The effect of impact-oscillatory loading is one of the main causes that lead to the extension of the fatigue life of materials.It was shown previously that cyclic loading can be used to extend the fatigue life of sheet plastic materials subjected to the preliminary impact-oscillatory loading. This type of loading causes dynamic non-equilibrium processes (DNP) in materials, which lead to the formation of dissipative structures in materials and on their surface. The density of these dissipative structures is less than that of the base metal. In this paper, the results of investigations into the relief and hardness of surface layers modified by impact-oscillatory loading are analyzed on the example of five structural materials. The signs of a regular, orderly system of microextrusions formed on flat surfaces of all materials due to DNP are considered along with the alignment of roughness parameters R Experimental investigations into the mechanical behavior of plastic materials under dynamic non-equilibrium processes (DNP) require further study and generalization of material deformation patterns ,2,3,4,5.Sheet titanium and aluminum alloys, as well as stainless steels, are widely used for the manufacture of modern aviation and rocket structures. During operation, they are subjected to complex types of loading, in particular, cyclic ones ,12,13,14It should be emphasized that practically no data has been reported in literature on the realization of dynamic non-balanced processes in materials due to the influence of force fields, which are created by additional force impulse loading. Changes in the mechanical properties of materials and their surface layers due to additional force impulse loading applied under DNP directly affect the workability and residual life of many critical structures that operate under variable loads.A new effective method for modifying the initial mechanical properties of materials by means of impulse introduction of power energy under impact-oscillatory loading should be developed and tested. This will make it technologically easier and cheaper to improve the physical and mechanical properties of materials and their surface layers ,22,23. PSophisticated physical methods were used to study real dissipative structures formed in materials after DNP. The density of these dissipative structures is less than that of the base material. Thus, aluminum alloys are characterized by newly formed dissipative structures in the form of thin-layer structures interconnected at different structural levels ,28. Two-Particularly noteworthy is that this process can be controlled, and its parameters can be regulated by changing the intensity of the impulse introduction of energy into the material at room temperature .Previously, attempts were made to physically substantiate the revealed mechanical effects of impact-oscillatory loading on extending the fatigue life of materials. In particular, to study the kinetics of changes in the surface layers during the impulse introduction of energy into the aluminum alloy D16ChATW, a special monocrystalline sensor was firmly fixed with a Pasco Fix adhesive,  on the surface of specimens. After that, shooting was performed. The rate of shooting the specimen surface during impact-oscillatory loading was 600 fps. The form of relief was considered as one of the parameters that allow estimating the effect of impact-oscillatory loading on the surface condition of the material . In the It should be noted that similar research by other authors was also focused on changes in the surface roughness of aluminum and titanium alloys in the process of large and superplastic deformations. However, it was shown that in the case of static loading (SL), the surface roughness of materials increases with an increase in the deformation level and depends on the structure of the grain size ,25,26.The purpose of this research was to evaluate the relief topography of surface layers after dynamic deformations caused by DNP in materials of different classes, and to evaluate the hardness of surface layers of materials after DNP, as compared to the effect of the static load at the same level of deformation.Tests were performed on sheets of industrial aluminum alloys D16ChATW and 2024-T351, two-phase (α + β phase) titanium alloys VT23 and VT23M, and stainless steel 12Kh17 with a thickness of 3 mm. Only one sheet of each material was used for making specimens. To evaluate the topography of surface layers, specimens a from alOne side of all specimens a was polAs is known, there are several possible practical variants to control the impulse introduction of power energy into materials under impact-oscillatory loading . In thisimpε—was chosen as a parameter that characterizes the intensity of the impulse introduction of energy into the materials. The choice of impε as a parameter that characterizes the intensity of the impulse introduction of energy into the alloys greatly simplifies the test procedure under impact-oscillatory loading. In this case, the modes of impact-oscillatory loading can be created using the hydraulic test machines of varying rigidity. This eliminates the need for complex calculations of a particular force influence applied to the specimen depending on the total pulse applied to the mechanical system. In addition, such procedure is intended for real technological processes.A sudden increase in the strain under the impulse introduction of energy—Changes in the topography of the polished flat surfaces of specimens in the initial state and after DNP were evaluated using the 3D Optical Surface Metrology System “Leica DCM8”  for the reliability of research, the relief parameters were compared in the central regions of specimens .Let us note that the topography of flat surfaces of the two aluminum alloys analyzed is very different in the initial state. However, after DNP, the structures formed on the surfaces of alloys D16ChATW and 2024-T351 have both similarities and differences. Thus, the uniformity of the relief profile increases significantly after DNP in both alloys see d. Howeveimpε = 0.85%) manifest themselves, first of all, in the straightened relief and newly-formed fibrous structure (see impε = 0.82%), the effects of changes in the topography of flat specimen surfaces after DNP are more striking. In addition, a fibrous relief structure is created after DNP. The significant difference in the variation of the relief topography for alloys VT23 and VT23M can be explained by a significant difference in the percentage composition of α and β phases in the alloys. In the titanium alloy VT23, the β-phase is 43 wt.%, α-phase is 57 wt.%; in the titanium alloy VT23M, the β-phase is 22 wt.%, and α-phase is 78 wt.% [ture see c,d. The  78 wt.% .z and Ra were chosen as the main parameters that characterize changes in the relief . To construct a diagram showing the dependence of hardness on the level of residual strains under static loading, specimens were tensioned statically to two levels of strain: 3.23% and 6.46%. In the third stage, all tested specimens, including a completely unstrained specimen, were polished on one side, and a grid with 12 identical rectangles was applied to the polished part . Then, u0)/HV0 × 100% was used to calculate variations in surface hardness after static tension (ST) and DNP + ST. The following values were obtained, It should be emphasized that steel hardness, compared with the initial state, increases both after static tension and DNP, but with different intensities, The static deformation of steel is of the “classical” type, because surface hardening occurs due to the accumulation of dislocations in the low-angle grain boundaries . This asSteels are usually characterized by a tendency to localize strains. As a result, larger volumes of the material are involved in plastic deformation, and a lengthy stage of strain hardening is preserved. The latter allows maintaining a high ultimate strength, albeit less than the initial. Subsequently, the localized accumulation of structural defects leads to a decrease in ductility, which was observed in our case.In contrast to the volume of the material, the preceding plastic flow in the surface layer causes the formation of a folded surface structure (microextrusions). In zones of a pronounced local curvature, dislocations appear in the folds, which penetrate deep into the material. As a result, the surface becomes inhomogeneous, because surface irregularities are generally “softer” than those of the base material . Under sThe ambivalent nature of a decrease in ductility under the constant yield strength and a slight decrease in strength are associated with several effects applied under DNP:The results obtained are intended, primarily, for aircraft and machine building, as well as for the strength calculation of metal parts that are sensitive to the accumulation of plastic strains, for instance, under various types of impact loading.A quantitative evaluation of the relief topography of surface layers of materials of different classes after dynamic deformations in the process of DNP has been conducted, and hardness of surface layers of the material after DNP was evaluated.z and Ra of the relief profile. For the D16ChATW alloy, the unevenness of the profile roughness Rz in the studied region was 39.8% in the initial state and 23.3% after DNP. For alloy VT23, they are 50% and 27.3%, respectively. For alloy VT23M, they are 25.1% and 11.8%, respectively. On the other hand, for alloy 2024-T351, the unevenness of the profile roughness increased after DNP from 18.7% to 37.5%. This is due to the appearance of a fibrous structure in the longitudinal direction.After the realization of DNP, practically all materials showed the signs of a regular ordered system of microextrusion formed along the axis of loading throughout the relief. In addition, DNP affects the alignment of roughness parameters Rz) decreased after DNP, even with a significant increase in the dynamic strain (impε = 6.3%). This contradicts the well-known reports about an increase in roughness parameter Rz with an increase in the strain under static tension. Similar effects are also manifested in the alignment of the roughness parameter Ra of the relief profile. Only for the VT23M alloy, this value increased slightly after DNP. For all other materials, these values decreased significantly after DNP.It is interesting to note that for all the materials under investigation, the absolute values of roughness parameters  of 1555, the average hardness of the alloy was 1872 after ST and 1735 after DNP at the same level of strain (ε = 18.2%).In contrast to the volume of the material, the preceding plastic flow in the surface layer causes the formation of a folded surface structure (microextrusions), leading to an increased strain localization under DNP. The static tension is characterized by “classical” deformation, with surface hardening due to the accumulation of dislocations within the low-angle grain boundaries.


Laser triangulation (LT) is widely used in many fields due to its good stability, high resolution and fast speed. However, the accuracy in these applications suffers from severe constraints on the data acquisition accuracy of LT. To solve this problem, the optical triangulation principle, the object equation of the optical path relationship and the deviation of the laser spot centroid are applied to deduce a mathematical model. Therefore, the image sensor inclination errors can be quantitatively calculated, and the collected data are compensated in real time. Further, a threshold sub-pixel gray-gravity (GG) extraction algorithm is proposed; the gradient function and Gaussian fit algorithm are used to set thresholds to remove the impact of the spot edge noise area on the center location; and polynomial interpolation is employed to enhance the data density of the traditional GG method, thus improving the data acquisition accuracy of LT. Finally, the above methods are applied to on-machine measurement of the American Petroleum Institute (API) thread and the screw rotor, respectively. The experimental results prove that the proposed method can significantly improve the measurement accuracy of free-form curved surfaces using LT and that the improved laser spot center extraction algorithm is more suitable for free-form curved surfaces with smaller curvature and more uniform curvature changes. In recent years, non-contact optical instruments based on laser triangulation (LT) have been increasingly used in size measurement in the fields of automobiles ,2, automMany factors can interfere with the data acquisition accuracy of LT, which can be generally divided into three categories: the inherent characteristics of LT, the measurement environment and the surface properties and geometries of the measured object. Furthermore, many scholars have conducted extensive studies on these three aspects. The impact of the inherent characteristics of LT on its data acquisition accuracy can be further divided into two factors: the nonlinearity of the triangulation model and the fluctuation of the laser beam. The problem that the nonlinearity of the triangulation model affects the measurement accuracy of LT is usually solved by using the calibration method. Sun et al.  and ZhanThe in-depth study of the above LT-based data acquisition accuracy manifests that various influencing factors can lead to the deviation of the spot center on the image sensor, and then the occurrence of measurement errors. Consequently, the rapid and accurate spot center extraction can help enhance the accuracy of LT. To meet the requirements of spot center extraction with high accuracy, fast speed, good robustness and low noise, the sub-pixel center extraction algorithm has attracted more attention. The gray-gravity (GG) method is widely applied to spot center extraction due to its simple operation and fast calculation speed, but it is particularly sensitive to noise, resulting in lower accuracy ,20. AddiTo solve the above problems, LT error compensation and LT spot center extraction are researched in this paper. Firstly, for LT error compensation, this paper takes advantage of the optical triangulation principle and the geometric relationship of optical paths to establish an image sensor inclination error model and analyzes the effects of various measurement parameters on errors by using the laser displacement sensor (LDS) (KEYENCE LKH080) as the research object. Secondly, for LT spot center extraction, a variable threshold sub-pixel GG extraction algorithm is proposed. In this algorithm, the gradient function and Gaussian fit algorithm are used to set thresholds to eliminate the noise interference. Finally, research results are applied to on-machine measurement of the American Petroleum Institute (API) thread and the screw rotor. The experimental results prove that the above algorithm can substantially improve the measurement accuracy of free-form curved surfaces using LT. Moreover, the comparison between the two sets of on-machine experimental results reveals that the variable threshold sub-pixel GG extraction algorithm is more suitable for free-form curved surfaces with smaller curvature and more uniform curvature changes.x presents the displacement of the measured object plane, x′ presents the displacement of the spot image on the CCD, α presents the angle between the optical axis of the receiving lens and the laser beam, β presents the angle between the optical axis of the receiving lens and the CCD surface, L presents the object distance of the receiving lens, L′ presents the image distance of the receiving lens, Δ presents the angle between the laser beam and the CCD surface and h presents the distance between Focus H of the receiving lens and Point A on the CCD surface. The following equation can be derived in accordance with the theorem of similar triangles:The LT-based sensor mainly comprises a laser driver, a laser diode, a focusing lens, a receiving lens, an image sensor (charge coupled device (CCD)) and a signal processing circuit. The fundamentals can be seen in x of the measured object by using the image point displacement x′ presented on the CCD surface via the receiving lens. To guarantee the data acquisition accuracy in practical applications, it is essential to satisfy both Gauss’s law, which is derived from Snell’s law of refraction, and the Scheimpflug principle, namely the receiving lens and the CCD receiving surface of the image sensor intersect at Point O of the incident beam.Equation (1) is the theoretical equation for the LT measurement principle, which indicates that LT reflects the actual displacement φ denotes the scattering half angle of the reflected beam, β denotes the inclination angle between the reflected light and the CCD receiving surface, Δ denotes the displacement between the theoretical Centroid E and the actual Centroid D and Point H and distance h are as mentioned above. It can be seen from β appears . This causes the spot centroid theoretical Position E detected by the CCD to not coincide with the actual Position D of the spot centroid, and generates the deviation Δ. Accordingly, the error model is deduced according to the following steps:Firstly, the laser beam scattering rate is defined as:Then, it is obtained that:In light of the above equations, it is further obtained that:Therefore, the deviation error Δ of the spot center on the image sensor is:α, β, L and L′ vary with the measuring distance s and the remainder are the structural design parameters of LT. The change law of each parameter with s can be calculated from the geometric relation in When Δ is brought into the measuring equation of the direct optical triangulation principle, the image sensor inclination error can be obtained as follows:α, β and s can be derived upon the theorem of similar triangles and the sine theorem as follows:The relations among L, L′ and s can be derived as follows:In light of the theorem of similar triangles and the cosine theorem, the relations among s. To clarify the relationship between s and prepare for the follow-up experiments, KEYENCE LKH080 LDS is taken as an example here . The LDS used in this paper is a red laser, and the G value and B value of its spot image are both 0. For this reason, the pixel color can be represented only by the R value. Set the R value function of the spot as The gradient value is the increment of unit distances in the direction of the maximum changing rate of k1 value can be adjusted according to the positioning accuracy degree. Furthermore, the k1 value is taken as follows: The value is set at 0.1 intervals within , and the measurement index should not only effectively eliminate the edge noise area, but also retain the sufficient effective area for the next threshold determination. KEYENCE LKH080 LDS spots used in this paper are calculated by using the gradient operator in Equation (14), with the result that the effect is optimum when k1 = 0.2. After scanning the spot image over again, the area surrounded by pixels whose R gradient value is equal to the identification threshold value is named the primary threshold area S1, the image in S1 is retained and transformed into a grayscale image, with the gray function denoted as 2 is determined in S1.The maximum R value gradient function of the spot can be found by scanning the whole spot image and conducting gradient operation of the R value of each pixel. The As described in 1 be:B is the light intensity matrix in S1, A is the position matrix in S1 and K is the undetermined coefficient matrix. Since:i-th row of matrix A is:K is:E.Let the fit equation set of points in the primary threshold area SI. Subsequently, the identification threshold is set, with k2 times I as the threshold, and the determination method of the k2 value is exactly the same as that of the k1 value, with k2 = 0.5 given herein. The area where the gray value is greater than the mark threshold k2I is defined as the high-level threshold area S2, and the gray value in S2 is processed by the Gaussian filters. Considering the large-scale data collected by LT and the strict requirements for real-time data processing, we choose the polynomial interpolation that can better balance the calculation accuracy and the calculation efficiency to densify the filtered spot image. In comparison to polynomial interpolation, spline interpolation has better calculation accuracy, but lower calculation efficiency in the case of a large amount of data and high interpolation density. Additionally, the noise of the spot image is effectively reduced after the variable threshold processing, and hence, polynomial interpolation can meet the accuracy requirements. Therefore, we perform polynomial fit interpolation densification on the filtered spot image at a pitch of 0.1 pixels, and the coordinates of the spot center are obtained by using the GG method for the densified sub-pixel points upon the following equations:The extreme value point The length of each pixel of the CCD image sensor used in this paper is 10 μm. When the measurement sensitivity (the ratio of the displacement of the measured surface to the displacement of the spot center detected on the image sensor) reaches the maximum value of 26.86, the measurement error of the imaging spot center can reach 1 pixel, and the measurement error of the measured surface can reach 0.269 mm. It can thus be found that the interpolation and densification of pixel points can effectively increase the positioning accuracy of the spot center. The flowchart of the variable threshold sub-pixel GG extraction algorithm proposed in this section is shown in p, thread height h and half of thread angle α/2.This section applies the above methods to on-machine measurement of API thread parameters. API threads are mainly used for the conjunction between drill rods in the oil and gas drilling industry and play a role in transmitting the huge torque required for drilling from the wellhead to the bottom-hole bit. As this kind of thread bears large torque and high sealing requirements, it is subject to extremely strict requirements for its contour parameter accuracy. However, the contour parameters are measured by using the monomial parameters gauge (MPG) in every current oil field service station. The main contour parameters of the API thread encompass pitch The minimum internal thread to be measured was the NC23  type, and its maximum diameter was only 66.97 mm, while the shell of LKH080 LDS used in this paper was 100 mm long and could not be extended into the interior for measurement, so the mirror panel was used for auxiliary measurement. Through studying various non-contact measurement devices for thread parameters, it can be obtained that each and every measurement device took the thread axial section as the measurement object and then calculated the mathematical relationship between the thread parameters to be measured and the measurement data. Accordingly, the contour data acquisition of one certain API thread axial section was the core task throughout the measurement. The data acquisition scheme for API thread axial sections is shown in X, an axial feed axis Z and a spindle, for which the Z-axial positioning accuracy was 0.01 mm/500 mm and the straightness of axial rail was 0.05 mm/1000 mm. The CNC system of SCK230 was Mitsubishi M70.On the SCK230 CNC lathe, we experimented with on-machine measurement of the processed NC50 API external thread typically used in oil drilling, of which the axial length was 11 mm, as shown in Z-axis encoder via the controller. Triggered by the valid impulse edge, the sensor synchronously output the measured analog signal to the controller through Ethernet. After one scan was finished by the sensor, the coordinates of the thread axial sections were acquired and then compensated and reconstructed by the data processing system. Further, the required thread parameters were calculated upon the extracted feature points, determining the processing quality. Finally, the results were communicated to the CNC system via RS232 serial ports, and lathing was conducted on the unqualified workpiece for correction as per the given cutter compensation, thus accomplishing the closed loop process of the on-machine measurement. The processes of the on-machine measurement experiment for the NC50 thread are detailed as follows: The measurement parameters in the data processing system were set, such as the encoder trigger frequency, measurement speed, sensor’s initial position, measured thread type and measured thread length, and then, these parameters were synchronized to the CNC system and controller via different RS232 serial ports. The sensor was furnished with an external signal input that was mounted on the NC turret via a mechanical support. With the movement of the NC turret at a given measurement speed driven by the servo motor, an impulse signal of a certain frequency was transmitted to the input by the To compare the advantages of the variable threshold sub-pixel GG extraction algorithm proposed in this paper with the traditional GG method, this section utilizes the above two methods to scan the same axial section of the NC50 thread once, respectively, with the results shown in X-axis, 1000 mm for the Y-axis and 800 mm for the Z-axis, the maximum permissible error of extent (MPEE) was (2 + L/300) μm, the maximum permissible error of probing (MPEP) was 3.5 μm, the resolution was 0.1 μm, the guaranteed lab temperature was 20 ± 2 °C, the space gradient of temperature was 1 °C/m3 and the relative humidity was 40–70%. All the indicators conformed to the requirements of ISO10360-2. The processes of measuring the API thread by using CMM were as follows: As the drilling pipe with the API thread on both ends was approximately 10 m in length and 300 kg in weight, it was impossible to acquire the thread contour data by using CMM. Before measurement, the API threaded joint was necessarily cut off with a saw machine, and the section was accurately machined with a grinder. The API thread was placed on the workbench of CMM with the ground surface as the reference surface. CMM was equipped with a special measuring software for taper thread surfaces. The software could automatically fulfill the probe calibration upon the diameter and contact direction of the selected needle tip. At the time of measurement, firstly, the computer-aided design (CAD) model for the measured thread was imported into the software with the measurement mode of closed linear scan selected. Subsequently, the scanning starting point and scanning direction point were determined on the CAD model. Finally, the scanning control mode, step length and single point were selected, thus accomplishing the measurement of the API thread using CMM. The LDS data fit method was also used to fit the data collected by CMM and calculate the corresponding parameters.To verify the application effect of the proposed LT data acquisition method in thread curved surface measurement, firstly, the axial section of the measured API thread was marked and the measurement position and measurement phase of the mark were recorded. Then, the comparative measurement of axial sections was experimentalized by using the coordinate measuring machine (CMM) and MPG, respectively, as shown in The API thread parameters obtained by the three measurement methods along the same measuring path are shown in h, half of the thread angle α/2 and pitch p. The main factors affecting the measurement uncertainty of thread height h are: LDS resolution and linearity errors of LDS, Z-axial positioning accuracy of machine tools and straightness of the axial rail, environmental temperature changes and measurement repeatability. Among these, the measurement uncertainty caused by measurement repeatability was calculated by using the Type A evaluation method, while the measurement uncertainty caused by other factors was calculated by using the Type B evaluation method. These influential factors are analyzed in detail below.Furthermore, to ensure the integrity of measurement results by OMM 3, the evaluation of measurement uncertainty should be made against thread height hu1 = 0.1 μm. Furthermore, it shows that the linearity error of LDS was ±0.02% FS, while the nominal value of the NC50 thread height was 3.095 mm. The error conformed to a uniform distribution, and if coverage factor hu2 generated by the linearity error of LDS within the measurement range is:Z-axial positioning accuracy of SCK230 was 0.01 mm/500 mm, and the resulting errors obeyed a uniform distribution. If hu3 introduced by the Z-axial positioning accuracy of the machine tool is:The hu4 introduced by itself was 0.32 μm.Similarly, the axial rail straightness of SCK230 was 0.05 mm/1000 mm, and the measurement uncertainty component t was 21.3 °C, 10 measurements of API threads were implemented by using OMM 3 in a short time, and the measurement uncertainty component caused by the environmental temperature change hu5 is:α denotes the coefficient of linear expansion of materials, with its value taken as α = 1.1 × 10−6/°C and dh denotes the nominal value 3.095 mm for the NC50 thread height, then hu5 = 0.004 μm.When the room temperature uh5 caused by the measurement repeatability of thread height, and its standard deviation was calculated by using Bessel’s formula:n denotes the number of repeated measurements, ix denotes each measurement result and n measurements. Based on the 10 measurements of thread height obtained by using OMM 3 in hs = 0.0015 μm was calculated, and the measurement uncertainty introduced is:The Type A evaluation method was applied to the measurement uncertainty hu of thread height h by OMM 3 was calculated by using the square root of the sum of squares:As the above measurement uncertainty components are mutually independent, the combined uncertainty h, the measurement uncertainty of pitch p and half of thread angle α/2 were evaluated. The main factors affecting the measurement uncertainty of pitch p in OMM 3 were LDS resolution, Z-axial positioning accuracy of the machine tool and the straightness of the axial rail, environmental temperature changes and measurement repeatability. In accordance with the above calculation method, the standard deviation of 10 measurements of pitch p was 0.0012 μm, and the combined uncertainty pu = 0.40 μm. Furthermore, the main factors affecting the measurement uncertainty of half of thread angle α/2 in OMM 3 were LDS resolution and linearity errors, Z-axial positioning accuracy of the machine tool and the straightness of the axial rail, environmental temperature changes and measurement repeatability. In accordance with the above calculation method, the standard deviation of 10 measurements of half of thread angle α/2 was 0.91′ and the combined uncertainty was αu/2 = 2.76′. Furthermore, the uncertainly values of each thread parameter obtained by using OMM 3 are listed in Based on the method for calculating the measurement uncertainty of thread height This section applies the LT data acquisition method in n = 5 commonly used in engineering is shown in d1, minor diameter d2 and lead F. Lead F is the length of one thread on the generatrix moving along the spiral line for one cycle, and pitch w = F/n functions as the alternative measurement parameter for the lead. Meanwhile, d1 and minor diameter d2, LDS keeps still, and the screw rotor rotates one revolution along the C-axis. In the course of measuring pitch w, the screw rotor keeps still, and LDS moves parallel to the axial centerline of the screw rotor along the Z-axis.The spiral curved surface of the screw rotor is formed by the motion of the rotor generatrix  along the spiral line, with the diameter scope from 40 mm–200 mm and the length scope from 1000 mm–8000 mm. The 3D model for the 165-type screw rotor with the thread number X, an axial feed axis Z and a spindle C, for which the Z-axis positioning accuracy was 0.01 mm/500 mm and the straightness of the axial rail was 0.05 mm/1000 mm. The CNC used in LXK300X was SINUMERIK 828D.In accordance with the manual measurement method (only the major diameter and minor diameter of one cross-section to be measured within one pitch), the on-machine measurement experiment for the finished five-head 165-type screw rotor was performed by the LXK300X CNC spiral groove milling machine, for which the pitch measurement length was 140 mm, as shown in C-axis and Z-axis encoders, workpiece rotation speed, sensor moving speed, measured thread type and measured thread length. Then, these parameters were synchronized to the numerical control system and controller via different RS232 serial ports. While measuring major diameter d1, minor diameter d2 and pitch w, the C-axis rotary encoder and Z-axis ball screw encoder were respectively transmitted to the external signal input of the sensor upon the aforesaid measuring scheme. At the time of the servo motor driving, an impulse signal of a certain frequency was transmitted by the encoder to the input through the controller; the synchronous output of the measured analog signal was performed by the sensor to the controller via Ethernet triggered by the valid impulse edge; the signal after the A/D conversion in the controller was transmitted to the data processing system in the computer via Ethernet. In accordance with the extracted feature points, the required parameters were calculated, the results were communicated to the CNC system through RS232 serial ports and the unqualified workpiece was corrected by turning, thus completing the whole closed loop process of on-machine measurement. The experimental flow of the on-machine measurement of screw rotors is detailed below. Before the experiment started officially, the measurement parameters were set up in the data processing system, such as the trigger frequency of To verify the application effect of the proposed LT data acquisition method in spiral curved surface measurement, firstly, the axial section of the measured screw rotor was marked and the measurement position and measurement phase of the mark were recorded. Then, the comparative measurement experiment for the same screw along the same path was performed by using CMM and MPG. The CMM measurement experiment is shown in d1, minor diameter d2 and pitch w. The main factors affecting the measurement uncertainty of major diameter d1 and minor diameter d2 are LDS resolution and linearity errors, environmental temperature changes and measurement repeatability. Furthermore, the main factors affecting the measurement uncertainty of pitch w are LDS resolution, Z-axial positioning accuracy of the machine tool, straightness of the axial rail, environmental temperature changes and measurement repeatability. In accordance with the method for evaluating the measurement uncertainty of thread parameters, the standard deviation of 10 measurements of the screw rotor’s major diameter d1 was 0.0029 μm, and the combined uncertainty du1 = 1.80 μm; the standard deviation of 10 measurements of the screw rotor’s minor diameter d2 was 0.0032 μm, and the combined uncertainty du2 = 1.79 μm; the standard deviation of 10 measurements of the screw rotor’s pitch w was 0.0012 μm, and the combined uncertainty wu = 4.65 μm. Furthermore, the uncertainty values of each screw rotor parameter obtained by using OMM 3 are likewise listed in To ensure the integrity of measurement results by OMM 3, it is also necessary to evaluate the measurement uncertainty of the screw rotor’s major diameter F = 200 mm/min and the measured thread is 11 mm long, and then, the one-trial measurement time by using OMM 3 is only 7.2 s.The straight comparison of the two sets of data in F = 200 mm/min, the measuring length is 140 mm and the spindle rotation speed is 10 r/min, it spends 52.1 s in using OMM 3 to conduct one-trial measurement of one screw rotor pitch, which meets the requirements of rapid measurement of large-size workpieces in online production.Through the comparison of the parameters acquired by the three measurement methods with the corresponding nominal values, it can be concluded that the differences are all within the tolerance zone, which indicates that the measured screw rotor is qualified. Compared with the measurement accuracy of OMM 1 and OMM 2, the proposed image sensor inclination error model can increase the measurement accuracy of free-form curved surfaces using LT. Further, compared with the measurement accuracy of OMM 1, OMM 2 and OMM 3, the variable threshold sub-pixel GG center extraction algorithm highly improves the LT data acquisition accuracy in free-form curved surface measurement. Through the comparison of the data acquired by OMM 3 and MPG, the measurement accuracy of the on-machine measurement method proposed in this paper is higher than that of the traditional MPG, and the former saves the measurement time and also improves the measurement accuracy by 70%. The comparison of the results by OMM and by CMM also shows that the screw rotor measurement results obtained by using the proposed LT data acquisition method are even closer to those of the CMM with higher measurement accuracy. Additionally, the measurement uncertainty of OMM 3 for each parameter of the 165-type screw rotor is 1.80 μm for major diameter, 1.79 μm for minor diameter and 4.65 μm for pitch, respectively. Similarly, the above uncertainty values are the repeatability indicators of the screw rotor measuring system using OMM 3, and they are also not complete or comprehensive. As the sensor feed speed is Judging from the standard deviation of 10 measurements of each parameter, it can be seen that the variable threshold sub-pixel GG extraction algorithm has realized high-accuracy acquisition of laser spots, effectively controlled the dispersion of measurement results and better ensured the measuring stability. Additionally, through the comparison of the data in To increase the data acquisition accuracy of LT, this paper starts with the LT principle, delves into the LT geometrical optical path system, analyzes the cause for generating image sensor inclination errors and deduces a mathematical model that can quantitatively calculate the error compensation amount based on the deviation of the spot centroid. Through the established model, the influence law of the measuring distance on the data acquisition accuracy of LT is achieved. The research results are successfully applied to measurement of free-form curved surfaces. Further, the variable threshold sub-pixel GG extraction algorithm is proposed. The gradient function and Gaussian fit algorithm are used to set thresholds to remove the interference of spot edge noise in the traditional GG method. Additionally, polynomial interpolation is used to increase the spot sub-pixel point density, thus improving the extraction accuracy of the spot center using LT. Furthermore, the above research results are used in on-machine measurement of API threads and screw rotors, respectively. The measurement results prove that the image sensor inclination error model is effectively accurate and has the identical effect of compensating the collected data of free-form curved surfaces in different states. The improved spot center extraction algorithm can boost the data acquisition accuracy of LT and be better applied to measurement of free-form curved surfaces with smaller curvature and more uniform curvature changes. To sum up, the combination of the said two can greatly improve the measurement accuracy of free-form curved surfaces using LT.


Genetic and pharmacological inhibition of the mechanistic Target Of Rapamycin Complex 1 (mTORC1) promotes health and longevity in organisms ranging from yeast to mice, and may also have rejuvenative effects in dogs and humans. A potential barrier to the translation of rapamycin-based therapies to the clinic are the side effects of rapamycin, which include metabolic disruption. We and others have demonstrated that many of these side effects are mediated not by inhibition of mTORC1, but by “off-target” inhibition of a second mTOR complex, mTORC2. However, the effect of inhibiting mTORC2 on the healthspan and longevity of mammals has been largely unaddressed. Here, we will discuss our research exploring the contribution of mTORC2 signaling in three different tissues to the healthspan, metabolism, and longevity of mice.


Mediterranean River Basins.Human activities and consequent pollution have put the freshwater and marine ecosystems of the Mediterranean region under pressure, with high risk of eutrophication phenomena. In this study, an extended version of the Geospatial Regression Equation for European Nutrient losses model (GREEN), originally developed for estimating nutrient loads from diffuse and point sources in Europe, was extended to include additional nutrient sources using a grid cell discretization. The spatial resolution is 5 arc minute and the model inputs consist of the latest and best available global data.3), 0.11 Tg/y of total phosphorus (TP) and 0.03 Tg/y of orthophosphate (P-PO4) were discharged in the Mediterranean Sea. The source apportionment analysis showed that the main contributor to total nitrogen and nitrate loads is agriculture followed by natural background, while for orthophosphate dominant sources include wastewater and scattered dwellings. Two scenarios were investigated to assess sustainable water and nutrient management options, showing that the reduction of 50% of nitrogen surplus leads to a significant reduction of nitrogen emission in regions characterized by high intensity agriculture, while the upgrading of wastewater treatment plants to tertiary level was more efficient for TP reduction.The results of this study show that during 2003–2007 (baseline), 1.87 Tg/y of total nitrogen (TN), 1.22 Tg/y of nitrates (N-NO It communicates with the Atlantic Ocean through the Strait of Gibraltar and with the Black Sea through the Dardanelles.The Mediterranean is an oligotrophic well oxygenated sea with naturally low nutrient concentration due to the anti-estuarine circulation through the Gibraltar Strait driven by the excess of net evaporation over precipitation . HoweverHere, the eutrophication phenomena due to nutrient inputs from land-based pollution sources is a major environmental problem and the geographical distribution of eutrophication in the Mediterranean Sea occurs in densely populated areas characterized by intensive economic activities. Severe eutrophication has been reported for several coastal areas including the Gulf of Lions, the Adriatic, Northern Aegean and the South Levantine seas. 2. Concrete measures for the environmental protection of the Mediterranean Sea were taken in 1975 with the Barcelona Convention and over the last 30 years large scientific efforts focused on characterizing water and contaminant (including nutrients) discharge in the Mediterranean Sea. Detailed nutrient discharges into the Mediterranean were provided by In this context, our research presents a robust modelling framework for assessing water nutrient pollution in the Mediterranean and evaluating the impact of management strategies on water quality. In particular, our study intends to quantify the more recent nitrogen  and phosphorus  fluxes to determine the relative importance of different nitrogen and phosphorus sources and to identify hotspots areas of higher pollution where priority actions should focus. The main innovative aspect of the work resides in the development of a simple conceptual model, GREEN-Rgrid , Rhone (France), Po , Drin-Buna (Albania), Neretva (Bosnia and Herzegovina), Ebro (Spain), Tiber , Adige , Seyhan and Ceyhan (Turkey). Together they account for about half of the average freshwater input by rivers into the Mediterranean Sea  , 13% cropland, 8% fodder, 18% grassland and 3% urban areas and water. The main crops are wheat, sorghum, oil crops, maize, barley and temperate fruits. About 17% of the arable land is irrigated   and the 003–2007 . The mos2.2The modelling approach used in this study, GREEN-Rgrid, is a conceptual statistical regression model that links nutrient inputs to water quality measurements. It is an extended version of the Geospatial Equation for European Nutrient losses, GREEN, developed by 3) and orthophosphate (P-PO4). The model was written in R  and can be used to estimate total nitrogen (TN) and phosphorus (TP), nitrate , and nutrients delivered directly to water bodies (point sources) . DiffuseDiffuse sources transit first through the soil unsaturated and saturated zones before reaching a stream and consequently undergo a preliminary reduction in the soil profile due mostly to the denitrification (nitrogen) and storage processes. Once into the streams or water bodies these nutrients are subject to a second reduction due to algae growth, atmospheric losses, and storage/deposition. Point sources of nitrogen and phosphorus are only retained in streams and lakes. The GREEN-Rgrid considers a routing grid cell structure to establish the emitting-receiving grid cell relationship, where the upstream nutrient load is added as an additional point source to the receiving downstream grid cell.L is the annual nutrient load (ton/y), SUR is the nutrient (nitrogen and phosphorus) surplus in the grid cell (ton/y), PS are the point sources (ton/y), UL is the upstream load (ton/y), S, R are the soil and river reduction factors in each grid cell (dimensionless), RES is the nutrient retention in lakes/reservoirs (dimensionless), and i represents the grid cell.The load at the outlet of a grid cell is expressed as:S is a function of precipitation plus irrigation (when present).S is parametrized as exponential decreasing function as follows:x (dimensionless) is the inverse of the sum of precipitation and irrigation (for each grid cell i) normalized by the maximum inverse of the sum of precipitation and irrigation (α (dimensionless) is a calibration parameter. The maximum scaling method was used to avoid negative values of the calibration parameter α  and of two calibration parameters A and B (both dimensionless) that describe the losses in the river network:C (dimensionless) is a calibration parameter, and n is a fixed coefficient retrieved from The river retention factor 3/s) simulated for the period 2000-2014 by the LISFLOOD model . This is in complete agreement with A global river network and routing structure with 5 arc minute resolution was developed following a procedure described by 2.The global HydroLakes database  was used2.3.23) reported at country level by AQUASTAT  of year i, retrieved from In particular, the annual potential evapotranspiration was estimated as a function of annual temperature according to The consumptive water use of irrigation is defined as the volume of water needed to compensate for the deficit between potential evapotranspiration and effective precipitation over the crop growing period. The net irrigation volume at country level was thus spatialized based on the distribution of the difference PET-PCP in irrigated cells.The SPAM model provides for 42 crops and four levels of agriculture intensification, the crop-specific physical area, harvest area (sum of areas considering multiple-harvest in a year), yield and production (product of yield and harvest area). Data are available for the year 2005 (average of 3 years centered on 2005) for four production systems including irrigated high inputs production, rainfed high inputs production, rainfed low inputs production, rainfed subsistence production . The cro2.3.3Information on nutrient sources at high spatial resolution is difficult to retrieve or is only partially available at large scale . For thi2.3.3.1A landuse dataset was created in order to spatialize the nutrient inputs from agricultural, urbanized and natural areas. The GLOBCOVER 2009 map  was used2.3.3.2The diffuse sources of N and P considered in this study include nitrogen and phosphorus surplus on cropland and grassland areas, atmospheric deposition in natural areas , nutrient transported via erosion, nutrient in washoff, phosphorus weathering and scattered dwellings (people not connected to a wastewater collecting system).The cropland and fodder nitrogen and phosphorus surpluses were calculated as the difference between the sum of mineral and manure fertilizers, plant fixation (only for nitrogen), atmospheric deposition (only for nitrogen) and nutrient uptake by crops and fodder. The nutrient surplus in grassland areas was calculated as the difference between the sum of mineral and manure fertilizers, atmospheric deposition (only for nitrogen) and a 60% of all nutrient inputs .3 losses of N content) reported in The N and P mineral fertilizers on cropland at 5 min resolution were obtained by downscaling the total amount of net mineral fertilizers available at country scale from FAOSTAT  for the We distributed the national net mineral fertilizers in each grid cell on non-leguminous crops based on the nitrogen content of the yield, and on fodder based on the deficit between nitrogen fixation and nitrogen uptake. The remaining fertilizer non applied on crop or fodder was distributed uniformly on grassland areas.Crop uptake was estimated at grid cell as the product of dry yield . The distribution of total nitrogen deposition between the landcover classes in each grid cell was proportional to the area of each class.Nitrogen atmospheric deposition was retrieved from global rasters of 1 degree resolution from the World Data Centre for Precipitation Chemistry web site (2/y) for each of the classes as described in The phosphorus release from weathering was calculated based on the lithological map GLIM , that prNutrient emissions from built-up areas (washoff) were calculated at grid cell level as the product of urban population and the specific N and P emission for inhabitant proposed by N and P emissions via erosion into surface waters were calculated as the product of three factors: (i) soil erosion loss (ton/y), (ii) nutrient content in the top soil, and (iii) sediment delivery ratio. In particular, soil erosion loss was estimated for the period 2000–2014 using the modified RUSLE model .2.3.3.3Nutrient inputs produced by human settlements connected to sewers, wastewater treatment plants, industries and paved areas were considered as point sources (hereafter WWTP) in the model and were estimated taking into account urban and rural population, emission rates per person, the percentage of urban and rural population connected to wastewater treatment plants and their treatment level. The methodology to define these nutrient specific emissions from points sources (kg/person) at grid cell level consisted in determining the nutrient point sources at country level and then to downscale them using population density as spatial proxy. The product of nutrient specific emission, the connected population and the treatment level efficiency resulted in the gridded point sources map at 5 min. We distinguish the rural and urban population inside each grid cell using the GHSL datasets  availablSpecific domestic emissions were estimated according to the methodology described by A summary of the major inputs used by the model for the major river basins discharging into the Mediterranean Sea is given in 2.3.43, TN, P-PO4 and TP, respectively. For Northern African countries and Turkey, we managed to collect 9 values of annual nitrate concentration and 4 values for orthophosphate.Times series of annual loads of nitrate, orthophosphate, total nitrogen and total phosphorus are needed for the calibration of the model GREEN-Rgrid. We collected time series of daily and annual nutrient concentrations from different sources for the period 2000–2014. At global scale we retrieved annual data from the GEMS/Water Data Center ; at Euro3 and P-PO4 measurements. The Nile River is the largest ungauged basin in the Mediterranean. Similar problems of limited availability of water quality data were reported by Albeit the efforts in collecting monitoring data, these monitoring stations resulted limited in space covering mainly the Rhone River Basin with around 28% of all measurements, the Po with 15% of TP and TN observations, and the Ebro with around 28% of N-NO3 and P-PO4 were considered only if at least 8 values per year were available. In addition, when total nitrogen was not available, it was calculated as the sum of Total Kjeldahl Nitrogen, nitrates and nitrites. Finally, we checked that for any specific monitoring point and for any specific period the values of N-NO3 and P-PO4 were lower than TN and TP, respectively. The annual concentration was then converted to annual load multiplying the concentration with the flow obtained from LISFLOOD  multiplied by the slope of the regression line between simulated and observed; RSR is the ratio of the RMSE between simulated and observed values and the standard deviation of the observations, and PBIAS is the percent bias between simulated and observed values. These statistics were also used to investigate the robustness of the model calibration in addition to graphical plots of the predicted versus measured loads showing the agreement between measurement and model estimations.The calibration of the model was performed for the period 2003–2007 using a Latin Hypercube algorithm. Only the basins with available monitoring data were selected during the calibration. The calibration of the nutrient components was performed finding the optimal values of model parameters using the ideal point error (IPE) approach that is a dimensionless composite index that measures model performance with respect to an ideal point in a fficient , bR2 is R2) multiplied by the slope of the regression line between simulated and observed (bR2) indicates the degree of linear relationship between simulated and observed data. A bR2 value close to one indicates a better performance. However, it is very sensitive to high values. The Nash–Sutcliffe efficiency (NSE) is a normalized statistic that ranges from −∞ to 1, with 1 indicating a perfect match. NSE tends to give more importance to higher values and lesser importance to lower values . We defined thus the IPEw as follows:a)3 and TN:•η); 1000 runs were performed; the optimal value was found calculating the IPE based on the comparison between the annual observed and simulated N-NO3 loads;Estimate the load of nitrate originating from atmospheric deposition in natural areas in basins with fraction of natural areas (forest + bare + shrub) greater than 50% , estimate the optimal η for TN in the basins with fraction of natural areas (forest + bare + shrub) greater than 50%; 1000 runs were performed; the optimal value was found calculating the IPE based on the comparison between the annual observed and simulated TN loads;Using the previous calibrated dataset for N-NO•η for TN, estimate the optimal, A, B and C for TN minus N-NO3 previously calibrated in all basins with data available. 1000 runs were performed; the optimal values were found calculating the IPEw based on the comparison between the annual observed and simulated TN loads;Using the calibrated Calibration of N-NOb)4 and TP:•α, A, B and C for P-PO4 in all basins with data available. 1000 runs were performed; the optimal values were found calculating the IPEw based on the comparison between the annual observed and simulated P-PO4 loads;Estimate the optimal •4 estimate the optimal α, A, B and C for TP minus P-PO4 in all basins with data available. 1000 runs were performed; the optimal values were found calculating the IPEw based on the comparison between the annual observed and simulated TP loads.Using the previous calibrated dataset for P-POCalibration of P-POThe calibration was performed considering all the available data due to the limited number of measurements in North Africa. The procedure was organized according to the following steps:Finally, the parameter values obtained during the calibration were used to extrapolate the model estimation in all the grid cells of the Mediterranean region. Due to the limited data availability, all monitoring data was used during the calibration process, so the model could not be validated. It must be stressed that the modelled results obtained in the southern basins should be interpreted with care because of the scarcity of monitoring data. These results could be significantly improved with the development of effective monitoring programmes to track improvement of water quality .Finally, it must be pointed out that the calibrated parameter set is unique for the whole Mediterranean but the retention factors are specific to a grid cell since we use in Equations 2 to 5 the precipitation and irrigation amount as well as the discharge specific to each cell.2.5w). The main purpose of these graphs is to show the distribution of the sampling points as well as to give an idea of the parameter sensitivity. They have the advantage to help identifying the most appropriate range to achieve the highest performance, and thus reducing the uncertainty in model prediction. In addition, the sensitivity of each parameter with respect to the others was assessed, relating the randomly generated parameters (Latin Hypercube) against the objective function value as follows:g is the objective function, b is the parameter, μ and β are the coefficients of regression and m is the number of simulations. The t-value and the significance level of each parameter were used to identify the relative significance of each parameter bi.The sensitivity analysis of the model parameters was assessed using dotty plots. These are plots of parameter values of relative changes versus the objective function ; and improvement of WWTP treatment efficiency assuming that all wastewater is treated to the tertiary level (S2). S1 consists in the reduction of the nutrient surplus in each grid cell in the Mediterranean region and thus it is assumed that crop yield is not affected as all crops still receive fertilizers in excess of their requirements. S2 increases where possible the treatment efficiency at the tertiary level, this is expected to have high impact in the southern part of the Mediterranean Sea where a large portion of the collected wastewater is discharged directly into the sea without any treatment .33.1The final results were obtained after the application of the sensitivity analysis. The analysis of the dotty plots for each parameter of the calibrated variables has allowed reducing the ranges of sampling, thus reducing the uncertainty in the estimation of the optimal parameter values.A and B which are related to river retention, while orthophosphate and total nitrogen are mostly controlled by α and C which are related to soil and lake retention.3 and P-PO4. This was observed also in The model calibration yielded results in good agreement with the measured data for each of the calibrated variables . The cal3.23, 0.11 Tg/y of TP and 0.03 Tg/y of P-PO4 are discharged into the Mediterranean Sea. The Nile, Po, Rhone and Ebro were the main river basins that contribute to the nutrient discharge in the Mediterranean Sea .We estimated that N-NO4 fluxes , which r3.33 (81%). These percentages increase to more than 95% for P-PO4 and TP. The major part of retention of total nutrient inputs occurs in soils. More than 50% of diffuse sources of N-NO3, TN and P-PO4 were captured before reaching the river network, while around 38% of TP diffuse sources were retained. In rivers the retention was estimated around 18% for N-NO3, 25% for TN and 6% for P-PO4, while the reduction of TP was the highest, around 34%. Lake retention was approximately similar to that obtained for rivers, albeit slightly lower. For N-NO3 and TN lake retention was estimated around 13% and 9%, respectively. The lowest values were obtained for P-PO4 (around 6%), while the highest value was for TP (27%). These percentages are in the range of those reported in literature: for instance, It is noteworthy that more than 80% of total inputs are retained for TN (84%) and N-NO3.4Nitrogen surplus in cropland and fodder constitutes the dominant source of nitrate (48%) and total nitrogen (37%) discharged into the sea, followed by natural background with 32% and 22%, respectively. Phosphate loads are mainly composed by discharge from wastewater treatment plants (48%) and by scattered dwellings (19%) . For totThe source apportionment for the whole Mediterranean region is mostly controlled by the situation of its main river basins including the Nile, Po, Ebro and Rhone river basins. In these areas the actions to reduce nitrogen should focus on cropland and grassland, and phosphorus needs also to be kept under control, as it might be rapidly recycled from water sediments . Therefo3.53 by 29%, TP by 13% and P-PO4 of 7%  has been increasing in the South-East Spanish coast, in the Ligurian–Provençal basin, and in the Rhodes Gyre region, while it has been decreasing in the North Adriatic Sea, off the Rhone River mouth, and in the Aegean Sea. The evidence also indicates that eutrophication problems persist in the area of influence of the Nile Delta . These t, 32, 38 . The hig-limited . In addi-limited  at the oThe persistent and widespread eutrophication processes that impact especially enclosed coastal bays in the Mediterranean Sea resulted in a huge effort in the last half century to control the phenomena. Understanding the amount of nitrogen and phosphorus discharged to the sea, their sources by a given sector, and the losses (retention) in the river basin is crucial to plan management strategies for the protection of coastal ecosystems and their services. The modelling framework presented in this study allows quantifying nutrient fluxes to the sea considering the contribution of natural processes and different sources including agriculture and domestic activities.The estimations of soils, rivers and lakes contribution to the retention of nitrogen and phosphorus forms, like those provided in this study , can helIn reference to the major challenges that the Mediterranean area will face in future years, i.e. intensification of economic activities, population increase, urban sprawling and climate changes, the scenarios S1 and S2 of this study provided significant management options. In particular, they provide the potential effectiveness of mitigation measures on the various forms of nitrogen and phosphorus. It is noteworthy that due to the structure of GREEN-Rgrid we can assess trade-offs scenarios in particular those linked to change of land use and change of irrigated areas and associated impacts on crop production and fertilizer requirements.Despite the current conflict in Syria and the related political instability of some countries of the area, economic activities and population are expected to increase in North Africa and Middle East. The expansion of the economic sectors and agriculture may increase water demand by 18% by 2025, mainly in the Southern and Eastern countries . The coaAs a consequence of the population increase, higher direct discharges of nutrient through sewage systems can be expected in the Mediterranean coasts. Under a growing population, upgrading wastewater treatment to tertiary level, especially for direct discharges into the sea, is a necessary measure to protect the marine and coastal environment. Reducing nitrogen surplus on agricultural soils together with collecting wastewaters and upgrading treatment levels, as exemplified by scenarios S1 and S2 in this study, are necessary measures to protect the water resources and coastal and marine ecosystems in the Mediterranean basin, and to ensure the long-term sustainability of the economic activities and ecosystem services in the region. These measures are also relevant in view of the future climatic and demographic challenges the region will face regarding nutrients in the agriculture-water nexus.In conclusion, the assessment and modelling tool presented in this study have shown how the interlinkage between water and agriculture can be explored, considering the basin-coastal relationship and nutrient sources and sinks from different sectors in an integrated way, making it a valuable tool not only for the Mediterranean area but also for all the other seas.


MED12 gene mutations and suggests its onset in the side population of embryonic myoblasts of the female reproductive system, which later gave rise to multiple small and medium fibroids. The single and usually large-size fibroids are induced by predominantly epigenetic disorders in LM SC, provoked by enhanced expression of the HMGA2 gene caused by its hypomethylation and epigenetic deregulation enhanced by hypoxia, muscle tension, or chromosome instability/aberrations. The pathogenomics of both genetic and epigenetic programs of LM with many peculiarities at the beginning later became rather similar and partly overlapped due to the proximity of their gene nets and epigenetic landscape. Pathogenomic studies of LM open ways for elaboration of novel strategies of prevention and treatment of this common disease.We review recent studies dealing with the molecular genetics and basic results of omics analysis of uterine leiomyoma (LM)—a common benign muscle tumor of the uterus. Whole genome studies of LM resulted in the discovery of many new gene nets and biological pathways, including its origin, transcriptomic, and epigenetic profiles, as well as the impact of the inter-cell matrix in LM growth and involvement of microRNA in its regulation. New data on somatic cell mutations ultimately involved in the origin, distribution and growth of LM are reviewed. Putative identification of LM progenitor SC (stem cells) giving rise to maternal fibroid nodes and junctional zones provide a new clue for hypotheses on the pathogenomics of LM. The reviewed data are consistent with at least two different but probably intimately interacted molecular mechanisms of LM. One of them (the genetic hypothesis) is focused primarily on the  Leiomyoma (LM) (fibromyoma)—a common benign tumor of the uterus—is an important medical and social problem, given the high incidence (up to 40% in women of reproductive age) ,2,3. TheOCT-4, NANOG, DNMT3B, and GDF3 [OCT-4 and NANOG are expressed and are capable of differentiating into myoblasts, osteoblasts, lipocytes, chondrocytes, and other mesenchymal derivatives [OCT-4 gene using a new method for detecting the surface marker Stro1/CD44 [Fibroid progenitor cells remained unknown for a long time ,7,8. In and GDF3 . The oriand GDF3 . Accordiivatives ,13. The ro1/CD44 .TGF-β (transforming growth factor β), ACVR1 , PDGF (platelet-derived growth factors), and TNF-α  genes that regulate the metabolism of steroid hormones estrogen and progesterone. In this case, the expression profile of regulatory microRNAs  changes significantly. Disorder expression relates primarily to regulatory genes (TGF-β and ACVR1), which determine the characteristics of the interaction of fibroid cells and the intercellular matrix. Given the crucial role of ECM in the development of LM, effective control of its size with the help of drugs is considered as a new promising strategy for drug therapy of LM [The precipitating factors and molecular mechanisms of tumor transformation of the smooth muscle cells of LM are actively being studied. It is known that an important role in this is played by various stressful effects, especially hypoxia and muscle contractions of the uterus during menstruation, pregnancy, and childbirth . Groups py of LM .The growth of myometrium and connective tissue suggests the presence of appropriate SCs that have recently been identified ,13. It iThe decisive role in the initiation of tumor growth and the appearance of different types of LM are determined by genetic factors . There iMED12, HMGA2, FH, and COL4A5-COL4A6 genes [The main genetic drivers of LM include the A6 genes .MED12 gene encodes one of the proteins of the mediator complex involved in the regulation of the activity of the key transcription enzyme, RNA polymerase 2. Somatic mutations of the MED12 gene are detected in 70%–75% of patients with LM [MED12 gene mutations also occur in adenomyosis  [MED12 gene occur in ontogeny remains unknown.1. The  with LM ,27 and atriosis)  and in mtriosis) . When muHMGA2 gene encodes a non-histone chromatin protein that belongs to high mobility group proteins, and regulates transcription processes. The HMGA2 gene contains three DNA-binding domains (AT hooks), through which a protein binds to nuclear DNA at loci rich in AT dinucleotides. HMGA2 is involved in the assembly of protein complexes that regulate gene transcription. With rare exceptions, HMGA2 gene expression is high during embryogenesis and drops sharply after birth [HMGA2 gene depends on the dinucleotide repeat (TCTCT (TC) n) located at 500 bp above the starting ATG codon of the HMGA2 gene and correlates with the TC repeat length [2. The er birth . The expt length .FH) encodes an enzyme in the tricarboxylic acid cycle and is associated with the development of hereditary leiomyomatosis. FH is a classic tumor suppressor gene, since all tumors caused by mutations in this gene exhibit somatic loss of the wild-type allele. Mutations in the FH gene stimulate the development of tumor LM in case of its biallelic inactivation; the mutative rate of this gene in patients that suffered from LM is 10.5% with biallelic loss of FH [3. The fumaratehydratase gene  with a COL4A5-COL4A6 deletion [COL4A5 and COL4A6 genes is the IRS4 gene [4. deletion . It is aRS4 gene .MED12 gene and overexpression of the HMGA2 gene have long been considered to be mutually exclusive, i.e., in different LMs changes (mutations or overexpression) of only one of these genes were detected [MED12 gene (1) and with chromosomal rearrangements that affect the expression of the HMGA2 gene (2). The real interaction of these genes in LM is more complicated [MED12 gene and expression of the HMGA2 gene yielded results indicating the possible interaction of the products of the corresponding genes in the pathogenesis of LM. In samples of myomatous nodes with a MED12 gene mutation, almost half of the cases show increased expression of the HMGA2 gene, which is also registered in myomas without MED12 mutations [HMGA2 gene is most likely the primary link that launches the genetic program for the development of LM. It can be a consequence of various reasons, such as chromosomal rearrangement affecting the 12q15 region or hypomethylation of the HMGA2 gene, which may be reflected in the combination of this process with the presence of mutations in the MED12 gene. The secondary inducers of LM, most likely, can be other chromosomal rearrangements that do not affect chromosome 12, but directly or indirectly affect the expression of the HMGA2 gene.Mutations of the detected . The preplicated . A simulutations . The autAn important role in the pathogenesis of LM is played by the activation of Wnt/b-catenin and Wnt/MAPK metabolic signaling pathways . It is tMED12 gene acts as a physiological modifier of β-catenin; however, when a mutation occurs, this function of the MED12 gene is lost. Moreover, TGF-β receptors are expressed in SCs, which activate mitogenic protein kinase (MAPK) proteins, which regulate cell–cell interactions, renewal, and proliferation of SCs [MED12 gene (up to 250 kb), a DNA sequence (rs5937008) was found that induces tumorigenesis and promotes the occurrence of mutations in the MED12 gene. In tumors with the “high” risk allele (rs5937008), mutations in the MED12 gene occurred significantly more often than in the absence of a risk allele [HMGA2 gene, LMs develop mainly due to activation of the PLAG1 proto-oncogene and induction of the WIF1 gene, an inhibitor of the Wnt/β-catenin metabolic pathway. The presence of mutations in the MED12 gene and, in part, in the RAD51B gene (responsible for DNA repair and involved in the HMGA2 gene) induces overexpression of the SFRP1 gene, an inhibitor of the Wnt metabolic pathway. Biallelic inactivation of the fumaratehydratase gene causes activation of the oncogenic transcription factor NRF2 (NFE2L2 gene). The IRS4 gene is a LM driver for deletions in the COL4A5 and COL4A6 genes. IRS4 encodes an insulin receptor substrate-4 that can stimulate proliferation by enhancing IGF-1 function. These features of the molecular pathogenomics of LM should be considered in the treatment of LM [HMGA2 gene, activation of the insulin-like growth factor IGF2BP2 gene occurs. Suppression of this signaling pathway is considered promising for the treatment of LM with overexpression of the HMGA2 gene [In normal SCs, the n of SCs . It is ik allele . The resnt of LM . In partGA2 gene .MED12 gene mutations occur twice as often as in solitary tumors (61% and 32%) [COMT Val/Val genotype frequency is twice as high as among patients with solitary LM (40% and 20.3%) and among the controls (40% and 18.6%) [MED12 gene is mapped, the exon 2 mutations of this gene, as well as the results of cytogenetic analysis convincingly proved that the LMs are of monoclonal origin; however, the clones of tumor cells in different myomatous nodes can be different, i.e., have different mutations that determine the individual characteristics of their molecular pathogenesis [Molecular genetic studies of fibroids have provided new data on the clonal origin of this tumor and the nonrandom association of mutations with the type of tumor. In particular, it was found that in multiple uterine fibroids, and 32%) . Among pd 18.6%) . Our mologenesis ,38.PROGINS (progesterone receptor gene) according to individual authors is not a risk factor for the development of LM [In addition to the group of genes considered, mutations of which can be a direct cause of the development of LM, hundreds of genes associated with various forms, severity, and characteristics of the clinical course of the disease have been identified. Most of them were detected by the GWAS method and by comparing the allelic frequencies of each candidate gene in normal individuals and in patients. The gene network of LM is represented by genes responsible for the metabolism of steroid hormones and their receptors, proliferation genes, cell contacts, angiogenesis, and growth factors, including oncogenes, pro-inflammatory cytokines and their suppressors, microRNA genes, and methylation ,39. Alrent of LM .p53 gene [Important information on the pathogenomics of LM was obtained by analyzing the expression profiles of these genes. It was found that the level of estrogen, its ER-α receptor, and corresponding mRNA in LM cells were significantly higher than in normal myometrium . Estrogep53 gene .EGF, HB-EGF, VEGF, bFGF, PDGF, TGF-b, and ADM) varies significantly [TGF-β3) gene, which significantly increases the synthesis of ECM proteins  by suppressing the expression of genes that regulate the degradation of these proteins [TGFB1 gene, and stably reduced for genes of connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61) [Depending on the stage of development, localization, and type of tumor, gene expression of major growth factors  .Many cytokines, including tumor necrosis factor (TNF-α), interleukins (IL-1 and IL-6), as well as chemokines and their receptors  are involved in the development of LM .TGFB3 gene of the TGF-β3 subunit  is overexpressed in LM cells [An important factor in the growth of LM, as already mentioned, is the extracellular matrix. In addition to the factors already mentioned that determine the growth of ECM, vitamin D plays a significant role in its development . The maiLM cells .WNT and HOX), MED12, steroid hormone metabolism genes and their receptors, collagen genes and ECM metabolism genes, many oncogenes and their suppressors, proliferation and growth factor genes, as well as apoptosis genes and their regulators. A comprehensive GWAS analysis of 15,453 patients with LM and 392,628 women in the control group revealed 22 loci in which 1428 SNPs were identified, and more than 30 candidate genes were found. The latter belong to two groups: 1) genes responsible for genomic stability , including genes of telomeric regions of chromosomes—TP53 and AT; and 2) genes that regulate the development of the urogenital system , as well as the marker protein gene CD44 associated with mutations of the MED12 gene.Hundreds of candidate genes and dozens of metabolic pathways make up the LM gene network . The latACP1, PTH, and NRT2 are negatively associated with LM sizes. A small LM is characterized by a protective combination of alleles of the acid phosphatase ACP1 gene and the non-receptor protein tyrosine phosphatase type 2 gene (Protein Tyrosine Phosphatase Non-Receptor Type ACP1 *B/* B-PTPN22 *C/*C) [TERT, TERC, and OBFC1, were noted. At the same time, telomere sizes in LM cells are smaller than in normal myometrium cells. A particularly significant decrease in telomeres is observed with unfavorable combinations of the alleles of the TERT , TERC (rs10936600), and OBFC1 (rs1265164) genes [The analysis of mutations and allelic variants of LM genes involved in the development of the female reproductive system is important for the search for new drugs and promising biomarkers of the disease. Thus, acid phosphatase genes 2 *C/*C) . In LM c4) genes . MutatioIn addition to heredity, an undoubted role in the genesis of LM is determined by epigenetic factors. All the main mechanisms of regulation of gene activity  in the pathogenomics of LM are often disturbed .FOXO1, TERT, and WNT4 [Numerous data have been obtained that indicate global disorders in methylation/demethylation of the genome in LM cells ,50,51. Tand WNT4 . A signiand WNT4 . Many ofand WNT4 . Epigeneand WNT4 . They reGenes that regulate the development of the female reproductive system and genome stability determine a hereditary predisposition to LM . It is bThe novelty of this study is validating the position of LM on the decisive role of ECM in increasing tumor mass and the associated factors, as well as, according to some experts, the need to shift the center for targeted therapy of this disease from the myomatous cell component of LM to suppress the growth of the ECM mass .MED12 and HMGA2 genes play an important role, the pathological effect of mutations of which is realized through dysfunction of various metabolic pathways, primarily Wnt/ß-catenin and Wnt/MAPK, and also prolactin and insulin-like growth factor (IGF) [HMGA2 gene is changed, LMs develop mainly due to the activation of the PLAG1 proto-oncogene and the induction of the WIF1 gene, an inhibitor of the Wntβ-catenin metabolic pathway. Mutations in the MED12 gene and, in part, in the RAD51B gene (responsible for DNA repair and involved in the HMGA2 gene) cause overexpression of the SFRP1 gene, an inhibitor of the Wnt metabolic pathway, and activation of the oncogenic transcription factor NRF2 (AKR1B10 gene) in the fumarase gene.There is no doubt that among the factors involved in the tumor degeneration of stem/progenitor cells, the or (IGF) . ImportaMED12 gene or overexpression of the HMGA2 gene can occur in LM. It has recently been found that LM cells with a MED12 gene mutation may also have increased expression of the HMGA2 gene, i.e., the products of these genes are possibly functionally conjugated [HMGA2 gene are associated with overexpression of this gene in LM cells [HMGA2 gene can induce an abnormal cell response to damaging factors: Mechanical transduction associated with periodic myometrial remodeling. The action of the growing intercellular matrix may contribute to the appearance of chromosome rearrangements, including chromosome 12, and, as a result, lead to overexpression of the HMGA2 gene. In LM cells with altered HMGA2 gene expression, the insulin-like growth factor IGF2BP2 gene is activated, and therefore suppression of this signaling pathway is considered promising for the treatment of LM with HMGA2 mutation [The results of the transcriptome analysis confirm and complement the data from the study of fibroids with various gene mutations. For a long time, it was believed that either mutations of the njugated . IndirecLM cells , which, mutation .MED12 gene mutations is more characteristic. Their presence in almost 70% of patients with LM, of course, cannot be attributed only to spontaneous somatic mutagenesis. It is believed that one of the reasons for the high mutability of exon 2 of the MED12 gene is the presence of a specific high-risk site (rs5937008) located 250 kb above the MED12 gene [MED12 mutation, which carry the “high risk” allele. It is possible that cells with a mutation in the MED12 gene, due to overexpression of the SFRP1 gene, an inhibitor of the Wnt metabolic pathway or other metabolic changes associated with impaired mutant gene, gain additional survival benefits. The molecular mechanism for selecting cells with a MED12 gene mutation remains unknown.Chromosomal rearrangements are typical for single large nodes of LM, while for multiple LMs, the presence of D12 gene . The mecMED12 mutations, X-chromosome inactivation patterns on which the MED12 gene is mapped, as well as chromosome analysis data convincingly prove that LM is a monoclonal disease; however, tumor cell clones in different myomatous nodes may be different, i.e., have different mutations that determine the individual characteristics of molecular pathogenesis.The results of studying the distribution characteristics of COMT gene, with the development of multiple and single myomas [ACP1 gene and PTPN22 gene with LM sizes [A clear correlation was found between the frequency and types of mutations, as well as the frequencies of alleles and genotypes of a number of genes, one of which is the e myomas , as wellLM sizes .It has been established that microRNAs are the regulators of LM growth, and, first of all, miR-15b, which increases the expression of genes that control cell proliferation and affects the receptivity of estrogen and progesterone .Important information on the pathogenomics of LM has been obtained in recent years using a genome-wide analysis of allelic associations and analysis of candidate gene expression. Two large-scale population studies of LM revealed the presence of 22 loci associated with LM, and identified dozens of genes responsible for maintaining the integrity of the genome, including genes that determine telomerase synthesis and sizes of telomeric regions of chromosomes, a large group of genes associated with malignant and benign hormone-dependent tumors and genes that control the embryonic development of the female reproductive system ,56.The pathogenetic mechanisms of interaction of numerous candidate genes and metabolic pathways of LM have not yet been studied sufficiently and require clarification. At the same time, it seems likely that the presence of various types of LM and the characteristics of the clinical and pathomorphological manifestations of the disease are determined not only by the main driver mutations, but also by numerous candidate genes that are expressed starting from the earliest stages of the tumor, possibly, in some cases, in utero .Recent studies have significantly expanded our understanding of the pathogenomics of LM, particularly regarding the parental (progenitor) cells of LM, the gene networks of the disease, the features of intergenic interactions, and the functions of the main driver mutations that potentiate the development of LM. New strategic therapies have been outlined.MED12 gene, which arise in the SC of the uterine myometrium under the influence of unfavorable factors . The mutations result in metabolic pathway dysfunctions associated with the proliferation of myoblasts and the formation of an extracellular matrix . The results of these abnormalities are multiple medium-sized LM nodes According to the epigenetic hypothesis, the main driving force (driver) of LM is overexpression of the HMGA2 gene, caused by many external factors . Overexpression of the HMGA2 gene leads to activation of the PLAG1 proto-oncogene and induction of the WIF1 gene, an inhibitor of the Wnt/β-catenin metabolic pathway. The results of epigenetic disorders are usually large solitary LM.A review of the available data suggests the presence of at least two mechanisms for the development of LM: genetic and epigenetic. Most likely, the primary link in the LM genetic program is the mutations of the IGF2BP2 gene is promising for the treatment of fibroids with overexpression of the HMGA2 gene. Given the crucial role of ECM in the development of LM, effective control of its size (suppression of the TGF-β and ACVR1 genes) is considered as a new promising strategy for the pharmacotherapy of LM.The pathogenomics of LM opens up new strategic paths for the prevention, diagnosis and treatment of this disease. In particular, suppression of the signaling pathway associated with the activation of the insulin-like growth factor The identification of candidate genes for LM and unfavorable combinations of minor alleles and their epigenetic regulation opens up new possibilities for assessing the risk of developing LM and the features of its clinical manifestation. In so doing, one can also develop approaches for early prevention and new methods of treatment for this socially significant gynecological disease.