More Like this

1. Two novel loci underlie natural differences in Caenorhabditis elegans abamectin responses

   https://doi.org/10.1371/journal.ppat.1009297  

   Evans, Kathryn S.; Wit, Janneke; Stevens, Lewis; Hahnel, Steffen R.; Rodriguez, Briana; Park, Grace; Zamanian, Mostafa; Brady, Shannon C.; Chao, Ellen; Introcaso, Katherine; et al (March 2021, PLOS Pathogens)

   Nutman, Thomas B. (Ed.)

   Parasitic nematodes cause a massive worldwide burden on human health along with a loss of livestock and agriculture productivity. Anthelmintics have been widely successful in treating parasitic nematodes. However, resistance is increasing, and little is known about the molecular and genetic causes of resistance for most of these drugs. The free-living roundworm Caenorhabditis elegans provides a tractable model to identify genes that underlie resistance. Unlike parasitic nematodes, C . elegans is easy to maintain in the laboratory, has a complete and well annotated genome, and has many genetic tools. Using a combination of wild isolates and a panel of recombinant inbred lines constructed from crosses of two genetically and phenotypically divergent strains, we identified three genomic regions on chromosome V that underlie natural differences in response to the macrocyclic lactone (ML) abamectin. One locus was identified previously and encodes an alpha subunit of a glutamate-gated chloride channel ( glc-1 ). Here, we validate and narrow two novel loci using near-isogenic lines. Additionally, we generate a list of prioritized candidate genes identified in C . elegans and in the parasite Haemonchus contortus by comparison of ML resistance loci. These genes could represent previously unidentified resistance genes shared across nematode species and should be evaluated in the future. Our work highlights the advantages of using C . elegans as a model to better understand ML resistance in parasitic nematodes. 

   more » « less
2. Photothermal-responsive nanosized hybrid polymersome as versatile therapeutics codelivery nanovehicle for effective tumor suppression

   https://doi.org/10.1073/pnas.1817251116  

   Zhang, Hongbo; Cui, Wenguo; Qu, Xiangmeng; Wu, Huayin; Qu, Liangliang; Zhang, Xu; Mäkilä, Ermei; Salonen, Jarno; Zhu, Yueqi; Yang, Zhou; et al (March 2019, Proceedings of the National Academy of Sciences)

   Effective cancer therapies often demand delivery of combinations of drugs to inhibit multidrug resistance through synergism, and the development of multifunctional nanovehicles with enhanced drug loading and delivery efficiency for combination therapy is currently a major challenge in nanotechnology. However, such combinations are more challenging to administer than single drugs and can require multipronged approaches to delivery. In addition to being stable and biodegradable, vehicles for such therapies must be compatible with both hydrophobic and hydrophilic drugs, and release drugs at sustained therapeutic levels. Here, we report synthesis of porous silicon nanoparticles conjugated with gold nanorods [composite nanoparticles (cNPs)] and encapsulate them within a hybrid polymersome using double-emulsion templates on a microfluidic chip to create a versatile nanovehicle. This nanovehicle has high loading capacities for both hydrophobic and hydrophilic drugs, and improves drug delivery efficiency by accumulating at the tumor after i.v. injection in mice. Importantly, a triple-drug combination suppresses breast tumors by 94% and 87% at total dosages of 5 and 2.5 mg/kg, respectively, through synergy. Moreover, the cNPs retain their photothermal properties, which can be used to significantly inhibit multidrug resistance upon near-infrared laser irradiation. Overall, this work shows that our nanovehicle has great potential as a drug codelivery nanoplatform for effective combination therapy that is adaptable to other cancer types and to molecular targets associated with disease progression. 

   more » « less
3. PartialFibers: An efficient method for predicting Drug-Drug Interactions

   Bumin, Aysegul; Huang, Kejun; Kahveci, Tamer (December 2023, Springer)

   Drug resistance is one of the fundamental challenges in modern medicine. Using combinations of drugs is an effective solution to counter drug resistance as is harder to develop resistance to multiple drugs simultaneously. Finding the correct dosage for each drug in the combination remains to be a challenging task. Testing all possible drug-drug combinations on various cell lines for different dosages in wet-lab experiments is infeasible since there are many combinations of drugs as well as their dosages yet the drugs and the cell lines are limited in availability and each wet-lab test is costly and time-consuming. Efficient and accurate in silico prediction methods are surely needed. Here we present a novel computational method, PartialFibers to address this challenge. Unlike existing prediction methods PartialFibers takes advantage of the distribution of the missing drug-drug interactions and effectively predicts the dosage of a drug in the combination. Our results on real datasets demonstrate that PartialFibers is more flexible, scalable, and achieves higher accuracy in less time than the state of the art algorithms. 

   more » « less
4. Virulence attenuating combination therapy: a potential multi-target synergy approach to treat Pseudomonas aeruginosa infections in cystic fibrosis patients

   https://doi.org/10.1039/c9md00566h  

   Shaw, Elana; Wuest, William M. (March 2020, RSC Medicinal Chemistry)

   The World Health Organization considers the discovery of new treatments for P. aeruginosa a top priority. Virulence attenuating combination therapy (VACT) is a pragmatic strategy to improve bacterial clearance, repurpose outmoded antibiotics, improve drug efficacy at lower doses, and reduce the evolution of resistance. In vitro and in vivo studies have shown that adding a quorum sensing inhibitor or an extracellular polymeric substance repressor to classical antibiotics synergistically improves antipseudomonal activity. This review highlights why VACT could specifically benefit cystic fibrosis patients harboring chronic P. aeruginosa infections, outlines the current landscape of synergistic combinations between virulence-targeting small-molecules and anti-pseudomonal drugs, and suggests future directions for VACT research. 

   more » « less
5. DiI staining of sensory neurons in the entomopathogenic nematode Steinernema hermaphroditum

   https://doi.org/10.17912/micropub.biology.000516  

   Garg P, Tan CH (February 2022, microPublication biology)

   Steinernema hermaphroditum entomopathogenic nematodes (EPN) and their Xenorhabdus griffiniae symbiotic bacteria have recently been shown to be a genetically tractable system for the study of both parasitic and mutualistic symbiosis. In their infective juvenile (IJ) stage, EPNs search for insect hosts to invade and quickly kill them with the help of the symbiotic bacteria they contain. The mechanisms behind these behaviors have not been well characterized, including how the nematodes sense their insect hosts. In the well-studied free‑living soil nematode Caenorhabditis elegans, ciliated amphid neurons enable the worms to sense their environment, including chemosensation. Some of these neurons have also been shown to control the decision to develop as a stress-resistant dauer larva, analogous to the infective juveniles of EPNs, or to exit from dauer and resume larval development. In C. elegans and other nematodes, dye-filling with DiI is an easy and efficient method to label these neurons. We developed a protocol for DiI staining of S. hermaphroditum sensory neurons. Using this method, we could identify neurons positionally analogous to the C. elegans amphid neurons ASI, ADL, ASK, ASJ, as well as inner labial neurons IL1 and IL2. Similar to findings in other EPNs, we also found that the IJs of S. hermaphroditum are dye-filling resistant. 

   more » « less