Diseases emerging from wildlife have been the source of many major human outbreaks. Predicting key sources of these outbreaks requires an understanding of the factors that explain pathogen diversity in reservoir species. Comparative methods are powerful tools for understanding variation in pathogen diversity and rely on correcting for phylogenetic relatedness among reservoir species. We reanalysed a previously published dataset, examining the relative effects of species' traits on patterns of viral diversity in bats and rodents. We expanded on prior work by using more highly resolved phylogenies for bats and rodents and incorporating a phylogenetically controlled principal components analysis. For rodents, sympatry and torpor use were important predictors of viral richness and, as previously reported, phylogeny had minimal impact in models. For bats, in contrast to prior work, we find that phylogeny does have an effect in models. Patterns of viral diversity in bats were related to geographical distribution (i.e. latitude and range size) and life history . However, the effects of these predictors were marginal relative to citation count, emphasizing that the ability to accurately assess reservoir status largely depends on sampling effort and highlighting the need for additional data in future comparative studies. This study provides key support for the idea that bats are special as zoonotic reservoirs, because they host more zoonotic viruses per species than rodents. It also identifies key bat ecological traits that correlate with increased zoonotic viral diversity, e.g. bat species with smaller litters, larger body masses, greater longevity, more litters per year and geographical distributions overlapping with many other bat species (sympatry) carry a greater number of zoonotic viruses. It has since provided the basis for additional studies  . The autes e.g. ,20,23) a,23 aet aet al. found that phylogeny explained little of the residual variation in their models predicting viral diversity in bats and rodents. The authors note that this was surprising, considering the strength of phylogenetic signal in other species’ traits [In interspecies comparisons, phylogenetic methods have become commonplace to control for the statistical non-independence of species due to shared common ancestry ,25. Clos’ traits . Althoug’ traits , the lac’ traits  is unexp’ traits –36). Add’ traits ,37. Theret al., we reanalysed the data used in their study, applying more recent comparative methodologies and phylogenies. Luis et al. [et al. [et al. using the same BE [Given the importance of phylogeny in other comparative studies involving bats, and the lack of phylogenetic signal found by Luis s et al.  used phys et al. , impleme [et al.  phylogen same BE  phylogen same BE  phylogen same BE , we also same BE  and rode same BE  that res2.2.1.et al. [λ) model (see §2.2 below) and, depending on the analysis, one of three phylogenetic trees [λ) to calculate phylogenetic signal in the individual species' traits listed above (where λ was restricted to 0 ≤ λ ≤ 1).All data used in our analyses were taken from electronic supplementary material, table S14 of Luis et al. . As in tet al. ), migratet al. ), geograet al. , to contet al. ,25. To cet al.  with a lic trees ,41,42. Tic trees  phylogenic trees , we alsoic trees , we also2.2.et al. [phytools v. 0.5–20 [Like Luis et al. , we perfet al. . Failinget al. . For eacet al. ; Shi & Ret al. , hereaftet al. , hereaft. 0.5–20 . For allet al. [caper v. 1.0.1 [et al. (i.e. To examine which species’ traits correlate with either number of zoonotic viruses (i.e. those viruses capable of infecting humans) or total number of viruses in the bat and rodent species included in Luis et al. , we ran et al.  with Pagv. 1.0.1 . We re-rc) scores and assumed that models with AICc scores that differed by less than or equal to 2 units had similar support [R2).We ranked all PGLS models using corrected Akaike information criterion , we als2.4.et al. [et al. [Multi-collinearity between explanatory variables is common in ecological datasets. Many statistical methods are sensitive to collinearity and failing to address the relationships between variables can bias statistical inference . To dealet al.  employ aet al. . VIFs do [et al.  while encaper package [phylolm package v. 2.6 [Prior to running PGLS models, we examined the distribution of our response variables  for bats, rodents and the bat/rodent combined data. We log-transformed these response variables to reduce skewness and checked subsequent PGLS models to ensure that residuals were homogeneous and normally distributed . We then package  used aboe v. 2.6  to obtai3.3.1.et al.  using the BE  phylogenS13 from ).3.2.et al. where the first three principal components  accounted for 88% of the variance in bat life-history strategies and 93% of the variance in rodent life-history strategies [In all of our phylogenetic PCAs, the first phylogenetic principal component (pPC1) explained more than 99% of the life-history trait variation across species for bats, rodents and the bat/rodent combined data, regardless of the phylogeny used . This is in contrast with Luis rategies . The firrategies . Using trategies  tree, pPet al. data, using the same phylogeny as in the original paper [et al. [Reanalysis of the Luis al paper , but incal paper , our bes [et al. , which cFor rodents, using , our besReanalysis of the combined bat/rodent data using  altered 3.3.As outlined above in §3.2, pPC1 explained more than 99% of the life-history trait variation across species for bats, rodents and the bat/rodent combined data using the updated S&R  and F&S et al. found sympatry, citations and PC1 to be important [For bats, using the more recent S&R  phylogenmportant . Our besmportant  tree.et al. [For rodents, using the more recent F&S  phylogenet al.  , but in contrast to above, did not explain any of the residual variation in the PGLS model for total viral richness .When we adopted an alternative modelling framework using VIFs to remove collinear variables and including all remaining traits in PGLS models to examine relative effect sizes, citation count was often the only significant predictor in models . However, in the PGLS model for total number of viruses carried by bats, both citation count and litter size were significant . Citation count had a positive relationship with total viral diversity, while litter size had a negative relationship . For numλ < 0.0001; electronic supplementary material, tables S30 and S31).For rodents, citation count was the only significant predictor in models for number of zoonotic and total number of viruses carried by species (tables S30–S31). In both models, citation count had a positive relationship with rodent viral diversity . Additioλ = 0.1762; electronic supplementary material, table S34 and λ = 0.2735; electronic supplementary material, table S35).For the combined bat and rodent PGLS model examining total viral richness, citation count was the only significant predictor  and had a positive relationship with total viral richness . For number of zoonotic viruses in the bat/rodent combined data, citations, sympatry and no torpor use were all significant terms . All of these traits had a positive relationship with number of zoonotic viruses . In both PGLS models, phylogeny explained some additional residual variation . We found phylogeny had little effect in only our PGLS model for total viral richness when all ecological predictors were included . Previous work has found that phylogeny explains little residual variance in the relationship between viral richness and ecological traits in bats ,20,21. HFor rodents, our reanalysis did not alter the importance of phylogeny, bolstering the inference that species relationships are less important for explaining residual variation in rodent reservoir status. Although it is difficult to postulate why phylogeny does not impact the residual error structure in our models for rodents, we can speculate on what may drive lack of signal within patterns of viral richness and ecological traits in rodents . Given the challenges associated with extensively characterizing viral diversity, to date researchers have probably sampled only a small proportion of the viruses harboured by wild mammals . ConsideOur results highlight that the phylogenetic tree used for comparative inference can impact species' trait correlates of viral infection. Although the BE  supertreWith a phylogenetic principal components analysis (pPCA), we were able to explain most of the variation (more than 99%) in the life-history traits of bats and rodents with a single phylogenetic principal component (pPC1). Again, this emphasizes the need to appropriately account for species' relationships throughout comparative analyses . Furtheret al. [et al. note there is a current lack of understanding about what may drive the relationship between torpor use and viral persistence in reservoir species [Regardless, both our best and full model approaches confirm the potential importance of ecological traits for predicting patterns of viral richness. The majority of our models contained species' sympatry, which prior work has shown correlates positively with patterns of parasite richness –23,64,68et al.  also finet al. . Reducedet al. ,72. In fet al. . Howeveret al. . This, pet al.  may limi species , highligAlthough we may be able to make broad inferences about the potential importance of ecological traits for driving patterns of viral richness in reservoir species, our reanalysis emphasizes that patterns of viral diversity are largely driven by citation count. In most of our PGLS regressions, citation count was often the only significant term and had a much larger effect size relative to ecological traits. This was particularly true for bats, where ecological traits exhibited marginal effects relative to citation count . Further, in our PGLS models containing all ecological predictors, although citation count did not always have the largest standardized effect size, its effect was consistent and not as variable as other traits (i.e. lack of torpor use or IUCN status) (et al. [et al. [While there are barriers to including more data in comparative analyses, such as a lack of natural history information for many species, the importance of species-level citation count brings to light that some of the patterns in this dataset could also be artefacts of the subset of species sampled. Bats and rodents are the two most speciose mammalian orders, comprising well over 60% of living mammalian diversity (approx. 2277 species of rodents  and appret al.  used a n [et al. ,68 shoulWe examined how methodological choices influence the outcomes of phylogenetic comparative analyses examining species' trait correlates of viral diversity. However, modern phylogenetic methods allow us to do much more than use phylogeny as a statistical control. They allow us to appreciate the evolutionary history of species, better understand patterns of biological diversity, trace character traits back through evolutionary time and make inferences about the evolution of those traits. For example, studies have used phylogeny to examine the risk of host pathogen shifts in primates  and pred


Aquatic and terrestrial environment and human health have been seriously threatened with the release of metal-containing wastewater by the rapid growth in the industry. There are various methods which have been used for removal of ions from the environment, such as membrane filtration, ion exchange, membrane assisted liquid extraction and adsorption. As a sort of special innovation, a polymerization technique, namely molecular imprinting is carried out by specific identification for the target by mixing it with a functional monomer. After the polymerization occurred, the target ion can be removed with suitable methods. At the end of this process, specific cavities, namely binding sites, are able to recognize target ions selectively. However, the selectivity of the molecularly imprinted polymer is variable not only because of the type of ligand but also charge, size coordination number, and geometry of the target ion. In this review, metal ion-imprinted polymeric materials that can be applied for metal ion removal from different sources are discussed and exemplified briefly with different metal ions. Contamination of water with heavy metal ions affects the ecosystem seriously and this creates important problems [Pollution of water is a significant worldwide threat. Various kinds of chemical pollutants have been discharged to the environmental water by different industries and agricultural applications . Modern problems . The exiproblems .There are different methods used for the removal of metal ions from water and wastewater such as membrane processes, chemical precipitation, extraction, ion exchange and adsorption . MoleculThe form of the molecularly imprinted polymer can be a micro-/nanosized particle, hydrogel, cryogel, or monolith with template specific binding sites . The binMolecularly imprinted polymers can be prepared for any molecule depending on the application area. More than 10,000 molecules and biological structures like metal ions, hormones, proteins and cells have been imprinted successfully ,13,14,15Here, molecularly imprinted polymer applications for different metal ions are reviewed and various examples with metal ions discussed according to their contributions to the literature. Mercury is a metal that occurs naturally and is released primarily through geothermal activity on Earth . The toxZhang et al.  synthesiMergola et al.  publishe2/g with a size range of 63–140 µm. They also observed a maximum adsorption capacity of 0.45 mg/g. According to the results, they showed that the mercury (II)-imprinted polymeric beads could be used several times without reducing their adsorption capacities. In another study, Andaç et al.  preparedXu et al.  synthesiCopper is also a common toxic ion and excessive amounts of copper are dangerous to the environment and organisms. Copper pollution affects the ecosystem of urban areas. In addition, copper commonly affects the chemoreception and chemosensory abilities of aquatic animals which underlie key interactions including finding prey, avoiding predators, and detecting conspecifics . TherefoA multi-ion imprinting method was proposed for pre-concentration and removal of different ions (copper (II), mercury (II), cadmium (II) and nickel (II)) by Fu et al. . The phyRen et al.  preparedKong et al.  developeLead arises commonly associated with zinc, copper and silver ores in the environment. It is generally employed for several industrial applications such as paint, cables, pesticides and pipelines and the main anthropogenic input is through the fossil fuel of combustion engines . Among oMishra et al.  reportedDenizli and his research group synthesized amino acid-based lead (II)-imprinted polymeric cryogels . They caEsen et al.  preparedR2 = 0.9998) was obtained in the range of 0.2−50 μg/L. The limit of detection and quantification values was calculated as 0.06 and 0.19 μg/L, respectively. Real sample studies were also performed with lake and tap water, and according to the results, recovery values varying from 95.5 to 104.6% were obtained.A highly selective lead (II)-imprinted polymer was prepared by Cai et al.  based onCadmium is a poisonous and cancer-causing metal that can happen as a food contaminant and worldwide pollutant. Long-term occupational exposure to high cadmium concentrations may cause lung cancer, kidney and bone damages and hematuria . Varianc2/g with a size range of 63–140 µm in diameter (Cadmium (II)-imprinted polymeric beads were prepared for removal of cadmium ions from cadmium-overdosed human plasma by Andaç et al. . They mediameter . They alRahangdale et al.  reportedCadmium (II)-imprinted polymeric materials were also prepared by Li et al. . They prChromium is also extensively used in different industries like leather tanning, photography and metal cleaning. Industrial wastewater containing heavy metal ions discharged to the environment and their accumulation is an important source of water pollution . ChromiuN-methacryloyl-(l)-histidine was polymerized as seen in A molecularly imprinted polymeric adsorbent for chromium (III) analysis was prepared by Birlik et al. . First, N-methacryloylamido histidine in order to prepare a pre-complex and then chromium (VI)-imprinted polymeric nanoparticles were synthesized using the surfactant-free emulsion polymerization. The particle size was measured to be 155.3 nm. Selectivity studies were performed with chromium (III) ion and according to the results, chromium (VI)-imprinted polymeric nanoparticles showed high affinity to chromium (VI) ion. The chromium (VI)-imprinted polymeric nanoparticles were used several times without decreasing their chromium (VI) adsorption capacities. Another study about chromium (VI)-imprinted polymeric nanoparticles was conducted by Uygun et al. . These rNickel is a silvery-white transition metal that takes on a high polish. The toxicity of nickel depends on the way of its exposure and the solubility of the compound like other metals .Zhou et al.  preparedErsöz et al.  preparedIn a study conducted by Tamahkar et al. , nickel In addition to the metal ions mentioned above, there are also other metals like manganese, aluminum, and cobalt which cause environmental pollution as well. These metals are briefly mentioned in this section. Manganese is a metal ion which is used in electrochemical, chemical, food and pharmaceutical applications. It is also used in ferrous metallurgy generally. Despite the fact that it is fundamental for human life, at levels exceeding 0.1 mg/L, the existence of manganese (II) in drinking water over the limits may cause accumulation and impact the nervous system .Khajeh-Sanchooli et al.  prepared2/g with a size range of 63–140 μm. Elemental analysis was also conducted and the results showed that the aluminum (III)-imprinted polymeric beads contained 640 μmol/g. The maximum adsorption capacity was 122.9 μmol/g. The aluminum (III)-imprinted polymeric beads can be used numerous times and the results showed that there is no significant decrease in their adsorption capacities.In a study conducted by Andaç et al. , aluminuk = 4.17) is higher than the nonimprinted polymer (k = 0.74). These finding suggest that this methodology will introduce new opportunities in the area of removing metal ions and radioactive nuclides.A cobalt (II)-imprinted polymeric material was synthesized by Yuan et al.  in order2/g, while the second one was 78.6 m2/g. The decrease of adsorption capacities of the cryogels were calculated as 38.5% for copper (II), 39.1% for lead (II), 66.9% for zinc (II) and 69.9% for cadmium (II). The maximum adsorption capacities of the cryogel were found for lead (II), cadmium (II), zinc (II) and copper (II) to be 7620, 5800, 4340 and 2540 µg/g, respectively. According to the results, ion-imprinted cryogels could be reused without a critical decrease in the adsorption capacity even after ten adsorption–desorption processes. All these studies have been summarized according to different parameters  in Tekin et al.  preparedExtraction and measurement of metal ions from the aqueous environment remains a serious problem because of their toxicity and cancer risk. Because of this reason, ion-imprinted polymeric materials have been developed further over the last two decades. Especially, they have gained great attention in many areas of science such as chemistry, physics, biology, biochemistry and biotechnology. The most important reason is owing to its selectivity and affinity to the target molecules . Molecul


AIAA J.56, 346–380) is undertaken to assess the progress and overall contributions of LES towards a better understanding of jet noise. In particular, we stress the meshing, numerical and modelling advances which enable detailed geometric representation of nozzle shape variations intended to impact the noise radiation, and sufficiently accurate capturing of the turbulent boundary layer at the nozzle exit. Examples of how LES is currently being used to complement experiments for challenging conditions (such as highly heated pressure-mismatched jets with afterburners) and guide jet modelling efforts are highlighted. Some of the physical insights gained from these numerical studies are discussed, in particular on crackle, screech and shock-associated noise, impingement tones, acoustic analogy models, wavepackets dynamics and resonant acoustic waves within the jet core. We close with some perspectives on the remaining challenges and upcoming opportunities for future applications.In the last decade, many research groups have reported predictions of jet noise using high-fidelity large-eddy simulations (LES) of the turbulent jet flow and these methods are beginning to be used more broadly. A brief overview of the publications since the review by Bodony & Lele (2008, This article is part of the theme issue ‘Frontiers of aeroacoustics research: theory, computation and experiment’. It is now becoming part of the tool set being used outside of academic research, i.e. in research and development efforts directed at design and implementation of concepts aiming to reduce the emitted noise. While the cost of jet noise predictions using LES remains relatively high, the computations have leveraged the continued advancements in high-performance computing and numerical methods, and, as a result, significant strides have been made during the last 10–15 years. These have brought improved quantitative accuracy in noise predictions both in terms of the overall sound pressure level (OASPL) directivity and spectral shape for a given observer direction. The purpose of this article is to present a concise overview of the progress made using LES and draw attention to some areas where LES is now contributing to the field of jet aeroacoustics. This is not an exhaustive review—only the most salient aspects are discussed. In combination with other broader reviews of aeroacoustics and jet noise , it is h2.(a)quasi-realistic jet mean flow profiles near the nozzle exit. The turbulence resolving simulations started with the emulated mean flow seeded with perturbations using various approaches aiming to capture realistic jet flow turbulence. It was hoped that as the flow evolved, say after the first jet diameter or so, the physical discrepancy associated with not directly representing the nozzle and the boundary layer state at the nozzle exit accurately would be reduced, allowing comparison with laboratory measurements for the jet flow and its near- and far-field noise. As reviewed by Bodony & Lele [The jet LES studies available in 2008 used several pragmatic compromises . Most imy & Lele , achieviRe = UjD/ν simulated was reduced to be in the 0.1 to 5 × 105 range in most of these early jet studies [Uj is the jet velocity and D is the nozzle exit diameter. Without nozzle geometry, there was no high-Reynolds number wall-bounded flow to consider. The choice of reduced Re was made to limit the modelling contributions, based on the argument that independence on Reynolds number in the jet plume is reached for Re≥100 000 [Re increases, the large scale part remains relatively fixed, i.e. scales with D. At the same time, the dissipative scales shift to smaller spatial scales and broaden the Strouhal number St = fD/Uj range of noise to higher frequencies f, but may not significantly change the main jet characteristics such as peak radiation levels, OASPL directivity, etc. This does not mean that Re is an unimportant parameter, but rather that, above a certain value, the Reynolds number mainly affects the jet plume and radiated noise indirectly through the changes in nozzle-exit boundary layer state and early shear layer development. Furthermore, at high Reynolds numbers, the turbulence shows higher internal intermittency, i.e. the turbulent kinetic energy (TKE) dissipation rate, Kolmogorov scales etc. fluctuate more in different realizations of the flow. The upshot of this is that the probability of extreme events (which have quite a low probability), as well as high-order statistics of the turbulent flow and noise, may change with Reynolds number. This must be kept in mind when studying intermittent phenomena, such as crackle, or wave-packet intermittency.Another important compromise was that the Reynolds number  studies , where U≥100 000  or 400 0≥100 000 . While tRe = 106, which means that both the boundary layers and shear layers are likely to be transitional or turbulent, even under favourable pressure gradient. However, inclusion of the physical geometry in high Re flows leads to additional meshing and modelling challenges that need to be addressed without making the computational costs prohibitive. First, how to robustly generate tractable grids that appropriately capture the relevant geometric details for complex realistic nozzles? Second, how to efficiently resolve and/or model the thin turbulent boundary layer flow inside the nozzle? For laboratory jets, significant research on both topics has been undertaken and is discussed in the next two sections. As remarked by Freund [Rather than discuss these limitations of the previous tools, we will focus on the elements which have allowed the physically realistic simulations in recent years. Nowadays, it is well recognized that the state of the nozzle-exit boundary layer is an important parameter of the jet flow development and noise radiation. Therefore, most current simulations explicitly include a nozzle at the inlet of the computational domain and are performed at realistic Reynolds number. Whether it is for laboratory jet flows or full-scale nozzles at practical operating conditions, the nozzle-diameter-based Reynolds number is typically reported over y Freund , these e(b)The choices of mesh topology and numerical discretization are closely linked and directly steer the dispersion and dissipation errors, especially important in aeroacoustics. Historically, four approaches have been widely used to address the mesh-generation challenge in computational fluid dynamics: multi-block structured meshes, overset grids, Cartesian  meshes and generalized unstructured grids . Structured meshes with high-order spatial discretization gained early popularity in jet noise simulations –13, initet al. have pursued detached-eddy simulations (DES), LES and hybrid methods for jet aeroacoustics and broader applications in a finite volume structured grid solver ‘NTS’ with multi-block overlapping grids. They use discretizations which blend central differencing with upwinding along with different levels of turbulence scale resolving models. A different finite element based unstructured discretization underlies the ‘JENRE’ solver [et al. [et al. [et al. [Further progress in jet computations has resulted from the use of general unstructured meshes. Shur ’ solver  at Naval’ solver ,28, and ’ solver  to evalu [et al.  present  [et al.  have dev [et al.  reported [et al. .Similarly to the NTS solver, the early version of the compressible flow solver ‘Charles’ developed at Cascade Technologies used a blend of relatively non-dissipative central flux and more dissipative upwind flux on hexahedral-dominant unstructured grids with mesh adaptation. The method has successfully provided accurate jet noise predictions for a range of relatively simple geometrical configurations , but sti(c)et al. [grey zone where the flow transitions from RANS to LES mode.The need to accurately capture the thin boundary layers at the nozzle exit in their natural state (laminar or turbulent) was deemed as a critical future step by Bodony & Lele . A varieet al.  have devet al. [Re = 105. The initially laminar boundary layers were tripped inside the pipe nozzle by adding low-level random disturbances uncorrelated in the azimuthal direction, with specific amplitudes chosen to achieve targeted levels of peak turbulence at the nozzle exit. As an alternative to this tuned numerical forcing, other tripping procedures inspired by roughness strips used in experiments have been suggested, including geometrical tripping [When the nozzle interior flow is directly computed in LES, it remains impractical to fully resolve the high Reynolds number boundary layer turbulence. In many older studies, the nozzle boundary layers were assumed to be laminar, the Reynolds number was reduced and disturbances were introduced at the inlet  or insidet al. ,15 investripping , where atripping , where tRe with initially laminar boundary layers [et al. [et al. [M = Uj/c∞ = 0.9 turbulent jet at Re = 106 and led to fully turbulent nozzle-exit boundary layers with significant improvement of the flow field and noise predictions. Subsequently, the study was extended to a range of Mach M = 0.4, 0.7 and 0.8 for the same converging-straight pipe nozzle, with similar accuracy in flow and noise predictions. All the simulations were performed in close collaboration with a companion experiment at Pprime Institute in Poitiers (France), and matched the experimental Reynolds number. Combined with appropriate resolution in the shear layers and jet plume (see next section), these modelling approaches resulted in sub-dB prediction accuracy for most relevant inlet angles ϕ and frequencies St = fD/Uj .While the early simulations with the Charles solver were also performed at reduced y layers , later ey layers . The mody layers –42 to mo [et al. , wall-mo [et al.  and has  [et al. –47. As s [et al. , the com(i)u′ increase monotonically with distance as the shear layer spreads. For laminar shear layer, however, an overshoot in u′ along the lipline occurs due to transition and then approaches values consistent with turbulent shear layer self-similarity. Brès et al. [As already discussed, the turbulent jet flow which emerges from a nozzle begins with relatively thin shear layers. If the nozzle interior boundary layer is turbulent the near-lip shear layer is naturally turbulent. For laminar exit flow the shear layer becomes turbulent rapidly due to instabilities whose wavelength scales with the initial shear layer (momentum) thickness. If the flow at nozzle exit is already turbulent, the TKE and streamwise rms velocity s et al.  report ts et al. ,15 in ths et al. . Therefo(ii)Prediction of far-field radiated noise from jet flow LES requires a hybrid approach, where the important scales of turbulence within the noise-producing region of the jet are resolved, and the propagation of the small amplitude acoustic fluctuations from the near-field source region to the far field is computed analytically. The Ffowcs Williams–Hawkings (FW–H) equation  is one oacoustic data recorded on that distant surface might be corrupted by significant numerical errors. In particular, Bodony & Lele [et al. [et al. [et al. [In the FW–H approach, the turbulent flow volume is surrounded by an acoustic data surface, i.e. FW–H surface, on which the time-varying data is saved as the jet LES is computed, and the quadrupole contributions from the volume-distributed noise sources outside of the FW–H surface are neglected. In a post-processing step, the far-field radiated sound is calculated using the FW–H surface data via analytically known Green's function for a stationary or uniformly moving ambient medium. The placement of FW–H surface, and the spatial and temporal resolution of the data saved on FH-W surface are important. If the FW–H surface lies inside the turbulent flow, the data collected on it do not include the sound produced by the turbulent flow lying outside of it and (vigorous) crossing of turbulence across the surface is a contributor to spurious acoustics. On the other hand, if the FW–H surface is placed too far away from turbulent jet, predictions based on it might also be incorrect because the y & Lele  pointed  [et al.  introduc [et al. ,50 and i [et al.  proposed3.in situ or laboratory testing.One way that LES are contributing to a better understanding of jet noise is as a complement to experiments, in particular, for tactical exhaust systems. Detailed measurements in full-scale engines are costly and difficult, and most laboratory facilities are limited to smaller-scale jets at lower temperatures. For such high-speed heated jet from realistic nozzle configurations, LES can arguably provide insight on the jet flow field and acoustic field in a more flexible and cost-effective way than most (a)To investigate the impact of inlet temperature non-uniformity on the jet flow and noise, LES were performed with the Charles solver for heated over-expanded supersonic jets issued from a faceted military-style nozzle . The numϕ. The results of this proof-of-concept LES study indicate that there is merit to the idea pioneered in experiments at lower temperature when taking into consideration more realistic conditions. Much work remains to fully analyse the LES data generated by this investigation, along with more concepts worthy of examination to improve the simulations and noise mitigation.(b)et al. [et al. [et al. have shown that crackle is emitted as a weak shocklet, whose shock-like signature can be traced all the way to the eddying motions in the jet shear layer. They also noted that high-frequency shocklets are emitted from the near-nozzle shear layer, consistent with Mach wave emission from eddies moving at Ortel convective Mach number Mco = (1 + Mj)/(1 + c∞/cj); however, the intense crackle emissions were found to move more rapidly and were relatively infrequent as shown in et al. [Ffowcs Williams et al.  identifiet al. ; its souet al. ,57, the  [et al. ,59 is a n et al.  stress tn et al.  of F-35 (c)Harper-Bourne & Fisher  interpreet al. [et al. [et al. [In recent years LES of hot supersonic jets including over-expanded and under-expanded conditions have been investigated by many groups. These studies have included axisymmetric, chevroned and rectangular nozzles and cold, heated and highly heated conditions. While most effort has been devoted to the validation of the LES predictions , some anet al.  studied et al. , althouget al.  analysedet al.  better c [et al. ,70 study [et al.  applied Tam ,73, and et al. [et al. [Recent research on screech and other resonant acoustic phenomena see §§b, such aet al.  in jet s [et al. ,87 detai4.Since Lighthill  introduc(a)As reviewed by Jordan & Colonius , there het al. [One spectral approach ideally suited for turbulent jets is the frequency domain version of spectral proper orthogonal decomposition , referreet al. , SPOD ‘iet al. , and ideresolvent analysis has emerged from dynamical system theory. This analysis of turbulent mean flows is based on the assumption that large-scale coherent structures can be modelled as responses of a linear operator to stochastic forcing [Another frequency-domain technique called  forcing . Most re forcing  and demo forcing .M = 1.5 case seen in figure 7g–j, which are at the root of aft-angle supersonic jet noise, and the waves highlighted in figure 7m,n, which identify different acoustic resonance phenomena M = 0.9 LES database [et al. [et al. [et al. [M < 1.0. Indeed, at M = 0.9, both the upstream and downstream-propagating waves were observed in the jet core in the simulations, as well as the corresponding discrete tones in the near-field acoustic pressure very close to the nozzle exit for the LES and the companion experiments. While it had been postulated [Besides its contributions towards the understanding of the most energetic large scale coherent wavepacket structures that dominate the shear layer, the database  was also [et al.  and Schm [et al. , these w [et al.  developestulated  that comstulated  et al. [LES-informed modelling of aeroacoustic sources, and in particular for jet noise sources, has been anticipated at least since the 1980s . The devet al.  and the et al. ,109 and et al. , i.e. thet al.  and otheet al. ,112 usin5.Looking back at the list of key open issues identified by Bodony & Lele  in theirRe wall-bounded turbulence such as nozzle-interior boundary layers. Turning off the SGS model yielded erroneous profiles for turbulent fluctuations and also incorrect boundary layer profile [For all mesh topologies, the interplay between the modelling choices regarding the treatment of subfilter scale motions and the numerical bandwidth of the discretization schemes used, determines the effective bandwidth of the simulation results. While comprehensive cross-comparisons across different LES solvers and modelling of fine-scale motions are still lacking, some observations can still be made. Simulations with schemes employing minimum numerical dissipation require SGS modelling to prevent tail up of energy at the shortest scales . In this profile . Numeric profile ,115. Fur profile ,116, andSt = 1.5 − 3. While this frequency range is sufficient for supporting the modelling effort of the peak noise radiation, acoustic resonance and wavepacket dynamics [et al. [M = 0.9 turbulent jet previously discussed and showed that the frequency limit was increased from St ≈ 2 to 4 by doubling the resolution in the jet plume in all directions. For the refined LES case, the unstructured mesh contained 69 million cells (up from 16 million), the simulation time step was decreased by half (because of CFL constraints) and the CPU cost  was increased 10-fold. Overall, this approach comes with a significant increase in computational cost, only partly mitigated by advancements in high-performance computing, and it is still unclear if tractable resolution can yield sufficiently high bandwidth predictions for practical applications. As an alternative to (or in combination with) finer grids, Bodony & Lele [generalized acoustic analogy approach [The other concern raised by Bodony & Lele  was thatdynamics ,89,99, l [et al.  conducteapproach  applied approach ,118. Theapproach  and stocapproach ,121 coulIn terms of research opportunities, prediction and reduction of the noise radiated by hot, supersonic jets has been a traditional research driver. Recent studies of strongly heated supersonic jets ,122 undeet al. [The trend towards higher bypass ratio, larger engines for commercial aircraft has elevated the importance of installation effects. Tyacke et al.  have devet al. , non-ciret al. , multi-sPrediction of the vibro-acoustic environment associated with rocket launch has driven considerable research in recent years . Such caFrontier system will feature future-generation AMD CPUs and Radeon GPUs. Some jet simulations have already been performed on GPUs by Markesteijn, Semiletov & Karabasov (see [In terms of high-performance computing, the current trend is towards mixed architectures and incorporating some GPU computing for the jet simulation will likely be necessary to leverage these enhancements. Indeed, the Oak Ridge National Laboratory has recently announced the selection of Cray and AMD to provide the laboratory with its first exascale supercomputer for 2021 deployment. Poised to deliver greater than 1.5 exaflops of HPC and AI processing performance, the sov (see  and the sov (see  with ref6.We have attempted to provide a concise overview of the developments in jet LES during the last decade since the review by Bodony & Lele . Much pr


S-depalmitoylases in live cells and tissues’ by Michael W. Beck et al., Chem. Sci., 2017, DOI: ; 10.1039/c7sc02805aCorrection for ‘Michael addition-based probes for ratiometric fluorescence imaging of protein  The authors regret that there was an error in ref. 30 of the original article. The correct reference, including the two relevant journals, is presented herein as The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


Replying to S. Tiegs et al. Nature Communications 10.1038/s41467-019-13303-1 (2019)1 highlight the significance and relevance of the findings of Comer-Warner et al.2 on greenhouse-gas emissions from streambed sediments but raise questions about some aspects of the experimental design. We support their call for more detailed field and laboratory-based studies on this subject. However, we believe that their concerns relate to uncertainties and limitations in the experimental design that were discussed explicitly in the original paper (and accompanying transparent peer review process—available online), or represent criticisms related to highly improbable minor anomalies that may unnecessarily dismiss experimental results as discussed below.Tiegs et al.1 , which propagate the arbitrary dismissal of important research due to philosophical criticisms of pseudoreplication7. For instance, Davies et al.4 have shown that the exact formation of suitable hypotheses based on mechanistic understanding can account for pseudoreplication within experimental design. Without such underlying hypotheses the number of necessary potential controls are infinite and hence infeasible. Furthermore, problems of pseudoreplication may be reduced if appropriate statistics addressing the pseudoreplication are used, for example through inclusion as random effects in linear mixed effects models8. While we welcome the contribution of Tiegs et al.1 to this longstanding discourse, our response aims particularly at those elements that advance the discussion beyond a repetition of previous pseudoreplication controversies7.It should be noted in a broader context that previous compelling articles have challenged arguments aligned to those of Tiegs et al.2 was based on a hypothetico-deductive approach that focused on the key predictors (i.e. controls and proxies for processes) derived from state-of-the-art understanding of our target variables (CO2 and CH4 emissions). This research design provided a framework for robust statistical analysis through clearly defined hypothesised processes and mechanisms in order to support meaningful statistical analyses.The research design of Comer-Warner et al.1 express concerns that Comer-Warner et al.2 included all samples within the same batch in the same incubator. We did not account for week of incubation (i.e. batch) within the statistical model as we do not consider that there is a reasonable mechanism by which sample incubation week was impacted by this experimental approach and the associated consistent sample storage over the course of batch incubations. We find Tiegs et al.1 argumentation that batch-specific conditions “likely differed in unknown ways” from batches tested in other weeks highly unconvincing. Moreover, we do not consider isolative segregation to have any discernible impact on the experimental results, as discussed below. In fact, we are convinced that the results of our experiments are more robust by exposing all experimental temperature treatments to the same incubation environment, rather than introducing unnecessary uncertainty and risk of technical failure or variance in performance through the use of different incubators, as suggested by Tiegs et al.1. Notably, the differences between the temperature at the top and bottom of the incubator were very small . Furthermore, non-linearity and threshold responses of greenhouse-gas fluxes to temperature have previously been found in a variety of ecosystems, e.g., refs. 14.Additionally, Tiegs et al.


Cohen AJ, Brauer M, Burnett R, et al. Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the Global Burden of Diseases Study 2015. Lancet 389: 1907–182016; —In this Article, the following changes have been made to the supplementary appendix. In table 1, for the Pinault et al11 study, the country, the CEV (Stroke)-Relative Risk (95% CI), and the IHD-Relative Risk (95% CI) have been corrected (p 11); the second Pinault et al11 reference has been changed to Thurston et al ; a footnote has been added stating that the indicated data were from “Additional, unpublished analyses, provided by the principal investigator at the authors' request” (p 12); the first Miller et al15 reference has been changed to Puett et al (2011); the LC-Relative Risk for Turner et al has been corrected (p 12); and the reference list has been updated. These corrections have been made to the online version as of May 23, 2017.


Previously, Aydogdu et al. [μm-diameter dextranomer microspheres in a stabilized hyaluronic acid gel recruited numerous myofibroblasts around the dextranomer particles, a foreign body inflammatory reaction with a high density in CD68 positive cells, stimulating an enhancement in collagenous stroma [We read with great interest and appreciated very much the article written by Üre et al. . In theiu et al. , comparis stroma . Moreoves stroma . We beli


It was so named because of its occurrence in shark liver oil, which contains large quantities and is considered its richest source. However, it is widely distributed in nature, with reasonable amounts found in olive oil, palm oil, wheat-germ oil, amaranth oil, and rice bran oil. Squalene, the main component of skin surface polyunsaturated lipids, shows some advantages for the skin as an emollient and antioxidant, and for hydration and its antitumor activities. It is also used as a material in topically applied vehicles such as lipid emulsions and nanostructured lipid carriers (NLCs). Substances related to squalene, including β-carotene, coenzyme Q10 (ubiquinone) and vitamins A, E, and K, are also included in this review article to introduce their benefits to skin physiology. We summarize investigations performed in previous reports from both  Squalus spp.) liver oil, which contains large quantities and is considered its richest source [Human skin, covering the entire outer surface of the body, is the largest organ and is constantly exposed to sunlight stress, including ultraviolet (UV) light irradiation. The skin tissue is rich in lipids, which are thought to be vulnerable to oxidative stress from sunlight. Squalene A is a stt source . It is tExperimental studies have shown that squalene can effectively inhibit chemically induced skin, colon, and lung tumorigenesis in rodents . The pro1  in the hair follicles to lubricate the skin and hair of animals . In humaSqualene is not very susceptible to peroxidation and appears to function in the skin as a quencher of singlet oxygen, protecting human skin surfaces from lipid peroxidation due to exposure to UV light and other sources of oxidative damage , as discTruly one of nature’s great emollients, squalene is quickly and efficiently absorbed deep into the skin, restoring healthy suppleness and flexibility without leaving an oily residue. New cosmetic emulsions with biomimetic molecules have been investigated using experimental designs . That stet al. [vernix caseosa (VC) substitute can be an innovative barrier cream for barrier-deficient skin. This is because of the excellent properties of VC in facilitating stratum corneum hydration. Different lipid fractions were isolated from lanolin and subsequently mixed with squalene, triglycerides, cholesterol, ceramides, and fatty acids to generate semi-synthetic lipid mixtures that mimic the lipid composition of VC. The results showed that the rate of barrier recovery increased and was comparable to VC lipid treatment. Okuda et al. [p < 0.05).In general, occlusion leads to increased skin hydration due to reduced water loss. Rissmann et al.  revealeda et al.  also fouIn vitro experimental evidence indicates that squalene is a highly effective oxygen-scavenging agent. Subsequent to oxidative stress such as sunlight exposure, squalene functions as an efficient quencher of singlet oxygen and prevents the corresponding lipid peroxidation at the human skin surface [et al. [t-butyl-4-hydroxytoluene. They also reported that squalene is not particularly susceptible to peroxidation and is stable against attacks by peroxide radicals, suggesting that the chain reaction of lipid peroxidation is unlikely to be propagated with adequate levels of squalene present on the human skin surface. Aioi et al. [2-) generation in rats in order to elucidate the mechanism whereby this compound decreases erythema induced by 1% lauroylsarcosine (LS) ointment. LS (200~400 μg/mL) caused overt production of O2- from cultured keratinocytes and peritoneal exudate leukocytes. O2- was significantly reduced by the addition of squalene (100 μg/mL). These results suggest that a possible role of squalene for alleviating skin irritation is by suppression of O2- production, which is dependent on different mechanisms of action of superoxide dismutase.Squalene has been reported to possess antioxidant properties.  surface . Kohno e [et al.  found thi et al.  studied et al. [O-tetradecanoylphorbol-13-acetate. The mice were treated with 5% squalene and at the end of the prevention study, there was a 26.67% reduction in the incidence of tumors in the squalene-treated group. In a related branch of research, a protective effect was observed when squalene was given before and/or during carcinogen treatment. Experimental studies have shown that squalene can effectively inhibit chemically induced skin tumorigenesis in rodents [During the past few years, squalene was found to show protective activities against several carcinogens . Desai eet al.  reported rodents .Squalene is also used as a material or additive in topically applied vehicles such as lipid emulsions and nanostructured lipid carriers (NLCs).et al. [in vitro transfection activity of emulsions was lower than that of liposomes in the absence of serum, the activity of squalene emulsions, for instance, was approximately 30 times higher than that of liposome in the presence of 80% (v/v) serum (p < 0.05).Lipid emulsions are potentially interesting drug delivery systems because of their ability to incorporate drugs with poor solubility within the dispersal phase . An emulet al.  preparedet al. [in vitro and in vivo gene transfer. In addition, Wang et al. [in vivo analgesic activity of the emulsions was examined by a cold ethanol tail-flick test. The squalene system showed the ability to provide controlled delivery to prolong the analgesic duration in rats. The toxicity determined by erythrocyte hemolysis was also low for squalene emulsions.Kim et al.  found thg et al.  indicateSolid lipid nanoparticles (SLNs) are a new generation of oil-in-water nanoparticulate systems and are attracting attention as novel colloidal drug carriers. Distinct advantages of SLNs are the solid state of the particle matrix, the ability to protect chemically labile ingredients, and the possibility of modulating and prolonging drug release. NLCs are a novel type of lipid nanoparticle with a solid particle matrix possessing structural specialties and improvements such as an increased loading capacity, long-term physical and chemical stability, triggered release, and potentially supersaturated topical formulations. NLCs are produced by mixing solid lipids with spatially incompatible lipids leading to a lipid matrix with a special structure. Depending on the method of production and composition of the lipid blend, different types of NLCs can be obtained . The baset al. [® and squalene (12% w/v) showed respective mean particle sizes of 200 nm. The lipophilicity of NLCs decreased with an increase in the squalene content in the formulations. Psoralen derivatives  for psoriasis treatment were loaded in NLCs to examine their ability to permeate via the skin. Enhanced permeation and controlled release of psoralen were both achieved using NLCs with squalene. The in vitro permeation results showed that NLCs stabilized with Tween® 80 increased the 8-methoxypsoralen flux 2.8 times over that of a conventional emulsion.Fang et al.  found thet al. [et al. [Squalene monohydroperoxide (SQOOH) is a primary oxidized lipid produced from squalene by solar UV. It is produced at the human skin surface due to natural exposure to sunlight during daily activities. Recent studies demonstrated that repeated application of SQOOH to the skin can induce skin roughness and wrinkles in the hairless mouse . Uchino et al.  also rep [et al.  demonstret al. [p < 0.001). This may provide a useful model for studying skin aging, particularly with regard to the collagen content.Chiba et al.  studied 1O2 quencher and unique free radical scavenger [et al. [Dunaliella salina  protected human skin from UV light-induced erythema. Bando et al. [in vivo study focused on determining the mechanism of action of β-carotene against UVA-induced skin damage by characterizing β-carotene oxidation products. BALB/c mice were fed a β-carotene-supplemented diet, and homogenates from the dorsal skin were prepared after three weeks for UVA irradiation. The results indicated that dietary β-carotene accumulated in the skin and acted as a protective agent against UVA-induced oxidative damage, by quenching 1O2.Many other polyprenyl compounds structurally similar to squalene exist in nature and perform critical biological functions. β-Carotene is well known to be a potent cavenger . This pr [et al.  demonstro et al.  found thet al. [A number of studies have demonstrated that dietary β-carotene protects human skin from UV light-induced erythema, but little is known about the protective effect of dietary β-carotene on UVA-induced skin photoaging . Antilleet al.  showed tp < 0.05).β-Carotene was partially successful in treating a photosensitivity disorder, erythropoietic protoporphyria, of which singlet oxygen is believed to be an important mediator. Several studies were performed to examine whether β-carotene protects against UV-induced erythema in healthy humans, with widely differing reported effects. The incidence of nonmelanoma skin cancer was reported to be inversely related to serum β-carotene concentrations, and earlier experimental UV-carcinogenesis studies found β-carotene to be photoprotective . HoweverCoenzyme Q10 is an important lipophilic antioxidant synthesized by the body . Topicalet al. [Coenzyme Q10 is a popular antioxidant used in many skin care products to protect the skin from free radical damage. The effects of coenzyme Q10 and colorless carotenoids on the production of inflammatory mediators in human dermal fibroblasts treated with UV radiation and possible synergistic effects of these two antioxidants were evaluated by Fuller et al. . Treatmeet al. [et al. [2 UVB, and assayed the levels of thymine dimers produced in epidermal DNA 2 h following UVB exposure. The results demonstrated that epidermal retinyl esters have a biologically relevant filter activity and suggest, besides their pleomorphic biologic actions, a new role for vitamin A that is concentrated in the epidermis (p < 0.05). Moreover, Alberts et al. [Squalene and some of its related substances, including vitamin A, were examined in an animal model to determine the existence of chemopreventive effects. Varani et al.  pointed  [et al.  applied s et al.  concludein vitro and in vivo [in vitro and in vivo skin absorption levels of retinol in the fuzzy rat. Results from those studies were used to help interpret the significance of the in vitro retinol human skin reservoir in determining systemic absorption (p < 0.001) [et al. [in vitro Franz diffusion assembly, and formulations were applied for 6 and 24 h. Vitamin A concentrations in the skin tissue suggested a certain drug localizing effect. High retinol concentrations were found in the upper skin layers following application of SLN preparations, whereas the deeper regions showed only very low vitamin A levels (p < 0.05).Vitamin A-derived agents still continue to be used to treat acne. Furthermore, retinoids act as chemopreventive and/or chemotherapeutic agents for several types of cancer. They have major effects on the growth and differentiation of normal, premalignant, and malignant epithelial cells both  in vivo . Retinol in vivo . Retinol< 0.001) . Jenning [et al.  evaluatein vivo. It is thought to play an important role in skin protection [et al. [R,R,R-a-tocopheryl acetate, 62.5 IU/kg diet) for 26 weeks. Vitamin E reduced the tumor yield in mice given UV and arsenite by 2.1-fold (p < 0.001). Those results show that vitamin E can strongly protect against arsenite-induced enhancement of UV-caused carcinogenesis.Vitamin E is the most potent lipid-soluble antioxidant otection . Uddin e [et al.  examinedet al. [p < 0.05). Those results demonstrated that topical administration of α-tocopherol protects cutaneous tissues against oxidative damage induced by UV irradiation in vivo.Vitamin E is a group of eight different compounds, but only two of the forms, α-tocopherol and γ-tocopherol, are commonly found in the human body . Lopez-Tet al.  investiget al. [N,N-dimethylglycinate hydrochloride (γ-TDMG), could protect against UV-induced skin damage in hairless mice. Topical pre- or post-application of a 5% (93 mM) γ-TDMG solution in water/propylene glycol/ethanol (2:1:2) significantly prevented sunburned cell formation, lipid peroxidation, and edema/inflammation, which were induced by exposure to a single dose of UV irradiation at 5 kJ/m2 . Those results suggest that the topical application of γ-TDMG may be efficacious in preventing and reducing UV-induced inflammation.Yoshida et al.  investiget al. [in vivo. Therefore, topical formulations containing α-tocopherol at concentrations ranging from 0.1% to 1% are likely to be effective skin care measures to enhance antioxidative protection of the skin barrier. According to the antioxidant network theory, combinations with co-antioxidants such as vitamin C may help enhance the antioxidant effects and stability of vitamin E [Ekanayake-Mudiyanselage et al.  recentlyitamin E . A betteet al. [Vitamin K is another squalene-related substance that exhibits benefits to skin physiology. Lou et al.  examinedet al. [in vitro skin penetration and transdermal delivery of vitamin K , and whether these parameters were enhanced by lipid-based drug delivery systems. The experimental results demonstrated that the topical delivery of vitamin K incorporated in a lipophilic vehicle was low. It could be enhanced (~3-fold increase) by monoolein-based systems, which may be useful in increasing the effectiveness of topical vitamin K therapy.The application of vitamin K to the skin has also been used to suppress pigmentation and resolve bruising. Lopes et al.  investigSqualene appears to be critical in reducing free radical oxidative damage to the skin. Although epidemiological, experimental, and animal evidence suggests antitumor properties, few human trials have been conducted to date to verify the role of squalene in cancer therapy. Further studies are needed to explore the usefulness of squalene for treating skin. Several implications can be drawn from this review. Squalene shows several advantages for skin tissues. It is also useful as a material in topically applied vehicles. Substances related to squalene such as β-carotene, coenzyme Q10, and vitamins A, E, and K also exhibit their benefits for skin physiology. Topical administration via the skin is an important route to supplement these compounds within skin tissues. The present success of squalene and its analogs shows the promise of further clinical trials for skin use.


Plasmodium protozoa causing malaria.Ursolic acid (UA) is a natural terpene compound exhibiting many pharmaceutical properties. In this review the current state of knowledge about the health-promoting properties of this widespread, biologically active compound, as well as information about its occurrence and biosynthesis are presented. Particular attention has been paid to the application of ursolic acid as an anti-cancer agent; it is worth noticing that clinical tests suggesting the possibility of practical use of UA have already been conducted. Amongst other pharmacological properties of UA one can mention protective effect on lungs, kidneys, liver and brain, anti-inflammatory properties, anabolic effects on skeletal muscles and the ability to suppress bone density loss leading to osteoporosis. Ursolic acid also exhibits anti-microbial features against numerous strains of bacteria, HIV and HCV viruses and  Ursolic acid  fruit peel, marjoram (Origanum majorana) leaves, oregano (Origanum vulgare) leaves, rosemary  leaves, sage  leaves, thyme (Thymus vulgaris) leaves, lavender (Lavandula angustifolia) leaves and flowers, eucalyptus  leaves and bark, black elder (Sambucus nigra) leaves and bark, hawthorn (Crataegus spp.) leaves and flowers, coffee (Coffea arabica) leaves and the wax layer of many edible fruits [Ursolic acid and related triterpene compounds like oleanolic acid, betulinic acid, uvaol or α- and β-amyrin are widespread in plants. Their content and composition differs between various species, due to the presence and activity of the enzymes responsible for their synthesis. Amongst plants matrices with a high content of ursolic acid and of potentially practical significance as a source of this compound one can mention apple  which is a five-carbon building block utilized to create all terpenic compounds. For many years it has been believed that the mevalonate pathway (MVA) is the exclusive source of this compound. In this cytosol-carried metabolic pathway two molecules of Acetyl-CoA (created in the citric acid cycle) are transformed to one molecule of IPP through a six stage process. Recent investigations have discovered another route, the deoxyxylulose/methylerythritiol phosphate (DXP) pathway. In this plastid-located process isopentyl diphosphate is synthesized from pyruvate and glyceraldehyde-3-phosphate . SynthesThe second stage of UA production is synthesis of 2,3-oxidosqualene and its cyclisation leading to formation of α-amyrin. Molecules of IPP and its isomer dimethylallyl diphosphate (DMAPP) are used to create squalene (through the intermediates geranyl pyrophosphate and farnesyl pyrophosphate). Then squalene epoxidase oxidizes this compound to 2,3-oxidosqalene. The group of enzymes named oxidosqualene cyclases (OSCs) is responsible for the cyclisation and rearrangement of the terpenoid chain leading to the formation of various scaffolds, including α-amyrin .The last stage is modification of α-amyrin by group of cytochrome P450 enzymes called α/β-amyrin 28-monooxygenases. The methyl group-containing C-28 is oxidized to a carboxyl thus finishing the UA biosynthesis process .Ursolic acid is one of the most promising substances of biological origin when it comes to the prevention and therapy of cancer. Novel pharmacological strategies do not rely only on the destruction of tumor cells, but also modulate their metabolism to prevent angiogenesis and metastasis, enforce differentiation of cells and protect healthy tissues against inflammation and oxidative stress that may lead to neoplasm formation.in vitro and in vivo is shown in UA can be described as a multi-tasking agent; it influences several cell signaling enzymes and simultaneously protects it against carcinogenic agents. The summary of the studies describing ursolic acid’s impact on carcinomas It should be noted that in the majority of mentioned works the authors were testing pure compounds or attributed therapeutic properties to ursolic acid. There are also numerous studies describing the effects of plant extract without assigning the activity to a particular compound; the authors did not include them in this work.To fully understand modus operandi of anti-cancer drugs one must take a closer look at cell signaling. This very complex system of communication coordinates all cellular activities and responses on extracellular signals. The schematic diagram of the main intracellular signal routes is presented in The anticancer activity of ursolic acid is associated with its ability to influence the activity of several enzymes. Therefore it is able to modulate processes occurring inside tumor cells activating routes leading to cell death  and suppressing ones leading to the proliferation, growth and migration of cancer.The MAPK/ERK and PI3K/AKT/mTOR signaling cascades play critical roles in the transmission of signals from growth factor receptors to regulate gene expression. Both these pathways are responsible for anti-apoptotic and drug resistance effects in cells . The abiHigh expectations are also surrounding UA impact on nuclear factor κB. Activity of NF-κB is connected with reaction on such stimuli as cytokines, free radicals or antigens, and it plays crucial role in immunologic answer against infection. Malignant cells are characterized by abnormally high activity of this transcription factor, what leads to intense proliferation and make NF-κB one of the main targets of modern oncotherapy . Capabilet al. [Forkhead box (FOX) proteins are family of transcription factors playing crucial role in regulating expression of genes involved in cell growth. FOXM1 has been recognized as exceptional important as its aberrant upregulation might be inducing genomic instability and leading to malignant transformation . FOXM1 het al.  in theirApoptosis is the process of programmed cell death occurring as a result of activation of the specific cellular pathways. In contrast to necrosis, this process is highly regulated and leads to chromosomal DNA fragmentation. The induction of apoptosis by various agents is an important part of modern cancer therapies. Unfortunately apoptosis in cancer cells is often blocked by the activity of mutated genes regulating the cell cycle. Therefore different steps of the apoptotic process should be targeted to bypass such blocks .in vitro and in vivo. This aptitude is often connected with the Bcl-2 apoptosis regulators activity. This group of evolutionarily related proteins consist of both pro- and anti-apoptotic agents and is regarded as crucial in regulation of cell death through intrinsic apoptotic pathway [Apoptosis induction is the uppermost anti-cancer activity of ursolic acid. It has been reported in dozens of papers, as regards several cancer types, both  pathway . Ursolic pathway ,38,39,65Caspases are family of cysteine proteases playing essential role in apoptosis. They are final step of cell death pathways and are responsible for e.g., DNA fragmentation, cleavage of nuclear proteins and as a result blebbing and cell death . Inhibitet al. [Sequencing of the human genome shown that retrotransposable elements make up about 45% of the human DNA. Almost all of these elements contain genes responsible for reverse transcriptase (RT) coding. In most tissues expression of RT-coding genes is very low, however high expression is distinctive for undifferentiated cells like embryos, germ cells or tumor cells. Sciamanna et al.  revealedet al. [Role of ursolic endogenous reverse transcriptase as a mediator of ursolic acid properties was reported by Bonaccorsi et al. . Their wAngiogenesis is the formation of new blood vessels from other pre-existent ones during development, growth, wound repair or the female reproductive cycle. Angiogenesis is one of cancer’s hallmarks since it is required for both tumor progression and dispersal of metastatic cells. This resulted in the fact that the inhibition of angiogenesis has become an alternative therapeutic approach to cancer therapy. The angiogenic process is activated by intracellular signals that activate resting endothelial cells, which are stimulated to release degrading enzymes allowing endothelial cells to migrate, proliferate, and finally differentiate to form new vessels. Any of these steps might be a potential target for pharmacological compounds .et al. [et al. [Anti-angiogenic properties of ursolic acid are usually attributed to inhibition of the downregulation of matrix metalloproteinases activity. Metalloproteinases are group of the enzymes involved in degradation of extracellular matrix. Their activity in tumor tissues is elevated due to increased demand for oxygen and glucose of neoplasm. UA inhibiting activity against MMP-9 has been confirmed by several research teams, however activity against MMP-2 remains subject of discussion: Huang et al.  reported [et al.  did not The connection between inflammation and cancer had been suggested as early as in 1863 by Rudolf Virchow. Currently chronic inflammation, with concomitant activity of cytokines and increased production of reactive oxygen species, is recognized as a cancerogenesis-promoting condition . The cycSeveral tests of the anti-carcinogenic activity of ursolic acid against different induction sources have been conducted. These test included chemical agents (such as benzo(a)pyrene, azoxymethane and tobacco smoke extract) ,96,97,98The ultimate goal of every cancer research is the implementation of the compound to clinical use. Currently ursolic acid is undergoing phase I trials to evaluate its safety and adverse effects in patients. Due to poor water solubility and low bioavailability ursolic acid had been administered as a liposomes. So far results of only three such studies have been published ,118,119—The liver is one of the most important organs of the body. It is responsible for a wide range of metabolic functions, including detoxification of xenobiotics, production of hormones and digestive enzymes, glycoside and fat-soluble vitamins storage and the decomposition of red blood cells. Due to its strategic location and multidimensional functions the liver is prone to many diseases, like hepatitis, hepatic steatosis, cirrhosis, cholelithiasis and drug-induced liver damage. Fortunately liver is the only internal organ capable to regenerate—as little as 25% of the original mass can reconstruct its full size.et al. [Eucalyptus tereticornis extract against ethanol toxicity in isolated rat hepatocytes. They found that this triterpene was able to decrease the loss of hepatocyte viability by as much as 76%. A similar problem has been studied by Saravanan et al. [in vivo using alcohol-administered rats. They reported that UA increased the level of circulatory antioxidants and serum protein and decreased the total bilirubin level and lipid peroxidation markers. Histopathological observations were in correlation with biochemical parameters. Paracetamol and tetrachloride were other liver-intoxicating agents tested by Shukla et al. [et al. [Ursolic acid showed good protective activity against a wide range of liver-threatening substances. Saraswat et al.  were tesn et al. , this tia et al.  and Mart [et al. , respectet al. [et al. [The impact of UA on metabolic disorders in high fat diet-fed mice and rats was surveyed in research conducted by Sundaresan et al.  and Li e [et al. . The firet al. [Wang et al.  were looet al. [Interesting results were acquired by Jin et al. . They diCardiovascular diseases are the major causes of mortality and morbidity in industrialized countries. They are responsible for about 30% of all deaths worldwide. Amongst the most common disorders of the cardiovascular system one can mention myocardial infraction (commonly known as heart attack), stroke, atherosclerosis, hypertension and varicose veins. Although not all cardiovascular diseases are life threatening, all of them significantly decrease life quality and generate enormous social and financial costs .et al. [The first study which reported the impact of UA on the cardiovascular system was conducted by Somova et al. . It reveet al. [et al. [in vivo on Wistar rats, respectively. Shimada and Inagaki focused on the inhibitory effect on angiotensin I-converting enzyme (ACE), which plays an important role in the regulation of blood pressure.Further research has been carried out in various directions. Vasorelaxant properties of ursolic acid were investigated by Aguirre-Crespo et al. , Rios et [et al.  and Shim [et al. . The firet al. [et al. [Ursolic acid has been also used as a compound with a potent protective effect in artificially induced (by isoproterenol administration) myocardial infarction. Senthil et al.  were tes [et al. ,135. It  [et al. . They inet al. [et al. [Administration with ursolic acid also prevents injuries to blood vessels. Pozo et al.  revealed [et al.  the authet al. [et al. [The impact of ursolic acid on atherosclerosis is the subject of dispute amongst scientists since some studies show potentially beneficial effects while others show potentially negative effects . For exaet al.  reported [et al.  describeet al. [The potentially harmful effect of UA intake has been presented by Kim et al. . They diExcitotoxicity and oxidative stress are two phenomena that have been repeatedly described as being implicated in a wide range of disorders of the nervous system. Such ailments include several common idiopathic neurological diseases, traumatic brain injury, and the consequences of exposure to certain neurotoxic agents. Both excitoxicity and oxidative stress result from the failure of normal compensatory mechanisms to maintain cellular homeostasis and may lead to permanent damaging of the brain and decrease of cognitive functions .et al. [The first research focusing on the protective effect of ursolic acid on neurons has been conducted by Shih et al. . Neuronaet al. [Lu et al.  were invet al.  reportedet al. [et al. [Suppressing NF-κB by ursolic acid as a method to attenuate cognitive deficits and avoid brain damage has been reported by Wang et al.  and Li e [et al. . Their met al. [Wu et al.  describeet al. [The impact of UA on the brain is not limited to the cellular level. Machado et al. , encouraet al. [Research conducted by Colla et al.  confirmeet al.  revealedSkeletal muscles contraction powers the human body’s movements and is essential for maintaining stability. Muscle tissue accounts for almost half of the human body mass and, in addition to its power-generating role, is a crucial factor in maintaining homeostasis. Given its central role in human mobility and metabolic function, any deterioration in the contractile, material, and metabolic properties of skeletal muscle has an extremely important effect on human health.The term sarcopenia originates from the Greek words sarx (flesh) and penia (loss) and is used to describe the degenerative loss of muscle mass (atrophy) and its quality associated with aging. This expression is used to describe both: cellular processes  and their outcomes such as decreased muscle strength, decreased mobility and function, increased fatigue and reduced energy needs. In addition, reduction of muscle mass in aged individuals has been associated with decreased survival rates following critical illnesses. It is estimated that sarcopenia affects more than 50% of people aged 80 and older .et al. [in vivo test on mice confirmed these capacities. Orally administered UA induced muscle hypertrophy, reduced denervation-induced muscle atrophy and changed the gene expression in muscles. Researchers connected triterpene activity with enhancing insulin/IGF-1 (insulin-like growth factor) signaling. A later paper by the same team [To develop potential therapy against skeletal muscle atrophy Kunkel et al.  identifiame team  reports et al. [in vitro and in vivo. They found that UA elevated the expression of anti-aging genes SIRT1 (ca. 35 folds) and PGC-1a (ca. 175 folds). In vivo tests on a mice model revealed a decreased level of cellular energy charges (such as ATP and ADP) and increased proliferation and neomyogenesis in muscle cells. The authors draw the conclusion that UA can be considered as a potential candidate for the treatment of pathological conditions associated with muscular atrophy and dysfunction, such as skeletal muscle atrophy, amyotrophic lateral sclerosis (ALS) and sarcopenia.Bakhtiari et al.  were invThe direct impact of UA on muscle strength was surveyed by a Korean team led by Bang . SixteenBone is a dynamic tissue that undergoes continual adaptation during life to attain and preserve skeletal size, shape and structural integrity. It consists of highly specialized cells, mineralized and unmineralized connective tissue matrix, and spaces that include the bone marrow cavity, vascular canals, canaliculi, and lacunae. When the skeleton reaches maturity, its development continues in the form of a periodic replacement of old bone with new at the same location. This process is called remodeling and is responsible for the complete regeneration of the adult skeleton every 10 years. The purpose of remodeling in the adult skeleton is not entirely clear, although in bones that are load bearing, this process most likely serves to repair fatigue damage and to prevent excessive aging and its consequences. Several types of cells are involved in the remodeling process, but the two most important are osteoblasts (bone-forming cells) and osteoclasts  .The activity of osteoblasts and osteoclasts is crucial for maintaining proper bone structure and is regulated by differentiation from mesenchymal precursor cells and apoptosis. Several factors  can cause an imbalance between excessive osteoclastogenesis and inadequate osteoblastogenesis. The result is bone loss leading to osteopenia and osteoporosis . Pharmacet al. [in vivo, in a mouse calvarial bone.Lee et al.  were theet al. [Eriobotrya japonica) was able to significantly decrease bone mineral density in oviarectomized mice by inhibiting osteoclast production. Dose-depended inhibitory effect of the extract on the differentiation of osteoclasts without any cytotoxicity was observed. A later paper by this research team [Tan et al.  found thrch team  presentset al. [The possible mechanism of osteoclastogenesis inhibition by UA was evaluated by Jiang et al. . The reset al. [et al. [Yu et al.  were inv [et al.  was alsoet al. [So far the influence of ursolic acid on other organs has been described only in a limited number of papers. The impact on skin has been investigated by two teams. One led by Both  has beenet al.  present et al. [et al. [Ding et al.  and Pai  [et al.  conducteet al. [The protective effect of ursolic acid has been also tested by Chen et al.  in lipopin vitro determination of minimal inhibition concentration (MIC) of UA and other triterpenes against different strains of bacteria [et al. [The fight against bacterial infections is one of the most important tasks of medicine. The development of antibiotics in the 1940s gave physicians a powerful tool against infections and has saved the lives of millions of people. However, because of the widespread and sometimes inappropriate use of these substances, strains of antibiotic-resistant bacteria have begun to emerge. These newer, stronger bacteria pose a significant threat to human health and a challenge to drug researchers. Therefore, there is a continuous search for new, safe antimicrobial agents, including those from natural sources. A number of researches has been performed to evaluate the anti-bacterial properties of ursolic acid and related compounds . Some ofbacteria ,173,174. [et al.  focused Mycobacterium tuberculosis has been investigated by Woldemichael et al. [et al. [Calceolaria pinnifolia and Chamaedora tepejilote. Further research by Jiménez-Arellanes et al. [Ursolic acid activity against tuberculosis-causing l et al.  and Jimé [et al. . They prs et al.  confirmeet al. [Enterococci and Kim et al. [Staphylococcus aureus. Both studies showed that UA can be used simultaneously with antibiotics to enhance their activity.The ability to overcome bacterial resistance against antibiotics was also tested by Horiuchi et al.  who focum et al.  who usedet al. [Hu et al.  conducteet al. [Proteobacteria.The impact of orally delivered ursolic acid on intestinal microbiota was studied by Feng et al. . Their rThe human immunodeficiency virus (HIV) and human hepatitis C virus (HCV) infections are chronic and wide-spread illnesses that represent serious public health problems. According to a 2012 UNAIDS report on the global AIDS epidemic, about 34 million people were living with HIV, 2.5 million had acquired new HIV infections and 1.7 million had died of HIV-related causes worldwide during 2011.et al. [50 near 1 µM. The expected mechanism of action was dimerization inhibition. Kashiwada et al. [HIV-1 protease is a retroviral aspartyl protease that is essential for the life-cycle of HIV. It cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion. Due to its importance in metabolism this enzyme became the prime target for drug therapy. In 1996 Quere et al.  found tha et al.  confirmea et al. ,189,191.et al. [Ligustrum lucidum. Virus spreading was inhibited, at least partly, by suppressing NS5B RNA-dependent RNA polymerase. Garcia-Risco et al. [Calluna vulgaris) and they confirmed UA activity against human hepatitis virus C.It is also estimated that about 3% of the global population is infected with the hepatitis C virus. Chronic hepatitis C infection is the leading cause of cirrhosis, hepatocellular carcinoma and liver transplantations in developed countries . Anti-HCet al.  reportedo et al.  investiget al. [Mallotus peltatus extract. Investigators claimed that UA was probably inhibiting the early stage of multiplication and can be used as an anti-HSV agent.Research conducted by Bag et al.  showed tPlasmodium.Malaria is the parasitic disease with the greatest impact—it affects around 40% of the world’s population, spanning across more than 100 countries. Its etiological agent is a protozoa belonging to the genus Satureja parvifolia and Morinda lucida. Innocente et al. [et al. [In 2006 two independent research teams led by van Baren  and Cimae et al.  and Dell [et al.  developeet al. [Leishmania amazonensis. The curative effect of triterpene-rich fraction was similar to amphotericin B , however the dose required to eliminate microbes was smaller. Moreover, triterpenic fraction did not cause microscopic alterations in the liver, spleen, heart, lung, and kidney of the experimental groups.Yamamoto et al.  investigTrypanosoma cruzi infections was reported by de Silva Pereirra et al. [The influence of UA on the treatment of a et al.  They fouUrsolic acid, betulinic acid and six of their derivatives were tested against eleven mucocutaneous and cutaneous mycotic agents . The MICet al. [Nycanthes arbor-tristis against Brugia malayi and Wuchereria bancrofti—tropical filariae responsible for elephantiasis. They discovered that UA was able to induce apoptosis of these nematodes by downregulating and altering the level of some key antioxidants.The activity of UA was also examined against parasites. Saini et al.  evaluateUrsolic acid is a widespread compound of plant origin exhibiting wide range of the pharmacological activities. The biggest attention amongst scientists has been captured by the role that UA can play in treatment and prevention of cancer. Amongst other intriguing features of this triterpene anti-microbial properties and protective effect on internal organs against chemical-damage should be mentioned. However some studies point out negative effects of administration of this compound, suggesting that impact of UA on human’s health in some cases can be compared to the double-edged sword. Analysis of literature indicates that various effects can be linked to one phenomenon. The example might be inhibition of NF-κB activity, which leads to cancer cells apoptosis, anti-inflammatory effects and bone-forming activity.