Atmospheric pollutant data for PM10 and NO2 in µg/m3 for the Madrid region were provided by the Spanish Environmental Ministry (MITECO). Daily incidence, daily hospital admissions per 100.000 inhabitants, daily ICU admissions and daily death rates per million inhabitants were used as dependent variables. These data were provided by the ISCIII Spanish National Epidemiology Center. Generalized linear models with Poisson link were performed between the dependent and independent variables, controlling for seasonality, trend and the autoregressive nature of the series.There are studies that analyze the role of meteorological variables on the incidence and severity of COVID-19, and others that explore the role played by air pollutants, but currently there are very few studies that analyze the impact of both effects together. This is the aim of the current study. We analyzed data corresponding to the period from February 1 to May 31, 2020 for the City of Madrid. As meteorological variables, maximum daily temperature (Tmax) in ºC and mean daily absolute humidity (AH) in g/m10 and NO2, both showed a positive association with the dependent variables. Only PM10 was associated with the death rate. Associations were established between lags 12 and 21 for PM10 and between 0 and 28 for NO2, indicating a short-term association of NO2 with the disease. In the two-variable models, the role of NO2 was predominant compared to PM10.The results of the single-variable models showed a negative association between Tmax and all of the dependent variables considered, except in the case of deaths, in which lower temperatures were associated with higher rates. AH also showed the same behavior with the COVID-19 variables analyzed and with the lags, similar to those obtained with Tmax. In terms of atmospheric pollutants PM2, is associated with a higher incidence and severity of the disease. The impact that these environmental factors are small (in terms of relative risk) and by themselves cannot explain the behavior of the incidence and severity of COVID-19.The results of this study indicate that the environmental variables analyzed are related to the incidence and severity of COVID-19 in the Community of Madrid. In general, low temperatures and low humidity in the atmosphere affect the spread of the virus. Air pollution, especially NO There is currently no clear scientific evidence that environmental factors such as temperature and humidity affect the spread of the new SARS-CoV-2 virus or the slowing of transmission. What is known is that the influence of environmental factors is lesser compared to the public health measures implemented to contain the virus . The reaOn the other hand, studies have analyzed the role of local level air pollution, which seems to be an environmental factor that can aggravate the COVID-19 disease process and increase its severity. However, the possible effect on the spread of the virus is still in question, especially if particulate matter (PM) pollutants are capable of serving as a viable means of transport for the new SARS-CoV-2 virus . AnotherWhile many publications have addressed the influence of environmental factors on the incidence and severity of COVID-19, the majority of these studies use different methodological approximations. There are studies that report simple correlations between the health variables related to COVID-19 and air pollution  or in thWhile it is true that the majority of published studies show methodological deficiencies both terms of the time series analyzed and the control variables  admissions and the number of deaths due to COVID-19. Data were provided by the National Center for Epidemiology at the Carlos III Institute. The data for this period related to the population of the Community of Madrid were supplied by the National Statistics Institute (INE). Based on these data, we calculated the following: COVID-19 incidence rate per 100,000 inhabitants; rate of emergency hospital admissions for COVID-19 per 100,000 inhabitants; rate of ICU hospital admissions for COVID-19 per 1,000,000 inhabitants and COVID-19 death rate per 1,000,000 inhabitants.The independent variables consisted of meteorological data and air pollution data.Meteorological data were the values of daily maximum temperature (Tmax), minimum temperature (Tmin), and average temperature (Tmed) in Celsius and daily average relative humidity (RH) in percent.3 were obtained based on average relative humidity and average daily humidity [The values of average absolute daily humidity (AH) in g/mhumidity .These values constitute the average value of the observations corresponding to the AEMET stations located in the Community of Madrid and were provided by the State Meteorological Agency (AEMET).10 and NO2 in μg/m3, obtained by using the average of the values measured in the stations located in the Community of Madrid. These data were provided by the Ministry of Ecological Transition and Demographic Change (MITECO).The air pollution data were the average daily values of the concentrations of PMFourteen-day average values were calculated based on the average daily values for these independent variables.First, time lags with p-values below 0.05 were detected that existed between the different variables for the rates of COVID cases described. Cross-correlation functions (CCF) were established between the residuals of the prewhitened series for these variables. Prewhitening was carried out through ARIMA single-variable modeling. Knowing time lags was necessary to analyze the temporality of case detection, hospital admission and admission to the ICU, and death.Generalized linear models with Poisson link (GLM) were carried out between the dependent (positive COVID rates) and independent  variables. In these models we controlled for the series trend and seasonality for 120, 90, 60 and 30 days, and the autoregressive nature of the series. Also, we have controlled for weekly seasonality.y represents each of the dependent variables previously commented, a is the intercept. βn represents the coefficient of each of the n variables. n1 is trend, seas represents each of the variables used to control seasonality, env represents each of the environmental variables, lag represents the lagged variable of order g, in which X has been replaced by the dependent variable and environmental variables and ε the represents residuals of the model; each of them at the i observation.where p-values below 0.05 between the dependent variables and the independent variables (p < 0.005).GLM were carried out between each dependent variable and the average daily values of the independent variables, and later with the 14-day average values. This single-variable modeling allowed us to determine which of the daily temperatures we worked with presented better associations with dependent variables. In this way, time lags were established that produced associations with The range of lag days considered in the analysis is from 0 to 28 days to take into account the time that took place between the occurrence of symptoms and worsening of symptoms and arrival at the hospital , 21 and β with β as the absolute value of the estimator obtained in the Poisson modeling. A negative coefficient in the estimator indicates that an increase in the independent variable is associated with a decrease in the dependent variable. The RR is calculated by an increase of 1 µg/m3 of PM10 and NO2; 1 ºC in the maximum temperature (Tmax) and 1 g/m3 in the absolute humidity (AH) value.Later, two-variable models were carried out, including the air pollution variables and the meteorological variables. Finally, all variables models were carried out between the entire dependent and independent variables introducing the control variables described. Based on the absolute values of the estimators, relative risks (RR) were calculated in the form RR = eWe used a back-stepwise process for variable selection, and statistical significance was set at a p-value of p < 0.05. Over- or under-dispersion have been controlled.Table 2 and PM10 in Fig. 10, there are periodic increases in the average daily concentrations of the pollutant. In contrast, in the case of maximum daily temperatures , between incidence and ICU admissions for lags 0 and 7 (at short term), and between incidence and deaths for lags 7, 11 and 13 (at medium term). There were associations with p-values below 0.05 between admissions and ICU admissions for lags 0 and 9 (at short and medium term), and finally, there were associations with p-values below 0.05 between ICU admissions and deaths for the lags 7, 9, 14 and 28 (at medium and long term). For example, Fig. Table 2 and PM10.Table 10 there was an association with p-value below 0.05, with positive coefficients for the four COVID-19 rates analyzed. These associations were established between the lags of 12 and 21 (at medium and long term). On the other hand, the average daily concentrations of NO2 also showed an association with p-value below 0.05, with positive coefficients for the COVID-19 variables, except for the death rate. In addition to the similar lags obtained for PM10, NO2 showed a short-term association (lags 0 and 5) that was not found for PM10. Once two-variable models were carried out that included average daily concentrations of PM10 and NO2 the association of NO2 was predominant in all of the models.Regarding PMIn contrast to the pollutant variables, the meteorological variables analyzed showed associations with p-values below 0.05 with negative coefficients both for maximum daily temperature (Tmax) and absolute humidity (AH). In general Tmax was associated with all of the COVID variables, both in the medium-term (lags 7–14) and in the long-term (lag 27), but less so than AH. There was no association with the mortality rate. In two-variable models the impact of AH was predominant over Tmax.2 was predominant over PM10, except for the admissions rate; there was a short-term association of NO2 on incidence; and an association of AH and Tmax.Also Table 10 and NO2, which was not the case for Tmax and AH. The models with all variables showed the predominance of the associations related to NO2 compared to those of PM10 as well as those of AH compared to Tmax already described.Finally, Table Table Given the analysis of many different factors, this section is structured into different parts to facilitate reading and comprehension.During the time this analysis was carried out, PCR tests for detecting positive cases of COVID-19 were only used for those people who presented symptoms compatible with the disease. According to a later prevalence study, SARS-CoV-2 in Spain (ENE-COVID) , “One inThis severity of diagnosed cases would also explain the existence of the association in lag 0 between the incidence and rates of hospital admission and even ICU admission. That is to say, these were people who were diagnosed with the disease and were admitted due to its severity to the hospital and even the ICU on the same day of diagnosis. The lags found between the incidence rate and hospital admissions in lags 6, 7 and 10 (at short and medium term) are also compatible with the time that took place between the occurrence of symptoms and worsening of symptoms and arrival at the hospital , 21. On 10 and NO2, clearly showed a trend of decline, which could be explained by the restrictions on mobility that took place in Madrid after the declaration of the state of alarm on March 14. The decline observed in the concentrations of the pollutants in the last week of the study, compared to the first, were 34.5% for PM10 and 66.8% for NO2, which shows the marked anthropic origin of the NO2 in Madrid and the important natural origin component (including processes of resuspension) of PM10 concentrations [10 can be observed in Fig. 10 and NO2 are similar to those found in other cities in Spain during the confinement [The time evolution of the concentrations of the pollutants analyzed, PMtrations . “Peaks”finement , 28.10 and NO2 and the COVID-19 incidence rate, the rate of hospital admissions and ICU admissions. There is even an association with p-value below 0.05 detected between PM10 and the death rate.Table There are two biological mechanisms that could explain the existence of these associations . On one 2.5 could act on the balance of inflammatory M1 and anti-inflammatory M2 macrophage polarizations, a fact that might be involved in air pollution-induced immune disorders and diseases.The other mechanism is based on the fact that air pollution weakens the immune system in the short term. There is growing evidence that pollution can induce oxidative stress, resulting in the production of free radicals, which in turn, may damage the respiratory system, reducing the resistance to viral and bacterial infections . Air pol10), given that the resulting particle is larger and less dense a respiratory droplet, which could increase the time it remains in the atmosphere. However, other research also carried out in Italy suggests the opposite in terms of the possible transmission of the virus via material particles [Furthermore, in the case of PM concentrations, there is another possible mechanism related to the transmission of the virus. According to a study carried out in Lombardia , traces articles . Other sarticles .10 and for NO2, are compatible with both the needed incubation times of the virus  for NO2 with the incidence rate, hospital admission rate and ICU admission rate, is noteworthy. We understand that such a short-term association cannot be justified by the damage of NO2 to the immunological system in the short-term and supporting infection mechanisms, as has been reported, but rather by the worsening of prior respiratory and cardiovascular pathologies. The concentrations of NO2 in Madrid are related to both an increase in mortality due to circulatory causes [The lags in which associations were established with the different disease indicators in our analysis, both for PM 12 days ) and the 12 days . In all y causes , 42 and y causes , 42, as y causes , especiay causes .10 and NO2 together with the dependent variables related to COVID-19 analyzed show more robust associations for NO2 than for PM10 in all cases. Prior studies carried out in Madrid related to the impact of both PM10 [2 [2 RR: 1.012  compared to PM10 RR: 1.009 . While these RR slightly overlap, this greater risks of NO2 could account for the fact that NO2 shows a more robust association in the two-variable models that combine both primary pollutants with a high collinearity   showed more robust behavior compared to the variables related to COVID-19 rates in the modeling process than average and minimum daily temperatures, thus it was selected as the variable for the analysis. There was a greater number of associations with p-values below 0.05 and greater statistical significance. The finding that Tmax was more closely related to COVID-19 rates than Tmin may be counter-intuitive. One explanation could be that Tmin is usually recorded around 7 a.m., a time when very little human activity occurs outdoors, while Tmax is usually recorded at around 4 p.m. .The increasing trend in maximum daily temperature and the increasing trend in absolute daily humidity (AH) shown in Fig. The results shown in Table On the other hand, the serological study of the prevalence of SARS-CoV-2 in Spain (ENE-COVID)  indicateSeasonal respiratory viruses are transmitted through aerosols, large respiratory droplets, or by direct contact with fomites . Lower tOn the other hand, the results of our study show that higher temperatures correlates with lower incidence and severity of the disease. This may be compatible with a protective association of the temperature. Similar results have been found in other studies carried out in different parts of the world, including China , 53, theExtreme temperatures can also affect morbidity and mortality due to different causes , 57. HowThe association of AH is predominant in the two-variable models compared to Tmax, both for daily values as well as 2-week averages. This result agrees with what was found in a study of eight U.S. cities  which co2 over PM10 and of AH over Tmax.In general, the behavior of the models with all variables was similar to that of the two-variable models Table , both in2, show that it is not the higher daily levels of pollution that most correlated the incidence and severity of the disease; rather it is the average values. This supports that the preventive public health measures related to pollution and COVID-19 must be structural and aimed at decreasing the pollution in the city, as opposed to conjectural measures to avoid episodic situations.The higher RR values obtained for the 14-day average values as compared to daily values Table , especiaThe RR of these environmental factors are small (in terms of relative risk) and, by themselves, cannot explain the behavior of the incidence and severity of COVID-19, which is explained by social distancing and public health measures not considered in our analysis, this assumption is similar to the findings founded in the First report of the WMO COVID-19 Task team . Only RROne of the principal strengths of this study is the longitude of the series used. Although the series was of 212 days, or 4 months, it is longer than the majority of studies carried out to date. The duration of the series allowed for carrying out generalized linear models with control variables such as trend, seasonality and the autoregressive component. In addition, it also allows for models with all the variables that include both meteorological and pollution-related variables, which is a significant improvement compared to the many investigations carried out to date in this field, that have used two variables correlations corresponding to series of 30 days.Another strength of this study is the robust nature of the findings, first between the lags in which associations were established, which are coherent with biological mechanisms that link the different variables analyzed and the incidence and severity of the disease with the period of incubation and the course of the disease. This analysis was possible thanks to the daily data on COVID-19 variables as opposed to accumulated data or data averaged over time.In addition, not only was a single association found between an indicator and the disease, rather there were four indicators with coherent results between them. This robustness extends as well to the relationship between the two variables and models with all variables and to the results obtained for the daily as well as averaged series. On the other hand, not only daily values are used but also averages of 0–14 days, which eliminates the weekly seasonality that exists in the dependent and independent variables. The longitude of the series is also, paradoxically, a weakness. Only a 4-month period was considered, without accounting for the complete annual variation.3 (daily average). This value was not reached any day in the study period.About the study design, the analysis is a descriptive observational study. Specifically, it is a population-based ecological study. Generally, in epidemiological studies it constitutes a level of basic evidence. This type of study does not allow a causal relationship; but it constitutes useful exploratory approach . AnotherOn the other hand, the conditions under which the data were obtained correspond to a period in which the declaration of cases only occurred when people already presented important symptoms of the disease.The study conducted by the authors corresponds to an ecological time series design, with all the epidemiological limitations inherent in this type of study, especially the ecological fallacy. Both of the aforementioned points show the need for prudence in extrapolating the results to other situations in time other than those corresponding to the time this study was carried out. Nevertheless, this study could be evaluated with other methodologies that could complement the analysis carried out, a methodology such as propensity score matching , even a , is associated with a higher incidence and severity of the disease. The 14-day average values imply a greater risk than daily values.The results of this study indicate that the environmental variables analyzed are related to the incidence and severity of COVID-19 in the Community of Madrid. In general, low temperatures and low humidity in the atmosphere are associated with increased spread of the virus. Air pollution, especially NO2However, the RR of these environmental factors are small and by themselves cannot explain the behavior of the incidence and severity of COVID-19, which is explained by social distancing and public health measures not considered in our analysis.


The effect of triazino-indole derivative (Trisan) on hypoxia-inducible factor (HIF) expression level in the organ of Corti, when administering it for therapeutic and preventive purposes, was investigated using an acoustic trauma model in experimental animals . Cytoflavin was used as a comparator product. Study product Trisan (1% solution) was injected intravenously, intramuscularly and intraperitoneally, in the dose of 5, 7 and 10 mg/kg 2 h after the acoustic trauma for therapeutic purposes and in the dose of 5, 7 and 10 mg/kg for 3 days before the acoustic trauma for preventive purposes. IHC methods were used to investigate the organ of Corti. Trisan was observed to increase HIF expression in hair cells and neurons of the spiral ganglion in case of acoustic trauma. Depending on the dose, the increased HIF-1 expression in hair cells and spiral ganglion occurred both after therapeutic and preventive use of Trisan. Maximum HIF expression in hair cells and ganglion was noted at the therapeutic and preventive drug dose of 10 mg/kg. Following experimental results, we conclude that the otoprotective effect of triazino-indole derivative is realized via its effect on HIF metabolism, which makes it a target molecule for the drug. In the modern world, the prevalence of noise-induced hearing loss has arguably reached epidemic proportions . Prior rAccording to prior research, hypoxia resistance of hair cells in the organ of Corti is realized through the path associated with an HIF molecule . It was HIF belongs to a basic helix–loop–helix (bHLH) class of transcription proteins found in all mammalian cells and tissues. It is required for transcription activation in cells under hypoxia conditions through the erythropoietin gene . The HIFThe HIF-1α quantity is regulated by VHL protein (Von Hippel–Lindau), which is involved in its ubiquitination and proteasome degradation due to E3 ligase . HydroxyOur research involving an acoustic trauma model demonstrates that HIF-1α expression level can indeed be used to assess the degree of tissue hypoxia .Currently, there are ongoing efforts to identify tools for pharmacologic correction of hypoxic damage of the organ of Corti caused by acoustic trauma using HIF as their target what formed the base of the present study.Objective of the study. To assess hypoxia-inducible factor HIF-1α expression in cells of the organ of Corti and its morphologic changes using an acoustic trauma model while administering triazino-indole derivative.The experiments were performed using 123 female mice of F1 hybrids of CBA and C57BL/6 line with weight of not less than 17 g aged 4–12 weeks. The mice were delivered from the laboratory animal farm of the Russian Academy of Medical Sciences “Rappolovo” . The experiments were performed 14 days after the animals adjusted to the vivarium conditions. All experimental research was performed in accordance with the requirements of the “European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes” , rules of laboratory practice  and methodical recommendations on performing preclinical studies. Euthanasia of mice was carried out using a lethal dose of anaesthesia used in the experiment, i.e., intraperitoneal injections of Telazol (50–70 mg/kg).We studied a new triazino-indole derivative (Trisan) 3-[ and frequency band of 3–100,000 Hz  for 3 h. The noise level of 107 dB corresponded to the level measured using the Brüel & Kjaer measuring system (Denmark): 6.5 mm of the calibration microphone of type 4145, preamplifier 2633 and measuring amplifies 2606 in the location point of the tympanic membrane of the test ear.Animals were injected with the study product Trisan, 1% solution, intravenously, intramuscularly and intraperitoneally with single-use syringes. The ready-made 1% solution of Trisan was diluted with physiological saline  for convenient injection. The drug was administered in the dose of 5, 7 and 10 mg/kg 2 h after the acoustic trauma for therapeutic purposes. The drug was administered in the dose of 5, 7 and 10 mg/kg for 3 days before the acoustic trauma for preventive purposes. The comparator product Cytoflavin was diluted and injected in the dose of 1.7 mL/kg by the same method. The experimental animals in the control group received physiological saline.After completing the experiment, the organ of Corti was removed as part of the excised temporal bone, fixed with 10% normal (pH 7.4) formaldehyde solution for 12 h. The obtained fixed samples were decalcified by incubation in the rapid decalcification solution  for 30 min. Mice brain samples were processed using conventional techniques in the Excelsior AS tissue processor , with isopropyl alcohol and paraffin wax. After that, a rotary microtome was used to prepare 5 μm thick cross-sections. Those cross-sections were then put on slides and coloured with haematoxylin and eosin.The IHC tests were done with Autostainer 480S , UltraVision Mouse HRP  and mouse monoclonal antibodies for HIF1  according to the recommendations of equipment and reagent manufacturers. The IHC samples were scanned in Pannoramic Midi scanner ; the QuantCenter image analysis platform  was used to calculate the HIF1-positive area (in %) of the modiolus and other areas of the brain. The colour was assessed using a mean cytochemical coefficient developed by the authors. The colour intensity in case of HIF-1α expression was designated with figures from 1 to 6.When analysing the experimental results of the specimens of the control and Cytoflavin groups , we noteWhen the therapeutic dose of 5 mg/kg was administered, we observed low HIF-1 expression in the cells of the receptor apparatus and moderate HIF-1 expression in the cells of the spiral ganglion. When the therapeutic dose of 7 mg/kg was administered, we observed moderate HIF-1 expression in the cells of the receptor apparatus and the cells of the spiral ganglion. The pronounced HIF-1 expression was observed after administering the therapeutic dose of 10 mg/kg injected 2 h after the acoustic trauma .The preventive use of the drug 3 days before the acoustic load in the dose of 5 mg/kg resulted in moderate HIF-1 expression by the hair cells, low-level expression in the cells of the spiral ganglion. Administration of the dose of 7 mg/kg resulted in moderate HIF-1 expression in the cells of the receptor apparatus and the cells of the spiral ganglion. Injection of the dose 10 mg/kg resulted in pronounced HIF-1 expression in the cells of the receptor apparatus and the cells of the spiral ganglion .In our study, we found that increased HIF-1 expression in the hair cells and spiral ganglion was observed depending on the increase of the drug dose both in case of the therapeutic and preventive use of triazino-indole derivative (Trisan). This coincided with electrophysiologic changes in experimental animals. This pattern suggests that HIF is indeed the target molecule for the drug and that the drug can regulate its level in the cells and neural pathways of the internal ear. The maximum HIF expression in the hair cells and ganglion was observed after administration of the preventive and therapeutic dose of 10 mg/kg.Prior literature contains reports of experiments demonstrating the use of drugs to increase HIF-1 expression. One of the methods for this is to block enzymes involved in HIF deactivation ,22. For Recent studies have shown that microRNA, which regulate gene expression endogenously through the RNA-interference path, allow for selective action of HIF molecule, thereby increasing its stability . A methoAccording to the results of our study, triazino-indole derivative (Trisan) has an otoprotective action due to its effect on HIF expression level, most likely, because it blocks the enzymes involved in its degradation (prolyl hydrolases). This makes it possible to consider this drug as a promising pathogenetic agent for prevention and treatment of noise-induced hearing loss.Basing on the results of our study and analysis of prior research, we conclude that triazino-indole derivative (Trisan) has an otoprotective action due to its effect on HIF expression level as a target molecule for the drug. As the dose of Trisan increases, there is an appropriate increase of HIF-1 expression in the hair cells and the spiral ganglion. We suppose that the mechanism of action of the drug is associated with blocking the enzymes involved in its proteosome degradation (prolyl hydroxylase).


Ultrathin silver films with low loss in the visible and near-infrared spectrum range have been widely used in the fields of metamaterials and optoelectronics. In this study, Al-doped silver films were prepared by the magnetron sputtering method and were characterized by surface morphology, electrical conductivity, and light transmittance analyses. Molecular dynamics simulations and first-principles density functional theory calculations were applied to study the surface morphologies and migration pathway for the formation mechanisms in Al-doped silver films. The results indicate that the migration barrier of silver on a pristine silver surface is commonly lower than that of an Al-doped surface, revealing that the aluminum atoms in the doping site decrease the surface mobility and are conducive to the formation of small islands of silver. When the islands are dense, they coalesce into a single layer, leading to a smoother surface. This might be the reason for the observably lower 3D growth mode of silver on an Al-doped silver surface. Our results with electronic structure insights on the mechanism of the Al dopants on surface morphologies might benefit the quality control of the silver thin films. Ultrathin metallic films are used for innovative applications, such as flexibility transparent electrodes ,2, opticTo address the issue of the roughness of ultrathin silver films, numerous approaches have been applied. A widely used method is to deposit a seed layer before the silver film. Ciesielski et al. investigated the crystallinity and optical parameters of silver layers of 10–35 nm thickness using a 2–10 nm-thick germanium wetting layer pre-deposited on fused silica substrates . Some reIn this paper, the roles of aluminum doping in silver film are studied by experiment and first-principles calculations. The surface morphologies for the layer-by-layer growth of silver on an amorphous silicon dioxide surface with aluminum as a dopant are studied by molecular dynamics (MD) simulations. The surface migration behavior of both silver and aluminum on pristine and Al-doped silver surfaces is investigated using first-principles calculations with the frame of Density Functional Theory (DFT). To understand the stabilities of adsorption models, the adsorption energies of silver and aluminum adatoms with different migration paths are systematically examined.−3 Pa before the deposition process. The rotating speed of the substrate tray was set to be 20 rpm/min, and no deliberate heating was applied to the substrate during the whole deposition. The metallic films were prepared by the sputtering of silver and aluminum targets at room temperature. The chamber was cooling by circulating water (25 °C). The substrate was attached to a stainless-steel holder with good thermal conduction, and the temperature rise of substrate can be neglected [The samples were prepared using magnetron sputtering equipment . Polished silica glass substrates were used for the deposition of silver films. The substrates were cleaned using ultrasonic deionized water and then dried using nitrogen gas. The chamber was pumped to an initial pressure of 3 × 10eglected ,22. The x-axis) × 85.53 Å (y-axis) × 120.00 Å (z-axis). The substrate region was filled with amorphous silicon dioxide; that is, the atoms in the substrate were arranged in a disorderly manner, corresponding to the silica glass substrate in the macro system. The deposition atoms of silver and aluminum were injected from the top of deposited film region. The Tersoff potential [Although the formation and evolution of the rough morphology of metallic film on an oxidized substrate were understood from a thermodynamic point of view ,24, moleotential , embeddeotential , and Lenotential  were use−5 eV. The nonlocal van der Waals interactions corrections are considered [The adsorption and migration pathway of deposition of a pre-deposited silver surface were studied by first-principles calculations within the frame of density functional theory. The Quantum Espresso package ,31, versnsidered .Slab models consisting of a substrate layer and vacuum layer were used for simulations, as shown in 1 to D1, as shown in 2 to D2. Path 3 represents the migration of adatom from S3 to D3, as shown in Three series of paths were considered to reveal the effects of aluminum doping on the preferred adsorption configuration and migration of adatoms. Path 1 represents the migration of adatom from SEad of an adsorbed atom on silver surface is defined as follows [Etotal is the total energy of the substrate with the adsorbed atom, Esurface stands for the total energy of the substrate, and Eadatom is the total energy of an isolated adsorbed atom.The adsorption energy  follows :Ead = EtSilver thin films with different aluminum components were prepared by magnetron sputtering equipment. The sputtering power of the silver target was kept as constant, while the sputtering power of the aluminum target and total deposition time varied. The deposition parameters are listed in The results of the surface morphologies of the samples are shown in The room temperature sheet resistances of silver films were measured using a four-probe meter. Sample 1 was undoped silver film, and its sheet resistance was 23.6 Ω/sq. Sample 2 was Al-doped silver film with 100 W aluminum target sputtering power, and its sheet resistance was 3.1 Ω/sq, which is much lower than that of undoped silver film. It is indicated that the degree of surface smoothness has a positive effect on sheet resistance, and that doping a small amount of aluminum atoms not only helps to form smooth silver films but also makes its sheet resistance smaller. The sheet resistance of the Al-doped silver film with aluminum sputtering power of 100 W, 200 W, and 300 W is 3.1 Ω/sq, 2.4 Ω/sq, and 6.3 Ω/sq, respectively. The sheet resistance of Al-doped silver film as a function of aluminum target power is shown in The surface morphologies of Al-doped silver film with different deposition times were also analyzed. The sputtering powers of silver and aluminum targets were kept constant while the deposition times were set to 9 s, 15 s, and 25 s, respectively. The corresponding AFM results are shown in The transmittance spectra of the Al-doped silver films are shown in The atomic-scale deposition of aluminum doped silver films on amorphous silicon dioxide substrate with different aluminum compositions and different deposition time were studied by molecular dynamics simulations. The open visualization tool (OVITO)  was usedThe radial distribution function (RDF) of the Ag–Ag bond and Ag–Al bond of the Al-doped silver film deposited in different aluminum composition are calculated by OVITO and shown in To obtain a more detailed description of the atomic origin of aluminum doping effects on the initial deposition on Al-doped silver films, first-principles computational studies of the adsorption and migration of aluminum and silver adatom on a pristine silver and an Al-doped silver surface are presented. The absolute adsorption energies for silver adatom on a pristine Ag (111) and an Al-doped Ag (111) surface are shown in 2 site, which is located in the middle of the bridge between the S1 site and D1 site, and it is close to the hollow site above the three-fold silver atoms. The maximal adsorption energy and corresponding adsorption distance of silver along path 1 are 3.518 eV and 2.289 Å, respectively. In the case that the silver atom at D1 is replaced by an aluminum atom, the maximum adsorption energy and minimum adsorption distance of silver that migrate along path 1 are not at the D2 site but are closer to the D1 site. The corresponding energy and distance are 4.098 eV and 2.182 Å, respectively. The calculation results show that the silver adatoms tend to be adsorbed at the site near the aluminum doping atom, the adsorption distance is smaller, and the bond between the adatom and the surface is stronger. For the same reason, the subsequently deposited silver atoms can also be adsorbed in the vicinity of the aluminum atom. In the case that silver migrates along another pathway perpendicular to path 1, the energetic adsorption position appears in the hollow site, and the corresponding adsorption energy on the pristine Ag (111) surface is 3.694 eV, which is larger than that in the case of path 1. From the standpoint of the minimum energy of the system, the silver adatom on top of the silver substrate atom is considered to be unstable because it moves toward the bridge site, close to the hollow site. From the crystallographic point of view, the initial stacking growth sequence of the Ag (111) layer continues the FCC stacking of the substrate [The results show that the adsorption energy of silver on the Al-doped Ag (111) surface along path 1 and path 2 is higher than that of the pristine Ag (111) surface. Therefore, the silver atoms deposited on the Al-doped Ag (111) surface are more stable. The preferred adsorption position for silver on a pristine Ag (111) surface along path 1 is the Dubstrate ,45; hencThe maximal adsorption energy along path 2 increased to 4.191 eV with aluminum doping, which revealed that aluminum doping improves the formation of silver adatom deposition in the FCC-stacked sequence. It can be seen from According to the transition-state theory ,47, the 1 on a pristine Ag (111) surface is smaller than that on an Al-doped Ag (111) surface, as the aluminum atoms migrate along path 1 and path 2, and the adsorption energy of the aluminum adatom at the D1 site of pristine Ag (111) becomes lower than that of Al-doped Ag (111) due to aluminum doping.The Al-doped surface not only affects the adsorption and migration of the silver adatom but also impacts the subsequent deposition of dopant atoms. The calculation results shown in We also consider the adsorption pathway on Ag (100) surfaces. The maximal adsorption energy of aluminum adsorption on pristine Ag (100) and Al-doped Ag (100) is 4.436 eV and 4.594 eV, respectively. The corresponding adsorption distance of aluminum on pristine Ag (100) and Al-doped Ag (100) is 2.073 and 2.177 Å, respectively. Aluminum doping increases the adsorption energy of aluminum on the Ag (100) plane, which suggests that aluminum atoms are more likely to grow epitaxially along another direction. The migration barriers of aluminum adatom on pristine Ag (111) and Al-doped Ag (111) along path 1 are 0.699 eV and 0.704 eV, respectively. However, the migration barriers of aluminum adatom on pristine Ag (111) and Al-doped Ag (111) along path 2 are 0.877 eV and 0.694 eV, respectively. The calculation results reveal that the presence of aluminum-doped atoms slightly increases the migration barrier of aluminum atoms for path 1, while it greatly decreases the migration barrier of aluminum atoms along path 2. In the case of the Ag (100) plane, the corresponding value on pristine and Al-doped surface is 0.629 eV and 0.823 eV, respectively. Aluminum doping significantly reduces the migration length of aluminum atoms on the (100) plane of the silver layer.In a word, the adsorption energy of the aluminum adatom is larger than that of the silver atom at the same adsorption site on the silver surface. The corresponding adsorption distances of aluminum adatoms are lower than those of silver adatoms. It is difficult for silver atoms to move on the surface of silver doped with aluminum, and the surface migration and diffusion length is short. This further explains the fewer three-dimensional silver growth patterns observed on the Al-doped silver surface.Charge density can reveal the charge transition and bonding polarization direction between adatom and surface atoms ,49. The Compared with the pristine silver interface, the electronic accumulation degree increases around the silver adatom, resulting in improved ionicity nearby. However, the overlap degree of an electron cloud at the interface of aluminum adatom with the doping atoms decreases. The aluminum atoms at the doping position greatly affect the charge distribution between the adsorbed atoms and the substrate.In this work, the impact of aluminum doping on the surface formation mechanism was studied. The results of fabricating silver nanofilms through an aluminum co-sputtering process revealed that a small amount of aluminum reduces the surface roughness and promotes the sheet resistance of Al-doped silver film, while excessive aluminum deteriorates the surface roughness and decreases the sheet resistances. The theoretical calculation results show that the adsorption energy of silver adatoms on the Al-doped silver surface is higher than that of the pristine silver surface, and silver adatoms tend to be adsorbed at the site near the aluminum doping atom. The aluminum atoms in the doping configurations decrease the surface mobility of silver by increasing the diffusion barrier for silver adatoms approaching the aluminum center. Aluminum doping atoms provide energetically favorable nucleation sites for the incoming silver atoms, which enhances the nuclei density of the silver layer on the surface, leading to an improved surface morphology. Our results might be helpful in surface quality control of the ultrathin silver films.


The latitudinal position of mid-latitude storm tracks has large climate impacts affecting the distribution of precipitation, temperature, humidity, and winds over the extratropics. By the end of this century, climate models project a poleward shift of summer mid-latitude storm tracks in the Southern Hemisphere. Most previous mechanisms for the poleward shift of the storm tracks focused on the role of atmospheric temperature changes. However, the relative roles of other climate system components in the projected storm tracks’ shift have not been examined to date. Here it is shown that thermodynamic ocean coupling is responsible for the future poleward shift of the storm tracks as it overcomes the effect of dynamic ocean coupling to shift the storm tracks equatorward. These results stress the importance of using full-physics ocean models to investigate the future shift of the storm tracks, and of better monitoring ocean coupling processes to improve our preparedness for future climate changes. Mid-latitude storm tracks control most of the weather and climate variability in the extratropics. Here the authors show that, in the Southern Hemisphere, ocean processes will act to shift the summer storm tracks poleward in coming decades. On the other hand, summer storms are projected to weaken in the Northern Hemisphere and to shift poleward in the Southern Hemisphere5. The latter will have large climate impacts not only at mid-latitudes, but also at high latitudes and in the subtropics; a poleward shift of the storm tracks will increase the storm activity at high latitudes, and reduce it in the subtropics. Several studies have documented a poleward shift of the storms over recent decades10, however, this recent shift is likely attributed to both stratospheric ozone depletion and an increase in greenhouse gas concentrations11. Although the ongoing recovery of the ozone hole is expected to oppose the poleward shift of the storms in the early 21st century13, the unabated emission of greenhouse gases into the atmosphere is projected to shift the storms poleward over the 21st century.The weather and climate in the extratropics are primarily set by mid-latitude storms, as they modulate precipitation, humidity, temperature, and winds on daily to multi-decadal timescales. It is thus critical to investigate the future changes in mid-latitude storms to better assess their climate impacts in the coming decades. By the end of this century, climate models project an overall intensification of winter storms in the Southern Hemisphere and over the downstream region of the North Atlantic storm track18 (a poleward decline in temperature in a stably stratified fluid give rise to baroclinic instability19), as well as changes in the tropopause height20, and in the eddy phase speed23, might be responsible for shifting the storm tracks. In addition, future storms were found to propagate further poleward from their source latitudes, which leads to an additional shift of the storms24.Different mechanisms were argued to explain the poleward shift of the storm tracks. Since mid-latitude storm tracks arise from baroclinic instability, previous studies suggested that a shift in baroclinicity via changes in both the meridional and vertical temperature gradients20, where the effects of active ocean and sea-ice were missing, prevented an accurate assessment of the mechanism underlying the poleward shift of the storms.Most above mechanisms have focused on the direct role of the atmospheric temperature response to anthropogenic emissions in modulating the storm tracks’ position. However, other climate components may also play an important role in the future position of the storm tracks, by affecting the atmosphere’s mean state. For example, the use of fixed sea surface temperature in many of the above studies25). Previous idealized model simulations, using atmosphere-only runs, found a poleward shift of the storm tracks in response to increasing the global mean sea surface temperature26; surface warming was argued to shift the storm tracks poleward by warming the upper level tropical troposphere (via the moist adiabatic lapse rate), and shifting the baroclinicity poleward17. In addition, changes in the meridional surface temperature gradient were also argued to affect the position of the storm tracks26. The use of idealized simulations  and forcings  has prevented the above studies from quantifying and investigating the relative role of ocean coupling in the projected shift of the storm tracks by the end of this century.Indeed, ocean coupling processes were also argued to modulate the position of mid-latitude storm tracks  and dynamic  components, in the recent and projected poleward shift of mid-latitude storm tracks. This decomposition of ocean coupling also allows one to assess how reliable are models that lack time varying OHFC  in investigating the shift of the mid-latitude flow.The aim of this work is thus to examine and quantify the role of ocean coupling in shifting mid-latitude summer storm tracks in the Southern Hemisphere ) over the 21st century. The focus is on the summer in the Southern Hemisphere, since, unlike in the Northern Hemisphere or other seasons, summer storm tracks in the Southern Hemisphere exhibit a robust shift in climate model projections by the end of this century31), and are forced under the Historical (through 2005) and the Representative Concentration Pathway 8.5 forcings . Fig. 35, “Methods”). As was shown in previous studies17, in DJF, Southern Hemisphere mid-latitude EKE is projected to weaken on its equatorward flank (blue colors), and to intensify on its poleward flank (red colors), which is suggestive of a poleward shift  is calculated across CMIP5 models , with one standard deviation of ±1.47∘ across the models (gray bars). Note that CMIP5 models adequately capture the recent (over the 1979–2019 period) observed trend in ϕEKE; the recent shift of mid-latitude storm tracks from two reanalyses (JRA55 and Era-Interim) fall well within the shift in CMIP5 models . All ensembles are conducted using the Community Earth System Model (CESM136), forced with the same Historical and RCP8.5 forcings as in CMIP5, but differ in their ocean coupling processes. The first ensemble37, which uses the full configuration of CESM1 (hereafter refer to as FULL), including a full-physics ocean component, comprises any effects of ocean coupling on the response of EKE to anthropogenic emissions. In the second ensemble , while thermodynamic coupling is active, dynamic coupling is fixed at the climatological preindustrial values of the fully-coupled model; this is done by replacing only the full-physics ocean with a slab ocean model with fixed OHFC and mixed-layer depth (Methods). Thus, since both ensembles are initialized from a similar preindustrial climatology  both dynamic and thermodynamic ocean coupling are fixed; this is done by fixing the sea surface temperature in the slab ocean model configuration at preindustrial values . Thus, while comparing the EKE in the FULL and NOM ensembles allows isolating the role of net ocean coupling in the EKE response, comparing the SOM and NOM ensembles allows isolating the role of thermodynamic coupling (the effects of ocean-atmosphere and ocean-sea-ice heat fluxes on the mixed-layer temperature) (see “Methods” for more details on the ensembles). Note that isolating the role of ocean coupling includes all processes that affect the future position of the storm tracks via changes in the ocean coupling component in question, including any effects that dynamic and thermodynamic ocean coupling may have on each other.∘ . Since, under the RCP8.5 scenario, CO2 concentrations are expected to approximately quadruple by the end of this century, the idealized abrupt 4 × CO2 experiment allows to qualitatively assess the role of ocean coupling in shifting the EKE poleward. Unlike in the NOM ensemble, where only the sea surface temperature is fixed at preindustrial values, here both sea surface temperature and sea-ice are fixed at preindustrial values. Thus, comparing the fully-coupled and atmosphere-only models isolates the role of both ocean and sea-ice coupling in the EKE shift. Similar to CESM1, without an active ocean, the EKE in IPSL-CM6A-LR is not expected to shift poleward in response to quadrupling of CO2 concentrations; changes in ocean/sea-ice account for nearly all of the EKE shift  and sea-ice coupling are not likely to qualitatively affect the above results, as the important role of ocean coupling to shift the storm tracks poleward is evident also using the fully-coupled and atmosphere-only configurations of CESM2 (the CMIP6 version of CESM) under quadrupling of CO2 concentrations , which were found using fixed sea surface temperature models.Decomposing the effect of ocean coupling to dynamic , linearized about a time and zonal mean state (“Methods”). Such analysis allows one to investigate the growth rate of the eddies, which is a widely used metric for the baroclinicity of the flow39 . In particular, using the zonal mean zonal wind, static stability, and tropopause height, averaged over the last 20 years of either the 20th or 21st centuries, the maximum growth rate is calculated at each latitude over the equatorward and poleward flanks of the 20th century EKE (each flank is defined as 12.5∘ poleward/equatorward of ϕEKE). The response  of the difference in the growth rate between the poleward and equatorward flanks (Δ(σp − σe)) yields the changes in baroclinicity associated with the EKE shift: positive values indicate of a poleward shift in baroclinicity, and negative values an equatorward shift in baroclinicity.I now turn to investigate the role of ocean coupling in the poleward shift of EKE. First, I follow previous studies17, in the FULL ensemble, the growth rate increases more on the poleward flank of the storm tracks, relative to the equatorward flank , which implies a poleward shift in baroclinicity, and thus of EKE. Second, as with the EKE shift, also here ocean coupling is responsible for the shift in the growth rate , via changes in thermodynamic coupling , while dynamic coupling acts to reduce the shift in the growth rate . Thus, further investigating the changes in the growth rate can provide a better understanding on how ocean coupling affects the EKE shift.The resulting changes in the growth rate capture the behaviour of the EKE shift across the ensembles Fig. b. First,The relative simplicity of the linear normal mode instability analysis allows one to investigate the contribution of each of the input parameters  to shift the growth rate poleward. In particular, the 21st century growth rate is recalculated using the 21st century value of only one of the mean fields, while all other mean fields are fixed at their 20th century values; the resulting response  yields the contribution of each of the mean fields to changes in the growth rate. Note, the sum of the relative contribution from each mean field adequately captures the growth rate of the 21st century  is found to have a minor effect on the growth rate changes. I, thus, next investigate the effect of thermodynamic coupling on the zonal wind, and of dynamic coupling on the tropopause height. Note that the larger effect of ocean coupling, and in particular of thermodynamic coupling, on the poleward shift in the growth rate, relative to its effect on the shift in EKE . The EKE shift is mostly linked to the increase in the vertical shear of the zonal wind; the EKE is associated with the increase in the zonal wind at upper levels over the poleward flank of the jet, and the reduction in zonal wind at lower levels at the jet’s core.The contribution of thermodynamic coupling to the response of the mean zonal wind is shown in Fig. 14. This result adds to previous findings on the importance of upper level changes in baroclinicity in shifting the mid-latitude storm tracks17.To better understand how thermodynamic coupling modulates the vertical shear of the zonal wind, and thus the EKE position, I next explore the effects of thermodynamic coupling on the meridional temperature gradient, which is in balance with the zonal wind shear. Thermodynamic coupling accounts for most of the global warming temperature pattern Fig. b: by warHp − He)). The tropopause height is defined, following the WMO, as the lowest level where the lapse rate reaches 2 Kkm−1, and stays, on average, below 2 Kkm−1 in all higher levels within 2 km40. OHFC acts to reduce the tropopause height more on the poleward flank of the EKE than on the equatorward flank by ~150 m , and isothermal stratosphere, the response of the tropopause height to anthropogenic emissions can be written as follows, Ts), tropospheric lapse rate, and stratospheric temperature (Tstrat), respectively. Note that the sum of the relative contributions of the righthand side terms account for ~90% of Δ(Hp − He). Thus, the above equation is adequate to investigate the effects of OHFC on the tropopause height.To further reveal the effects of dynamic coupling on the tropopause height, I follow previous studiesp − OHFCe) in Fig. The terms that are responsible for the effect of OHFC to reduce the tropopause height more on the poleward flank, than on the equatorward flank of the EKE, are the surface and stratospheric temperature responses , which was shown to affect the simulated recent changes in mid-latitude eddy heat fluxes48, might also hinder the models’ ability to accurately simulate the future shift of the storm tracks. Thus, better monitoring ocean-atmosphere heat fluxes (which are responsible for the future poleward shift of the storm tracks) and the Southern Ocean dynamics , and improving their parameterizations in climate models, would allow us not only to better assess the future changes in the storm tracks, but also to improve climate change adaption strategies.Given the large climate impacts of the poleward shift of mid-latitude storm tracks it is critical to improve our understanding on ocean coupling processes, as they are found here to control the future position of the storm tracks. In particular, the large effects of both dynamic and thermodynamic coupling on the future position of the storm tracks highlight the importance of analyzing the storm tracks’ shift using fully-coupled models, where both dynamic and thermodynamic ocean coupling are present, rather than using slab-ocean models. Furthermore, while climate models adequately capture the poleward shift of mid-latitude storm tracks over recent decades , g is gravity, ps is surface pressure, p is pressure, u and v are the zonal and meridional winds, respectively, and prime denotes deviation from monthly mean (denoted by overbar). I here choose to define the eddies as deviation from monthly mean, since output of daily data is not available in the CESM ensembles (output of monthly data of kinetic energy is available in CESM). Nonetheless, defining the eddies using a band-pass filter of 2.5–6 days50 or as deviations from monthly mean yields a very similar shift of the storm tracks by the end of this century  . Reanalyses constrain atmospheric models with observations , thus provide the best estimate for the state of the atmosphere in recent decades. The use of models in reanalyses is critical as it allows one to overcome the fact that observations of atmospheric variables are not continuous in space and time.To validate that the models adequately simulate the recent changes in EKE, I compare the recent (1979-2019) EKE trends in models to the EKE trends from two different reanalyses (The ECMWF Era-Interim37). The first member in each ensemble is initialized from a multi-century preindustrial control simulation, and run from 1850 to 1920 under the Historical forcing. In 1920, all other members branch of the first member using a very small perturbation to the air temperature , and OHFC is dynamic coupling (−∇ ⋅ (vT); both horizontal and vertical heat transport). The first ensemble comprises 40 members and uses the full configuration of the CESM137 (FULL). The presence of a full-physics ocean in FULL allows ocean coupling (SHF and OHFC) to affect the poleward shift of the storm tracks over the 20th and 21st centuries. In the second ensemble (SOM), which comprises 20 members, only the fully-physics ocean is replaced with a slab ocean model  with fixed OHFC and mixed-layer depth , calculated at each location from the climatology of the preindustrial run of the full configuration of CESM1, using the mixed-layer temperature equation53. Thus, since in SOM dynamic coupling cannot affect the shift of the storm tracks, the difference in the storm tracks response to anthropogenic emissions between the FULL and SOM ensembles allows isolating and quantifying the role of dynamic coupling  in the poleward shift of mid-latitude storm tracks.The sole difference across the ensembles is ocean coupling, which can be investigated via the mixed-layer temperature equation, In the third ensemble (NOM), which also comprises 20 members integrated using the slab ocean model of CESM1, the sea surface temperature is fixed at preindustrial values . Thus, since in NOM there is no active ocean coupling , the difference in the storm tracks response between the FULL and NOM ensembles allows isolating and quantifying the role of ocean coupling in the poleward shift of mid-latitude storm tracks. Furthermore, the difference in the storm tracks response between the SOM and NOM ensembles allows isolating the effect of thermodynamic coupling on the storm tracks’ response . Thus, by construction, the sum of the effect of thermodynamic coupling (the difference between SOM and NOM) and dynamic coupling (the difference between FULL and SOM) yields the net effect of ocean coupling (the difference between FULL and NOM), as inferred from fixed sea surface temperature runs. The isolation of each ocean coupling component includes all of its indirect effects on the future position of the storm tracks via any other climate components.n, and at each year over the 1920–2100 period, I calculate the standard deviation over all combination of n ensemble members (or up to 1000 random combinations), and then average over all combinations and over all years. 98% of the variability of the latitudinal position of the storm tracks in the FULL, SOM, and NOM is already captured using 14, 11, and 9 members in each ensemble, respectively  has available daily data, needed for calculating the EKE, under the CMIP6 piControl, abrupt-4xCO2, piSST and piSST-4xCO2 experiments. I compare the storm tracks’ response in CESM1 under the RCP8.5 scenario to the storm tracks’ response under quadrupling of CO2 concentrations, since by 2100, CO2 concentrations are projected to approximately quadruple, relative to preindustrial values, according to the RCP8.5 scenario. I also examine the shift in EKE in CESM255 in the above runs, which allows me to examine the effect of different forcing agents on the role of ocean coupling in shifting the storms.To qualitatively validate the key role of ocean coupling to shift the storm tracks poleward in CESM1, and to ensure that it is independent on the specific formulations of the CESM1, I also analyze the poleward shift of the storm tracks in a different model: the IPSL-CM6A-LRLastly, I also examine the shift in EKE under the Historical and SSP5-8.5 experiments (using the r1i1p1f1 member) of the following 20 CMIP6 models: ACCESS-CM2, ACCESS-ESM1-5, BCC-CSM2-MR, CanESM5, CESM2-WACCM, CMCC-CM2-SR5, EC-Earth3, EC-Earth3-Veg, FGOALS-g3, GFDL-CM4, INM-CM4-8, INM-CM5-0, IPSL-CM6A-LR, MIROC6, MPI-ESM1-2-HR, MPI-ESM1-2-LR, MRI-ESM2-0, NorESM2-LM, NorESM2-MM, TaiESM1.39, I numerically solve the conservation of interior quasigeostrophic potential vorticity  and of buoyancy at the vertical boundaries, linearized about the zonal mean state (denoted by overbars),ψ = ϕ/f is the streamfunction, ϕ is the geopotential, f is the Coriolis parameter, ρ is density and β is the meridional derivative of f. The tropopause height is defined, following the WMO, as the lowest level where the lapse rate reaches 2 Kkm−1, and stays, on average, below 2 Kkm−1 in all higher levels within 2 km40.Using a linear normal mode instability analysis I investigate by which processes ocean coupling affects the poleward shift of mid-latitude storm tracks. Following previous studiesk and ω are the zonal wavenumber and frequency, respectively, Eq. ω as the eigenvalues). The zonal mean fields , averaged over either the 1980–1999 or 2080–2099 periods, are used to solve the resulting eigenvalue problem. The imaginary component of the resulting eigenvalues represents the growth rate of the waves (a widely used measure for the baroclinicity of the flow), and I here analyze the fastest growth rate. Note that unlike simpler metrics for the growth of the waves  or for baroclinicity , the above equation accounts for vertical variations in the zonal wind shear  and static stability, which are important for capturing the future changes in EKE.By assuming a plane wave solution of the form, mentclass2pt{minimSupplementary Information


The structure of the CQMA and CQMA-co-HEMA copolymers was confirmed by a CHN elementary analysis, Fourier transform infra-red (FTIR) and nuclear magnetic resonance (NMR) analysis. The absence of residual aggregates of HCQ or HCQMA particles in the copolymers prepared was confirmed by a differential scanning calorimeter (DSC) and XR-diffraction (XRD) analyses. The gingival epithelial cancer cell line (Ca9-22) toxicity examined by a lactate dehydrogenase (LDH) assay revealed that the grafting of HCQ onto PHEMA slightly affected (4.2–9.5%) the viability of the polymer carrier. The cell adhesion and growth on the CQMA-co-HEMA drug carrier specimens carried out by the -2,5-diphenyltetrazolium bromide) (MTT) assay revealed the best performance with the specimen containing 3.96 wt% HCQ. The diffusion of HCQ through the polymer matrix obeyed the Fickian model. The solubility of HCQ in different media was improved, in which more than 5.22 times of the solubility of HCQ powder in water was obtained. According to Belzer, the in vitro HCQ dynamic release revealed the best performance with the drug carrier system containing 4.70 wt% CQMA.The Poly(2-chloroquinyl methacrylate- This medication is an antimalarial widely used in the treatment of systemic lupus erythematosus, rheumatoid arthritis, malaria and other autoimmune diseases ,2. It is−1 [In the absence of an established treatment regimen, many drug reuse strategies have been emerging to treat corona virus disease (COVID-19) . Indeed,−1 . These t−1 . On the −1 .Poly(2-hydroxyethyl methacrylate) (PHEMA) has exhibited very interesting properties in its application in the biomedical field due to its high water content, its non-toxicity and its favorable biocompatibility. This polymer is easily synthesized by free-radical polymerization involving 2-hydroethyl methacrylate as the monomer and azobisisobutyronitile (AIBN) as the initiator. The ease of handling by the formulation chemistry has allowed this polymer a wide application in the biomedical field, such as contact lenses ,19, keraco-2-hydroxyethylmethacrylate) (CQMA-co-HEMA). The structures of monomers and copolymers obtained were characterized by the Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR) and CHN elementary analyses. The absence of free drug particles aggregated incrusted in the copolymer matrix was confirmed by DSC and XRD methods. The cell toxicity was examined by the lactate dehydrogenase (LDH) assay on the gingival epithelial cancer cell line (Ca9-22) and the cell adhesion and growth on the CQMA-co-HEMA drug carrier was examined by the 3--2,5-diphenyltetrazolium bromide (MTT) test. The in vitro dynamic release of the HCQ base from these drug carrier systems occur in different pH media through a retroesterification reaction, in which the influence of the swelling capacity of the drug carrier system, the drug content grafting in the copolymer and pH media are investigated.In this work, to increase the solubility of the HCQ base in pH-neutral media (intestines) and reduce the amount of HCQ released in acidic media (stomach), a new monomer (CQMA) involving HCQ and methacryloyl chloride was synthesized via a catalytic esterification reaction. The new monomer obtained was copolymerized at different ratios with 2-hydroxyethylmethacrylate (HEMA) using the radical polymerization route to obtain poly(2-chloroquinylmethacrylate-HEMA (purity 98%), triethylenetetramine (purity > 97%), methacryloyl chloride (purity ≥ 97%), AIBN (purity 99%) and chloroform (purity ≥ 99%) were supplied from Sigma-Aldrich . Plaquenil commercial trade tablets were manufactured and commercialized by Aventis Pharma Limited , Sanofi , Kyowa Hakko . All the chemicals were used without further purification except the monomer which was purified by distillation under reduced pressure.A determined amount of 200 mg of Plaquenil tablets was finely ground using a quartz mortar, then added in small portions with continuous stirring in distilled water until complete dissolution (~72 h). Two drops of phenolphthalein indicator were added to the aqueous solution, then titrated by 2% by volume ammonia solution until pink color persisted. In order to extract HCQ from the aqueous solution, the obtained solution was then transferred in a separator funnel containing equivalent amount of diethyl ether. HCQ was extracted from the organic layer by vaporization of diethyl ether using a rotary evaporator. The purity of HCQ was confirmed by NMR analysis. The physicochemical characteristics of this molecule are gathered in −1) passed. The whole was placed in an ice bath for 10 min. The excess of methacryloyl chloride diluted in chloroform was then added dropwise with moderate stirring to the preceding solution using an addition bulb. The reaction took place in a dark atmosphere under a stream of nitrogen and under reflux during the whole period of the reaction. CQMA was isolated from the reaction mixture by a complete evaporation of solvent and liquid residual reactants using rotary system. The residual HCQ was removed by washing the CQMA obtained three times by an excess of distillated water, then dried in a vacuum oven until constant mass.CQMA was synthesized by an esterification reaction involving HCQ and methacryloyl chloride using triethylenetetramine as a catalyst according to the reaction in CQMA was copolymerized with HEMA at 60 °C through a free-radical polymerization route under nitrogen gas using AIBN as initiator . Differe−1 at room temperature and acquired with a total of 32 scans per spectrum and resolution of 2 cm−1. The 1H NMR and 13C NMR spectra of samples were taken at 400 and 100 MHz, respectively, on a spectrometer  using deuterated dimethyl sulfoxide (DMSO-d6) as a solvent. The DSC thermograms were traced by a Shimadzu DSC 60A  system previously calibrated with indium. In total, 8–10 mg of monomer and copolymer powders was packed in aluminum DSC pans before being placed in a DSC cell, then heated under nitrogen gas from 30 to 200 °C at a heating rate of 20 °C·min−1. Data were collected from the second scan run for all samples. No degradation phenomena of HCQ, CQMA and CQMA-co-HEMA samples were observed in all DSC thermograms in the investigated temperature range, noting that the Tg value was estimated as the midpoint of the heat capacity change with temperature and the Tm at the top of the melting peak. X-ray diffraction of pure HCQ and CQMA microparticles and copolymers was recorded by  diffractometer using an anode tube of Cu working with voltage of 40 KV and a generator current of 100 mA.The new synthesized monomer and copolymers were characterized by different techniques. The FTIR spectra of the samples were recorded on a Nicolet iS10 spectrometer , equipped with an attenuated total reflection  accessory. Spectra were obtained over a region of 4000–500 cmThe range of diffraction angle was 0–80 two theta. The samples were used as thin films, except that of pure HCQ and prepared CQMA which were analyzed as powder. SEM images of film samples before and after the release process were performed on a JEOL JSM-6610LV scanning electron microscope (SEM)  at an accelerating voltage of 10 kV. The surface and cross-sections of samples were first sputter-coated with a thin layer of gold and then observed at magnification range of 300–3000×.2 atmosphere conditions and cell culture medium were changed every two days.The gingival epithelial cancer cell line (Ca9-22) was obtained from RIKEN BioResource Research Center, Tsukuba, Japan. Ca9-22 cells were cultured in RPMI-1640 medium , supplemented with L-glutamine, 5% fetal bovine serum (FBS)  and antibiotics . Cell cultures were performed at 37 °C in humidified incubator with 5%; CO3 cells/wells were seeded directly in biomaterial sample, then cultured for 24 h with RPMI medium. After 24 h of adhesion cells, an MTT assay was performed as described by Semlali et al. [OD is the optical density.Each biomaterial was placed in 24-well plates and cancer gingival cells at 100 × 10i et al. ,26. Brie5/well in 24-well cell culture plates for 48 h. The LDH activity was assessed in culture supernatants collected from cell adhered in different biomaterials for 48 h. LDH activity was measured using LDH  [Ca9-22 cells were seeded at 10 Canada) . Triton co-HEMA films of known masses and thicknesses were immersed in excess of water at 37 °C in media of pH 1, 3, 5 and 7. These samples were then removed after time intervals, wiped with tissue paper from water droplets deposited on both surfaces, then immediately weighed. Each operation lasted until the films were saturated (constant weight). Each process was triplicate and the masses of media absorbed were taken from the arithmetic average. The swelling of the film sample in weight percent was calculated according to Equation (2):t and ot, respectively. t.The mass transfer of media in the polymers was carried out by gravimetric method . CQMA-coco-HEMA films with a square surface area of 4 cm2 and an average thickness of 1.23 mm were suspended in 100 mL of water/hydrochloric acid solution at pH fixed at 1, 3, 5 and 7, and stirred at 100 rpm at 37 °C. Aliquots of 0.5 mL were withdrawn at time intervals and immediately replaced by water at the same pH media just after analysis. This operation kept a constant volume of media during the release process and reflected as much as possible what was actually happening in the intestines in which the HCQ released was absorbed gradually. The concentration of drug released during this period was calculated taking into account the volume of medium removed for quantitative analysis. The total mass of HCQ released during this period (tm) was calculated from its concentration deduced from the UV–visible calibration curve indicating the change in the absorbance versus the concentration of medication. It is important to note that, during the drug release process, the pH of the medium was practically not affected by the small amount of HCQ released and, hence, the addition of a buffer solution to stabilize the pH of the medium was not necessary. The percentage of HCQ released, R (wt%), in the media during a certain time, t, was calculated from Equation (3):CQMA-co-HEMA copolymers were confirmed by FTIR, NMR and elemental analyses. The absence of HCQ and CQMA residual particles aggregated in the copolymer samples was highlighted by DSC, XRD and SEM analyses.The chemical structures of the CQMA monomer and CQMA-The elemental composition of CQMA was confirmed by the CHN analysis through the consistent comparison of the experimental data with those calculated, and the results obtained are summarized in The composition of the copolymer in CQMA and HEMA monomeric units was also determined by this same method and the results obtained were gathered in −1 assigned to the hydroxyl group of the pure HCQ indicating the formation of this monomer. The CQMA spectrum confirmed the structure of this monomer through the apparition of the same absorption bands attributed to both HCQ and mathacryloyl methacrylate, except that of –OH stretching frequency which appeared in the HCQ spectrum at 3385 cm−1. Indeed, the main signals that appeared on the CQMA spectrum were the aromatic C–H stretching frequency at 2915 cm−1, aromatic C=C stretching frequency in two regions at 1634 and 1457 cm−1, the C–Cl stretching frequency at 1056 cm−1 and the C–N bending frequency at 1157 cm−1. The two absorption bands observed at 2500 and 2600 cm−1 were probably assigned to residual quaternary ammonium salts, resulting from the reaction involving methacryloyl chloride and triethylenetetramine during the monomer preparation.The FTIR spectrum of CQMA in co-HEMA copolymer of different compositions. These spectra showed the combination of the absorption bands attributed to the two monomers HEMA and CQMA, except that which characterized the vinyl C=C double bond of the two monomers of average intensity at 1635 cm−1 represented in −1 in the CQMA monomer  observed at 52.4 ppm, which was directly linked to the hydroxyl group of HCQ, which shifted to the higher chemical shifts (63.5 ppm), indicating the formation of the ester group of the CQMA monomer.co-HEMA copolymer was confirmed by the 13C NMR analysis from the comparison of their spectra with that of the PHEMA homopolymer. Indeed, as shown in The structure of the CQMA-The DSC thermograms of the pure HCQ and CQMA monomers were grouped for comparison in co-HEMA, Tg, at 95 °C, which agreed with that of the literature [Tg towards low temperatures, which increased with the CQMA content. This appeared to be evident due to the effect of the steric hindrance of the chloroquinyl methacrylyl substituent of the CQMA units. Indeed, according to Reimschuessel [Tgs are important. The large spacing between the polymer chains caused by this substituent facilitated the sliding of the chains between them, and this reflected the reduction in Tg values. On the other hand, the more the number of these units increase in the copolymer, the less the Tg values.For CQMA-terature , while tchuessel , the morco-HEMA copolymers with different compositions are shown in co-HEMA, which slightly shifted from 20.0 to 21.2° 2 theta with the CQMA content, was due to the lack of crystallographic order of the polymeric chains; thus, leading to the formation of amorphous structures which was mainly caused by the steric hindrance of the substituent on both sides of the polymer chains. The absence of the main signals attributed to the CQMA monomer crystals observed in its spectrum at 12.3, 22.0 and 25.02 theta in the spectra of the copolymers indicated the absence of residual particles of chloroquinyl methacrylate non polymerized incrusted in the copolymer matrix; thus, confirming the results of DSC.The X-ray diffractograms of the CQMA monomer, PHEMA homopolymer and CQMA-co-HEMA copolymer films. As can be seen in the blank PHEMA image, there was a smooth, non-porous, wave-shaped surface devoid of any aggregated residual particles of HCQ or CQMA. The image (on the right) shows the HCQ particles clustered together as endangered snowflakes, indicating the presence of moderate attractive electrostatic forces between them. Micrographs of CQMA-co-HEMA films showed pores of different shapes and sizes on their surfaces, which varied depending on the amount of HCQ grafted. Indeed, the CQMA-co-HEMA5 and CQMA-co-HEMA7 samples exhibited surface morphologies containing spherical pores of sizes between 3 and 70 µm, and were much denser in the case of the film sample containing 5% of CQMA by weight. The CQMA-co-HEMA10 image showed a smooth surface containing significantly fewer pores of similar sizes to the two previous copolymer films. The film surface of the highest HCQ-loaded copolymer sample (CQMA-co-HEMA15) exhibited fewer spherically shaped or compressed pores, probably due to the mechanical stress during film preparation.co-HEMA films was calculated at different pH media from Equation (3) and the results obtained are plotted in The swelling behavior of any hydrogel is an important key which controls the amount and transfer of drug released from a drug carrier system to a target external medium. The mechanism of the swelling of a polymer gel in a liquid medium mainly involves two important factors, which are the affinity of the polymer–solvent type and the diffusion dynamics of the absorbate in the absorbent material. The affinity of the polymer with respect to the absorbate is governed, mainly, by the difference between their solubility parameters. On the other hand, the diffusion dynamics of the molecules of the absorbate in the absorbent polymer matrix are controlled by various parameters such as the degree of the crosslinking of the polymer ,34, the co-HEMA system to swell did not vary continuously with the pH medium, regardless of the copolymer composition. Indeed, for the drug carrier systems containing a CQMA content equal or superior to 6.22 wt%, the swelling degree at saturation reached a maximum in pH media 3 and 7, then passed by a minimum when the pH medium was 5, while for the CQMA-co-HEMA system containing less CQMA (4.70 wt%), the variation in the swelling rate at equilibrium reached its maximum at pH medium 3, then continuously decreased to reach a minimum at pH 7. Similar results were also obtained by different authors on the swelling capacity of PHEMA-containing amine groups [N,N-dimethylaminoethyl methacrylate (DMAEMA) monomers. At a high CQMA content (9.68 and 14.82 wt%), the increase in the release dynamic in the neutral pH medium was probably due to the elimination of HCQ from the copolymer through a retroesterification reaction, which was favorable in the medium at pH 7 as shown in As can be observed from these curve profiles, the capacity of the CQMA-e groups ,40. These groups  in the cco-HEMA copolymer at equilibrium as a function of the CQMA content. These curve profiles revealed a linear dependence of the swelling capacity for the copolymer with the CQMA content in pH medium 5 and logarithmic in pH 1, 3 and 7. As can also be seen from these data, in any pH medium investigated, the swelling rate of copolymers increased quickly when the CQMA content in the copolymer ranged between 4.70 and 7.22 wt%, while an increased linearly in pH medium 5 in all the investigated composition ranges was seen. The increase in the swelling capacity of the copolymer with the CQMA content could be explained by two main factors: (i) the increase in the solvation of the chloroquinyl methacrylate substituent through the protonation of the amine group which occurred in acidic media and (ii) the increase in the density of the hydrogen bonds between the hydroxyl of water and that of the HEMA unit through an increase in the free volume between the copolymer chains created by the bulky chloroquinyl methacrylate substituent. At a certain limit of the CQMA content, the hydrophobic character of the ester substituent intervened by limiting the solvation of the copolymer, which reflected the slowing down of the swelling capacity of copolymers containing more than 7.22 wt% in the CQMA unit, notably in pH medium 1, in which a plateau was obtained resulting from a pseudo-equilibrium between a decrease in the hydrophilicity of the copolymer due to the formation of ester (chloroquinyl methacrylate) and, simultaneously, an increase in the solvation of HCQ due to the protonation of its amine groups.co-HEMA15 (A5) and 3.07 ± 0.10% for the virgin PHEMA used as the reference. The increase in cell cytotoxicity was due to the effect of HCQ released as an anti-oral cancer agent  seemed to have the best performance (0.64 ± 0.19) compared to that of the reference film (virgin PHEMA) (0.23 ± 0.002). Beyond this amount grafted into the polymer, this performance almost returned again to that of the virgin polymer with a slight increase (0.27 ± 0.01) and a slight decrease (0.20 ± 0.008) when the CQMA content was 14.82 and 9.68 wt%, respectively. The adhesion of cells to a polymeric material could be managed by three essential factors which were toxicity, chemical affinity between the two target entities and surface porosity. In this case, according to the toxicity test , in which the concentration obtained during this same period did not exceed 22.61 mg·L−1, regardless of the pH of the medium. This seemed to be obvious, since 4.70 wt% as the HCQ/HEMA starting composition was not sufficient to release a sufficient amount of HCQ to reach or approach the saturation of the medium. Compared to the solubility of dissolved HCQ in powder form, this value was slightly lower. For example, the maximum concentration of HCQ released in the water of the CQMA-co-HEMA15 system varied between 186 and 261 mg·L−1 when the pH of the medium went from 1 to 7 without observing any precipitation or cloudiness for one week. This represented an improvement of over 5.22 to 9.38 times the solubility of HCQ when dissolved in the powder form. In the case of the CQMA-co-HEMA5 system, in which the release dynamics continued to increase  [l is the film thickness, D value is determined when the permanent regime of the release process is reached and the HCQ particles deposited on the surface of the material are totally washed. Under such conditions, the profile of the D curve as a function of time would be significant and accurately reflect the dynamic of the drug released into the aqueous solution inside the carrier material. D as a function of the reverse of time plotted from the data of co-HEMA materials obeyed a Fickian model and also indicated that the release dynamics of this drug from these hybrid materials were mainly governed by a diffusion mechanism through the copolymer matrix. Under these conditions, the steady state of the liberation process was reached and it was possible to build our investigation on the second zone of the liberation process in which the steady state was reached.According to Lin et al. , for a rtion (4) ,46,47,48co-HEMA system on the release behavior of hydroxychloroquine was carried out in different pH media during 72 h of the release process and the results obtained are plotted in The swelling capacity of a polymer in an aqueous medium is a fundamental property and considered as a key in the field of drug delivery. Indeed, this parameter regulates the amount of drug released, controls both the rate of diffusion of the penetrate into the polymeric carrier and its dissolution in the medium in which the drug is released ,50,51,52co-HEMA drug carrier system on the release dynamics during 24 and 72 h of the process. For both durations, these curve profiles revealed a significant increase in the HCQ released when the concentration of this medication in the drug carrier system did not exceed 7.22% by weight, then stabilized or decreased more or less quickly depending on the pH medium at a higher HCQ content. This could be explained mainly by two opposing factors which acted simultaneously on the swelling capacity of the drug vehicle system depending on their capacities to act and the content of CQMA in the copolymer. In fact, an increase in the hydroxychloroquinyl ester group as a substituent of the copolymer acted negatively on the hydrophilic power of the CQMA-co-HEMA system. This had an effect of reducing the quantity of water necessary for the reaction of retroesterification (drug regeneration reaction) and also reduced the dissolution of HCQ released inside the polymeric matrix.co-HEMA system, which depended on its CCQMA/PHEMA composition.On the other hand, an increase in the steric hindrance of this substituent also promoted an increase in the free volume between the chains of the copolymer, facilitating the penetration of more water molecules. In this situation, a competition between these two opposite effects, which essentially depends on the amount of HCQ grafted into the copolymer, governs the dynamics of HCQ release in the medium. Finally, we could conclude from the results obtained that the ability to release HCQ in these different media was governed by the more or less hydrophilic character of the CQMA-co-HEMA drug carrier systems was performed at pH media 1, 3, 5 and 7, and the results obtained for 24 and 72 h are plotted for comparison in co-HEMA7 and CQMA-co-HEMA10 drug carrier systems, which contained 7.22 and 9.68 wt% of CQMA, respectively, completely changed from those observed at 24 h. Indeed, two extremums were observed for the drug carrier system containing 7.22 wt% of CQMA content in which a maximum release of 29.7 wt% of HCQ was observed in Ph 3 and a minimum of 26.6 wt% in pH medium 5, while that with 9.68 wt% of CQMA content reached a maximum release of 63 wt% in this same pH medium. The explanation for such behavior appeared to be complicated by the fact that two main antagonistic factors may simultaneously intervene in the drug release mechanism: the first being chemical which resides in the reaction of retro-esterification which generates the HCQ and the second being physical which resides in the hydrophilic character of the copolymer. The intensity of each depends on the pH of the medium and the CQMA content in the drug carrier system. Indeed, the chemical factors were the reactions of retro-esterification which took place in a neutral pH medium which regenerated the HCQs in the presence of an excess of water, leading to the release of a large amount of drug, and the reaction of esterification which took place in an acidic medium, which, on the contrary, promoted the formation of insoluble ester, which disfavored the release of the drug as shown in co-HEMA system was already discussed in the previous section. Indeed, at a high CQMA content, the swelling capacity of the polymer was also affected by the pH medium, since the more acidic the medium the less swelling of the system. This was due to the formation of the ester which was insoluble in water. Contrarily, as can be revealed in the previous section, a minimal amount of CQMA in the copolymer, less than 7.22% by weight, promoted an increase in the swelling capacity.The nature of the environment in which drugs are released greatly influences the dynamics of drug release in a target organ. Indeed, various studies have been carried out on the influence of the medium such as the pH ,54, the co-HEMA drug carrier system based on the drug amount released the instantaneous release rate and the duration of the release process, deduced from the slopes of the pseudo-linear portions of the kinetic curves of The study of the performance of the CQMA-co-HEMA drug carrier systems with a higher CQMA content. The first zone observed during the first hours of the release process was between 10 and 30 h depending on the composition of the copolymer and the pH of the medium. During this period, a significant amount of HCQ was released, probably due to the large difference between the chemical potential for dissolving HCQ outside and inside the polymer matrix. For the CQMA-co-HEMA5 drug carrier system, a rapid release dynamic (0.43–0.53 wt%/h) was observed during the second zone which was located between 120 and 134 h in which 6.0 to 18.2% of HCQ by weight was released depending on the pH medium. For drug carrier systems initially containing a higher CQMA content, the second zone was short (32–43 h) and relatively fast (0.10–0.63 wt%/h). This step was considered as a transit zone in which 9.0–22.0% of drug by weight was released during this period depending on the CQMA content in the copolymer and the pH of the medium. The third zone observed for CQMA-co-HEMA drug carrier systems containing 4.70, 9.68 and 14.82 wt% CQMA was the longest (91–116 h) and also the slowest , wherein 7.0–13.0 wt% HCQ was released depending on the initial content of CQMA in the drug carrier system and the pH medium. The gradual decrease in the release dynamics of these drug delivery systems can mainly be explained thermodynamically by a gradual decrease in the difference between the chemical potentials of the HCQ dissolution inside and outside the polymer matrix up until the equilibrium is reached, taking into account the various parameters of interaction between the various components of the copolymer and that of the medium. The performance of the drug carrier systems was determined from the criteria that stipulate: the maximum of drug released in neutral pH medium , minimum drug release in acidic pH medium (stomach), stable release rate and longest release period. According to Belzer et al. [co-HEMA5 system was the most efficient, because it was able to reduce the release of HCQ in the stomach to 2.40 wt% of the total quantity released for the fast GITTs and 6.69 wt% for the slow GITTs.As can be seen from these curve profiles, the release dynamic of HCQ showed two principal pseudo stable zones for the specimen containing 4.70 wt% of CQMA and a supplementary transit zone for the CQMA-r et al. , the meaco-2-hydroxyethyl methacrylate drug carrier systems with different compositions were also successfully synthesized through a radical copolymerization route involving the synthesized 2-chloroquinyl methacrylate and 2-hydroxyethylmethacrylate. This method was able to obtain, in aqueous medium, a generator of a desired percentage of 2-hydroxychloroquine regularly and slowly released during a long period through a retro-esterification reaction. The cell toxicity examined by the LDH assay revealed that the grafting of HCQ onto PHEMA was slightly affected (4.2–9.5%) and the cell adhesion and growth on the CQMA-co-HEMA drug carrier specimens carried out by the MTT assay revealed the best performance with the specimen containing 4.70 wt% CQMA. A significant improvement of 5.22 to 9.38 times the solubility of HCQ over that in powder form was obtained when it was released from CQMA-co-HEMA systems. The results of the in vitro release dynamics of HCQ from these systems showed very encouraging results in which the system initially containing 4.70% of CQMA by weight showed the best performance.Very interesting results were obtained from this investigation. Indeed, 2-chloroquinyl methacrylate as a new monomer could be easily synthesized through a catalytic reaction involving methacryloyl chloride in the presence of triethylenetetramine. Poly(2-chloroquinyl methacrylate-