Novel mint-stalks derived biochar for the adsorption of methylene blue dye: Effect of operating parameters, adsorption mechanism, kinetics, isotherms, and thermodynamics.

The pyrolysis of mint stalks and lemon peels was performed to synthesize mint-stalks (MBC) and lemon-peels (LBC) derived biochars for adsorbing methylene blue (MB). The preparation, characterization, and application of MBC in adsorption have not been reported in the literature. MBC showed higher surface area and carbon content than that of LBC. The removal ratios of MB were 87.5% and 60% within 90 min for MBC and LBC, respectively at pH 7, temperature of 30oC, adsorbent dose of 0.5 g/L, and MB concentration of 5 mg/L. The optimal MBC dose was 1 g/L achieving a removal efficiency of 93.6% at pH 7, temperature of 30oC, contact time of 90 min, and initial dye concentration of 5.0 mg/L. The adsorption efficiency decreased from 98.6% to 31.33% by raising the dye concentration from 3.0 mg/L to 30 mg/L. Further, the increase of adsorbent dose to 10 g/L could achieve 94.2%, 90.3%, 87.6%, and 84.1% removal efficiencies of MB in the case of initial concentrations of 200 mg/L, 300 mg/L, 400 mg/L, and 500 mg/L, respectively. MBC showed high stability in adsorbing MB under five cycles, and the performed analyses after adsorption reaffirmed the stability of MBC. The adsorption mechanism indicated that the adsorption of MB molecules on the biochar's surface was mainly because of the electrostatic interaction, hydrogen bonding, and π-π stacking. Pseudo-second-order and Langmuir models could efficiently describe the adsorption of MB on the prepared biochar. The adsorption process is endothermic and spontaneous based on the adsorption thermodynamics. The proposed adsorption system is promising and can be implemented on a bigger scale. Moreover, the prepared biochar can be implemented in other applications such as photocatalysis, periodate, and persulfate activation-based advanced oxidation processes.

Connexin-Containing Vesicles for Drug Delivery.

Connexin is a transmembrane protein present on the cell membrane of most cell types. Connexins assemble into a hexameric hemichannel known as connexon that pairs with another hemichannel present on a neighboring cell to form gap junction that acts as a channel or pore for the transport of ions and small molecules between the cytoplasm of the two cells. Extracellular vesicles released from connexin-expressing cells could carry connexin hemichannels on their surface and couple with another connexin hemichannel on a distant recipient cell to allow the transfer of the intravesicular content directly into the cytoplasm. Connexin-containing vesicles can be potentially utilized for intracellular drug delivery. In this review, we introduced cell-derived, connexin-containing extracellular vesicles and cell-free connexin-containing liposomes, methods of preparing them, procedures to load cargos in them, factors regulating the connexin hemichannel activity, (potential) applications of connexin-containing vesicles in drug delivery, and finally the challenges and future directions in realizing the promises of this platform delivery system for (intracellular) drug delivery.

Camptothecin structure simplification elaborated new imidazo[2,1-b]quinazoline derivative as a human topoisomerase I inhibitor with efficacy against bone cancer cells and colon adenocarcinoma.

Camptothecin is a pentacyclic natural alkaloid that inhibits the hTop1 enzyme involved in DNA transcription and cancer cell growth. Camptothecin structure pitfalls prompted us to design new congeners using a structure simplification strategy to reduce the ring extension number from pentacyclic to tetracyclic while maintaining potential stacking of the new compounds with the DNA base pairs at the Top1-mediated cleavage complex and aqueous solubility, as well as minimizing compound-liver toxicity. The principal axis of this study was the verification of hTop1 inhibiting activity as a possible mechanism of action and the elaboration of new simplified inhibitors with improved pharmacodynamic and pharmacokinetic profiling using three structure panels (A-C) of (isoquinolinoimidazoquinazoline), (imidazoquinazoline), and (imidazoisoquinoline), respectively. DNA relaxation assay identified five compounds as hTop1 inhibitors belonging to the imidazoisoquinolines 3a,b, the imidazoquinazolines 12, and the isoquinolinoimidazoquinazolines 7a,b. In an MTT cytotoxicity assay against different cancer cell lines, compound 12 was the most potent against HOS bone cancer cells (IC50 = 1.47 µM). At the same time, the other inhibitors had no detectable activity against any cancer cell type. Compound (12) demonstrated great penetrating power in the HOS cancer cells' 3D-multicellular tumor spheroid model. Bioinformatics research of the hTop1 gene revealed that the TP53 cell proliferative gene is in the network of hTop1. The finding is confirmed empirically using the gene expression assay that proved the increase in p53 expression. The impact of structure simplification on compound 12 profile, characterized by the absence of acute oral liver toxicity when compared to Doxorubicin as a standard inhibitor, the lethal dose measured on Swiss Albino female mice and reported at LD50 = 250 mg/kg, and therapeutic significance in reducing colon adenocarcinoma tumor volume by 75.36 % after five weeks of treatment with compound 12. The molecular docking solutions of the active CPT-based derivative 12 and the inactive congener 14 into the active site of hTop1 and the activity cliffing of such MMP directed us to recommend the addition of HBD and HBA variables to compound 12 imidazoquinazoline core scaffold to enhance the potency via hydrogen bond formation with the major groove amino acids (Asp533, Lys532) as well as maintaining the hydrogen bond with the minor groove amino acid Arg364.

Assessment of heavy metals at mangrove ecosystem, applying multiple approaches using in-situ and remote sensing techniques, Red Sea, Egypt.

Mangrove areas are considered the most retention zone for heavy metal pollution as it work as an edge that aggregates land and sea sediments. This study aims to examine if the heavy metals' existence in the mangrove sediment is related to contamination or natural resources. In addition, it gives an interpretation of the origin of these metals along the Egyptian Red Sea coast. Twenty-two samples of mangrove sediments were collected and then, analyzed for metals (Mn, Ni, Cu, Fe, Cd, Ag, and Pb) using inductively coupled plasma mass spectroscopy (ICP-MS). Integration between the in-situ data, contamination indices, and remote sensing and geographical information science (GIS), and multivariate statistical analysis techniques (PCA) were analyzed to assess and clarify the spatial origin of heavy metals in sediment at a regional scale. The average concentration of heavy metals from mangrove sediments were shown to be substantially lower than the referenced value, ranging from moderate to significant except the levels of Ag were very high. The heavy metals concentrations were expected to be naturally origin rather than anthropogenic and that be confirmed by mapping of Red Sea alteration zones spots. These alteration zones are parallel to mangrove sites and rich by several mineralization types including heavy metals that are carried by flooding to the coastline. Remote sensing and GIS techniques successfully contributed to interpreting the pattern of the origin of heavy metals and discharging systems that control the heavy metals concentration along the Red Sea coast.

Effect of the amount of cationic lipid used to complex siRNA on the cytotoxicity and proinflammatory activity of siRNA-solid lipid nanoparticles.

When preparing siRNA-encapsulated solid lipid nanoparticles (siRNA-SLNs), cationic lipids are commonly included to condense and lipophilize the siRNA and thus increase its encapsulation in the SLNs. Unfortunately, cationic lipids also contribute significantly to the cytotoxicity and proinflammatory activity of the SLNs. Previously, our group developed a TNF-α siRNA-SLN formulation that showed strong activity against rheumatoid arthritis unresponsive to methotrexate in a mouse model. The siRNA-SLNs were composed of lecithin, cholesterol, an acid-sensitive stearoyl polyethylene glycol (2000) conjugate, and siRNA complexes with 1,2-dioleoyl-3trimethylammonium-propane (DOTAP), a cationic lipid. The present study was designed to study the effect of the amount of DOTAP used to complex the siRNA on the cytotoxicity and proinflammatory activity of the resultant siRNA-SLNs. A small library of siRNA-SLNs prepared at various ratios of DOTAP to siRNA (i.e., nitrogen to phosphate (N/P) ratios ranging from 34:1 to 1:1) were prepared and characterized, and the cytotoxicity and proinflammatory activity of selected formulations were evaluated in cell culture. As expected, the siRNA-SLNs prepared at the highest N/P ratio showed the highest cytotoxicity to J774A.1 macrophage cells and reducing the N/P ratio lowered the cytotoxicity of the siRNA-SLNs. Unexpectedly, the cytotoxicity of the siRNA-SLNs reached the lowest at the N/P ratios of 16:1 and 12:1, and further reducing the N/P ratio resulted in siRNA-SLNs with increased cytotoxicity. For example, siRNA-SLNs prepared at the N/P ratio of 1:1 was more cytotoxic than the ones prepared at the N/P ratio 12:1. This finding was confirmed using neutrophils differentiated from mouse MPRO cell line. The DOTAP release from the siRNA-SLNs prepared at the N/P ratio of 1:1 was faster than from the ones prepared at the N/P ratio of 12:1. The siRNA-SLNs prepared at N/P ratios of 12:1 and 1:1 showed comparable proinflammatory activities in both macrophages and neutrophils. Additionally, the TNF-α siRNA-SLNs prepared at the N/P ratios of 12:1 and 1:1 were equally effective in downregulating TNF-α expression in J774A.1 macrophages. In conclusion, it was demonstrated that at least in vitro in cell culture, reducing the amount of cationic lipids used when preparing siRNA-SLNs can generally help reduce the cytotoxicity of the resultant SLNs, but siRNA-SLNs prepared with the lowest N/P ratio are not necessarily the least cytotoxic and proinflammatory.

Targeted treatment of triple-negative-breast cancer through pH-triggered tumour associated macrophages using smart theranostic nanoformulations.

Triple-negative breast cancer (TNBC) represents 15-25 % of the new breast cancer cases diagnosed worldwide every year. TNBC is among the most aggressive and worst prognosis breast cancer, mainly because targeted therapies are not available. Herein, we developed a magnetic theranostic hybrid nanovehicle for targeted treatment of TNBC through pH-triggered tumour associated macrophages (TAMs) targeting. The lipid core of the nanovehicle was composed of a Carnaúba wax matrix that simultaneously incorporated iron oxide nanoparticles and doxorubicin (DOX) - a chemotherapeutic drug. These drug-loaded wax nanovehicles were modified with a combination of two functional and complementary molecules: (i) a mannose ligand (macrophage targeting) and (ii) an acid-sensitive sheddable polyethylene glycol (PEG) moiety (specificity). The TAMs targeting strategy relied on the mannose - mannose receptor recognition exclusively after acid-sensitive "shedding" of the PEG in the relatively low tumour microenvironment pH. The pH-induced targeting capability towards TAMs was confirmed in vitro in a J774A.1 macrophage cell line at different pH (7.4 and 6.5). Biocompatibility and efficacy of the final targeted formulations were demonstrated in vitro in the TNBC MDA-MB-231 cell line and in vivo in an M-Wnt tumour-bearing (TNBC) mouse model. A preferential accumulation of the DOX-loaded lipid nanovehicles in the tumours of M-Wnt-tumour bearing mice was observed, which resulted both on an efficient tumour growth inhibition and a significantly reduced off-target toxicity compared to free DOX. Additionally, the developed magnetic hybrid nanovehicles showed outstanding performances as T2-contrast agents in magnetic resonance imaging (r2 ≈ 400-600 mM-1·s-1) and as heat generating sources in magnetic hyperthermia (specific absorption rate, SAR ≈ 178 W·g-1Fe). These targeted magnetic hybrid nanovehicles emerge as a suitable theranostic option that responds to the urgent demand for more precise and personalized treatments, not only because they are able to offer localized imaging and therapeutic potential, but also because they allow to efficiently control the balance between safety and efficacy.

5-Fluorouracil With Microneedling Modulates Wound Healing in a Murine Model: An Immunohistochemical Analysis of Mechanism and Dose Efficacy.

PURPOSE: The purpose of this study is to assess the dose-dependent immunohistopathological effects of intradermal microneedle-delivered 5-fluorouracil (5-FU) for postincisional wound healing in a murine model. METHODS: A prospective experimental study was performed. Twelve hairless mice were randomized into 4 treatment groups for postincisional wound treatment: microneedling with topical saline, or microneeding with topically-applied 5-FU at concentrations of 25 mg/ml, 50 mg/ml, or 100 mg/ml. Two surgical wounds were created on each animal. Combination wound treatments were performed on postoperative days 14 and 28, and cutaneous biopsies were obtained on day 56. Specimens were analyzed by a dermatopathologist, blinded to the treatment group, for collagen thickness, lymphocytic infiltration, histiocytic response, sub-epidermal basement membrane zone thickness, and myofibroblast density. RESULTS: Histopathologic evaluation showed increased collagen thickness, lymphocyte infiltration, and granuloma density in the groups undergoing microneedling treatment with 5-FU, compared to saline. Immunohistochemical analysis revealed a trend toward thicker basement membranes with higher concentrations of 5-FU used, reaching statistical significance between controls and those treated with 100 mg/ml 5-FU ( p = 0.0493). A trend toward decreasing myofibroblast density with increasing doses of 5-FU was noted. No postincisional or treatment complications were observed. CONCLUSIONS: Our results demonstrate that microneedling is an effective topical subepithelial drug delivery system, and further suggest a beneficial dose-dependent immunomodulatory effect of 5-FU on intermediate wound healing when used in combination with microneedling. We recommend a 5-FU dose at the mid-range 50 mg/ml concentration to simultaneously maximize efficacy and minimize complication risk.

Apoptotic body-inspired nanoparticles target macrophages at sites of inflammation to support an anti-inflammatory phenotype shift.

Chronic inflammation is a significant pathological process found in a range of disease states. Treatments to reduce inflammation in this family of diseases may improve symptoms and disease progression, but are largely limited by variable response rates, cost, and off-target effects. Macrophages are implicated in many inflammatory diseases for their critical role in the maintenance and resolution of inflammation. Macrophages exhibit significant plasticity to direct the inflammatory response by taking on an array of pro- and anti-inflammatory phenotypes based on extracellular cues. In this work, a nanoparticle has been developed to target sites of inflammation and reduce the inflammatory macrophage phenotype by mimicking the anti-inflammatory effect of apoptotic cell engulfment. The nanoparticle, comprised of a poly(lactide-co-glycolide) core, is coated with phosphatidylserine (PS)-supplemented cell plasma membrane to emulate key characteristics of the apoptotic cell surface. The particle surface is additionally functionalized with an acid-sensitive sheddable polyethylene glycol (PEG) moiety to increase the delivery of the nanoparticles to low pH environments such as those of chronic inflammation. In a mouse model of lipopolysaccharide-induced inflammation, particles were preferentially taken up by macrophages at the site and promoted an anti-inflammatory phenotype shift. This PEGylated membrane coating increased the delivery of nanoparticles to sites of inflammation and may be used as a tool alone or as a delivery scheme for additional cargo to reduce macrophage-associated inflammatory response.

Comparison of the efficacy of Fractional Radiofrequency Microneedling alone and in combination with platelet-rich plasma in neck rejuvenation: a clinical and optical coherence tomography study.

BACKGROUND: Esthetic improvement of the neck and cervicomental angle remains one of the most challenging aspects of rejuvenation. Fractional radiofrequency microneedling demonstrated significant skin tightening and lifting of lower third of the face. AIM OF WORK: To evaluate and compare fractional radiofrequency microneedling alone and in combination with autologous platelet-rich plasma (PRP) in neck rejuvenation. METHODS: 20 patients with mild to moderate neck laxity were randomized to receive 3 sessions of either fractional radiofrequency microneedling +PRP (group A) or fractional radiofrequency microneedling monotherapy (group B). Evaluation was done using optical coherence tomography to detect dermis thickness, measurement of cervicomental angle, a score done by two investigators blinded to used modality (GAIS) and patient satisfaction score. RESULTS: Both Groups showed a statistically significant improvement in all parameters. Comparing the two groups, the mean dermal thickness after treatment was higher in group A compared with B but was found statistically insignificant. More favorable results were reported in group A according to GAIS. Other parameters showed comparable results. CONCLUSION: Fractional microneedle radiofrequency with insulated microneedles offers a safe and effective modality for mild to moderate neck laxity when used alone or in combination with PRP. It remains questionable whether combining fr-RF microneedling with PRP provides more favorable results in terms of efficacy and side effects.

PD-1 siRNA-Encapsulated Solid Lipid Nanoparticles Downregulate PD-1 Expression by Macrophages and Inhibit Tumor Growth : PD-1 siRNA-Encapsulated Solid Lipid Nanoparticles.

The present study was designed to test the hypothesis that programmed cell death-1 (PD-1) siRNA can downregulate PD-1 expression in macrophages in culture and in tumor tissues in mice and inhibit tumor growth in a mouse model. PD-1 siRNA was encapsulated in solid lipid nanoparticles (SLNs), and the physical properties of the resultant SLNs were characterized. The ability of the PD-1 siRNA-SLNs to downregulate PD-1 expression was confirmed in J774A.1 macrophages in culture and in tumor tissues in mice. Moreover, the antitumor activity of the PD-1 siRNA-SLNs was evaluated in a mouse model. The PD-1 siRNA-SLNs were roughly spherical, and their particle size, polydispersity index, and zeta potential were 141 ± 5 nm, 0.17 ± 0.02, and 20.7 ± 4.7 mV, respectively, with an siRNA entrapment efficiency of 98.9%. The burst release of the PD-1 siRNA from the SLNs was minimal. The PD-1 siRNA-SLNs downregulated PD-1 expression on J774A.1 macrophage cell surface as well as in macrophages in B16-F10 tumors pre-established in mice. In mice with pre-established B16-F10 tumors, the PD-1 siRNA-SLNs significantly inhibited the tumor growth, as compared with siRNA-SLNs prepared with non-functional, negative control siRNA. In conclusion, the PD-1 siRNA-SLNs inhibited tumor growth, likely related to their ability to downregulate PD-1 expression by tumor-associated macrophage (TAMs).

Aerosolizable siRNA-encapsulated solid lipid nanoparticles prepared by thin-film freeze-drying for potential pulmonary delivery.

Lipid nanoparticles are increasingly used for drug and gene delivery, including the delivery of small interfering RNA (siRNA). Pulmonary delivery of drug molecules carried by lipid nanoparticles directly into the lung may improve the treatment of certain lung diseases. The present study was designed to test the feasibility of engineering aerosolizable dry powder of lipid nanoparticles by thin-film freeze-drying (TFFD). Solid lipid nanoparticles (SLNs) comprised of lecithin, cholesterol, and a lipid-polyethylene glycol conjugate were prepared by solvent evaporation. Dry powders of the SLNs were prepared by TFFD, spray drying, or conventional shelf freeze-drying. The physical and aerosol properties of the dry powders as well as the physical properties of the SLNs reconstituted from the dry powders were evaluated. The particle size, polydispersity index, and the zeta potential of the SLNs were preserved after they were subjected to TFFD and reconstitution, but not after they were subjected to conventional shelf freeze-drying and reconstitution, and the dry powder prepared by TFFD showed better aerosol performance properties than that prepared by spray drying. SLNs encapsulated with siRNA can also be successfully transformed into aerosolizable dry powder by TFFD, and subjecting the siRNA-encapsulated SLNs to TFFD did not negatively affect the function of the siRNA. It is concluded that TFFD represents a promising method to prepare aerosolizable dry powder of lipid nanoparticles.

Gap Junction Liposomes for Efficient Delivery of Chemotherapeutics to Solid Tumors.

Chemotherapeutic delivery is limited by inefficient transport across cellular membranes. Here, we harness the cellular gap junction network to release therapeutic cargos directly into the cytosol. Specifically, cell-derived vesicles, termed connectosomes, contain gap junction transmembrane proteins that open a direct passageway to the cellular interior. Connectosomes were previously shown to substantially improve chemotherapeutic delivery in vitro. Here, we test connectosomes in vivo, using a murine breast tumor model. We demonstrate that connectosomes improve chemotherapeutic delivery to cellular targets within tumors by up to 16-fold, compared to conventional drug-loaded liposomes, suggesting an efficient alternative pathway for intracellular delivery.

Effect of the Ratio of Betamethasone to TNF-α siRNA Coencapsulated in Solid Lipid Nanoparticles on the Acute Proinflammatory Activity of the Nanoparticles.

There is evidence that encapsulating glucocorticoids into nucleic acid-containing nanoparticles reduces the inflammatory toxicities of the nanoparticles. Herein, using betamethasone acetate (BA), a glucocorticoid, and a solid lipid nanoparticle formulation of siRNA, we confirmed that coencapsulating BA into the siRNA solid lipid nanoparticles significantly reduced the proinflammatory activity of the siRNA nanoparticles in a mouse model. Using TNF-α siRNA, we then showed that the BA and TNF-α siRNA coencapsulated into the solid lipid nanoparticles acted as a dual anti-inflammatory and synergistically reduced TNF-α release by mouse macrophages in culture following stimulation with lipopolysaccharide, as compared to solid lipid nanoparticles encapsulated with TNF-α siRNA or BA alone. Importantly, upon studying the effect of the ratio of BA and TNF-α siRNA on the proinflammatory activity of the resultant nanoparticles, we identified that BA and TNF-α siRNA coencapsulated solid lipid nanoparticles prepared with a BA to TNF-α siRNA weight ratio of 2:1 induced the lowest proinflammatory cytokine production by macrophages in culture. This result was in comparison to nanoparticles prepared with BA to TNF-α siRNA ratios both higher and lower than 2:1 (i.e., 4:1, 1:1, and 0.5:1) and is likely due to differences in molecular interactions among the various components in the BA and TNF-α-siRNA coencapsulated solid lipid nanoparticles at these ratios. Encapsulating glucocorticoids into siRNA-nanoparticles represents a viable strategy to reduce the proinflammatory activity of the nanoparticles; however, the ratio of the glucocorticoid to siRNA in the nanoparticles requires optimization.

Quality of life after different approaches of orthognathic surgery: a randomized controlled study.

BACKGROUND: Over the last decade, the accuracy of 3D computer-assisted orthognathic surgery has been extensively investigated. However, patient-reported outcome measures have been rarely reported for this technology. This study aimed to assess quality of life following orthognathic surgery using CAD/CAM bone splints compared to the classic occlusal wafers in patients with dentofacial deformities. METHODS: Thirty-two patients were randomly allocated into two groups where group I utilized CAD/CAM splints and patient specific osteosynthesis for maxillary positioning and group II utilized occlusal wafers fabricated on a semi-adjustable articulator. Patients were assessed using orthognathic quality of life Questionnaire (OQLQ) preoperatively and 6 months postoperatively. RESULTS: Mean OQLQ overall score change of 24.375±11.96 took place in group I patients while group II showed a mean change of 23±8.39. CONCLUSIONS: The study showed evident improvement in quality of life following orthognathic surgery compared to before surgery. However, computer-assisted surgery did not show any significant improvement over the classic approach.

Cellular uptake, cytotoxicity and in-vivo evaluation of Tamoxifen citrate loaded niosomes.

One of the main challenges in Tamoxifen cancer therapy is achieving localized, efficient and sustained delivery without harming normal healthy organs. This study focused on evaluating Tamoxifen Citrate (TMC) niosomes for localized cancer therapy through in-vitro breast cancer cytotoxicity as well as in-vivo solid anti-tumor efficacy. Different niosomal formulae were prepared by film hydration technique and characterized for entrapment efficiency% (E. E), vesicle size, morphology, and in-vitro release. The cellular uptake and anti-cancer activity were also tested in-vitro using MCF-7 breast cancer cell line. Moreover, in-vivo anti-tumor efficacy was examined in Ehrlich carcinoma mice model through reporting solid tumor volume regression and tissue TMC distribution. The obtained niosomes prepared with Span 60: cholesterol (1: 1 molar ratio) showed a distinct nano-spherical shape with EE up to 92.3%± 2.3. Remarkably prolonged release of TMC following diffusion release behavior was detected. The optimized formula showed significantly enhanced cellular uptake (2.8 fold) and exhibited significantly greater cytotoxic activity with MCF-7 breast cancer cell line. In-vivo experiment showed enhanced tumor volume reduction of niosomal TMC when compared to free TMC. Based on these results, the prepared niosomes demonstrated to be promising as a nano-size delivery vehicle for localized and sustained TMC cancer therapy.

Role of cytochrome P450s in insecticide resistance: impact on the control of mosquito-borne diseases and use of insecticides on Earth.

The fight against diseases spread by mosquitoes and other insects has enormous environmental, economic and social consequences. Chemical insecticides remain the first line of defence but the control of diseases, especially malaria and dengue fever, is being increasingly undermined by insecticide resistance. Mosquitoes have a large repertoire of P450s (over 100 genes). By pinpointing the key enzymes associated with insecticide resistance we can begin to develop new tools to aid the implementation of control interventions and reduce their environmental impact on Earth. Recent technological advances are helping us to build a functional profile of the P450 determinants of insecticide metabolic resistance in mosquitoes. Alongside, the cross-responses of mosquito P450s to insecticides and pollutants are also being investigated. Such research will provide the means to produce diagnostic tools for early detection of P450s linked to resistance. It will also enable the design of new insecticides with optimized efficacy in different environments.