It has been stated clearly that nanofillers could make an enhancement on the mechanical performances of dental composites. In order to address current shortage of traditional dental composites, fillers in forms of nanofibers or nanotubes are broadly regarded as ideal candidates to greatly increase mechanical performances of dental composites with low content of fillers. In this review, the efforts using nanofibers and nanotubes to reinforce mechanical performances of dental composites, including polymeric nanofibers, metallic nanofibers or nanotubes, and inorganic nanofibers or nanotubes, as well as their researches related, are demonstrated in sequence. The first purpose of current paper was to confirm the enhancement of nanofibers or nanotubes' reinforcement on the mechanical performances of dental restorative composite. The second purpose was to make a general description about the reinforcement mechanism of nanofibers and nanotubes, especially, the impact of formation of interphase boundary interaction and nanofibers themselves on the advanced mechanical behaviors of the dental composites. By means of the formation of interface interaction and poststretching nanofibers, reinforced effect of dental composites by sorts of nanofibers/nanotubes has been successfully obtained. In the past few decades, as a result of safety and esthetic consideration, dental composites have been generally accepted to substitute conventional “dental amalgams.” The curing mode of dental composites is free radical polymerization induced by light. Generally speaking, we usually take Camphorquinone as common photoinitiator and ethyl-4-(dimethylamino) benzoate (4EDMAB)  as commoIn the academia and industry, nanofibers and nanotubes have already been employed to strengthen dental composites. Introduction of nanofibers or nanotubes allows obtaining targeted materials with high performance in various fields. Nanofillers are very different from traditional fillers due to their large specific surface area, high aspect-ratio and unique microstructure . AdditioBased on the above information, for the sake of satisfying increasingly high requirement for dental resin composites' mechanical performances, the research was conducted to make a further confirmation about the enhanced effects of nanofillers in forms of nanofibers/nanotubes. In this review, the methods using nanofibers and nanotubes to reinforce mechanical performances of dental composites are demonstrated in sequence, including inorganic nanofibers/nanotubes, polymeric nanofibers/nanotubes, and metallic nanofibers. The first purpose of current paper is to confirm the enhancement of nanofibers or nanotubes' reinforcement on the mechanical performances of dental restorative composite. The second purpose is to make a general description about the reinforcement mechanism of nanofibers and nanotubes, especially, the influence of formation of the mutual permeating structure and nanofibers themselves on the mechanical performances of the dental composites.2 is unfitted to be reinforcing filler in dental composites. In general, when glass fillers in scale from dozens of nanometers to few microns are employed to reinforce the dental composites, the corresponding dental resin composites strengthen by micron-scaled glass fillers are unsuitable for broader uses under high stress circumstances, such as in case of replacement of cusps. Researchers have made a study about the enhancement of dental composites using certain glass fibers (with diameters of about ten microns) [Generally, inorganic fillers with a certain mass proportion are usually employed to reinforce the dental resin composites. Among lots of inorganic fillers, glass is the most usually used inorganic fibers during the reinforcement of dental composites. The following factors may interpret the reason why glass is most usually used. Firstly, the most essential demands of dental restoration composites could be satisfied by addition of appropriate amounts of glass. Secondly, glass possesses an index of refraction very close to that of the dental resins, equipping the resultant composites with semitransparent surfaces. Also, it is just for the reason of index of refraction mismatch with dental resins that crystalline SiOmicrons) ; howeverBoth polymeric and inorganic nanofibers (with diameters of a few nanometers) can be fabricated feasibly and conveniently by means of established electrospinning technique, and we name these nanofibers “electrospun nanofibers” usually . By way In terms of enhancement of dental composites, the nanoscaled glass fibers are believed to be so much better than conventional micron-scaled glass particles/fibers. It is the characteristics of electrospun nanofibers  that enable nanoscaled glass fibers to assume wanted structure, morphology, and performances. The following mechanism may explain the reason why small content of nanoscaled glass fibers can reinforce the dental composites drastically. When dental resin composites are under external pressure or three-body friction, microcracks are easily tended to be produced in the body of dental matrix. Although the cracks are formed, the gap between crack planes is not a vacuum and thin and long glass fibers exist in the middle section bearing load constantly, until glass fibers are broken completely. So, we can make an easy understanding that crack expansion is inhibited by the fibers, and meanwhile the matrix will become more powerful. In comparison with micron-scaled glass fibers, the nanoscaled glass fibers are thinner and also have substantial surface Si–OH groups which could interact with various silane coupling agents. Consequently, the interfacial adhesion force between the nanoscaled silanized glass fiber and the dental resin matrix will go more powerful.In many of electrospun inorganic nanofibers, great attention has been given to glass nanofibers by researchers owing to well-understood pretreatment and extensive applications in various aspects . Chen etIn addition, even if electrospun glass nanofibers suffer from powerful ultrasonic violence, the whole morphology of electrospun glass nanofibers could be well maintained indicating that the glass nanofibers possess both natural morphology and structure. So we have every reason to believe that the electrospun glass nanofibers can be the most promising candidate in the reinforcement of dental resin composites.Hydroxyapatite (HAP), tetracalcium phosphate, and dicalcium phosphate anhydrous are typical and biocompatible calcium phosphates fillers –36. For Lots of single crystals in level of nanometers make up fibrillar silicate. palygorskite, whose reserve is the largest in China and America, is the most rich fibrillar silicate minerals in all types of fibrillar silicate minerals in the natural world. Silicate single crystals (about 100–3000 nm in length and 10–25 nm in diameter) are the most basic components of fibrillar silicate and micron-scaled particles can be formed by stacking mentioned single crystals , 39. HigThe most commonly used method to prepare kinds of ultrafine nanofibers is electrospinning because of its convenience and simplicity –44. The In the course of preparing nylon 6 nanofibers by electrospinning , accelerVariety of nanofibers can be fabricated successfully by means of electrospinning technique. Generally speaking, nozzle is connected with positive electrode, and the collector is usually linked with cathode. The polyacrylonitrile/poly (methyl methacrylate) (PAN/PMMA) membrane was smoothly prepared by electrospinning by Lin et al. . By way Some shortcomings still exist in nonwoven nanofibers (diameters in the range of 500–800 nm) as reinforcing filler in spite of a few achieved accomplishments. Report said that irregular alignment of nanofibers leads to a decreased crystallinity and thus influencing the intensity of nanofibers membranes seriously .Lately, for the sake of raising the strength of electrospun nanofibers, much attention has been focused on the poststretching handling of nanofibers (diameters in the range of 300–500 nm) , 53. It So, we can completely consider that mechanical performance  of electrospun nanofibers membranes can be enhanced clearly by the process of poststretching treatment. Furthermore, compared with normal electrospun PAN/PMMA nanofibers, dental composites strengthened by poststretching nanofibers possess better mechanical performance . Ultimately, Sun et al. believed that formation of partial interpenetrating network in the interface and enhanced strength of poststretching nanofibers are the biggest reason why the mechanical performances  of Bis-GMA dental composites can be intensified by poststretching PAN/PMMA nanofibers with special structure.By means of electrospinning which is a convenient, simple, and practical technique, we can prepare various nanofibers in the scale from some micrometers to nanometers . But, owing to relatively low mechanical properties of natural nanofibers, they are usually not used as fillers to reinforce dental composites –60. ThroAs we know, polymer nanofibers take on lots of advantages, such as wide range of scale, distinctive structure, super-high specific aspect ratio, and outstanding mechanical performances. Selection of diverse polymer species, mix of different polymers, various treatment ways of nanofibers, and other factors could have a substantial influence on the structure, composition, and performance of electrospun nanofibers. By electrospinning technique, we enable sorts of nanofillers (such as kinds of inorganic nanoparticles) to impregnate the body of composites uniformly. For example, we could put multiwalled carbon nanotubes (MWCNT) to dissolve in the particular polymer solutions, and then we could obtain continuous nanofibers containing carbon nanotubes which can be used as nanofiller by electrospinning technique. Chronakis  successfThe simplicity of modification on both surface and internal of polymer nanofibers is another reason why we focus on the polymer nanofibers . Various3N4 and SiN ceramic whiskers [Despite dental resin composites are broadly applied to restore tooth. The service life of composites is far shorter than that of amalgams because of inner cracks and fracture . In ordewhiskers –74. Sincwhiskers . Particuwhiskers . The reaIn terms of strength and service life, dental amalgams are far better than that of composites enhanced by majority of inorganic fillers. The applications of dental composites strengthened by much of inorganic fillers are restricted seriously just because of reason above –79. Currμm and Young's modulus of halloysite nanotubes is in the scope from 230 to 340 GPa. Moreover, safety, biocompatibility, and easy handling are also the characteristics of halloysites. Compared with montmorillonite, halloysite is more easy to exfoliate into single halloysite nanotubes (HNTs) and to scatter in the dental composites evenly.Being different from fibers in scale of microns, nanoscaled crystals make up hallosite . HalloysThe room among stacked layers may account for the reason. The room among silicate layers in montmorillonite is smaller than that of hallosite; hence, the interaction of montmorillonite is more powerful than that of hallosite. Hence, as to hallosite, it is not necessary to replace metal ions with special reagent at all. The halloysite nanotube in halloysite can be split fully in the presence of polar solvents and mechanical agitation. Moreover, as a result of existence of rich Si–OH group on the external of halloysite nanotubes (HNTs), the silanized halloysite nanotube could be closely connected with dental resin matrix via tremendously powerful interfacial linking force. The enhancement of Bis-GMA/TEGDMA dental resins or composites boosted by various contents of HNTs was studied by Chen et al. . For spl2. Eventually, what we hope is excellent scattering and substantial bonding force of single-walled carbon nanotubes after addition into the dental composites, and we also expect that the performances could be enhanced tremendously. The impregnation of modified single-walled carbon nanotubes indeed brings about enhancement of dental resin composites obviously by the statistical analysis. Moreover, other researchers indeed demonstrated that the carbon nanotubes could be a very promising scaffold material for dental materials [As everyone knows, carbon nanotubes possess astonishing mechanical performances and excellent biocompatibility –88. For aterials .Boron nitride nanotubes, which possess tremendous tensile strength, have a similar structure to carbon nanotubes . ExactlyTitania Nanotubes. The appearance of nanomaterials provides an opportunity to advance the mechanical performances of dental composites and bone cements to a new level [2 nanotubes and dental matrix. Certainly, this late-fashioned nanofiller coupled with the current fillers could be employed together to strengthen flowable and usual dental composites with no damage in biocompatibility.ew level , 101. Khew level . Nanotubew level  carried Generally speaking, the nanofibers take on the shape long and thin and possess diameters at hundreds of nanometers. Nanotubes have the tubular structure and slightly bigger diameters. As with surface properties, lots of functional groups exist on the surface of nanofibers, such as –OH group, but these groups do not exist on the nanotubes commonly, so we should conduct a treatment on the nanotubes before their usage. Owing to distinctive structure of nanotubes, they usually have relatively high strength than nanofibers, but it does not mean that nanotubes are better fillers than nanofibers. For reinforcement of dental composites, it mostly depends on the condition of nanofillers themselves and their status in the matrix, such as dispersion, interbonding, and other influence factors. As long as we take full and reasonable advantage of these nanofillers, the substantial increase on mechanical performance of dental composites will be acquired definitely .Through the study of so many cases of enhancement of nanotubes/nanofibers, a reinforcing mechanism could be seen clearly. Namely, under high external pressure, microcracks tend to be created in the body of dental composites. However, the room of cracks is not empty, nanofibers or nanotubes still exist in the middle of cracks plane and function across planes. Thereby, cracks are prevented via the remaining fillers. Hence, much of the stress is transmitted through the fillers into the resins, and that is the reason why the nanofillers must be largely tougher than the resin matrices. Of course, the Van der Waals' force via physical entanglement and chemical bonding between nanofillers and matrix lays the theoretical foundation for the improvement of dental composites' performance. The enhanced performances of composites boosted by poststretching PAN/PMMA nanofibers are the best example of previous viewpoint. So, powerful mechanical performances and ultrasmall scale are the necessary condition for valid bridging fillers.Another strengthening mechanism is that uniform dispersion of fillers throughout the matrices is needed. Supposing that the immersed parts of fillers are irregular in appearance, it will tend to form the stress concentration easily. Also, stress concentration is the main reason for creating small cracks in the matrix, thus damaging the properties of composites. Therefore, to produce the biggest effect of chemical bond, nanofillers should be dispersed as uniform as possible. The nanofillers which are highly aligned along some orientation (such as across the cracks) could impede the growth of crack, thus raising the mechanical behavior of dental resin and reinforcing the dental composites.Last strengthening mechanism but most importantly is the interaction between nanofillers and composites. In the course of preparing composite materials, what we should consider most is the interactions between fillers and resin matrix, namely, interfacial adhesion. In the condition of filler-strengthened dental composites, interfacial properties have a crucial impact on the performances of resulting dental composites. High fillers surface area could raise the extent of entanglement between various fillers and surrounding dental resin and the best case is the formation of the mutual permeating structure in the middle of fillers and the dental matrix, which bring about a specific interface in the nanometer scale. At the same time, powerful interfacial binding force between different phases aimed to hinder the movement of polymer chains is prospected to be produced, and then corresponding mechanical performances of resultant dental composites will be reinforced. For the purpose of enhancing the interfacial chemical binding, various measurements will be taken, such as functioning of nanofillers. As to this strengthening mechanism, extremely strong chemical bond between nanofillers and matrix is the most vital factor for reinforcing.So, in my opinion, the potential reinforcement mechanism is that extreme toughness nanofibers and nanotubes are fabricated. Provided that immersed parts of fillers are irregular in appearance, it will tend to form the stress concentration easily. Also, stress concentration is the main reason for generating small cracks in the matrix, thus damaging the properties of composites. Then we disperse them uniformly in the dental matrix in some direction and when the microcrack emerges. Powerful bonding between nanofibers and nanotubes will impede the growth of cracks, which will greatly facilitate the reinforcement of dental composites . In brieIn this review, the efforts using nanofibers and nanotubes to reinforce mechanical performances of dental composites, including polymeric nanofibers/nanotubes, metallic nanofibers, and inorganic nanofibers/nanotubes, as well as their researches related, are demonstrated in sequence. We demonstrated the use of kinds of nanofibers or nanotubes to reinforce dental composites. Addition of nanofibers or nanotubes could acquire composites materials with distinct performances in lots of areas. Nanofillers are very different from traditional fillers largely because of their scale in nanometers and special microstructure, and we can make a substantial increase on the mechanic properties of resin composites by means of nanotechnology. On the way to conquer current flaws of traditional dental composites, fillers in forms of nanofibers or nanotubes are the most promising fillers to raise the mechanical performances of dental composites tremendously at a low content. We also make a general understating of the potential reinforce cement mechanism, the reinforcement effect which greatly depends on nanofillers' toughness, condition of nanofillers' dispersion in the body, and powerful bonding between nanofillers (in forms of nanofibers or nanotubes) and matrix. It is because we already have a broad understanding of the influence factor of reinforcement effect that we have a clear direction for the future development.In the future, a further study on the mechanism of reinforcing the dental composites should be carried on, as well as the influence factor of reinforcement effect. Only when we master the mechanism of reinforcing the dental composites well and the influence factor of reinforcement effect can we make a further increase reinforcement of the dental composites. Additionally, more novel methods of preparing nanofibers or nanotubes will be introduced. In order to put the mechanical performances of dental resin composites to a completely new level, more tough nanofillers should be fabricated, the method of dispersing nanofillers more uniformly should be found, and interfacial adhesion between fillers and the body should be more and more powerful.


Mycobacterium bovis) is of major economical concern in many countries; approximately 15 000 to 20 000 cattle are infected per year in Ireland. The objective of this study was to quantify the genetic variation for bTB susceptibility in Irish dairy and beef cattle.Infection of livestock with bovine tuberculosis  collected from the years 2001 to 2010 from dairy and beef herds were included in the analysis. Only animal level data pertaining to periods of herd bTB infection were retained. Variance components for bTB were estimated using animal linear and threshold mixed models and co-variances were estimated using sire linear mixed models.Using a linear model, the heritability for susceptibility to bTB in the entire dataset was 0.11 and ranged from 0.08 (heifers in dairy herds) to 0.19 (heifers in beef herds) among the sub-populations investigated. Differences in susceptibility to bTB between breeds were clearly evident. Estimates of genetic correlations for bTB susceptibility between animal types  were all positive (0.10 to 0.64), yet different from one. Furthermore, genetic correlations for bTB susceptibility between environments that differed in herd prevalence of bTB ranged from 0.06 to 0.86 and were all different from one.Genetic trends for bTB susceptibility observed in this study suggest a slight increase in genetic susceptibility to bTB in recent years. Since bTB is of economic importance and because all animals are routinely tested at least once annually in Ireland and some other countries, the presence of genetic variation for bTB susceptibility suggests that bTB susceptibility should be included in a national breeding program to halt possible deterioration in genetic susceptibility to bTB infection. Mycobacterium bovis. Infection of livestock with bTB has an estimated global cost of €2 billion annually [Bovine tuberculosis (bTB) is an infectious chronic respiratory disease caused by annually , due mosannually , primariannually , althougannually ,6. When annually . Re-emerannually -10, withannually .Meles meles) populations in which bTB is endemic [The existence of wildlife reservoirs for bTB is a major contributing factor to the continued infection of bTB in livestock. In Ireland and the UK, cattle share their environment with wild badger  for bTB resistance in national genetic evaluations. As well as being useful for incorporation into breeding programs, these EBV could also be useful phenotypes for subsequent genomic analysis.Ireland has operated a compulsory bTB eradication program since the late 1950s. The current national program consists of a mandatory registration system for herds, an individual bovine identification system, a computerised movement monitoring system, an animal health computer system, as well as a comprehensive program of disease surveillance and control. Two forms of surveillance are used in Ireland. Field surveillance for bTB is performed annually in each herd through the routine use of the single intra-dermal comparative tuberculin test (SICTT) ,15. TestM. bovis) into the neck of the animal. This inoculate will cause an immune reaction to the tuberculin in animals that are sensitised to antigens in bovine tuberculin and results in an inflammatory response and localised swelling at the injection site that reaches its greatest intensity 48 to 72 h post-injection. To distinguish animals infected with different strains of Mycobacterium from those infected with M. bovis, animals are also injected at a different site with avian tuberculin (from M. avium). The outcome of the SICTT is determined by the relative difference in the thickness of skin-folds in reaction to the bovine and avian tuberculins. Using the so-called standard interpretation , if the relative bovine-avian difference in skin-fold test is greater than 4 mm, the animal is considered a ‘standard reactor’, if between 1 and 4 mm, a ‘standard inconclusive reactor’, and otherwise, a ‘non-reactor’ [Field surveillance using the SICTT involves intradermal injection of bovine tuberculin  are achieved, at which point herd bTB-free status is regained. In restricted herds, a lower threshold  of the SICTT is used, such that all animals with a bovine-avian difference of at least 2 mm are considered a ‘reactor under severe interpretation’ and animals with a bovine reaction less than 2 mm greater than an avian tuberculin reaction are considered an ‘inconclusive reactor under severe interpretation’. Additional skin tests are always undertaken on herds that are contiguous to, or otherwise linked to, infected herds, and in herds that are located in 'at-risk' areas. Herds are also re-tested for bTB six months after they have re-gained bTB free status.In the present study, a ‘herd-episode of bTB infection’ refers to the full period of herd restriction triggered by disclosure of bTB infection within a herd . The herTuberculin skin test results from 22 381 herd-episodes in 16 717 dairy, beef and mixed herds were collected between 2001 and 2010, inclusive. Herds were classified as either dairy, beef or mixed, determined by the average breed composition of cows in each herd. Herds were defined as dairy herds if the average breed composition of that herd was ≥90% dairy breed, while herds were defined as beef herds if the average breed composition of that herd was ≥30% beef breed. All other herds were defined as mixed herds. The total number of breeds represented across all herd-episodes was 35, with the mean number of breeds per herd-episode being 2.3; 5571 herd-episodes had more than one breed present during a herd-episode, across both dairy and beef herds.Only positive and inconclusive results were recorded in the database. During these herd-episodes, there were a total of 183 955 ‘standard reactors’ and ‘reactors under severe interpretation’, 20 884 ‘standard inconclusive reactors’, and 1896 ‘inconclusive reactors under severe interpretation’. Confirmed bTB lesions were identified in 50 614 reactors from postmortem examinations and/or tissue culture samples. The national animal identification and movement system, which monitors animal movements in and out of herds, was used to identify animals present in herds at the time of testing. In total, 1 357 791 animals were present during herd-episodes but did not test positive or inconclusive for bTB. Animals were only included if they had moved into a herd more than six weeks prior to the start of a herd-episode. In the present study, only ‘standard reactors’ and ‘reactors under severe interpretation’ were considered to be infected with bTB; thus the inconclusive reactors were removed from the dataset. Animals with no recorded sire were discarded.Animal age at the start of each herd-episode was determined. Female animals that were more than 30 months old or had calved at least once by the start of the herd-episode were classified as cows, and otherwise as heifers. Male animals that were less than 36 months at the start of the herd-episode were classified as steers , and otherwise as bulls. Due to the paucity of data (n = 1822), bulls were subsequently discarded from the dataset. The final dataset consisted of 21 872 steers, 105 914 cows and 56 904 heifers; of these, 22 573 were reactors and 162 117 were nonreactors.sirei and dami are the proportion of breed i in the sire and dam, respectively.Considerable cross-breeding exists in Irish herds. For example, 58% of herd-episodes in beef herds contained animals with direct dairy ancestry. Many cows in beef herds are first or second crosses from dairy herds. Following VanRaden and Sanders , heterosVariance components for bTB susceptibility, as a binary trait (i.e. reactor or not reactor), were estimated using both an animal linear mixed model and a threshold animal model in ASreml . VariancGenetic correlations for bTB susceptibility between animal type  were estimated using bivariate sire models to evaluate whether bTB was genetically the same trait in the different populations. To test whether the genetic correlations between animal types differed from one, using the linear model, a likelihood ratio test was performed between each model and an analysis where the genetic correlation between animal types was constrained to be one. In addition, using the linear model, a likelihood ratio test was performed between each model and a model where the genetic variances in each animal type were constrained to be equal.Sire estimated breeding values (EBV) for bTB susceptibility were generated from the univariate animal model using only cow records. The mean EBV per breed was obtained for (1) all sires with daughter records for bTB in the data and (2) all sires with at least ten daughter records for bTB in the data. Mean EBV per year of birth was calculated to quantify genetic trends. Only sires born after 1992 were included to calculate the mean EBV per breed and genetic trends, because animals born before 1992 were too distant from the actual phenotypic data. The prevalence of bTB infection in the daughters of sires was calculated as the ratio of non-infected to infected daughters present during a herd-episode. Only sires with more than 50 daughters in more than ten herds were included in this analysis.Herd-episodes were split into four categories based on mean bTB prevalence to define different environments: very low , low , high  and very high . (Co) variance components were estimated within each environment using both linear and threshold animal models. For comparative purposes, variance components estimated using the linear animal model were also transformed to the liability scale using the standard transformation . GeneticThe mean prevalence of bTB infection in the entire dataset  was 0.11  had greater heritability estimates than cows. The genetic standard deviation (SD) for susceptibility to M. bovis infection, when estimated across all animals, was 0.094 and was greatest in heifers from beef herds and lowest in heifers from dairy herds (Table The estimate of heritability of susceptibility to Estimates of the genetic correlation for bTB susceptibility was 0.55 between cows and heifers (standard error (se) = 0.048), 0.10 between cows and steers (se = 0.104), and 0.64 between steers and heifers (se = 0.082). The likelihood ratio test between nested models revealed that all genetic correlation estimates were significantly different from one (P <0.001).Figure From the linear model using the full dataset, Holstein-Friesian sires had the lowest mean EBV compared to all other breeds  and lowest for those in herd-episodes of very low prevalence . Using a threshold animal model, the estimate of heritability was lowest for animals in herd-episodes of very low prevalence of bTB infection  and greatest for those in herd-episodes of very high prevalence (>0.75). The genetic SD for bTB susceptibility, estimated using the linear animal model, was lowest for the extreme bTB prevalence categories, with the genetic SD of very low  and very high  prevalence categories being approximately equal to half that of the low  and high  prevalence categories  [In this study on dairy and beef cattle, a heritability of 0.11 for susceptibility to bTB was estimated using a linear model, which is between documented estimates of most production diseases  and anim avium) -27, whicm avium) . FurtherDespite the similarities in heritability estimates among the different studies, the genetic variance estimates for susceptibility to bTB reported in the present study were two to three times greater than those documented by Bermingham et al.  in a subPreviously reported data on between-breed differences in susceptibility to bTB corroborate our results. For example, Ameni et al.  reportedThe observed recent genetic trends in susceptibility to bTB Figure  suggest The genetic variance of susceptibility to bTB in environments with different bTB prevalence levels has not previously been documented. The pattern of genetic variances of susceptibility to bTB in environments with different bTB prevalence levels, estimated using an animal linear mixed model, was similar to the trend in genetic variances estimated for somatic cell score in environments with different herd average somatic cell scores  i.e. it. EstimatThe estimates of the genetic correlation of susceptibility to bTB between cows and heifers in the present study (0.55) was similar to the estimate of 0.53 documented by Bermingham et al.  comparinM. bovis . This suggests that the genetic background of susceptibility to bTB in environments under a very high pathogen load is different to that in environments under a lower pathogen load. Calus et al.  observeds . It musIncomplete exposure of animals to the pathogen, resulting in some animals not having the opportunity to express their genotype for the disease. The degree of underestimation is linear with the decreased probability of complete exposure. The strict inclusion criteria for herd-episodes imposed in the present study aimed at maximising the probability of complete exposure. However, complete exposure may not have been reached in some cases. With the observed prevalence of bTB of 0.11 in the entire dataset , be measurable or correlated with a measureable phenotype, and exhibit genetic variation. Bovine tuberculosis is of economic importance ,7, which


To compare the diagnostic value of coronary CT angiography (CCTA) with use of 2 image postprocessing methods (CCTA_S) and (CCTA_OS) and original data (CCTA_O) for the assessment of heavily calcified plaques.Fifty patients  with suspected coronary artery disease who underwent CCTA and invasive coronary angiography (ICA) examinations were included in the study. Image data were postprocessed with “sharpen” and smooth reconstruction algorithms in comparison with the original data without undergoing any image postprocessing to determine the effects on suppressing blooming artifacts due to heavy calcification in the coronary arteries. Minimal lumen diameter and degree of stenosis were measured and compared between CCTA_S, CCTA_OS, and CCTA_O with ICA as the reference method. The area under the curve (AUC) by receiver-operating characteristic curve analysis (ROC) was also compared among these 3 CCTA techniques.P < 0.05), with no significance differences for detection of coronary stenosis in the left circumflex and right coronary arteries (P > 0.05).On a per-vessel assessment, the sensitivity, specificity, positive predictive value and negative predictive value, and 95% confidence interval (CI) were 100% , 33% , 41% , 100%  for CCTA_O, 94% , 66% , 57% , and 95%  for CCTA_S, 94% , 44% , 44% , and 97%  for CCTA_OS, respectively. The AUC by ROC curve analysis for CCTA_S showed significant improvement for detection of >50% coronary stenosis in left anterior descending coronary artery compared to that of CCTA_OS and CCTA_O methods (CCTA with “sharpen” reconstruction reduces blooming artifacts from heavy calcification, thus, leading to significant improvement of specificity and positive predictive value of CCTA in patients with heavily calcified plaques. However, specificity is still moderate and additional functional imaging may be needed. Studies in vitro and in vivo investigating the effects of different IR techniques on calcium score analysis showed that CCTA with use of IR significantly reduced calcium volume and calcium scores,17 leading to improved diagnostic value of CCTA in heavily calcified coronary arteries,18 while others reported no significant effects on measurements of calcified plaque volume using IR compared to FBP.19In recent years, the use of IR has been mainly focused on lowering radiation dose of CCTA in comparison with the conventional approach of filtered back projection (FBP).8 Due to limited information on the effects of image processing methods on the calcified coronary plaques,20 the purpose of this study is to apply the appropriate image postprocessing reconstruction derived from our preliminary findings to a group of patients with heavily calcified coronary plaques. We hypothesized that diagnostic value of CCTA, in particular, the specificity and positive predictive value (PPV) might be improved in the evaluation of heavily calcified plaques with use of the appropriate image processing method.We have recently reported our experience of using different image postprocessing algorithms in the assessment of CCTA images with high calcium scores, and showed the improved visualization of coronary artery lumen with use of image postprocessing “sharpen” algorithm.This retrospective study reviewed 100 consecutive patients who were referred for the assessment of suspected coronary artery disease (CAD) with CCTA on ≥64-slice CT scanners between March and August 2014. Eligible patients included adults with at least one coronary artery segment with calcified plaques identified on CCTA, with invasive coronary angiography (ICA) performed as the reference method for diagnosis of coronary artery stenosis. Patients were not eligible if they had any of the following conditions: known allergy for contrast media, prior history of coronary artery bypass surgery, prior coronary stenting, impaired renal function with serum creatinine level >1.5 mg/dL, or unable to control heart rate less than 65 beats per minute despite use of beta-blockers. Fifty patients were excluded due to the following reasons: coronary plaques other than calcified type  (n = 15), ICA was not available for comparison (n = 30), and coronary stenting (n = 5). The final cohort consisted of 50 patients with patient characteristics shown in Table CCTA image acquisition was obtained as part of clinical cardiac CT examinations; therefore, the need for institutional review board approval was waived by the local ethics committee for this study. No informed consent was obtained from the patients, given the retrospective nature of the study.21 Intravenous contrast medium  was administered during each scan with details described in our previous study.21 Images were reconstructed with a slice thickness of 0.6 to 0.75 mm and a reconstruction interval of 0.5 to 0.6 mm for the first- and second-generation dual-source CT, slice thickness of 0.5 mm and reconstruction interval of 0.25 mm for 640-slice CT, respectively.The patients were scanned with a first-generation dual-source CT , or a second-generation dual-source CT (Somatom Definition Flash); or 640-slice CT , with corresponding 20 patients (40%) for 64-slice CT, 15 patients (30%) for 128-slice CT, and 15 patients (30%) for 640-slice CT, respectively. The imaging protocol has been previously described in detail.21 Therefore, this study analysis is considered comparable between the different vendors.Although data were acquired with different CT scanners, our previous study did not show any significant difference in the diagnostic value between different multislice CT vendors.22 Details of the image processing algorithms used in this study have been described in our recent report. The ImageJ software provides default functions to perform the image processing conveniently. It also allows users to conduct nondefault image processing techniques with flexibility. For example, the default ImageJ “sharpen” function shows the most effective outcomes and it is actually a function to carry out the convolution filtering with the following kernel (convolution matrix/mask).Original 2D axial CT images in DICOM  and curved planar reformatted images were processed by a Windows 7 64-bit workstation with open source software ImageJ v 1.49b  using common spatial domain processing approaches.-1 -1 -1-1 12 -1-1 -1 -1The use of ImageJ “sharpen” function has been proved to effectively suppress artifacts due to heavy calcification, thus, this image postprocessing algorithm was selected for evaluation of CCTA images in this study. In addition, another commonly used approach, smoothed image subtracted from original data and the outcome integrated with the original image subsequently was also included in the image analysis. The default ImageJ function was used to smooth images in this approach. It is again based on the convolution filtering technique with the use of the following kernel.1 1 11 1 11 1 18 In summary, 3 different imaging datasets were analyzed in 50 patients, namely: CCTA original data (CCTA-O), CCTA with use of “sharpen” algorithm (CCTA-S), and CCTA original data integrated with the outcome of smoothed image subtracted from the original (CCTA-OS).This technique is more commonly known as the 3 × 3 mean filtering. The image subtraction process was handled by the default ImageJ “image calculator” function.21 Measurements were performed by 2 researchers  who were unaware of the results of ICA. Two reviewers assessed CCTA and ICA images separately with an interval of 2 weeks. Any discrepancy was resolved by a reading session in which both reviewers read images together to reach a consensus. Three consecutive measurements of the MLD at each coronary lesion were obtained, and the mean value was averaged to avoid intraobserver disagreement.Data were transferred to a separate workstation equipped with Analyze V 11.0  for image postprocessing and analysis. The minimal lumen diameter (MLD) of three main coronary arteries  was measured using the same approach as described in our previous study.The percentage of coronary lumen reduction (stenosis) was calculated using the following formula: 23 When there were multiple calcified plaques present in the coronary arteries, measurements were performed at the most severely calcified lesions as this study only focused on the heavily calcified plaques.RD refers to the reference normal diameter of coronary artery. The degree of coronary lumen stenosis was determined significant when the percentage of reduction was measured >50%.Invasive coronary angiography (ICA) was performed by femoral or radial approach. The MLD was measured in projections showing the most severe narrowing of three main coronary arteries  by a radiologist with more than 15 years of experience in cardiac imaging. Similarly, 3 consecutive measurements of the MLD within the same lesion were obtained, and the mean value was averaged.P-value of <0.05 was considered statistically significant.Statistical analyses were performed using SPSS 21.0 . All continuous variables were expressed as the mean ± standard deviation, while categorical variables were presented as frequencies or percentages. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the detection of significant stenosis (>50%) on CCTA were calculated for individual three main coronary arteries with ICA as the gold standard. Receiver-operating characteristic (ROC) curve analysis was used to evaluate the diagnostic value of CCTA using different image postprocessing approaches in the measurement of MLD and detection of coronary stenosis compared to ICA. The areas under the ROC curves (AUCs) were compared among these three methods. A difference with A total of 102 calcified coronary arteries from 50 patients were detected and analyzed. Calcified plaques were found in 47 LAD, 28 LCx, and 27 RCA arterial branches, respectively. ICA showed coronary stenosis greater than 50% in 26 (52%) patients, with a total of 33 coronary arteries. More than half of calcified plaques  were found to involve the LAD. Twenty patients had 1-vessel disease, 5 patients had 2-vessel disease, and the remaining 1 patient had 3-vessel disease.P < 0.05).We randomly selected 20 cases (60 vessels) for interobserver variability and the comparison of MLD measurements between CCTA and ICA. The 2 readers blindly measured MLD and RD on these techniques individually, with results showing high correlation between these values performed by two observers  for CCTA_O, CCTA_S, and CCTA_OS in individual and all of the 3 coronary arteries are presented in Table P < 0.05)    Fig. A, with nFigure Findings of this study show that the use of image postprocessing method, the “sharpen” reconstruction algorithm significantly improves the specificity and PPV for CCTA detection of coronary stenosis in patients with heavily calcified plaques. These improvements are most likely due to the suppression of blooming artifacts resulting from the heavy calcification in the coronary arteries, thus, leading to better coronary lumen visualization and assessment of degree of stenosis.25 The specificity of CCTA was reported to be as low as 19% in patients with highly calcified plaques, according to these studies. Our results are consistent with these findings as the specificity of CCTA ranges from 18% to 44% in the CCTA images if no image postprocessing was implemented. The low specificity often leads to unnecessary downstream testing such as ICA or myocardial perfusion imaging, which increases additional cost and radiation dose to patients, thus restricting the clinical application of CCTA. It is therefore important to address this challenge in patients with heavily calcified plaques who undergo CCTA examination.Advances in CT technology have enhanced the diagnostic value of CCTA, making it a widely used less-invasive imaging modality in the diagnosis of CAD. However, studies based on single centre and multicentre experiences have demonstrated the negative impact of high calcium scores on the specificity and PPV of CCTA.28 A number of studies have applied this technique to patients with high calcium scores for assessment of diagnostic value of CCTA, but results are contradictory.29 Renker et al18 compared IR with FBP in 55 patients with Agatston scores of more than 400, and they found that the specificity and PPV were increased from 91.2% and 61.1% to 95.5% and 76.9% at per-segment level, 66.7% and 78.9% to 79.2% and 85.7% at per-patient level, corresponding to the CCTA with use of FBP and IR, respectively. Authors also reported that CCTA images using IR significantly lowered the calcification volume compared with those FBP images. This correlates with other studies indicating the significant reduction in calcium score and volume score with use of IR in CCTA compared to FBP images.17 However, other researchers showed no significant impact of IR on calcium volume or measurement of coronary lumen diameter.30 Thus, it is recommended that applying IR algorithms in CCTA images with high calcification be cautious due to these conflicting results.IR has been increasingly used in cardiac and noncardiac CT imaging because it improves image quality by reducing image noise, while in the meantime significantly lowering the radiation exposure to patients.20 compared subtracted with conventional CCTA images in 11 patients with 55 calcified coronary segments, with ICA as the reference method. At per-segment level, subtraction CCTA shows improvement in specificity which is 59%, compared to the 48.7% with conventional CCTA. The AUC by ROC analysis also shows significant improvement, increasing from 0.741 to 0.905, corresponding to conventional and subtraction CCTA, respectively. The present study was designed according to our previous report which tested a number of image postprocessing algorithms, with “sharpen” reconstruction algorithm confirmed to be most effective in reducing blooming artifacts.8 Results of this study further verify the usefulness of CCTA using “sharpen” algorithm in the assessment of calcified coronary arteries. Despite improved diagnostic value being achieved when comparing CCTA_S with CCTA_O or CCTA_OS, the specificity and PPV are still relatively low (<70%), which could generate more ICA or myocardial perfusion imaging. A study by Chow et al31 showed significant decrease of normal ICA examinations from 31.5% to 26.8% after CCTA was implemented into clinical practice. However, other studies reported no impact of introduction of CCTA on the number of ICA examinations.33 A recent study by Zorlak et al34 did not show any significant difference in downstream testing between CCTA and SPECT (single-photon emission computed tomography). Due to its limitation of being an anatomical test assessing coronary stenosis, combining CCTA and functional assessment tools has been shown to increase the specificity and positive predictive value, thereby improving the diagnostic workup of patients with significant coronary artery disease.36 This could be another research direction for assessment of heavily calcified plaques.Use of image postprocessing technique seems to be an alternative approach when dealing with highly calcified plaques in CCTA images. Despite limited data available in the literature, results of using image postprocessing algorithms in calcified coronary arteries are promising. Tanaka et al22 ICA remains the gold standard for the identification and detection of coronary stenosis, but it fails to provide information about coronary wall, plaque composition, or volume.37 Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) are the invasive imaging modalities which allow for quantitative analysis of plaque characteristics, in particular, differentiation of plaque origin by demonstrating the plaque and coronary wall surface changes.39 Correlation of CCTA findings with IVUS or OCT will enable us to quantitatively assess these calcified plaque features, but this is not the focus of our present study.The limitations of CCTA overestimation of coronary lumen diameter and stenosis in the presence of severe calcification will not be completely overcome with image postprocessing methods. This has been confirmed in the present study, especially the very low values of AUC by MLD, indicating the low reliability of using MLD for evaluation of coronary lumen diameter due to calcified plaques. Although results in this study have shown significant improvements with use of “sharpen” reconstruction, the diagnostic value of specificity and PPV are still moderate (<70%) in the assessment of highly calcified plaques, indicating the high percentage of false positive results with CCTA. The origin of a calcified plaque may contribute to the moderate performance of CCTA. When a plaque is in close proximity to the coronary surface or intima, it may progress into luminal narrowing, which can be detected on ICA as lumen stenosis, while a plaque arising from the adventitia is likely to be viewed as significant stenosis on CCTA due to false positive results but it may be observed as normal or mild stenosis on ICA.41 Third, while this study clearly shows the feasibility of using “sharpen” reconstruction for reduction of blooming artifacts in calcified coronary plaques, this algorithm still needs to be optimized to further improve the diagnostic performance and clinical application of CCTA in clinical practice. Furthermore, other image processing algorithms including some advanced beam hardening algorithms were not applied to our images, thus, the potential benefit of these image processing algorithms cannot be commented. Finally, although our images were acquired with 64- or more slice CT scanners, the spatial resolution (0.5 mm) of the current standard CCTA is inferior to that of the high-definition CT (0.23 mm) which shows improved analysis of calcified plaques for high resolution CCTA.42 Further research of combining image processing algorithms with high resolution CT in the analysis of calcified plaques deserves to be investigated.Some limitations in this study should be acknowledged. First, the number of eligible patients is relatively low. The small sample size with a limited number of calcified plaques in all 3 coronary arteries limits the generalization of our results. Further studies in a large cohort are needed to verify our findings. Second, no calcium scoring was performed in this study group. Calcium scoring by noncontrast CT is usually performed to assess the coronary calcification which is regarded as a reliable predictor of cardiac events in patients with different age groups. However, recent studies showed no additional benefit to the addition of calcium scoring to contrast-enhanced CT as CCTA can be performed alone with acquisition of more diagnostic information.In conclusion, this study suggests that specificity and PPV of detecting coronary stenosis with CCTA in heavily calcified plaques can be significantly improved with use of “sharpen” reconstruction. However, specificity is still moderate and additional functional imaging may be needed. The enhanced diagnostic performance of CCTA may contribute to reducing the unnecessary invasive or follow-up procedures in patients with extensive calcification in the coronary arteries.


The optical hybridization of the electronic states in strongly coupled molecule–cavity systems have revealed unique properties, such as lasing, room temperature polariton condensation and the modification of excited electronic landscapes involved in molecular isomerization. Here we show that molecular vibrational modes of the electronic ground state can also be coherently coupled with a microcavity mode at room temperature, given the low vibrational thermal occupation factors associated with molecular vibrations, and the collective coupling of a large ensemble of molecules immersed within the cavity-mode volume. This enables the enhancement of the collective Rabi-exchange rate with respect to the single-oscillator coupling strength. The possibility of inducing large shifts in the vibrational frequency of selected molecular bonds should have immediate consequences for chemistry. Coherent coupling of light with electronic transitions has led to phenomena such as polariton lasing and superfluidity. Shalabney et al. now couple the optical modes of micro-cavity to the vibrational modes of a molecule at room temperature and thereby alter the chemical behaviour of the molecule. For each of these modes, the atoms vibrate in specific directions that correspond to the observable vibrational transitions measured in infrared (IR) spectroscopy. The relatively high frequencies of molecular vibrational transitions ωc tuned to the molecular vibrational transitions. Then, as a consequence of their high frequencies in the IR regime, vibrational resonances are characterized by small thermal occupation factors First, it is possible to perform direct resonant dipolar coupling by engineering micro-scaled cavities with a fundamental mode In the following, we demonstrate the coherent coupling between molecular vibrational transitions and an optical mode of a microcavity, leading to the possibility to swap, at room temperature, excitations coherently between the molecular oscillators and the optical mode. To do so, we have exploited two crucial features offered by polymers. First, the possibility to have an isolated, practically homogeneous, spectral signal associated to a specific vibrational molecular normal mode. Second, the capacity offered through the bulky extension of the polymer film inserted in a Fabry–Perot microcavity to have within a volume of strong optical confinement  a large number of resonators. The colocalization of the optical and mechanical modes induces a collective enhancement of the resonant coupling rate between the vibrational resonators and the cavity mode, reaching the regime of strong coherent coupling. In other words, a macroscopic coherent mechanical mode is now generated by strong coupling.−1. Still, there are specific environments where molecules can display much simpler spectra from which it is possible to select and manipulate chosen vibrational normal modes. Polymeric phases are in this context particularly interesting to explore, since free rotations of molecular moieties are frozen-out and the excitation spectrum of the polymer is determined solely by electronic and vibrational contributions. One should also consider low-frequency vibrations of the polymer lattice itself. Yet, given the small wavenumbers for such lattice vibrations (less than ca. 100 cm−1) compared with the vibrations of individual bonds , the two classes of motions can be clearly separatedIR spectra associated with gas-phase molecules usually display features where rotational transitions are coupled to vibrational ones. The resulting well-known complexity of rovibrational molecular spectra leads to spectral components separated by wavenumbers <10 cmQ of the expectation value of the dipole moment This situation allows us to define the molecular Hamiltonian from a ‘double-adiabatic approximation’ where a slow component (inter-molecular lattice vibrations) is separated from a fast subsystem describing intra-molecular motionsWe emphasize that our coupling scheme only involves the fundamental electronic state. The low vibrational occupancy number implies moreover that only the fundamental level of the vibrational spectrum is populated. At such low excitations, the molecular vibrations occur within a mean electronic potential that is well treated in the harmonic approximation. We are thus finally dealing with a mechanical normal mode in its harmonic quantum ground state, which constitutes the engaging feature of molecular vibrations in this context—see We will further assume that the change in the ground-state dipole moment when interacting with the cavity light mode can be limited to fundamental transitions, leaving aside higher-order combination transitions and overtones. This corresponds to a simple first-order expansionv=±1.of the vibrational dipole operator with respect to the equilibrium nuclear configuration in the harmonic mean potential of the electronic ground state (indicated by the subscript 0)Under these assumptions, it is straightforward to treat in the dipole approximation the conservative interaction between a single molecular vibrational  mode and the field in the cavity. This leads to the following Hamiltonian describing the coherent coupling regime:Qc=(a+a†) corresponds to the optical position quadrature related to the photon a(a†) annihilation (creation) operators associated with the cavity field at the position r of the molecular vibration bond, and Qv=(b+b†) corresponds to the vibrational position quadrature related to phonon b(b†) annihilation (creation) operators, as a consequence of the mean potential harmonic approximation. While Qv quadrature corresponds not to electronic oscillations, but to a  motion of atoms within the molecules.where In this approximation, the coupling strength readsV is the cavity mode volume and μ involved in the bond vibration. We also account for an orientation factor ħΩ is well below 1 μeV for typical molecular vibrational transitions in the vacuum field of a microcavity. Therefore, this cannot exceed radiative and non-radiative damping rates of the system, including cavity losses. As well known, however, the situation becomes different when several resonators are coupled to the same cavity mode.where N is the ensemble of indiscernible resonators. Considering the very large number of resonators available in condensed systems, this enhancement can rise orders of magnitude, as observed in particular in organic systems567891011121314Indeed, the spatially coherent single-mode cavity field drives all the coupled resonators in phase with each other. This induces coherence among the resonators within the whole mode volume and leads to the definition of a macroscopic collective dipole, made of a large number of coupled transitions over which the excitation is delocalized. In the simplest case, neglecting all sources of inhomogeneous broadening−1 (215 meV) as shown in ħΓv~3.2 meV extracted from the full width at half maximum (FWHM). This results in an associated mechanical quality factor Qv~70. Considering a typical 1 Debye dipole moment associated with the (C=O) bond in a polymeric phase3 V m−1 at the resonant frequency ωc, a conservative estimate of the coupling rate turns out to be of the order of ħΩ~0.1 μeV estimated from a diffraction-limited V~(λ/n)3 mode volume (n being the polymer background refractive index). This is much smaller than both the mechanical damping rate ħΓv and the cavity decay rate ħκ~17 meV (see below). In such conditions, it is thus impossible to strongly couple a single molecular vibration to the cavity vacuum field. However, the extremely high density, ρ, of (C=O) bonds in the polymer can in principle enable the formation of a collective dipole within the cavity-mode volume, as discussed above. With one (C=O) bond per monomer, this density corresponds to approximately ρ=1021 cm−3  bond has a symmetric stretching frequency at 1,740 cmcm−3 see . This shTo demonstrate this, a specific Fabry–Perot cavity was engineered to have a first mode in the mid IR (MIR) range resonant with the (C=O) vibrational transition . This tuħΩR~20.7 meV exceeds all decoherence rates  and therefore corresponds to the regime of strong coupling. This leads to the formation of two new opto-vibrational modes for the system, as illustrated in As shown in ρC of coupled molecules. With the same figures given above, this concentration can be estimated to be of the order of ρC~4.4 × 1020 cm−3. This number turns out to be slightly smaller than the expected (C=O) bond density ρ  bond, coherent coupling is achieved at room temperature. In addition, the high mechanical product Qv·ωv/2π holds promises in the context of transient spectroscopy. Indeed, while our discussion was here limited to the electronic ground state and first vibrational transition, one can envision to actually pump transiently the vibrational manifold. This might lead to inverted population dynamics in connection with polariton vibrational lasingΩR/κ close to 1 can be reached. This could lead to nonlinear behaviour in the IR regime similar to that recently demonstrated for polariton Bose–Einstein condensation22Exploiting specific properties of polymers, we have been able to demonstrate for the first time the regime of vibrational strong coupling. The microscopic nature of our individual resonators leads to a practically perfect thermal decoupling of the molecular vibrations. Indeed, with f, since The strong coupling of vibrational modes demonstrated here could have profound consequences for chemistry, as well as biochemistry. We have already shown that the rate and yield of a chemical reaction can be modified by strongly coupling an electronic excited state to the vacuum fieldThe possibility of modifying chemical reaction rates, as described above, seems plausible based on several earlier experiments where bulk properties were modified by strong coupling, such as the already cited photochemical reaction, work-function and the ground-state energy624All authors contributed to all aspects of this work.How to cite this article: Shalabney, A. et al. Coherent coupling of molecular resonators with a microcavity mode. Nat. Commun. 6:5981 doi: 10.1038/ncomms6981 (2015).Supplementary Figure 1, Supplementary Table 1, Supplementary Notes 1-4, and Supplementary References


TM technology. Polyethylene glycols with molecular weights of 2 000, 6 000, 10 000 and 20 000 g/mol, which can be used to moderate the release profile of incorporated pharmacologically active compounds, served as model molecules. They were terminated by aromatic isocyanate and incorporated into the nanofibers. The release of these molecules into an aqueous environment was investigated. The influences of the molecular length and chemical composition of the nanofibers on the release rate and the amount of released polyethylene glycols were evaluated. Longer molecules released faster, as evidenced by a significantly higher amount of released molecules after 72 hours. However, the influence of the chemical composition of nanofibers was even more distinct – the highest amount of polyethylene glycol molecules released from polyvinyl alcohol nanofibers, the lowest amount from polylactide nanofibers.Nanofibers were prepared from polycaprolactone, polylactide and polyvinyl alcohol using Nanospider To date, numerous drug delivery systems have been developed, such as hydrogels that carry drugs or highly sophisticated electronic microchips –2. The rDue to the internal architecture, nanofibers are well suited for various medicinal applications, such as carriers for cell cultivation –5, tissuAlthough several methods of nanofiber preparation have been invented , electroIn the recent years, much effort has been devoted to modifying the electrospinning process, so coaxial, multi-jet, or side-by-side techniques were developed –17. HoweTM technology as an alternative approach based on a needle-free method represents the perspectives for industry due to the high production capacity, stability and easy maintenance [In contrast, Nanospiderntenance –19. Thisntenance ,20.Generally, nanofibers that carry drugs follow several basic designs – nanofibers with homogenous structures in which the drug is dispersed throughout the polymer matrix, core–shell nanofibers for which the matrix carrying the drug is covered by pure polymer –22 and nco-glycolic acid) matrix [In this work, we designed a nanofibrous carrier in which the model molecule is dispersed throughout the polymer matrix. For the purposes to evaluate the influence of molecular size on the release rate and the total released amount in general, polyethylene glycols with molecular weights of 2,000, 6,000, 10,000 and 20,000 g/mol were selected as model molecules. Polyethylene glycol (PEG) is a hydrophilic polyether commercially available in various molecular weights with narrow distribution. It is widely used in various medical applications, for example as surfactant, solvent or tablet excipient. Apart from these applications the PEG has significant effect on the drug release. It has been shown that addition of PEG molecules is an efficient way to modify the release of hydrophobic paclitaxel from poly(lactic acid-) matrix  or prote) matrix . In presPrior to use, linear PEGs were terminated with phenyl isocyanate to incorporate spectrophotometrically detectable groups . The reaThe needle-free electrospinning process was optimized for each type of nanofiber with respect to the different physicochemical properties of polymers. SEM images revealed that the textures of all resultant samples were homogenous and free of heterogeneities or artifacts –c. It ca2/g) and smallest for PLA (4.7 m2/g). These differences are due to the needle-free electrospinning method. Needle-free electrospinning does not allow the fine-tuning of parameters, but the disadvantage of this method is balanced by the fact that it may allow the large-scale production. The possible effect of these characteristics is discussed further below.The properties and behavior of each polymer during electrospinning were unique. The process parameters, such as the polymer mixture composition, voltage, electrode distance, temperature or humidity, were individually and precisely adjusted in order to produce structures that were as similar as possible. However, the morphological characterization revealed several differences in the parameters of resultant samples . The thiThe porosities determined by mercury porosimetry ranged from 77.4% for PCL nanofibers to 86.6% for PLA nanofibers. These differences may have slightly influenced the release of incorporated molecules. However, the mercury porosimetry measurements were conducted in a vacuum. In an aqueous environment, in which the nanofibers are supposed to be used, the porosity may differ due to the variable water content between nanofibers, which is the result of their variable swelling.The release experiments revealed two trends – the release rate depends on the molecular weight of model PEGs as well as on the type of nanofibrous carrier. Although we expected that long molecules will be anchored in nanofibrous structures and so more strongly retained, we observed the opposite effect. Larger molecules were apparently released faster than smaller ones see . Figure The formation of PEG domains can be also supported by the formation of a crystalline phase. Larger PEGs are more likely to crystalize. During the formation of a crystalline phase, the domains of the crystalline polymer are formed separately from the remaining system, which makes them more accessible to water and easier to release.The release of PEG molecules from PCL, PVA and PLA nanofibers varied, as evidenced by the amount of released model molecules after 72 h  comparedDespite attempts to ensure the similar nanofibrous structures, the varied morphology may be also responsible for the variation in the PEG release rate. The release of model molecules directly correlated with the specific surface areas and inversely correlated with the fiber diameters. A higher specific surface area provides a larger area for interaction with the surrounding liquid and consequent faster release of drug molecules. A larger fiber diameter increases the distance that molecules located in the middle of fiber must diffuse through to reach the periphery of the material, which prolongs release times. The porosity of nanofibers did not appear to affect the release rate. A larger porosity may increase the volume of liquid that surrounds the fibers and consequently accelerate the release, but this effect was not observed and may have been suppressed by other factors, i.e., the degree of hydrophilicity of nanofibers.The obtained results showed the successful preparation of morphologically comparable nanofibrous materials with incorporated PEG molecules. It was demonstrated that combination of chemically different polymers and PEG of various molecular weights leads to materials with significantly different release kinetics of PEGs. These basic findings on relationships between PEG size and polymer structure on release kinetics were done in respect that even PEG serves as additive compound it has main effect on the release of potentially incorporated drug –28. EspeThe release kinetics of polyethylene glycol molecules of various molecular weights from nanofibers prepared from polycaprolactone, polylactide and polyvinyl alcohol were assessed. The release rate and the total released amount positively correlated with molecular weight of the incorporated molecules. This trend was observed for all of the prepared nanofibrous carriers. The strongest effect appeared for PVA fibers containing hydroxy functional groups, i.e., 90% of PEG 20 model molecules released within 72 h. These findings can be applied to develop nanofibrous drug carriers for the local delivery of hydrophobic pharmacologically active compounds, because the release of auxiliary hydrophilic molecules can effectively control the drug release kinetics.Mw ≈ 80 kDa) and trifluoroacetic acid were obtained from Sigma, St. Louis, MO, USA. PVA was provided by Nippon Gohsei, Osaka, Japan. PLA (Mw ≈ 100 kDa) was kindly provided as a sample from Natureworks, Blair, NE, USA. Phosphoric acid (85 wt % aqueous solution), N,N-dimethylformamide, tetrahydrofuran and dichloromethane were obtained from Penta, Prague, Czech Republic. The deionized water was produced by Milli-Q Millipore, Bedford, MA. Polypropylene nonwoven spunbond material used as a substrate for all polymers was purchased from ATEX, Milan, Italy. Polyethylene glycols with molecular weights of 2,000, 6,000, 10,000 and 20,000 were supplied by RAPP Polymere GmbH, Tübingen, Germany.PCL  for 3 days. The water content was determined using the Karl-Fischer method and was reduced from ca. 6000 ppm (not dried) to ca. 400 ppm (dried).The derivatization reaction scheme is shown in TM technology [2. Model PEGs of various molecular weights were added to the polymer mixtures at a concentration of 3 wt %. PCL was dissolved in a 1:1 (w/w) mixture of tetrahydrofuran and N,N-dimethylformamide at a concentration of 10 wt %. The electrospinning parameters were 6 rpm, 15 cm and 5.5 kV/cm. The maximum temperature was 30 °C, and the maximum relative humidity was 35%. PLA was dissolved in a 2:1 (w/w) mixture of dichlormethane and trifluoroacetic acid at a concentration of 12 wt %. This mixture was held at 22 °C to maintain the viscosity of this polymer (due to very fast solvent evaporation). The electrospinning parameters were 4 rpm, 15 cm and 5.3 kV/cm. PVA was dissolved in water/phosphoric acid at a concentration of 11 wt %. The electrospinning parameters were 2 rpm, 13 cm and 45–55 kV/cm. The relative humidity was 25–30%, and the temperature was 22 °C. The PVA layers were crosslinked thermally in a drying oven at 145 °C for 15 min to reach their proper stability [The nanofibers were prepared with the Nanospiderchnology –22. The tability –28.The structures of the prepared nanofibers were observed with a scanning electron microscope TS 5130 VEGA, TESCAN, Czech Republic. The samples were dried at 80 °C under vacuum overnight and platinum sputtered. Similar preparation procedure was used for the samples after immersion into the water for 72 h. The mean fiber diameter was determined from 30 measurements on the SEM images at a magnification of 5000×. Mercury porosimetry measurements were made using an Autopore IV 9500 porosimeter, Micromeritics, USA, and the specific surface areas were calculated based on nitrogen absorption/desorption isotherms recorded on an ASAP 2020 apparatus Micromeritics, USA.Samples of nanofibers (0.3 g) were placed into glass vials filled with 5 mL of distilled water. The samples were continuously shaken at room temperature for 5 days. At specific time points, 0.5 mL of solution was withdrawn, and the same amount of fresh water was added. The concentration of PEG was determined based on a calibration curve using a high performance liquid chromatography apparatus Shimadzu Prominence 20, USA with UV detection at a wavelength of 234 nm. The accumulative weight and relative percentage of the released PEGs were then calculated. This experiment was conducted for each of the above-mentioned nanofibers  and PEGs of various molecular weights.


Molecular descriptors and fingerprints have been routinely used in QSAR/SAR analysis, virtual drug screening, compound search/ranking, drug ADME/T prediction and other drug discovery processes. Since the calculation of such quantitative representations of molecules may require substantial computational skills and efforts, several tools have been previously developed to make an attempt to ease the process. However, there are still several hurdles for users to overcome to fully harness the power of these tools. First, most of the tools are distributed as standalone software or packages that require necessary configuration or programming efforts of users. Second, many of the tools can only calculate a subset of molecular descriptors, and the results from multiple tools need to be manually merged to generate a comprehensive set of descriptors. Third, some packages only provide application programming interfaces and are implemented in different computer languages, which pose additional challenges to the integration of these tools.A freely available web-based platform, named ChemDes, is developed in this study. It integrates multiple state-of-the-art packages  for computing molecular descriptors and fingerprints. ChemDes not only provides friendly web interfaces to relieve users from burdensome programming work, but also offers three useful and convenient auxiliary tools for format converting, MOPAC optimization and fingerprint similarity calculation. Currently, ChemDes has the capability of computing 3679 molecular descriptors and 59 types of molecular fingerprints.http://www.scbdd.com/chemdes. The source code of the project is also available as a supplementary file.ChemDes provides users an integrated and friendly tool to calculate various molecular descriptors and fingerprints. It is freely available at  Molecular descriptors are experimentally-measured or theoretically-derived properties of a molecule . More spVarious molecular descriptors and fingerprints have been developed in previous studies for quantitative molecular representation. Besides their extensive usage in the aforementioned regular applications , molExisting tools for molecular descriptor and fingerprint calculation include DRAGON , BlueDesIn this study, we developed a freely-available web-based platform called ChemDes, which provides an online service to the public for calculating a variety of molecular descriptors and fingerprints conveniently and instantly. More specifically, ChemDes can compute 3679 descriptors and 59 types of molecular fingerprints, including, e.g., the one-dimensional bulk properties of compounds, the two-dimensional topological and charge indices, and more complex three-dimensional (3-D) descriptors. Additionally, ChemDes provides three useful auxiliary tools, named ChemCONV, ChemMOP and ChemFPS, for convenient format converting, MOPAC optimization and fingerprint similarity calculation, respectively. We thus believe ChemDes is a useful platform that better suits the needs in related chemoinformatics and bioinformatics studies.Numpy, scikit-learn and Pandas. Moreover, some packages or tools used in ChemDes such as Pybel and RDKit all provide the Python application program interfaces (APIs). This makes it possible to integrate these different resources in the Python language framework.Python programming language has been becoming very active in the research community because of its scalability and rich library functions. In ChemDes, Python is chosen as the main development language because it could work well with other tools or packages developed by different programming languages, and they have good interaction and compatibility with each other. There are also plenty of libraries for the scientific computation such as The whole system runs on an ECS (elastic compute service) server of Aliyun. The number of CPU cores and memory are automatically allocated to the running instances on demand, which ensures the elastically stretchable computing capability. Django is chosen as a high-level Python web framework to encourage the rapid development and clear design. According to its model-visualization-control (MVC) design pattern, the whole system is divided into three main components: the back-end calculating program, the back-end control program and the front-end visualization program. At the back-end, the authors use uWSGI + Nginx as the web server, and use MySQL database for data storage and retrieval. At the front end, the website is designed in accordance with W3C standards. In addition, the JavaScript and jQuery are also utilized to accomplish some complex interaction processes which could effectively avoid potential problems of some strict runtime environment and security risks.input, file, open, write, getcwd and setcwd from Python I/O system to accomplish the file reads and writes. In order to rapidly handle large files, the other methods like Chunks are used to make sure the success of uploading and storing large files. In addition, relative paths instead of absolute paths are also used to enhance the transportability of the platform. Herein, ChemDes only accepts molecular file types in the formats of SMILES and SDF. However, before transferred to the back-end calculating program, these inputs must be validated by the format authentication and the format validation programs. Moreover, the SDF format input will accept an extra validation of format legitimacy through a piece of JavaScript program at the front end. After the structure identification, molecules will be parsed and instantiated as different molecular objects such as pybel.Molecule, rdk.Molecule (myMol) and Molecule (myCDKMolecule). Different molecular objects have different attributes and methods, which is the main premise of calling the corresponding calculating functions. Herein, the authors integrated the corresponding molecular wrappers and realized the molecular information exchange between different molecular objects. Once these molecular objects are successfully obtained, the back end calculating program could call them to calculate the corresponding molecular descriptors.The Input/output system, as the basic part of the ChemDes platform, is mainly responsible for the input or output of the strings, commands and files. ChemDes uses the functions like SMILES or SDF in these situations. This will be an effective way to avoid the exception caused by these situations.To facilitate the user’s application to the ChemDes platform, a useful auxiliary tool called ChemCONV was developed to realize the format conversion between dozens formats of molecular files. ChemCONV allows users to import 7 types of formats and export 11 types for extensive applications, and it also realized the batch computing by submitting a molecular file with multiple molecules. We suggest that all formats of molecular files should be firstly converted to When 3-D molecular descriptors are calculated, chemical structures should be optimized in advance to obtain 3-D coordinates or atom charge information. Herein, the authors choose MOPAC  to accomcalc_fun module is developed to reorganize the related APIs and assure a unified way to call the functions. It also responds to work out the corresponding descriptor names and their types. For example, it picks out the functions like CalcChi0n, CalcChi0v and CalcChi1n from the rdkit.rdMolDescriptors and puts them into connectivity descriptors, the functions like CalcNumRings, CalcNumAmideBonds and CalcNumRotatableBonds into constitutional descriptors. A result_wash module is also developed to deal with different results and to allow for uniform access to the descriptor values via the methods from the alternative logical branches. Obviously, it is a barrier to interoperability that one programming language usually cannot simultaneously access more than one toolkit. Among these toolkits, CDK, BlueDesc and PaDEL are Java software and do not have exactly APIs for Python. In order to access Java libraries from CPython, the Python library JPype is needed. This starts an instance of the Java virtual machine and uses the Java native interface to communicate back and forth. By using JPype, we are allowed to obtain the Java class or call the Java functions related to the APIs listed here.ChemDes integrates seven toolkits to calculate a large number of molecular descriptors and fingerprints, including Pybel , RDKit, max-requests, harakiri and keepalive_timeout. By employing the certain architectures, the balance between system resource occupation and computational efficiency is maintained; the good independence and safety of a long time data operation and file access from different requests are also guaranteed.A web-based platform must have robust multitasking architectures to enable different users to obtain services at the same time. To meet this need, the Nginx + uWSGI architecture is used. We use the preforking operational mode of uWSGI with the multiply interpreters. uWSGI serves responses to the Nginx via the WSGI protocol. The dynamic data from interaction between Python computational program and uWSGI will then interact with Nginx, and the latter will serves results to the clients in form of static contents. Additionally, in order to meet time requirement for data operation, the authors have optimized some related parameters of Nginx and uWSGI such as To provide an online computing service based on web, the user interface should be convenient and easy-to-use for the users. Herein, the user interface of ChemDes consists of four main modules: “Webserver”, “Library”, “Tools” and “Help”. The “Webserver” is the main entrance for users to calculate molecular descriptors. It provides different entrances according to the sources and types of molecular descriptors. The “Library” module provides the detailed definitions and references for all molecular descriptors and fingerprints that can be calculated by ChemDes. It would be very convenient to check and interpret the meaning of each molecular descriptor. The “Tools” module provides the entrance for the three auxiliary tools . These three useful auxiliary tools help the users conveniently perform format converting, MOPAC optimization and fingerprint similarity, respectively. At last, the “Help” module provides detailed instructions of all the major functions of this platform, and some frequently asked questions and the solutions are also listed there. The users could also ask more questions and provide some suggestions to help us improve the ChemDes platform. In addition to the four main parts mentioned above, there are also some other functions that will not be described in details here. For example, the functions of structural examination and visualization from JSDraw . These fChemDes computes 1-D/2-D descriptors representing molecular properties and structural information from the molecular graph. Most of them have garnered considerable interest because of the ease of generation and the fast speed with which these computations can be completed. They have been extensively used in modeling various physicochemical properties as well as biological activities. Currently, ChemDes allows users to compute 2618 1-D/2-D molecular descriptors conveniently. As we know, 1-D/2-D molecular representations, however, do not contain any stereo chemical information, which limits the applications that require the properties depending on internal coordinates or absolute orientation or different conformations. Therefore, we incorporated the 3-D descriptors to represent the 3-D structural features of chemicals. This platform can be used to compute 1053 3-D molecular descriptors. In particular, each molecule will be pre-optimized by MOPAC to obtain the 3D coordinates essential for this calculation. According to the different molecular representations, the molecular descriptors are divided into 20 logical blocks. A list of all molecular descriptors covered by ChemDes is summarized in Table Molecular fingerprint is a frequently-used abstract representation which allows the computationally efficient handling and comparison of chemical structures. It plays an important role in database search/clustering, similarity screening and molecular diversity analysis. Several toolkits provide a few fingerprinting algorithms, however, these algorithms are dispersive and do not have uniform inputs and outputs sometimes. Besides, it is not easy to use them for users without programming skills. In context of this, ChemDes is developed to compute 59 types of fingerprints without these limitations. Likewise, we have organized and classified the molecular fingerprints. A list of molecular fingerprints covered by ChemDes is summarized in Table In order to make the calculation of molecular descriptors more sophisticated, a customized calculation module is developed. As described above, we have analyzed and classified all the molecular descriptors that ChemDes covers, and then divided these descriptors into several subsets. On the basis of this, we designed and added this module to allow users to calculate certain types of descriptors according to their requirements. This module, firstly, meets the requirements of selecting different types of molecular descriptors to calculate. Secondly, users can also customize different kinds of optimization for 3-D molecular structure information. Thirdly, this module makes it convenient to achieve a study or comparison of the performance of various molecular descriptors. For example, using different types of molecular descriptors with their detailed definitions would be very helpful to variable selection and model explanation when the users establish QSAR models. Besides, it should be an efficient way to save system resources and to make a better user experience that users choose this kind of computation.Molecular descriptors can be categorized according to different angles and situations. The main basis that we divide these molecular descriptors into 20 logical blocks is as follows: (a) the elaboration of molecular descriptors from Handbook of Molecular Descriptors ; (b) theFor the purpose of further comparison and study, we retain descriptors that have the same names and come from different toolkits. ChemDes makes it easy to compare the results obtained by different toolkits for the same descriptors. This could be useful when identifying bugs, applying a test suite, or finding the strengths and weaknesses of particular implementations. For example, when different toolkits calculate the same descriptors, it may indicate a bug in one or the other toolkit while the calculated values are not highly correlated.In order to give a clear and meaningful visualization of the relationship between the descriptors covered by ChemDes and those calculated by the other toolkits, the full comparison is performed using a Venn diagram , as show*.mop for MOPAC software, *.c3d1 for Chem3D, *.sy2 for Sybyl. ChemMOP supplies geometry and energy information by optimizing molecules using MOPAC. ChemMOP enables users to export 6 types of formats containing 3-D coordinates and provides charge and energy information for wide applications, such as molecular orbital descriptors for the analysis of electron transition in some chemical reactions. ChemFPS provides nine types of similarity measures for users to compare chemical structures. (d) ChemDes possesses advantages of cross-platform and interoperability. Users can access this platform via almost all the operation system types  and client types ; The calculating results and input/output files from ChemDes can be directly used in other calculations or studies. Of course, such a web-based platform may also have its disadvantages. It’s probably much more difficult to calculate molecular descriptors of a large numbers of chemicals at one time, because a webserver must meet the requirements of a robust system and requests from multiple users. It has been shown, however, that these problems can be overcome by cutting down on the number of chemicals submitted at once and optimizing some related parameters like timeout at the back end.As described above, we have detailedly presented the ChemDes platform that covers 3679 molecular descriptors with diverse types and 59 types of molecular fingerprints. Compared with the other similar dedicated software instead of with general QSAR software that have descriptor calculation features or programming libraries, ChemDes has several significant advantages: (a) ChemDes is freely available to the public and requires no programming skills. In some cases, molecular descriptor calculation can usually be an important step at the whole project such as QSAR/QSPR, similarity searching, and virtual screening. Researchers just need a freely and easily accessible way to obtain the values, so being free is very helpful. Furthermore, for some pharmacologists and biological scientists, they usually focus more on practical results and data rather than tedious deployment or programming process. Their major focus is rather different from the focus from computational chemistry or chemoinformatics scientists. By using ChemDes they can achieve their goals more rapidly and directly. (b) ChemDes has integrated various molecular descriptors and fingerprints from the toolkits written in different programming languages. As we can see that three types of popular programming languages are used in these toolkits, including C++, Python and Java. On the one hand, limited features represented by a single toolkit will be not so good for users to do a comprehensive comparison and selection. On the other hand, in some cases, it is very difficult or infeasible to restore to a runtime environment with the same configuration of the authors, because most of the toolkits are in form of software or packages which probably have a certain dependence on the operation system and some third-part procedures to a large extent. ChemDes overcomes these problems by accomplishing these complicated tasks on the server side. (c) ChemDes integrates MOPAC software and incorporates three useful tools . ChemDes innovatively combines MOPAC software in a web-based platform to optimize chemical structures. ChemCONV realizes the conversion between various molecular formats conveniently. It allows users to import 7 types of formats and export 11 types for extensive applications, such as Considering the amazing rate at which data are accumulated in chemistry and biology fields, new tools that process and interpret large and complex data are increasingly important. The proposed webserver makes a step in this direction providing a way to fully integrate molecular representation information into an easy-to-use web platform. ChemDes provides a convenient and online way to calculate various molecular descriptors and fingerprints. It does not require the time-consuming process of deploying or programming. After representation, different statistical learning tools can be applied for further analysis and visualization of the data. Several studies from different applications show how ChemDes was used to describe various molecular features and establish a model in a routing way. It can be applied to a broad range of scientific fields such as QSAR/SAR, similarity search, absorption, distribution, metabolism, elimination and toxicity (ADMET) prediction, virtual screening, and various interaction data analysis . We expeThe current version of ChemDes has a number of strengths that make them useful for a wide variety of applications in chemoinformatics and computational biology. The usefulness of the features covered by ChemDes has been extensively tested by a number of published studies of the development of statistical learning algorithms for analyzing various chemical and biological problems. The similarity principle is prominent in medicinal chemistry, although it is well known as the similarity paradox, i.e., those very minor changes in chemical structure can result in total loss of activity. Based on different similarities, various molecular fingerprint systems were used for identifying novel drug targets. Campillos et al. proposed a novel method to identify new targets based on the similarity of side effects by Daylight-type topological fingerprints. A method to predict protein targets based on chemical similarity of their ligands was proposed by Keiser et al. . using DThe main advantages of our proposed webserver are summarized as follows: (1) ChemDes contains a selection of molecular features to analyze, classify, and compare complex molecular objects. They facilitate the exploitation of machine learning techniques to drive hypothesis from complex small molecule datasets, and interaction datasets. The comparative wide coverage of descriptors ensures users to choose the suitable descriptor types relevant to the subject they are studying. (2) ChemDes provides the detailed information about molecular descriptors and how to calculate them in the ‘Library’ and ‘Help’ sections. This helps the researcher to understand the meaning of each descriptor and to interpret the model. (3) ChemDes integrates MOPAC software and incorporates three useful tools . This helps the researchers to apply ChemDes to perform molecular structure optimization, molecular format conversion, and similarity calculation.Owing to the modular structure of ChemDes, extensions or new functionalities can be implemented easily without complex and time-consuming alterations of the website backstage code. In future work, we plan to apply the integrated features on various biological research questions, and to extend the range of functions with new promising descriptors for the coming versions of ChemDes.Project name: ChemDes. Project home page: http://www.scbdd.com/chemdes. Operating system(s): Platform independent. Programming language: Python, Java, JavaScript, HTML, CSS. Other requirements: Modern internet browser supporting HTML5 and JavaScript. The recommended browsers: Safari, Firefox, Chrome, IE (Ver. >8). License: MIT. Any restrictions to use by non-academics: None