Emulsion pump station is widely used to provide power for full-mechanized coal mining face equipment. With the development of the mining technique of longwall face and the extensive use of large mining height and high working resistance of the hydraulic support, the fluid supply pressure is more unstable and the pressure impact is increasingly intensified. The intelligent control of the emulsion pump station is the key to the development of the stable fluid supply technology at the working face. This paper develops a new on-line adaptive learning technique to improve the response speed of pumping station based on the optimal control algorithm of adaptive dynamic programming (ADP). The state space model of the working face fluid supply system in the process of no-load column lifting of hydraulic support is first established using the flow relationship, and the effectiveness of the proposed control algorithm is then verified by simulation validation. Moreover, combined with a certain fluid supply system of a fully mechanized caving face in Shandong Energy Xinwen Group XinJulong Co., Ltd, a technical scheme of adaptive stable fluid supply is verified in engineering practice. The results indicate that the fluid supply system using the proposed control algorithm has a favorable tracking effect on the ideal trajectory, and the tracking error can converge to near zero. The output pressure of the fluid supply system using the stable fluid supply technology is more stable, and the practical effect is good, which meets the demand of stable fluid supply in the mining face. With the increase of coal mining depth, hydraulic supports with large mining height and high working resistance are widely used, and the length of working face and the number of supports are increasing, which leads to the instability of fluid supply pressure and the increasingly aggravating pressure influence2.The fluid supply system of full-mechanized coal mining face consists of emulsion pump station, accumulator station, fuel tank, fluid supply and return pipeline and its accessories, etc. As the power source, the emulsion pump station can supply fluid and power for the hydraulic support of the working faceIt can only play an auxiliary role to improve the fluid supply circuit in the coal mining face and install an accumulator station in the fluid supply system in terms of unstable fluid supply pressure and intensified impact in the face. To fundamentally solve the above problems, it is necessary to adopt advanced algorithms to realize the intelligent control from the perspective of emulsion pump station, so as to supply fluid on demand and stabilize the system pressure. Therefore, according to the characteristics of the face, to improve the response speed of emulsion pump station, it is of crucial significance to design an adaptive control algorithm to make the hydraulic system more stable.3 studied the fluid supply system at the working face and developed a distributed monitoring system to monitor the emulsion pump station in real time. Li and Wei4 calculated the number of hydraulic supports in operation according to the pressure characteristics and time history, so as to change the flow of the station and lay a theoretical foundation for multi-pump linkage control. Ting and Hong5 studied the coal mining face fluid supply system, and obtained a conclusion that controlling the start and stop of the emulsion pump based on pressure sensor can effectively reduce energy consumption. Zhao et al.6 proposed an intelligent variable frequency speed control system to reduce the energy consumption of the station. Tan et al.7 introduced a pressure control method of emulsion pump station based on Elman neural network (NN), and verified the effectiveness of the method through simulation and comparison. Wang and Li8 took the fluid supply system of Taran Gaole Coal Mine as the research object, and suggested using the control mode of frequency converter combined with combination switch to realize constant pressure fluid supply in the coal mining face. Qi9 prejudged the power demand of the support by predicting the haulage speed of the shearer, and then used the hybrid particle swarm multi-objective optimization algorithm to realize the intelligent adjustment of the pressure flow of the station. Wei et al.10 brought forward that by establishing the connection between the full-mechanized mining fluid supply system and the electro-hydraulic control system of the hydraulic support, the fluid demand for the face can be predicted and the fluid can be supplied on demand. By making simulation analysis of the intelligent constant pressure fluid supply system, Mei Sun pointed out that the system has a vital influence on the performance of the hydraulic support11. Fu et al.12 proposed a stabile-pressure fluid supply principle with reasonable flow in advance based on the operating characteristics of the support. Tian et al.13 studied the application of PLC in the frequency conversion and constant pressure control system of mine emulsion pump station, and founded that the system based on PLC can effectively reduce energy consumption. Li et al.14 studied the intelligent fluid supply technology in the coal mining face, and elaborated the key technologies such as intelligent on-demand fluid supply control technology and remote fluid supply technology.Intelligent control of emulsion pump station is the key to the development of the stable fluid supply technology in the coal mining face. In this respect, many control results are shown to emulsify pump such that Li et al.15 drew a conclusion that the three-inlet and three-return fluid supply pipeline is beneficial to reduce the pressure loss. By constructing mathematical models of pipeline and load, Li et al.16 concluded that parameters such as pipe length and pipe diameter can affect the stability of hydraulic system. Zhao et al.17 used Matlab/Simulink to analyze the transient state of high-pressure pipeline and simulated the dynamic characteristics of pressure transient. Zhao18 built the simulation model of trapezoidal and three-inlet and three-return fluid supply pipeline, and concluded that the latter can reduce the pressure loss and improve the column lifting speed. Li19 analyzed the layout of emulsion pump station at the working face with large mining height and the circular fluid supply program, and verified its rationality through theoretical arithmetic. Wiens20 initiated a distributed gradient line tower model and conducted modeling analysis of the fluid pipelines, which ensure faster calculation speed and higher precision.To ensure the support effect of the hydraulic support and make the equipment movement at the working face more stable and accurate. Shu et al.21 built a simulation model of hydraulic accumulator, and analyzed the influence of accumulator volume on its effect. Li et al.22 analyzed the influence of accumulator parameters on its performance, and verified it using experiments. Van de Ven23 created a new variable-area piston constant-pressure accumulator, which can keep the accumulator at a constant pressure during the oil output. Ding et al.24 studied the effect of accumulator absorbing pressure pulsation of hydraulic pump, and proposed methods to increase the available capacity of accumulator. Bi et al.25 studied the absorption law of accumulator to system pressure and flow fluctuation by combining the method of simulation and experiment. Wan et al.26 studied the influence of accumulator parameters and accumulator station configuration scheme on the stability of fluid supply system in the coal mining face, and formulated configuration optimization scheme for the specific working face.In order to further improve the stability of fluid supply in the coal mining face, Mamcic and BogdeviciusIt can only play an auxiliary role to upgrade the long-distance fluid supply circuit and configure an accumulator station in terms of improving the stability of fluid supply in the coal mining face. But it can reduce pressure loss, alleviate hydraulic shock, and compensate system flow to a certain extent. Using advanced intelligent control method to realize the real-time response of emulsion pump under different working conditions is the key to improve the stability of fluid supply in the face. However, the current intelligent fluid supply technology in the coal mining face cannot ensure the speed and stability. The researches on intelligent fluid supply technology are mostly limited to detecting the system pressure and adjusting the fluid supply of pumping station based on unloading valve control technology (multi-pump linkage), frequency conversion constant pressure fluid supply technology or their combination. As the multi-pump linkage has low control accuracy and frequency conversion and constant pressure has slow response, the fluid supply system cannot accurately provide the required power, and there remains a certain impact of fluid supply pressure and flow fluctuation, which affects the control accuracy of the coal mining face support system. Therefore, in light of the specific coal mining face and based on the optimal control algorithm via adaptive dynamic programming (ADP), this paper develops a new online adaptive learning technology to track the system state in real time, and adaptively adjust and output the corresponding stable fluid supply flow. By establishing the state space model of the fluid supply system, the proposed algorithm is simulated and validated, and the technical scheme of stable fluid supply is proposed using the actual working conditions of the working face, which provides reference for engineering practice.28, it is not easy to solve Hamilton–Jacobi–Bellman (HJB) equation, thus, Werbos proposed ADP to solve the above problems29. The ADP structure based on single-layer critic NN can reduce computational complexity and realize optimal tracking control30.For the optimal control of nonlinear systemsIn this paper, the tracking error and reference trajectory are used to construct the augmented system, and the modified HJB equation can be obtained by constructing the performance index function. To solve the HJB equation on-line, a new adaptive learning algorithm is proposed to directly learn the unknown critic NN weights. The calculation efficiency can be improved since only the critic NN is used.u is the control input.Considering a continuous-time nonlinear system:u to make the system states x track the ideal trajectory xd that is, Assuming that the system in Eq.  is contret and the ideal tracking trajectory xd. According to the system and the ideal tracking trajectory, we haveTo realize the optimal tracking control, an augmented system is constructed based on the tracking error Define Based on the above operations, we can consider the tracking control as the regulation control problem of the augmented system .u should be found to minimize the following performance index function:X and control input u respectively.In order to realize the optimal control of the system, a control The derivative of the performance index function  along th JX = ∂J/∂X.According to the optimal criterion, the Hamiltonian function can be derived asJ*(X) asDefine the optimal performance index function Set J*X in  by using single-layer critic NN. Assuming that the performance index function J*(X) is continuous, the optimal performance index function J*(X) is:l represents the number of neurons, and The core of ADP is to estimate the optimal performance index function XX, respectively.The derivative of W, σ, and WM, σN, σM, δε are all positive constants.We assume W is unknown, therefore, the approximate performance index function is:In fact, the ideal NN weight The ideal optimal control can be obtained from Eqs.  and 11)11):14\doThe actual optimal control can be obtained from Eqs.  and 13)13):15\dou, it is necessary to update the unknown critic NN weights W and guarantee its convergence, enabling the system output x to track the ideal trajectory xd. However, the adaptive learning algorithm used in most ADP methods can only ensure that the critic NN weights are uniformly and ultimately bounded (UUB), instead of converging to the ideal weights. Therefore, this paper proposes a new adaptive learning method to update the critic NN weights while ensuring convergence.In order to obtain the optimal control solution Substituting Eq.  into Eq.To design an adaptive law to update the critic NN weights, the known term in the (16) is defined asSubstituting  into 1616, we caW is unknown. Therefore, it is necessary to design a learning algorithm, which is driven by the parameter estimation error, to learn the unknown weight solution.According to Eq. , only thDefine filter matrices θ asWe construct the auxiliary variable From Eqs.  and 20)20), we hIt can be obtained from Eqs. –21) tha tha21) tThe use of estimation error in the adaptive learning algorithm can ensure the convergence of the weights of the estimated NN. Therefore, the following adaptive laws can be designed to calculate O1 is positive definite. Therefore, a Lyapunov function When the regression vector satisfies the continuous excitation condition, the matrix εv and the excitation level κ. Ideally, when εHJB = 0, the estimation error Therefore, the estimation error The proposed control method can be implemented on-line without any off-line learning. Moreover, the designed adaptive law can ensure that the critic NN weights converge to the neighborhood of its ideal weights. Based on the estimated NN weight  control  can conv control , i.e., \W. Hence, it outperforms the gradient based adaptive law, which was tailored for ADP synthesis.The adaptive law  is driveted from  with thefined in , they cashown in , \documeEmulsion pump station supplies fluid to hydraulic support and other equipment through fluid supply pipeline. Figure In the process of safety support of the hydraulic support, the fluid demand of hydraulic support for lifting, pushing, lowering and pulling is different, and the way of support moving is quite different. Therefore, this paper studies with an example of a single support moving in sequence.tz is the operating time of the single hydraulic support, which is s; Lz is the width of hydraulic support, which is m; vc is the speed of shearer, which represents m/min.In order to match the speed of shearer, the support should finish a complete action flow every time the shearer passes through the width of a support. Then the relationship between the operating time of single hydraulic support and the speed of shearer is as follows:The operating time of hydraulic support equals the sum of the time of lifting, pushing, lowering and moving, i.e.,In the operating process of hydraulic support, the fluid supply flow required for column lifting is the largest. However, the insufficient fluid supply often leads to deficient pressure, thus affecting the operating speed. Therefore, the fluid supply of a single hydraulic support is taken as the research object and other supports and related pipelines at the working face are ignored to analyze the column lifting process.If the volume loss of emulsion pump station is ignored, the output flow is equal to the product of rotational speed and displacement, that isQ0 represents the effective flow; QL represents the leakage in the column, the follow Qc needs to be increased due to the compressibility of oil in hydraulic cylinder and pipeline; f is the system leakage, and q is the flow into (out of) the accumulator.A1 is the piston area of the lower cavity of the column, and y is the piston displacement.L is the leakage coefficient in the column, and ΔP is the pressure difference between the two sides of the piston.P1 is the pressure of the lower cavity of the column, and P2 is the pressure of the upper cavity of the column.The output flow of emulsion pump can be divided into five parts:P2, a constant, is equal to the back pressure of the fluid.V is the oil volume in the working cavity of the column and the oil inlet pipeline, and β is the effective volume elastic modulus of the system, which is 0.7–1.4 × 103 MPa.When the column is undergoing no-load rising, δ power of the flow, that isK is the pressure loss coefficient, and δ = 2. According to the experimental data, there are some errors.In the fluid supply system of the working face, the total pressure loss is proportional to the P2 is:The pump station pressure The system leakage is:Va0 serves as the initial volume of gas in the accumulator, N is the gas polytropic index, and It is generally equipped with a large-capacity accumulator station in the emulsion pump station system, which is used to absorb pressure shock and pulsation, serve as an auxiliary power source, and so on. Its influence on the flow of the system is as follows:Combining the above five equations, the following equations can be obtained:Simplifying:The driving force of the piston is generated by the pressure difference between the two sides. The force balance equation is established by carrying out the force analysis of the piston:Adding the auxiliary equation Transforming to matrix form:Suppose the state vector The output equation of the system isΔP is the system output,If The above are the state space models of the fluid supply system.According to the actual configuration of the system, the frequency conversion control of the pump station is realized based on the state space model built in “According to the action characteristics of hydraulic support in the process of no-load column lifting and the actual situation of fluid supply system, the relevant parameters are calculated as follows:So:The initial state of the system is:The ideal trajectory during the action is:If the state vector of the augmented system is To realize the optimal tracking control of the system, it is necessary to use NN reconstruction to minimize the performance index function. Therefore, the regression vector of the NN is designed as:0, and the learning gain In the simulation validation, the initial NN weight is Figure ΔP is disturbed to simulate the real working condition and make simulation analysis. Figures In order to further verify the effectiveness of the proposed control algorithm, Figure These simulation results verify the effectiveness of the control method proposed in this paper.To achieve the purpose of supplying fluid on demand and stabilizing the system pressure, the adaptive control method proposed in this paper is adopted to realize the intelligent adjustment of emulsion pump station, and accurately and timely match the fluid demand of hydraulic support.To reduce the pressure loss and improve the response speed of the system, the working face adopts a network-type fluid supply system, the long-distance high-pressure hose for fluid supply is changed into a steel pipe, and the pipeline diameter is appropriately increased.To further stabilize the system pressure, the fluid supply system at the working face uses an 8 × 63 L accumulator station, a small accumulator is added for each emulsion pump, and auxiliary accumulators are added at the end of the fluid inlet pipeline.In view of the actual working conditions of a certain working face in XinJulong, considering the control mode of emulsion pump station, pipeline layout, accumulator configuration and other factors, the adaptive stable fluid supply technical scheme is proposed as follows:According to the above analysis, combined with the actual situation of the working face, the configuration of the working face is properly adjusted, and the output pressure of the emulsion pump station is monitored in real time by applying the adaptive stable fluid supply technology. The application site of the stable liquid supply technology in the working face is shown in Fig. According to Figs. The optimal control algorithm based on ADP is described, and the augmented system is constructed based on the tracking error and ideal trajectory of the system output. In addition, the performance index function is constructed according to the tracking error and control input, and the critic NN is used for reconstruction to estimate on-line.Through the flow relationship, the state space model of the fluid supply system in the working face is built by analyzing the action of hydraulic support lifting the column with no load driven by the fluid supply of the emulsion pump station, and comprehensively considering the factors such as the leakage in the column, the compressibility of emulsion, the leakage of pipeline system and the accumulator.The proposed algorithm is applied to the fluid supply system for simulation validation, which shows that the system has a favorable tracking effect on the ideal trajectory, and the tracking error can converge to near zero.According to the specific working face, the technical scheme of adaptive stable fluid supply is put forward and verified in engineering practice. By comparing the actual output pressure of the pump station, it can be concluded that the output pressure of the system is more stable after the application of the stable fluid supply technology, which meets the demand of stable fluid supply at the working face with a good practical performance.The control method of emulsion pump station in the fluid supply system of the working face is the key to realize the stable fluid supply technology of the working face. In this paper, a new on-line adaptive learning technique is proposed to design the optimal tracking control of the fluid supply system at the working face. In terms of specific working face, the technical schemes of the adaptive stable fluid supply are proposed and verified in engineering practice. The conclusions of this paper are as follows:


Pseudomonas aeruginosa with difficult-to-treat resistance are likely to receive meropenem (MEM) as an empiric therapy before escalation to broader agent such as ceftolozane/tazobactam (C/T) after antimicrobial susceptibility data are available. We assessed if pre-exposure to MEM impacted the development of C/T-resistance upon C/T exposure.Patients infected with P. aeruginosa isolates were assessed. Isolates were exposed to 16 mg/L MEM concentration for 72h, interrupted by wash step every 24h to avoid drug degradation and antibiotic carryover. Then, isolates were serially passaged in the presence of C/T as two groups: MEM-exposed group inoculated with MEM pre-exposed isolates and non-MEM control group. Three consecutive passages took place at a C/T concentration of 10 mg/L for 72h. After 24 h intervals, samples were serially diluted, plated onto Mueller Hinton agar, and incubated to quantify bacterial densities (log10 cfu/mL). Samples were plated on drug free and drug containing agar (C/T concentration 16 mg/L) where growth on C/T agar indicated resistance development. Resistant population was calculated by dividing the cfu/mL on C/T containing plates by the cfu/mL on drug free agar . Percentage of C/T-resistant population was compared between MEM-exposed and MEM non-exposed passages of each isolate.Six clinical Table 1). In three isolates, MEM exposure significantly increases the prevalence of resistance development against C/T; the percentage of resistance population for the three isolates were 100%, 31%, and 3% for the MEM-exposed versus 0%, 0.35%, and ≤0.0003% in the unexposed groups. One isolate had similar percent resistant population at 72 h between groups (≤0.003 and ≤0.005%). The remaining isolates showed no development of resistance in either group.At 72 h, resistant populations were detected in 4/6 isolates (in vivo and clinical data are needed to further assess the clinical implications of these findings.Previous MEM exposure may pre-dispose to C/T resistance development upon exposure limiting therapeutic utility. Resistance may be a result of the stress exposure or molecular level mutations conferring cross-resistance. Further Samantha Nicolau, PhD, Sanofi Pasteur: full time research scientist Patricia J. Simner, PhD, Affinity Biosensors: Grant/Research Support|BD Diagnostics: Advisor/Consultant|BD Diagnostics: Grant/Research Support|Entasis: Advisor/Consultant|GeneCapture: Stocks/Bonds|Merck: Advisor/Consultant|OpGen Inc: Board Member|OpGen Inc: Grant/Research Support|OpGen Inc: Honoraria|Qiagen Sciences Inc: Advisor/Consultant|Qiagen Sciences Inc: Grant/Research Support|Shionogi Inc: Advisor/Consultant|T2 Biosystems: Grant/Research Support David P. Nicolau, PharmD, Allergan: Advisor/Consultant|Allergan: Grant/Research Support|Cepheid: Advisor/Consultant|Cepheid: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Tetraphase: Advisor/Consultant|Tetraphase: Grant/Research Support|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support|Wockhardt: Advisor/Consultant|Wockhardt: Grant/Research Support Christian M. Gill, PharmD, Cepheid: Grant/Research Support|Entasis therapeutics: Grant/Research Support|Everest Medicines: Grant/Research Support|Shionogi: Grant/Research Support


Cancer is a heterogeneous disease and tumours of the same type can differ greatly at the genetic and phenotypic levels. Understanding how these differences impact sensitivity to treatment is an essential step towards patient-specific treatment design. In this paper, we investigate how two different mechanisms for growth control may affect tumour cell responses to fractionated radiotherapy (RT) by extending an existing ordinary differential equation model of tumour growth. In the absence of treatment, this model distinguishes between growth arrest due to nutrient insufficiency and competition for space and exhibits three growth regimes: nutrient limited, space limited (SL) and bistable (BS), where both mechanisms for growth arrest coexist. We study the effect of RT for tumours in each regime, finding that tumours in the SL regime typically respond best to RT, while tumours in the BS regime typically respond worst to RT. For tumours in each regime, we also identify the biological processes that may explain positive and negative treatment outcomes and the dosing regimen which maximises the reduction in tumour burden. Understanding the biological mechanisms underpinning cancer and developing effective therapeutic protocols to improve patient prognosis are fundamental aims of cancer research. Existing treatment modalities, such as radiotherapy (RT) and chemotherapy (CT), are applied via highly-regulated dosing protocols . Nor does it describe how secondary tumours are established, i.e., metastasis.In previous work , and the oxygen concentration, c(t), and can be written as follows:c, with proportionality constant c drops below a threshold value, c and c, with rate constant The model comprises two time-dependent ordinary differential equations (ODEs) for the tumour volume, Since the model , 2) dis dis2) diRadiobiology. RT is used to treat more than Radiation induces direct and indirect cytotoxic effects by causing DNA damage to cancer cells that is fatal if left unrepaired. Direct effects arise from interactions between ionising particles and DNA and indirect ones from interactions between ionising particles and water, which create reactive oxygen species that subsequently react with DNA. Indirect effects are the most common, which is why hypoxic, i.e., poorly oxygenated, tumours are often radio-resistant  monolayer or three-dimensional (3D) spheroid experiments. As such, they provide information about the long-term proportion of cell death rather than how the cell death rate changes over time. In contrast, a time-dependent description of RT cell kill can account for different types of damage (direct vs. indirect), damage repair and cell death following insufficient repair  model McMahon . The LQ r Curtis . Such a r Curtis  and adopPaper structure. This paper is structured as follows. In Sect. R over the time period H is the Heaviside function defined in . We. We2). Wmentclass2pt{minimT, proliferate, die due to nutrient insufficiency and consume oxygen for proliferation and maintenance as in Eqs. . Th. ThT, prT, although at different rates. More specifically, they proliferate at a rate proportional to the oxygen concentration, c, and the available space, with proportionality constant c, with rate constant T and T cells, c and Sub-lethally damaged cells, Lethally-damaged cells, One final and important assumption we make is that radiation only affects tumour cells, i.e., we neglect any effects RT may have on tumour angiogenesis, vascular remodelling and injury. This simplifying assumption enables us to focus on elucidating how mechanisms of growth arrest influence one particular type of tumour response to RT, i.e., the cellular response.We non-dimensionalise Eqs. –9) by i by i9) bR) are summarised in Sect. This paper focusses on studying the impact of two distinct growth arrest mechanisms on the qualitative tumour response to RT. We, therefore, fix parameters related to tumour cell responses to RT at the values stated in Table g and k based on parameter values found in the literature and preliminary numerical simulations. For Further, we define tumour growth parameters as in our previous work , we, we\docuentclass1pt{minima in Eqs. , we showg vary  and/or that elicit a weaker angiogenic response would be in the NL regime, while tumours growing in well-perfused regions  and/or that elicit a stronger angiogenic response would be in the SL regime. Tumours growing in well-perfused regions that are highly proliferative and, therefore, more likely to outgrow their nutrient supply, would be in the BS regime. In Sect. In summary, in the absence of treatment , Eqs. –13) des des\docuNOur aim is to understand the qualitative response of tumours in nutrient limited (NL), space limited (SL) and bistable (BS) regimes to a range of fractionated radiotherapy (RT) treatments. As a first step, we create three virtual tumour populations as follows. We first fix all tumour growth model parameters, except mentclass2pt{minimD to We then define the RT protocols of interest. We vary the dose amount https://github.com/chloeacolson/InvestigatingTumourResponsesRadiotherapy.) For simplicity, we impose the initial conditionsFor each set of tumours and each RT protocol, we solve Eqs. –13) num num13) nFor each simulation, we record In this section, we investigate the response of tumours in the NL, SL and BS virtual populations to fractionated RT. For each regime, we initially study tumour response to a conventional fractionation schedule consisting of Typical responses to a conventional fractionation schedule. Fig. T and Figure Q1, Q3) values of Q1, Q3) values of Figure nditions , the latIn both regimes, we observe outliers, which undergo much larger reductions in The influence of the oxygen consumption rates, andon treatment outcome following a conventional fractionation schedule. We now investigate the role of entclass1pt{minimaComparing the response of tumours While oxygen levels are higher in tumours see Fig. a, their Figure els Fig. a, RT celOverall, we have shown that both low values of Figure }$$q_1,q_$$\end{doc, is at least 10-fold higher than for high values of Figures c throughout treatment and, in particular, the weekly average oxygen concentration remains above For tumours Figure Overall, we have shown that two mechanisms can contribute to the increased efficacy of RT for certain tumours in a SL regime. These mechanisms are cell death due to RT and limited tumour regrowth between RT doses. Their relative contributions depend on the values of The effect of the dosing schedule on typical tumour response. We now consider how, for a fixed total dose, the dose rate, R, and the number of fractions per week, R and R  than the typical tumour in this regime. Tumours which are sufficiently near to the boundary of the BS and SL regimes and consume little oxygen for maintenance experience larger than average decreases in viable cell volume as RT cell death is enhanced by higher oxygen levels. By contrast, tumours which are close to the boundary between the BS and SL regimes, but not sufficiently close, undergo larger than average increases in viable volume, regardless of the value of The effect of the dosing schedule on typical tumour response. For the virtual population of tumours in a BS regime, we show in Fig. R, and the number of fractions per week, R) and a higher dose rate  and bistable regimes. We now investigate the long-term response to RT by studying post-treatment tumour growth dynamics and, in particular, the tumour steady states attained following treatment.We first perform a steady state analysis of the system –13) to  to 13) t in Eqs. –(13) andIf then Eq.  gives24\If then Eq.  implies hen, Eq.  implies e system –13) mus mus\docue system –23) wit wit\docuWe have shown that RT preserves the steady states and growth regimes observed in the absence of treatment. We conclude that, given The steady state analysis showed that tumours in a BS regime may attain either a NL or a SL steady state following treatment. In particular, such tumours may undergo large increases in tumour volume in response to RT as they switch from a NL steady state to a larger SL steady state. Recall the tumours Tumours In contrast to tumours fined in . They arWe now consider how the dosing schedule affects the long-term dynamics of tumours in a BS regime. In Fig. These results suggest that a lower RT dose and dosing frequency may prevent uncontrolled increases in tumour volume following RT for tumours in BS regimes. As with our observations for short-term treatment responses, this challenges the assumption that a higher dose, applied with a higher frequency, will lead to a greater reduction in tumour volume.Cancer is a heterogeneous disease. In particular, tumours can exhibit widely varying responses to treatments. As a result, the success of existing therapies, which are typically applied following a “one-size-fits-all approach”, can be highly variable. Patient-specific treatment design could aid in overcoming these barriers to treatment efficacy, but this requires increased understanding of the factors which affect tumour sensitivity to treatment. In this paper, we investigated how two distinct mechanisms of growth arrest can influence tumour responses to radiotherapy (RT).We extended an existing model of solid tumour growth which distinguishes between nutrient limited (NL) and space limited (SL) growth control  and/or RT cell kill. The additional SL-specific mechanism is a consequence of low rates of RT cell kill for NL tumours due to low oxygenation. This explains how the different growth arrest mechanisms that characterise the NL and SL regimes can affect short-term tumour response to RT. In the long-term, tumours in the NL and SL regimes always return to their pre-treatment steady state volume, irrespective of the effects of RT during treatment. Our model, therefore, predicts that any change in the tumour burden during radiation is transient for these tumours. This result follows from our simplifying assumption that the vascular volume remains constant during tumour growth and RT. We explain below how we could extend the model to relax this assumption.We also found that most tumours in the BS regime respond badly to RT in the short-term, as their viable and total cell volumes increase during RT. As for monostable regimes, outliers which lie, in parameter space, near the boundary between BS and SL regions, exhibit more extreme responses to RT. In these cases, the intratumoural oxygen concentration is close to, and smaller than, A final key result relates to RT dosing schedules. We found that, in SL regimes, applying larger doses at higher frequency typically increases RT efficacy, whereas, in NL and BS regimes, administering lower doses at lower frequency can increase RT efficacy for outliers and lessen, or prevent, large increases in tumour burden across the virtual cohorts. The latter is a counter-intuitive result and challenges the assumption that giving the maximum tolerable dose is the best course of treatment. In practice, we are unlikely to know in which growth regime a patient’s tumour lies when treatment starts. It would be interesting, in future work, to investigate whether we can determine a tumour’s growth regime by monitoring its response to a given treatment protocol. If we can establish that a tumour is in a SL regime, then this would allow us to adapt the treatment protocol to maximise the reduction in tumour burden, e.g., by increasing the RT dose or dosing frequency. Alternatively, if a tumour is in a NL or BS regime, then it might be preferable to halt treatment early in order to prevent large increases in tumour burden.in vitro assays involving 2D monolayers, where all tumour cells have abundant nutrient and proliferate until they reach confluence  improves with higher doses applied at higher frequency, it would be interesting to incorporate a trade-off between anti-tumour effects and detrimental side-effects. For example, we could model the damage experienced by surrounding healthy tissue following each RT dose and impose a maximum value of cumulative damage over the RT protocol, above which the RT toxicity is considered intolerable (e.g., see Hanin and Zaider


Fluorescent molecular sensors, often referredto as “turn-on”or “turn-off” fluorescent probes, are synthetic agentsthat change their fluorescence signal in response to analyte binding.Although these sensors have become powerful analytical tools in awide range of research fields, they are generally limited to detectingonly one or a few analytes. Pattern-generating fluorescent probes,which can generate unique identification (ID) fingerprints for differentanalytes, have recently emerged as a new class of luminescent sensorsthat can address this limitation. A unique characteristic of theseprobes, termed ID-probes, is that they integrate the qualities ofconventional small-molecule-based fluorescent sensors and cross-reactivesensor arrays . On the one hand, ID-probes can discriminate betweenvarious analytes and their combinations, akin to array-based analyticaldevices. On the other hand, their minute size enables them to analyzesmall-volume samples, track dynamic changes in a single solution,and operate in the microscopic world, which the macroscopic arrayscannot access.Here, we describe the principles underlying theID-probe technology,as well as provide an overview of different ID-probes that have beendeveloped to date and the ways they can be applied to a wide rangeof research fields. We describe, for example, ID-probes that can identifycombinations of protein biomarkers in biofluids and in living cells,screen for several protein inhibitors simultaneously, analyze thecontent of Aβ aggregates, as well as ensure the quality of small-moleculeand biological drugs. These examples highlight the relevance of thistechnology to medical diagnosis, bioassay development, cell and chemicalbiology, and pharmaceutical quality assurance, among others. ID-probesthat can authorize users and protect secret data are also presentedand the mechanisms that enable them to hide (steganography), encrypt(cryptography), and prevent access to (password protection) informationare discussed.The versatility of this technology is furtherdemonstrated by describingtwo types of probes: unimolecular ID-probes and self-assembled ID-probes.Probes from the first type can operate inside living cells, be recycled,and their initial patterns can be more easily obtained in a reproduciblemanner. The second type of probes can be readily modified and optimized,allowing one to prepare various different probes from a much widerrange of fluorescent reporters and supramolecular recognition elements.Taken together, these developments indicate that the ID-probe sensingmethodology is generally applicable, and that such probes can bettercharacterize analyte mixtures or process chemically encoded informationthan can the conventional fluorescent molecular sensors. We thereforehope that this review will inspire the development of new types ofpattern-generating probes, which would extend the fluorescence moleculartoolbox currently used in the analytical sciences. RoutB.; UngerL.; ArmonyG.; IronM. A.; MarguliesD.Medication Detection by a CombinatorialFluorescent Molecular Sensor. Angew. Chem.Int. Ed.2012, 51, 12477–12481.; hence, they can generate distinct identificationpatterns for different analytes. Recently, these cross-reactive sensorarrays, also termed differential sensors20  havebeen applied to differentiate between biomolecules in aqueous solutionsor between cells. With such systems, the biomolecule analytes canbe distinguished according to the optical fingerprints, generated by the nonspecific probes in an array (29The olfactory receptors (ORs) are an exceptionalgroup of proteinsthat do not bind to their targets according to the “lock-and-key”principle. Unlike enzymes, antibodies, or most receptor proteins,which normally interact with one target, each OR can nonselectivelyinteract with a wide range of volatile compounds.an array 1B.20−292910 In contrast, most differential sensors  synthetic receptors on one molecular scaffold1C. BindiID-probe 1C is rea31 various unimolecular analytical systems of thisclass have been developed and used for different applications.The term unimolecularID-probe refers to pattern-generating sensorsin which the various recognition elements and fluorescent reportersare covalently attached. Since the inception of the first ID-probe,3.11 (1) was designed to discriminate between differentcarbohydrates and carbohydrate-based medications (1 consists ofa cis-amino proline scaffold appended with threephenyl boronic acids (BAs) and four dyes, namely, naphthalene (Naph),fluorenyl (Flu), anthracene (An), and dansyl (Dan). The BAs form thediol-binding receptors, whereas the dyes serve as fluorescent reporters.These dyes were selected owing to their partially overlapping absorptionand emission spectra, affording intramolecular FRET communication.In addition, Dan is a solvatochromic probe, whereas the An-BA conjugateshave been shown to act as carbohydrate sensors that are activatedvia several potential mechanisms.10 Incubating 1 with different medications resulted in markedly distinctfluorescence signatures  aggregatesis based on the “turn-on” response of thioflavin T (ThT)to Aβ fibrils. Although fibril formation has been associatedwith Alzheimer’s disease (AD) progression, various studiesindicate that intermediate Aβ aggregate species, such as lowmolecular weight (LMW) oligomers ,and sulfo-Cy5 (sCy5) that serve as a FRET donor, acceptor/donor, andacceptor, respectively. In addition, it consists of two amyloid binders:a bis-KLVFF peptide, which enables it to bind LMW oligomers, and ThT,which can interact with fibrils, protofibrils, and high molecularweight (HMW) oligomers. We have shown that changes that occur in Aβaggregation states can be straightforwardly differentiated, in a singlesolution, according to the unique optical fingerprints generated by 2 , a bis-ethacrynic amide (bis-EA), and an anti-PDGFDNA aptamer (Apt), known to bind to different members of the MMP,GST, and PDGF isoform families, respectively. For the fluorescentreporters of 4, we selected two solvatochromic dyes:nitrobenzoxadiazole (NBD), Nile red (NR), as well as cyanine 5.5 (Cy5.5)and cyanine 7 (Cy7). Incubating 4 with different isoformsleads to the generation of distinct emission fingerprints  assay that can simultaneously detectsmall-molecule inhibitors of distinct proteins.To show that ulations4D. The i3.432 is to use fluorescentmolecular probes to secure information.43 We realizedthat the small scale of ID-probes, together with their ability togenerate distinct optical signatures, should make them superior toother molecular information protection systems intended to hide (steganography),encrypt (cryptography), or prevent access (password-protection) toinformation.An exciting direction in molecularlogic and computing3.4.144 was based on a fluorescent molecular switchthat “turns-on” only when specific chemical and opticalinputs are introduced in the correct order. Although a variety ofmolecular keypad locks have been developed since then,43 they were generally designed to recognize specific inputs and produceonly a few output signals. This prevented them from authorizing multiplepasswords.The first molecular keypad lock, developed by Margulies and Shanzer,1  and d-xylose (X) in different orders (iv vs v) or at different concentrations(ii vs vi and iii vs vii). In this scheme, very simple codes, namely,X, G, XX, GG, XG, and GX, can be distinguished. By introducing additionalchemical inputs and analyzing the patterns generated in response tolonger code entries, we showed that 1 can, in principle,authorize 81 different 4-digit combination codes.36Our expectation that ID-probe 1 2A could 3.4.22 Oneof the most famous cipher machines ever developed is the Enigma machine,which was used to encrypt messages during World War II. What significantlycomplicated cracking the enigma code was the enormous difficulty toreproduce the initial settings in enigma’s rotors. The needto set up the correct initial state of the device ensured that evenif an enemy acquired an identical Enigma machine, decrypting messageswould be extremely challenging.A key principle underlying the function of cryptographic (cipher)machines is the ability to convert a text message into nearly (pseudo)random letters. It occurred to us that the unpredictable fluorescencepatterns that ID-probes generate could provide the means to encryptand decrypt secret messages using randomly selected chemical inputsand a molecule-size cipher machine.5 , SRB, and Nile blue (NB), the aminoproline scaffold of 5 is appended with various recognitionelements for binding distinct chemical species  (II). The intensityvalues, recorded every 20 nm, provide the encryption key. Adding theencryption key to the numeric message affords an encrypted message(cipher text) (III) that can be safely sent to the recipient. To decryptthe message, the recipient needs to generate the decryption key bysetting up the correct initial state of the system and measure the fluorescence spectrum of 5 in the presenceof the same chemical input (IV → V). The original message isrevealed by subtracting the decryption key from the cipher text (VI).Two additional layers of protection were reported in this work.2 One is password protection. We have shown that,with some chemical inputs, 5 can act as a molecular keypadlock. Hence, with such inputs, the enemy also needs to know the “chemicalpassword” needed to generate the decryption key. The finallayer of protection is steganography. We showed that, similar to secretinks, low quantities of the molecular cipher machine (5) can be concealed on paper and sent to recipients by regular mail.This not only complicates its detection—it also complicatesits characterization, which would be needed if an enemy attempts toreproduce the molecular device. Overall, this work showed that crackingmessages encrypted by ID-probes is almost impossible because theyare protected by three different defense mechanisms: steganography,cryptography, and by entering a password, which are used to hide,encrypt, or prevent access to the information, respectively.Encrypting a message with ysimple 6C.The sysimple 6C-Iand 434 The use of oligodeoxynucleotides(ODNs) to scaffold these probes endows them with inherent water solubilityand provides a simple means to construct multiple different ID-probeswith tailor-made molecular architectures.One limitationof the unimolecular ID-probes previously discussed2–6 is th4.16 , and recognition and signaling elements . Quadruplexassembly takes place in two steps. First, a holliday junction is generatedin the presence of lithium ions. Then, sodium ions are added thatinduce the formation of a G-quadruplex. Our design is inspired byprevious studies showing the creation of synthetic receptors and sensorsfrom symmetric, intermolecular, and parallel DNA G-quadruplexes.45 A unique feature of our design, however, isthat it provides the means to create an asymmetric and antiparallelG-quadruplex structure. In this way, libraries of ID-probes that beardistinct synthetic receptors and fluorescent reporters (R1-R4) can be readily created  fluorescent probe,10 whereas ODN-3 and ODN-4 bear the fluorescentreporters, namely, Cy3, Cy5 and FAM, Dan, or NBD.Fast and efficient methods for analyzingprotein glycosylation could improve our ability to diagnose diseasesor control the quality of therapeutic glycoproteins. Although massspectrometry and lectin arrays are commonly used in glycoprotein analysis,these methods are generally not high throughput. The self-assembledID-probe 7 8A4 was dsurement 8B. The srement   and two FRET acceptors  affordedan exceptional fluorescent molecular sensor (ID-probe 7) whose fluorescence is affected by changes in five different photophysicalprocesses: PET, ICT, FRET, internal conversion, and excimer emission.Based on ourprevious studies on protein surface sensorson state 8B. The ain (hCG) 8C, a gly5cis-amino proline scaffold with different dyes and synthetic receptors,we have demonstrated the possibility of tailoring such probes (ID-probes 1–5) to different applications, such aspharmaceutical quality assurance, medical diagnosis, analytical proteomics,and information protection. Despite this progress, making this technologyrelevant to real-world applications would require novel methods tooptimize the ID-probes’ performance, for example, by enhancingtheir differentiation ability or by simplifying their preparation.One way to address these problems is by generating self-assembledID-probes, such as probes 6 and 7. Althoughthis approach offers a simple means to generate multiple ID-probesand select the best ones for a desired application, it also has somelimitations. For example, the DNA scaffold may dissociate under certainconditions; hence, applying self-assembled ID-probes to sense analytecombinations in an intracellular environment could be challenging.Moreover, because small alterations in the concentration of the ODNsconstituting the self-assembled ID-probes can change their fluorescencepatterns, achieving batch-to-batch reproducibility with such probesrequires extra caution when manufacturing them. We hope this perspectivewill inspire scientists to develop additional means to further enhancethe properties of ID-probes and consequently, expand the ways andforms in which this emerging class of sensors could be utilized.With this Account,we hope to attract attention to the emergenceof a new class of fluorescent molecular sensors, termed ID-probes,which integrate the properties of unimolecular fluorescent sensorsand cross-reactive sensor arrays. On the one hand, such probes candiscriminate between a wide range of analyte combinations, akin topattern-generating arrays. On the other hand, similar to small-molecule-basedprobes, they can analyze small-volume samples, track changes thatoccur in a single solution, and operate in the microscopic world,where macroscopic arrays cannot access. By modifying a


This study investigates the effect of fluid elasticity on axisymmetric droplets colliding with pre-existing liquid films, using both numerical and experimental approaches. The numerical simulations involve solving the incompressible flow momentum equations with viscoelastic constitutive laws using the finite volume method and the volume of fluid (VOF) technique to track the liquid’s free surface. Here, the Oldroyd-B model is used as the constitutive equation for the viscoelastic phase. Experiments are also performed for dilute viscoelastic solutions with 0.005% and 0.01% (w/w) polyacrylamide in 80:20 glycerin/water solutions, in order to ensure the validity of the numerical solution and to investigate the elasticity effect. The formation and temporal evolution of the crown parameters are quantified by considering the flow parameters, including the fluid’s elasticity. The results indicate that the axisymmetric numerical solutions reasonably agree with the experimental observations. Generally, the fluid’s elasticity can enlarge the crown dimension at different thicknesses of the fluid film. Moreover, at intermediate values of the Weissenberg number, the extensional force in the crown wall can control the crown propagation. Furthermore, the results reveal that the effects of the Weber number and the viscosity ratio on this problem are more significant at higher values of the Weissenberg number. In Newtonian fluids, the regimes of the drop impact on liquid film have been classified by Manzello and Yang7 and Rein9. The studies on the drop impact on a liquid film by Rein8, Cossali et al.10, Wang and Chen11, and Rioboo et al.12 have revealed that the crown in Newtonian fluids is formed at large impact Weber numbers and large drop velocities.The dynamics of the crown formation due to the impact of a drop onto a thin liquid film is of interest in fluid mechanics and engineering applications. The drop impact on liquid film has several significant applications, particularly in inkjet printing, coating, spraying, painting, and cooling processes. The complexity of the drop impact dynamic makes this phenomenon important. Many studies13 have theoretically introduced the concept of a kinematic discontinuity. In this study, the results show that the crown radius varies exponentially with time. Roisman and Tropeal14 have theoretically developed a model for the general case of the drop impact on a wetted surface while ignoring surface tension and viscous forces. They have shown their model to be suitable for high-impact velocities, low viscosities, and thin liquid films, and their results agree with previous experimental studies. Also, they have considered the shape of the crown geometry in the case of an oblique impact and the interaction of two drops’ impact onto a liquid film. Trujillo and Lee15 have analytically and numerically modeled the crown formation in a droplet splashing problem. They have introduced a model for propagating the crown formed during the droplet impact. They have presented their results in both viscid and inviscid situations, while their model is also suitable for considering a drop's splashing on a thin fluid film. Cossali et al.16 have experimentally represented the time evolution of the crown geometrical parameters and the secondary droplet size. Their results have indicated that the crown shape strongly depends on the surface tension, but the film thickness does not significantly affect the crown characteristics. The experimental investigation of the drop impact on a liquid film by Levin and Hobbs17 has revealed that the crown radius has a square root dependence on time. This relation has also been reported by Cossali et al.16. Okawa et al.18 have experimentally studied the splashing thresholds during the drop impact onto a fluid film. They have used different fluids to investigate the effects of the critical Weber number and the fluid film thickness on the splashing thresholds.Over the last few decades, various theoretical, numerical, and experimental works have analyzed the impact phenomenon in Newtonian fluids. Numerical simulation is an alternative method to model complex two-phase flows. In a numerical simulation, the tracking of the interface deformation between the phases is critical and can be treated by different numerical techniques, for example, the Marker and Cell (MAC) method, the volume of fluid (VOF) technique, the lattice Boltzmann method (LBM), the level-set method (LSM), etc. For instance, Yarin and Weiss19 have numerically investigated the transition between the splashing and the deposition for the droplet impact on a thin liquid film. Their results have shown that, at early instances of the drop impact, a square root relation is observed between the crown radius and time, while the viscosity shows no meaningful effect on the crown evolution. Mukherjee and Abraham20 have numerically investigated the crown shape in the drop impact on a liquid film using a high-density ratio lattice Boltzmann model. They have found that, on thin films, the crown radius and height growth rates have the same trend with increasing the film thickness; however, they have reported an opposite trend for thicker films. Furthermore, an increase in the surrounding gas density results in a decrease in the growth rate of the crown dimension, while the gas viscosity has a minor effect on the crown height and radius. Coppola et al.2 have performed numerical simulations on a two-dimensional drop impact on a thin film. They have simultaneously employed the Navier–Stokes equations and the VOF method to solve the problem while considering viscous, inertia, and surface tension forces in the governing equations. They have presented the results of their simulations for early and intermediate instants of the impact. Their simulations quantifies the velocity, pressure fields, and interface shapes for different parameters. They have emphasized that the impact problem is essentially three-dimensional, and the axisymmetric assumption is unacceptable when the instability occurs in the circular lamellae. Both viscous and inviscid assumptions have been considered in analytical and numerical solutions in previous works, taking into account the effects of the film thickness, the droplet velocity, and the wall friction on the crown dynamics in Newtonian fluids.Josserand and Zaleski22. Lampe et al.23 have experimentally investigated the water drop impact on viscoelastic wormlike micelle polymer solutions. They have studied the effects of the viscoelastic fluid properties and its compositions as well as the fluid film thickness, on the progress of the crown shape, the formation of satellite droplets, and the evolution of the Worthington jet. They have introduced a correlation for the onset of splashing of secondary droplets for a thick film of the viscoelastic fluid. Tome et al.25 have numerically investigated the viscoelastic drop impact on the same liquid pool. They have employed the MAC technique to simulate three-dimensional free surface flows, presenting results for different Reynolds and Weissenberg numbers while neglecting the effect of the surface tension force. Their simulations have emphasized the significant effect of viscoelasticity on the two-phase flow. Izbassarov et al.26 have developed a numerical solver for suspending rigid and deformable particles in viscoelastic fluids. They have employed different methods to specify the interface between the phases involved while validating their solver for different cases of non-Newtonian fluids’ single- and two-phase flows. Recently, Rezaie et al.28 have numerically studied the impact of a two-dimensional (plane) drop onto a pre-existing liquid film in a viscoelastic fluid. In their work, they have applied the finite volume method (FVM) and the VOF technique to solve the governing equations, which included a non-linear constitutive equation. In their analysis, they have considered the elastic and surface tension forces, finding that the viscoelasticity has a major influence on the formation and temporal evolution of the crown shape.However, the effects of the fluid’s rheological properties, especially the elasticity and the nonlinear viscosity, have so far received less attention in the literature27, our axisymmetric simulations provide more realistic and precise results. Secondly, by conducting accompanying experiments, the validity of the present numerical simulations is examined, while a deeper insight is gained into the effects of the flow parameters. In the experimental part, two Boger fluids are used as the viscoelastic phase to investigate the effects of rheological properties on the drop impact onto fluid films. In the numerical part, the Oldroyd-B model is used as the constitutive equation for the viscoelastic phase, and the surrounding air is considered a Newtonian fluid. The FVM and VOF techniques are used to solve the governing equations. Finally, the effects of the main flow parameters, including the Weissenberg number, the viscosity ratio, the film thickness, and the Weber number, on the evolution of the crown are investigated in detail.The present work investigates, numerically and experimentally, the effect of fluid’s elasticity, and extensional viscosity on axisymmetric drop impacts onto pre-existing liquid films, with the following novelties. Firstly, compared to the two-dimensional plane analysis3) and 50 × 50 × 2 (mm3) Plexiglas cells for different thicknesses of the fluid film. A syringe is used to release the fluid from an appropriate needle, producing a drop of different sizes. Also, backlight projectors are used to capture high-quality pictures with a distinguishable boundary.The schematic illustration of the experimental setup is presented in Fig. Mw = 5 × 106 g/mol) in 20/80  and 100 ppm (0.01 wt%) of polyacrylamide . In this test, a droplet of the polymeric sample with a diameter of 6 mm was put between two parallel plates. The upper plate moves rapidly with a linear motor. A linear strike is employed for the motion of the upper plate with a strike time of 50 ms. The extension height is 9 mm, and the Hencky strain is 1.312. The number of data points for the B1 and B2 samples is 7442 and 6735, respectively. The diameter of samples is measured using a laser micrometer. The micrometer's resolution, wavelength, and power are 0.01 mm, 780 nm, and 1.7 mW, respectively. The data from these tests are shown in Fig. D and a width equal to 2.5D. Moreover, D, g, U0, ρ1, ρ2, and h are the drop diameter, the acceleration of gravity, the drop velocity, the densities of fluid one and fluid two, and the film thickness, respectively. In this study, both the drop and liquid film are viscoelastic Boger liquids, while the surrounding air is a Newtonian fluid. Therefore, the equations of motion, i.e., the continuity and momentum equations, for the viscoelastic fluid flow in incompressible and isothermal conditions can be expressed as:31:A schematic of the drop impact onto the fluid film is portrayed in Fig. 32. In Eq. .According to Fig. At walls:At the vertical axisymmetric boundary:At the top boundary:34. The overall algorithm for the isothermal two-phase flow of the viscoelastic flow is based on the Pressure-Implicit with Splitting of Operators (PISO) presented in27.The OpenFOAM software package is employed to discretize and solve the governing equations based on the FVMR) and the height (Z)  and the height (Z) are:The dimensionless forms of the radius , the Reynolds number (150 ≤ Re ≤ 200), the Weber number (200 ≤ We ≤ 800), the dimensionless fluid film (0.2 ≤ H ≤ 0.35), and the viscosity ratio (0.1 ≤ β ≤ 0.5), while the Bond number (Bo) is kept constant at Bo = 1.2.As mentioned in section “t = 0). Moreover, an image processing technique is utilized to measure the velocity of the droplet prior to its contact with the liquid film. This velocity is used as impact velocity. As the drop impacts onto the liquid film, a liquid jet is ejected from the contact line of the drop and the liquid layer. This jet propagates and spreads with time. According to Fig. 35.The time sequence of the drop’s impact onto the liquid film is presented in Fig. 13 theoretically predict that the variation of the crown radius is proportional to the square roots of time for Newtonian fluid  and radius (R*) is displayed in Fig. The effect of the fluid’s elasticity on the time variation of the crown height  to h = 2 (mm), the maximum crown height grows by 29% and 6.8% for the Boger and Newtonian fluids, respectively. In the viscoelastic fluid, the elasticity of the fluid film can conserve a greater amount of the impact energy, enhancing the crown dimensions. Moreover, the impact of the fluid film thickness on the crown dynamics is smaller due to the larger amount of viscous dissipation in the Newtonian fluid. The time sequence of the crown shape at different fluid film thicknesses is presented in Fig. In the impact problem, the liquid film thickness significantly affects the crown dynamics. Figure The above experimental results are presented for the axisymmetric case. In our experiments, as the drop’s inertia and the fluid’s elasticity increase and decrease, the axisymmetric form of the crown’s rim may become unstable, perhaps due to Plateau-Rayleigh instability-type instabilities. Therefore, the presentation of our numerical results in the upcoming section  with the dimensionless time is selected as a comparative parameter. Three different grid sizes, i.e., 400 × 800, 800 × 1600, and 1600 × 3200, are used for the grid study. Non-uniform grids are chosen, and these grids are refined near the impact area to better capture the interface between the phases. The variation of the dimensionless radius of the crown (R*) with time for three different grid sizes is presented in Fig. A grid independence analysis is conducted to ensure our numerical results' accuracy. The variation of the dimensionless crown radius  is descended under gravity with an initial velocity of 1 (m/s) at a distance of 0.04 (m) from the center of the drop to the rigid drywall. The Oldroyd-B viscoelastic model is selected for the drop phase, and the continuous phase is selected as a Newtonian fluid. In this comparison, the dimensionless parameters are * and R*) are in reasonable agreement with the experimental results for small to intermediate times. The numerical and experimental results significantly differ for larger times; this deviation is meaningful for B2. It can be predicted that the source of this error may come from the constitutive equation considered. Also, the crown shape for our numerical and experimental results is illustrated in Fig. Figure 25. However, the plane 2D results can be used to recognize drop impact phenomena.The differences between the plane and axisymmetric two-dimensional simulations and experimental results are represented in Fig. t* = 6, the dimensionless crown height (Z*) and the crown radius (R*) increase by 11.5% and 2.3%, respectively. Furthermore, Fig. The variation in the crown dimensions, as a function of the dimensionless time, for different Weissenberg numbers are presented in Fig. t* = 2.8 is demonstrated in Fig. Wi, the crown reaches its maximum height earlier than the case at lower values of Wi.The effect of the Reynolds number on the maximum crown height at different Weissenberg numbers is illustrated in Fig. The effect of the Weissenberg number on the magnitude of the shear stress field is also shown in Fig. H) at different Weissenberg numbers. As the fluid film thickens, the crown radius decreases, and the crown height increases at different times. By increasing the fluid film thickness, the kinetic energy of the drop is used to penetrate into the thicker liquid film that opposes the radial movement of the fluid. Moreover, as the film thickness increases, the elastic fluid film recovers a higher portion of the impact energy of the drop, leading to an increase in the vertical elevation of the crown. According to Fig. Z*. At t* = 2.8, the effect of the film thickness on the crown shape and the velocity field is depicted in Fig. Figure –4  to larger values of 103, the maximum height increases. With an increase in Wi, i.e., at higher Wi = 1. In the viscoelastic flow, the dimensionless form of the extensional viscosity (Trouton ratio) is defined as follows38:In Fig. Wi ≈ 1, the extensional viscosity has a maximum value in the range of Wi = 0.1–Wi = 100. Therefore, the extensional force prevents the growth of the crown height at moderate Weissenberg numbers (Wi = 0.1 … 1). On the other hand, as the Weissenberg number is increased further to 1000, a higher portion of the impact energy can be conserved by the fluid film. The conserved elastic energy helps to increase the maximum crown height at higher values of the Weissenberg number.As seen in Fig. Wi, the crown height increases by increasing the viscosity ratio. This is due to a higher polymer viscosity in viscoelastic solution, causing to enhances the elasticity of the polymeric solution. Hence, the effect of Figure Wi, the influence of the viscosity ratio on the crown characteristics is negligible. The maximum crown height is compared at three viscosity ratios of 0.1, 0.3, and 0.5 in Fig. Wi ≥ 10), the crown maximum height is increased as the viscosity ratio increases. As Wi is decreased (Wi ≤ 0.1), the variation of β converges to the same value and, therefore, it becomes invariable to the viscosity ratio. In elastic flows with small values of the Weissenberg number (Wi ≤ 0.1), the viscoelastic constitutive equation is insensitive to the variation of the viscosity ratio. On the other hand, for high elastic flows (Wi ≥ 10), β has a major effect on the viscoelastic flow that enhances the elasticity of the polymeric solution. As seen in Fig. Wi ≈ 1. According to Fig. Wi = 1, a larger amount of the impact energy is dissipated with respect to large Weissenberg numbers. Therefore, it is clear that, at moderate Weissenberg numbers (Wi ≈ 1), the viscosity ratio parameter can suppress the crown spreading. The effect of the viscosity ratio on the crown shape is displayed in Fig. t* = 2.8.On the other hand, at lower Z* and R*) at different Weber and Weissenberg numbers. The results are reported for a range of Weber numbers between We = 200 and We = 800, at different Weissenberg numbers. The Weber number shows the ratio of the inertia to the surface tension force. As it can be seen from Fig. * = 5, the parameter of Z* increases 555%, 328% and 273% for Wi = 1, Wi = 10 and Wi = 100, respectively. As a result, by increasing the fluid’s elasticity, the rate of increase of Z* decreases.Figure * parameter increases at different Weissenberg numbers. Moreover, as the Weissenberg number increases, the Weber number strongly influences Z*. In this study, the inertia force increases by increasing the drop velocity, leading to the dominance of the inertial force over the surface tension force. As a result, the drop inertial force increases the size of the crown. When the drop momentum is increased, the liquid layer spreads out more rapidly, and the crown can expand to greater heights. Moreover, Fig. Figure We = 800), the crown wall is thinner, whereas for a lower Weber number (We = 200), the surface tension force resists the enlargement of the crown wall; therefore, the body of the crown wall is thicker.The shape of the crown at different Weber and Weissenberg numbers is illustrated in Fig. Numerical and experimental investigations are conducted to understand the effect of a fluid’s viscoelasticity on the crown formation and propagation due to a drop impact onto a liquid film. Firstly, an experimental study (using high-speed imaging) is performed to investigate the effect of the relevant parameters on the impact problem. Also, the validity of the present numerical investigation is evaluated/confirmed by comparing the results with both the present experimental observation and the past numerical studies. In the numerical part, the governing equations are solved using a two-dimensional axisymmetric solver based on the FVM. The Oldroyd-B model was considered as the constitutive equation. The VOF technique was applied to track the interface between the phases.In the experimental part, the effects of the drop diameter, the film thickness and the drop velocity are mainly considered. To analyze the crown dynamics via experiments, the crown height and radius variation are presented versus the aforementioned parameters. The experimental results indicate that increasing the fluid’s elasticity can increase the crown wall height. Also, the crown dimensions increase by increasing the drop size, the fluid film thickness and the drop velocity .H ≈ 0.2), whereas, at large values of the film thickness (H ≈ 0.35), the crown dynamics have not affected severely from the fluid’s elasticity. By decreasing the Weissenberg number, the maximum value of the shear stress increases in the crown base, which dissipates the drop's initial kinetic energy. In contrast, as the Weissenberg number increases, the kinetic energy of the drop is conserved during the impact period. Moreover, the results indicate that, at the moderate Weissenberg numbers (0.1 ≤ Wi ≤ 1), the extensional force plays an important role in the dynamics of the crown, controlling the crown propagation. The results also indicate that, by increasing the fluid film thickness, the rate of increase of the crown height increases, while the time variation of the crown radius decreases. The influence of the viscosity ratio on the crown dynamics strongly depends on the Weissenberg number. For highly elastic flows (Wi ≥ 10), the viscosity ratio helps to enlarge the crown dimensions, whereas, for intermediate values of the Weissenberg number (0.1 ≤ Wi ≤ 1), the viscosity ratio suppresses the crown propagation. It is found that the Weber number has a significant impact on the crown dimensions. Increasing the Weber number increases the time variation of the crown parameters due to the weakening of the surface tension force. The results also indicate that the effect of Weber number on crown dynamics is more significant for larger values of the Weissenberg number. It is worth mentioning that the impact of a viscoelastic drop onto an elastic substrate would constitute a cognizant route for future work39.In the numerical part, the effects of the Weissenberg number, the viscosity ratio, the Weber number, and the dimensionless film thickness on the flow field are investigated. The results of the numerical investigation show that the fluid’s elasticity can increase the crown dimensions significantly for small values of the film thickness (Supplementary Video 1.Supplementary Video 2.Supplementary Video 3.


By virtue of the kinetic lability of these pools, it is suggested that the isolation of such species by chromatography methods will not be possible, but rather mass spectrometric techniques should be adopted. Iron-sensitive fluorescent probes, which have been developed for the detection and quantification of LIP, are described, including those specifically designed to monitor cytosolic, mitochondrial, and lysosomal LIPs. The potential of near-infrared (NIR) probes for  Such ring sizes are associated with unfavourable entropy differences. The non-chelating structure (2)  agrees w2+·GS (2) and hexaaquo·Fe2+ (1), with the glutathione complex dominating. The concentration of [Fe(H2O)6]2+ (1) is linearly related to the total concentration of cytosolic iron(II) and is predicted to vary between 10−8 M and 5 × 10−7 M for a range of total iron(II) concentration between 1 µM and 10 µM. Clearly, the large excess of glutathione does not prevent [Fe2+]cytosol from acting as a potential signal for iron(II) sensors, such as the IRP 1/aconitase- and IRP 2/FBXL5-linked systems. Because of the high kinetic lability of iron(II), this system will be close to equilibrium and therefore at pH 7 the speciation plot depicted in 2+·GS will occur at a slow rate, the resulting iron(III) will be rapidly reduced back to iron(II) (Over the concentration ranges of GSH (2–10 mM) and iron(II) (0.5–5 µM), the two major cytosolic iron(II) species are reliably predicted to be Feiron(II) , in a fa1 values being 2.7 /[GSSG] is higher than that found in the cytosol  = 1.1–1.25 mM ,33 and . Speciat cytosol . 2+·GS binds to glutaredoxins, proteins that are required for iron cluster assembly and heme biosynthesis  + [Fe2+·probe]. In principle, Kprobe, [Fe2+·probe], and [probe] can be determined. In order to minimise the efflux from the cell, the acetoxy methoxy group (AM) has been successfully introduced. AM enhances the membrane permeability of the probe, but cytosolic esterases rapidly cleave the AM esters to the more hydrophilic carboxylate function (Equation (2)). As a result, the now hydrophilic probe remains trapped within the cytosol  is measured from the change in fluorescence upon the addition of SIH and the binding constant of iron(II) to the probe. However, the relevant binding constant for calcein is not certain; iron(II) certainly binds to the carboxylate functions of calcein, but physical measurements have demonstrated that iron also binds to phenolic groups on calcein, which can favour autoxidation of iron(II) to iron(III) [As indicated by the discussion centred on Equation (1) using such probes, it is, in principle, possible to determine the concentration of LIP. The concentration of ron(III) . Thus thPlasmodium falciparum can be monitored during cell culture  is metabolized by cytosol esterases to Phen green SK (10), as shown in Equation (4), and hence is largely trapped in the cytosol. However, a small proportion of 10 gains access to the mitochondria and lysosomes [7) has been utilized to measure cytosolic LIP by using an ex-situ calibration method [ysosomes . Phen grn method ,71. WhenRho Nox-1 (5) is reported to be selectively sensitive to the presence of iron(II) [4)2Fe(SO4)2 register an increase in fluorescence intensity (5) can detect iron(II) in the presence of physiological levels of GSH.iron(II) , and conntensity . As indiHydroxypyridin-4-one (HOPO)-containing probes have been investigated for the quantification of LIP [11) achieves rapid entry into cells without the necessity of using AM or acetyl esters. However, this ability to penetrate plasma membranes provides CP655 access to both lysosomes and mitochondria, thus providing a measure of cellular LIP as opposed to cytosolic LIP. A further limitation of this class of fluorescent probes is that they are not trapped intracellularly and will efflux once the incubation media is changed [n of LIP . Under b changed . However6). We have synthesized a range of such molecules and, as a result, identified Cytosense LI as being suitable for the quantification of cytosolic LIP. Time-lapse fluorescent microscopy demonstrates that Cytosense LI enters cells rapidly and responds to the addition of iron presented as a complex with 8-hydroxyquinoline  levels [) levels ,75. TheyMitochondrial Probes. As mitochondria are the main utilizers of iron in the cell, as well as being a major source of the superoxide anion, O2−•, iron homeostasis is critically important. An increase in the mitochondrial iron burden is likely to be linked to associated pathology, for instance with Friedreich’s ataxia where there is inefficient iron sulfur cluster synthesis [ynthesis . The mit12) are such examples where the positive charge formally associated with the central phosphorus atom is delocalized over the three phenyl rings, resulting in a low electron density. This, together with the overall lipophilic character of the molecule, enables rapid penetration of membranes. This useful property of lipophilic cations has been utilized to target fluorescent iron sensors in the mitochondrion. Both Petrat’s [13) to monitor mitochondrial iron levels. Rhodamine is a positively charged fluorescent molecule where the single positive charge is delocalized on both nitrogen atoms and over the plane of the tricyclic structure. By adopting methods developed for the cytosol, estimates of the mitochondrial LIP were made. The values for mitochondria of different cells were found to be distributed over a wide concentration range, centred around 12 µM [One widely adopted method of targeting molecules to the mitochondrial matrix is by attachment to delocalized lipophilic cations. By taking advantage of the substantial negative electrochemical potential maintained across the inner mitochondrion membrane , delocalized cations are able to cross the membrane and hence be accumulated with a distribution driven by the Nernst potential, typically in excess of 1000-fold. Triphenyl phosphonium salts , it becomes possible to monitor the mitochondrial LIP. BP19 (14) has been utilized to monitor the mitochondrial LIP of cultured fibroblasts obtained from Friedreich’s ataxia patients [Largely as a result of the above limitation, a different approach has been introduced for monitoring the mitochondrial matrix LIP. A series of peptides have been prepared, members of which are capable of being targeted to and accumulated in mitochondria. These peptides contain alternate hydrophobic and basic amino acids and typically contain between 4 to 6 residues. Using this general design, a series of small fluorescent peptides have been synthesized that are selectively accumulated by mitochondria . By incopatients . The meapatients  that the15) has been introduced for the measurement of mitochondrial LIP [Rho Nox-1 (5), namely more control studies are required to establish iron(II) selectivity. Another phenanthroline-based mitochondrial probe Mitoferrofluor (16) has been investigated for the detection of iron(II) [2+ in both polarized and depolarized mitochondria.A mitochondria-targeted, NO-containing fluorescent probe Mito-FerroGreen  . This prLysosomal targeting Probes. The endosomal/lysosomal compartment of cells contains a relatively high level of labile iron, largely resulting from the breakdown products of both mitochondria [chondria  and ferrchondria . Chelatichondria ,87. The chondria . Howeverchondria .17) has been demonstrated to only be located in endosomal/lysosomal compartments in macrophages [The hydroxypyridinone SF34 , has been reported to be localized in the lysosomal compartment of human adenocarcinoma (MCF-7) cells, and this property has been utilized to report differences in lysosomal LIP levels [The P levels .in vivo. This is primarily due to the unique properties of NIR light and its interaction with biological tissues. Namely, by exploiting a region of the electromagnetic spectrum, which is less absorbed and scattered , NIR light is known to offer several advantages, such as increased tissue penetration, limited autofluorescence by endogenous molecules, and, thus, minimized background interference, along with reduced photobleaching of the fluorophores and photodamage to the tissues. All this leads to an enhanced signal-to-noise ratio by NIR agents and, thus, clearer and more reliable imaging results for in vivo imaging. In this context, NIR-based agents represent promising tools for the study of intracellular iron levels in organs and tissues, which would be challenging or impossible to access with shorter-wavelength probes . Iron-targeted NIR probes have been developed with this purpose in mind [in vivo investigations of iron-related disorders, including neurodegeneration and other syndromes by the imbalance of iron homeostasis. Typically, these probes are designed in such a way that ensures high specificity for iron, exhibiting a change in their fluorescence properties upon binding to the metal, thereby enabling the monitoring of its dynamics in the cytosol with enhanced sensitivity and spatial resolution. Noteworthily, the ability to selectively detect iron(II) and/or iron(III) species is of great importance to the understanding of the roles of this metal in biological processes. This has the potential to facilitate the identification of new and tailored therapeutic interventions for diseases characterized by iron-overload or, in general, altered physiological levels of iron. To date, a limited number of NIR probes for iron(III) have been developed, and there is only a single report on the application of iron(II)-sensitive NIR probes for in vivo imaging [The development and application of near-infrared (NIR) technologies is also under investigation, in order to facilitate our understanding of the nature of cytosolic iron pools  in mind ,93,94 to imaging ,96. 19), CAM (20), LS1 (21), and DFOm-NPs (22)  (NPs (22) . Howeverreported ,100,101,reported ,103, as reported ,105,106.19)  coupled to a large Stokes shift (195 nm), along with a detection limit of 51 nM for iron(II). However, the selectivity of this probe for iron(II) remains to be established as indicated earlier in this review. Additionally, a far-red probe  was reported as an effective imaging probe for the detection of Fe(II) levels in mouse models of inflammation [In the context of iron(II)-targeted imaging, Zheng and collaborators developed the fluorescent probe DCI-Fe(II) (19) , which chemistry , being rammation . In a siammation ,102.in vivo imaging, Zhu et al. reported the synthesis of a cyanine-based NIR agent  (N-(2-hydroxyethyl)acetamide groups to specifically chelate iron [in vivo imaging would require further assessment in animal models. Li et al. introduced the iron-targeted NIR probe LS1 (21) (21 (21) can be extensively used for in vivo imaging. In 2019, Kang and colleagues reported NIR probes coupled with deferoxamine (DFO) [m-NPs, 22)  probes for 20, CAM)  equippedate iron . This agLS1 (21) , which u(21) (21  at 777 nne (DFO) . The desNPs, 22) , which iin vivo. The non-invasive nature and high sensitivity of these probes may offer valuable insights into the complexities of iron homeostasis and metabolism, as well as its implications in health and disease. As the field of bioimaging continues to advance, more elaborate and/or effective probes are likely to be developed.These examples demonstrate the diversity and potential of NIR probes for the measurements of iron levels This review provides information on the chemical nature of LIP and outlines the function of this important metabolic pool. The possible variation of LIP chemistry in the cytosol, mitochondria, lysosomes, and nucleus is discussed. The precise chemical structures of the major components need to be identified in biological matrices and this is likely to be achieved by ICP-MS techniques.in vivo conditions will be more difficult, but NIR probes are under development for this purpose. Undoubtedly, the ability to visualize and quantify iron dynamics in living organisms is expected to have a significant impact on the development of targeted therapeutic interventions for iron-related pathological conditions.The potential of using iron-sensitive probes for the quantification of LIP is considered, and a range of applications of such probes is described. The quantification of LIP by the use of iron-specific fluorescent probes is currently under development, but it is now possible to monitor LIP levels in cytosolic, mitochondrial, and lysosomal pools of cells in suspension. Such measurements made under


We evaluated the activity of ceftazidime-avibactam (CAZ-AVI) and aztreonam-avibactam (ATM-AVI) and comparators against common BLs detected in US hospitals.Escherichia coli  and Klebsiella pneumoniae  displaying MIC values ≥ 2 mg/L for at least 2 of the following: ceftazidime, ceftriaxone, aztreonam, or cefepime; (2) Enterobacter cloacae (n=452) and Citrobacter spp. (n=169) displaying MIC values ≥ 16 mg/L for ceftazidime and/or ≥ 2 mg/L for cefepime; and (3) ENT (n=240) displaying elevated carbapenem (meropenem and/or imipenem) MIC results at > 1 mg/L.A total of 21,853 Enterobacterales (ENT) isolates collected during 2020–2021 were susceptibility (S) tested by reference broth microdilution methods. Isolates submitted to whole genome sequencing were: (1) CAZ-AVI inhibited all ESBL-producers  including EC, KPN, and isolates producing CTX-M enzymes (Table). Meropenem-vaborbactam (MEV) inhibited 99.8–100% and ceftolozane-tazobactam (CT) inhibited 67–93.6% of these isolates. ATM-AVI inhibited > 99.4%  of the isolates regardless of the ESBL type or organism. Meropenem S rates against ESBLs ranged from 97.8 to 99.7%. Among other classes, amikacin and tigecycline were the most active agents, inhibiting 78.1% and 97.7% of the ESBL-producing isolates. A total of 97.7% of the isolates had intermediate colistin MIC values. All isolates carrying transferrable AmpC genes were S to CAZ-AVI, ATM-AVI, and MEV and 99.1% were susceptible to meropenem, but only 79.1% were S to CT. These included 82 CMY-producers. Among carbapenemase producers (n=165), CAZ-AVI, ATM-AVI, and MEV susceptibility rates were 81.2%, 98.8% and 80.6%. The only comparator displaying activity against these isolates was tigecycline (93.3% susceptible).Avibactam combinations were active against common BL-producing isolates from US hospitals, including carbapenemase-producing isolates for which therapeutic options are limited. ATM-AVI was the most active agent against carbapenemase-producers when applying the aztreonam breakpoints for comparison.Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Timothy Doyle, MS, AbbVie: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support