Melodia: A Python Library for Protein Structure Analysis.

SUMMARY: Analysing protein structure similarities is an important step in protein engineering and drug discovery. Methodologies that are more advanced than simple RMSD are available but often require extensive mathematical or computational knowledge for implementation. Grouping and optimising such tools in an efficient open-source library increases accessibility and encourages the adoption of more advanced metrics. Melodia is a Python library with a complete set of components devised for describing, comparing and analysing the shape of protein structures using differential geometry of three-dimensional curves and knot theory. It can generate robust geometric descriptors for thousands of shapes in just a few minutes. Those descriptors are more sensitive to structural feature variation than RMSD deviation. Melodia also incorporates sequence structural annotation and three-dimensional visualisations. AVAILABILITY AND IMPLEMENTATION: Melodia is an open-source Python library freely available on https://github.com/rwmontalvao/Melodia_py, along with interactive Jupyter Notebook tutorials. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Scaffold-based 3D cell culture models in cancer research.

Three-dimensional (3D) cell cultures have emerged as valuable tools in cancer research, offering significant advantages over traditional two-dimensional (2D) cell culture systems. In 3D cell cultures, cancer cells are grown in an environment that more closely mimics the 3D architecture and complexity of in vivo tumors. This approach has revolutionized cancer research by providing a more accurate representation of the tumor microenvironment (TME) and enabling the study of tumor behavior and response to therapies in a more physiologically relevant context. One of the key benefits of 3D cell culture in cancer research is the ability to recapitulate the complex interactions between cancer cells and their surrounding stroma. Tumors consist not only of cancer cells but also various other cell types, including stromal cells, immune cells, and blood vessels. These models bridge traditional 2D cell cultures and animal models, offering a cost-effective, scalable, and ethical alternative for preclinical research. As the field advances, 3D cell cultures are poised to play a pivotal role in understanding cancer biology and accelerating the development of effective anticancer therapies. This review article highlights the key advantages of 3D cell cultures, progress in the most common scaffold-based culturing techniques, pertinent literature on their applications in cancer research, and the ongoing challenges.

Addressing emerging issues in entomology: 2023 student debates.

The Entomological Society of America (ESA) Student Debates is an annual student competition at the ESA Annual Meeting organized by Student Debates Subcommittee (SDS) members of the ESA Student Affairs Committee. In conjunction with the 2023 ESA Annual Meeting theme, 'Insects and influence: Advancing entomology's impact on people and policy', the theme of this year's student debate was 'Addressing emerging issues in entomology'. With the aid of ESA membership, the SDS selected the following debate topics: (1) Should disclosure of artificial intelligence large language models in scientific writing always be required? and (2) Is it more important to prioritize honey bee or native pollinator health for long-term food security within North America? Four student teams from across the nation, composed of 3-5 student members and a professional advisor, were assigned a topic and stance. Over the course of 5 months, all team members researched and prepared for their assigned topic before debating live with an opposing team at the 2023 ESA Annual Meeting in National Harbor, Maryland. SDS members additionally prepared and presented introductions for each debate topic to provide unbiased backgrounds to the judges and audience for context in assessing teams' arguments. The result was an engaging discussion between our teams, judges, and audience members on emerging issues facing entomology and its impact on people and policy, such as scientific communication and food security, that brought attention to the complexities involved when debating topics concerning insects and influence.

Transferrin-Targeted Liposomes in Glioblastoma Therapy: A Review.

Glioblastoma (GBM) is a highly aggressive brain tumor, and its treatment is further complicated by the high selectivity of the blood-brain barrier (BBB). The scientific community is urgently seeking innovative and effective therapeutic solutions. Liposomes are a promising new tool that has shown potential in addressing the limitations of chemotherapy, such as poor bioavailability and toxicity to healthy cells. However, passive targeting strategies based solely on the physicochemical properties of liposomes have proven ineffective due to a lack of tissue specificity. Accordingly, the upregulation of transferrin receptors (TfRs) in brain tissue has led to the development of TfR-targeted anticancer therapeutics. Currently, one of the most widely adopted methods for improving drug delivery in the treatment of GBM and other neurological disorders is the utilization of active targeting strategies that specifically target this receptor. In this review, we discuss the role of Tf-conjugated liposomes in GBM therapy and present some recent studies investigating the drug delivery efficiency of Tf-liposomes; in addition, we address some challenges currently facing this approach to treatment and present some potential improvement possibilities.

Locally abundant, endangered Mariana swiftlets impact the abundance, behavior, and body condition of an invasive predator.

Invasive predators are known to have negative consumptive and non-consumptive effects on native species, but few examples show how the abundance of native prey may influence an established invasive predator. We compared invasive brown treesnakes (Boiga irregularis; BTS) found in caves occupied by endangered Mariana swiftlets (Aerodramus bartschi) to snakes found in nearby forests and caves without birds to quantify how the abundance of native avian prey impacts BTS abundance and behavior on Guam. From 2011 to 2017 we removed 151 BTS in caves occupied by swiftlets and never observed BTS in caves without birds. Notable locations included snakes foraging near swiftlets and in holes that allowed cave access and escape from capture. Of 43 BTS with gut contents, 27 (63%) contained swiftlets. BTS in swiftlet-occupied caves had greater fat mass compared to forests, indicating access to swiftlets may increase body condition and promote reproduction. Number of ovarian follicles was significantly greater in female snakes from swiftlet-occupied caves compared to those from ravine, but not limestone forests; evidence of male BTS being more capable of reproduction was limited (i.e., fewer non-discernible but not significantly larger testes in snakes from caves). Assuming other limiting factors are considered, altering the functional response of predators through the modification of caves or interdiction lures to exclude or hinder the largest BTS could bolster swiftlet populations by increasing nesting refugia in currently-occupied caves and facilitate recolonization of historical caves.

In vitro comparison of treatments and commercially available solutions on mortality of Angiostrongylus cantonensis third-stage larvae.

On Hawai'i Island, an increase in human neuroangiostrongyliasis cases has been primarily associated with the accidental ingestion of Angiostrongylus cantonensis L3 in snails or slugs, or potentially, from larvae left behind in the slug's slime or feces. We evaluated more than 40 different treatments in vitro for their ability to kill A. cantonensis larvae with the goal of identifying a safe and effective fruit and vegetable wash in order to reduce the risk of exposure. Our evaluation of treatment lethality was carried out in two phases; initially using motility as an indicator of larval survival after treatment, followed by the development and application of a propidium iodide staining assay to document larval mortality. Treatments tested included common household products, consumer vegetable washes and agricultural crop washes. We found minimal larvicidal efficacy among consumer-grade fruit and vegetable washes, nor among botanical extracts such as those from ginger or garlic, nor acid solutions such as vinegar. Alkaline solutions, on the other hand, as well as oxidizers such as bleach and chlorine dioxide, did show larvicidal potential. Surfactants, a frequent ingredient in detergents that lowers surface tension, had variable results, but dodecylbenzene sulfonic acid as a 70% w/w solution in 2-propanol was very effective, both in terms of the speed and the thoroughness with which it killed A. cantonensis L3 nematodes. Thus, our results suggest promising directions for future investigation.

Hotspots API: A Python Package for the Detection of Small Molecule Binding Hotspots and Application to Structure-Based Drug Design.

Methods that survey protein surfaces for binding hotspots can help to evaluate target tractability and guide exploration of potential ligand binding regions. Fragment Hotspot Maps builds upon interaction data mined from the CSD (Cambridge Structural Database) and exploits the idea of identifying hotspots using small chemical fragments, which is now widely used to design new drug leads. Prior to this publication, Fragment Hotspot Maps was only publicly available through a web application. To increase the accessibility of this algorithm we present the Hotspots API (application programming interface), a toolkit that offers programmatic access to the core Fragment Hotspot Maps algorithm, thereby facilitating the interpretation and application of the analysis. To demonstrate the package's utility, we present a workflow which automatically derives protein hydrogen-bond constraints for molecular docking with GOLD. The Hotspots API is available from https://github.com/prcurran/hotspots under the MIT license and is dependent upon the commercial CSD Python API.

Drop on a bent fibre.

Inspired by the huge droplets attached on cypress tree leaf tips after rain, we find that a bent fibre can hold significantly more water in the corner than a horizontally placed fibre (typically up to three times or more). The maximum volume of the liquid that can be trapped is remarkably affected by the bending angle of the fibre and surface tension of the liquid. We experimentally find the optimal included angle (∼36°) that holds the most water. Analytical and semi-empirical models are developed to explain these counter-intuitive experimental observations and predict the optimal angle. The data and models could be useful for designing microfluidic and fog harvesting devices.

Brown tree snake (Boiga irregularis) population density and carcass locations following exposure to acetaminophen.

Mass aerial delivery of dead mouse baits treated with acetaminophen has been evaluated as a means to reduce brown tree snake (Boiga irregularis) populations over large areas, increasing the likelihood of wide-scale eradication on Guam. Given the high density of snakes in some areas of their invasive range, eradication efforts could result in a resource pulse that may influence food web dynamics and the indirect transport of acetaminophen among trophic levels. We evaluated abundance, habitat type, and snake size (i.e., age) within two study sites on Guam, a secondary limestone forest (upland) and an abandoned coconut plantation (coastal), to determine how experimentally dosing snakes with acetaminophen is likely to influence carrion availability. We found snakes trapped in 3.24 ha plots occurred in greater abundance (population size = 72.5 snakes; SE = 8.8) and were significantly larger (978.6 mm, SE = 14.9) in the coastal than in the upland site (population size = 26.9, SE = 21.5; length = 903.0 mm, SE = 15.9). Despite these differences, carcasses of snakes that died after consuming acetaminophen-laced mice (80 mg) were recovered in consistent locations between sites, with 92 % located on the ground, 4 % in trees, and 4 % found in rock cavities at both sites. Given that most snakes were found on the ground rather than in the tree canopy, our results suggest that many poisoned snake carcasses will be accessible to a wide range of potential scavengers, possibly influencing food web dynamics and potentially contributing to indirect toxicant transfer within affected ecosystems.

Kinetics of Ultrasonic Drug Delivery from Targeted Micelles.

To minimize the adverse side effects of conventional chemotherapy, a targeted micellar drug carrier was investigated that retains hydrophobic drugs in its core and then releases the drug via ultrasonic activation. This paper compares the percent drug release from folated versus non-folated micelles by insonation at 70 kHz and different acoustic power densities. The encapsulated drug is Doxoru- bicin (Dox). A physical model of zero-order release with first-order re-encapsulation was used to fit the experimental kinetic data. Additionally, the acoustic activation power density and Gibbs free energy were introduced and calculated for folated and non-targeted micelles. The data suggests an important role of inertial cavitation in drug release and the presence of a power density threshold for inertial cavitation.

Polyphony: superposition independent methods for ensemble-based drug discovery.

BACKGROUND: Structure-based drug design is an iterative process, following cycles of structural biology, computer-aided design, synthetic chemistry and bioassay. In favorable circumstances, this process can lead to the structures of hundreds of protein-ligand crystal structures. In addition, molecular dynamics simulations are increasingly being used to further explore the conformational landscape of these complexes. Currently, methods capable of the analysis of ensembles of crystal structures and MD trajectories are limited and usually rely upon least squares superposition of coordinates. RESULTS: Novel methodologies are described for the analysis of multiple structures of a protein. Statistical approaches that rely upon residue equivalence, but not superposition, are developed. Tasks that can be performed include the identification of hinge regions, allosteric conformational changes and transient binding sites. The approaches are tested on crystal structures of CDK2 and other CMGC protein kinases and a simulation of p38α. Known interaction - conformational change relationships are highlighted but also new ones are revealed. A transient but druggable allosteric pocket in CDK2 is predicted to occur under the CMGC insert. Furthermore, an evolutionarily-conserved conformational link from the location of this pocket, via the αEF-αF loop, to phosphorylation sites on the activation loop is discovered. CONCLUSIONS: New methodologies are described and validated for the superimposition independent conformational analysis of large collections of structures or simulation snapshots of the same protein. The methodologies are encoded in a Python package called Polyphony, which is released as open source to accompany this paper [http://wrpitt.bitbucket.org/polyphony/].

Prevention and removal of lipid deposits by lens care solutions and rubbing.

PURPOSE: Despite the prevalence of silicone hydrogel (SiHy) contact lenses, there are relatively few studies that evaluate the efficacy of multipurpose lens care solutions (MPSs) in reducing lipid deposition on these lenses and the effect of rubbing on the removal. Therefore, we used an in vitro soaking and rubbing model to compare the effectiveness of borate buffered saline (BBS) and two commercial MPSs, PureMoist and Biotrue, in preventing sorption of representative polar and nonpolar lipids. METHODS: Radiolabeled cholesterol (CH) and dipalmitoylphosphatidylcholine (DPPC) were sorbed on two SiHy lenses (senofilcon A and balafilcon A) from an artificial tear fluid. Deposition and removal were evaluated by quantitative solvent extraction and scintillation counting. RESULTS: The efficiencies of the MPSs in reducing lipid deposition are somewhat dependent on lens material. Both DPPC and CH sorption on senofilcon A are greater when lenses are preconditioned in BBS compared with preconditioning in either MPS (p < 0.05). However, neither MPS affects lipid sorption on balafilcon A lenses (p > 0.05). As for removal of presorbed lipids, neither PureMoist, Biotrue, nor BBS removed CH in the absence of rubbing. When a simulated rubbing protocol was used, minimal but detectible CH was removed (p < 0.05) from senofilcon A and balafilcon A lenses (likely only from the lens surface). These commercial solutions were not substantially better than BBS in removing DPPC, with or without rubbing (p > 0.05). CONCLUSIONS: These data suggest that MPSs do not appreciably alter lipid sorption. Rubbing lenses removes a small amount of sorbed lipids. Yet, we recommend that MPSs be used as they may disinfect SiHy lenses and may clean their surfaces of large particles.

Ultrasound sensitive eLiposomes containing doxorubicin for drug targeting therapy.

This study describes a novel nanocarrier of emulsion liposomes (eLiposomes) composed of a perfluoropentane nanodroplet within the aqueous interior of a DPPC liposome, along with the anticancer drug doxorubicin (Dox). The eLiposome containing Dox (eLipoDox) displayed good release of Dox upon insonation with low intensity ultrasound at 20-kHz, 1.0-MHz and 3.0-MHz. More release occurs in vitro at 20-kHz than at the higher frequencies. Controlled delivery was demonstrated by applying ultrasound (US) to HeLa tumor cells in vitro. The confocal images of Dox release to cells indicate that eLipoDox is an effective carrier of chemotherapeutic agent, and releases Dox to the cell cytosol upon insonation. This novel drug delivery system promises to provide more effective US therapy and tumor treatment and has the potential to reduce the side effects of cardiotoxicity caused by Dox. FROM THE CLINICAL EDITOR: In this paper, an ultrasound-sensitive doxorubicine-carrying nanoliposome delivery system is reported. Doxorubicin release as a result of ultrasound exposure is clearly demonstrated, paving the way to potential clinical applications with the aim of reducing the systemic toxicity and enhanced local delivery of this compound.

Potential citric acid exposure and toxicity to Hawaiian hoary bats (Lasiurus cinereus semotus) associated with Eleutherodactylus frog control.

We examined potential exposure of Hawaiian hoary bats (Lasiurus cinereus semotus) to citric acid, a minimum risk pesticide registered for control of invasive Eleutherodactylus frog populations. Hoary bats are nocturnal insectivores that roost solitarily in foliage, federally listed as endangered, and are endemic to Hawaii. Oral ingestion during grooming of contaminated fur appears to be the principal route by which these bats might be exposed to citric acid. We made assessments of oral toxicity, citric acid consumption, retention of material on fur, and grooming using big brown bats (Eptesicus fuscus) as a surrogate species. We evaluated both ground application and aerial application of 16 % solutions of citric acid during frog control operations. Absorbent bat effigies exposed to ground and aerial operational spray applications retained means of 1.54 and 0.02 g, respectively, of dry citric acid, although retention by the effigies was much higher than bat carcasses drenched in citric acid solutions. A high dose delivered orally (2,811 mg/kg) was toxic to the big brown bats and emesis occurred in 1 bat dosed as low as the 759 mg/kg level. No effect was observed with the lower doses examined (≤ 542 mg/kg). Bats sprayed with 5 ml of 16 % (w/w) citric acid solution showed no evidence of intoxication. In field situations, it is unlikely that bats would be sprayed directly or ingest much citric acid retained by fur. Based on our observations, we believe Hawaiian hoary bats to be at very low risk from harmful exposure to a toxic dose of citric acid during frog control operations.

Encapsulation and release of calcein from herceptin-conjugated eLiposomes.

Achieving an optimal therapeutic level is crucial in effectively eradicating cancer cells during treatment. However, conventional chemotherapy-associated systemic administration of anticancer agents leads to many side effects. To achieve the desired control over the target site, active targeting of HER2-positive breast cancer cells can be achieved by conjugating liposomal vesicles with Human Epidermal growth factor Receptor 2 (HER2) and inducing release of the encapsulated drug using ultrasound. To further enhance the delivery efficiency, nanoemulsion droplets exhibiting responsiveness to low-frequency ultrasound are encapsulated within these lipid vesicles. In this study, we prepared four different liposomal formulations, namely pegylated liposomes, emulsion liposomes (eLiposomes), HER-conjugated liposomes, and HER-conjugated eLiposomes, each loaded with calcein and subjected to a thorough characterization process. Their sizes, phospholipid concentration, and amount of antibody conjugation were compared and analyzed. Cryogenic transmission electron microscopy was used to confirm the encapsulation of nanoemulsion droplets within the liposomes. The drug-releasing performance of Herceptin-conjugated eLiposomes was found to surpass that of other liposomal formulations with a notably higher calcein release and established it as a highly effective nanocarrier. The study showcases the efficacy of calcein-loaded and Herceptin-conjugated eLiposomes, which demonstrate rapid and efficient drug release among other liposomal formulations when subjected to ultrasound. This discovery paves the way for a more targeted, efficient, and humane approach to cancer therapy.

High-throughput molecular gut content analysis of aphids identifies plants relevant for potato virus Y epidemiology.

Aphids are phloem-feeding insects that reduce crop productivity due to feeding and transmission of plant viruses. When aphids disperse across the landscape to colonize new host plants, they will often probe on a wide variety of nonhost plants before settling on a host suitable for feeding and reproduction. There is limited understanding of the diversity of plants that aphids probe on within a landscape, and characterizing this diversity can help us better understand host use patterns of aphids. Here, we used gut content analysis (GCA) to identify plant genera that were probed by aphid vectors of potato virus Y (PVY). Aphids were trapped weekly near potato fields during the growing seasons of 2020 and 2021 in San Luis Valley in Colorado. High-throughput sequencing of plant barcoding genes, trnF and ITS2, from 200 individual alate (i.e., winged) aphids representing nine vector species of PVY was performed using the PacBio sequencing platform, and sequences were identified to genus using NCBI BLASTn. We found that 34.7% of aphids probed upon presumed PVY host plants and that two of the most frequently detected plant genera, Solanum and Brassica, represent important crops and weeds within the study region. We found that 75% of aphids frequently probed upon PVY nonhosts including many species that are outside of their reported host ranges. Additionally, 19% of aphids probed upon more than one plant species. This study provides the first evidence from high-throughput molecular GCA of aphids and reveals host use patterns that are relevant for PVY epidemiology.

Enhancing Curcumin's therapeutic potential in cancer treatment through ultrasound mediated liposomal delivery.

Improving the efficacy of chemotherapy remains a key challenge in cancer treatment, considering the low bioavailability, high cytotoxicity, and undesirable side effects of some clinical drugs. Targeted delivery and sustained release of therapeutic drugs to cancer cells can reduce the whole-body cytotoxicity of the agent and deliver a safe localized treatment to the patient. There is growing interest in herbal drugs, such as curcumin, which is highly noted as a promising anti-tumor drug, considering its wide range of bioactivities and therapeutic properties against various tumors. Conversely, the clinical efficacy of curcumin is limited because of poor oral bioavailability, low water solubility, instability in gastrointestinal fluids, and unsuitable pH stability. Drug-delivery colloid vehicles like liposomes and nanoparticles combined with microbubbles and ultrasound-mediated sustained release are currently being explored as effective delivery modes in such cases. This study aimed to synthesize and study the properties of curcumin liposomes (CLs) and optimize the high-frequency ultrasound release and uptake by a human breast cancer cell line (HCC 1954) through in vitro studies of culture viability and cytotoxicity. CLs were effectively prepared with particles sized at 81 ± 2 nm, demonstrating stability and controlled release of curcumin under ultrasound exposure. In vitro studies using HCC1954 cells, the combination of CLs, ultrasound, and Definity microbubbles significantly improved curcumin's anti-tumor effects, particularly under specific conditions: 15 s of continuous ultrasound at 0.12 W/cm2 power density with 0.6 × 107 microbubbles/mL. Furthermore, the study delved into curcumin liposomes' cytotoxic effects using an Annexin V/PI-based apoptosis assay. The treatment with CLs, particularly in conjunction with ultrasound and microbubbles, amplified cell apoptosis, mainly in the late apoptosis stage, which was attributed to heightened cellular uptake within cancer cells.

Targeted Cancer Therapy-on-A-Chip.

Targeted cancer therapy (TCT) is gaining increased interest because it reduces the risks of adverse side effects by specifically treating tumor cells. TCT testing has traditionally been performed using two-dimensional (2D) cell culture and animal studies. Organ-on-a-chip (OoC) platforms have been developed to recapitulate cancer in vitro, as cancer-on-a-chip (CoC), and used for chemotherapeutics development and testing. This review explores the use of CoCs to both develop and test TCTs, with a focus on three main aspects, the use of CoCs to identify target biomarkers for TCT development, the use of CoCs to test free, un-encapsulated TCTs, and the use of CoCs to test encapsulated TCTs. Despite current challenges such as system scaling, and testing externally triggered TCTs, TCToC shows a promising future to serve as a supportive, pre-clinical platform to expedite TCT development and bench-to-bedside translation.

Recent Breakthroughs in Using Quantum Dots for Cancer Imaging and Drug Delivery Purposes.

Cancer is one of the leading causes of death worldwide. Because each person's cancer may be unique, diagnosing and treating cancer is challenging. Advances in nanomedicine have made it possible to detect tumors and quickly investigate tumor cells at a cellular level in contrast to prior diagnostic techniques. Quantum dots (QDs) are functional nanoparticles reported to be useful for diagnosis. QDs are semiconducting tiny nanocrystals, 2-10 nm in diameter, with exceptional and useful optoelectronic properties that can be tailored to sensitively report on their environment. This review highlights these exceptional semiconducting QDs and their properties and synthesis methods when used in cancer diagnostics. The conjugation of reporting or binding molecules to the QD surface is discussed. This review summarizes the most recent advances in using QDs for in vitro imaging, in vivo imaging, and targeted drug delivery platforms in cancer applications.