LociScan,a tool for screening genetic marker combinations for plant variety discrimination

To reduce the cost and increase the efficiency of plant genetic marker fingerprinting for variety discrimination,it is desirable to identify the optimal marker combinations.We describe a marker combination screening model based on the genetic algorithm(GA)and implemented in a software tool,Loci Scan.Ratio-based variety discrimination power provided the largest optimization space among multiple fitness functions.Among GA parameters,an increase in population size and generation number enlarged optimization depth but also calculation workload.Exhaustive algorithm afforded the same optimization depth as GA but vastly increased calculation time.In comparison with two other software tools,Loci Scan accommodated missing data,reduced calculation time,and offered more fitness functions.In large datasets,the sample size of training data exerted the strongest influence on calculation time,whereas the marker size of training data showed no effect,and target marker number had limited effect on analysis speed.

A Study on the Effects of Different Interaction Combinations and Language Levels on Continuous Writing in Online Environments

This study was conducted with non-English sophomore students,aiming to explore the effects of different interaction combinations and language levels on continuous writing in an online environment,and compare the differences in lexical alignments and composition quality of learners with different interaction combinations and language levels in the same continuous writing task through experiments.The results show that the mean values of the word-phrase alignment of the paired group were higher than those of the individual group in different interaction combinations,and the two groups showed significant differences;in terms of composition quality,the individual group was better than the paired group,but there was no significant difference between the two groups in terms of task continuation.Secondly,the word-phrase alignment and composition scores of the different language-level groups were higher than those of the same language-level groups,and there was a significant difference between the two groups in terms of word-phrase alignments,but not in terms of composition scores.The results of this study can be useful and informative for second language teachers in future continuous teaching in online environments.

The Research on the Logic and Value of“Two Combinations”

Through the comprehensive analysis of the connotation and logic,inheritance and innovation and the value of social governance,and the dialectical relationship of“two combination”,the inheritance of the idea of Marxism,the inheritance of excellent traditional culture and the governance of contemporary society.

Characterization of subunits encoded by Sn RK1 and dissection of combinations among these subunits in sorghum(Sorghum bicolor L.)

Sucrose nonfermenting-related protein kinase 1(SnRK1)is one of the critical serine/threonine protein kinases.It commonly mediates plant growth and development,cross-talks with metabolism processes and physiological responses to biotic or abiotic stresses.It plays a key role in distributing carbohydrates and sugar signal transporting.In the present study,eight SnRK1 coding genes were identified in sorghum(Sorghum bicolor L.)via sequences alignment,with three forαsubunits(SnRK1α1 to SnRK1α3),three forβ(SnRK1β1 to SnRK1β3),and one for bothγ(SnRK1γ)andβγ(SnRK1βγ).These eight corresponding genes located on five chromosomes(Chr)of Chr1–3,Chr7,and Chr9 and presented collinearities to SnRK1s from maize and rice,exhibiting highly conserved domains within the same subunits from the three kinds of cereals.Expression results via qRT-PCR showed that different coding genes of SnRK1s in sorghum possessed similar expression patterns except for SnRK1α3 with a low expression level in grains and SnRK1β2 with a relatively high expression level in inflorescences.Results of subcellular localization in sorghum leaf protoplast showed that SnRK1α1/α2/α3/γmainly located on organelles,while the rest four of SnRK1β1/β2/β3/βγlocated on both membranes and some organelles.Besides,three combinations were discovered among eight SnRK1 subunits in sorghum through yeast two hybrid,includingα1-β2-βγ,α2-β3-γ,andα3-β3-γ.These results provide informative references for the following functional dissection of SnRK1 subunits in sorghum.

Dynamic simulation analysis of molten salt reactor-coupled air-steam combined cycle power generation system

A nonlinear dynamic simulation model based on coordinated control of speed and flow rate for the molten salt reactor and combined cycle systems is proposed here to ensure the coordination and stability between the molten salt reactor and power system.This model considers the impact of thermal properties of fluid variation on accuracy and has been validated with Simulink.This study reveals the capability of the control system to compensate for anomalous situations and maintain shaft stability in the event of perturbations occurring in high-temperature molten salt tank outlet parameters.Meanwhile,the control system’s impact on the system’s dynamic characteristics under molten salt disturbance is also analyzed.The results reveal that after the disturbance occurs,the controlled system benefits from the action of the control,and the overshoot and disturbance amplitude are positively correlated,while the system power and frequency eventually return to the initial values.This simulation model provides a basis for utilizing molten salt reactors for power generation and maintaining grid stability.

Back to the drawing board:Overview of the next generation of combination therapy for inflammatory bowel disease

Inflammatory bowel disease(IBD)is entering a potentially new era of combined therapeutics.Triantafillidis et al provide an insightful review of the current state of combination therapy,with a focus on the use of a combined biologic and immunomodulator,as well as emerging data on the future potential of dual-biologic therapy(DBT).While current evidence for DBT is limited,encouraging safety profiles and ongoing trials suggest a brighter future for this approach.The importance of controlled trials should be stressed in establishing new treatment paradigms.Ongoing prospective randomized trials of DBT and perhaps future combinations of biologics and small molecule therapies will hopefully guide the next generation of IBD care.

Combination treatment of inflammatory bowel disease:Present status and future perspectives

The treatment of patients with inflammatory bowel disease(IBD),especially those with severe or refractory disease,represents an important challenge for the clinical gastroenterologist.It seems to be no exaggeration to say that in these patients,not only the scientific background of the gastroenterologist is tested,but also the abundance of“gifts”that he should possess(insight,intuition,determ-ination,ability to take initiative,etc.)for the successful outcome of the treatment.In daily clinical practice,depending on the severity of the attack,IBD is treated with one or a combination of two or more pharmaceutical agents.These combin-ations include not only the first-line drugs(e.g.,mesalazine,corticosteroids,antibiotics,etc)but also second-and third-line drugs(immunosuppressants and biologic agents).It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied.Therefore,a part of these patients are going to surgery.In recent years,several small-size clinical studies,reviews,and case reports have been published combining not only biological agents with other drugs(e.g.,immunosuppressants or corticosteroids)but also the combination of two biologi-cal agents simultaneously,especially in severe cases.In our opinion,it is at least a strange(and largely unexplained)fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few.As mentioned above,there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations.The appropriate dosage,the duration of the administration,the suitable timing for checking the clinical and laboratory outcome,as well as the treatment side-effects,should be the subject of intense clinical research shortly.In this editorial,we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients.We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival

BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration.Nevertheless,erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes.We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential(Δψm),facilitate tumor cell uptake ofΔψm-sensitive agents,disrupt mitochondrial homeostasis,and subsequently trigger tumor cell death.Erlotinib has not been tested for this effect.AIM To determine whether erlotinib can elevateΔψm and increase tumor cell uptake ofΔψm-sensitive agents,subsequently triggering tumor cell death.METHODSΔψm-sensitive fluorescent dye was used to determine how erlotinib affectsΔψm in pancreatic adenocarcinoma(PDAC)cell lines.The viability of conventional and patient-derived primary PDAC cell lines in 2D-and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone(MitoQ),aΔψm-sensitive MitoQ.The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0.The preclinical efficacy of the twodrug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.RESULTS Erlotinib elevatedΔψm in PDAC cells,facilitating tumor cell uptake and mitochondrial enrichment ofΔψm-sensitive agents.MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses,while erlotinib pretreatment potentiated low doses of MitoQ.SynergyFinder suggested that these drugs synergistically induced tumor cell lethality.Consistent with in vitro data,erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

Grain Yield,Biomass Accumulation,and Leaf Photosynthetic Characteristics of Rice under Combined Salinity-Drought Stress

Simultaneous stresses of salinity and drought often coincide during rice-growing seasons in saline lands,primarily due to insufficient water resources and inadequate irrigation facilities.Consequently,combined salinity-drought stress poses a major threat to rice production.In this study,two salinity levels(NS,non-salinity;HS,high salinity)along with three drought treatments(CC,control condition;DJ,drought stress imposed at jointing;DH,drought stress imposed at heading)were performed to investigate their combined influences on leaf photosynthetic characteristics,biomass accumulation,and rice yield formation.Salinity,drought,and their combination led to a shortened growth period from heading to maturity,resulting in a reduced overall growth duration.Grain yield was reduced under both salinity and drought stress,with a more substantial reduction under the combined salinity-drought stress.The combined stress imposed at heading caused greater yield losses in rice compared with the stress imposed at jointing.Additionally,the combined salinity-drought stress induced greater decreases in shoot biomass accumulation from heading to maturity,as well as in shoot biomass and nonstructural carbohydrate(NSC)content in the stem at heading and maturity.However,it increased the harvest index and NSC remobilization reserve.Salinity and drought reduced the leaf area index and SPAD value of flag leaves and weakened the leaf photosynthetic characteristics as indicated by lower photosynthetic rates,transpiration rates,and stomatal conductance.These reductions were more pronounced under the combined stress.Salinity,drought,and especially their combination,decreased the activities of ascorbate peroxidase,catalase,and superoxide dismutase,while increasing the contents of malondialdehyde,hydrogen peroxide,and superoxide radical.Our results indicated a more significant yield loss in rice when subjected to combined salinity-drought stress.The individual and combined stresses of salinity and drought diminished antioxidant enzyme activities,inhibited leaf photosynthetic functions,accelerated leaf senescence,and subsequently lowered assimilate accumulation and grain yield.

Combinations of Right Half-Plane Mappings and Vertical Strip Mappings Convex in the Vertical Direction

In this paper, we explore the linear combinations of right half-plane mappings and vertical strip mappings. We demonstrate that the combinations of these harmonic mappings are convex in the vertical direction provided they are locally univalent and sense-preserving. Furthermore, we extend this analysis to a more general case by setting specific conditions. Additionally, we take some common parameters such as as the dilatation of these harmonic mappings, and prove the sufficient conditions that their combinations are locally univalent and convex in the vertical direction. Several examples are constructed by the Mathematica software to demonstrate our main results.

Using harmonic beam combining to generate pulse-burst in nonlinear optical laser

The ultrashort lasers working in pulse-burst mode reveal great machining performance in recent years. The number of pulses in bursts effects greatly on the removal rate and roughness. To generate a more equal amplitude of pulses in burst with linear polarization output and time gap adjustable, we propose a new method by the harmonic beam combining(HBC).The beam combining is commonly used in adding pulses into the output beam while maintaining the pulse waveform and beam quality. In the HBC, dichroic mirrors are used to combine laser pulses of fundamental wave(FW) into harmonic wave(HW), and nonlinear crystals are used to convert the FW into HW. Therefore, HBC can add arbitrarily more HW pulses to generate pulse-burst in linear polarization with simple structure. The amplitude of each pulse in bursts can be adjusted the same to increase the stability of the burst, the time gap of each pulse can be adjusted precisely by proper time delay. Because HBC adds pulses sequentially, the peak power density of the burst is the same as each pulse, pulses can be combined without concern of back-conversion which often occurs in high peak power density. In the demonstration, the extendibility of HBC was verified by combining two beams with a third beam. The combined efficiency rates were larger than 99%, and the beam quality of each beam was maintained at M^(2)≈1.4.

Combination Activity of Standard Antituberculosis Drugs and Extracts of Medicinal Plants Commonly Used in Traditional Treatment of Tuberculosis in Uganda

Introduction: Resistance to antituberculosis drugs and adverse drug reactions remain the leading causes of tuberculosis therapeutic failure globally. Despite the increasing acceptance of medicinal plant use in combination with conventional antituberculosis drugs in treatment of tuberculosis (TB) in Uganda, there is paucity of knowledge on their combination effect. Aim: This research aimed to determine combination activity of standard antituberculosis drugs with extracts of Zanthoxylum leprieurii Guill. & Perr. and Rubia cordifolia L., the two common antituberculosis medicinal plants in Uganda, against pansensitive (H37Rv) and multi-drug resistant (MDR) Mycobacterium tuberculosis strains. Materials and Methods: Two reference MTB strains (H37Rv and MDR strain) were inoculated on Middlebrook 7H11 medium containing a combination of standard antituberculosis drugs and methanol extracts of Z. leprieurii and R. cordifolia at varying concentrations. The number of colonies on the plates was observed and counted weekly for up to 8 weeks. In vitro combination activity was determined using proportion method. Mean percentage inhibition was calculated for the reduction of number of colonies on drug-extract combination medium in relation to drug-extract-free control medium. Results: Drug-extract combinations showed good combination activity against Mycobacterium tuberculosis strains when compared with individual standard anti-TB drugs. This was more exhibited against MDR strain. There was however a reduction in percentage inhibition when extracts were combined with ethambutol and streptomycin against H37Rv strain. Conclusions: Zanthoxylum leprieurii and Rubia cordifolia in combination with standard anti-TB drugs exhibited increased in vitro activity against Mycobacterium tuberculosis, especially MDR-TB strain. This justifies the local use of these plants in traditional treatment of tuberculosis especially in resistant cases in Uganda.

A Bioequivalence Study of Empagliflozin/Metformin Fixed-Dose Combination in Healthy Subjects under Fasting Conditions

Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fasting conditions. Methods: This was a phase I, randomized, single-dose, two-period, two-sequence, crossover study to evaluate the bioequivalence (BE) profiles of two fixed-dose combinations (FDCs) of empagliflozin/metformin. Cmax, AUC0-t and AUC0-∞ from test and reference formulations were evaluated to access BE. The plasma concentrations were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. Of the 24 subjects enrolled, 23 completed both periods of the study. The two formulations test and reference were considered bioequivalent if 90% confidence interval (CI) fell within 80.00% - 125.00% for Cmax, AUC0-t and AUC0-∞. Tolerability and safety were assessed throughout the study. Results: The pharmacokinetic (PK) parameters were similar between the test product (T) and reference product (R) Synjardy®. The 90% CI of the test/reference ratios of log-transformed PK parameters point estimates was Cmax: 89.87% (85.68% - 94.27%), AUC0-t: 87.91% (83.65% - 92.39%) and AUC0-∞: 87.16% (82.80% - 91.75%) to empagliflozin and Cmax: 92.19% (87.95% - 96.65%), AUC0-t: 91.38% (84.42% - 98.91%) and AUC0-∞: 93.78% (83.82% - 104.93%) to metformin respectively (90% CI for all PK parameters fell within 80.00% - 125.00%). Conclusion: Our results demonstrated BE between the test and reference formulations of oral tablets of empagliflozin 12.5 mg/metformin 1000 mg (FDC) in healthy male subjects under fasting conditions.

Enhancing metformin-induced tumor metabolism destruction by glucose oxidase for triple-combination therapy

Despite decades of laboratory and clinical trials,breast cancer remains the main cause of cancer-related disease burden in women.Considering the metabolism destruction effect of metformin(Met)and cancer cell starvation induced by glucose oxidase(GOx),after their efficient delivery to tumor sites,GOx and Met may consume a large amount of glucose and produce sufficient hydrogen peroxide in situ.Herein,a pH-responsive epigallocatechin gallate(EGCG)-conjugated low-molecular-weight chitosan(LC-EGCG,LE)nanoparticle(Met–GOx/Fe@LE NPs)was constructed.The coordination between iron ions(Fe3+)and EGCG in this nanoplatform can enhance the efficacy of chemodynamic therapy via the Fenton reaction.Met–GOx/Fe@LE NPs allow GOx to retain its enzymatic activity while simultaneously improving its stability.Moreover,this pH-responsive nanoplatform presents controllable drug release behavior.An in vivo biodistribution study showed that the intracranial accumulation of GOx delivered by this nanoplatform was 3.6-fold higher than that of the free drug.The in vivo anticancer results indicated that this metabolism destruction/starvation/chemodynamic triple-combination therapy could induce increased apoptosis/death of tumor cells and reduce their proliferation.This triple-combination therapy approach is promising for efficient and targeted cancer treatment.

Pressure stimulated current in progressive failure process of combined coal-rock under uniaxial compression:Response and mechanism

Effective monitoring of the structural health of combined coal-rock under complex geological conditions by pressure stimulated currents(PSCs)has great potential for the understanding of dynamic disasters in underground engineering.To reveal the effect of this way,the uniaxial compression experiments with PSC monitoring were conducted on three types of coal-rock combination samples with different strength combinations.The mechanism explanation of PSCs are investigated by resistivity test,atomic force microscopy(AFM)and computed tomography(CT)methods,and a PSC flow model based on progressive failure process is proposed.The influence of strength combinations on PSCs in the progressive failure process are emphasized.The results show the PSC responses between rock part,coal part and the two components are different,which are affected by multi-scale fracture characteristics and electrical properties.As the rock strength decreases,the progressive failure process changes obviously with the influence range of interface constraint effect decreasing,resulting in the different responses of PSC strength and direction in different parts to fracture behaviors.The PSC flow model is initially validated by the relationship between the accumulated charges of different parts.The results are expected to provide a new reference and method for mining design and roadway quality assessment.

Adaptive H_(∞)Filtering Algorithm for Train Positioning Based on Prior Combination Constraints

To solve the problem of data fusion for prior information such as track information and train status in train positioning,an adaptive H∞filtering algorithm with combination constraint is proposed,which fuses prior information with other sensor information in the form of constraints.Firstly,the train precise track constraint method of the train is proposed,and the plane position constraint and train motion state constraints are analysed.A model for combining prior information with constraints is established.Then an adaptive H∞filter with combination constraints is derived based on the adaptive adjustment method of the robustness factor.Finally,the positioning effect of the proposed algorithm is simulated and analysed under the conditions of a straight track and a curved track.The results show that the positioning accuracy of the algorithm with constrained filtering is significantly better than that of the algorithm without constrained filtering and that the algorithm with constrained filtering can achieve better performance when combined with track and condition information,which can significantly reduce the train positioning error.The effectiveness of the proposed algorithm is verified.

Numerical Investigation of Combined Production of Natural Gas Hydrate and Conventional Gas

Natural gas hydrate(NGH)is generally produced and accumulated together with the underlying conventional gas.Therefore,optimizing the production technology of these two gases should be seen as a relevant way to effectively reduce the exploitation cost of the gas hydrate.In this study,three types of models accounting for the coexistence of these gases are considered.Type A considers the upper hydrate-bearing layer(HBL)adjacent to the lower conventional gas layer(CGL);with the Type B a permeable interlayer exists between the upper HBL and the lower CGL;with the type C there is an impermeable interlayer between the upper HBL and the lower CGL.The production performances associated with the above three models are calculated under different conditions,including only a depressurized HBL(only HBL DP);only a depressurized CGL(only CGL DP);and both the HBL and the CGL being depressurized(HBL+CGL DP).The results show that for Type A and Type B coexistence accumulation models,when only HBL or CGL is depressurized,the gas from the other layer will flow into the production layer due to the pressure difference between the two layers.In the coexistence accumulation model of type C,the cumulative gas production is much lower than that of Type A and Type B,regardless of whether only HBL DP,only CGL DP,or HBL+CGL DP are considered.This indicates that the impermeable interlayer restricts the cross-flow of gas between HBL and CGL.For three different coexistence accumulation models,CGL DP has the largest gas-to-water ratio.

Lenvatinib combined with sintilimab plus transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma

BACKGROUND Recently,combination therapy has shown a better trend towards improved tumour response and survival outcomes than monotherapy in patients with hepatocellular carcinoma(HCC).However,research on triple therapy[lenvatinib+sintilimab+transarterial chemoembolization(TACE)]as a first-line treatment for advanced HCC is limited.AIM To evaluate the safety and efficacy of triple therapy as a first-line treatment for advanced HCC.METHODS HCC patients with Barcelona Clinic Liver Cancer stage C treated with triple therapy were enrolled.All patients were treated with lenvatinib every day and sintilimab once every 3 wk.Moreover,TACE was performed every 4-6 wk if necessary.The primary outcome of the study was overall survival(OS).The secondary outcomes were the objective response rate(ORR),disease control rate(DCR),and incidence of adverse events.RESULTS Forty HCC patients who underwent triple therapy were retrospectively analysed from January 2019 to January 2022.With a median follow-up of 8.5 months,the 3-,6-,and 12-mo OS rates were 100%,88.5%,and 22.5%,respectively.The ORR and DCR were 45%and 90%,respectively.The median progressive free survival and median OS were not reached.Common complications were observed in 76%of the patients(grade 3,15%;grade 4,2.5%).CONCLUSION Combination therapy comprising lenvatinib,sintilimab and TACE achieved promising outcomes in advanced HCC patients and had manageable effects.

A Subdivision-Based Combined Shape and Topology Optimization in Acoustics

We propose a combined shape and topology optimization approach in this research for 3D acoustics by using the isogeometric boundary element method with subdivision surfaces.The existing structural optimization methods mainly contain shape and topology schemes,with the former changing the surface geometric profile of the structure and the latter changing thematerial distribution topology or hole topology of the structure.In the present acoustic performance optimization,the coordinates of the control points in the subdivision surfaces fine mesh are selected as the shape design parameters of the structure,the artificial density of the sound absorbing material covered on the structure surface is set as the topology design parameter,and the combined topology and shape optimization approach is established through the sound field analysis of the subdivision surfaces boundary element method as a bridge.The topology and shape sensitivities of the approach are calculated using the adjoint variable method,which ensures the efficiency of the optimization.The geometric jaggedness and material distribution discontinuities that appear in the optimization process are overcome to a certain degree by the multiresolution method and solid isotropic material with penalization.Numerical examples are given to validate the effectiveness of the presented optimization approach.

Combinational therapy with Myc decoy oligodeoxynucleotides encapsulated in nanocarrier and X-irradiation on breast cancer cells

The Myc gene is the essential oncogene in triple-negative breast cancer(TNBC).This study investigates the synergistic effects of combining Myc decoy oligodeoxynucleotides-encapsulated niosomes-selenium hybrid nanocarriers with X-irradiation exposure on the MDA-MB-468 cell line.Decoy and scramble ODNs for Myc transcription factor were designed and synthesized based on promoter sequences of the Bcl2 gene.The nanocarriers were synthesized by loading Myc ODNs and selenium into chitosan(Chi-Se-DEC),which was then encapsulated in niosome-nanocarriers(NISM@Chi-Se-DEC).FT-IR,DLS,FESEM,and hemolysis tests were applied to confirm its characterization and physicochemical properties.Moreover,cellular uptake,cellular toxicity,apoptosis,cell cycle,and scratch repair assays were performed to evaluate its anticancer effects on cancer cells.All anticancer assessments were repeated under X-ray irradiation conditions(fractionated 2Gy).Physicochemical characteristics of niosomes containing SeNPs and ODNs showed that it is synthesized appropriately.It revealed that the anticancer effect of NISM@Chi-Se-DEC can be significantly improved in combination with X-ray irradiation treatment.It can be concluded that NISM@Chi-Se-DEC nanocarriers have the potential as a therapeutic agent for cancer treatment,particularly in combination with radiation therapy and in-vivo experiments are necessary to confirm the efficacy of this nano-drug.