UC Davis

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A clinical need exists for more effective intravitreal (IVT) drug delivery systems (DDS). This study tested the hypothesis that a novel biodegradable, injectable microsphere-hydrogel drug delivery system loaded with aflibercept (aflibercept-DDS) would exhibit long-term safety and biocompatibility in a non-human primate (NHP) model. We generated aflibercept-loaded poly (lactic-co-glycolic acid) microparticles with a modified double emulsion technique then embedded them into a biodegradable, thermo-responsive poly (ethylene glycol)-co-(L-lactic-acid) diacrylate/N-isopropylacrylamide hydrogel. Aflibercept-DDS (50 µL, 15 µg) was injected into the right eye of 23 healthy rhesus macaques. A complete ophthalmic examination, intraocular pressure (IOP), corneal pachymetry, specular microscopy, A-scan biometry, streak retinoscopy, spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), and electroretinography (ERG) were performed monthly. Globes from 7 NHPs were histologically examined. Aflibercept-DDS was visualized in the vitreous up to 9 months post-IVT injection, slightly impeding fundoscopy in 4 of 23 eyes; no other consistent abnormalities were appreciated during ophthalmic examination. The IOP and total retinal thickness remained normal in all animals over all timepoints. Central corneal thickness, endothelial cell density, axial globe length, and refractive error did not significantly differ from baseline. Scotopic mixed rod-cone implicit times and amplitudes along with photopic cone response implicit times and amplitudes did not significantly differ from control values. No retinal or choroidal vascular abnormalities were detected with FA and normal retinal architecture was preserved using SD-OCT. Intravitreal injection of a biodegradable aflibercept-DDS was safe and well tolerated in NHPs up to 24 months.

Osteosarcoma is an aggressive primary malignant bone tumor associated with high rates of metastasis and poor 5-year survival rates with limited improvements in approximately 40 years. Standard multimodality treatment includes chemotherapy and surgery, and survival rates have remained stagnant. Overall, response rates to immunotherapy like immune checkpoint inhibitors have been disappointing in osteosarcoma despite exciting results in other epithelial tumor types. The poor response of osteosarcoma to current immunotherapies is multifactorial, but a key observation is that the tumor microenvironment in osteosarcoma is profoundly immunosuppressive, and increasing evidence suggests a significant role of suppressive myeloid cells in tumor progression and immune evasion, particularly by myeloid-derived suppressor cells. Targeting suppressive myeloid cells via novel agents are attractive strategies to develop novel immunotherapies for osteosarcoma, and combination strategies will likely be important for durable responses. In this review, we will examine mechanisms of the immunosuppressive microenvironment, highlight pre-clinical and clinical data of combination strategies including colony-stimulating factor 1 (CSF-1) receptor, phosphoinositide 3-kinase (PI3K), CXCR4, and checkpoint inhibition, as well as the role of canine models in elucidating myeloid cells as targets in osteosarcoma immunotherapy.

The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for drug dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance, which could be influenced by differences in microbiota, and yet no study design has capitalized upon this natural variation. We leveraged natural behavioral variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained sustained antinociception. Mice that did not develop tolerance maintained a higher capacity for production of the short-chain fatty acid (SCFA) butyrate known to bolster intestinal barriers and promote neuronal homeostasis. Both fecal microbial transplantation (FMT) from donor mice that did not develop tolerance and dietary butyrate supplementation significantly reduced the development of tolerance independently of suppression of systemic inflammation. These findings could inform immediate therapies to extend the analgesic efficacy of opioids.

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Cement production is a large global industry that is a significant source of carbon dioxide (CO2) emissions, from both energy-derived and process-derived sources. Cement is crucial for concrete, the most widely used building material. There are growing pushes for policies that encourage cement production with net-zero greenhouse gas emissions. Effective policymaking requires understanding the barriers to adoption of emission-lowering strategies, the existing policy framework, and potential regulations for emission reduction. In this work, we examine these parameters within the context of California’s recent net-zero emissions cement bill, Senate Bill 596, focusing on six key decarbonization strategies. We highlight key barriers for these mechanisms and policy strategies that could support a transition to lower emissions. Some crucial actions are public procurement and replacement of prescriptive design codes with performance-based approaches to create a marketplace for novel cements; refine models and conduct pilot projects to study novel cement or mixture performance, durability and costs; and increase awareness with education and communication campaigns directed at stakeholders. Policy actions can be adopted and adapted in other regions that will design net-zero emissions policies.

The 2020 Mw 6.4 Petrinja, Croatia, earthquake triggered widespread liquefaction along the Kupa, Glina, and Sava rivers. The locations of liquefaction ejecta and lateral spreading were identified through a combination of field reconnaissance and interrogation of aerial photographs. Superimposing those locations on the regional geologic map revealed the liquefaction vulnerability of Holocene terrace and flood deposits, Holocene deluvium-proluvium, and Pleistocene loess deposits. Liquefaction caused damage to the land and structures, with ejecta observed both near and far from residential structures. In the free field, the ejection of silty and sandy soil accompanied the extensive ground fracturing. At residential properties, ejecta led to differential settlement, cracks in foundations, walls, and floors, and contamination of water wells. Lateral spreading resulted in the formation of ground and building cracks, house sliding and tilting, pipe breakage, and pavement damage. This article documents these observations of liquefaction and draws conclusions regarding the patterns of liquefaction observed in this earthquake. These observations will be a valuable addition to liquefaction triggering databases as there are relatively few earthquakes with magnitudes less than 6.5 that triggered extensive liquefaction, and they provide additional case histories of liquefaction in Pleistocene deposits.

Global groundwater depletion is a pressing issue, particularly in regions dependent on groundwater for agriculture. Agricultural Managed Aquifer Recharge (Ag-MAR), where farm fields are used as spreading grounds for flood water, is a promising strategy to replenish groundwater, but it raises concerns about pesticide leaching into aquifers, posing risks to both drinking water quality and ecosystems. This study employs a physically based unsaturated flow model, a Bayesian probabilistic approach and novel towed transient electromagnetic (tTEM) data to determine the fate and transport, especially the maximum transport depths (MTDs) of four pesticide residues (Imidacloprid, Thiamethoxam, Chlorantraniliprole, and Methoxyfenozide) in three 70-m-thick unsaturated zones (P1, P2, P3) of California's Central Valley alluvial aquifer. The results show that Ag-MAR significantly increased MTDs across all profiles for all pesticides and with higher variability in pesticide transport depths compared to the natural rainfall scenario. Profile P2, with the highest sand content exhibited the deepest MTDs under Ag-MAR, indicating a strong influence of soil texture on pesticide transport. While natural capillary barriers at the depth of 2.5-20 m impede water flow under natural rainfall conditions, the high-pressure infiltration during Ag-MAR overcomes these barriers, leading to deeper water and pesticide movement. Among various evaluated pesticides, Methoxyfenozide exhibited the smallest absolute MTDs but the largest relative increases in MTDs (RMTDs) under Ag-MAR due to its persistence and low mobility, posing a higher risk of deep transport during intensive recharge events. In contrast, Thiamethoxam showed the largest MTDs under both scenarios but smaller RMTDs due to its high mobility, suggesting a more consistent transport behavior regardless of recharge practices. The findings highlight the importance of understanding both site-specific and pesticide-specific behaviors to mitigate groundwater contamination risks during large water applications.

Methods to sequester and store atmospheric CO2 are critical to combat climate change. Alkaline-rich bioashes are potential carbon fixing materials. This work investigates potential co-benefits from mineralizing carbon in biomass ashes and partially replacing high embodied greenhouse gas (GHG) Portland cement (PC) in cement-based materials with these ashes. Specifically, rice hull ash (RHA), wheat straw ash (WSA), and sugarcane bagasse ash (SBA) were treated to mineralize carbon, and their experimental carbon content was compared to modeled potential carbonation. To understand changes in the cement-based storage materials, mortars made with CO2-treated WSA and RHA were experimentally compared to PC-only mortars and mortars made with ashes without prior CO2 treatment. Life cycle assessment methodology was applied to understand potential reductions in GHG emissions. The modeled carbonation was ∼18 g-CO2/kg-RHA and ∼180 g-CO2/kg-WSA. Ashes oxidized at 500 °C had the largest measured carbon content (5.4 g-carbon/kg-RHA and 35.3 g-carbon/kg-WSA). This carbon appeared to be predominantly residual from the biomass. Isothermal calorimetry showed RHA-PC pastes had similar heat of hydration to PC-pastes, while WSA-PC pastes exhibited an early (at ∼1.5 min) endothermic dip. Mortars with 5 % and 15 % RHA replacement had 1–12 % higher compressive strength at 28 days than PC-only mortars, and milled WSA mortars with 5 % replacement had 3 % higher strength. A loss in strength was noted for the milled 15 % WSA, the CO2-treated 5 %, and the 15 % WSA mortars. Modeled reductions in GHG emissions from CO2-treated ashes were, however, marginal (<1 %) relative to the untreated ashes.