongest promoter. Our research indicates a dual evolutionary role for the incremental increases in TOSPEAK transcriptional interference of GDF6 enhancers in the incremental evolutionary development of the wrist and larynx in hominids and the human capacity to speak and their retrogression with the reduction of TOSPEAK transcription in the affected family.
High-Frequency Irreversible Electroporation (H-FIRE) Induced Blood-Brain Barrier Disruption Is Mediated by Cytoskeletal Remodeling and Changes in Tight Junction Protein Regulation
Partridge, Brittanie R.; Kani, Yukitaka; Lorenzo, Melvin F.; Campelo, Sabrina N.; Allen, Irving C.; Hinckley, Jonathan; Hsu, Fang-Chi; Verbridge, Scott S.; Robertson, John L.; Davalos, Rafael V.; Rossmeisl, John H. Jr. (MDPI, 2022-06-11)
Glioblastoma is the deadliest malignant brain tumor. Its location behind the blood–brain barrier (BBB) presents a therapeutic challenge by preventing effective delivery of most chemotherapeutics. H-FIRE is a novel tumor ablation method that transiently disrupts the BBB through currently unknown mechanisms. We hypothesized that H-FIRE mediated BBB disruption (BBBD) occurs via cytoskeletal remodeling and alterations in tight junction (TJ) protein regulation. Intracranial H-FIRE was delivered to Fischer rats prior to sacrifice at 1-, 24-, 48-, 72-, and 96 h post-treatment. Cytoskeletal proteins and native and ubiquitinated TJ proteins (TJP) were evaluated using immunoprecipitation, Western blotting, and gene-expression arrays on treated and sham control brain lysates. Cytoskeletal and TJ protein expression were further evaluated with immunofluorescent microscopy. A decrease in the F/G-actin ratio, decreased TJP concentrations, and increased ubiquitination of TJP were observed 1–48 h post-H-FIRE compared to sham controls. By 72–96 h, cytoskeletal and TJP expression recovered to pretreatment levels, temporally corresponding with increased claudin-5 and zonula occludens-1 gene expression. Ingenuity pathway analysis revealed significant dysregulation of claudin genes, centered around claudin-6 in H-FIRE treated rats. In conclusion, H-FIRE is capable of permeating the BBB in a spatiotemporal manner via cytoskeletal-mediated TJP modulation. This minimally invasive technology presents with applications for localized and long-lived enhanced intracranial drug delivery.
Life Cycle Impact Assessment of Iron Oxide (Fe3O4/γ-Fe2O3) Nanoparticle Synthesis Routes
Rahman, Asifur; Kang, Seju; McGinnis, Sean; Vikesland, Peter J. (2022)
The synthesis of superparamagnetic iron oxide nanoparticles (FeOx-NPs) has rapidly developed over the past decade due to their wide-ranging applications in research and technology. However, at present there exists very limited knowledge about the environmental impacts of the various input materials and the energy required for different FeOx-NP synthesis approaches. In this study, we used cradle-to-gate life cycle assessment (LCA) to analyze and compare the environmental impacts of FeOx-NPs produced via seven common synthesis routes. Four different functional units (i.e., mass, mean particle size, specific surface area, and saturation magnetization) were used to normalize the environmental impacts and evaluate the corresponding changes. Overall, physical and biological synthesis routes exhibited high environmental impacts due to their higher input material and energy requirements. Interestingly, biological syntheses had the highest environmental impacts due to their reliance on bacterial culture media. All of the chemical synthesis routes had lower environmental impacts except the thermal decomposition method, which had higher environmental impacts due its use of non-polar organic solvents during synthesis. The lab-scale LCA inventory data and analysis presented here addresses the existing data gaps and helps guide future research for FeOx-NP synthesis under industrial conditions. The information generated by this effort aids in the identification of environmentally friendly and sustainable production pathways for FeOx-NPs.
A study on interfacial behaviors of epoxy/graphene oxide derived from pitch-based graphite fibers
Kim, Seong-Hwang; Zhang, Yinhang; Lee, Jong-Hoon; Lee, Seul-Yi; Kim, Yeong-Hun; Rhee, Kyong Yop; Park, Soo-Jin (2021-11-12)
Graphene oxide (GO) is a versatile material with inherent unique properties that can be used in a wide range of applications. GO is produced from graphitic materials including graphite, and its properties can depend on the nature of stacking in the graphene structures. In this study, GO was prepared from pitch-based graphite fibers via the modified Hummer's method and subsequently incorporated into an epoxy matrix to obtain grapheneloaded nanocomposites (EP/GO). Presented experimental results revealed that the addition of 0.6 wt% GO yielded an similar to 110% increase in the fracture toughness. The corresponding fracture energies as well as the flexural strengths and flexural modulus exhibited similar trends to the fracture toughness. The thermophysical properties of the EP/GO, to further demonstrate the reinforcing effectiveness of GO, were also observed. Collectively, these results indicate that GO investigated in the study can be a viable reinforcement candidate to develop next-generation nanocomposites with multifunctional properties.
Detectability of the Critically Endangered Araucaria angustifolia Tree Using Worldview-2 Images, Google Earth Engine and UAV-LiDAR
Saad, Felipe; Biswas, Sumalika; Huang, Qiongyu; Corte, Ana Paula Dalla; Coraiola, Márcio; Macey, Sarah; Carlucci, Marcos Bergmann; Leimgruber, Peter (MDPI, 2021-11-30)
The Brazilian Atlantic Forest is a global biodiversity hotspot and has been extensively mapped using satellite remote sensing. However, past mapping focused on overall forest cover without consideration of keystone plant resources such as Araucaria angustifolia. A. angustifolia is a critically endangered coniferous tree that is essential for supporting overall biodiversity in the Atlantic Forest. A. angustifolia’s distribution has declined dramatically because of overexploitation and land-use changes. Accurate detection and rapid assessments of the distribution and abundance of this species are urgently needed. We compared two approaches for mapping Araucaria angustifolia across two scales (stand vs. individual tree) at three study sites in Brazil. The first approach used Worldview-2 images and Random Forest in Google Earth Engine to detect A. angustifolia at the stand level, with an accuracy of >90% across all three study sites. The second approach relied on object identification using UAV-LiDAR and successfully mapped individual trees (producer’s/user’s accuracy = 94%/64%) at one study site. Both approaches can be employed in tandem to map remaining stands and to determine the exact location of A. angustifolia trees. Each approach has its own strengths and weaknesses, and we discuss their adoptability by managers to inform conservation of A. angustifolia.
Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation
Hendricks-Wenger, Alissa; Aycock, Kenneth N.; Nagai-Singer, Margaret A.; Coutermarsh-Ott, Sheryl; Lorenzo, Melvin F.; Gannon, Jessica; Uh, Kyungjun; Farrell, Kayla; Beitel-White, Natalie; Brock, Rebecca M.; Simon, Alexander; Morrison, Holly A.; Tuohy, Joanne L.; Clark-Deener, Sherrie; Vlaisavljevich, Eli; Davalos, Rafael V.; Lee, Kiho; Allen, Irving C. (Nature Research, 2021-04-07)
New therapies to treat pancreatic cancer are direly needed. However, efficacious interventions lack a strong preclinical model that can recapitulate patients’ anatomy and physiology. Likewise, the availability of human primary malignant tissue for ex vivo studies is limited. These are significant limitations in the biomedical device field. We have developed RAG2/IL2RG deficient pigs using CRISPR/Cas9 as a large animal model with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. In this proof-of-concept study, these pigs were successfully generated using on-demand genetic modifications in embryos, circumventing the need for breeding and husbandry. Human Panc01 cells injected subcutaneously into the ears of RAG2/IL2RG deficient pigs demonstrated 100% engraftment with growth rates similar to those typically observed in mouse models. Histopathology revealed no immune cell infiltration and tumor morphology was highly consistent with the mouse models. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. The ample tumor tissue produced enabled improved accuracy and modeling of the electrical properties of tumor tissue. Together, this suggests that this model will be useful and capable of bridging the gap of translating therapies from the bench to clinical application.

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