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Enhancing Acute Migraine Treatment: Exploring Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for the Nose-to-Brain Route

Migraine has a high prevalence worldwide and is one of the main disabling neurological diseases in individuals under the age of 50. In general, treatment includes the use of oral analgesics or non-steroidal anti-inflammatory drugs (NSAIDs) for mild attacks, and, for moderate or severe attacks, triptans or 5-HT1B/1D receptor agonists. However, the administration of antimigraine drugs in conventional oral pharmaceutical dosage forms is a challenge, since many molecules have difficulty crossing the blood-brain barrier (BBB) to reach the brain, which leads to bioavailability problems. Efforts have been made to find alternative delivery systems and/or routes for antimigraine drugs. In vivo studies have shown that it is possible to administer drugs directly into the brain via the intranasal (IN) or the nose-to-brain route, thus avoiding the need for the molecules to cross the BBB. In this field, the use of lipid nanoparticles, in particular solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), has shown promising results, since they have several advantages for drugs administered via the IN route, including increased absorption and reduced enzymatic degradation, improving bioavailability. Furthermore, SLN and NLC are capable of co-encapsulating drugs, promoting their simultaneous delivery to the site of therapeutic action, which can be a promising approach for the acute migraine treatment. This review highlights the potential of using SLN and NLC to improve the treatment of acute migraine via the nose-to-brain route. First sections describe the pathophysiology and the currently available pharmacological treatment for acute migraine, followed by an outline of the mechanisms underlying the nose-to-brain route. Afterwards, the main features of SLN and NLC and the most recent in vivo studies investigating the use of these nanoparticles for the treatment of acute migraine are presented.

Torres, Joana (ORCID:0000000327276229)

Simulations suggest offshore wind farms modify low-level jets

Abstract. Offshore wind farms are scheduled to be constructed along the East Coast of the US in the coming years. Low-level jets (LLJs) – layers of relatively fast winds at low altitudes – also occur frequently in this region. Because LLJs provide considerable wind resources, it is important to understand how LLJs might change with turbine construction. LLJs also influence moisture and pollution transport; thus, the effects of wind farms on LLJs could also affect the region’s meteorology. In the absence of observations or significant wind farm construction as yet, we compare 1 year of simulations from the Weather Research and Forecasting (WRF) model with and without wind farms incorporated, focusing on locations chosen by their proximity to future wind development areas. We develop and present an algorithm to detect LLJs at each hour of the year at each of these locations. We validate the algorithm to the extent possible by comparing LLJs identified by lidar, constrained to the lowest 200 m, to WRF simulations of these very low LLJs (vLLJs). In the NOW-WAKES simulation data set, we find offshore LLJs in this region occur about 25 % of the time, most frequently at night, in the spring and summer months, in stably stratified conditions, and when a southwesterly wind is blowing. LLJ wind speed maxima range from 10 m s−1 to over 40 m s−1. The altitude of maximum wind speed, or the jet “nose”, is typically 300 m above the surface, above the height of most profiling lidars, although several hours of vLLJs occur in each month in the data set. The diurnal cycle for vLLJs is less pronounced than for all LLJs. Wind farms erode LLJs, as LLJs occur less frequently (19 %–20 % of hours) in the wind farm simulations than in the no-wind-farm (NWF) simulation (25 % of hours). When LLJs do occur in the simulation with wind farms, their noses are higher than in the NWF simulation: the LLJ nose has a mean altitude near 300 m for the NWF jets, but that nose height moves higher in the presence of wind farms, to a mean altitude near 400 m. Rotor region (30–250 m) wind veer is reduced across almost all months of the year in the wind farm simulations, while rotor region wind shear is similar in both simulations.

17 WIND ENERGY

Reticular Structural Diversification of Zirconium Metal–Organic Frameworks Through Angular Ligand Configuration Control

Reticular chemistry offers practical guidelines for enlarging and enriching the arsenal of metal–organic frameworks (MOFs). However, reticular expansion to access mesoporous structures remains challenging due to limitations in achieving precise control over both the size and configuration during building units’ extension. Herein, we combine ligand isomerization and functionalization strategies to regulate the ligand configuration by systematically replacing aryl C–H groups with N atoms, resulting in angular dicarboxylate ligands with various symmetries. The assembly between a 4,4′-(pyridine-2,6-diyl)dibenzoic acid ligand (1N, C 2 symmetry) and 12-connected Zr 6 cluster leads to the formation of a pseudo ftw topology framework (NU-2611), where one pair of nose-to-nose 1N ligands resembles a tetra-topic ligand. When a 6,6′-(1,3-phenylene)dinicotinic acid ligand (2N, C S symmetry) was used, another pseudo ftw network NU-2612 was obtained with a 2-fold framework interpenetration. Interestingly, the planar [2,2′:6′,2″-terpyridine]-5,5″-dicarboxylic acid ligand (3N, C 2V symmetry) yielded an intriguing mesoporous Zr-MOF with kag topology. NU-2613 represents the first example of kag Zr-MOF designed to include large, well-defined mesopores. The diversity of these MOFs was further enhanced through post-synthetic metalation of linkers. Particularly, metalation of the chelating 3N ligand with Fe 3+ in NU-2613 enables efficient catalytic transformation within the functionalized channels. This work contributes insight into the reticular expansion of Zr-MOFs by finely-tuning the ligand planarity, advancing the structure diversification of mesoporous frameworks for specific applications.

Cluster chemistry

Multiparameter optical fiber sensing for energy infrastructure through nanoscale light–matter interactions: From hardware to software, science to commercial opportunities

Monitoring of energy infrastructure through robust yet economical sensing platforms is becoming an area of increased importance, with ubiquitous applications including the electrical grid, natural gas and oil transportation pipelines, H2 infrastructure (storage and transportation), carbon storage, power generation, and subsurface environments. Plasmonic and functional nanomaterial enabled fiber optic sensors show excellent promise for a wide range of sensing applications due to their versatility to be engineered for specific analytes of interest while retaining inherent advantages of the optical fiber sensor platform. Through the design of novel sensing layers, the optical transduction mechanism and wavelength dependence can also be tailored for ease of integration with low-cost interrogation systems enabling an inexpensive yet highly functional optical fiber sensing platform. In addition, recent advances in artificial intelligence and machine learning theoretical methods have been leveraged to simultaneously extract multiple parameters through multi-wavelength interrogation such that unique wavelengths can also serve as unique sensing elements, analogous to electronic nose sensor technologies. The concept of an optical fiber based “photonic nose” via multiple interrogation wavelengths and/or sensor nodes offers a compelling platform technology to realize multiparameter speciation of chemical analytes within complex gas mixtures. In this Perspective, we further generalize the notion of multiparameter sensing through the novel “photonic nervous system” concept based upon low-cost, functionalized optical fiber sensor probes monitoring a variety of distinct analyte classes (physical, chemical, electromagnetic, etc.) simultaneously to provide broad situational awareness via integrated sensors.

Su, Yang-Duan (ORCID:0000000214820902)

Naphthalene-DNA Adduct Formation in a Lung Airway Explant Model: The Role of Bioactivation and Naphthalene Metabolites

Humans are widely exposed to naphthalene. Once inhaled or ingested, naphthalene is metabolized by cytochrome P450 and other enzymes to form toxic metabolites known to harm lung epithelial cells. Naphthalene metabolites circulate in the blood. Chronic naphthalene inhalation promotes lesions in the epithelium of the mouse lung and rat nose. Oral naphthalene exposure leads to DNA adduct formation in mouse lung, but the contributions of different enzymatic pathways and the metabolites they generate are not fully understood. This study explores the influence of naphthalene metabolites on DNA adduct formation in the lungs of two species (mice and primates). To isolate the lung response, conducting airway explants containing Club cells, a target for pulmonary naphthalene toxicity, were microdissected from live lung tissue and incubated with 14 C-naphthalene or its metabolites: 14 C-1,2-naphthoquinone or 14 C-naphthalene-1,2-dihydrodiol. Explants were incubated for 1 h, then processed immediately (T1), or were transferred to clean media for the remainder of the 24 h (T24), to monitor 14 C in DNA over time. Accelerator mass spectrometry analysis revealed the formation of DNA adducts by all three radiolabeled compounds by T24. Our results support the notion that P450 enzymes of the Cyp2abfgs subfamily contribute to naphthalene-induced DNA adduct formation (approximately 4-fold reduction in male mice lacking the Cyp2abfgs genes, P < 0.01). The finding that naphthalene-1,2-dihydrodiol, a stable metabolite, formed DNA adducts (102–117 adducts/10 8 nucleotides) at 24 h following addition to the culture media validates the concern that circulating naphthalene metabolites can contribute to DNA adduct formation in the lung. DNA adducts persisted to 24 h after exposure in both mouse and primate airways and at comparable levels between species (77.8 vs 129 adducts/10 8 nucleotides, respectively). Together, these results support the importance of a potential genotoxic mechanism of naphthalene and its metabolites in vivo in both mice and nonhuman primates, and possibly also in humans.

Biological and medical sciences

Thermally unstable roosts influence winter torpor patterns in a threatened bat species

Abstract Many hibernating bats in thermally stable, subterranean roosts have experienced precipitous declines from white-nose syndrome (WNS). However, some WNS-affected species also use thermally unstable roosts during winter that may impact their torpor patterns and WNS susceptibility. From November to March 2017–19, we used temperature-sensitive transmitters to document winter torpor patterns of tricolored bats (Perimyotis subflavus) using thermally unstable roosts in the upper Coastal Plain of South Carolina. Daily mean roost temperature was 12.9 ± 4.9°C SD in bridges and 11.0 ± 4.6°C in accessible cavities with daily fluctuations of 4.8 ± 2°C in bridges and 4.0 ± 1.9°C in accessible cavities and maximum fluctuations of 13.8 and 10.5°C, respectively. Mean torpor bout duration was 2.7 ± 2.8 days and was negatively related to ambient temperature and positively related to precipitation. Bats maintained non-random arousal patterns focused near dusk and were active on 33.6% of tracked days. Fifty-one percent of arousals contained passive rewarming. Normothermic bout duration, general activity and activity away from the roost were positively related to ambient temperature, and activity away from the roost was negatively related to barometric pressure. Our results suggest ambient weather conditions influence winter torpor patterns of tricolored bats using thermally unstable roosts. Short torpor bout durations and potential nighttime foraging during winter by tricolored bats in thermally unstable roosts contrasts with behaviors of tricolored bats in thermally stable roosts. Therefore, tricolored bat using thermally unstable roosts may be less susceptible to WNS. More broadly, these results highlight the importance of understanding the effect of roost thermal stability on winter torpor patterns and the physiological flexibility of broadly distributed hibernating species.

Biodiversity & Conservation

Survival and Age at Maturity in Head-Started Wood Turtles ( Glyptemys insculpta ) with Implications for Population Recovery

A small relict population of Glyptemys insculpta (Wood Turtle) was discovered on a protected area in New Jersey in 2006. Marking and radio-tracking of the old founder individuals helped to determine movement patterns and habitat use. Monitoring of nesting females revealed that nesting habitat and nest success was limited due to invasive plants, human landscape alteration, and Procyon lotor (Raccoon) depredation. We initiated habitat restoration including creation of protected nesting areas, mowing in winter, invasive plant removal, and adjacent landowner education. Here, we direct-released hatchlings from protected nests from 2006 to 2015, yet only a few were detected in subsequent years. Between 2011 and 2023, some or all of each hatchling cohort were head-started indoors at a high school for 9 months. We have continuously radio-tracked all head-starts from the 2011 cohort and portions of the 2012–2014 cohorts. Head-started turtles found their own food, established home ranges, and hibernated communally with founder adults. Subsidized Raccoons, mowers, automobiles, and flooding events—all human-instigated—were the causes of mortality. The first males and first females from the 2011 head-start cohort reached maturity in 2017 and 2019, respectively, at ages 6–8, younger than expected by 4–5 years. Successful reproduction by head-starts was confirmed by viable hatchlings produced in 2019, 2020, and 2023. Head-starting can pull a relict population out of the nose-dive to extirpation when used in conjunction with habitat-restoration practices, but it must be conducted with persistence and continuity over at least the number of years it takes for the earliest cohorts to reach maturity and begin producing offspring of their own.

59 BASIC BIOLOGICAL SCIENCES

Measurement of the Cathode Recess

The 113 MHz SRF gun for the coherent electron cooling is designed with adjustable position of the cathode vs. the nose piece of the quarter wave gun as it is shown in Fig. 1. By changing the cathode position we modify the profile of the accelerating field. By retracting the cathode, we reduce the surface field but increase the focusing component as it shown in Fig. 2. The optimal position is defined by the beam dynamics and is found based on simulations.

43 PARTICLE ACCELERATORS

Implementation of a High-Mach Integral Boundary Layer Method for Arbitrary Streamlined Body Geometry

The Momentum-Energy Integral Technique (MEIT) is an integral boundary layer method for the high-Mach flow regime used to approximate heat transfer and viscous force quantities of interest along streamlines of an inviscid flow solution on the surface of a flight vehicle. This method allows rapid mid-fidelity estimation of these quantities which would otherwise require a much more expensive viscous flow solution to produce. Integral boundary layer methods like MEIT have been around for decades, though usually only formulated for simple geometries such as 2-dimensional wing shapes or axi-symmetric nose shapes. The implementation discussed herein has been generalized to apply to any 3-dimensional streamlined body geometry through correct treatment of the curvilinear axes (streamline attached) momentum and energy entrainment terms, and handling of arbitrary stagnation region geometry. This implementation is provided as a software package for the Python environment, along with readers for common inviscid flow solution providers such as NASA’s CART3D flow solver.

97 MATHEMATICS AND COMPUTING

Sweden surpasses the UNAIDS 95-95-95 target: estimating HIV-1 incidence, 2003 to 2022

Background: Sweden reached the UNAIDS 90–90–90 target in 2015. It is important to reassess the HIV epi- demiological situation due to ever-changing migration patterns, the roll-out of PrEP and the impact of the COVID-19 pandemic. Aim: We aimed to assess the pro- gress towards the UNAIDS 95–95–95 targets in Sweden by estimating the proportion of undiagnosed people with HIV (PWHIV) and HIV incidence trends. Methods: We used routine laboratory data to inform a biomarker model of time since infection. When available, we used previous negative test dates, arrival dates for PWHIV from abroad and transmission modes to inform our incidence model. We also used data collected from the Swedish InfCareHIV register on antiretroviral therapy (ART). Results: The yearly incidence of HIV in Sweden decreased after 2014. In part, this was because the fraction of undiagnosed PWHIV had decreased almost twofold since 2006. After 2015, three of four PWHIV in Sweden were diagnosed within 1.9 and 3.2 years after infection among men who have sex with men and in heterosexual groups, respectively. While 80% of new PWHIV in Sweden acquired HIV before immigration, they make up 50% of the current PWHIV in Sweden. By 2022, 96% of all PWHIV in Sweden had been diag- nosed, and 99% of them were on ART, with 98% virally suppressed. Conclusions: By 2022, about half of all PWHIV in Sweden acquired HIV abroad. Using our new biomarker model, we assess that Sweden has reached the UNAIDS goal at 96–99–98.

60 APPLIED LIFE SCIENCES