UC Davis

Background

Methods

Results

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Trial registration

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.

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.

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.

Polychlorinated biphenyls (PCBs) are neurotoxic hazardous materials that may cause toxicity via the gut-liver-brain axis. This study investigated PCB × microbiome interactions in adult female mice exposed orally to an environmental PCB mixture. Female mice (6-week-old) were exposed daily for 7 weeks to peanut butter containing 0, 0.1, 1, or 6 mg/kg/day of PCBs. Twenty hours after the final exposure, the cecal content was collected to characterize the microbiome composition and predicted function. PCB and its metabolites in feces were analyzed using gas chromatography-tandem mass spectrometry (GC-MS/MS), while cecal content was assessed with liquid chromatography-high resolution mass spectrometry (LC-HRMS). PCB exposure influenced the abundance of microbial taxa and predicted functions within the cecal content. Complex PCB and metabolite mixtures were detected in the gastrointestinal tract. Network analysis revealed associations between specific parent PCBs and metabolites with changes in the abundance of bacteria in the gastrointestinal tract. These findings demonstrate that individual PCBs and their metabolites significantly influence the abundance of specific bacteria in the gastrointestinal tract following oral PCB exposure. These findings inform further research targeting the microbiome to attenuate the adverse health outcomes of PCB exposure.

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.

Walnut orchards in Mediterranean climates are characterized by wet winters that can lead to nitrogen (N) leaching. Cover cropping can help alleviate N losses from leaching, but using cover crops as a N management strategy in orchards requires understanding and quantifying N mineralization and availability throughout the growing season. This study measured total N input, N derived from fixation, and N mineralization rates from cover crop residues across four cool-season cover crop treatments: a clover mixture, a clover-grass mixture, a multiplex mixture, and resident vegetation. We grew cover crops in two consecutive years in a California walnut orchard and measured changes in the N status of orchard soils. By using isotopically labeled cover crop residues, we were able to determine the mineralization rate of cover crop N. We found that the multiplex treatment consistently provided the greatest carbon and N inputs. Moreover, the multiplex treatment also had the most N inputs derived from fixation. Clover and multiplex aboveground residues had the largest N mineralization rates, and the decomposition of these residues on the soil surface appeared to prime N mineralization in the topsoil. In our study, the multiplex treatment offered the greatest overall N benefits, likely due to the overall success of this treatment in establishment and biomass production. Moreover, we found that the non-leguminous species in the multiplex treatment appeared to also utilize and sequester fixed N from the leguminous covers, demonstrating a relatively unexplored benefit of this multiplex cover crop mixture.

The densification and X-ray scattering of mesoporous silica (SBA-15) were measured simultaneously under gigapascal (GPa) pressures. The results are compared to previous work on amorphous silica (aSiO2) and demonstrate the feasibility of measuring the densification of aSiO2 nanomaterials with small angle X-ray scattering (SAXS) in-situ in a diamond anvil cell. Compared to fused silica, the position of the SBA-15 first sharp diffraction peak (FSDP) is 7 times more sensitive to pressure and has a transition in its pressure dependance at a lower pressure (∼2 GPa vs. ∼13 GPa). SBA-15 has two densification regimes, low-density amorphous and high-density amorphous, which have equations of state comparable to low-density amorphous and high-density amorphous fused silica. The transition between these two regimes occurs at a lower pressure than for fused silica (∼1.5 GPa vs. ∼13 GPa). The results suggest that there is no direct relationship between the FSDP position and the aSiO2 density during compression.