Ionic liquids as the effective technology for enhancing transdermal drug delivery: Design principles, roles, mechanisms, and future challenges

Ionic liquids (ILs) have been proven to be an effective technology for enhancing drug transdermal absorption. However, due to the unique structural components of ILs, the design of efficient ILs and elucidation of action mechanisms remain to be explored. In this review, basic design principles of ideal ILs for transdermal drug delivery system (TDDS) are discussed considering melting point, skin permeability, and toxicity, which depend on the molar ratios, types, functional groups of ions and inter-ionic interactions. Secondly, the contributions of ILs to the development of TDDS through different roles are described: as novel skin penetration enhancers for enhancing transdermal absorption of drugs;as novel solvents for improving the solubility of drugs in carriers;as novel active pharmaceutical ingredients (API-ILs) for regulating skin permeability, solubility, release, and pharmacokinetic behaviors of drugs;and as novel polymers for the development of smart medical materials. Moreover, diverse action mechanisms, mainly including the interactions among ILs, drugs, polymers, and skin components, are summarized. Finally, future challenges related to ILs are discussed, including underlying quantitative structure-activity relationships, complex interaction forces between anions, drugs, polymers and skin microenvironment, long-term stability, and in vivo safety issues. In summary, this article will promote the development of TDDS based on ILs.

Monitoring Study of Long-Term Land Subsidence during Subway Operation in High-Density Urban Areas Based on DInSAR-GPS-GIS Technology and Numerical Simulation

During subway operation,various factors will cause long-term land subsidence,such as the vibration subsidence of foundation soil caused by train vibration load,incomplete consolidation deformation of foundation soil during tunnel construction,dense buildings and structures in the vicinity of the tunnel,and changes in water level in the stratum where the tunnel is located.The monitoring of long-term land subsidence during subway operation in high-density urban areas differs from that in low-density urban construction areas.The former is the gathering point of the entire urban population.There are many complex buildings around the project,busy road traffic,high pedestrian flow,and less vegetation cover.Several existing items requiremonitoring.However,monitoring distance is long,and providing early warning is difficult.This study uses the 2.8 km operation line between Wulin Square station and Ding’an Road station of Hangzhou Subway Line 1 as an example to propose the integrated method of DInSAR-GPS-GIS technology and the key algorithm for long-term land subsidence deformation.Then,it selects multiscene image data to analyze long-termland subsidence of high-density urban areas during subway operation.Results show that long-term land subsidence caused by the operation of Wulin Square station to Ding’an Road station of Hangzhou Subway Line 1 is small,with maximumsubsidence of 30.64 mm,and minimumsubsidence of 11.45 mm,and average subsidence ranging from 19.27 to 21.33 mm.And FLAC3D software was used to verify the monitoring situation,using the geological conditions of the soil in the study area and the tunnel profile to simulate the settlement under vehicle load,and the simulation results tended to be consistent with the monitoring situation.

Reflection and transmission of elastic waves through a couple-stress elastic slab sandwiched between two half-spaces

The reflection and transmission of elastic waves through a couple-stress elastic slab that is sandwiched between two couple-stress elastic half-spaces are studied in this paper. Because of the couple-stress effects, there are three types of elastic waves in the couple-stress elastic solid, two of which are dispersive. The interface conditions between two couple-stress solids involve the surface couple and rotation apart from the surface traction and displacement. The nontraditional interface conditions between the slab and two solid half-spaces are used to obtain the linear algebraic equation sets from which the amplitude ratios of reflection and transmission waves to the incident wave can be determined. Then,the energy fluxes carried by the various reflection and transmission waves are calculated numerically and the normal energy flux conservation is used to validate the numerical results. The special case, couple-stress elastic slab sandwiched by the classical elastic half-spaces, is also studied and compared with the situation that the classical elastic slab sandwiched by the classical elastic half-spaces. Incident longitudinal wave(P wave) and incident transverse wave(SV wave) are both considered. The influences of the couplestress are mainly discussed based on the numerical results.It is found that the couple-stress mainly influences the transverse modes of elastic waves.

Genome-wide identification and expression analysis of NtbHLH gene family in tobacco(Nicotiana tabacum)and the role of NtbHLH86 in drought adaptation

The bHLH transcription factors play pivotal roles in plant growth and development,production of secondary metabolites and responses to various environmental stresses.Although the bHLH genes have been well studied in model plant species,a comprehensive investigation of the bHLH genes is required for tobacco with newly obtained high-quality genome.In the present study,a total of 309 NtbHLH genes were identified and can be divided into 23 subfamilies.The conserved amino acids which are essential for their function were predicted for the NtbHLH proteins.Moreover,the NtbHLH genes were conserved during evolution through analyzing the gene structures and conserved motifs.A total of 265 NtbHLH genes were localized in the 24 tobacco chromosomes while the remained 44 NtbHLH genes were mapped to the scaffolds due to the complexity of tobacco genome.Moreover,transcripts of NtbHLH genes were obviously tissue-specific expressed from the gene-chip data from 23 tobacco tissues,and expressions of 20 random selected NtbHLH genes were further confirmed by quantitative real-time PCR,indicating their potential functions in the plant growth and development.Importantly,overexpressed NtbHLH86 gene confers improve drought tolerance in tobacco indicating that it might be involved in the regulation of drought stress.Therefore,our findings here provide a valuable information on the characterization of NtbHLH genes and further investigation of their functions in tobacco.

The APETALA2 homolog CaFFN regulates flowering time in pepper

Flowering time is an important agronomic trait that contributes to fitness in plants.However,the genetic basis of flowering time has not been extensively studied in pepper.To understand the genetics underlying flowering time,we constructed an F 2 population by crossing a spontaneous early flowering mutant and a late-flowering pepper line.Using bulked segregant RNA-seq,a major locus controlling flowering time in this population was mapped to the end of chromosome 2.An APETALA2(AP2)homolog(CaFFN)cosegregated with flowering time in 297 individuals of the F 2 population.A comparison between the parents revealed a naturally occurring rare SNP(SNP2T>C)that resulted in the loss of a start codon in CaFFN in the early flowering mutant.Transgenic Nicotiana benthamiana plants with high CaFFN expression exhibited a delay in flowering time and floral patterning defects.On the other hand,pepper plants with CaFFN silencing flowered early.Therefore,the CaFFN gene acts as a flowering repressor in pepper.CaFFN may function as a transcriptional activator to activate the expression of CaAGL15 and miR156e and as a transcriptional repressor to repress the expression of CaAG,CaAP1,CaSEP3,CaSOC1,and miR172b based on a qRT-PCR assay.Direct activation of CaAGL15 by CaFFN was detected using yeast one-hybrid and dual-luciferase reporter assays,consistent with the hypothesis that CaFFN regulates flowering time.Moreover,the CaFFN gene association analysis revealed a significant association with flowering time in a natural pepper population,indicating that the CaFFN gene has a broad effect on flowering time in pepper.Finally,the phylogeny,evolutionary expansion and expression patterns of CaFFN/AP2 homologs were analyzed to provide valuable insight into CaFFN.This study increases our understanding of the involvement of CaFFN in controlling flowering time in pepper,thus making CaFFN a target gene for breeding early maturing pepper.

Unstable Allotetraploid Tobacco Genome due to Frequent Homeologous Recombination, -. Segmental Deletion, and Chromosome Loss

The types of mutations and their corresponding frequencies are difficult to measure in complex genomes. In this study, a high-throughput method was developed to identify spontaneous loss-of-function alleles for the resistance gene N and the transgenic avirulence gene P50 in allotetraploid tobacco. A total of 2134 loss- of-function alleles of the N gene were identified after screening 14 million F1 hybrids. Analysis of these mutants revealed striking evolutionary patterns for genes in polyploids. Only 14 of the loss-of-function mutations were caused by spontaneous point mutations or indels, while the others were caused by home- ologous recombination （with a frequency of 1/12 000） or chromosome loss （1/15 000）. Loss of the chromosome with the PS0 insertion occurred at a similar frequency （1/13 000）, and the frequency of spon- taneous segmental deletion in this chromosome was 1/16 000. Both homeologous recombination and chromosome loss considerably decreased the viability of the mutants. Our data suggest that the high mutation rate in polyploids is probably due to the occurrence of homeologous recombination and the toler- ance of large mutations such as chromosome loss in polyploid genomes. Frequent mutations tend to drive polyploids to extinction unless a novel mutation helps the polyploid to effectively compete with diploids or find a new ecological niche.

Relection of elastic waves at the elastically supported boundary of a couple stress elastic half-space

The relection elastic waves at the elastically supported boundary of a couple stress elastic half-space are studied in this paper. Different from the classical elastic solid, there are three kinds of elastic waves in the couple stress elastic solid, and two of them are dispersive. The boundary conditions of a couple stress elastic half-space include the couple stress vector and the rotation vector which disappear in the classical elastic solids. These boundary conditions are used to obtain a linear algebraic equation set, from which the amplitude ratios of relection waves to the incident wave can be determined. Then, the relection coeficients in terms of energy lux ratios are calculated numerically, and the normal energy lux conservation is used to validate the numerical results. Based on these numerical results,the inluences of the boundary parameters, which relect the mechanical behavior of elastic support, on the relection energy partition are discussed. Both the incident longitudinal wave（the P wave） and incident transverse wave（the SV wave） are considered.