The use of both oxygen therapy methods  in combination with SDT corrected the ABS in a shorter time and more effectively, which was due to the better restoration of the carbonate buffer system. Although we did not find proof that novel oxygen-related therapeutic procedures such as NOT and HBO in combination with SDT improved the alcohol withdrawal symptoms, it helped with the faster restoration of the acid-base state.In alcohol withdrawal syndrome (AWS), pathophysiological mechanisms cover acid-base disturbances that affect the clinical picture of this state. An earlier study found that oxygen therapy methods in combination with pharmacotherapy improved the cognitive state in persons suffering from AWS. As impairments in the acid-base state influence the general health, timely and effective correction of these acid-base disturbances could result in a potential improvement in the treatment of the alcohol withdrawal symptoms. Therefore, the aim of this study was to evaluate the effectiveness of non-compressed oxygen therapy (NOT) and hyperbaric oxygenation (HBO) in combination with standard drug therapy (SDT), based on the dynamics of the acid-base state (ABS) in blood during AWS. HBO is the use of oxygen under pressure, whereas NOT uses oxygen without pressure. A comparative assessment of the acid-base state biomarkers was made in 160 patients with a moderate alcohol withdrawal state (3 groups), namely, in patients who underwent SDT only (control group/CG;  Alcohol withdrawal syndrome (AWS) is a result of the several pathophysiological mechanisms. After a sharp cessation of alcohol consumption, the inhibitory effect of ethanol on the central nervous system ends, which leads to an increase in the excitatory effect of glutamate and changes in neurotransmitter systems –4. In AWActive transmembrane electrolyte transport is one of the most important components of the energy-dependent process. Inorganic electrolytes provide up to 96% of the total osmotic pressure of blood , 6. The Patients with alcohol dependence (AD) syndrome have lower serum concentrations of potassium, magnesium, bicarbonate, calcium, and phosphate as well as a lower arterial pH. The severity of AWS correlates with the dynamics of the ABS markers, circulating blood volume, and water-electrolyte balance. Also with AWS, disturbances in homeostasis may occur with acidosis or alkalosis. The causes of the ABS disturbances can be respiratory, metabolic, or a combination of both. Acidosis is a deviation of ABS, characterized by an excessive content of acid anions in the blood and tissues with a decrease in pH –13.Alcohol withdrawal syndrome of any severity requires mandatory treatment for the prevention of severe complications as epileptic seizures, Wernicke encephalopathy or dementia, and the treatment of already developed disorders as malnutrition or electrolyte and acid-base imbalance . For a sHyperbaric oxygen (HBO) therapy involves the use of oxygen under pressure to facilitate tissue healing and has been used routinely for over 40 years in the medicine. Currently, HBO is a well-established therapy for several pathological states including air or gas embolism, carbon monoxide poisoning, decompression sickness, and wounds/soft tissue infections . Tissue As disturbances in ABS can influence overall health , we hypoA total of 160 male patients with moderate AWS were examined. The study group was recruited from people successively admitted to the hospital for the treatment of the AWS. All of the patients suffered from AD and were inpatients receiving treatment at the Republican Scientific and Practical Center for Mental Health in Belarus: 62 people underwent HBO (SG2) and 56 NOT (SG1) together with SDT and 42 underwent only SDT in accordance with the protocols of medical help (CG). Biochemical analyses were carried out on the 1st, 3rd, and 7th day of the treatment.The most recent alcohol consumption of the subjects took place the day before admission to inpatient treatment. Clinical examination of the somatic status was carried out according to the generally accepted scheme. The exclusion criteria were the presence of chronic diseases that might influence ABS biomarkers or contraindications in the HBO: non-alcoholic liver disease, acute and chronic pancreatitis, chronic renal failure, viral hepatitis, metabolic diseases (diabetes), obstruction of the Eustachian tubes, increased body temperature, epilepsy, claustrophobia, oncological diseases, acute inflammatory processes, severe cardiovascular disease, bleeding and trauma, and addiction to psychoactive substances other than ethanol.For the SDT treatment of the AWS, parenterally and orally, diazepam was used, in a dose not exceeding 40 mg/day. In addition, intravenous natrium chloratum injections, multielectrolyte fluids, and glucose were used. In the HBO group, the patients received an HBO session one time a day for 7 days. The pressure in the HBO chamber reached 0.2 MPa (2.0 ATA) and lasted 30 min. At the end of treatment, the pressure gradually decreased over a period of 10–15 min. The patients in the NOT group were, similarly to HBO, put into an HBO chamber one time a day for 7 days, but the NOT patients received oxygen without pressure for the same time period.The study was approved by the local Bioethical Committee of Belarusian State Medical University (N 8/124.15.08.2017) and conducted in accordance with the Helsinki Declaration. Informed written consent was obtained from all the subjects after explaining the nature, purpose, and potential risks of the study.To assess the severity of AWS symptoms, Clinical Institute for Withdrawal Assessment-for Alcohol (CIWA-A) scale was used . In patiClinical verification and diagnosis of AD were carried out by qualified specialists in accordance with the diagnostic (research) criteria of International Classification of Diseases (ICD)-10  presenc.The study of anamnestic data, including the previous features of the course of disease, assessment of the quality, and effectiveness of the clinical dynamics of AWS, was carried out by using the Belarusian index of severity of addiction for clinical use and training  and “scales of dynamics of psychopathological disorders in AWS, post-withdrawal state, remission” , 20. The2 and pO2), saturation , levels of hemoglobin, glucose, Ca++, Na+, actual bicarbonate (HCO3−), extracellular fluid base excess/base excess (BEecf), blood base excess/actual base excess (BEb), standard bicarbonate (SB), total blood oxygen concentration (O2Ct), oxygenation (O2Cap), and alveolar-arterial gradient (D(A-a)O2). The abovementioned parameters were determined by using the routine laboratory methods on the Osmotech OPTI Blood Gas Analyzer. ABS biomarkers were evaluated on the 1st, 3rd, and 7th day of the treatment.The biochemical study included an assessment of blood ABS with the analysis of its most relevant components: pH, partial pressure of carbon dioxide oxygen in the blood  and within the group  by using the t-test. A comparison of the groups by a qualitative binary feature was carried out by using the χ2 criterion, and the odds ratio was calculated. A mixed design ANOVA (3 time-points response × 3 groups) was used to test the differences in acid-base disturbances over the course of the 1st, 3rd, and 7th day of treatment between the SG1 . To assess the normality of distribution, the Kolmogorov-Smirnov test was used. Taking into account the normality of the distribution, the methods of parametric statistics were used. A comparison of the mean values between groups was carried out by using one-way analysis of variance  and urban (60.3%) areas. The educational level was secondary (30.6%), secondary specialized (56.5%), and higher (12.9%). There were no statistically significant differences between the groups in the time of nicotine dependence and number of smoked cigarettes per day (from 94 to 97% were smokers). The time of AD in the groups was: in CG, 17.6 ± 2.2 years; in SG2, 20.9 ± 2.6 years; and in SG1, 16.5 ± 2.1 years (mean ± SD). The average duration of the most recent chronic alcohol drinking period was: in the control group, 14.6 ± 1.7 days; in SG2, 14.6 ± 1.7 days; and in SG1, 13.5 ± 2.3 days, with no statistical differences.+) underwent significant changes during the treatment. Some of these indicators for most of the subjects were within the range of standard values. The data were analyzed in two ways, namely, within-group and between-group differences.The analysis of the levels of blood ABS indicators presented in Although 7 days of therapy in groups with oxygen methods  significantly changed the pH values, its levels did not differ significantly for more than +0.1 from the normal range.3−) in all the groups are higher than the reference ranges (7.35–7.45). Although we found a significant difference during the 7-day period (within-group) of AWS only in HCO3 in the CG group O2.e t-test . Mixed A2, pO2, and SO2 but not for pH, hemoglobin, glucose, Ca2+, and Na+ values. Statistical within-group differences were located only for the number of persons (%) with indicators pO2 < N.2 values decreased significantly.In groups where the methods of oxygen therapy were used, compared with CG, the number of subjects with low pO+) were within the reference ranges in the vast majority of subjects in all the groups, and the applied methods of treatment did not have a significant effect on this indicator.The levels of ionized sodium O2 than the reference ranges. For parameters, such as HCO3− and BEecf, this is relevant from the third day from the start of therapy, and for the rest, from the first day. The data in We found no statistically significant differences between the groups or within groups in the CIWA-A scores  and no correlations between the CIWA-A scores and ABS markers.Evidence of the positive influence of oxygen therapy methods on cognitive functions during the AWS can be found in the medical literature . As we hOur results demonstrate that by the seventh day of therapy in groups with the oxygen therapy methods used in the complex treatment, the results of the pH levels did not differ significantly from the results exceeding the norm by +0.1. The pH index on the seventh day of therapy shows that in the SG1 and SG2 groups, there were phenomena of subcompensated alkalosis, which was not observed in CG , Table 13− levels than the normal/reference ranges (N), with pCO2 levels close to normal or low , which was not observed in the control group.When analyzing the pH indicator, we noticed that subjects with moderate AWS had alkalosis phenomenon , Table 1l or low . In thesunctions . The useBase excess is the metabolic component of ABS dysfunction. A positive value indicates metabolic alkalosis, a negative value indicates metabolic acidosis. The indicator of uncompensated metabolic alkalosis covers an increase in pH above 7.45 and an increase in the following values: BEecf, BEb, and SB. BE is defined as the amount of strong acid that must be added to each liter of fully oxidized blood to return the pH to 7.40 under normal conditions –12. The 2 and pCO2 . In CG, the average group pCO2 was lower than the standard ones . Higher pH values, together with the normal pCO2 values, can confirm the biochemical diagnosis of metabolic alkalosis. A tendency toward observing a decrease in pCO2 in the CG group may indicate a more serious condition . The average group values of SO2 in groups with oxygen therapy from the first day of AWS recovered to the standard values, which could not be seen in the CG group. In CG, the mean group values of SO2 were lower than the reference ranges throughout the entire treatment period . To improve SO2 values in the complex treatment of AWS, the HBO method was a priority, although the use of NOT also made it possible to restore SO2 from the first day of its use. The number of persons (%) with pCO2 under the normal values in CG was also greater (p < 0.05) than in groups with the oxygen therapy. It indicated that the oxygen therapy methods were more effective than only SDT in the correction of the severity of metabolic alkalosis in AWS. In groups with oxygen therapy, compared with CG, the number of subjects with low pO2 values decreased significantly  and oxygen content (O2Cap) starting from the first day of the AWS therapy were within the reference ranges in all the studied groups. The use of the HBO method in complex treatment more effectively influenced these indicators compared with the NOT method in combination with SDT and the use of SDT alone O2 is useful in identifying the source of hypoxemia. This measurement helps locate the problem as either intrapulmonary or extrapulmonary . High values of the A-a gradient are due to impaired oxygen transfer/gas exchange. They are usually associated with diseases of alveolar membrane, diffuse connective tissue diseases, or inadequacy of the ventilation-perfusion ratio. A high alveolar-arterial oxygen gradient may indicate low oxygen tension in mixed venous blood, low cardiac output, high oxygen consumption, or low hemoglobin concentration Oulmonary , 22. Accntration  as well 2+, or Na+ throughout the entire period of care. Even though statistically significant differences in the hemoglobin levels were presented (2+ levels below the reference ranges had no significant positive dynamics in its correction during AWS (+) were within the normal range O2. Although HCO3− values had significant effect only for groups, a significant decrease in HCO3− value only in the CG group and a lack of decrease in oxygen intervention groups  may point on the treatment effect. Therefore, in this case, the lack of effect (as in the case of other ABS markers) may not exclude in fact the effect of oxygen therapy (NOT and HBO). In contrast, it may even indicate a positive oxygen therapy effect.In the mixed ANOVA design, we showed significant interactions for time and groups in the pCOt values . The effSome limitations of this study may be due to the lack of the results of ABS markers in the healthy control group and before the treatment in the SG1, SG2, and CG groups, which could show normal levels of indicators in comparison to the treatment. Another limitation is that only male participants were recruited to the study. Other methodological limitations could also have an impact on our results. The data of our study were analyzed in two ways, namely, within-group and between-group differences. A comparison of intragroup indicators may indicate the possible influence of a method on certain indicators. Intergroup differences may point out the advantages of a particular method on the dynamics of the levels of a certain biological marker. As there were no correlations found between the CIWA-A scores and ABS markers, it might be due to the indirect effect of ethanol metabolites on ABS state and their indirect link with abstinence symptoms.2, and pO2 levels; more effectively restores the saturation levels, starting from the first day of the AWS therapy, with the relative priority of the HBO method; reduces the D(A-a)O2 levels much more effectively from the first day of therapy in comparison with the use of SDT alone and restores oxygen deficiency; and more effectively includes reserve capabilities of the body for the restoration of ABS mainly due to the bicarbonate (hydrocarbonate) buffer system. We can also conclude that the applied methods of treatment in all groups did not significantly affect the indicators of excess of bases, actual hydrocarbonate, and standard bicarbonate, which might be quite acceptable in metabolic alkalosis. Although the novel oxygen-related therapeutic procedures such as NOT and HBO in combination with standard drug therapy did not improve the alcohol withdrawal symptoms, it helped with the faster restoration of the ABS state. Further studies, with a control group before the oxygen therapy, should elaborate more extensively on the time and group effects of oxygenation on the AWS.We found that subjects with moderate AWS had metabolic alkalosis phenomena. The use of oxygen therapy methods in combination with SDT in comparison to SDT alone allows for faster and more efficient correction of the markers of the metabolic alkalosis, as evidenced by the dynamics of the pH, pCOThe original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Local Bioethical Committee of Belarusian State Medical University (N 8/124.15.08.2017). The patients/participants provided their written informed consent to participate in this study.DK and AK: conceptualization. DK, AK, IK, and LK: data curation and formal analysis. DK, AK, and IK: investigation and methodology. AK: project administration and supervision. DK, AK, IK, NW, and LK: writing–original draft. NW: writing–review and editing. All authors contributed to the article and approved the submitted version.This study was supported in part by grants from Belarusian State Medical University (Belarus) and from Medical University of Bialystok .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Using the previously developed cell model of a charged membrane and the principles of linear thermodynamics of irreversible processes (the Onsager approach), exact and approximate  analytical formulae for calculating the osmotic and electroosmotic permeability of the membrane in aqueous solutions of 1:1 electrolyte at constant electric current density and concentration gradient were suggested. The formulae have been successfully verified by our own experimental data for the extrusion cation-exchange membrane MF−4SC p.29 in NaCl solution up to concentrations of 3 M. The contribution of electroosmotic and osmotic water fluxes to the total water transport through the mentioned individual perfluorinated ion-exchange membrane under conditions close to the process of electrodialysis concentrating was experimentally estimated. The cases of co- and counter-directed osmotic and electroosmotic water fluxes are studied. A good correspondence between theoretical and experimental results was obtained, which made it possible to determine the physicochemical parameters of the electromembrane system . The achieved results make it possible to fully characterize existing and promising types of ion-exchange membranes based on the developed cell model of a charged membrane. Determination of the coefficients of osmotic and electroosmotic permeability of membranes whose matrix carries a fixed charge is an important task in the characterization of both commercially available and new composite and hybrid ion-exchange materials obtained by modifying their properties by adding various organic or inorganic dopants. However, when studying the transport properties of membranes, the question often arises—were experimental measurements of these characteristics carried out correctly? This question can be answered from the point of view of thermodynamics of nonequilibrium processes  by apply2O/F0 (F0 is the Faraday constant). The overestimated value obtained was explained by the authors so that it is not the primary solvation number but determines all the water that migrates with the ion when an external electric field is applied—that is, the dynamic hydration number. In [As early as 1956, attempts were made to separate the total flux of water carried through the membrane when an external electric field was applied to water in the composition of solvate ion shells and free water . PerfluoDw = 2.04 × 10−10 m2/s, which is associated with the difference in osmotic pressure caused by the ionic concentration gradient on both sides of the membrane. This value is about an order lower than the diffusion coefficient of water in a pure solution. In the same work, it was shown that the electroosmotic transfer of water is proportional to the applied current density, does not depend on the concentration gradient across the membrane and is 6.4 (±1.5) mol H2O/F0. In [Interest in the research of electroosmotic and osmotic water transfer in ion-exchange membranes is associated with their application in electrodialysis apparatuses, where the fluxes of free and bound water are a negative factor that leads to the dilution of the process solution. It was shown in ,4 that dO/F0. In , the totO/F0. In  determinIn a recent paper , we onceIn recent years, alternative energy sources, including solid polymer fuel cells, the heart of which is a perfluorinated cation-exchange membrane of the Nafion type, have become an important subject of research ,11,12. CDue to the complexity of experiments to determine the total flux of water, as well as the separate determination of electroosmotic and osmotic fluxes through ion-exchange membranes, the question of the theoretical determination of these characteristics, knowing other properties of membranes, has always been on the agenda ,30,31,32Due to the fact that a theoretical assessment of the mechanism of water transfer in membranes is possible only for a membrane pair in an electrodialysis device, the question of determining the contributions of osmotic and electroosmotic water transport to the total water transport through an individual membrane has remained open until recently. To solve this problem, we performed experiments under conditions close to the real electrodialysis process but with an individual membrane of Nafion type (MF−4SC). In this paper, for the first time, we suggested analytical formulae for determining the osmotic and electroosmotic permeability of a real and ideal cation-exchange membrane as a function of an equilibrium concentration of electrolyte. These formulae were obtained based on the cell model of a charged membrane ,33,34,35C0 is the equilibrium concentration of electrolyte in the cell, R is the universal gas constant, T is the absolute temperature, and the indices “1” and “2” indicate the left and right sides of the membrane located in the measuring cell filled with an electrolyte solution.When modeling nonequilibrium isothermal processes occurring in an idealized membrane consisting of identical porous cells , it is ch, the diffusion The membrane is characterized by the thickness Thermodynamic forces are set independently in the experiment. As dependent thermodynamic parameters measured in the experiment, we will use the flux densities of (1) solvent olyte) J . Then thKinetic coefficients lated in ,33,34,35lated in ,31.Here we will consider only the transfer of solvent (water) through a charged membrane under the combined action of gradients of electrical and chemical potentials and the absence of a pressure drop across the membrane:U can change sign since the current density, in this case, is equal to U:It follows from relation (2) that, depending on the directions of the gradients of the electrical and chemical potentials, the solvent transfer rate We introduce permeabilities at a constant value of direct current:And at a constant gradient of chemical potential (concentration):Since F0 is the Faraday constant, m0 is the macroscopic porosity of the membrane, kD is the specific hydrodynamic permeability of the ionite grain (gel), µo is the viscosity of the solution.Formula (6) allows calculating the solvent flux through the membrane when applying both direct current and a concentration drop. At the same time, for the electroosmotic and osmotic permeability of an ideal negatively charged (cation-exchange) membrane, we have the following formulae, respectively,e system ,33,34,35In the general case of non-ideal membranes, formulae that are analogous to (7) and (8) are significantly complicated and can be obtained using expressions (4) and (5) and the kinetic coefficients lated in ,34,35.Formula (6), when divided by a molar volume of water, Here, for the sake of brevity, new dimensionless parameters are introduced:From expressions (11) and (13), it is possible to obtain a relationship between water transport numbers having different natures:+ ion decreases by almost 40%. This is due to a decrease in the amount of water in the hydrate shell of the sodium ion with an increase in the concentration of the external electrolyte solution.The obtained experimental data for the total water flux and the contributions of osmotic and electroosmotic mechanisms of water transport through the extrusion MF−4SC p.29 membrane are presented in Thus, for the MF−4SC p.29 membrane, the contribution of the electroosmotic component to the total water flux was calculated, which decreases from 70% to 45% with an increase in the difference of solution concentrations on both sides of the membrane from 0.45 to 2.7 M. Under these conditions, the value of the osmotic water flux increases by 40%, and the electroosmotic flux decreases by 30–40%.3 and its macroscopic porosity m0 = 7.7%. The remaining physicochemical parameters of the cell model were found using a special procedure for the one-time minimization of the deviation of the experimental values of the electroosmotic and osmotic transport numbers from their theoretical values. To do this, we used exact formulae for the specified transport numbers, which are not given here due to their bulkiness. The numerical procedure is similar to the one described in our paper [C10) and on the right (C20) sides of the membrane was chosen as the equilibrium concentration C0.The experimental data presented in ur paper . ApproxiL13, the dependence of which on the concentration is plotted in L13, there should be no pressure and electric potential differences on the membrane, and the potential chemical difference should remain constant. At the same time, it follows from formulae (5) and (13) that under constant current density and constant concentration gradient, osmotic permeability and osmotic transport number of water can have negative values at low electrolyte concentrations. The second reason for this unexpected effect may be the insufficient accuracy of the applied theory at very low concentrations when the thickness of the electrical double layers cannot be neglected. Note that the monotonous drop in the electroosmotic number of water transport with an increase in the equilibrium concentration of the electrolyte, recorded in 1), was also observed for the heterogeneous cation-exchange membrane MK-40, studied in the work already mentioned above [As can be seen from ed above . As can The same parameter values  were useAs can be seen from It should be noted that the developed water transfer model is applicable to any charged membranes, including those used in electrobarofiltration. In particular, our cell model will allow calculating water transfer due to the simultaneous action of pressure and electrical and chemical potential gradients when using promising electrospun nanofibrous membranes utilized for water and wastewater treatment .h = 220 microns.The object of research was extrusion perfluorinated sulfonated cation-exchange MF−4SC p.29 membrane . The thickness of the membrane was equal to Deionized water and NaCl  were used in this experiment to obtain the salt solutions of the needed concentration.3. The Ag/AgCl polarizing electrodes (3) were incorporated into the cell chambers. The cell hermetic was achieved by means of thin rubber spacers between the cell chambers and was tested after each filling with electrolyte solution through funnels (7), the cell being without current flow for 30 min. The ratio of electrolyte concentrations on different sides of the membrane was 10. To reduce the possibility of concentration polarization, magnetic stirrers (4) were used in the cell chambers. Special attention during the experiments was paid to the state of reversibility of the polarizing electrodes (3). The investigated membrane was fixed between the cell chambers, and the system was checked for pressurizing; after that, a direct current was passed through the membrane from a DC source (5), and the changes in the liquid volume in the capillary tubes (2) were registered as a function of time. The meniscus movements were followed in both capillaries and gave results for the rate of the water flux, which agreed within a 1% error. Measurements were repeated at each concentration several times, and the current was inverted after each run.The measurement of the total water flux is made based on the change in solution volume when passing a certain current through the investigated membrane (1). The cell consisting of two compartments equipped with measuring graduated capillaries (2) is shown in So, the total water flux ber cell  with theV in the capillaries of the cell at given current density I during the time τ were used to calculate the total S is the working area of the membrane . The current strength (30 mA) was kept constant, which was equivalent to the current density I = 168.7 A/m2.The obtained values of the change in the volume of solution C10/C20 on different sides of the membrane was equal to 10. The osmotic flux was calculated from Equation (16) also using the obtained experimental data of the change in the volume of solution V inside the capillaries.Osmotic flux ame cell  under thReal electromembrane processes of concentrating electrolytes are carried out both in concentration and in electric fields. As a result, various fluxes appear in the electromembrane cell: diffusion, electroosmotic, and osmotic. The electroosmotic flux Based on the cell model of a charged membrane, analytical formulae for calculating the osmotic and electroosmotic permeability of the membrane in aqueous solutions of 1:1 electrolyte at constant electric current density and constant concentration gradient are suggested, which are exact for a real membrane and approximate for an ideally selective membrane. The exact formulae obtained have been successfully verified on our own experimental data for the extrusion cation exchange membrane MF−4SC p.29 in NaCl solution up to concentrations of 3 M. The cases of co- and counter-directed osmotic and electroosmotic water fluxes are considered. A good correspondence between theoretical and experimental results was obtained, which made it possible to determine the physicochemical parameters of the electromembrane system . The proposed model can be easily used to calculate osmotic and electroosmotic water transfer through an arbitrarily charged membrane  with the combined superposition of electric and concentration fields. The results obtained here make it possible to completely characterize existing and promising types of ion exchange and other charged membranes based on the developed cell model of a charged membrane.


In this research, the typical residential area of Lhasa in Tibet was taken as the research object, the experimental scheme was prepared using an orthogonal test, and the simulation was carried out using ENVI-met to explore the influences of the green configuration, water area, and ground reflectance, as well as their interaction with the thermal environment in winter and summer under alpine climate conditions. Taking the physiological equivalent temperature (PET) as the optimization index, the optimal design scheme for the synergistic effect of the residential landscape elements was determined. The results were as follows. (1) The order of the landscape configuration factors was as follows: green configuration > water area > leaf area index > ground reflectance in summer. In winter, the order was green configuration > water area > ground reflectance > leaf area index (LAI). (2) With the combined driving of the orthogonal test and the numerical simulation, the optimal scheme of the landscape elements was determined, which was “tree shrub lawn, water area ratio 16%, ground reflectance 0.5, and LAI = 3 m According to the sixth report of the Intergovernmental Panel on Climate Change (IPCC), global warming caused by human activities is 1.0 °C higher than before industrialization, global warming is continuing, and the risk of extreme weather events is further increasing . The urbDetermining how to create a healthy outdoor thermal environment based on nature-based solutions has become a hot research topic, and it is particularly important to improve the outdoor thermal environment in residential areas because they are the basis for many outdoor activities. The landscape environmental factors that are closely related to the outdoor thermal environment and thermal comfort of a residential area mainly include greening, water bodies, and underlying surface. In terms of greening, in hot and arid areas, choosing trees that can reduce solar radiation is the most effective urban design strategy for reducing physiological equivalent temperature (PET) . The res(1)To clarify the primary and secondary effects and advantages of various landscape elements on an outdoor thermal comfort under high altitude and cold climate conditions.(2)To clarify the synergistic relationship between landscape elements and their interaction with outdoor thermal comfort under high altitude and cold climate conditions.(3)To put forward the experimental scheme and strategy of landscape element allocation optimization in a residential area for the conditions of high altitude and a cold climate.Based on the above literature review, we found that the impact of landscape elements on the regional thermal environment in different climatic zones has been studied many times before, and that their research results were also different from each other, but studies of the synergy mechanism between various landscape elements are still relatively lacking. Each city is in a specific regional atmospheric environment, and the differences in urban climate affect the mechanism of improvement of landscape elements for the outdoor thermal environment. China’s Tibet region is affected by its special geographical location, climatic conditions, and religious culture. The impact of landscape elements on the thermal environment is different from those of other climatic zones. Local residents carry out a large number of outdoor activities every day, and frequent and long-term outdoor activities put forward higher requirements for the outdoor environment. However, there are relatively few studies on high-altitude cold climate zones, and it is difficult to provide theoretical support for improving the quality of the living environment in extremely cold climates. Therefore, in this study, in order to better understand the impact of residential landscape elements on the outdoor thermal environment and thermal comfort in a high-altitude cold climate area, taking Lhasa as an example, the thermal environment of a residential area with different landscape element configurations was numerically simulated based on the orthogonal experimental design method. The PET was taken as the optimization objective, and the simulation results were analyzed with intuitive analysis and variance analysis. The main objectives were as follows:Lhasa is located in the middle of the Qinghai Tibet Plateau, with an altitude of 3650 m. The plane of the city of Lhasa is distributed in a belt from east to west. Two mountains (South Mountain and North Mountain of Lhasa) sandwich the city, and a river (Lhasa River) passes through the city. It is a typical axial development city , as showIn this research, 60 residential areas were investigated and analyzed based on the following two factors . (1) ArcThe Lhasa area is affected by strong radiation, and the demand for shade space in summer is greater than that in winter. There is also a greater objective demand for the comfort of the outdoor space thermal environment in summer and winter . In thisThe research framework of this study is shown in According to previous survey data, in this research, the residential area model of parallel north–south layout was set, with a single building height of six stories, a total building height of 18 m, a building surface width of 70 m, and a depth of 15 m. The space between the buildings was 24 m in the north–south direction and 6 m in the east–west direction, and the width of the roads around the residential area was 10 m. Considering the influence of the boundary of the building model on the simulation area, half blocks were added around the simulation center. The entire simulation area was 250 m × 150 m × 38 m, the number of grids was 50 × 50 × 38, and the unit grid size was 5 m × 3 m × 1 m. The standard model was initially established, as shown in 2/m3. Therefore, we set the LAI to 1, 3, and 5. Thus, D then stands for different LAIs based on the JX-A1 condition. The factors and their level simulation conditions are shown in With the premise that the green area of the public green space was not less than 70% , A stand13) was selected to prepare the test plan. There were 81 comprehensive test schemes for the four-factor, three-level model. After the orthogonal test method was used, only 27 representative working conditions for In this research, an orthogonal standard table L27  . Rayman The PET values of the four factors at three levels and their average values were calculated in order to draw the PET trend diagram . The res2/m3 in the morning was the best, LAI = 5 m2/m3 in the afternoon and evening was the best, and the order of the optimal levels was LAI = 5 m2/m3> LAI = 3 m2/m3 > LAI = 1 m2/m3. The results showed that: (1) The tree, shrub, and lawn, and shrub + lawn combination modes were the best in the morning, the tree + shrub + lawn combination mode was the best in the afternoon, and the tree + lawn combination mode was the worst in winter. Considering the greater demand for sunshine space in the Lhasa area in winter, the comprehensive ranking of its level was tree + shrub + lawn > shrub + lawn > tree + lawn. (2) The ground reflectance of 0.5 in the morning and afternoon was the best, and the order of its levels was ground reflectance 0.5 > ground reflectance 0.3 > ground reflectance 0.2. (3) The water area proportion was negatively correlated with the PET, and the PET decreased with the increase of the water area. (4) The LAI = 3 m2/m3 in the morning and afternoon was the best, and the order of the best levels was LAI = 3 m2/m3 > LAI = 1 m2/m3 > LAI = 5 m2/m3.The level indexes of each factor, K1, K2, and K3, and the average values K1, K2, and K3, were compared, and the ranking of the superior level of each factor was analyzed. In summer, the comfortable range of the PET was selected as the optimal target: (1) For the greening configuration, the combination mode of tree + lawn and shrub + lawn was the best in the morning. The combination mode of tree + shrub + lawn was the best in the afternoon and evening, and the order of its level was tree + shrub + lawn > tree + lawn > shrub + lawn. (2) The ground reflectance of 0.5 was the best in the morning, and that of 0.3 was the best in the afternoon and evening. The order of the levels was ground reflectance 0.3 > ground reflectance 0.5 > ground reflectance 0.2. (3) The proportion of water area was negatively correlated with the PET, and the PET decreased with increasing water area. (4) For the leaf area index of the trees, LAI = 1 mThe statistical product service solutions (SPSS) statistical analysis software from IBM was used to analyze the significance of each influencing factor. The version of IBM SPSS statistics 22 was adopted in this research. The analysis of variance is shown in On a summer morning, the Sig. values were less than 0.05, except for the interaction between the green configuration and the ground reflection and the interaction between the water area and the ground reflection, which had a significant impact on the PET of the outdoor public activity space in the residential area. According to the F value, the significant order of the influencing factors was green configuration > water area > ground reflectivity > leaf area index of trees > interaction between green configuration and water area. The influence of the factors on the test indexes was significantly enhanced in the afternoon and evening, and the interaction between the greening configuration and the ground reflectance was not significant. The significant order of the influencing factors was greening configuration > water area > leaf area index of trees > ground reflectance > interaction between surface reflectance and water area > interaction between greening configuration and water area.In winter, except for the interaction between the greening configuration and the ground reflectance, the Sig. values were less than 0.05 in the morning, which had a significant impact on the PET in the outdoor public activity space. According to the F value, the significant order of the influencing factors was greening configuration > water area > ground reflectivity > leaf area index of trees > interaction between water area and ground reflectance > interaction between greening configuration and water area. In the afternoon, the order of influencing factors was greening configuration > water area > ground reflectivity > leaf area index of trees > interaction between ground reflectance and water area.j, and its interactions, are shown in The contribution rate of each factor ρIn general, the green configuration and the water area in winter and summer played a decisive role in the thermal environment of the outdoor activity space in the residential area. In summer, the improvement effect of the water area gradually increased with time, and the improvement effect of the ground reflectance and leaf area index of the trees was weaker than the other two factors. In winter, the influence of the ground reflectance and LAI of the trees on the PET was weaker than that in summer. Among the three interactions, the interaction of the water area with the green configuration and the ground reflectance had a more obvious influence on the PET in summer, the interaction of the water area with the ground reflectance had the most obvious influence on the PET in winter, and the interaction between the green configuration and the ground reflectance had less influence in winter and summer. Therefore, in the selection of the best combination of interaction factors in future research, the interaction between water area, greening configuration, and ground reflectance should be considered.It can be seen from the above that the factors with significant interactions were the water area and the greening configuration, as well as the water area and the ground reflectance, i.e., A and B, as well as B and C. The calculation results for the interaction of the PET average values corresponding to each factor level in winter and summer and the three periods are shown in s and PETw represent the weighted average calculation values of the PET in summer and winter, respectively. By comparing the ratio of the PET in winter and summer, the optimal allocation scheme of the outdoor activity space in the residential area in winter and summer was comprehensively evaluated. The smaller the ratio was, the better the experimental scheme was in winter and summer. The plane diagram for winter and summer and the comprehensive optimal scheme are shown in 2/m3”; the optimal test scheme was 21 in winter, that is, “tree-shrub-lawn, water area 16%, ground reflectance 0.5, LAI = 3 m2/m3”; the optimal test scheme for two seasons was 21. The weighted averages of 27 test schemes were calculated and sorted according to the advantages and disadvantages of the test schemes. The optimization results are shown in Therefore, the optimization results for the summer and winter test schemes were as follows: (1) For the combination of tree + shrub + lawn, the greening configuration was the best in the two seasons. The planting of trees and shrubs should follow the principle of “shading in summer and wind prevention in winter”. Planting tall deciduous trees on the west side of the activity site could not only cause the activity space to have more sunshine in the morning, but also form the shade space in the afternoon or evening. (2) For the water area, the appropriate area of the water body should be set up according to the needs of the users of the active space and with the premise of ensuring the scope of the activity. In addition, the interaction between the water body and the trees is significant, and the combination of the water body and the trees could enhance the improvement of the thermal environment. (3) For the ground pavement, it is advisable to choose lower-surface materials with relatively high reflectivity and high permeability, such as permeable brick, grass planting brick, or a light-colored granite floor. (4) The LAI of trees was not suitable to be too large or too small, which could meet the requirements of shade in summer and sunshine in winter.2/m3” were the optimal levels of various landscape elements. This result was also confirmed by existing studies, but there were also some differences. For example, by studying the thermal acceptability of residents for different landscape element configurations, Li. confirmed that the setting of shrubs improved the outdoor space acceptance rate in winter but reduced the outdoor thermal acceptance rate when the solar radiation was strong in summer. High reflection ground reduced the heat acceptance rate of outdoor space in summer and improved the heat acceptance rate of outdoor space in winter 24], and n winter . The resn winter  showed tn winter , showed n winter  were alsg layout , the morg layout , the difg layout ,42, and g layout . Therefo(1)Green configuration was the key factor affecting the residential outdoor thermal environment, followed by the water area. The improvement potential of the tree leaf area index and ground reflectance on outdoor thermal comfort was relatively weak.(2)The interaction between the water area, greening configuration, and ground reflectivity affected the thermal comfort of outdoor public spaces in residential areas.(3)2/m3”.In winter and summer, the optimal landscape element allocation scheme for the outdoor activity space in the residential area of Lhasa for the conditions of high altitude and cold climate was as follows: “arbor + shrub + lawn”, “water area of 16%”, “ground reflectance of 0.5”, and “tree leaf area index of 3 mThrough the analysis and discussion of the impact of the landscape element configuration of outdoor activity space on the thermal comfort in residential areas in Lhasa, the following three conclusions were drawn:Based on the above conclusions, the appropriate landscape element combination scheme was determined according to the functional requirements with the objectives of climate suitability, comfort, energy conservation, and functionality. The optimization scheme could directly refer to the optimized layout mode shown in


Curcumin has been demonstrated to exhibit photosensitized bactericidal activity. However, the full exploitation of curcumin as a photo-pharmaceutical active principle is hindered by fast deactivation of the excited state through the transfer of the enol proton to the keto oxygen. Introducing an asymmetry in the molecular structure through acting on the phenyl substituents is expected to be a valuable strategy to impair this undesired de-excitation mechanism competing with the therapeutically relevant ones. In this study, two asymmetric curcumin analogs were synthesized and characterized as to their electronic-state transition spectroscopic properties. Fluorescence decay distributions were also reconstructed. Their analysis confirmed the substantial stabilization of the fluorescent state with respect to the parent compound. Nuclear magnetic resonance experiments were performed with the aim of determining the structural features of the keto–enol ring and the strength of the keto–enol hydrogen bond. Electronic structure calculations were also undertaken to elucidate the effects of substitution on the features of the keto–enol semi-aromatic system and the proneness to proton transfer. Finally, their singlet oxygen-generation efficiency was compared to that of curcumin through the 9,10-dimethylanthracene fluorescent assay. In thoperties ,10,11,12operties ,14 and coperties ,16, to aoperties ,18 and aoperties ,20 propeoperties , since toperties ,23,24. Loperties ,26,27. Msic ones ,29, to bsic ones ,33,34,351 as a photosensitizer is hindered by the occurrence of a plethora of deactivation mechanisms involving, as a common feature, the transfer of the enol proton to the keto oxygen in the first excited singlet state, S1, with concomitant dissipation of the excitation energy to overcome the excited-state intramolecular proton transfer (ESIPT) reaction activation potential barrier and relaxation to the ground state [1 explicates its photosensitized activity are not fully understood yet [1 would, in any case, enhance the probability for any phototoxic reaction to take place. The stability of the S1 state and the excited-state dynamics of a fluorophore can be probed through the measurement of its time-resolved fluorescence decay distribution [1 was the object of several in-depth time-resolved fluorescence studies [1 average fluorescence lifetime is in the range of tens to hundreds of picoseconds in a wide range of organic solvents differing in polarity and hydrogen-bonding properties, with the main non-radiative decay mechanism being ESIPT and the rate-limiting step of this mechanism being the rearrangement of solvent molecules that partially quench keto–enol intramolecular hydrogen bonding (KEIHB). During the last decade, our group has been engaged in the characterization of the excited-state dynamics and reactive oxygen species (ROS)-generation efficiency of several naturally occurring as well as synthetic curcumin analogs [On the other hand, the full exploitation of nd state ,42,43,44tood yet ,46, the ribution ,48. In t studies ,38,49,50 analogs ,42,43,442 and 3  experiments were performed with the aim of determining the structural features of the keto–enol ring and the effects of solvent on the KEIHB strength. Electronic structure calculations were also undertaken to elucidate the effects of substitution on the features of the keto–enol semi-aromatic system and the proneness to proton transfer. Finally, the relative efficacy of 2 and 3 compared to curcumin in photosensitizing the production of ROS in vitro was preliminary assessed through the 9,10-dimethylanthracene (DMA) fluorescent assay.In the present study, the two asymmetric curcumin analogs nd 3 see  were syn2 are reported hereafter. The same studies performed on compound 3 are detailed in The spectral properties of 2 were acquired in all of the solvents of 1 as well as other curcuminoids and β-diketones [The absorption spectra of iketones ,43,44,522 appear to be only slightly dependent on the environment, although a modest red shift and a loss in structure is observed by changing from inert (cyclohexane and toluene) to reactive environments. This behavior partially contrasts with that of 1 , for which the benchmarks of the environmental properties were more evident in the spectral features. Indeed, an additional shift to longer wavelengths was observed in the absorption peak by dissolving the compound in H-bonding compared to non-H-bonding solvents. The absorption peaks of 1 in the different solvents are reported beneath the ones of 2 in The NMR spectroscopy and in silico calculations support the above conclusion (vide infra). The absorption peak wavelength in the various solvents is reported in 2 as detailed in the Materials and Methods section in all solvents excluding cyclohexane and ethylene glycol, where the low solubility of 2 forced us to filter the sample prior to spectrum acquisition in order to avoid severe scattering. It is in the range of 30,000 M−1cm−1 and does not appear to depend systematically on the solvent properties.The molar extinction coefficient at the absorption peak was determined for 2 are broad and structureless, with the exception of those acquired in non-polar solvents in which two distinct bands can be resolved. In toluene, the spectrum exhibits two peaks, while in cyclohexane, the longer-wavelength band appears as a shoulder. The peak emission wavelengths are reported in 1, the dependence is not trivially amenable to bare polarity effects. Indeed, in H-bonding solvents , fluorescence is systematically red-shifted with respect to polar weakly H-bonding solvents of comparable polarity. Nonetheless, the solvent-induced red-shift is much reduced for 2 with respect to the parent compound ,Reketonization (occurring in non-polar solvents and triggered by the lower polarity of the trans-diketo with respect to the enol tautomers),Solvent rearrangement-moderated ESIPT ,Intermolecular charge/energy transfer with H-bonding solvent molecules.The fluorescence decay of solvents . In the solvents  and conssolvents ,42,43,442 in terms of the same mechanisms. It turns out that direct ESIPT occurs only in cyclohexane, with a decay time similar to that measured for 1, but with much lower probability. Concomitantly, reketonization occurs on timescales very similar to those measured for 1, but with higher probability. The same considerations also hold true in the second non-polar solvent we tested, toluene, in which 1 was not previously characterized. Its decay is two-exponential, with time constants τ1 < 30 ps and τ2 = (332 ± 2) ps, and relative amplitude of the shortest component f1 = 0.72 ± 0.02, while for compound 2, the shorter decay component is not even resolved, suggesting that direct ESIPT takes place with negligible probability and the main decay mechanism is reketonization. The net effect is a two-fold increase in the average S1-state lifetime in non-polar environments  [2 than for 1 in all of the solvents except butanol. However, concomitantly, fluorescence photons are emitted at a higher rate by the former compound.The calculated values of ctively) . The non3 were acquired in all of the solvents of 3, the keto–enol equilibrium seems to be shifted towards the enol tautomers, with the diketo tautomers appearing at most in traces, as confirmed by both the NMR and in silico calculations (vide infra). The absorption peak wavelength in the various solvents is reported in 3 are slightly, though systematically, blue-shifted with respect to those of both 1 and 2, which might indicate a reduced charge conjugation in 3. Interestingly, the same observation pertained to dicinnamoylmethane (DCMeth), a symmetric, non-phenyl substituted curcuminoid [abs,DCMeth in the third column of The absorption spectra of cuminoid , whose a3 are less dependent on the environment than those of both 1 and 2, although a loss in structure can be still observed by changing from inert (cyclohexane and toluene) to reactive environments. This behavior is, again, similar to the one exhibited by DCMeth [Moreover, the spectral features of y DCMeth .3 in all tested solvents is in the range of 30,000 M−1cm−1 and does not appear to depend systematically on the solvent properties. Moreover, it is slightly, but systematically, lower than that of 2, stemming from further support of a reduced charge conjugation in 3.The molar extinction coefficient of 3 in the different solvents of abs, are reported in The peak fluorescence emission wavelengths of 1 rather than of DCMeth. First, the spectra of 3 are broad and structureless, with the exception of those acquired in non-polar solvents. In cyclohexane, the spectrum exhibits two peaks with a further shoulder at long wavelengths, while in toluene, the spectrum consists of a main peak and a red-shifted shoulder. Conversely, those of DCMeth were double-peaked in all of the tested solvents , the fluorescence is systematically red-shifted with respect to polar weakly H-bonding solvents of comparable polarity. The fluorescence quantum yield of 3 (see fourth column in 1 in non-polar (cyclohexane and toluene) and slightly polar (chloroform and dichloromethane) solvents, while it is comparable in highly polar environments and sizably lower in H-bonding solvents with the only exception of ethylene glycol. The comparison with 2 unravels a systematic reduction in the quantum yield for 3 with respect to the other asymmetric compounds, which might correlate with the specific phenolic substituents. Indeed, DCMeth was characterized by a particularly low quantum yield in all solvents [Unlike the absorption spectra, the emission spectra appear to resemble those of solvents  , are also listed in the fifth column.The best-fitting parameters retrieved from the fit of the experimental decay distributions measured for 2 is observed, with 3 displaying a three-exponential decay pattern in cyclohexane and an essentially single-exponential decay in toluene. However, in cyclohexane, the ESIPT rate appears to be much faster for 3 than for both 1 and 2, and is comparable with that measured in DCMeth. Moreover, the relative probability of 3 to decay by means of direct ESIPT is comparable with that measured for 1, and is much higher than that of 2. Reketonization occurs on timescales similar to those typical of both 1 and 2, and faster than for DCMeth.In inert environments, a behavior similar to that of 3 is comparable to that of 1 and inferior to that of 2 . Conversely, in toluene, like for 2, the main decay transient has the time constant typical of reketonization dynamics. The effect is a two-fold increase in the average S1-state lifetime of 3 with respect to 1 in this solvent. In both non-polar solvents, the presence of traces of the non-polar trans-diketo isomer is denounced by the longest-lived component.The net effect is that the overall stability of the excited state of 3 seems to exhibit a behavior similar to that of 1. The decay patterns are essentially single-exponential, suggesting that solvent rearrangement-moderated ESIPT is the main decay mechanism. This latter occurs systematically on faster timescales with respect to both 1 and 2. The residual, long-lived component resolved in the weakly polar solvents chloroform and dichloromethane (ε < 10) can be ascribed to traces of anti-diketo isomer, which were also observed in DCMeth in solvents of comparable polarity. The survival of traces of 3 in the trans-diketo isomer even in mildly polar environments agrees with a reduced polarity difference between the latter and the enol tautomers with respect to 1 and 2.In polar, weakly H-bonding solvents, 3 are multi-exponential in most of the other solvents, revealing complex and hardly interpretable deactivation photophysics. In H-bond-accepting solvents, benchmarks of the DCMeth excited-state dynamics are recognizable in the decays of 3. Indeed, for both 3 and DCMeth, the fluorescence decay patterns in DMF and DMSO are dominated by a transient with time constant in the range typical of direct ESIP mechanisms. Some valuable hints can be extracted from this analogy. Indeed, in the case of DCMeth, the enhanced proneness to decay by direct ESIPT in any environment was ascribed to the formation of a particular variant of the closed enol tautomer having c2ν symmetry, in which the enol proton resulted in being delocalized and equally shared between the two keto oxygens, together with the closed enol structure with the enol proton localized in proximity to either one of the two keto oxygens adopted by 1 and several other curcuminoids. In particular, because in the c2ν structure the enol proton is more acidic, the latter is expected to be dominant in H-bond-accepting solvents, where a transient transfer of the enol proton to the H-bond-accepting moieties might be responsible for fostering the exchange of the proton itself between the two keto oxygens. This mechanism was invoked in [3 in H-bond-accepting solvents suggests that, as in DCMeth, the keto–enolic ring is more likely to assume the symmetric c2ν structure than in 1 and 2. Moreover, explicit-solvent simulations on 3’s interactions with DMF unraveled a sufficiently strong affinity between the enol proton of 3 and the solvent carbonylic oxygen (with an equilibrium distance of 2.43 Å) to distort the hydrogen-bonding structure, reducing the enolic O–H distance by 0.03 Å and increasing the distance between the proton and the ketonic oxygen by 0.22 Å. In our view, this finding suggests a reduced likelihood for the direct ESIPT and prefigures the transient solute–solvent proton transfer described above as being likely to take place for 3 as well. A second transient accounts for roughly 1/3 of the excited-state deactivation events and has a lifetime in the range of a few hundred picoseconds, typical of the solute/solvent charge/energy transfer dynamics observed in H-bonding solvents for DCMeth, 1, and 2. Finally, a third component is barely detectable, which we ascribe to decay through solvent rearrangement-moderated ESIPT. The latter is similar, in time and amplitude, to the homologous contributions measured in the decays of DCMeth and 2 in H-bond acceptors, while the same deactivation mechanism occurs on significantly shorter timescales for 1, suggesting the formation of a looser intermolecular H-bond between the solvents’ H-bond-accepting moieties and the enol proton in the parent compound.The decays of voked in  to expla1, 2, and DCMeth, as well as for 3 itself in H-bond acceptors, an additional decay component is resolved in methanol and ethylene glycol, whose time constant is in the range typical of direct ESIPT, which was observed in all alcoholic solvents for DCMeth. This suggests that, in the case of these solvents, a sort of bridging interaction between the enol proton, the H-bond-accepting moiety of the alcohol, the protic moiety, and the unshielded keto oxygen might be established. Interestingly, these solvents are those endowed with the highest Kamlet–Taft acidity parameters among those used in this study. Moreover, the bridging effect seems to be most effective in promoting the enol proton transfer in methanol, which is the smallest solvent and is thus more likely to juxtapose between the enol and keto moiety of 3.In alcohols, the decay dynamics seem to depend on the specific solute/solvent interactions. Indeed, although the intermolecular charge/energy transfer dynamics occur in all alcohols on timescales similar to those observed for this mechanism in 3 with respect of 2 and even of 1. However, the electron-withdrawing character of non-substituted phenyl rings in the molecular structure of a curcuminoid was postulated to have a highly destabilizing effect on the excited state [3 compared to DCMeth, the most unstable curcuminoid we have examined until now, which bears non-substituted phenyl rings at both sides of the keto–enol system, and whose average excited-state lifetimes are reported in the last column of The overall effect of these complex excited-state dynamics is to destabilize the excited state of ed state  through flk, and the non-radiative decay rate constant, nrk, from the measured avτ and fluoϕ, according to Equations (2) and (3). The calculated values of flk and nrk in the tested solvents are reported in 1 are listed in 3 than for DCMeth in polar, weakly H-bonding solvents, where it is in the same order of magnitude as that of 1, while in both inert and H-bonding environments, the tendency to decay through non-radiative pathways of 3 and DCMeth are comparable. In all of the solvents, the radiative decay rate of 3 is in the same order of magnitude of that of 1 and is much higher than that measured for DCMeth.The excited-state dynamics can be further investigated by estimating the values of the radiative decay rate constant, 2 and 3 were characterized by 1H and 13C nuclear magnetic resonance spectroscopy in dichloromethane-d2 at room temperature. The 1H spectra are reported in 2) and 3) of the Curcuminoids As can be inferred by the spectra in 13C-NMR spectrum of 2 and 3 clearly revealed two distinct resonances for quaternary C-O carbons, at 183.7 ppm and 183.5 ppm for species 2 and at 184.7 ppm and 182.5 ppm for species 3  by means of 1H-NMR  and H-bond-accepting (dimethyl sulfoxide-d6), revealed a rather small variation in the chemical shift of the enolic proton involved in KEHIB  − δOH enol(CDCl3)) [1, 2, and 3, and was found to be less than 0.1, which confirms the presence of a very strong intramolecular hydrogen bond through a six-membered ring system , as well for the same tautomers of species 2 and 3 in the first excited state (ES), were optimized as indicated in 1, 2, and 3 when in the GS; the structures obtained for 2 and 3 in the ES are quite similar to the one in the GS and are, thus, not shown. De facto, the major difference between the equilibrium geometries in the two electronic states is related to the slight contraction of the enolic O-H bond length upon electronic excitation . Electronic and Gibbs energies relative to the lowest energy species are also provided alongside the structural details. Notice that two isomers are shown for both 2 and 3 as the latter are asymmetric. As for the relative Gibbs energy ordering of the latter, it is invariably found that the most stable isomers have the proton involved in the tautomeric process localized on the side of the phenyl ring whose substituents have been modified; however, in all cases, the energy difference between the two enolic isomers is extremely small, and the two species ought to have quite similar populations. Similar conclusions can be reached by comparing relative electronic energies. Local minimum energy structures were also optimized for diketo tautomers, with the results invariably suggesting the enolic forms to be, at least, 5 kcal/mol (21 kJ/mol) more stable than any of the diketo isomers.Equilibrium geometries for the enolic tautomers of species 2 and 3. In particular, one is led to conclude that the dynamically averaged position of the enolic proton ought to lie symmetrically between the two oxygen atoms involved in the proton transfer in the case of both species.The transition state (TS) geometries for the proton transfer between the enolic tautomers were also located and are shown in 2 and 3 in their first ES. Thus, the electronic energy results suggest that the proton is preferentially located, as in the GS structures, the energy differences between the enolic tautomers are quite small. Our fitting of the ES energies obtained during the relaxed scans along the hydroxyl bond length involved in the proton transfer suggests only small changes in height compared to the GS situation . Consequently, the enolic proton should still be considered fluxional in all cases.Substantially similar conclusions can be reached for the proton transfer process involving 1, 2, and 3 may possibly be correlated with differences in relative acidity between the species, we also estimated the relative energetics involved during the proton exchange between the most stable enolic form of a species with the (anionic) conjugate base of another. Choosing 1 as a common reference, transferring a proton to the conjugate base of 2 and 3 involves, respectively, a change in the standard Gibbs energy of 0.16 and 1.33 kcal/mol. The latter results, hence, appear in good agreement with what was deduced based only on the decay times.To support the analysis and rationalization of the results for the ES dynamics, which suggested the long time component of the ES depopulation process to be ascribable to solvent rearrangement-mediated ESIPT, and that the relative times scales deduced for 1 (red squares), 2 (blue dots), and 3 (magenta triangles) and that measured in the absence of photosensitizer are shown. In both toluene (panel (a)) and acetonitrile (panel (b)), the presence of any of the tested curcuminoids in solution induces a DMA fluorescence that decreases over time more steeply than that measured in their absence. We ascribe this behavior to an increase in the DMA oxidation rate due to photosensitized 1O2 production. Accordingly, the fluorescence versus time patterns were fitted to single exponential decay functions, and the retrieved decay constants were assumed to be proportional to the 1O2 generation rates of the three tentative photosensitizers. Their values are listed in 1O2 generation rates relative to 1 in the same solvent are also reported and compared to the corresponding avτ ratios.In 1O2 generation is not believed to be the main photosensitizing mechanism for curcuminoids, the relative 1O2 generation rates roughly scale with the relative avτ, suggesting that the stabilization of the excited state is indeed a relevant strategy to pursue optimized photosensitized activity for this class of pharmaceutical active principles. The slight discrepancies between the relative 1O2 generation rates and the corresponding avτ ratios may be ascribed to differences in the curcuminoids’ photodegradation rates. Indeed, our control experiments  unraveled that, among the three tested curcuminoids, 1 is the most photolabile in toluene, while 3 is the most photolabile in acetonitrile (data not shown). Most importantly, the scaling only holds once the environment in which the photosensitizing reaction is to occur is fixed, indicating that the environmental conditions are crucial in establishing the extent of production of the reactive species. Accordingly, although the excited-state lifetime is longer in the polar environment, the 1O2 generation appears to be fostered by a non-polar reaction medium.Although it is worth recalling here that Chemicals and samples preparation. Because the significant content of demethoxy and bis-demethoxycurcumin was reported for commercial curcumin samples, pure 1 was synthesized as described in [2 and 3 were synthesized according to the procedure described in [d8, chloroform-d1, dichloromethane-d2, acetonitrile-d3, and dimethylsulfoxide-d6. Deuterated solvents were provided by Merck.ribed in . The asyribed in . In the ribed in , of the Steady-state spectroscopy. The UV-Vis absorption spectra were recorded with a Perkin Elmer Lambda 2 spectrophotometer. The molar extinction coefficients were determined through linear fit of absorbance versus concentration plots. The latter were obtained by measuring the spectra of at least five solutions of different concentrations for each solvent. To this end, a stock solution with concentrations in the millimolar range was prepared by weight, and suitably diluted samples with peak absorbance in the range 0.1–1 were obtained using precision micro-pipettes and cross-checking the volumes by weight.Fl, were estimated relative to a fluorescence standard, namely, a solution of dimethyl-POPOP in cyclohexane (ϕFl = 0.95) [Fl values reported hereafter are averaged over three parallel samples, with errors given by the pertaining standard deviation.The fluorescence emission and excitation spectra were measured with a PTI Fluorescence Master System fluorimeter. This was interfaced with the acquisition software Felix2000, which performed real-time spectra correction with respect to the excitation lamp spectral radiance and the detector quantum efficiency. Fluorescence quantum yields, ϕ = 0.95) . In so d = 0.95) . The ϕFl1H and 13C spectra were acquired at 400 MHz and 100 MHz, respectively, at room temperature (T = 298 K), with pulse delay 10 s, on 1.5 10−2 M solutions of 1, 2, and 3 in the deuterated solvents quoted above.The NMR measurements were performed with a Bruker ADVANCE 400 spectrometer. Then, Time-resolved fluorescence. The fluorescence decay patterns were reconstructed by means of a TCSPC apparatus endowed with <30 ps temporal resolution, which is described in more detail in [2 minimization algorithm implemented within the data analysis software Origin 7. For each decay pattern, the number of decay components was determined by adding components one by one until further addition resulted in the determination of more than one component with the same decay constant. The decay times and relative amplitudes reported in the Results and Discussion section are the averages of the values obtained from the fits of six measured decay patterns, with errors expressed in terms of the corresponding standard deviations.etail in . BrieflySpectrofluorimetric detection of photosensitized ROS generation. The relative efficiency of 2 and 3 with respect to 1 in photosensitizing singlet oxygen (1O2) generation was assessed in toluene and acetonitrile by exploiting the DMA fluorescence assay [2 fluorimetry quartz cells to carry out the fluorescence measurements.ce assay . Due to 1O2 generation measurements were performed using the PTI fluorimeter to convey the suitable light dose to the photosensitizers and simultaneously detect the probe response. The samples were illuminated in a 20 nm-wide band centered at 420 nm, setting the lamp power at 85 W. With these instrumental settings, the spectral radiance of the lamp in the selected band is comparable to that of sunlight. The DMA fluorescence was excited out-of-peak by the same light used to elicit photosensitization, and detected in real time for 10 min in a 2 nm-wide band around the 395 nm emission peak. Control measurements were carried out in the same experimental conditions on DMA alone. Since the DMA fluorescence was observed to decrease slightly over time, even in the absence of photosensitizers, likely due to a combination of residual oxidation and photobleaching, the data were corrected by dividing point-by-point the decays obtained in the presence of the photosensitizer by those obtained with the DMA alone, after the suitable normalization and baseline subtraction of each data string. Further control experiments, conducted on the photosensitizers in the absence of DMA, evidenced that photodegradation, although being significant for all three compounds on longer timescales, can be neglected over the 10 min acquisition time chosen for 1O2 generation estimation. For these studies, excitation was elicited with the same light dose , but the fluorescence of the photosensitizers was monitored over time in a 2 nm-wide band around their emission peaks.The Theoretical modeling. Electronic structure calculations were carried out employing the B3LYP/6-31++G method for both ground and excited states. The latter were obtained using the Time-Dependent Density Function Theory approach, as implemented in the Gaussian09 suite of codes. The local geometry optimization for both ground and excited states started from suitable putative geometries; as for the former cases, these were obtained using a force field-based representation of the structural energies. Optimizations over the excited state surfaces were instead started using the local ground state minima as parent structures, as no major structural changes were expected upon excitation. Indeed, we verified a posteriori the correctness of such assumption. The transition state (TS) geometries for the enol proton transfer in both ground and excited states were initially located in an approximate way via relaxed scans along the oxygen–hydrogen bond length; given the availability of analytical second derivatives, the approximate ground-state TS geometries were further refined. Fitting with a second-degree polynomial was instead exploited to determine the TS energy and equilibrium distance for proton transfer in the excited state.Curcuminoids are being increasingly investigated as photosensitizers. Their optimal exploitation is hindered by their very fast decay from the excited state. The propensity to undergo excited-state intramolecular proton transfer of the enol proton has a major role in such instability. In this article, we tested the benefits induced by the asymmetrization of the molecular structure on the inhibition of proton-transfer mechanisms by analyzing two synthetic phenyl-substituted curcumin analogs. Although the excited-state dynamics have shown to be dependent on the specific aromatic ring substituents chosen to pursue asymmetrization, our results demonstrate that for both asymmetric curcuminoids, the excited-state proton transfer is both slower and significantly less probable than for the corresponding symmetric curcuminoid, thus encouraging further synthetic efforts in this field.


In addition, it was found that the main contribution to the buffer capacity of a PMC is made by the entire shell of the microcapsule and not just its surface. At the same time, the buffer capacity of the capsules has non-linear growth with an increase in the number of PMC shell layers. It is presumably associated either with a decrease in the polyelectrolyte layer with an increase in their number or with a decrease in the permeability of hydrogen protons.Polyelectrolyte microcapsules are used in the development of new forms of targeted delivery systems, self-healing materials, sensors, and smart materials. Nevertheless, their buffer capacity has not been practically studied, although that characteristic makes it possible to estimate the change in the state of protonation of the entire polyelectrolyte system. This is necessary both for creating a buffer barrier system for pH-sensitive compounds  and for the correct interpretation of the results of research and studying of the PMC structure. The buffer capacity of a PMC can be affected by the concentration of microcapsules in solution and the number of shell layers since the listed parameters affect other physicochemical properties of the PMC shell. This includes, for example, the electrical conductivity, permeability (of ions), osmotic pressure, charge density, etc. In this regard, we studied the change in the buffer capacity of polyelectrolyte microcapsules depending on their concentration and the number of shell layers. As a result, it was found that with an increasing concentration of microcapsules, the buffering capacity of the PMC increases, but at the same time, in the pH range from 4 to 5.5, the calculated buffering capacity of 1 billion capsules decreases with increasing their concentration. This effect may be associated with a decrease in the available -NH A solution’s buffer capacity (BC) is the ability to maintain a constant pH value when an acid or alkali is added . The bufPolyelectrolyte microcapsules (PMC) are supramolecular systems created by the layer-by-layer method . The stuDubrovsky et al. demonstrated the buffer capacity of polyelectrolyte microcapsules and the dependence of the behavior of the buffer capacity on the presence of an encapsulated protein , the ionn > 10  in the internal solution, which is associated with a change in the level of protonation of polyelectrolytes  and the buffer capacity of the entire system.The concentration of polyelectrolyte microcapsules may also be one of the reasons for the change in the buffer capacity of polyelectrolyte microcapsules. Qiyun Tang and Alan R. Denton found that changing the number of microcapsules leads to a non-linear pH shift, which is associated with a non-linear change in the ion densities inside the cavities of the PMCs . In addiThe number of capsules and the number of layers of the PMC shell are key parameters in developing targeted delivery systems, self-healing materials, sensors, and smart materials ,24,28. I3+ groups) also depend on the number of microcapsule shell layers and the number of microcapsules themselves. Thus, the parameters described above can also affect the behavior of the PMC buffer capacity.In previous works, we revealed the presence of a buffer capacity (BC) in polyelectrolyte microcapsules consisting of PAH and PSS. Additionally, we found the dependence of the buffer capacity’s behavior on the PMC shell’s composition, the presence of an encapsulated protein, the magnitude of ionic strength, and the temperature of the solution. These studies demonstrated that the buffer properties of microcapsules are determined by the charged regions of PAH (uncompensated with PSS) in the composition of their shell ,9. Howev9 microcapsules, 6.6 × 109 microcapsules, and 13.1 × 109 microcapsules. The results of this study are presented in We have studied BC with a different titer of polyelectrolyte microcapsules: 3.4 × 102 amino groups of PAH decrease, capable of acting as [H+] acceptors. However, at the same time, the number of donor -NH3+ groups does not decrease [3+ groups were hydrated after water rearrangement between the approaching charges [As can be seen from decrease ,19,29 be charges .3 and (PSS/PAH)3PSS. The results obtained are shown in The next stage of the research is the study of PMC’s buffer capacity with different shell compositions: (PSS/PAH)As seen in 3, (PSS/PAH)5, and (PSS/PAH)7. If the above assumption is correct, then the increased number of layers of PMC will increase the buffer capacity. To confirm this hypothesis, we measured the buffer capacity of a suspension of microcapsules with shell compositions (PSS/PAH)3+ groups) and the number of hydrophobic regions. As a result, it leads to a decrease in the buffer capacity of the microcapsule calculated per 1 layer.As can be seen from the results obtained A, with aThe polyelectrolytes polystyrene sulfonate sodium (PSS) and polyallylamine hydrochloride (PAH) with a molecular mass of 70 kDa, as well as ethylenediaminetetraacetic acid disodium salt dihydrate (EDTA), were purchased from Sigma . Sodium chloride, sodium sulfate, sodium carbonate, and calcium chloride were obtained from “Reahim”.2CO3, the 0.33 M CaCl2 was added. The stirring time was 30 s. The suspension was maintained until complete precipitation of the formed particles. The process of “ripening” of microspherolites was controlled with the help of a light microscope. Then, the supernatant was decanted, and the precipitate was washed with water and used to prepare PMC. The microparticles were obtained with an average diameter of 4.5 ± 1 μm.At a stirring of 0.33 M Na3 microspherulites, followed by the dissolution of CaCO3. At the moment of dissolution of the CaCO3 core, the inner space of PMC is filled by an interpolyelectrolyte complex [3 microspherulites surface was carried out in the polyelectrolytes solutions (concentration 2 mg/mL + 0.5 M NaCl). After each adsorption, the CaCO3 particles with adsorbed polyelectrolytes were triple-washed with a 0.5 M NaCl solution, which was necessary to remove unadsorbed polymer molecules. The particles were separated from the supernatant by centrifugation. After applying the required number of layers, the carbonate kernels were dissolved in a 0.2 M EDTA solution for 12 h. The resulting capsules were washed three times with water to remove core decay products. The microcapsules were obtained with an average diameter of 4.5 ± 1 μm. The size and number of microcapsules were measured using the dynamic light scattering method on a Zetasizer nano ZS device .The polyelectrolyte microcapsules were obtained by layer-by-layer adsorbing the negatively or positively charged polyelectrolytes onto CaCO complex . Layer-b3 (6.6 × 109 microcapsules in 8 mL of water) was titrated with acid or base solutions in the pH range from 4 to 9. Titration was done by manual measurement using a Hanna pH 211 pH meter. The acid or alkali (with a concentration of 0.001 M or 0.005 M) was added to the solution to change the pH of the solution by 0.02 or more. Buffering capacity was calculated from Equation (1) after estimating the slope of the titration curves at each point by the variation of the pH between previous and subsequent injections [BC—buffer capacityacid or alkaliC—concentration of HCl of NaOHacid or alkaliV—volume of HCl of NaOHsV—volume of solutioni—number of titrationA suspension of microcapsules (PSS/PAH)jections :(1)BC=Ca2 groups decreased) at high PMC concentrations. In addition, it was found that the main contribution to the buffer capacity of PMC is made by the entire shell of the microcapsule and not just its surface. At the same time, the buffer capacity of the capsules has non-linear growth with an increase in the number of PMC shell layers. This is presumably associated either with a decrease in the polyelectrolyte layer with an increase in their number or with a decrease in the permeability of hydrogen protons.In the course of this work, we studied the behavior of the buffer capacity of polyelectrolyte microcapsules depending on the concentration of capsules and the number of PMC shell layers. As a result, it was found that the buffering capacity of the entire suspension increases with increasing concentrations of microcapsules. However, at the same time, the calculated buffer capacity per 1 billion capsules in the pH range from 4 to 5.5 decreases with increasing concentration of PMC. This effect may be associated with an increase in the charge density of the capsule shell (the available -NH